Subsequently, contraction mediated mechanisms favoring glucose uptake last for ~3—6 h following a single bout of exercise. In time, insulin-sensitizing effects take over to explain improved glucose control Habitual exercise i.

Metformin is suggested to stimulate skeletal muscle glucose uptake and oxidation Moreover, metformin has been shown to lower intramuscular triglyceride content and bioactive acyl-chain bioactive lipids 38 , 39 through in part elevations in fat oxidation. Together, these observations indicate that metformin has effects on skeletal muscle energy metabolism that favor glucose homeostasis.

Because metformin is advised as a first-line pharmacological agent, we conducted a double-blind, randomized control trial to test the effect of exercise training with and without metformin on insulin sensitivity in people with prediabetes For 12 weeks, individuals were randomized to either: placebo, metformin, exercise training with placebo, or exercise training with metformin.

Insulin sensitivity was determined about 28 h post-exercise via the euglycemic-hyperinsulinemic clamp with glucose isotope tracers.

Tracers were utilized to determine the effects of metformin on skeletal muscle insulin sensitivity as well as hepatic glucose production. Although to date no follow up studies have been conducted using stable isotopes to understand skeletal muscle insulin-stimulated glucose disposal, recent work has tested the effect of metformin on aerobic or resistance exercise skeletal muscle cellular adaptation 33 , The results of these studies collectively show that metformin opposes skeletal muscle mitochondrial adaptations as well as inhibits fat-free mass accretion see below Cell Mechanisms for further discussion , which were directly correlated with attenuated gains in aerobic fitness as well as strength.

Together, these findings highlight that blunted fitness adaptation may relate to the reduced skeletal muscle insulin sensitivity response. In either case, this smaller gain in insulin sensitivity following the combination of exercise and metformin treatment does not apparently lead to stark blood glucose elevations 23 , 31 , Further work is warranted to better understand how the combination of drug-exercise therapies contributes to glycemic control across exercise doses, particularly in people with T2D.

For instance, recent work demonstrated that metformin increased carbohydrate utilization during high intensity interval exercise in insulin resistant adults when compared to exercise alone This may be of clinical relevance since carbohydrate use during exercise was related to insulin sensitivity as measured by the intravenous glucose tolerance test.

The findings of Ortega et al. Whether exercise intensity interacts with metformin to affect skeletal muscle insulin sensitivity in clinical populations remains to be tested to help understand if muscle is the primary driver of glycemic variation responses.

Indeed, people at risk for or with T2D, in particular, have impaired responses to insulin This highlights that the liver becomes insulin resistant and plays roles in both fasting and fed states. While fasting glucose and insulin may serve as a proxy for hepatic glucose production, and study of hepatokines, liver fat, or liver enzymes 43 may provide indirect estimates of hepatic function, use of stable isotopes along with hyperinsulinemic-clamps represent ideal methodologies to depict the role of the liver on glycemic control.

The exercise impact on hepatic glucose production is generally positive. One to seven days of aerobic exercise has been shown in people with T2D to increase hepatic insulin sensitivity 44 , Exercise training studies of ~12 weeks have also demonstrated favorable effects on hepatic insulin sensitivity 46 , with at least some of the effect being related to improved hepatokines i.

It cannot be ruled out though that discrepancies between short-term training studies may relate to exercise intensity, as higher intensity exercise activates AMPK in hepatocytes As a result, it seems that energy deficit, at least partially, created by exercise is an important mechanism improving hepatic insulin sensitivity.

Metformin improves hepatic insulin sensitivity. The mechanism by which metformin lowers hepatic glucose production is mainly thought to be through activation of AMPK and reduction in gluconeogenic enzymes 49 , although some suggest antagonism of glucagon may be important In addition, metformin is considered to increase fat oxidation in hepatocytes, thereby reducing the potential delirious effects of lipids on insulin signaling Recent work has suggested that metformin may benefit conditions of hepatic steatosis.

