The development of obesity in rhesus monkeys appears to be necessary, if not sufficient, for the development of insulin resistance and later non-insulin-dependent diabetes (type II diabetes) (Ausman et al., 1981; Hansen and Bodkin, 1986; Bodkin et al., 1995). Hansen and Bodkin (1986) characterized the development of obesity and diabetes in 42 male rhesus monkeys 3-28 years old and weighing 5-31.7 kg. All animals were fed ad libitum, and the diet was either a commercial monkey diet (Monkey Chow®, Purina Mills Inc., St. Louis, MO) or a liquid diet for humans (Ensure®, Ross Laboratories, Columbus, OH). Rhesus monkeys appeared to advance through a series of eight stages in which age, body weight, and percentage of body fat progressively increased, insulin resistance increased, and the plasma-glucose disappearance rate decreased. In about the sixth stage, when the monkeys’ average age was about 16 years, body weight had increased to over 17 kg, body fat was near 35% of body weight, and fasting plasma insulin had risen almost tenfold to over 415 µU·ml-1 of plasma. Glucose disposal rate, measured as the slope of the impaired glucose-tolerance test disappearance curve, had decreased by 33%. In the final two stages of progression to frank diabetes, plasma glucose disappearance rate fell another 30%, fasting plasma-glucose rose to over 10 mmol·L-1, body weight fell, and body fat decreased. In this study of 3-6 years, seven of 42 monkeys progressed to overt diabetes, and 14 showed transitions suggesting that they would eventually become diabetic. Although all monkeys were obese before the onset of type II diabetes, some monkeys with similar degrees of obesity showed no progression toward the disease. Thus, obesity appears to be necessary but not sufficient for diabetes development.

Whether intervention and weight reduction after the development of obesity might reduce the incidence of diabetes development was not examined. However, dietary restriction that prevents the development of obesity does prevent the development of impaired glucose tolerance, hyperglycemia, and hyperinsulinemia (Kemnitz et al., 1994b; Bodkin et al., 1995; Gresl et al., 2001) and of type II diabetes (Hansen and Bodkin, 1993). In the Hansen and Bodkin study (1993), eight adult male rhesus monkeys (average age, 11 years) were diet-restricted (just enough diet to maintain constant body weights) for an average of 7 years, whereas a group of 19 age-matched controls were fed ad libitum. At the end of the study, the diet-restricted group had an average body weight of 10.4 kg, whereas the ad libitum-fed group had an average body weight of 16.1 kg, with a range of values that were up to 100% greater than in the diet-restricted group. In the ad libitum group by the end of the study, four animals were frankly diabetic, and six had developed impaired glucose tolerance and hyperinsulinemia and were considered to be prediabetic. None of the animals that maintained normal weight in the diet-restricted group developed any of those changes in glucose metabolism. As the data indicate, diet restriction was effective in preventing both obesity and diabetes; again, the two disease syndromes are closely linked, although the molecular basis is unclear.

Examination of potential molecular interactions that might underlie the development of insulin resistance and type II diabetes in the rhesus monkey has been attempted. The insulin receptor has two isoforms that are derived from alternate splicing of exon 11 in the insulin-receptor gene, and this splice variation has been examined in obese, hyperinsulinemic rhesus monkeys (Huang et al., 1994; Huang et al., 1996). A patterned increase in the proportion of the shorter, exon 11-negative insulin-receptor mRNA in liver was described in rhesus monkeys as they progressed from normal through prediabetic to frank diabetic status (Huang et al., 1996). The pattern is similar to that seen in muscle (Huang et al., 1994), although the percentage of the exon 11-negative form of the insulin-receptor mRNA in muscle was almost twice that seen in liver, and the pattern of increase in this form of the insulin receptor is apparently similar to the pattern seen in humans (Huang et al., 1996). The functional significance of such a modification of the insulin receptor is not understood.

The presence of hyperleptinemia in obese, hyperinsulinemic rhesus monkeys has been reported (Bodkin et al., 1996). Leptin is a hormone made in adipose tissue; its absence has been found to be the cause of obesity in the genetically obese ob/ob mouse model by Friedman and colleagues (Zhang et al., 1994). The function of leptin is not completely understood, but it appears that when it is absent, satiety is not sensed and food consumption continues in an uncontrolled manner, leading to the gross obesity observed in the ob/ob mouse. Paradoxically, increased blood concentrations of leptin have been observed in obese humans (Maffei et al., 1995), presumably as a result of the increased mass of adipose tissue. The observation of increased leptin in obese rhesus monkeys, therefore, does not define the role of leptin in the development of obesity; it only shows similarities to the observations made in humans. The monkey studies did show a strong correlation between leptin concentrations and body fat and fasting plasma insulin concentrations (Bodkin et al., 1996), but correlations with glucose disposal were less remarkable. Ramsey et al. (2000) reported a correlation of 0.8-0.9 between body fat and blood leptin concentrations.

Other studies in rhesus monkeys showed that the response of the brain to leptin can be modulated by the ability of the hormone to cross the blood-brain barrier (Ramsey et al., 1998). Leptin directly infused into the brain decreased food intake by as much as 50%, whereas leptin injections into plasma had no effect on food intake, although plasma concentrations of leptin increased by as much as a factor of 100. The mechanism that facilitates leptin movement across the blood-brain barrier needs to



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