Insulin Resistance and the use of Metformin: Effects on Body Weight

| January 21, 2011

by Ruchi Mathur, MD, FRCPC

Dr. Mathur is Assistant Professor of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, California.

Bariatric Times. 2011;8(1):10–12

Abstract
Metformin is a widely perscribed drug for the treatment of diabetes and is often used off label for the treatment of prediabetes and insulin resistance. In addition to its primary use, metformin has often been cited as having weight loss benefits. 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.[1,2] Many investigators believe that insulin resistance is an important factor in the development of the metabolic syndrome.

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.[3]

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 3,200 patients with impaired glucose tolerance and randomized them to placebo lifestyle or metformin.[4] The authors of this landmark study noted the following:
1.    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.[5] It improves hyperglycemia primarily through its suppression of hepatic glucose production (hepatic gluconeogenesis) via activation of AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats.[6]

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.[9] As is evident, while there is a significant weight gain with rosiglitazone, the effect of metformin on weight is negligible. 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 first trial is the Biguanides and Prevention of Risks in Obesity Study.[10] This study enrolled 324 patients with waist-to-hip ratios of >0.95 in men and >0.80 in women  as a surrogate for insulin resistance.  Subjects were randomized to low-dose metformin 850mg daily or to placebo for one year. Data showed a trend toward benefit in the metformin group.

The second trial in Table 2 looked at 150 women with body mass index (BMI)>30mg/m2 and the third trial looked at men and women with morbid obesity.[11,12] These trials were short and small in number but demonstrated a decrease in body weight with metformin.

Table 3 lists subjects without diabetes with impaired glucose tolerance (IGT). The DPP trial enrolled a population of over 3,000 subjects with IGT and a mean BMI of 34kg/m2 with benefits as noted.[4] No effect was observed in a three-year Chinese study.[13] The final study listed in Table 3 is a Swedish study that showed metformin demonstrated some benefit in weight loss, but this was not statistically significant.[14]

A Caveat: Metformin and Weight in Women with Polycystic Ovary Syndrome
In the subgroup of women with polycystic ovary syndrome (PCOS), some trials showed benefit of up to six percent in weight reduction over placebo;[15] however, when a systematic review of the literature was performed, of the 13 randomized, controlled trials in women with PCOS, none showed an overall beneficial effect of metformin on weight loss.[16] Regardless, it appears benefit is greater if more than 1500mg daily of metformin is used and if the duration of treatment is greater than eight weeks. Thus, in a subgroup of women with PCOS, those who with obesity who are taking high doses of metformin for greater than two months, may show a weight loss benefit. This remains to be proven in larger studies as the subgroup analysis is too small to say definitively

What can we conclude about metformin for weight control in a nondiabetic population? While there are benefits to using metformin in nondiabetic populations (e.g., for the prevention type 2 diabetes), there is no compelling evidence to use metfomin to control body weight in nondiabetic populations. A caveat may be found in women with obesity and PCOS on long-term therapy.

Summary
Metformin is a widely used drug for the treatment of diabetes and the off-label treatment of prediabetes, metabolic syndrome, and insulin resistance. While prevention of diabetes in a high-risk population is seen with the use of metformin, the old standard of lifestyle modification appears to be more efficacious.

Metformin does remain a cornerstone of therapy for diabetes and is often used as first-line therapy. Overall, metformin appears to be a relatively weight-neutral drug, with some evidence of modest weight loss effect. Metformin appears to mitigate the weight gain seen by other agents used for the treatment of diabetes. At this time, using metformin as a primary weight loss agent in the nondiabetic population appears to be unwarranted in the majority of subpopulations. An exception to this may be women with PCOS.

Acknowledgment
This article is part of a series of articles being published in Bariatric Times that are based on sessions presented at the “Comprehensive Approach to the Treatment of Obesity,” by Cedars Sinai Medical Center on October 22, 2010.

References
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2.    Grundy SM. Hypertriglyceridemia, insulin resistance and the metabolic syndrome. Am J Cardiol. 1999;83(9B):25F–29F.
3.    Consensus Development Conference on Insulin Resistance. 5-6 November 1997. American Diabetes Association. Diabetes Care. 1998 21:310–314.
4.    Diabetes Prevention Program Research Group. The Diabetes Prevention Program: baseline characteristics of the randomized cohort. Diabetes Care. 2000;23:1619–1629.
5.    Tankova T. Current indications for metformin therapy. Rom J Intern Med. 2003;41:215–225.
6.    Grisouard J, Timper K, Radimerski TM, et al. Mechanisms of metformin action on glucose transport and metabolism in human adipocytes. Biochem Pharmacol. 2010;80(11):1736–1745.
7.    Correia S, Carvalho C, Santos MS, et al. Mechanisms of action of metfromin in type 2 diabetes and associated complications: an overview. Mini Rev Med Chem. 2008;8(13):1343–1354.
8.    Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854–865.
9.    Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin or glyburide monotherapy. N Engl J Med. 2006;355:2427–2443.
10.    Fontbonne A, Charles MA, Juhan-Vague I, et al. The effect of metformin on the metabolic abnormalities associated with upper body fat distribution BIGPRO study group. Diabetes Care. 1996;19:920–926.
11.    Gokcel A, Gumurdulu Y, Karakose H, et al. Evaluation of the safety and efficacy of sibutramine, orlistat and metformin in the treatment of obesity. Diabetes Obes Metab. 2002;4:49–55.
12.    Glueck CJ, Fontaine RN, Wang P, et al. Metformin reduces weight, centripital obesity, insulin, leptin, and low-density lipoprotein cholesterol in non diabetic, morbidly obese subjects with body mass index greater than 30. Metabolism. 2001;50:856–861.
13.    Yang Wenying, Lin Lixiang, Qi Jinwu, et al. The preventive effect of acarbose and metformin on the progression to diabetes mellitus in the IGT population: a 3 year multicenter prospective study. Chin J Endocrinol Metab. 2001;17:131–135.
14.    Lehtovirta M, Forsén B, Gullström M,  et al. Metabolic effects of metformin in patients with impaired glucose tolerance. Diabet Med. 2001;18:578–583.
15.    Hoeger KM, Kochman L, Wixom N, et al. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril. 2004;82:421–429.
16.    Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003;327(7421):951–953.

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