Review article
Pathogenesis of type 2 diabetes mellitus

https://doi.org/10.1016/j.mcna.2004.04.013Get rights and content

Section snippets

Normal glucose homeostasis

A discussion of the pathogenesis of type 2 diabetes mellitus must start with a review of mechanisms involved in the maintenance of normal glucose homeostasis in the basal or postabsorptive state (10–12 h overnight fast) and following ingestion of a typical mixed meal [1], [2], [3], [4], [5], [6], [7], [8], [9]. In the postabsorptive state the majority of total body glucose disposal takes place in insulin-independent tissues. Thus, approximately 50% of all glucose use occurs in the brain, which

Glucose homeostasis in type 2 diabetes mellitus

Type 2 diabetic subjects manifest multiple disturbances in glucose homeostasis, including: (1) impaired insulin secretion; (2) insulin resistance in muscle, liver, and adipocytes; and (3) abnormalities in splanchnic glucose uptake [1], [2], [20], [21].

Site of insulin resistance in type 2 diabetes

Maintenance of normal whole-body glucose homeostasis requires a normal insulin secretory response and normal tissue sensitivity to the independent effects of hyperinsulinemia and hyperglycemia to augment glucose uptake [1], [2], [3], [4], [5], [6], [7]. The combined effects of insulin and hyperglycemia to promote glucose disposal are dependent on three tightly coupled mechanisms (see Box 1): (1) suppression of endogenous (primarily hepatic) glucose production; (2) stimulation of glucose uptake

Dynamic interaction between insulin sensitivity and insulin secretion in type 2 diabetes

Insulin resistance is present in approximately 25% of the adult population [138], [139], [140]. The majority of these individuals, however, have normal glucose tolerance because the pancreatic beta cells are able to read the severity of insulin resistance and appropriately augment their insulin secretory rate. This dynamic interaction between insulin sensitivity and insulin secretion is demonstrated by results obtained in healthy, lean, young normal-glucose-tolerant women who received a

Role of the adipocyte in the pathogenesis of type 2 diabetes mellitus: the harmonious quartet

The majority (≥ 80%–90%) of type 2 diabetics in the United States are overweight or obese [147]. Both lean and especially obese type 2 diabetics are characterized by day-long elevation in plasma free fatty-acid concentration, which fails to suppress normally following ingestion of a mixed meal or oral glucose load [30]. FFA are stored as triglycerides in adipocytes and serve as an essential energy source during fasting conditions. Insulin is a potent antilipolytic hormone and restrains the

Cellular mechanisms of insulin resistance

The cellular events through which insulin initiates its stimulatory effect on glucose metabolism start with binding of the hormone to specific receptors that are present on the cell surface of all insulin target tissues [2], [160], [161], [162]. After insulin has bound to and activated its receptor, “second messengers” are generated, and these second messengers activate a cascade of phosphorylation-dephosphorylation reactions that eventually result in the stimulation of intracellular glucose

First page preview

First page preview
Click to open first page preview

References (248)

  • R.A. DeFronzo et al.

    Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin dependent diabetes mellitus

    J Clin Invest

    (1985)
  • L. Mandarino et al.

    Regulation of muscle glucose uptake in vivo

  • A. Mitrakou et al.

    Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM

    Diabetes

    (1990)
  • A.D. Cherrington

    Control of glucose uptake and release by the liver in vivo

    Diabetes

    (1999)
  • V. Grill

    A comparison of brain glucose metabolism in diabetes as measured by positron emission tomography or by arteriovenous techniques

    Ann Med

    (1990)
  • H. Bays et al.

    Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonsits provide a rational therapeutic approach

    J Clin Endocrinol Metab

    (2004)
  • L.C. Groop et al.

    Glucose and free fatty acid metabolism in non-insulin dependent diabetes mellitus. Evidence for multiple sites of insulin resistance

    J Clin Invest

    (1989)
  • R.N. Bergman

    Non-esterified fatty acids and the liver: why is insulin secreted into the portal vein?

    Diabetologia

    (2000)
  • G. Boden

    Role of fatty acids in the pathogenesis of insulin resistance and NIDDM

    Diabetes

    (1997)
  • A.D. Baron et al.

    Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics

    Diabetes

    (1987)
  • R.A. DeFronzo et al.

    Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange

    Proc Natl Acad Sci USA

    (1978)
  • D.J. Drucker

    Glucagon-like peptides

    Diabetes

    (1998)
  • J.J. Holst et al.

    The pathogenesis of NIDDM involves a defective expression of the GIP receptor

    Diabetologia

    (1997)
  • K.S. Polonsky et al.

    Non-insulin-dependent diabetes mellitus: a genetically programmed failure of the beta cell to compensate for insulin resistance

    N Engl J Med

    (1996)
  • E. Cerasi

    Insulin deficiency and insulin resistance in the pathogenesis of NIDDM: is a divorce possible?

    Diabetologia

    (1995)
  • R.A. Sicree et al.

    Plasma insulin response among Nauruans. Prediction of deterioration in glucose tolerance over 6 years

    Diabetes

    (1987)
  • M.F. Saad et al.

    The natural history of impaired glucose tolerance in the Pima Indians

    N Engl J Med

    (1988)
  • S.M. Haffner et al.

    Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans

    Diabetes

    (1995)
  • C. Weyer et al.

    A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance. Evidence for a pathogenic role of relative hyperinsulinemia

    Diabetes

    (2000)
  • C. Weyer et al.

    Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development

    Diabetes Care

    (2000)
  • W. Pimenta et al.

    Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first degree NIDDM relative

    JAMA

    (1995)
  • J. Eriksson et al.

    Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus

    N Engl J Med

    (1989)
  • G.M. Reaven et al.

    Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 hours in patients with NIDDM

    Diabetes

    (1988)
  • W.T. Garvey et al.

    Day-long integrated urinary C-peptide excretion

    Diabetes

    (1988)
  • A. Gastaldelli et al.

    Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study

    Diabetologia

    (2004)
  • B.C. Hansen et al.

    Heterogeneity of insulin responses: phases leading to type 2 (noninsulin-dependent) diabetes mellitus in the rhesus monkey

    Diabetologia

    (1986)
  • S.E. Kahn

    Clinical Review 135. The importance of β-cell failure in the development and progression of type 2 diabetes

    J Clin Endocrinol Metab

    (2001)
  • R.N. Bergman et al.

    The evolution of β-cell dysfunction and insulin resistance in type 2 diabetes

    Eur J Clin Invest

    (2002)
  • K.S. Polonsky

    Lilly Lecture 1994. The beta cell in diabetes: from molecular genetics to clinical research

    Diabetes

    (1995)
  • G.I. Bell et al.

    Diabetes mellitus and genetically programmed defects in β-cell function

    Nature

    (2001)
  • M.I. McCarthy et al.

    Genetic approaches to the molecular understanding of type 2 diabetes

    Am J Physiol

    (2002)
  • G.I. Bell et al.

    Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q

    Proc Natl Acad Sci USA

    (1991)
  • P.H. Froguel et al.

    Familial hyperglycaemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus

    N Engl J Med

    (1993)
  • H. Beck-Nielsen et al.

    Insulin action and insulin secretion in identical twins with MODY: evidence for defects in both insulin action and insulin secretion

    Diabetes

    (1988)
  • V. Mohan et al.

    Insulin resistance in maturity-onset diabetes of the young

    Diabetes Metab

    (1988)
  • S.C. Elbein et al.

    Molecular screening of the glucokinase gene in familial type 2 (non-insulin-dependent) diabetes mellitus

    Diabetologia

    (1994)
  • S. Efendic et al.

    Low insulin response: a marker of pre-diabetes

    Adv Exp Med Biol

    (1988)
  • M.J. Davies et al.

    Insulin deficiency rather than hyperinsulinaemia in newly diagnosed type 2 diabetes mellitus

    Diabet Med

    (1993)
  • K.-W. Chen et al.

    Earlier appearance of impaired insulin secretion than of visceral adiposity in the pathogenesis of NIDDM. 5-year follow-up of initially nondiabetic Japanese-American men

    Diabetes Care

    (1995)
  • P. Arner et al.

    Different etiologies of Type 2 (non-insulin-dependent) diabetes mellitus in obese and non-obese subjects

    Diabetologia

    (1991)
  • Cited by (0)

    View full text