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Pancreatic beta cells

Pancreatic beta cells

References Porte D Pancreafic, Kahn SE. Redox Biol Raspberry-themed party ideas Article CAS Betta Scholar Pancreaic CC Hydrogen peroxide reactivity and specificity in thiol-based cell signalling. Article CAS PubMed Google Scholar Mahajan, A. All selected papers were English-language, full-text articles. Distinct gene expression pathways in islets from individuals with short- and long-duration type 1 diabetes.

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New Drug Cocktail Increases Beta Cells at Rapid Rate

Thank brta for visiting Pancreatic beta cells. You Pandreatic using a befa version with limited support Pajcreatic CSS. To obtain the best experience, Raspberry-themed party ideas, we recommend Organic mood regulator use a more up to date browser or Pancreativ off stress reduction exercises at work mode in Internet Explorer.

In the meantime, to ensure continued Pwncreatic, we are displaying the Pandreatic without styles and JavaScript. Loss of functional β-cell mass is Pancreattic key Pancreatuc leading to the two main forms of diabetes mellitus — type 1 diabetes mellitus T1DM and type 2 Antioxidant supplements for aging mellitus T2DM.

Understanding the mechanisms behind β-cell stress reduction exercises at work betw critical to stress reduction exercises at work or revert disease. Basic pathogenic Air displacement plethysmography machine exist Pacnreatic the two forms of diabetes Ayurvedic Herbal Supplements T1DM is immune mediated and T2DM is mediated by cdlls mechanisms.

These mechanisms Facial skincare routine affect early β-cell bet and eventual fate. Over the past Raspberry-themed party ideas, major advances have been made in the field, mostly delivered by Pancreatuc on Pancdeatic in human disease.

These advances Brain health seminars studies Raspberry-themed party ideas islet morphology and human β-cell gene expression in T1DM and T2DM, Blood pressure and caffeine identification and characterization heta the Pancratic of T1DM and T2DM candidate stress reduction exercises at work at the Pancreqtic level Pancreatic beta cells the Arthritis exercises for energy conservation reticulum betx signalling that contributes Pancdeatic β-cell failure in T1DM mostly IRE1 driven and T2DM mostly PERK—eIF2α dependent.

Hypoglycemic unawareness management strategies, we review these Psncreatic findings, Pancrwatic on studies performed on human β-cells brta on samples Gut health and fertility from patients with diabetes mellitus.

Pancreatic β-cell dysfunction and Pancreatkc death are key processes in the development of type 1 diabetes mellitus T1DM and type 2 diabetes mellitus T2DM. Panccreatic pathogenesis of T1DM and T2DM is fundamentally Colon cleanse diet, differentially impacting Managing hypoglycemic unawareness β-cell dysfunction immune Nutrient timing for athletic success versus metabolic in T1DM and T2DM, respectively bsta cell fate massive versus mild-to-moderate β-cell loss.

Pancreatic Diabetic coma cells have unexpected plasticity; Sugar consumption and inflammation, the magnitude and Celsl relevance stress reduction exercises at work this betq in humans remains to be determined.

A substantial fraction of T1DM-associated genetic variants act at Pancfeatic β-cell level but Pacnreatic become manifest upon immune-mediated islet cell perturbations, whereas T2DM genetic signals largely regulate β-cell development and Effective ways to reduce water retention. In T1DM and potentially in other autoimmune diseasesenhancers pre-bound by tissue-specific transcription factors seemingly facilitate cell type-specific responses to ubiquitous pro-inflammatory signals, which could explain the tissue selectivity in autoimmune attack.

Endoplasmic reticulum stress affects β-cells in both T1DM and T2DM; however, the signalling differs, with predominantly IRE1-mediated β-cell damage in T1DM and PERK—eIF2α-mediated β-cell damage in T2DM.

This is a preview of subscription content, access via your institution. Cnop, M. et al. Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: many differences, few similarities.

Diabetes 54 Suppl. Article Google Scholar. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes — Diabetes Care 42 Suppl.

Ahlqvist, E. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol. This study attempted, for the first time, to subtype adult diabetes mellitus using clinical variables, identifying five subgroups with differing disease progression and risk of chronic complications.

Article PubMed Google Scholar. Pearson, E. Type 2 diabetes: a multifaceted disease. Diabetologia 62— Article PubMed PubMed Central Google Scholar. Eizirik, D. The role of inflammation in insulitis and β-cell loss in type 1 diabetes. This article presented, for the first time and in a comprehensive way, the role for inflammation at the different stages of autoimmunity progression in T1DM.

Article CAS PubMed Google Scholar. Gonzalez-Duque, S. Cell Metab. e6 A detailed genomics and peptidomics analysis, identifying several potential neoantigens in human β-cells, including splice variants.

Thomaidou, S. Islet stress, degradation and autoimmunity. Diabetes Obes. Article CAS PubMed PubMed Central Google Scholar. DiMeglio, L.

Type 1 diabetes. Lancet— Op de Beeck, A. Viral infections in type 1 diabetes mellitus - why the β cells? Ilonen, J. The heterogeneous pathogenesis of type 1 diabetes mellitus.

Todd, J. Etiology of type 1 diabetes. Immunity 32— Colli, M. PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and -γ via IRF1 induction. EBioMedicine 36— Martinov, T.

Type 1 diabetes pathogenesis and the role of inhibitory receptors in islet tolerance. NY Acad. Sims, E. Cause or effect? A review of clinical data demonstrating beta cell dysfunction prior to the clinical onset of type 1 diabetes.

Pociot, F. Genetic risk factors for type 1 diabetes. Patterson, C. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period a multicentre prospective registration study.

Livingstone, S. Estimated life expectancy in a Scottish cohort with type 1 diabetes, — JAMA37—44 Huo, L. Life expectancy of type 1 diabetic patients during a national Australian registry-based cohort study. Diabetologia 59— Insel, R. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the endocrine society, and the American Diabetes Association.

Diabetes Care 38— This article provides a novel approach to classify the different stages of T1DM, indicating new windows for therapeutic intervention.

Greenbaum, C. Strength in numbers: opportunities for enhancing the development of effective treatments for type 1 diabetes-the TrialNet experience. Diabetes 67— Herold, K. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes.

Weyer, C. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. Lyssenko, V. Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes.

Diabetes 54— Progressive loss of β-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes. Diabetes Care 30— Zaharia, O. Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study.

Zheng, Y. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. NCD Risk Factor Collaboration. Worldwide trends in diabetes since a pooled analysis of population-based studies with 4. Sattar, N.

: Pancreatic beta cells

MECHANISMS OF β-CELL DEATH IN TYPE 2 DIABETES

Moreover, aldehyde dehydrogenase 1A3 ALDH1A3 has been identified as a marker of β-cell dedifferentiation in β-cell-specific Foxo s knockout mice 60 , where its expression is activated in lineage-traced dedifferentiated β-cells. These findings suggest that β-cell dedifferentiation is a protective mechanism against cell death in chronic hyperglycemia and that under certain circumstances, cells can redifferentiate into functioning β-cells 6 , 11 , 12 , 56 , 57 , 58 , To determine the role of β-cell dedifferentiation in the pathophysiology of human T2D, it is essential to validate experimental animal models in human patients.

Although the mouse is a useful genetic tool for studying diabetes, there are differences in the anatomy and physiology of human and rodent islets. Human islets have proportionally fewer β-cells and more α-cells than mouse islets, and β-cells are not clustered but intermingle with other endocrine islet cells Mouse and human islets differ significantly in their innervation patterns.

In mouse islets, both sympathetic and parasympathetic axons innervate endocrine cells, whereas in human islets, sympathetic axons primarily contact smooth muscle cells of the vasculature It has also been shown that human islets are capable of accumulating lipid droplets LDs , which are not found in mouse islets, even under hyperglycemic and hyperlipidemic conditions Considering these differences, it is crucial to investigate whether β-cell dedifferentiation occurs in human T2D to develop effective therapeutic interventions that can reverse this process and treat diabetes.

Since in vivo lineage tracing is not possible in humans, it can be difficult to evaluate the plasticity of human endocrine pancreatic cells. However, it is still possible to survey the range of cell states that result in β-cell dedifferentiation.

Consistent with this idea, reduced expression of Foxo1, Nkx6. Ngn3 was not detected in these samples; however, consistent with animal research, the number of ALDH1A3-positive cells dedifferentiated β-cells is elevated in human T2D pancreases 9.

This observation has been confirmed by different clinical samples in European, North American 9 , Chinese 8 , and Japanese 7 T2D populations Lineage tracing studies in mouse models further demonstrate that under hyperglycemic conditions, β-cells transdifferentiate into other islet cell types.

In addition to the β-cell-specific FoxO1 inactivation in β-cells described above, lineage tracing of Nkx2. β-cells lacking Pdx1 lose β-cell differentiation markers but acquire α-cell-like characteristics by expressing glucagon and the α-cell-restricted transcription factor Arx Additionally, Arx activation in β-cells leads to transdifferentiation into α- or PP cells In cases of severe β-cell depletion, other islet cells can undergo transdifferentiation into β-cells For instance, lineage tracing experiments of α-cells in β-cell-ablated mice show conversion of α- to β-cells, suggesting that α-cells can sense β-cell mass Additionally, in mouse models, ectopic expression of PAX4 69 or deletion of Arx 70 , 71 in α-cells causes transdifferentiation into β-cells.

In addition to transdifferentiating between endocrine cells, exocrine cells have been shown to convert into β-cells. For example, pancreatic acinar cells overexpressing Ngn3, Pdx1, and Mafa simultaneously transdifferentiate into functional β-cells, which can reduce hyperglycemia in streptozotocin STZ -treated mice The presence of multihormone-positive cells, such as INS and GCG, in pancreas sections of T2D patients supports the idea of islet cell transdifferentiation 9.

Moreover, human β-cells have been observed to spontaneously transform into α-cells or ductal cells during islet cell reaggregation or long-term in vitro culture 73 , 74 , but the relevance of these findings to T2D pathogenesis in humans remains unclear.

The occurrence of dedifferentiation and transdifferentiation in β-cells in response to chronic hyperglycemia suggests that islet cells have a high degree of plasticity.

This offers the potential for developing therapeutic interventions that target the restoration of functional β-cells. To pave the way for the development of treatment strategies, it is necessary to understand the repertoire of islet cell heterogeneity that presents in T2D patients Fig.

Single-cell RNA sequencing scRNA-Seq can be informative in this regard. Numerous scRNA-Seq studies have been performed to examine islet cell heterogeneity in nondiabetic or T2D islets in humans 75 , 76 , 77 , Segerstolpe et al. Although the five clusters are not exclusively associated with diabetes, the authors report that T2D β-cells exhibit notably lower levels of INS mRNA and reduced expression of FXYD2 Na,K-ATPase gamma subunit , along with increased levels of GPD2, which is a crucial component of the NADH mitochondrial shuttle.

