Review: Mechanisms contributing to the development of type 2 diabetes

Abstract

We are in the midst of an explosion in the prevalence of type 2 diabetes with a key concern that this will translate into a major future burden of diabetes-related complications. To develop rational and effective means of preventing type 2 diabetes and its complications, we need to understand the mechanisms that predispose to the development of diabetes in at-risk individuals. In this brief review, we provide an overview of the principal metabolic changes that have been identified in at-risk individuals and how they contribute to the progression from normal glucose tolerance (NGT) through to type 2 diabetes. Specifically, both impaired insulin action and defective insulin secretion are key predictors of type 2 diabetes, and both are evident in at-risk individuals well before the development of frank diabetes. These changes are associated with an increased prevalence of adverse cardiovascular risk factors. It is clear, therefore, that the identification of at-risk individuals provides the opportunity to introduce measures to try to prevent the development of type 2 diabetes and the associated cardiovascular disease.

Keywords

type 2 diabetes impaired glucose tolerance impaired fasting glycaemia insulin resistance beta-cell dysfunction.

Get full access to this article

View all access options for this article.

References

IDF: Diabetic Atlas Second Edition. International Diabetes Federation, 2003.

Kohler C. , Temelkova-Kurktschiev T. , Schaper F. , Fucker K. , Hanefeld M. (Prevalence of newly diagnosed type 2 diabetes, impaired glucose tolerance and abnormal fasting glucose in a high risk population. Data from the RIAD study using new diagnostic criteria for diabetes). Dtsch Med Wochenschr 1999;124:1057-61.

Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.

Pan XR , Li GW , Hu YH et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-44.

Tuomilehto J. , Lindstrom J. , Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50.

Knowler WC , Barrett-Connor E. , Fowler SE et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002 ;346:393-403.

Holman RR , North BV , Tunbridge FK Possible prevention of type 2 diabetes with acarbose or metformin . Diabetes 2000;49(suppl 1):450-P.

Kobberling JTH. Empirical risk figures for first degree relatives of non-insulin dependent diabetics. Academic Press London:201-09.

Knowler WC , Pettitt DJ , Savage PJ , Bennett PH Diabetes incidence in Pima indians: contributions of obesity and parental diabetes. Am J Epidemiol 1981;113:144-56.

10.

Newman B. , Selby JV , King MC , Slemenda C. , Fabsitz R. , Friedman GD Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins . Diabetologia 1987;30:763-8.

11.

Knowler WC , Williams RC , Pettitt DJ , Steinberg AG Gm3;5,13,14 and type 2 diabetes mellitus: an association in American Indians with genetic admixture. Am J Hum Genet 1988 ;43:520-6.

12.

UK Prospective Diabetes Study 16. Overview of six years' therapy of type 2 diabetes - a progressive disease . Diabetes 1995;44:1249-58.

13.

Kahn SE Clinical review 135. The importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 2001;86:4047-58.

14.

Gerich JE Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes? Diabetes 2002;51(suppl 1):S117-S121.

15.

O'Rahilly S. , Turner RC , Matthews DR Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N Engl J Med 1988;318:1225-30.

16.

Schmitz O. , Porksen N. , Nyholm B. et al. Disorderly and nonstationary insulin secretion in relatives of patients with NIDDM. Am J Physiol 1997; 272:E218-E226.

17.

Golay A. , DeFronzo RA , Ferrannini E. et al. Oxidative and non-oxidative glucose metabolism in non-obese type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1988;31:585-91.

18.

Vaag A. , Henriksen JE , Beck-Nielsen H. Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1992;89:782-8.

19.

DeFronzo RA

Lilly lecture

1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM . Diabetes 1988;37:667-87.

20.

Rothman DL , Shulman RG , Shulman GI 31P nuclear magnetic resonance< measurements of muscle glucose-6-phosphate. Evidence for reduced insulin-dependent muscle glucose transport or phosphorylation activity in non-insulin-dependent diabetes mellitus. J Clin Invest 1992;89:1069-75.

21.