In particular, although metformin-induced similar reductions in the hepatic triglyceride content of Otsuka Long-Evans Tokushima Fatty OLETF rats under caloric restriction, compared to caloric restriction alone, the combined treatment lowered hepatic-derived inflammation more Additionally, metformin augmented the benefits of caloric restriction on lowering post-prandial circulating glucose in rodents, suggesting that metformin may impact the liver during energy deficit reduce diabetes and non-alcoholic fatty liver disease risk This observation of greater glycemic benefit was in parallel to greater beta-oxidation and mitochondrial mitophagy i.

To date, we are aware of only one study in humans that has systematically tested the effect of combining metformin with exercise on hepatic glucose production In this study, we showed that 12 weeks of metformin, exercise, or the combination of therapies maintained hepatic glucose production as measured by stable isotopes despite reductions in fasting plasma insulin.

This highlights that all treatments improved hepatic insulin sensitivity in middle-aged adults with prediabetes. Thus, it would seem the liver is unlikely to explain glycemic variation post-exercise. Further work in humans is required to understand, nevertheless, how exercise and metformin interact to affect hepatic function given that fatty liver disease is prominent in people with obesity and T2D, and fatty liver disease plays a critical role in the development of CVD.

Adipose tissue is the primary supplier of plasma free fatty acids FFA. FFAs provide energy to working tissues, including skeletal muscle and liver primarily during fasting states. In response to mixed meals i. However, when adipose tissue becomes resistant to the action of insulin, FFA concentrations rise in circulation and play an important role in the development of insulin resistance In fact, the release of FFAs from adipose tissue contributes, not only to declines in skeletal muscle and hepatic insulin sensitivity but also to endothelial dysfunction and reduced β-cell function in obesity, prediabetes, and T2D 55 — The reason FFAs contribute to this multi-tissue insulin resistance is beyond the scope of this review, but likely relates to elevated plasma FFA concentrations being linked with reduced mitochondrial function and metabolic flexibility 58 , Therefore, it would be reasonable to expect aerobic exercise interventions designed to improve oxidative capacity to not only protect against FFA-induced insulin resistance but also improve adipose insulin action.

Exercise confers several benefits to adipose tissue that include reductions in not only total fat mass but also visceral adiposity A consequence of this improved body fat mass has been proposed to decrease circulating FFAs as well as inflammatory mediators referred to as adipokines.

Indeed, we have shown that changes in circulating FFAs following moderate intensity training are directly related to improved peripheral insulin sensitivity 32 and short-term interval or continuous exercise increases adipose insulin sensitivity in adults with prediabetes While reductions in body fat following exercise training may be a key explanation for reducing circulating FFAs 60 in relation to improved peripheral insulin sensitivity and CVD risk reduction, fat loss is not required for improved adipocyte function.

In fact, we recently showed that energy deficit, but not fat mass reduction, is important for improving adipokine profiles during caloric restriction Moreover, Heiston et al.

demonstrated that just 2 weeks of aerobic interval or continuous exercise increased adiponectin and lowered leptin prior to clinically meaningful weight loss or reductions in fat mass in older adults with prediabetes Regardless, prior work 63 showed that hepatic insulin sensitivity was increased more following exercise training with a hypocaloric diet than when compared with a eucaloric diet during lipid-infusion.

This suggests that in addition to exercise, calorie restriction may protect the liver from obesity-driven insulin resistance more so than training alone, despite comparable peripheral insulin sensitivity Taken together, exercise, with or without caloric restriction, is an effective treatment for improving adipose tissue function.

Metformin is known to induce weight loss in adults with obesity, prediabetes, and T2D Metformin reduces circulating FFA in part through inhibiting lipolysis In fact, in murine adipocytes, metformin activated AMPK and blunted ANP as well as catecholamine-stimulated lipolysis 67 , While recent work suggests that oral metformin administration does not impact subcutaneous adipose tissue lipolysis during submaximal exercise in young lean men 70 , it remains possible that in clinical populations alterations in either adipose lipolysis or reduced clearance as well as esterification may contribute to higher plasma FFAs.