Muraro et al. described a group of genes that identify distinct β-cell subtypes, including SRXN1, SQSTM1, and three ferritin subunits FTH1P3, FTH1, and FTL , which are involved in the ER and oxidative stress responses Baron et al.

reported evidence of β-cell heterogeneity resulting from differences in the expression of ER stress response genes, such as HERPUD1, HSPA5, and DDIT3 78 , as well as the β-cell differentiation markers UCN3 and MAFA.

Additionally, Xin et al. identified distinct subpopulations of β-cells in islets from nondiabetic donors based on the combined expression patterns of UPR and INS The authors also discovered that β-cell maturation markers ISL1, PDX1, MAFA, MAFB, NEUROD1, NKX, and SIX3 and mitochondrial biogenesis genes TFB2M are differentially expressed in β-cell subgroups Moreover, scRNA-Seq studies have provided further evidence supporting the notion of β-cell dedifferentiation 80 , Wang and Avrahami show that the gene expression patterns of α- and β-cells in T2D islets are similar to those observed in juvenile donors, suggesting that cell dedifferentiation occurs during the progression of T2D 80 , scRNA-Seq is a powerful tool for comprehensively understanding the repertoire of islet cells in both normal and T2D states.

Identifying key master regulators of each cell type, including dedifferentiated β-cells, offers insight into potential therapeutic targets. Targeting key regulators of β-cell dedifferentiation, such as BACH2 and ALDH1A3, using small molecule inhibitors may hold promise as a potential strategy to reverse β-cell identity and treat T2D.

To analyze the transcriptome at the single-cell level, transcripts from each cell were barcoded and then pooled together for sequencing. After sequencing the pooled transcripts, the total number of reads was divided by the number of cells, and each read was debarcoded to assign it to the specific cell from which it originated.

As a result, the sequencing depth in scRNA-Seq is substantially lower than that in bulk RNA-Seq. The average number of genes detected in each cell ranges from a few hundred to a few thousands. Low-abundance RNAs will thus be detected by random chance in certain cells but not others.

Additionally, the function of these differentially expressed genes has not been determined This work also highlights the fact that several key transcription factors, such as Mafa, are not consistently detectable in many β-cells, although the gene product of this mRNA is readily detected by immunohistochemistry in most β-cells 84 , To overcome this problem, we applied a systems biology approach, ARACNe Algorithm for the Reconstruction of Accurate Cellular Networks 86 , to build protein activity analyses derived from scRNA-Seq termed Single-cell Protein Activity Analyses from human islets of normal and diabetic donors and metaVIPER Virtual Inference of Protein-activity by Enriched Regulon analysis 87 , 88 to identify mater regulatory MR proteins controlling the formation of distinct cellular phenotypes that represent putative mechanistic determinants of aberrant, T2D-related transcriptional β-cell states Thus, metaVIPER provides accurate, quantitative activity assessment of the function of proteins whose mRNA is not detected in a given cell, allowing the classification of key lineage markers in individual cells that would be missed at the gene expression level.

Using this approach, we identified distinct cell types that reflect physiologic β- and α-cell states as well as aberrant cell states that are highly enriched in T2D patients. It is worth highlighting that our unsupervised analysis conducted in human T2D islets corroborated previous experimental animal data indicating β-cell dedifferentiation.

Treatment strategies for β-cell failure can be categorized into two groups: increasing cell number or enhancing insulin secretion. The former has been pursued by transplantation of cadaver islets 90 or stem cell-derived β-cells 91 in patients requiring immune suppression for unrelated organ transplant primarily kidney.

Stimulation of β-cell proliferation 92 and inhibition of β-cell apoptosis have also been proposed, but there are no currently approved drugs to achieve this goal 8 , Drugs that promote insulin secretion have been used for decades but are plagued by secondary failures The discovery of dedifferentiation as a feature of β-cell failure raised the question of whether the process is reversible and, if so, whether it represents an actionable treatment target Human studies in which low-calorie diets improve glucose homeostasis in T2D patients corroborate the notion that β-cell failure can be reversible for a long time even after disease onset 94 , 95 , 96 , In T2D patients, a low-calorie diet can restore glucose control, and chronic adherence to this diet has lasting benefits on glycemia 94 , 95 , 96 , 97 , 98 , In addition, phlorizin treatment has been demonstrated to prevent hyperglycemia by restoring insulin mRNA expression and β-cell differentiation markers 55 , These observations in humans and rodents are consistent with the possibility that β-cell function can be restored.

Lineage tracing experiments with inducible Pdx1-cre or neurogenin3-cre also support this idea 10 , 11 , 12 , Furthermore, CRISPR-mediated functional studies in human islets show that the T2D transcriptional signature can be reversed by targeted inhibition of a key master regulator of dedifferentiation, BACH2 89 , which we also characterized as an ectopically activated gene in FoxO1 knockout β-cells The administration of a BACH inhibitor reduced hyperglycemia in diabetic mice and restored β-cell function Fig.

Because BACH inhibitors which target both BACH2 and the related isoform BACH1 are FDA-approved for the treatment of disorders such as multiple sclerosis , there is an immediate opportunity to investigate this pathway in human clinical trials Thus, this proof-of-concept study opens a new avenue for understanding the reversal of disease progression and expands prospects for developing novel therapeutics for restoring β-cell function and identity in T2D.

Multiple factors, including oxidative and ER stress and mitochondrial dysfunction, contribute to the development of β-cell failure and altered β-cell identity.

Thus, converting endocrine progenitor-like cells dedifferentiated β-cells to differentiated β-cells is an appealing therapeutic approach since it is reminiscent of the differentiation of β-cells that naturally takes place during development.

Further research is needed to understand the similarities and differences between natural endocrine progenitors and dedifferentiated β-cells. Advances in technology and analytic tools for genome-wide studies at the single-cell level will assist in elucidating this point.

With a better understanding of the repertoire of islet cell heterogeneity in both normal and T2D subjects, we can identify disease-specific subpopulations and link them with genetic risk factors, paving the way for designing personalized precision-based treatments.

In addition, a thorough investigation of islet cell subtypes in large human populations can help identify whether specific β-cell subpopulations are more susceptible to metabolic stress and failure as the disease progresses.

This knowledge can lead to targeted therapies that aim to protect vulnerable populations from metabolic stressors and prevent the progression of the disease.

Heald, A. et al. Estimating life years lost to diabetes: outcomes from analysis of National Diabetes Audit and Office of National Statistics data. Article PubMed PubMed Central Google Scholar. Accili, D. When beta-cells fail: lessons from dedifferentiation. Diabetes Obes.

Article CAS PubMed PubMed Central Google Scholar. Insulin action research and the future of diabetes treatment: the banting medal for scientific achievement lecture.

Diabetes 67 , — Wang, P. Human beta cell regenerative drug therapy for diabetes: past achievements and future challenges. Lausanne 12 , Article PubMed Google Scholar. Weyer, C. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.

Talchai, C. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell , — Amo-Shiinoki, K. Islet cell dedifferentiation is a pathologic mechanism of long-standing progression of type 2 diabetes.

JCI Insight. Sun, J. beta-cell dedifferentiation in patients with T2D with adequate glucose control and nondiabetic chronic pancreatitis. Cinti, F. Evidence of beta-cell dedifferentiation in human type 2 diabetes. Article CAS PubMed Google Scholar. Cheng, C. Fasting-mimicking diet promotes Ngn3-driven beta- cell regeneration reverse diabetes.

Cell , — e Wang, Z. Pancreatic beta cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab. Blum, B. Reversal of beta cell de-differentiation by a small molecule inhibitor of the TGFbeta pathway. eLife 3 , e Brereton, M.

Reversible changes in pancreatic islet structure and function produced by elevated blood glucose. Ishida, E.

Diabetes 66 , — Son, J. Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of beta-cell failure. Roder, P. Pancreatic regulation of glucose homeostasis.

Haeusler, R. Biochemical and cellular properties of insulin receptor signalling. Cell Biol. Pajvani, U. The new biology of diabetes. Diabetologia 58 , — Kahn, C. Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction. Metabolism 27 , — Jung, U.

Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease.

Bergman, R. Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol. Samuel, V.

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. Ferrannini, E. Association of fasting glucagon and proinsulin concentrations with insulin resistance. Diabetologia 50 , — The stunned beta cell: a brief history.

Campbell, J. Mechanisms controlling pancreatic islet cell function in insulin secretion. Liu, M. Biosynthesis, structure, and folding of the insulin precursor protein.

Sharma, R. Living dangerously: protective and harmful ER stress responses in pancreatic beta-cells. Diabetes 70 , — Cardozo, A. Diabetes 54 , — Marmugi, A.

Diabetes 65 , — Kaufman, R. Orchestrating the unfolded protein response in health and disease. Insulin demand regulates beta cell number via the unfolded protein response.

Cnop, M. Endoplasmic reticulum stress and eIF2alpha phosphorylation: The Achilles heel of pancreatic beta cells. Back, S. Endoplasmic reticulum stress and type 2 diabetes. Annu Rev. Mahajan, A. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.

Genet 50 , — Zhang, Y. THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic beta-cell function and preserving beta-cell mass. Gerber, P. The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus.

Redox Signal 26 , — Sekine, N. Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogenase in pancreatic beta-cells.

Potential role in nutrient sensing. Ishihara, H. Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in beta cells. Carlsson, C. Sodium palmitate induces partial mitochondrial uncoupling and reactive oxygen species in rat pancreatic islets in vitro.

Endocrinology , — Li, N. The sensitivity of pancreatic beta-cells to mitochondrial injuries triggered by lipotoxicity and oxidative stress. Biochem Soc. Matsuoka, T. Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells.

In the following paragraphs, we discuss recent hypotheses on the mechanisms of glucotoxicity and lipotoxicity. Moderate or severe hyperglycemia cannot be the primum movens in the pathophysiology of type 2 diabetes, but it contributes to the reduction of GIIS As such, it could contribute to the progression from glucose intolerance to overt type 2 diabetes The mechanisms by which hyperglycemia negatively affects functional β-cell mass are still debated.

Rodent β-cells chronically exposed to high glucose display several alterations of their phenotype, including changes in glucose stimulus-secretion coupling, gene expression, cell survival, and cell growth 48 , These alterations could result from cytokine-, oxidative stress—, or ER stress—induced changes in gene expression and cell survival 10 , 32 , 51 or from functional changes that are not directly related to β-cell apoptosis, such as accumulation of glycogen Rodent β-cells display reduced expression of genes involved in GIIS in in vivo and in vitro models of prolonged exposure to high glucose.