Petersen KF , Dufour S. , Befroy D. , Garcia R. , Shulman GI Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes . N Engl J Med 2004;350:664-71.

22.

Cusi K. , Maezono K. , Osman A. et al. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 2000;105:311-20.

23.

Pratipanawatr W. , Pratipanawatr T. , Cusi K. et al. Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation. Diabetes 2001;50:2572-8.

24.

Shepherd PR , Kahn BB Glucose transporters and insulin action-implications for insulin resistance and diabetes mellitus. N Engl J Med 1999;341: 248-57.

25.

Bonadonna RC , Del Prato S. , Bonora E. et al. Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM . Diabetes 1996;45:915-25.

26.

Jackson SBS , Lynn S. , Yeaman SJ , Turnbull DM , Walker M. Decreased insulin responsiveness for glucose uptake in cultured human skeletal muscle cells from insulin resistant non-diabetic relatives of type 2 diabetic families . Diabetes 2000;49:1169-77.

27.

Mitrakou A. , Kelley D. , Mokan M. et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance . N Engl J Med 1992;326:22-9.

28.

Robertson DA , Singh BM , Nattrass M. Impaired glucose tolerance in obesity is associated with insensitivity to insulin in multiple aspects of metabolism as assessed by a low dose incremental insulin infusion technique . Diabet Med 1991;8:718-25.

29.

Lillioja S. , Mott DM , Howard BV et al. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians . N Engl J Med 1988;318:1217-25.

30.

Berrish TS , Hetherington CS , Alberti KG , Walker M. Peripheral and hepatic insulin sensitivity in subjects with impaired glucose tolerance. Diabetologia 1995;38:699-704.

31.

Ferrannini E. , Mari A. Beta cell function and its relation to insulin action in humans: a critical appraisal. Diabetologia 2004;47:943-56.

32.

Lillioja S. , Mott DM , Spraul M. et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med 1993 ;329:1988-92.

33.

Weyer C. , Tataranni PA , Bogardus C. , Pratley RE Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development . Diabetes Care 2001;24:89-94.

34.

Haffner SM , Miettinen H. , Gaskill SP , Stern MP Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans. Diabetes 1995;44:1386-91.

35.

Weyer C. , Bogardus C. , Pratley RE Metabolic characteristics of individuals with impaired fasting glucose and/or impaired glucose tolerance. Diabetes 1999;48:2197-203.

36.

van Haeften TW , Pimenta W. , Mitrakou A. et al. Disturbances in beta-cell function in impaired fasting glycemia. Diabetes 2002 ;51(suppl 1):S265—S270.

37.

Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. Lancet 1999; 354:617-21.

38.

Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med 2001;161:397-405.

39.

Heldgaard PE , Olivarius Nde F. , Hindsberger C. , Henriksen JE Impaired fasting glycaemia resembles impaired glucose tolerance with regard to cardiovascular risk factors: population-based, cross-sectional study of risk factors for cardiovascular disease. Diabet Med 2004;21:363-70.

40.

Humphriss DB , Stewart MW , Berrish TS et al. Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families. Diabetologia 1997;40:1185-90.

41.

Haffner SM , Stern MP , Miettinen H. , Gingerich R. , Bowsher RR Higher proinsulin and specific insulin are both associated with a parental history of diabetes in non-diabetic Mexican-American subjects. Diabetes 1995;44:1156-60.

42.

Gulli G. , Ferrannini E. , Stern M. , Haffner S. , DeFronzo RA The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 1992;41:1575-86.

43.

Reaven GM Role of insulin resistance in human disease. Diabetes 1988; 37:1595-607.

44.

Stewart MW , Humphriss DB , Berrish TS et al. Features of Syndrome X in first-degree relatives of NIDDM patients . Diabetes Care 1995;18:1020-2.

45.

Laws A. , Stefanick ML , Reaven GM Insulin resistance and hypertriglyceridaemia in nondiabetic relatives of patients with non-insulin dependent diabetes. J Clin Endocrinol Metab 1989;69:343-7.