Abstract

To determine the natural history of the development of Type 2 (non-insulin-dependent) diabetes mellitus, basal plasma insulin and glucose levels and responses to intravenous glucose tolerance tests were determined over a period of 6 years in 42 adult male rhesus monkeys (Macaca mulatta). Among the 28 obese monkeys (percent body fat > 22%) over the age of 10 years, 9 developed overt Type 2 diabetes (fasting plasma glucose, > 7.8 mmol/l; and reduced glucose disappearance rates, KG < 1.5), and 14 monkeys have shown progressive changes which suggest that they may also become diabetic. Application of a highly constant antecedent diet and a consistent 16-h fast minimized experimental variability, and permitted the identification of 8 phases in the progression from normal lean young adult to overt Type 2 diabetes. The earliest changes which could be detected were a slight increase followed by a progressive rise in fasting plasma insulin levels and an increased insulin secretion in response to a glucose stimulus. These events preceded by several years the onset of a gradual deterioration of glucose tolerance. We found that hyper-, normo-, or hypoinsulinaemia could be associated with normoglycaemia or varying degrees of hyperglycaemia; however, the prospective longitudinal study of individual monkeys clearly identified this apparent heterogeneity of plasma insulin and glucose levels as reflecting sequential changes in a continuum of events preceding or accompanying the development of impaired glucose tolerance and Type 2 diabetes mellitus.

Keywords:Rhesus, monkeys, Macaca mulatta, obesity, glucose tolerance, hyperinsulinaemia, hyperglycaemia

Fig. 1. Changes in fasting plasma insulin and glucose levels and body weights of Monkey W during the progression to phase 8 (overt Type 2 diabetes).

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