These changes, which may play a role in the alterations of GIIS in rodent type 2 diabetes, have some similarities with those induced by cytokines 17 , On the other hand, several genes expressed at low levels in normal β-cells are induced by hyperglycemia, including hexokinase 1, lactate dehydrogenase and glucose-6 phosphatase.

In addition, pro- and anti-apoptotic factors, antioxidant enzymes, and some transcription factors are upregulated Some of these genes, such as c-Myc, A20, and heme-oxygenase 1, are induced by hyperglycemia and cytokines, suggesting that both conditions share some common mechanisms to alter the β-cell phenotype.

The suggestion that hyperglycemia increases β-cell production of IL-1β in human islets provides such a unified hypothesis for β-cell pathophysiology in type 1 and type 2 diabetes However, the pattern of hyperglycemia-induced β-cell genes is only partly similar to that induced by cytokines 17 , 18 , For instance, iNOS and IκBα, two NF-κB—dependent genes markedly induced by IL-1β, are not induced in rodent β-cells exposed to high glucose.

Other genes, such as lactate dehydrogenase A, the mitochondrial uncoupling protein UCP-2, and the transcription factor CREM, are induced by hyperglycemia 53 , 54 and downregulated by cytokines 17 , Furthermore, hyperglycemia induces β-cell hypertrophy, whereas cytokine treatment does not, and the induction of β-cell apoptosis by high glucose is much lower than that produced by cytokines.

These differences raise questions about the role of IL-1β—induced NF-κB activation in β-cell glucotoxicity. These doubts are strengthened by our observations that, under various culture conditions, exposure of rat or human islets or FACS-purified rat β-cells to high glucose does not increase IL-1β mRNA expression or NF-κB DNA-binding activity 56 ; Fig.

It is generally assumed that oxidative stress activates NF-κB activity in β-cells as in other cell types This does not seem to be the case, since acute 57 or overnight exposure to low concentrations of hydrogen peroxide does not increase rat islet NF-κB activity and iNOS expression Islet c-Myc and heme-oxygenase 1 expression are similarly induced by hydrogen peroxide and high glucose, and these effects are abrogated by the free radical scavenger N -acetyl- l -cysteine.

This suggests that β-cell glucotoxicity may, at least in part, result from an increase in β-cell oxidative stress and subsequent JNK activation that is NF-κB independent 51 , The main source of reactive oxygen species in the β-cell is probably the mitochondrial electron transport chain 58 , It is therefore possible that chronic stimulation of insulin secretion in states of insulin resistance induces oxidative stress.

It is well established that chronic hyperglycemia leads to β-cell degranulation and reduction in GIIS 48 , but the effect of hyperglycemia on the β-cell sensitivity to glucose is controversial.

A first group of studies indicates that the absence of a glucose-induced rise in ATP production, perhaps due to hyperglycemia-induced expression of uncoupling protein 2, is responsible for defective GIIS This glucose hypersensitization, which results from higher ATP production at low glucose concentrations, may be due to the accumulation of glycogen in β-cells 52 , This concept of β-cell glucose hypersensitivity fits with the presence of fasting hyperinsulinemia in type 2 diabetic patients and the observation based on autopsy material that their β-cells are actively engaged in proinsulin synthesis Thus, β-cell glucose desensitization is compatible with the concept that β-cell dysfunction partly results from β-cell apoptosis 10 , 51 , In contrast, β-cell glucose hypersensitization may result from changes in the expression of glycolytic enzymes decreased glucokinase and increased hexokinase 1 and lactate dehydrogenase expression , from the accumulation of glycogen at high glucose and its subsequent degradation at low glucose, or from other functional alterations of β-cells 48 , 62 , 64 , but not from apoptosis.

We have recently observed that overnight exposure of rat islets to low concentrations of hydrogen peroxide induces glucose desensitization and β-cell apoptosis that are both prevented by N -acetyl- l -cysteine. These results suggest that the various facets of β-cell glucotoxicity may result from different pathophysiological mechanisms.

These different pathophysiological mechanisms are compatible with the observations that 1 after 3 weeks of diet-induced diabetes in the gerbil Psammomys obesus , a stage at which the β-cell mass is decreased 67 , isolated islets were still glucose hypersensitive 62 ; and 2 human islets transplanted under the kidney capsule of hyperglycemic nude mice and maintained in vivo for 4 weeks have severely impaired GIIS, which can be dissociated from impaired glucose oxidation or protein synthesis and, under some conditions, from depleted insulin content or cell death 68 , Physical inactivity, energy-dense diets rich in saturated fat, and central obesity predispose individuals to type 2 diabetes.

Prospective studies in subjects at risk for diabetes have shown that the development of abdominal obesity is correlated with loss of β-cell function and hence glucose intolerance 70 ; M.

Vidal, R. Hull, K. Utzschneider, D. Carr, E. Boyko, W. Fujimoto, S. Kahn, unpublished data. Autopsy data suggest that the progressive decline in insulin secretion in type 2 diabetes is accompanied by a decrease in β-cell mass and that this is secondary to increased β-cell apoptosis.

Thus, it is conceivable that circulating adipose tissue—derived products, such as FFAs and adipokines, play a direct role in pancreatic β-cell dysfunction and death. A high plasma concentration of FFAs is indeed a risk factor for the development of type 2 diabetes, independently of its effects on insulin sensitivity Circulating FFAs are solubilized and transported in millimolar concentrations, by virtue of their tight binding to albumin.

FFAs acutely stimulate insulin secretion, but prolonged β-cell exposure to high FFA levels reduces GIIS in vitro 72 and in vivo, especially in individuals genetically predisposed to type 2 diabetes Studies in the ZDF rat indicate that high circulating FFAs and triglyceride levels induce triglyceride accumulation in pancreatic islets The associated rise in cytoplasmic FFA levels would increase ceramide formation and induce iNOS, resulting in NO-mediated β-cell apoptosis In our in vitro experiments 36 , 76 , 77 , we used physiological concentrations of palmitate and oleate.

FFAs are toxic to FACS-purified rat β-cells 36 , 76 and insulin-producing INS-1E cells Cytotoxicity depends on the unbound FFA concentration and is greater for palmitate than oleate. FFA-induced cell damage results in apoptosis and, to a lesser extent, necrosis in β-cells 76 and mostly in apoptosis in INS-1E cells The toxic effects of FFAs are potentiated when β-cells are concomitantly exposed to high glucose levels 78 , FFA cytotoxicity does not depend on mitochondrial FFA oxidation, because etomoxir, an inhibitor of carnitine palmitoyltransferase I, did not alter FFA-induced β-cell death, and bromopalmitate, a nonmetabolizable analog, was as toxic as palmitate FFA-induced cell death occurred in the absence of iNOS expression or NO production 36 , 76 , and it was not counteracted by antioxidant or free radical scavenging compounds 76 , suggesting that oxidative stress is not its main mediator.

Moreover, oleate or palmitate did not activate NF-κB in INS-1E or β-cells 36 , at low 6. Kharroubi, D. It was suggested that FFA cytotoxicity could be counteracted by the peroxisome proliferator—activated receptor-γ agonist troglitazone through lowering islet triglyceride content In our hands, however, troglitazone did not improve survival of FFA-exposed β-cells, but rather sensitized them to necrosis and apoptosis at low FFA concentrations Furthermore, FFA-induced cytoplasmic triglyceride accumulation was inversely correlated to β-cell death A mixture of oleate and palmitate caused the lowest cell death and the highest triglyceride accumulation, whereas bromopalmitate, which did not increase cellular triglycerides, exerted the highest toxicity These findings suggest that storage of excess FFAs as triglycerides protects the cell against accumulation of potentially deleterious fatty acyl-CoA.

FFA-induced β-cell toxicity might also occur at the ER level, where FFA esterification takes place. Using electron microscopy, we observed that the ER of FFA-exposed β-cells is dilated M. Both oleate and palmitate caused alternative splicing of XBP-1, activation of ATF-6, and induction of the ER chaperone BiP in INS-1E cells In addition to these specific ER stress markers, there was induction of ATF-4 and CHOP The mechanism by which FFAs cause ER stress remains to be elucidated, but over stimulation of FFA esterification in the ER might result in delayed processing and export of newly synthesized proteins, whereas saturated triglycerides may precipitate at their site of synthesis in the ER because of their high melting point.

If that is the case, these intriguing novel observations 36 , 82 , 83 place ER stress as a common molecular pathway for the two main causes of type 2 diabetes—namely insulin resistance and loss of β-cell mass.

The development of novel approaches to prevent β-cell death in diabetes depends on our knowledge of the mechanisms leading to β-cell demise. Thus, if the mechanisms of β-cell apoptosis were similar in type 1 and type 2 diabetes, it would be logical to search for common interventions in both forms of diabetes.

The NOD mouse and the BB rat are the most used animal models of type 1 diabetes 84 , but a new model for type 1 diabetes has been recently described—the IDDM LEW. This latter model is of particular interest, since IDDM rats have a well-preserved cellular immune system, there is no sex bias in the incidence of diabetes, and detailed studies of the events leading to β-cell death are possible see below.

These immune cells are activated 87 and express proinflammatory cytokines such as IL-1β, TNF-α, and IFN-γ 88 , IL-1β and TNF-α, but not IFN-γ, are detected in the infiltrating immune cells in the IDDM rat, but the pancreatic β-cells do not express these cytokines at any of the stages leading to overt diabetes 90 ; Fig.

Günther, H. Hedrich, D. Wedekind, M. Tiedge, S. Data from other models suggest that β-cells express chemokines such as MCP-1 and IP, which may contribute to the buildup of insulitis Detailed morphological studies in the IDDM rat, using both in situ PCR and immunohistochemistry A.

These observations suggest that proinflammatory cytokines are synthesized and released by the activated infiltrating immune cells, but not by the β-cells themselves, leading to apoptotic β-cell death in a paracrine fashion. Loss of pancreatic β-cell mass is slow in type 2 diabetes, and there is no evidence for mononuclear cell infiltration 2.

This is well documented in a number of type 2 diabetes animal models, including the Psammomys obesus sand rat 92 and the GK rat When Psammomys are placed on a high-carbohydrate diet, they rapidly evolve to a diabetic state because of the loss of endocrine pancreas function and β-cell destruction 48 , In contrast to the type 1 diabetes models see above , β-cell demise occurs mostly by necrosis The necrotic cells are removed by scavenger macrophages, which, at variance from the type 1 diabetes situation, are not activated and do not express the proinflammatory cytokines IL-1β, IFN-γ, or TNF-α Fig.