In either case, the elevated FFAs have been correlated attenuated gains in insulin sensitivity following metformin plus exercise therapy 23 , This may be clinically important as intrahepatic fat accumulation was lowered more after a diet and exercise than when lifestyle therapy was combined with metformin in obese adolescents The blunted improvement in hepatic steatosis in these adolescents is consistent with the view that elevated FFAs from adipose tissue travel through the portal vein to the liver for increasing hepatic lipid storage.

Collectively, this work highlights that adipose-derived metabolism may play a role in CVD risk following the co-prescription of metformin and exercise. Insulin promotes vasodilation in large conduit arteries and resistance arterioles as well as microvasculature perfusion Conduit and resistance arteries are important for the delivery of nutrients and oxygen to metabolically active tissues, whereas the microvasculature provides a critical role in the exchange of these substances.

In turn, adequate insulin-stimulated blood flow and endothelial function are essential for glucose regulation. This impaired glucose delivery may not only increase risk for T2D but also contribute to endothelial dysfunction through lower nitric oxide bioavailability.

Interestingly, people with insulin resistance have been noted to have normal fasting vascular function, but impaired conduit or microvascular insulin action This demonstrates that mechanisms underlying disease states may be unique in the fasted vs.

insulin-stimulated state. Habitual physical activity elevated insulin-mediated skeletal muscle glucose disposal and limb blood flow 65 , The dose at which exercise impacts vascular insulin sensitivity, however, is less clear.

Although recent work suggests that interval exercise improves flow-mediated dilation FMD , which measures large conduit arteries, more than continuous exercise in sedentary people 11 , 12 , 75 not all studies agree Interestingly, we recently studied the effect of interval vs.

continuous exercise on fasting and post-prandial arterial stiffness as well as endothelial function as measured by FMD in older adults with prediabetes 77 , We found that 2 weeks of high intensity interval or moderate continuous exercise reduced post-prandial arterial stiffness but had no overall effect on fasting or post-prandial FMD.

This latter finding is consistent with work showing that either a single bout or short-term exercise training at moderate continuous intensity can promote vasodilation after glucose-induced insulin stimulation in adults with and without T2D 79 — Therefore, exercise appears to exert unique effects on the vasculature in fasted compared with fed or insulin-stimulated states based on the intensity at which exercise is performed in clinical populations.

While these studies tested vascular function under a glucose load, no study to date has investigated the effect of lipid infusion on endothelial function before or during insulin-stimulation following training. However, aerobic fitness has been directly correlated with the preservation of insulin-stimulated microcirculatory function in healthy young adults Moreover, in healthy inactive young adults, 12 weeks of interval exercise was shown to increase brachial artery conduit artery function more so than continuous training alone during a high fat meal Together, fitness mediated mechanisms may be important for opposing FFA-induced vs.

glucose-induced skeletal muscle vascular insulin resistance. Metformin improves brachial artery FMD in people with type 1 diabetes 85 and polycystic ovarian syndrome Moreover, metformin treatment for 4 weeks increases forearm blood flow and glucose uptake following a 75 g glucose load in people with T2D Interestingly, this improvement in forearm blood flow corresponded with improved glucose tolerance and lower FFA levels, suggesting lower gluco-lipid toxicity may contribute to improved endothelial function.

Given that insulin-mediated glucose uptake is more closely associated with microvascular blood flow than total flow 88 , it is important to understand the role of metformin on microvasculature function.

To date, no data exist in humans studying the impact of metformin on microcirculatory function. Recently, Bradley et al. though showed that 2 weeks of metformin treatment improved microvascular responses during a euglycemic-hyperinsulinemic clamp in the muscle of high-fat fed rat In particular, metformin lowered body weight and FFAs as well as improved insulin-stimulated muscle Akt phosphorylation, which confirms improved insulin signaling.

Although there was no change in muscle AMPK phosphorylation, these findings suggest that metformin impacts nutrient exchange with skeletal muscle for glucose uptake. This is consistent with the notion that metformin increases eNOS phosphorylation in cultured endothelial cells While work in human microvasculature insulin sensitivity awaits further investigation, metformin appears to have a direct effect on vasculature insulin action in skeletal muscle.

