Insulin Resistance Is Not Necessarily an Essential Component of Type 2 Diabetes1

John E. Gerich

Department of Medicine, Physiology, and Pharmacology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Address all correspondence and requests for reprints to: Dr. John E. Gerich, Department of Medicine, Physiology, and Pharmacology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642.


    Introduction
 Top
 Introduction
 References
 
Insulin resistance and impaired insulin secretion are usually present in patients with classic type 2 diabetes as well as in most people with impaired glucose tolerance (1, 2). Both play important roles not only in determining whether diabetes occurs, but also in determining the magnitude of the accompanying hyperglycemia and other metabolic abnormalities (3, 4). The vast majority of patients with type 2 diabetes are obese. As obesity causes insulin resistance (5, 6), it is easy to understand why insulin resistance would be so commonly involved.

There is mounting evidence (7, 8, 9, 10, 11, 12, 13) suggesting that the fundamental pathological sequence of events that leads to classic type 2 diabetes in most instances is the superimposition of obesity-related insulin resistance upon a ß-cell with a genetically limited capacity to compensate. This view has recently received support from several studies (8, 13, 14, 15). In two of these (8, 13), it was found that when matched for obesity, normal glucose-tolerant, first degree relatives of patients with type 2 diabetes had impaired insulin secretion, but were not insulin resistant.

Similarly, in another study (14) it was shown that normal glucose-tolerant monozygotic twins of someone with type 2 diabetes had impaired ß-cell function, but normal insulin sensitivity; moreover, monozygotic twins who had developed impaired glucose tolerance had the same degree of impaired insulin secretion as those who had maintained normal glucose tolerance, but they had a greater body mass index and waist to hip ratio and were insulin resistant. Thus, one could infer that the addition of obesity-related insulin resistance caused deterioration of their glucose tolerance, and without this they might have maintained normal glucose tolerance. Accordingly, the acquired obesity-related insulin resistance could be viewed as essential in such individuals.

Consistent with this interpretation are the recent studies by Henriksen et al. (16). These investigators induced insulin resistance in offspring of type 2 diabetic patients by treatment with dexamethasone; those who were unable to mount a normal compensatory increase in insulin secretion had greater deterioration in their glucose tolerance than those with a normal compensatory increase in insulin secretion despite the induction of comparable insulin resistance.

These studies illustrate how an acquired form of insulin resistance, such as that due to obesity, could lead to the development of type 2 diabetes in individuals with an underlying, presumably genetic, defect in ß-cell function. Moreover, they provide an explanation for observations that weight loss can markedly improve and sometimes normalize insulin sensitivity in obese patients with type 2 diabetes (17, 18, 19).

However, what about the 10–15% of patients with type 2 diabetes who are not obese? Is insulin resistance also an essential factor in these individuals? There are numerous mechanisms by which nonobese individuals may be insulin resistant before or after they develop diabetes. High fat diets (20), decreased physical fitness (21), increased visceral fat accumulation (5, 22), smoking (23), pregnancy (24), certain commonly used medications (25), and hyperglycemia itself [i.e. glucose toxicity (26)] all can cause insulin resistance. Some also believe that insulin resistance is present in type 2 diabetes on a genetic basis independent of obesity (27, 28, 29, 30), although this issue is controversial (7, 8, 9, 10, 11).

In nonobese individuals who have become insulin resistant for reasons other than obesity, whether they become diabetic would depend on the balance between the severity of the insulin resistance and the ability of the ß-cell to compensate for the insulin resistance, just as is the case for obese individuals. Theoretically, a spectrum could exist: at one extreme, insulin resistance initially might be absent, and the immediate cause would be impaired insulin secretion; at the other extreme, impaired insulin secretion might be absent, and insulin resistance would be the immediate cause. I am unaware of any well documented cases of the latter situation.

As evidenced by the fact that most obese individuals and most pregnant women (some of whom may be severely insulin resistant) do not develop type 2 diabetes (6, 24) and the studies cited earlier by Henriksen et al. (16), the normal ß-cell usually increases its insulin secretion to compensate for insulin resistance, so that persistent hyperglycemia does not occur. Although the exact mechanism for this is not well understood, this may be due at least in part to the fact that the plasma glucose concentration is the primary stimulus for insulin release. An increase in plasma glucose evokes additional insulin secretion to restore euglycemia (31). Thus, it would seem unlikely for insulin resistance to cause diabetes without an underlying impairment in ß-cell function.