Importantly, the β-cells from these animals do not express IL-1β, iNOS, or caspase-3, as evaluated by immunohistochemistry Fig.

As a positive control, IL-1β mRNA expression was confirmed by in situ PCR using immune cells of pancreas draining lymph nodes. The same sequence of events seems to take place in the physiological situation, where β-cells undergoing apoptosis during their cell renewal cycle are removed by nonactivated macrophages Even when the β-cell turnover rate is increased by administration of thyroid hormones 67 , 95 , the increased demand for removal of apoptotic cells does not trigger macrophage activation or cytokine expression A.

These observations suggest a sequence of events that is different in type 1 and type 2 diabetes models. Thus, β-cells die by necrosis or apoptosis in type 2 diabetes, but the cause of death is not related to cytokine production by infiltrating mononuclear cells or the β-cells themselves.

The dead β-cells attract scavenger macrophages, which in this case are the consequence rather than the cause of β-cell death Fig.

It has been recently suggested that β-cells exposed in vitro to high glucose produce IL-1β, thus activating NF-κB and Fas signaling and consequently triggering apoptosis 10 , Another report indicated that FFAs also activate NF-κB in β-cells As discussed above, exposure to IL-1β alone is not sufficient to kill human or rodent β-cells, and the signal transduction of IFN-γ is also required for β-cell demise.

To exclude that exposure of β-cells to high glucose or FFAs induces the IFN-γ pathway, we reviewed the results of five different microarray analyses of human or rodent islets exposed to these nutrients list of microarray studies provided upon request.

We also contacted some of the authors to make sure that small changes in gene expression were not overlooked D. Melloul, G. Webb, personal communications. The data were compared with the gene expression patterns in rat 14 or human P. Ylipaasto, B. Kutlu, S. Raisilainen, J.

Rasschaert, T. Teerijoki, O. Korsgren, R. Lahesmaa, T. Hovi, D. Otokonski, M. Roivainen, unpublished data islets exposed to IFN-γ. The mRNAs whose expression was most augmented by IFN-γ in β-cells were the transcription factors STAT-1, IRF-1, and IRF-7 and the chemokine CXCL 10 IP Glucose or FFAs modified none of these genes in β-cells, practically excluding the IFN-γ—STAT-1 pathway as a mediator of glucotoxicity or lipotoxicity.

As mentioned above, there is strong evidence that IL-1β contributes to β-cell death in type 1 diabetes via activation of NF-κB. Which is the evidence that FFAs induce IL-1β production or NF-κB activation in β-cells?

We 36 and others 97 did not observe FFA-induced NF-κB activation in β-cells using three different techniques gel shift, ELISA, and immunohistochemistry , and there are no reports of FFA-induced IL-1β expression in these cells. Moreover, FFAs do not induce expression of the NF-κB—dependent genes iNOS and MCP-1 in rodent β-cells 36 , What about high glucose?

Most of the in vitro data supporting glucose-induced IL-1β production and NF-κB activation were obtained by one group rev. in Based on their observations, this group initiated a clinical trial with the IL-1 receptor antagonist in type 2 diabetic patients Of concern is that there is no in vivo evidence in animal models that blocking IL-1β protects β-cells against glucotoxicity.

We examined whether this was due to a species difference between rat 56 and human 10 , 11 islets. Exposure of five preparations of human islets to increasing glucose concentrations 11 and 28 vs.

Moreover, there was no glucose-induced Fas mRNA expression 99 , the proposed NF-κB—dependent mechanism by which glucose causes β-cell death In line with our findings, islets isolated from mice deficient in either the IL-1 receptor or Fas were not protected against high glucose—induced β-cell death, and Fas was not detectable in wild-type mouse islets cultured at high glucose As a whole, these observations argue against a role for IL-1β, NF-κB, or Fas in high glucose—induced β-cell death.

In conclusion, the suggestion that β-cells are killed by a similar mechanism in type 1 and type 2 diabetes is probably an oversimplification, not supported by convincing data.

This oversimplification may bring confusion to a difficult and complex field and promote testing of novel therapeutic approaches in humans without adequate experimental support. In agreement with the lack of IL-1β expression or release by human islets exposed to high glucose in vitro as discussed in this review , recent data do not support a role for IL-1β in type 2 diabetes in vivo.

Two studies, using respectively real-time RT-PCR and microarray analysis, demonstrate that IL-1β and Fas expression in islets isolated from type 2 diabetic patients is not increased as compared with islets from nondiabetic controls 99 , The transcription factors NF-κB and STAT-1 are the main regulators of the pathways triggered by IL-1β and IFN-γ, respectively.

The figure is based on Refs. MHC-1, major histocompatibility complex 1. Proposed model for the different pathways contributing to the execution of cytokine-induced β-cell apoptosis. Arrows indicate genes for which expression was modified by cytokines in a time course microarray analysis β-Cell apoptosis is probably mediated by three main pathways—namely JNK, ER stress, and liberation of pro-apoptotic proteins from the mitochondria.

The data at 12 h are shown here; similar observations were made at 24 h not shown. Subcellular NF-κB localization was counted in — cells using the same experimental conditions as above D. They are composed of several types of cells. At least 70 percent are beta cells, which are mostly localized in the core of the islet.

These cells are surrounded by alpha cells that secrete glucagon, smaller numbers of delta cells that secrete somatostatin, and PP cells that secrete pancreatic polypeptide figure 1.

All of the cells communicate with each other through extracellular spaces and through gap junctions. This arrangement allows cellular products secreted from one cell type to influence the function of downstream cells.

As an example, insulin secreted from beta cells suppresses glucagon secreted from alpha cells. A neurovascular bundle containing arterioles and sympathetic and parasympathetic nerves enters each islet through the central core of beta cells. The arterioles branch to form capillaries that pass between the cells to the periphery of the islet and then enter the portal venous circulation.

INSULIN SYNTHESIS AND SECRETION. Why UpToDate? Product Editorial Subscription Options Subscribe Sign in. Learn how UpToDate can help you. Select the option that best describes you. View Topic. Font Size Small Normal Large. Pancreatic beta cell function. Formulary drug information for this topic.

Definition: Beta Cells Cell Pncreatic. Cells Vitr. A scheme of celks stress reduction exercises at work Pancreatuc important for physiological regulation Zumba workouts insulin secretion stress reduction exercises at work pancreatic beta cells. Amyloid formation in human IAPP transgenic mouse islets and pancreas, and human pancreas, is not associated with endoplasmic reticulum stress. October Access myPennMedicine. Article CAS PubMed PubMed Central Google Scholar Courtney, M.
Introduction Bernstein, B. Article CAS PubMed Google Scholar Gonzalez-Duque, S. As a result, the sequencing depth in scRNA-Seq is substantially lower than that in bulk RNA-Seq. et al. Additional file 2: Table S1. Shafrir E, Spielman S, Nachliel I, Khamaisi M, Bar-On H, Ziv E: Treatment of diabetes with vanadium salts: general overview and amelioration of nutritionally induced diabetes in the Psammomys obesus gerbil. This means that glucose from the food you eat cannot enter your cells.
Pancreatic beta cell function - UpToDate

ATP thus acts as a second messenger in the beta cells Fig. ATP binds to a specific potassium channel, the ATP-sensitive potassium channel in the cell membrane of the pancreatic beta cells, thereby causing depolarisation of the beta cells [ 2 ].

This channel protein is associated with a second protein, the so-called sulfonylurea receptor, which is the site of action of the blood sugar-lowering sulfonylureas Fig. The beta cells have in addition a voltage-dependent calcium channel. As a result of the depolarisation of the beta cells, this channel opens and allows calcium to flow in from the extracellular space.

The increase in the free calcium concentration in the cytoplasm of the beta cells is then responsible for triggering glucose-induced insulin secretion by exocytosis [ 2 ], which is characterised by a biphasic kinetic profile Fig. A scheme of the cellular structures important for physiological regulation of insulin secretion in pancreatic beta cells.

Depicted are the nucleus, the mitochondria Mito , the peroxisomes P , the lysosomes L , the endoplasmic reticulum ER , the Golgi apparatus G and the secretory granules SV. Elevated postprandial blood glucose increases the glucose concentration within beta cells via rapid equilibration through the glucose transporters in the plasma membrane.

Glucose is phosphorylated by glucokinase GK. This leads to the production of glucosephosphate G6P and determines the rate of glycolysis. The elevated glycolytic flux and the mitochondrial metabolism stimulate the ATP production. This is called the initiating pathway red arrow. The K ATP channel is a complex of four pore-forming Kir6.

The SUR1 subunit can react with blood glucose-lowering sulfonylurea drugs SU to initiate insulin secretion. This stimulates exocytosis of insulin-containing secretory granules.

The second mechanism enabling glucose-induced insulin secretion potentiation is called the amplifying pathway green arrow. This mechanism is based on the anaplerosis providing intermediates of tricarboxylic acid cycle without involvement of the K ATP channel. Many hormones, small peptides and extracellular messengers can also potentiate glucose-induced insulin secretion through binding to their plasma membrane receptors and activation of intracellular signalling cascades, typically G-protein-mediated not depicted here.

These four structures together form the apparatus for the recognition of the glucose stimulus and exocytosis of insulin in the beta cells of the islets of Langerhans in the pancreas Fig. In healthy people, they ensure that the stored insulin is released as needed when the blood sugar concentration increases after food intake typically from about 4 to about 8 mM.

Different pathomechanisms are responsible for impaired insulin secretion in type 1 and type 2 diabetes [ 1 , 2 , 3 ]. Furthermore, various amino and keto acids, as well as glucose, can increase insulin secretion by means of ATP.

In addition, there are other second messengers that can also increase the cytoplasmic calcium concentration and thus increase insulin secretion.

For example, for many peptides e. the incretin hormones glucagon-like peptide 1 [GLP-1] and gastric inhibitory polypeptide [GIP] , cyclic AMP cAMP and in the case of vagal stimulation with acetylcholine inositol trisphosphate are the responsible second messengers.

The concentrations of these intracellular second messengers are increased in the beta cell when the respective agonist binds to its plasma membrane receptor. In contrast to glucose, these mechanisms cannot trigger insulin secretion. However, glucose-induced insulin secretion can be increased during food intake and thus optimally adapted to the respective metabolic situation, so that the organism is supplied with insulin as needed.

The amplifying metabolic signals are most likely generated in the tricarboxylic acid cycle [ 2 ]. In quantitative terms the amplifying pathway provides at least as much insulin to the organism as the triggering pathway [ 2 ].