Traditionally, chronic exercise reduces CVD risk by decreasing blood pressure, triglycerides TG , and inflammation Metformin is not only used to treat T2D but also it is suggested to lower CVD risk However, there are few data from randomized trials examining if metformin alters the vasculature adaptation to exercise.

From our observations of blunted insulin sensitivity following the combined treatment 32 , we studied the impact metformin would have on exercise-mediated improvements in CVD risk factors i.

When metformin and exercise were combined though, blunted reductions in systolic blood pressure and CRP were observed. These data were in line with others reporting that combining metformin with a low-fat diet and increase physical activity program had no further improvement in blood pressure Furthermore, our observations were confirmed in obese insulin resistant adolescents whereby the metformin plus lifestyle modification blunted reductions in CRP as well as fibrinogen Taken together, the metformin plus exercise therapy has strong clinical potential to oppose the reversal of chronic disease, including hypertension and metabolic syndrome.

Further work is required for elucidating the vascularture mechanism s e. Although these effects of insulin are clearly important for systemic glucose control, more recent work highlights that insulin also impacts memory, mood, and cognition 97 , Interestingly, Williams et al. In particular, this improvement in memory was related to increased blood oxygen level-dependent BOLD signaling as measured by functional MRI fMRI during the clamp Furthermore, improved memory was best in those individuals with the highest systemic insulin sensitivity.

This suggests that declines in insulin sensitivity may contribute to brain pathology in the hypothalamus Not surprisingly, this may relate to cognitive decline , cerebral atrophy as well as low brain blood flow and metabolism across aging Additionally, this altered brain insulin action may be a key pathological factor in regulating glycemic control in individuals with obesity, T2D, aging, and Alzheimer's disease , During exercise brain glucose uptake declines in an intensity-based manner This is likely the result of increased substrate availability e.

Interestingly, the latter findings were observed in the parietal-temporal and caudate regions, which are linked to Alzheimer's disease. In either case, there remains limited data in humans with obesity or T2D confirming the effects of exercise on brain insulin sensitivity in relation to glucose metabolism.

It was shown that lifestyle modification inducing weight loss, including increased physical activity and low-fat diet, increased brain insulin sensitivity in people with obesity as assessed by intranasal insulin spray Moreover, Honkala et al.

This intensity-based effect was observed despite both exercise intensities raising whole-body insulin sensitivity. This later finding of discordance with brain and periphery insulin action following high intensity exercise on tissue-specific glucose uptake, is consistent with the observation that people with increased brain glucose uptake in response to insulin have decreased insulin-stimulated skeletal muscle glucose disposal Because exercise is known to increase skeletal muscle insulin sensitivity, it is paramount to understand the role exercise dose on affecting insulin-mediated brain glucose metabolism.

Recently, wheel running in obese rats with T2D indicated that exercise was capable of improving insulin-stimulated posterior cerebral artery vasodilation in association with nitric oxide and reduced ET-1 signaling Moreover, Ruegsegger et al.

reported that exercise improved brain insulin sensitivity of rodents fed a high-fat diet The mechanism by which exercise increased brain insulin sensitivity appears related to increased ATP and reduced ROS generation by mitochondria.

Metformin has been suggested as a potential treatment for cognitive impairment Because metformin has been shown to promote peripheral insulin sensitivity, it would be reasonable to expect an impact on the brain.

A recent pilot trial was conducted whereby metformin was administered in patients with Alzheimer's disease It was reported that metformin was linked to improved learning, memory, and attention in individuals with mild cognitive impairment.

The reason metformin may improve this cognitive function in humans remains to be elucidated, but work in high-fat-fed rodents suggests that increased brain insulin sensitivity, as well as cerebral and hippocampal mitochondrial function, may play a role In addition, metformin is capable of crossing the blood-brain barrier and regulating tau phosphorylation in mouse models, thereby minimizing risk for Alzheimer's disease To date, no studies have examined how metformin in combination with exercise affects brain regulation of glycemic control.