On the other hand, there are well documented instances in which type 2 diabetes has developed in nonobese individuals in the absence of insulin resistance (7, 32, 33, 34, 35). Thus, at least in some individuals insulin resistance is not essential for the development of type 2 diabetes. Nevertheless, it should be pointed out that most of the above studies included small numbers of subjects who were not randomly selected from a defined population. Thus, it is not known in what proportion of nonobese type 2 diabetic patients the diabetes is the sole result of impaired insulin secretion. However, given the numerous lifestyle and otherwise acquired factors (1) that may adversely affect insulin sensitivity, this proportion might not represent the overwhelming majority of patients.

It is worth pointing out that in obese patients, although insulin resistance may be critical for developing diabetes, it may not be essential for persistence of diabetes. Several studies have demonstrated complete restoration of normal insulin sensitivity after weight reduction in obese individuals (17, 18, 19), but the diabetes has persisted. This implies an essential role for irreversibly impaired insulin secretion even in obese individuals. This view is consistent with the demonstration in the United Kingdom Prospective Diabetes Study of a progressive deterioration of ß-cell function over time in both obese and nonobese patients with type 2 diabetes (36).

Regardless of the controversy of whether impaired insulin secretion or insulin resistance is the essential or primary genetic defect in type 2 diabetes, available research data and clinical experience allow one to draw certain conclusions regarding therapy. Theoretically, treatment should be directed at the underlying pathological process even if one does not know its molecular basis. Efforts to improve insulin sensitivity deserve major emphasis in those patients in whom insulin resistance is the major problem, and conversely, efforts to improve ß-cell function or, when indicated, insulin administration should be of prime concern in those in whom impaired insulin secretion is the main problem.

Impaired insulin secretion can be considered to be universally present in all patients with type 2 diabetes, even those who are hyperinsulinemic. Similarly, insulin resistance can be considered to be universally present in all obese individuals with type 2 diabetes and probably many, if not most, nonobese patients. Practically speaking, therefore, in most patients the best therapeutic results will be obtained by efforts simultaneously directed at improving insulin secretion and reducing insulin resistance. Prevention of diabetes is another matter. Here one would expect that lessening the burden of insulin resistance on the ß-cell might be the most fruitful approach. A recent prospective trial (37) has shown diet and exercise to be effective measures. Whether other lifestyle changes and pharmacological approaches also work remains to be demonstrated.


    Acknowledgments
 
I thank Mary Little for her editorial support.


    Footnotes
 
1 This work was supported in part by NIH Grant NIDDK-20411. Back

Received February 11, 2000.

Accepted March 10, 2000.