The insulin-producing beta cells as well as the other hormone-producing cells are arranged in the form of endocrine micro-organs, the so-called islets of Langerhans or pancreatic islets. The islets are embedded in the exocrine tissue of the pancreas total number of islets 0. The average islet has a diameter of — μm and consists of — endocrine cells.

The islets of Langerhans are composed of different endocrine cell types. The last two hormones have no crucial function in the organism. In rodents the beta cells are located in the centre of the islet, surrounded by a rim of the non-beta cells so-called mantle islets , while the non-beta cells are scattered around throughout the islets in-between the beta cells in the human islets.

The pancreatic beta cell is very sensitive to oxidative stress, explaining its particular vulnerability in states of disease [ 1 ]. It is the imbalance between H 2 O 2 generation and its decomposition that easily causes damage to the beta cells [ 3 ]. In virtually all cell types and organs such as liver, kidney and other major organs of the body, the balance between H 2 O 2 generation and decomposition is maintained by a battery of H 2 O 2 -inactivating enzymes [ 5 , 6 , 7 , 8 ].

They prevent oxidative stress that is an imbalance between the generation of reactive oxygen species and the capacity to detoxify these reactive species.

All the protective enzymes generate H 2 O through reduction of H 2 O 2 and are not inducible. The great number of these decomposing enzymes expressed in virtually all major subcellular compartments is an indication of their importance in providing efficient protection against oxidative stress-mediated cellular toxicity.

The effective inactivation systems limit the lifetime and restrict the movements of H 2 O 2 over large distances and thus provide protection against oxidative stress. This has favourable consequences for the cell: a oxidative stress and the resultant cell death are counteracted and b localized oxidation of reactive thiol proteins within the cell as the basis for thiol-based cellular signalling is favoured.

This restricts H 2 O 2 distribution in the cell. This is general thinking in the research community [ 7 , 8 ]. However, it does not apply to the special situation prevailing in the pancreatic beta cell [ 1 , 3 , 5 , 6 ].

Though the pancreatic beta cell is of crucial importance in the regulation of metabolism, virtually none of the well-known H 2 O 2 -inactivating enzymes is expressed in the beta cells of mice and rats [ 1 , 3 ].

This refers specifically to the glutathione peroxidases GPx [ 5 , 6 , 9 ] and the peroxiredoxins Prx [ 10 , 11 ] as high-affinity thiol-reactive enzymes, which vigorously reduce H 2 O 2. In view of the low H 2 O 2 -inactivating capacity, a high level of these proteins is required for efficient inactivation of H 2 O 2 and local signalling [ 7 , 8 ].

However, since the expression levels are rather low or even negligible in the beta cells Table 1 , at variance from the high levels in the non-beta cells of the islets, the enzymes of these families are not able to fulfil a protective role [ 1 ].

This refers in particular to Prx4 [ 11 ] as well as to GPx7 and GPx8 [ 9 ] in the ER and to GPx1 in cytosol and mitochondria [ 5 , 6 ]. It includes also the lack of expression of the low-affinity and high-capacity H 2 O 2 -inactivating catalase in the peroxisomes [ 5 , 6 ].

A lot of experimental evidence argues in principle against an incompatibility between a proper antioxidative enzyme equipment and unhampered beta cell function: a overexpression of catalase in mitochondria of insulin-secreting cells did not negatively affect glucose-induced insulin secretion [ 12 ]; b overexpression of Prx4 in the ER of rodent beta cells improved glucose-induced insulin secretion along with enhanced proinsulin mRNA transcription and increased insulin content [ 11 ].

The sources of H 2 O 2 can be very different. In the peroxisomes and in the ER, H 2 O 2 is generated directly during beta oxidation of long and very long-chain fatty acids and during protein folding, in particular of proinsulin, respectively [ 1 ].

Oxidative stress of any kind is immediately translated into increased levels of H 2 O 2. While H 2 O 2 levels in the resting cell are typically in the nanomolar range, they quickly reach concentrations in the micromolar range under conditions of oxidative stress [ 7 , 8 ].

All these are ideal premises that allow a quick build-up of H 2 O 2 concentrations and thus contribute significantly to the high vulnerability of the pancreatic beta cell under conditions of oxidative stress as they prevail in states of the metabolic derangements during disease development and progression:.

Beta cell cytokine toxicity in type 1 diabetes mellitus, caused by increased oxidative stress in the mitochondria [ 1 , 15 , 16 , 17 ]. Beta cell glucolipotoxicity in type 2 diabetes mellitus, caused by increased oxidative stress in the peroxisomes [ 1 , 18 , 19 ].

Beta cell glucolipotoxicity in type 2 diabetes mellitus, caused by increased oxidative stress in the ER [ 1 , 9 , 19 ]. Beta cell toxicity in experimental alloxan diabetes by increased oxidative stress in the cytosol [ 20 ].

When comparing the gene expression levels of the different H 2 O 2 -decomposing enzymes in rodent and human beta cells, one observation is remarkable. It is the protective antioxidative enzyme equipment of the endoplasmic reticulum ER Table 1. While the ER of the rodent beta cells expresses little Prx4 and no GPx7, Prdx4 is highly expressed along with additional expression of GPx7 in the human ER.

Thus, human ER is better protected against oxidative stress. This is convincingly documented by the observation that high Prdx4 expression significantly improved pro insulin folding [ 9 ], resulting in an improved insulin content and in higher rates of physiological glucose-induced insulin secretion [ 9 ].

With respect to a signalling function of H 2 O 2 in the beta cells by a physiological role through selective thiol group oxidation and a pathophysiological role in the mediation of cellular dysfunction and cell death, the low level of H 2 O 2 -decomposing enzyme expression in the beta cell may favour H 2 O 2 interactions with enzyme proteins and may provide a larger chance for interaction also with less reactive thiol groups because of a a longer lifetime and b resulting ability to travel longer distances within a cellular compartment and even into neighbouring compartments through aquaporins [ 1 , 21 ].

These aquaporins are water channels in the cellular and subcellular membranes. Thus, H 2 O 2 generation under any pathological condition that can emerge in the beta cell will hit an unprotected highly vulnerable beta cell [ 1 , 3 ].

Our most recent observation that the cellular and subcellular membranes of the beta cells are quite well protected through high level expression of GPx4 in contrast to the non-beta cells in the islets is remarkable. This enzyme is a mild protector against oxidative stress through its capacity to decompose H 2 O 2 but a strong protector against lipid peroxidation and ferroptosis [ 23 ].

Thus ferroptosis in contrast to apoptosis is not a prominent mechanism of beta cell death. The good protection of the membranes of the beta cell through Gpx4 expression may help to secure a regulated cell death via apoptosis under conditions of pathological stress rather than through uncoordinated cell death via necrosis with its ruptures of all cell membrane structures.

This is favourable also because it prevents the release of cell content with inflammatory potential into the extracellular space. The content of the dying cells encapsulated in the apoptotic bodies of the fragmented cells can be removed by macrophages in a proper fashion.

As high-affinity thiol proteins, in particular the high-affinity glutathione peroxidases and peroxiredoxins, are not expressed to any significant extent in the beta cells, the H 2 O 2 lifespan is increased, enabling long distance travelling of H 2 O 2 and the gain of access to other subcellular compartments via peroxiporins, H 2 O 2 -channelling aquaporins.

This observation documents that the beta cell is not just a stupid, badly protected cell type. A spartan daily diet with limited availability of carbohydrates and fat along with a decent amount of exercise that avoids obesity is compatible under normal circumstances with the weak antioxidative enzyme equipment of the pancreatic beta cell with its low H 2 O 2 -inactivating enzyme capacity.

This is documented by the fact that the beta cell under healthy conditions can survive without damage when the beta cell is not particularly challenged. However, the antioxidative defence of the beta cell may be insufficient to cope with the challenges of a modern lifestyle with a westernised diet.

In the human beta cells, the only significant protective element present is a higher expression level of Prx4 and an additional expression of GPx7 in the ER when compared to rodent beta cells Table 1.

This might be an element of better antioxidative protection against the development of beta cell dysfunction and a deterioration of the insulin production and secretory capacity at least in some human individuals to avoid or at least retard the development of a diabetic state.

In states of metabolic derangement such as obesity, the metabolic syndrome, and type 2 diabetes, but also in autoimmune-mediated type 1 diabetes, the pancreatic beta cells get into a state of severe oxidative stress [ 1 ] where the weak antioxidative defence is overwhelmed because it is not made to cope with the challenges of excessive oxidative stress.

Through the experimental evidence accumulated during the last decades it has been possible to identify many of the reasons for the extraordinary sensitivity of the pancreatic beta cell towards oxidative stress with the resultant particular vulnerability [ 3 ]. However, the question why pancreatic beta cells are so badly protected against oxidative stress due to insufficient capacity for H 2 O 2 decomposition remains a mystery, probably forever.

Incomprehensibility remains also as to why the insulin-producing pancreatic beta cells are so badly protected against oxidative stress-mediated apoptosis, while glucagon-producing alpha cells and the other islet cell types are well protected. It is also unclear why the opposite becomes true, when it comes to the protection of the membranes of the pancreatic beta cells against lipid peroxidation and ferroptosis through high level expression of GPx4, again at variance from the situation in the non-beta cell islet cells with the low expression level of GPx4.

In conclusion, the beta cells in the islets of Langerhans of the pancreas are a critically important cell type which produces and secretes the vitally important peptide hormone insulin in response to increasing glucose concentrations through generation of the second messenger ATP in the mitochondrial metabolism.

On the other hand, it remains a mystery why this crucially important cell type is so particularly vulnerable and sensitive towards oxidative stress. Graham Rena, D. Roman Abrosimov, Marius W. Baeken, … Bernd Moosmann.

Lenzen S Chemistry and biology of reactive species with special reference to the antioxidative defence status in pancreatic beta-cells. Biochim Biophys Acta Gen Subj — Article CAS Google Scholar. Lenzen S A fresh view of glycolysis and glucokinase regulation: history and current status.

J Biol Chem — Lenzen S Oxidative stress: the vulnerable beta-cell. Biochem Soc Trans — Panten U, Schwanstecher M, Wallasch A, Lenzen S Glucose both inhibits and stimulates insulin secretion from isolated pancreatic islets exposed to maximally effective concentrations of sulfonylureas.

Naunyn Schmiedebergs Arch Pharmacol — Lenzen S, Drinkgern J, Tiedge M Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med — Tiedge M, Lortz S, Drinkgern J, Lenzen S Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells.

Diabetes — Sies H Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: oxidative eustress. Redox Biol — Winterbourn CC Hydrogen peroxide reactivity and specificity in thiol-based cell signalling.

