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  You are here : > Health Centers > Diabetes Health CenterPathogenesis of Type 2 Diabetes

Pathophysiology of Hyperglycemia

Pathogenesis of Type 2 DiabetesSep 22, 2008

An enormous amount of research has been dedicated to unraveling the pathophysiology of type 2 diabetes mellitus over the last 30 years. While a large number of reviews have been devoted to its description, this section follows the line of our recent seminar.

Insulin is the key hormone for regulating blood glucose. In general, normoglycemia is maintained by the balanced interplay between insulin secretion and the efficacy of insulin actions. In the fasting state, the major part of glucose is produced by the liver, and roughly half of it is used for brain glucose metabolism. 

The remainder is taken up by various tissues, mainly muscle and for a minor part adipose tissue. In this situation insulin levels are low,  and have no appreciable effect on muscle glucose uptake.

The normal liver is capable of increasing glucose production fourfold or more,  and the main effect of the relatively low insulin levels is to restrain liver glucose production. After a meal, insulin is secreted in larger amounts,  which diminishes liver glucose production even further and will lead to an enhancement of muscle (and adipose tissue) glucose uptake.

The normal pancreatic cell is capable of adapting to changes in insulin action, i.e., a decrease in insulin action is accompanied by upregulation of insulin secretion (and vice versa).

Normal pancreas beta-cell adaptation precludes development of diabetes in a large number of insulin-resistant subjects. (Fig. 1) illustrates the curvilinear relationship between normal beta-cell function and insulin sensitivity. When the adaptation of the beta cell is insufficient (“deviation from the hyperbola”),  the subjects will develop impaired glucose tolerance (IGT) or type 2 diabetes.

Figure 1 shows how beta-cell function is inadequately low for a given degree of insulin sensitivity.  Various studies (including follow-up studies in Pima Indians) have indeed shown that beta-cell dysfunction is critical in the pathogenesis of type 2 diabetes.

It is of note that even small increases in fasting (and postprandial) glucose occur in subjects with insulin resistance, which should stimulate insulin release (that is “traveling along” the hyperbola).

Thus, when insulin action decreases (for example in increasing obesity) the system normally compensates by increasing beta-cell function, in the face of higher fasting and 2-hour glucose concentrations. Even if this increase is small, it now appears that this may be toxic to beta cells (“glucose toxicity”).

Michael Stumvoll
Department of Medicine, University of Leipzig, Leipzig, Germany

Barry J. Goldstein
Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical
College of Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

Timon W. van Haeften
Department of Internal Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands


Provided by ArmMed Media

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