Accurate Assessment of β-Cell Function
The Hyperbolic Correction
- From the Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
Only in the last decade did modeling studies predict, and knockout experiments confirm, that type 2 diabetes is a “2-hit” disease in which insulin resistance is necessarily accompanied by β-cell defect(s) preventing the compensatory upregulation of insulin secretion. This long- delayed insight was associated with the development of a constant, the “disposition index,” describing the β-cell sensitivity-secretion relationship as a rectangular hyperbola. Shifts in insulin sensitivity are accompanied by compensatory alterations in β-cell sensitivity to glucose. Insulin-sensitive subjects do not require a massive insulin response to exogenous glucose to maintain a normal blood glucose. But if their insulin sensitivity decreases by 80%, as in late pregnancy, they need a fivefold greater insulin response to achieve an identical disposition index. Women with gestational diabetes have an insulin response similar to that of normal volunteers; at first glance, this suggests similar islet function, but the utility of the disposition index is to normalize this response to the amplitude of third trimester insulin resistance, revealing severe β-cell deficiency. The index is a quantitative, convenient, and accurate tool in analyzing epidemiologic data and identifying incipient impaired glucose tolerance. Separate major issues remain, however: the causes of insulin resistance, the causes of the failure of adequate β-cell compensation in type 2 diabetes, and the nature of the signal(s) from insulin-resistant tissues that fail to elicit the appropriate β-cell increment in sensitivity to glucose and other stimuli. The disposition index is likely to remain the most accurate physiologic measure for testing hypotheses and solutions to these challenges in whole organisms.
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Accepted for publication 13 June 2001.
DI, disposition index; FFA, free fatty acid; GDM, gestational diabetes mellitus; GLP-1, glucagon-like peptide-1; IGT, impaired glucose tolerance; SI, insulin sensitivity index.
The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier, Paris.