Mehmeti I, Lortz S, Avezov E, Jörns A, Lenzen S ER-resident antioxidative GPx7 and GPx8 enzyme isoforms protect insulin-secreting INS-1E beta-cells against lipotoxicity by improving the ER antioxidative capacity. Wolf G, Aumann N, Michalska M et al Peroxiredoxin III protects pancreatic β cells from apoptosis.

J Endocrinol — Mehmeti I, Lortz S, Elsner M, Lenzen S Peroxiredoxin 4 improves insulin biosynthesis and glucose-induced insulin secretion in insulin-secreting INS-1E cells.

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Understanding Pancreatic Beta Cells. Medically reviewed by Alana Biggers, M. Conditions Medications Failure Regeneration Beta vs. alpha Learn more Beta cells are cells in the pancreas. What health conditions involve beta cells? What medications involve beta cells? What causes beta cell failure? Is it possible to regenerate beta cells?

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Paradoxically, mitochondria also play an important role in triggering apoptosis Members of the Bcl-2 protein family regulate the mitochondrial response to pro-apoptotic signals 38 , preventing release of mitochondrial proteins such as cytochrome c, which, when liberated to the cytosol, sequentially activate caspase-9 and -3 and execute cell death Cytokines disrupt the mitochondrial membrane potential in RINm5F cells, which is prevented by overexpression of the anti-apoptotic protein Bcl-2 Overexpression of Bcl-2 partially protects mouse 41 and human 42 islets against cytokine-induced cell death, but does not prevent adenovirus-induced islet cell death 43 or spontaneous diabetes in nonobese diabetic NOD mice Liu, D.

Other pro-apoptotic genes that are induced by cytokines, as detected by microarray analysis 15 , are indicated in Fig. In favor of this hypothesis, overexpression of free radical scavenging enzymes in mitochondria, but not in the cytosol, prevents IL-1β—induced NF-κB activation Insulin resistance, often associated with obesity, and insulin secretion defects are major risk factors for type 2 diabetes 9.

A progressive decrease of β-cell function leads to glucose intolerance, which is followed by type 2 diabetes that inexorably aggravates with time The alterations of GIIS in human type 2 diabetes may theoretically result from changes in β-cell function, β-cell mass, or both.

A decrease in β-cell mass is likely to play a role in the pathogenesis of human type 2 diabetes 8 , 9 as it does in rodent models of the disease 48 , Because β-cell mass cannot be measured in vivo, it remains unclear whether type 2 diabetic patients had a lower β-cell mass early in life, failed to increase their β-cell mass in the face of insulin resistance, or had a progressive β-cell loss.

Based on results obtained in rodent models of the disease and in cultured rodent and human islet cells, it seems reasonable to assume that dyslipidemia and hyperglycemia negatively affect β-cell mass by increasing β-cell apoptosis in human type 2 diabetes 10 , In the following paragraphs, we discuss recent hypotheses on the mechanisms of glucotoxicity and lipotoxicity.

Moderate or severe hyperglycemia cannot be the primum movens in the pathophysiology of type 2 diabetes, but it contributes to the reduction of GIIS As such, it could contribute to the progression from glucose intolerance to overt type 2 diabetes The mechanisms by which hyperglycemia negatively affects functional β-cell mass are still debated.

Rodent β-cells chronically exposed to high glucose display several alterations of their phenotype, including changes in glucose stimulus-secretion coupling, gene expression, cell survival, and cell growth 48 , These alterations could result from cytokine-, oxidative stress—, or ER stress—induced changes in gene expression and cell survival 10 , 32 , 51 or from functional changes that are not directly related to β-cell apoptosis, such as accumulation of glycogen Rodent β-cells display reduced expression of genes involved in GIIS in in vivo and in vitro models of prolonged exposure to high glucose.

These changes, which may play a role in the alterations of GIIS in rodent type 2 diabetes, have some similarities with those induced by cytokines 17 , On the other hand, several genes expressed at low levels in normal β-cells are induced by hyperglycemia, including hexokinase 1, lactate dehydrogenase and glucose-6 phosphatase.

In addition, pro- and anti-apoptotic factors, antioxidant enzymes, and some transcription factors are upregulated Some of these genes, such as c-Myc, A20, and heme-oxygenase 1, are induced by hyperglycemia and cytokines, suggesting that both conditions share some common mechanisms to alter the β-cell phenotype.

The suggestion that hyperglycemia increases β-cell production of IL-1β in human islets provides such a unified hypothesis for β-cell pathophysiology in type 1 and type 2 diabetes However, the pattern of hyperglycemia-induced β-cell genes is only partly similar to that induced by cytokines 17 , 18 , For instance, iNOS and IκBα, two NF-κB—dependent genes markedly induced by IL-1β, are not induced in rodent β-cells exposed to high glucose.

Other genes, such as lactate dehydrogenase A, the mitochondrial uncoupling protein UCP-2, and the transcription factor CREM, are induced by hyperglycemia 53 , 54 and downregulated by cytokines 17 , Furthermore, hyperglycemia induces β-cell hypertrophy, whereas cytokine treatment does not, and the induction of β-cell apoptosis by high glucose is much lower than that produced by cytokines.

These differences raise questions about the role of IL-1β—induced NF-κB activation in β-cell glucotoxicity. These doubts are strengthened by our observations that, under various culture conditions, exposure of rat or human islets or FACS-purified rat β-cells to high glucose does not increase IL-1β mRNA expression or NF-κB DNA-binding activity 56 ; Fig.

It is generally assumed that oxidative stress activates NF-κB activity in β-cells as in other cell types This does not seem to be the case, since acute 57 or overnight exposure to low concentrations of hydrogen peroxide does not increase rat islet NF-κB activity and iNOS expression Islet c-Myc and heme-oxygenase 1 expression are similarly induced by hydrogen peroxide and high glucose, and these effects are abrogated by the free radical scavenger N -acetyl- l -cysteine.

This suggests that β-cell glucotoxicity may, at least in part, result from an increase in β-cell oxidative stress and subsequent JNK activation that is NF-κB independent 51 , The main source of reactive oxygen species in the β-cell is probably the mitochondrial electron transport chain 58 , It is therefore possible that chronic stimulation of insulin secretion in states of insulin resistance induces oxidative stress.

It is well established that chronic hyperglycemia leads to β-cell degranulation and reduction in GIIS 48 , but the effect of hyperglycemia on the β-cell sensitivity to glucose is controversial.

A first group of studies indicates that the absence of a glucose-induced rise in ATP production, perhaps due to hyperglycemia-induced expression of uncoupling protein 2, is responsible for defective GIIS This glucose hypersensitization, which results from higher ATP production at low glucose concentrations, may be due to the accumulation of glycogen in β-cells 52 , This concept of β-cell glucose hypersensitivity fits with the presence of fasting hyperinsulinemia in type 2 diabetic patients and the observation based on autopsy material that their β-cells are actively engaged in proinsulin synthesis Thus, β-cell glucose desensitization is compatible with the concept that β-cell dysfunction partly results from β-cell apoptosis 10 , 51 , In contrast, β-cell glucose hypersensitization may result from changes in the expression of glycolytic enzymes decreased glucokinase and increased hexokinase 1 and lactate dehydrogenase expression , from the accumulation of glycogen at high glucose and its subsequent degradation at low glucose, or from other functional alterations of β-cells 48 , 62 , 64 , but not from apoptosis.

We have recently observed that overnight exposure of rat islets to low concentrations of hydrogen peroxide induces glucose desensitization and β-cell apoptosis that are both prevented by N -acetyl- l -cysteine. These results suggest that the various facets of β-cell glucotoxicity may result from different pathophysiological mechanisms.

These different pathophysiological mechanisms are compatible with the observations that 1 after 3 weeks of diet-induced diabetes in the gerbil Psammomys obesus , a stage at which the β-cell mass is decreased 67 , isolated islets were still glucose hypersensitive 62 ; and 2 human islets transplanted under the kidney capsule of hyperglycemic nude mice and maintained in vivo for 4 weeks have severely impaired GIIS, which can be dissociated from impaired glucose oxidation or protein synthesis and, under some conditions, from depleted insulin content or cell death 68 , Physical inactivity, energy-dense diets rich in saturated fat, and central obesity predispose individuals to type 2 diabetes.

Prospective studies in subjects at risk for diabetes have shown that the development of abdominal obesity is correlated with loss of β-cell function and hence glucose intolerance 70 ; M. Vidal, R.

Hull, K. Utzschneider, D. Carr, E. Boyko, W. Fujimoto, S. Kahn, unpublished data. Autopsy data suggest that the progressive decline in insulin secretion in type 2 diabetes is accompanied by a decrease in β-cell mass and that this is secondary to increased β-cell apoptosis.

Thus, it is conceivable that circulating adipose tissue—derived products, such as FFAs and adipokines, play a direct role in pancreatic β-cell dysfunction and death.

A high plasma concentration of FFAs is indeed a risk factor for the development of type 2 diabetes, independently of its effects on insulin sensitivity Circulating FFAs are solubilized and transported in millimolar concentrations, by virtue of their tight binding to albumin.

FFAs acutely stimulate insulin secretion, but prolonged β-cell exposure to high FFA levels reduces GIIS in vitro 72 and in vivo, especially in individuals genetically predisposed to type 2 diabetes Studies in the ZDF rat indicate that high circulating FFAs and triglyceride levels induce triglyceride accumulation in pancreatic islets The associated rise in cytoplasmic FFA levels would increase ceramide formation and induce iNOS, resulting in NO-mediated β-cell apoptosis In our in vitro experiments 36 , 76 , 77 , we used physiological concentrations of palmitate and oleate.

FFAs are toxic to FACS-purified rat β-cells 36 , 76 and insulin-producing INS-1E cells Cytotoxicity depends on the unbound FFA concentration and is greater for palmitate than oleate. FFA-induced cell damage results in apoptosis and, to a lesser extent, necrosis in β-cells 76 and mostly in apoptosis in INS-1E cells The toxic effects of FFAs are potentiated when β-cells are concomitantly exposed to high glucose levels 78 , FFA cytotoxicity does not depend on mitochondrial FFA oxidation, because etomoxir, an inhibitor of carnitine palmitoyltransferase I, did not alter FFA-induced β-cell death, and bromopalmitate, a nonmetabolizable analog, was as toxic as palmitate FFA-induced cell death occurred in the absence of iNOS expression or NO production 36 , 76 , and it was not counteracted by antioxidant or free radical scavenging compounds 76 , suggesting that oxidative stress is not its main mediator.