This may be important given the collective body of literature demonstrates that metformin attenuates skeletal muscle insulin sensitivity 23 , 32 , 54 , and skeletal muscle is a key tissue proposed to secrete myokines that affect brain function and cognition Most agree that exercise or metformin therapy alone confer favorable effects on cellular pathways that regulate glycemic control across tissues for T2D and CVD risk reduction.

It now appears clear that the mechanism s by which exercise and metformin act to affect health interact on some yet to be determined pathway s that influences adaptation. Aerobic fitness i. Not surprisingly, elevations in VO 2 peak have been implicated in metabolic adaptations e.

A reason metformin could constrain gains in aerobic fitness relates to the observation that metformin partially inhibits Complex 1 of the mitochondrial electron transport system In turn, we examined the impact metformin has on VO 2 peak 10 weeks of exercise training in individuals with prediabetes This observation is consistent with new work highlighting that even acute administration of metformin raised perceptions of effort during exercise However, it is worth acknowledging that not all studies confirm that metformin decreases VO 2 peak.

In fact, some have shown metformin to raise exercise tolerance in people with coronary artery disease A possible reason metformin interacts with exercise-mediated skeletal muscle adaptation relates to lowering mitochondrial ROS generation We previously hypothesized that skeletal muscle contraction induced ROS generation is an important mediator of glucose and insulin metabolism adaptation, in part based on literature showing anti-oxidants blunt exercise health benefit Newer literature supports this idea suggesting that blunting NADPH oxidase 2 NOX2 -mediated ROS, which is responsible for GLUT-4 translocation, blunts glucose uptake during muscle contraction in both human and mouse models But, because metformin counters ROS signaling in muscle, it is possible that the post-exercise cellular signals important for mitochondrial capacity e.

This hypothesis was somewhat supported by prior work, whereby Sharoff et al. showed that metformin blunted the rise in AMPK activity during the immediate post-exercise period in insulin resistant adults, and this skeletal muscle observation directly correlated with attenuated insulin sensitivity However, new work suggests that acute metformin treatment for 4 days did not affect AMPK activity during exercise in skeletal muscle or adipose tissue of lean healthy men.

However, a novel observation was that metformin concentrations were detected in skeletal muscle, and it was proposed that longer duration e. We recognize though that not all studies support the action of metformin to reduce complex I of the mitochondria and impact indirectly AMPK, and this is an area of much debate Interestingly, it was proposed that metformin may impact immune function in older adults following resistance training, and alleviate inflammatory mediated processes that may hinder muscle accretion in response to resistance exercise This is consistent with the notion that metformin promotes polarization from M1 pro-inflammatory macrophages to M2 anti-inflammatory macrophages 49 as well as induces autophagy to attenuate Th2 immune cell activation and inflammation However, the results of the recent MASTERS trial showed no effect of metformin on resistance training-induced inflammation in skeletal muscle, despite the observation that lean body mass gains were blunted in relation to strength following the combined therapy compared with resistance exercise training alone.

This was shown to parallel AMPK activation as well as inhibition of p70S6K1 phosphorylation an immediate target of mTOR In fact, it is important to acknowledge that there are no suggestions for altered fasting glucose or liver insulin action in response to exercise plus metformin.

Moreover, although elevated FFA levels have been detected following the combined therapy, no studies have been specifically designed to understand adipose insulin sensitivity following exercise plus metformin treatment. Nor has there been work examining the interaction of exercise and metformin on vasculature or brain insulin sensitivity to understand the importance of blood delivery and neural control of glucose metabolism.

At this time, skeletal muscle appears to be a primary tissue regulating blood glucose, and additional cellular work is warranted to understand if these combined therapies lead to over-taxation of bioenergetic pathways that result in mal-adaptation.

This may be particularly important since new work suggests that exercise may alter the pharmacokinetics and increase the bio-availability of metformin in circulation Developing precise exercise programs for maximal glycemic control remains to be identified.

