Endocrinol Metab.  2019 Mar;34(1):47-52. 10.3803/EnM.2019.34.1.47.

Myths about Insulin Resistance: Tribute to Gerald Reaven

• Kim SH
• Abbasi F

• KMID: 2441678
• DOI: http://doi.org/10.3803/EnM.2019.34.1.47

Abstract

Gerald Reaven was often called the "father of insulin resistance." On the 1-year anniversary of his death in 2018, we challenge three myths associated with insulin resistance: metformin improves insulin resistance; measurement of waist circumference predicts insulin resistance better than body mass index; and insulin resistance causes weight gain. In this review, we highlight Reaven's relevant research that helped to dispel these myths associated with insulin resistance.

Keyword

Insulin resistance; Metformin; Waist circumference; Weight gain

MeSH Terms

Anniversaries and Special Events
Body Mass Index
Insulin Resistance*
Insulin*
Metformin
Waist Circumference
Weight Gain
Insulin
Metformin

Figure

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  Fig. 1 Gerald Reaven (1928 to 2018).

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  Fig. 2 Relationship among waist circumference, body mass index (BMI), and insulin resistance. (A) BMI and waist circumference are highly correlated with each other in both women (open circle, n=440) and men (solid triangle, n=311). Insulin resistance as quantified by measuring the steady-state plasma glucose (SSPG) during the insulin suppression test is positively and similarly associated with both (B) BMI and (C) waist circumference. All Pearson's r values were significant (P<0.001).

Reference

1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988; 37:1595–1607.

2. Fuentes AV, Pineda MD, Venkata KCN. Comprehension of top 200 prescribed drugs in the US as a resource for pharmacy teaching, training and practice. Pharmacy (Basel). 2018; 6:E43.

3. Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018; 41:2669–2701.

4. Bailey CJ. Metformin: historical overview. Diabetologia. 2017; 60:1566–1576.

5. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998; 352:854–865.

6. Pernicova I, Korbonits M. Metformin: mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014; 10:143–156.

7. Salpeter SR, Buckley NS, Kahn JA, Salpeter EE. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med. 2008; 121:149–157.

8. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979; 237:E214–E223.

9. Pei D, Jones CN, Bhargava R, Chen YD, Reaven GM. Evaluation of octreotide to assess insulin-mediated glucose disposal by the insulin suppression test. Diabetologia. 1994; 37:843–845.

10. Natali A, Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia. 2006; 49:434–441.

11. Morel Y, Golay A, Perneger T, Lehmann T, Vadas L, Pasik C, et al. Metformin treatment leads to an increase in basal, but not insulin-stimulated, glucose disposal in obese patients with impaired glucose tolerance. Diabet Med. 1999; 16:650–655.

12. Hollenbeck CB, Johnston P, Varasteh BB, Chen YD, Reaven GM. Effects of metformin on glucose, insulin and lipid metabolism in patients with mild hypertriglyceridaemia and non-insulin dependent diabetes by glucose tolerance test criteria. Diabete Metab. 1991; 17:483–489.

13. Reaven GM. Effect of metformin on various aspects of glucose, insulin and lipid metabolism in patients with non-insulin-dependent diabetes mellitus with varying degrees of hyperglycemia. Diabetes Metab Rev. 1995; 11:S97–S108.

14. Madiraju AK, Qiu Y, Perry RJ, Rahimi Y, Zhang XM, Zhang D, et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med. 2018; 24:1384–1394.

15. Abbasi F, Kamath V, Rizvi AA, Carantoni M, Chen YD, Reaven GM. Results of a placebo-controlled study of the metabolic effects of the addition of metformin to sulfonylurea-treated patients. Evidence for a central role of adipose tissue. Diabetes Care. 1997; 20:1863–1869.

16. Abbasi F, Carantoni M, Chen YD, Reaven GM. Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin. Diabetes Care. 1998; 21:1301–1305.

17. Swislocki AL, Chen YD, Golay A, Chang MO, Reaven GM. Insulin suppression of plasma-free fatty acid concentration in normal individuals and patients with type 2 (non-insulin-dependent) diabetes. Diabetologia. 1987; 30:622–626.

