, Volume 14, Issue 3, pp 141-148

Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice

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The diabetes syndromes produced by the two single gene mutations, obese (ob), and diabetes (db) are identical when both genes are expressed on the same inbred background, whereas on different backgrounds the syndrome changes from a severeobesity, moderate-diabetes to a severe life-shortening diabetes. The same initial sequence of events occurs in both conditions. Increased secretion of insulin and hyperphagia is followed by moderate hyperglycaemia with a further compensatory increase in insulin secretion followed by an expansion of the beta-cell mass. On the BL/6 inbred background, hypertrophy and hyperplasia of the beta cells continues until hyperglycaemia is controlled, whereas on the BL/Ks background, beta cell expansion fails and islet atrophy occurs causing insulinopenia, marked hyperglycaemia, and severe diabetes. The data presented here suggest that hyperphagia, hyperinsulinaemia, or both, early in development trigger the abnormal sequence of metabolic events leading to the obesity-diabetes state. These primary events interact with unknown genetic modifiers to produce either a juvenile or maturity-onset type of diabetes. An understanding of the mode of action of these background modifiers influencing the severity of diabetes in mice should lead to a better understanding of the ways in which unknown genetic and environmental factors contribute to human diabetes.

Based on the Claude Bernard Lecture delivered to the European Association for the Study of Diabetes in Geneva on September 30, 1977
This paper is dedicated to Dr. Katharine P. Hummel, an anatomist, and to the late Dr. Margaret M. Dickie, a geneticist, who both did their best to teach me, a biochemist, the fundamentals of their fields of interest. For their attempts to broaden my scope, I am truly grateful.