The collective literature suggests that, if anything, metformin attenuates the effects of exercise at improving insulin sensitivity at the level of skeletal muscle. Moreover, alterations in blood glucose, hypertension as well as inflammation have been noted.

While no study to date has shown blood glucose to worsen as reflected by higher blood glucose concentrations relative to the start of the combined treatment, the literature highlights that there are either null, additive, or blunted effects on glycemia.

The reason for this variability is not entirely clear but may relate to studies whereby people are habitual vs. naive metformin users or the outcome of interest.

In either case, it is clear the magnitude of benefit will vary based on what tissue or outcome is of interest. Systemic studies determining the benefit of different exercise doses as well as risk factors of people age, hypertension, dementia, T2D, etc. co-prescribed metformin would enable individualized treatments that favor glycemic control.

Further, these gains in aerobic fitness and muscle mass are not only relevant to aging men and women with or without chronic disease, but also children and adolescents.

But the effect of prescribing metformin with exercise in children and adolescents have on the rate of gain in these fitness outcomes is largely unknown in boys and girls. With emerging literature suggesting that off label or prophylactic use of metformin may be effective for weight management and obesity prevention in adolescents 54 , 71 , more children may be provided metformin and recommended to exercise.

This raises potential concern toward altered maturation growth rates and cardiometabolic risk during youth as well as then for later in life health risk compared with youth advised to exercise only with proper nutrition 54 , Thus, health care providers should be aware of these potential interactions to strike balance between current disease risk with long-term well-being.

We also recognize that people are not often prescribed only one medication, and further work is warranted to tease out the effects of multiple pharmacological agents or even dietary supplements e. in combination with exercise to gain a better understanding on glucose metabolism.

However, it is important to acknowledge that recent work has suggested that other glycemic medications, including GLP-1 agonists and SGLT-2 inhibitors, have been shown to interact with exercise — This highlights the potential for medications to interfere or add with exercise-mediated glycemic benefit.

Thus, there is potential for people to be at risk for developing T2D or cardiovascular abnormalities when co-prescribed treatments compared with those treated with exercise alone over time. Large-randomized clinical trials are critically needed to determine the effects combining exercise, with or without diet, and medications for improved evidenced-based practice.

SM wrote the majority of the review with NS providing edits. SM and NS collaborated on writing on the metformin and exercise on brain insulin sensitivity section.

NS drafted the figure with SM providing edits. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

We would like to thank Emily M. Heiston, Udeyvir Cheema and Anna Ballanytne for helpful discussions related to topics herein. National Diabetes Statistics Report CDC. html accessed April 23, Church TS, Blair SN, Cocreham S, Johannsen N, Johnson W, Kramer K, et al.

Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial. J Am Med Assoc. doi: PubMed Abstract CrossRef Full Text Google Scholar. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hamäläinen H, Ianne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.

N Engl J Med. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.

CrossRef Full Text Google Scholar. Houmard JA, Tanner CJ, Slentz CA, Duscha BD, McCartney JS, Kraus WE. Effect of the volume and intensity of exercise training on insulin sensitivity. J Appl Physiol. Dubé JJ, Allison KF, Rousson V, Goodpaster BH, Amati F.

This article reviews the concept of insulin resistance as it pertains to body weight and the effects of meformin on body weight in subgroups of patients with and without diabetes.

Introduction Insulin is an anabolic storage hormone produced by the beta cells in both a basal and a pulsatile fashion in response to food intake. Insulin is fundamental in allowing cells to uptake and use glucose.

Insulin also regulates gluconeogenesis along with processes, such as protein synthesis and lipogenesis. When we were evolving, the theory is that insulin was necessary because we lived a life of feast and famine. Those who could store calories had a survival benefit, thus insulin had a significant evolutionary role.

So, where and when did insulin become a bad thing? Likely, at the same time our evolutionary environment took a bit of a turn. These days, it is usual to go three hours without eating, and certainly not three days!

