Insulin Resistance Is a Poor Predictor of Type 2 Diabetes in Individuals with No Family History of Disease

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-03, Vol.100 (5), p.2724-2729
• Main Authors: Goldfine, Allison B., Bouche, Clara, Parker, Robert A., Kim, Caroline, Kerivan, Amy, Soeldner, J. Stuart, Martin, Blaise C., Warram, James H., Kahn, C. Ronald
• Format: Article
• Language: English
• Subjects: Adult; Age Factors; Aged; Biological Sciences; Blood Glucose - analysis; Cohort Studies; Diabetes; Diabetes complications; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - diagnosis; Diabetes Mellitus, Type 2 - genetics; Disease resistance; Families & family life; Family Health; Family history; Fasting; Female; Genetics; Glucose Tolerance Test; Group development; Humans; Insulin; Insulin - metabolism; Insulin Resistance; Male; Middle Aged; Obesity; Parents; Regression Analysis; Risk Factors; Time Factors; Type 2 diabetes mellitus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0438009100

In normoglycemic offspring of two type 2 diabetic parents, low insulin sensitivity (SI) and low insulin-independent glucose effectiveness (SG) predict the development of diabetes one to two decades later. To determine whether low SI, low SG, or low acute insulin response to glucose are predictive of diabetes in a population at low genetic risk for disease, 181 normoglycemic individuals with no family history of diabetes (FH-) and 150 normoglycemic offspring of two type 2 diabetic parents (FH+) underwent i.v. glucose tolerance testing (IVGTT) between the years 1964-82. During$25\pm6$years follow-up, comprising 2,758 person years, the FH- cohort$(54\pm9\>years)$had an age-adjusted incidence rate of type 2 diabetes of 1.8 per 1,000 person years, similar to that in other population-based studies, but significantly lower than 16.7 for the FH+ cohort. Even when the two study populations were subdivided by initial values of SIand SGderived from IVGTT's performed at study entry, there was a 10- to 20-fold difference in age-adjusted incidence rates for diabetes in the FH- vs. FH+ individuals with low SIand low SG. The acute insulin response to glucose was not predictive of the development of diabetes when considered independently or when assessed as a function of SI, i.e., the glucose disposition index. These data demonstrate that low glucose disposal rates are robustly associated with the development of diabetes in the FH+ individuals, but insulin resistance per se is not sufficient for the development of diabetes in individuals without family history of disease and strongly suggest a familial factor, not detectable in our current measures of the dynamic responses of glucose or insulin to an IVGTT is an important risk factor for type 2 diabetes. Low SIand low SG, both measures of glucose disposal, interact with this putative familial factor to result in a high risk of type 2 diabetes in the FH+ individuals, but not in the FH- individuals.