New concepts in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus

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Abstract

In the present review we have examined recent data concerning the pathogenetic factors known to contribute to the glucose intolerance in noninsulin-dependent diabetes mellitus (NIDDM). The following conclusions appear warranted: (1) insulin secretion in response to glucose is frequently, but not invariably, deficient in persons with fasting hyperglycemia. Basal insulin secretion, however, is normal and milder degrees of glucose intolerance can be associated with a normal or supernormal insulin response to glucose; (2) insulin resistance is almost uniformly present in patients with any degree of clinically detectable glucose intolerance. This insulin resistance is located both in the liver and in the peripheral tissues, principally the muscle; (3) hepatic resistance is present in the form of inappropriately high glucose production in the fasting state and deficient glucose uptake following glucose ingestion. Peripheral resistance manifests itself as reduced glucose uptake (mostly by muscle) after exposure to endogenous or exogenous insulin and reduced clearance of plasma glucose in the fasting state; (4) decreased binding of insulin to its cellular receptors is commonly found in patients with both chemical and overt diabetes. Insulin binding, however, may be normal in diabetic patients with severe insulin resistance. A significant postreceptor defect in glucose metabolism appears to be present in patients with marked fasting hyperglycemia; (5) a general conceptual framework for the pathogenesis of noninsulin-dependent diabetes mellitus is presented in which a defect (a) in the secretory activity of the beta cell, (b) in the interaction between the gastrointestinal tract and the liver, or (c) at the cellular level is in turn considered as the possible initiating event. Each pathogenetic sequence is discussed in the context of the available evidence and is tentatively associated with a clinical subset of patients.

From the therapeutic standpoint, three measures are presently available that are capable of ameliorating the insulin resistance in NIDDM. First, a regular program of physical activity is very likely to improve glucose tolerance through an enhancement of insulin sensitivity. Second, the newer generation sulfonylurea agents appear to provide a promising means of improving the insulin resistance. Third, dietary modification may prove useful in reducing the fasting plasma glucose concentration toward normal levels. The value of weight reduction, high fiber diet, substitution of fructose for glucose, and alterations in the carbohydrate content of the diet are discussed.

References (310)

  • A.D. Cherrington et al.

    Relationship between the plasma glucose level and glucose uptake in the conscious dog

    Metabolism

    (1978)
  • P.R. Bratusch-Marrain et al.

    Oral glucose tolerance test: effect of different glucose loads on splanchnic carbohydrate and substrate metabolism in healthy man

    Metabolism

    (1980)
  • E Ferrannini et al.

    The role of fractional glucose extraction in the regulation of splanchnic glucose metabolism in normal and diabetic man

    Metabolism

    (1980)
  • R.A. DeFronzo et al.

    Lack of a gastrointestinal mediator of insulin action in maturity-onset diabetes

    Lancet

    (1978)
  • W.W. Lautt

    Hepatic parasympathetic neuropathy as cause of maturity-onset diabetes?

    Gen Pharmacol

    (1980)
  • M.J. Perley et al.

    Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects

    J Clin Invest

    (1967)
  • E Cerasi et al.

    Decreased sensitivity of the pancreatic beta cells to glucose in prediabetic and diabetic subjects . A glucose dose-response study

    Diabetes

    (1972)
  • P.J. Savage et al.

    Hyperinsulinemia and hypoinsulinemia. Insulin responses to oral carbohydrate over a wide spectrum of glucose tolerance

    Diabetes

    (1975)
  • K Johansen

    Mild diabetes in young subjects. Clinical aspects and plasma insulin response pattern

    Acta Med Scand

    (1973)
  • K Kosaka et al.

    Insulin responses in equivocal and definite diabetes, with special reference to subjects who had mild glucose intolerance but later developed definite diabetes

    Diabetes

    (1977)
  • J.A. Colwell et al.

    Diminished insulin response to hyperglycemia in prediabetes and diabetes

    Diabetes

    (1967)
  • R.L. Lerner et al.

    Acute and steady-state insulin responses to glucose in nonobese diabetic subjects

    J Clin Invest

    (1972)
  • D.L. Rimoin et al.

    Diabetes mellitus among the Navajo. II. Plasma glucose and insulin responses

    Arch Intern Med

    (1968)
  • G Reaven et al.