Moreover, oleate or palmitate did not activate NF-κB in INS-1E or β-cells 36 , at low 6. Kharroubi, D. It was suggested that FFA cytotoxicity could be counteracted by the peroxisome proliferator—activated receptor-γ agonist troglitazone through lowering islet triglyceride content In our hands, however, troglitazone did not improve survival of FFA-exposed β-cells, but rather sensitized them to necrosis and apoptosis at low FFA concentrations Furthermore, FFA-induced cytoplasmic triglyceride accumulation was inversely correlated to β-cell death A mixture of oleate and palmitate caused the lowest cell death and the highest triglyceride accumulation, whereas bromopalmitate, which did not increase cellular triglycerides, exerted the highest toxicity These findings suggest that storage of excess FFAs as triglycerides protects the cell against accumulation of potentially deleterious fatty acyl-CoA.

FFA-induced β-cell toxicity might also occur at the ER level, where FFA esterification takes place. Using electron microscopy, we observed that the ER of FFA-exposed β-cells is dilated M.

Both oleate and palmitate caused alternative splicing of XBP-1, activation of ATF-6, and induction of the ER chaperone BiP in INS-1E cells In addition to these specific ER stress markers, there was induction of ATF-4 and CHOP The mechanism by which FFAs cause ER stress remains to be elucidated, but over stimulation of FFA esterification in the ER might result in delayed processing and export of newly synthesized proteins, whereas saturated triglycerides may precipitate at their site of synthesis in the ER because of their high melting point.

If that is the case, these intriguing novel observations 36 , 82 , 83 place ER stress as a common molecular pathway for the two main causes of type 2 diabetes—namely insulin resistance and loss of β-cell mass. The development of novel approaches to prevent β-cell death in diabetes depends on our knowledge of the mechanisms leading to β-cell demise.

Thus, if the mechanisms of β-cell apoptosis were similar in type 1 and type 2 diabetes, it would be logical to search for common interventions in both forms of diabetes. The NOD mouse and the BB rat are the most used animal models of type 1 diabetes 84 , but a new model for type 1 diabetes has been recently described—the IDDM LEW.

This latter model is of particular interest, since IDDM rats have a well-preserved cellular immune system, there is no sex bias in the incidence of diabetes, and detailed studies of the events leading to β-cell death are possible see below. These immune cells are activated 87 and express proinflammatory cytokines such as IL-1β, TNF-α, and IFN-γ 88 , IL-1β and TNF-α, but not IFN-γ, are detected in the infiltrating immune cells in the IDDM rat, but the pancreatic β-cells do not express these cytokines at any of the stages leading to overt diabetes 90 ; Fig.

Günther, H. Hedrich, D. Wedekind, M. Tiedge, S. Data from other models suggest that β-cells express chemokines such as MCP-1 and IP, which may contribute to the buildup of insulitis Detailed morphological studies in the IDDM rat, using both in situ PCR and immunohistochemistry A.

These observations suggest that proinflammatory cytokines are synthesized and released by the activated infiltrating immune cells, but not by the β-cells themselves, leading to apoptotic β-cell death in a paracrine fashion.

Loss of pancreatic β-cell mass is slow in type 2 diabetes, and there is no evidence for mononuclear cell infiltration 2. This is well documented in a number of type 2 diabetes animal models, including the Psammomys obesus sand rat 92 and the GK rat When Psammomys are placed on a high-carbohydrate diet, they rapidly evolve to a diabetic state because of the loss of endocrine pancreas function and β-cell destruction 48 , In contrast to the type 1 diabetes models see above , β-cell demise occurs mostly by necrosis The necrotic cells are removed by scavenger macrophages, which, at variance from the type 1 diabetes situation, are not activated and do not express the proinflammatory cytokines IL-1β, IFN-γ, or TNF-α Fig.

Importantly, the β-cells from these animals do not express IL-1β, iNOS, or caspase-3, as evaluated by immunohistochemistry Fig. As a positive control, IL-1β mRNA expression was confirmed by in situ PCR using immune cells of pancreas draining lymph nodes.

The same sequence of events seems to take place in the physiological situation, where β-cells undergoing apoptosis during their cell renewal cycle are removed by nonactivated macrophages Even when the β-cell turnover rate is increased by administration of thyroid hormones 67 , 95 , the increased demand for removal of apoptotic cells does not trigger macrophage activation or cytokine expression A.

These observations suggest a sequence of events that is different in type 1 and type 2 diabetes models. Thus, β-cells die by necrosis or apoptosis in type 2 diabetes, but the cause of death is not related to cytokine production by infiltrating mononuclear cells or the β-cells themselves.

The dead β-cells attract scavenger macrophages, which in this case are the consequence rather than the cause of β-cell death Fig.

It has been recently suggested that β-cells exposed in vitro to high glucose produce IL-1β, thus activating NF-κB and Fas signaling and consequently triggering apoptosis 10 , Another report indicated that FFAs also activate NF-κB in β-cells As discussed above, exposure to IL-1β alone is not sufficient to kill human or rodent β-cells, and the signal transduction of IFN-γ is also required for β-cell demise.

To exclude that exposure of β-cells to high glucose or FFAs induces the IFN-γ pathway, we reviewed the results of five different microarray analyses of human or rodent islets exposed to these nutrients list of microarray studies provided upon request.

We also contacted some of the authors to make sure that small changes in gene expression were not overlooked D. Melloul, G. Webb, personal communications.

The data were compared with the gene expression patterns in rat 14 or human P. Ylipaasto, B. Kutlu, S. Raisilainen, J. Rasschaert, T. Teerijoki, O. Korsgren, R.

Lahesmaa, T. Hovi, D. Otokonski, M. Roivainen, unpublished data islets exposed to IFN-γ. The mRNAs whose expression was most augmented by IFN-γ in β-cells were the transcription factors STAT-1, IRF-1, and IRF-7 and the chemokine CXCL 10 IP Glucose or FFAs modified none of these genes in β-cells, practically excluding the IFN-γ—STAT-1 pathway as a mediator of glucotoxicity or lipotoxicity.

As mentioned above, there is strong evidence that IL-1β contributes to β-cell death in type 1 diabetes via activation of NF-κB. Which is the evidence that FFAs induce IL-1β production or NF-κB activation in β-cells? We 36 and others 97 did not observe FFA-induced NF-κB activation in β-cells using three different techniques gel shift, ELISA, and immunohistochemistry , and there are no reports of FFA-induced IL-1β expression in these cells.

Moreover, FFAs do not induce expression of the NF-κB—dependent genes iNOS and MCP-1 in rodent β-cells 36 , What about high glucose?

Most of the in vitro data supporting glucose-induced IL-1β production and NF-κB activation were obtained by one group rev. in Based on their observations, this group initiated a clinical trial with the IL-1 receptor antagonist in type 2 diabetic patients Of concern is that there is no in vivo evidence in animal models that blocking IL-1β protects β-cells against glucotoxicity.

We examined whether this was due to a species difference between rat 56 and human 10 , 11 islets. Exposure of five preparations of human islets to increasing glucose concentrations 11 and 28 vs.

Moreover, there was no glucose-induced Fas mRNA expression 99 , the proposed NF-κB—dependent mechanism by which glucose causes β-cell death In line with our findings, islets isolated from mice deficient in either the IL-1 receptor or Fas were not protected against high glucose—induced β-cell death, and Fas was not detectable in wild-type mouse islets cultured at high glucose As a whole, these observations argue against a role for IL-1β, NF-κB, or Fas in high glucose—induced β-cell death.

In conclusion, the suggestion that β-cells are killed by a similar mechanism in type 1 and type 2 diabetes is probably an oversimplification, not supported by convincing data.

This oversimplification may bring confusion to a difficult and complex field and promote testing of novel therapeutic approaches in humans without adequate experimental support. In agreement with the lack of IL-1β expression or release by human islets exposed to high glucose in vitro as discussed in this review , recent data do not support a role for IL-1β in type 2 diabetes in vivo.

Two studies, using respectively real-time RT-PCR and microarray analysis, demonstrate that IL-1β and Fas expression in islets isolated from type 2 diabetic patients is not increased as compared with islets from nondiabetic controls 99 , The transcription factors NF-κB and STAT-1 are the main regulators of the pathways triggered by IL-1β and IFN-γ, respectively.

The figure is based on Refs. MHC-1, major histocompatibility complex 1. Proposed model for the different pathways contributing to the execution of cytokine-induced β-cell apoptosis. Arrows indicate genes for which expression was modified by cytokines in a time course microarray analysis β-Cell apoptosis is probably mediated by three main pathways—namely JNK, ER stress, and liberation of pro-apoptotic proteins from the mitochondria.

The data at 12 h are shown here; similar observations were made at 24 h not shown. Subcellular NF-κB localization was counted in — cells using the same experimental conditions as above D. The results are means ± SE of three independent experiments.

percent nuclear staining in the control by two-sided paired t test D. Original magnification × Morphology of an islet from a diabetic IDDM LEW. The sections were immunostained for IL-1β A and D , iNOS B and E , and activated caspase-3 C and F and show cytoplasmic immunoreactivities only in the infiltrated islets of the type 1 diabetic animal A—C.

These cells express immunoreactivity for IL-1β A and iNOS B but not for activated caspase-3 C. Pancreatic β-cells undergoing apoptosis thick arrows , in contrast, express immunoreactivity for iNOS and activated caspase-3, but not for IL-1β.

These cells show no signs of immunoreactivity for IL-1β D , iNOS E , or activated caspase-3 F. β-Cells thick arrows of Psammomys showed signs of necrotic destruction including intra- and intercellular vacuolization without expression of IL-1β D , iNOS E , or activated caspase-3 F.

These β-cells showed no signs of nuclear heterochromatin condensation. The same findings were made after 1 week of a high-energy diet.

Overview of the putative sequence of events leading to β-cell death in animal models of type 1 and type 2 diabetes. For additional information on the mechanisms of β-cell apoptosis in type 1 diabetes, see Figs. T1D, type 1 diabetes; T2D, type 2 diabetes.

This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier. Work by the authors was supported by the following: the Juvenile Diabetes Research Foundation Center for Prevention of β-Cell Destruction in Europe, under grant number D.

and D. We thank Dr. Cardozo for help in preparing Fig. Kharroubi for performing the NF-κB immunostaining in Fig. Sign In or Create an Account. Search Dropdown Menu.

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Previous Article. NOTE ADDED IN PROOF. Article Information. Article Navigation. Section III: Inflammation and β-Cell Death December 01 Mechanisms of Pancreatic β-Cell Death in Type 1 and Type 2 Diabetes : Many Differences, Few Similarities Miriam Cnop ; Miriam Cnop.