    References
 Top
 Introduction
 References
 

  1. Yki-Järvinen H. 1995 Role of insulin resistance in the pathogenesis of NIDDM. Diabetologia. 38:1378–1388.[Medline]
  2. Gerich J. 1997 Metabolic abnormalities in impaired glucose tolerance. Metabolism. 46:40–43.[Medline]
  3. Lillioja S, Mott D, Spraul M, et al. 1993 Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus: prospective studies of Pima Indians. N Engl J Med. 329:1988–1992.[Abstract/Free Full Text]
  4. Haffner S, Miettinen H, Gaskill S, Stern M. 1995 Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans. Diabetes. 44:1386–1391.[Abstract]
  5. Bjorntorp P. 1988 Abdominal obesity and the development of non-insulin-dependent diabetes mellitus. Diabetes Metab Rev. 4:615–622.[Medline]
  6. Kissebah A, Freedman D, Peiris A. 1989 Health risk of obesity. Med Clin North Am. 73:111–138.[Medline]
  7. Banerji M, Chaiken R, Gordon D, Kral J, Lebovitz H. 1995 Does intra-abdominal adipose tissue in black men determine whether NIDDM is insulin-resistant or insulin-sensitive? Diabetes. 44:141–146.[Abstract]
  8. Pimenta W, Kortytkowski M, Mitrakou A, et al. 1995 Pancreatic ß-cell dysfunction as the primary genetic lesion in NIDDM. JAMA. 273:1855–1861.[Abstract]
  9. Polonsky K, Sturis J, Bell G. 1996 Noninsulin-dependent diabetes mellitus: a genetically programmed failure of the ß cell to compensate for insulin resistance. N Engl J Med. 334:777–783.[Free Full Text]
  10. Cerasi E, Luft R. 1967 "What is inherited–what is added" hypothesis for the pathogenesis of diabetes mellitus. Diabetes. 16:615–627.[Medline]
  11. O’Rahilly S, Turner R, Matthews D. 1988 Impaired pulsatile secretion of insulin in relatives of patients with noninsulin-dependent diabetes. N Engl J Med. 318:1225–1230.[Abstract]
  12. Leahy J. 1990 Natural history of B-cell dysfunction in NIDDM. Diabetes Care. 13:992–1010.[Abstract]
  13. Van Haeften T, Dubbeldam S, Zonderland M, Erkelens D. 1998 Insulin secretion in normal glucose-tolerant relatives of type 2 diabetic subjects: assessments using hyperglycemic glucose clamps and oral glucose tolerance tests. Diabetes Care. 21:278–282.[Abstract]
  14. Vaag A, Henriksen J, Madsbad S, Holm N. 1995 Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus. J Clin Invest. 95:690–698.[Medline]
  15. Vauhkonen I, Niskanen L, Vanninen E, Kainulainen S, Uusitupa M, Laakso M. 1998 Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited: metabolic studies of offspring of diabetic probands. J Clin Invest. 101:86–96.[Abstract/Free Full Text]
  16. Henriksen J, Alford F, Ward G, Beck-Nielsen H. 1997 Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients. Diabetologia. 40:1439–1448.[CrossRef][Medline]
  17. Bak J, Moller N, Schmitz O, Saaek A, Pedersen O. 1992 In vivo action and muscle glycogen synthase activity in type II (noninsulin dependent) diabetes mellitus: effects of diet treatment. Diabetologia. 35:777–784.[Medline]
  18. Freidenberg G, Reichart D, Olefsky J, Henry R. 1988 Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus: effect of weight loss. J Clin Invest. 82:1398–1406.[Medline]
  19. Beck-Nielsen H, Pedersen O, Lindskov H. 1979 Normalization of the insulin sensitivity and the cellular insulin binding during treatment of obese diabetics for one year. Acta Endocrinol (Copenh). 90:103–112.[Medline]
  20. Swinburn B. 1993 Effects of dietery lipid on insulin action. Ann NY Acad Sci. 683:102–109.[Abstract]
  21. Nyholm B, Mengel A, Nielsen S, Moller N, Schmitz O. 1994 The insulin resistance of relatives of type 2 diabetic subjects is significantly related to a reduced VO2 max [Abstract]. Diabetologia 37:A28.
  22. Carey D, Jenkins A, Campbell L, Freund J, Chisholm D. 1996 Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes. 45:633–638.[Abstract]
  23. Targher G, Alberiche M, Zenere M, Bonadonna R, Muggeo M, Bonora E. 1997 Cigarette smoking and insulin resistance in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 82:3619–3624.[Abstract/Free Full Text]
  24. Buchanan T, Catalano P. 1995 The pathogenesis of GDM: implications for diabetes after pregnancy. Diabetes Rev. 3:584–601.
  25. Pandit M, Burke J, Gustafson A, Minocha A, Peiris A. 1993 Drug-induced disorders of glucose tolerance. Ann Intern Med. 118:529–539.[Abstract/Free Full Text]
  26. Yki-Järvinen H. 1992 Glucose toxicity. Endocr Rev. 13:415–431.[Medline]
  27. Olefsky J, Nolan J. 1995 Insulin resistance and non-insulin-dependent diabetes mellitus: cellular and molecular mechanisms. Am J Clin Nutr. 61:980S–986S.
  28. Beck-Nielsen H, Groop L. 1994 Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest. 94:1714–1721.[Medline]
  29. Warram J, Martin B, Krolewski A, Soeldener S, Kahn C. 1990 Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med. 113:909–915.[Medline]
  30. Saad M, Knowler W, Pettitt D, Nelson R, Charles M, Bennett P. 1991 A two-step model for development of noninsulin dependent diabetes. Am J Med. 90:229–235.[Medline]
  31. Porte D. 1991 ß-Cells in type II diabetes mellitus. Diabetes. 40:166–180.[Abstract]
  32. Arner P, Pollare T, Lithell H. 1991 Different aetiologies of type 2 (noninsulin-dependent) diabetes mellitus in obese and nonobese subjects. Diabetologia. 34:483–487.[Medline]
  33. Nesher R, Casa Della L, Litvin Y, et al. 1987 Insulin deficiency and insulin resistance in type II (noninsulin dependent) diabetes: quantitative contributions of pancreatic and peripheral responses to glucose homeostasis. Eur J Clin Invest. 17:266–274.[Medline]
  34. Kalant N, Leibovici D, Fukushima N, Kuyumjian J, Ozaki S. 1982 Insulin responsiveness of superficial forearm tissues in type 2 (noninsulin-dependent) diabetes. Diabetologia. 22:239–244.[Medline]
  35. Pigon J, Giacca A, Ostenson C-G, Lam L, Vranic M, Efendic S. 1996 Normal hepatic insulin sensitivity in lean mild noninsulin-dependent diabetic patients. J Clin Endocrinol Metab. 81:3702–3708.[Abstract]
  36. U.K. Prospective Diabetes Study Group. 1995 U.K. prospective diabetes study 16:Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 44:1249–1258.[Abstract]
  37. Pan X-R, Li G-W, Hu Y-H, et al. 1997 Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: The Da Qing IGT and Diabetes Study. Diabetes Care. 20:537–544.[Abstract]