    Study of the relationship between glucose and insulin responses to an oral glucose load in man

    Diabetes

    (1968)
  • E Cerasi et al.

    The plasma insulin response to glucose infusion in healthy subjects and in diabetes mellitus

    Acta Endocrinol (Kobenhavn)

    (1967)
  • G Tchobroutsky et al.

    Serial postprandial plasma insulin levels in 117 subjects with and without diabetes

    Diabetes

    (1973)
  • F.P. Alford et al.

    The significance of interpretation of mildly abnormal oral glucose tolerance

    Diabetologia

    (1971)
  • R Chiles et al.

    Excessive serum insulin response to oral glucose in obesity and mild diabetes. Study of 501 patients

    Diabetes

    (1970)
  • J.M. Olefsky et al.

    Insulin binding in diabetes. Relationships with plasma insulin levels and insulin sensitivity

    Diabetes

    (1977)
  • Y Fujita et al.

    Confirmation of impaired early insulin response to glycemic stimulus in nonobese mild diabetics

    Diabetes

    (1975)
  • R.S. Yalow et al.

    Comparison of plasma insulin levels following administration of tolbutamide and glucose

    Diabetes

    (1960)
  • J.R. Turtle

    Glucose and insulin secretory response patterns following diet and tolazamide therapy in diabetes

    Br Med J

    (1970)
  • G.M. Reaven et al.

    Steady-state plasma insulin response to continuous glucose infusion in normal and diabetic subjects

    Diabetes

    (1969)
  • M.T. McKiddie et al.

    Plasma insulin studies in two hundred patients with diabetes mellitus

    Q J Med

    (1969)
  • S Burrow

    Insulin response in glucose-tolerance tests

    Am J Clin Pathol

    (1967)
  • W.P. Jackson et al.

    Insulin excess as the initial lesion in diabetes

    Lancet

    (1972)
  • P Felig et al.

    Influence of maturity-onset diabetes on splanchnic glucose balance after oral glucose ingestion

    Diabetes

    (1978)
  • D.L. Rimoin

    Ethnic variability in glucose tolerance and insulin secretion

    Arch Intern Med

    (1969)
  • S.S. Fajans et al.

    The course of asymptomatic diabetes in young people as determined by levels of blood glucose and plasma insulin

    Trans Assoc Am Physicians

    (1969)
  • S.S. Fajans et al.

    Clinical and etiologic heterogeneity of idiopathic diabetes mellitus

    Diabetes

    (1978)
  • S.S. Fajans et al.

    Heterogeneity of insulin responses in latent diabetes

    Trans Assoc Am Physicians

    (1974)
  • S.S. Fajans et al.

    The various faces of diabetes in the young: changing concepts

    Arch Intern Med

    (1976)
  • J.C. Floyd et al.

    Secretion of insulin induced by amino acids and glucose in diabetes mellitus

    J Clin Endocrinol

    (1968)
  • R.G. Simpson et al.

    Early phase of insulin release

    Diabetes

    (1968)
  • H.S. Seltzer et al.

    Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus

    J Clin Invest

    (1967)
  • R.S. Yalow et al.

    Plasma insulin concentrations in nondiabetic and early diabetic subjects. Determinations by a new selective immuno-assay technic

    Diabetes

    (1960)
  • G Sartor et al.

    Ten-year follow-up of subjects with impaired glucose tolerance: prevention of diabetes by tolbutamide and diet regulation

    Diabetes

    (1980)
  • T.S. Danowski et al.

    Insulin patterns in equivocal glucose tolerance tests (chemical diabetes)

    Diabetes

    (1973)
  • G.M. Reaven et al.

    Is there a delay in the plasma insulin response of patients with chemical diabetes mellitus?

    Diabetes

    (1971)
  • A.L. Rosenbloom

    Insulin responses of children with chemical diabetes mellitus

    N Engl J Med

    (1970)
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    The authors' work on the sulfonylurea agents was supported by a grant from The Upjohn Company, Kalamazoo, Michigan. Much of the original data concerning the pathogenesis of noninsulin-dependent diabetes mellitus was generated from grants from the National Institutes of Health (AM 24092) and the Juvenile Diabetes Association. The work of Dr. Ferrannini was supported by Public Health Service International Research Fellowship 1-F05-TW02716-01. Dr. Koivisto was the recipient of a grant from the Finnish Ministry of Education.

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