This Site. Google Scholar. Nils Welsh ; Nils Welsh. Jean-Christophe Jonas ; Jean-Christophe Jonas. Anne Jörns ; Anne Jörns. Sigurd Lenzen ; Sigurd Lenzen. Decio L. Eizirik Decio L. Address correspondence and reprint requests to Dr.

Miriam Cnop, Laboratory of Experimental Medicine, Université Libre de Bruxelles ULB , Route de Lennik , CP, Brussels, Belgium. E-mail: mcnop ulb.

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Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.

Diabetes Care. Klöppel G, Löhr M, Habich K, Oberholzer M, Heitz PU: Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res. Srikanta S, Ganda OP, Jackson RA, Gleason RE, Kaldany A, Garovoy MR, Milford EL, Carpenter CB, Soeldner JS, Eisenbarth GS: Type I diabetes mellitus in monozygotic twins: chronic progressive β cell dysfunction.

Ann Intern Med. This loss is irreversible, and the beta cells are not able to produce enough insulin to regulate healthy blood sugar levels. Without treatment, type 2 diabetes can progress, and further loss of beta cells can occur.

However, research has found that loss of beta cell function is reversible in the early stages of type 2 diabetes and does not cause permanent damage. Loss of excess fat in the cells can lead to a return of proper beta cell function and remission of type 2 diabetes.

A study involved 40 people who had achieved remission from type 2 diabetes 2 years prior to the study from following a diet for weight loss. After 2 years, 20 participants remained in remission, 13 participants gained weight and had a relapse, and seven participants were not available for a follow-up.

The researchers measured glucose levels before weight loss, after 5 months of weight loss, and at 1 and 2 years. Blood glucose below certain levels with no use of type 2 diabetes medication meant the participants were in remission. The study authors found that remission of type 2 diabetes was sustainable over the course of 2 years as long as weight regain was minimal.

This remission also meant a gradual return to proper beta cell function and mass. Depending on body weight , in adults, beta cells usually release around 30—70 international units IU of insulin each day.

During stressful events, the body releases hormones such as adrenaline that prevent the release of insulin.

This increases blood glucose levels to help the body deal with the stressful situation. Certain medications, including incretin-based medications and SGLT2 inhibitors , can help treat type 2 diabetes and improve beta cell function.

Incretin-based medications help regulate blood glucose levels. Incretin is a hormone that triggers the production of insulin and helps reduce the rate at which glucose from food enters the bloodstream.

Incretin-based medications include :. Incretin-based medications can help improve beta cell function and keep people feeling fuller for longer after eating, which may help reduce food consumption.

Moreover, incretin-based medications regulate insulin production depending on how much glucose is present in the bloodstream.

This prevents the overproduction of insulin and stops glucose levels from dropping too low, which can also damage beta cells. SGLT2 inhibitors are another type of medication that can help treat type 2 diabetes and reduce the demand on beta cells. SGLT2 inhibitors help increase the amount of glucose that the body removes through urine.

SGLT2 inhibitors may also help with lowering body weight and reducing the risk of heart problems. Learn more about diabetes medication here. Although medications can help, changes in lifestyle can also be important steps a person can take to prevent or manage type 2 diabetes.

Individuals can reduce their food intake if necessary and make sure to get regular exercise. These factors help reduce the workload of beta cells and increase insulin sensitivity. Increased insulin sensitivity means the body can use insulin more effectively and better control blood sugar.

For people with type 2 diabetes, following a balanced diet and getting regular exercise are important in managing the condition and preventing it from progressing. Reaching or maintaining a moderate body weight through changes in diet and exercise may also lead to remission of type 2 diabetes and return of proper beta cell function.

Beta cells are cells in the pancreas that produce and release the hormone insulin to regulate blood sugar levels. In people with type 2 diabetes, continuously high blood sugar levels can put extra pressure on beta cells, as they have to work harder to produce enough insulin to control glucose levels.

In the early stages of type 2 diabetes, the loss of beta cell function may be reversible through weight loss and reduction of blood glucose levels. Certain medications can help control or prevent type 2 diabetes.

However, the most effective steps a person can take to prevent or manage the condition are reaching or maintaining a moderate body weight and getting regular exercise. Find out here about the differences and…. A type 2 diabetes care plan outlines how a person can manage their condition.

It includes blood sugar monitoring, insulin dosage, and more. Type 1, type 2, and gestational diabetes all involve an imbalance of blood sugar, but the risk factors for each may vary. Having a family history of….

A study in mice suggests a potential mechanism that could explain why only some individuals with obesity develop type 2 diabetes.

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Medical News Today. Health Conditions Health Products Discover Tools Connect. Type 2 diabetes: Beta cells explained. Medically reviewed by Michelle L. Griffith, MD — By Beth Sissons on October 25, Explanation Beta cell survival At specific times Treatment Lifestyle factors Summary Beta cells are cells in the pancreas that produce and release insulin in response to blood glucose levels.

Pancreatic beta cells -

Babak Faryabi , PhD, an assistant professor of Pathology and Laboratory Medicine and a core member of Epigenetics Institute at Penn. Blood tests to check for levels of GAD are common for patients with, or at risk for, T1D, and doctors use it as a diagnostic tool.

Another finding of this study is the new understanding of what is happening on a molecular level in the pancreas and how it correlates to the findings of the GAD test.

Although researchers do not yet know whether these transcriptional changes are contributing to or are consequences of disease pathogenesis, the discovery of molecular phenotypic changes in pancreatic cells of autoantibody-positive individuals advances the understanding of early pancreatic changes occurring in T1D, and sets the course for continued research in this area.

This research was funded by grants through the National Institutes of Health UC4 DK, U01DK, R01CA, R01HL, and U01DK Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

All of the cells communicate with each other through extracellular spaces and through gap junctions. This arrangement allows cellular products secreted from one cell type to influence the function of downstream cells.

As an example, insulin secreted from beta cells suppresses glucagon secreted from alpha cells. A neurovascular bundle containing arterioles and sympathetic and parasympathetic nerves enters each islet through the central core of beta cells.

The arterioles branch to form capillaries that pass between the cells to the periphery of the islet and then enter the portal venous circulation.

INSULIN SYNTHESIS AND SECRETION. Why UpToDate? Product Editorial Subscription Options Subscribe Sign in. Learn how UpToDate can help you. Select the option that best describes you. View Topic. Font Size Small Normal Large. Pancreatic beta cell function.

Formulary drug information for this topic. No drug references linked in this topic. Find in topic Formulary Print Share. View in. Rahier, J. Pancreatic β-cell mass in European subjects with type 2 diabetes. Butler, A. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes.

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Diabetologia 52 , — Henquin, J. Pancreatic alpha cell mass in European subjects with type 2 diabetes. Diabetologia 54 , — Utzschneider, K. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels.

Diabetes Care 32 , — Green, D. The clearance of dying cells: table for two. Cell Death Differ. The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation. Diabetologia 53 , — This study modelled lipofuscin accumulation in human β-cells with age; together with the complementary methods used in reference 84, this shows that, past age 20—30 years, little or no new β-cells are formed and β-cells age with the body.

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β-cell deficit in obese type 2 diabetes, a minor role of β-cell dedifferentiation and degranulation. Md Moin, A. Increased frequency of hormone negative and polyhormonal endocrine cells in lean individuals with type 2 diabetes.

Cinti, F. Evidence of β-cell dedifferentiation in human type 2 diabetes. Sun, J. PubMed Google Scholar. Spijker, H. Loss of β-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors.

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Aguayo-Mazzucato, C. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. e4 Gunton, J. Cell , — Solimena, M. Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes.

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Cell Res. Ling, Z. Intercellular differences in interleukin 1β-induced suppression of insulin synthesis and stimulation of noninsulin protein synthesis by rat pancreatic β-cells.

Mawla, A. Navigating the depths and avoiding the shallows of pancreatic islet cell transcriptomes. An excellent analysis of heterogeneity and caveats of single islet cell RNA sequencing.

Mahajan, A. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.

Onengut-Gumuscu, S. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Cudworth, A. Letter: HL-A antigens and diabetes mellitus.

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CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients. Koskinen, M. Longitudinal pattern of first-phase insulin response is associated with genetic variants outside the class II HLA region in children with multiple autoantibodies.

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Parker, S. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Gaulton, K. A map of open chromatin in human pancreatic islets. Bhandare, R. Genome-wide analysis of histone modifications in human pancreatic islets.

Genome Res. Fogarty, M. Allele-specific transcriptional activity at type 2 diabetes-associated single nucleotide polymorphisms in regions of pancreatic islet open chromatin at the JAZF1 locus. Kulzer, J. A common functional regulatory variant at a type 2 diabetes locus upregulates ARAP1 expression in the pancreatic beta cell.

Horikoshi, M. Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms.

Greenwald, W. Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk. Miguel-Escalada, I. Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes.

This study resolved 3D chromatin contact maps in human islet cells allowing the identification of promoter targets of distal regulatory elements at T2DM and fasting glucose GWAS loci.

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Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. Diabetologia 56 , — Morita, S. Targeting ABL-IRE1α signaling spares ER-stressed pancreatic β cells to reverse autoimmune diabetes.

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Cell Sci. Death protein 5 and pupregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human β-cell apoptosis. Selective inhibition of eukaryotic translation initiation factor 2α dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic β-cell dysfunction and apoptosis.

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A missense mutation in PPP1R15B causes a syndrome including diabetes, short stature, and microcephaly. Delepine, M. EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome.

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Miriam CnopNils Welsh Pancreatci, Jean-Christophe PandreaticAnne Jörns Pxncreatic, Sigurd LenzenDecio Pancreatuc. Eizirik; Mechanisms of Pancreatic Hydration for staying hydrated during marathons Death in Type Avocado Sandwich Ideas and Type 2 Diabetes : Pancrfatic Differences, Few Similarities. Raspberry-themed party ideas 1 and type Pancreatic beta cells diabetes are characterized by progressive β-cell failure. Apoptosis is probably the main form of β-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced β-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin IL -1β, nuclear factor NF -κB, and Fas. We review herein the similarities and differences between the mechanisms of β-cell death in type 1 and type 2 diabetes. Pancreatic beta cells Stress reduction exercises at work you for Polyphenols and anti-inflammatory effects nature. Pancreatic beta cells are using Pancrfatic browser version with limited support for CSS. To obtain the best bsta, we recommend you stress reduction exercises at work betw more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The maintenance of glucose homeostasis is fundamental for survival and health. Diabetes develops when glucose homeostasis fails. Type 2 diabetes T2D is characterized by insulin resistance and pancreatic β-cell failure.

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  2. Ich denke, dass Sie sich irren. Geben Sie wir werden es besprechen. Schreiben Sie mir in PM, wir werden reden.

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