Thus, what was once adaptive is now maladaptive as we continue to store as our ancestors did. Our environment has changed faster than our genetics. Insulin resistance is an impaired response to endogenous or exogenous insulin in cells, tissues especially skeletal muscle and adipose tissue , the liver, or the whole body.

Insulin resistance affects several organ systems and predisposes patients to several metabolic disorders. Connections between insulin resistance and other aspects of the metabolic syndrome, such as dyslipidemia, hypertension, prothrombotic state, and glucose intolerance, are complex.

Insulin resistance may contribute directly or indirectly to these conditions. It is important to note that insulin resistance predates diabetes by years. Assuming the metabolic effects of insulin resistance are in play years before a numeric diagnosis of diabetes, it is easy to see how the physiologic insults can occur prior to any awareness of the metabolic disarray.

Treating Insulin Resistance There are many ways to treat insulin resistance. A large-scale study called the Diabetes Prevention Program DPP trial took 3, patients with impaired glucose tolerance and randomized them to placebo lifestyle or metformin.

Intensive lifestyle intervention reduced the development of diabetes by 58 percent 2. Metformin reduced the development of diabetes by 31 percent 3. Lifestyle not to be forgotten or outdone was more effective than metformin alone in preventing the development of diabetes.

Metformin and Insulin resistance A number of investigators have looked at metformin as a treatment for weight loss, particularly in the presence of insulin resistance.

Metformin is a biguanide, an oral diabetic agent used often as first line treatment of diabetes. In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake, increases fatty acid oxidation,[7] and decreases absorption of glucose from the gastrointestinal tract.

Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. AMPK most likely also plays a role as metformin administration increases AMPK activity in skeletal muscle. AMPK is known to cause glucose transporter GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake.

Metformin and Body Weight in Type 2 Diabetes Table 1 is a list of randomized, controlled trials that examined the body weight of subjects with type 2 diabetes suboptimally controlled on diet.

The trials in this table are all greater than six-months duration. The landmark UKPDS study[8] seems to indicate that metformin exerts benefit in not gaining weight rather than in losing weight.

Table 2 is the Diabetes Progression and Outcomes trial. Overall, there is no indication of metformin-induced weight gain. However, there is also little to indicate a marked or significant weight loss in the groups receiving metformin relative to placebo.

What can we conclude about metformin for weight control in a diabetic population? As an adjunct to other therapies in diabetes metformin may mitigate weight gain seen with thiazolidinediones TZDs and sulfonylureas. We can also conclude that as an adjunct to insulin, metformin may ameliorate weight gain associated with insulin use perhaps in part by lowering insulin dosing by improving sensitivity.

Metformin and Body Weight in Individuals without Diabetes What is the role of metformin in controlling body weight in individuals without diabetes? Table 2 lists a few of the larger studies that reviewed this issue in subjects with obesity over a study period of greater than six months.

The result is higher blood glucose levels, and ultimately prediabetes or type 2 diabetes. Insulin has other roles in the body besides regulating blood glucose levels, and the effects of insulin resistance are thought to go beyond diabetes. For example, some research has shown that insulin resistance, independent of diabetes, is associated with heart disease.

Scientists are beginning to get a better understanding of how insulin resistance develops. For starters, several genes have been identified that make a person more or less likely to develop the condition.

It's also known that older people are more prone to insulin resistance. Lifestyle can play a role, too. Being sedentary, overweight or obese increases the risk for insulin resistance. It's not clear, but some researchers theorize that extra fat tissue may cause inflammation, physiological stress or other changes in the cells that contribute to insulin resistance.

There may even be some undiscovered factor produced by fat tissue, perhaps a hormone, that signals the body to become insulin resistant. Doctors don't usually test for insulin resistance as a part of standard diabetes care.

In clinical research, however, scientists may look specifically at measures of insulin resistance, often to study potential treatments for insulin resistance or type 2 diabetes. They typically administer a large amount of insulin to a subject while at the same time delivering glucose to the blood to keep levels from dipping too low.

The less glucose needed to maintain normal blood glucose levels, the greater the insulin resistance. Insulin resistance comes in degrees.