18. Shen SW, Reaven GM, Farquhar JW. Comparison of impedance to insulin-mediated glucose uptake in normal subjects and in subjects with latent diabetes. J Clin Invest. 1970; 49:2151–2160.

19. Sullivan JE, Brocklehurst KJ, Marley AE, Carey F, Carling D, Beri RK. Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett. 1994; 353:33–36.

20. Daval M, Diot-Dupuy F, Bazin R, Hainault I, Viollet B, Vaulont S, et al. Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes. J Biol Chem. 2005; 280:25250–25257.

21. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108:1167–1174.

22. Zhang T, He J, Xu C, Zu L, Jiang H, Pu S, et al. Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes. J Mol Endocrinol. 2009; 42:57–66.

23. Abbasi F, Blasey C, Reaven GM. Cardiometabolic risk factors and obesity: does it matter whether BMI or waist circumference is the index of obesity? Am J Clin Nutr. 2013; 98:637–640.

24. Piche ME, Poirier P, Lemieux I, Despres JP. Overview of epidemiology and contribution of obesity and body fat distribution to cardiovascular disease: an update. Prog Cardiovasc Dis. 2018; 61:103–113.

25. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009; 120:1640–1645.

26. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement: executive summary. Crit Pathw Cardiol. 2005; 4:198–203.

27. Reaven GM. The metabolic syndrome: requiescat in pace. Clin Chem. 2005; 51:931–938.

28. Reaven G. All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Diab Vasc Dis Res. 2005; 2:105–112.

29. Farin HM, Abbasi F, Reaven GM. Body mass index and waist circumference correlate to the same degree with insulin-mediated glucose uptake. Metabolism. 2005; 54:1323–1328.

30. Abbasi F, Malhotra D, Mathur A, Reaven GM, Molina CR. Body mass index and waist circumference associate to a comparable degree with insulin resistance and related metabolic abnormalities in South Asian women and men. Diab Vasc Dis Res. 2012; 9:296–300.

31. Sung KC, Ryu S, Reaven GM. Health Screening Group at Kangbuk Samsung Hospital. Relationship between obesity and several cardiovascular disease risk factors in apparently healthy Korean individuals: comparison of body mass index and waist circumference. Metabolism. 2007; 56:297–303.

32. Abbasi F, Mathur A, Reaven GM, Molina CR. Cardiometabolic risk in South Asian inhabitants of California: hypertriglyceridemic waist vs hypertriglyceridemic body mass index. Ethn Dis. 2016; 26:191–196.

33. Tchernof A, Despres JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013; 93:359–404.

34. Fung J. The obesity code. Brunswick: Greystone Books;2016.

35. Bhat S, Abbasi F, Blasey C, Reaven G, Kim SH. Plasma glucose and insulin responses to mixed meals: impaired fasting glucose re-visited. Diab Vasc Dis Res. 2011; 8:271–275.

36. Leavens KF, Birnbaum MJ. Insulin signaling to hepatic lipid metabolism in health and disease. Crit Rev Biochem Mol Biol. 2011; 46:200–215.

37. Zavaroni I, Zuccarelli A, Gasparini P, Massironi P, Barilli A, Reaven GM. Can weight gain in healthy, nonobese volunteers be predicted by differences in baseline plasma insulin concentration? J Clin Endocrinol Metab. 1998; 83:3498–3500.

38. McLaughlin T, Abbasi F, Carantoni M, Schaaf P, Reaven G. Differences in insulin resistance do not predict weight loss in response to hypocaloric diets in healthy obese women. J Clin Endocrinol Metab. 1999; 84:578–581.

39. McLaughlin T, Abbasi F, Lamendola C, Kim HS, Reaven GM. Metabolic changes following sibutramine-assisted weight loss in obese individuals: role of plasma free fatty acids in the insulin resistance of obesity. Metabolism. 2001; 50:819–824.

40. Gardner CD, Trepanowski JF, Del Gobbo LC, Hauser ME, Rigdon J, Ioannidis JPA, et al. Effect of low-fat vs low-carbohydrate diet on 12-month weight loss in overweight adults and the association with genotype pattern or insulin secretion: the DIETFITS randomized clinical trial. JAMA. 2018; 319:667–679.