The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the ␣ (NR1C1) and ␥ (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the ␦ (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPAR␦ agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Our results suggest that PPAR␦ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

Adiponectin is an adipose-specific plasma protein whose plasma concentrations are decreased in obese subjects and type 2 diabetic patients. This protein possesses putative antiatherogenic and anti-inflammatory properties. In the current study, we have analyzed the relationship between adiponectin and insulin resistance in rhesus monkeys (Macaca mulatta), which spontaneously develop obesity and which subsequently frequently progress to overt type 2 diabetes. The plasma levels of adiponectin were decreased in obese and diabetic monkeys as in humans. Prospective longitudinal studies revealed that the plasma levels of adiponectin declined at an early phase of obesity and remained decreased after the development of type 2 diabetes. Hyperinsulinemic-euglycemic clamp studies revealed that the obese monkeys with lower plasma adiponectin showed significantly lower insulin-stimulated peripheral glucose uptake (M rate). The plasma levels of adiponectin were significantly correlated to M rate (r ‫؍‬ 0.66, P < 0.001). Longitudinally, the plasma adiponectin decreased in parallel to the progression of insulin resistance. No clear association was found between the plasma levels of adiponectin and its mRNA levels in adipose tissue. These results suggest that reduction in circulating adiponectin may be related to the development of insulin resistance. Diabetes 50:1126 -1133, 2001

Exendin-4 is a 39 amino acid peptide isolated from the salivary secretions of the Gila monster (Heloderma suspectum). It shows 53% sequence similarity to glucagon-like peptide (GLP)-1. Unlike GLP-1, exendin-4 has a prolonged glucose-lowering action in vivo. We compared the potency and duration of glucose-lowering effects of exendin-4 and GLP-1 in hyperglycemic db/db and ob/ob mice. Whereas reductions in plasma glucose of up to 35% vanished within 1 h with most doses of GLP-1, the same doses of exendin-4 resulted in a similar glucose-lowering effect that persisted for >4 h. Exendin-4 was 5,530-fold more potent than GLP-1 in db/db mice (effective doses, 50% [ED50s] of 0.059 microg/kg +/-0.15 log and 329 microg/kg+/-0.22 log, respectively) and was 5,480-fold more potent in ob/ob mice (ED50s of 0.136 microg/kg+/-0.10 log and 744 microg/kg+/-0.21 log, respectively) when the percentage fall in plasma glucose at 1 h was used as the indicator response. Exendin-4 dose-dependently accelerated glucose lowering in diabetic rhesus monkeys by up to 37% with an ED50 of 0.25 microg/kg +/-0.09 log. In two experiments in which diabetic fatty Zucker rats were injected subcutaneously twice daily for 5-6 weeks with doses of exendin-4 up to 100 microg x rat(-1) x day(-1) (approximately 250 microg/kg), HbA1c was reduced relative to saline-injected control rats. Exendin-4 treatment was also associated in each of these experiments with weight loss and improved insulin sensitivity, as demonstrated by increases of up to 32 and 49%, respectively, in the glucose infusion rate (GIR) in the hyperinsulinemic euglycemic clamp. ED50s for weight loss and the increase in clamp GIR were 1.0 microg/kg+/-0.15 log and 2.4 microg/kg+/-0.41 log, respectively. In conclusion, acute and chronic administration of exendin-4 has demonstrated an antidiabetic effect in several animal models of type 2 diabetes.

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 greater than 22%) over the age of 10 years, 9 developed overt Type 2 diabetes (fasting plasma glucose, greater than 7.8 mmol/l, and reduced glucose disappearance rates, KG less than 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.

Mortality and morbidity were examined in 117 laboratory-maintained rhesus monkeys studied over approximately 25 years (8 dietary-restricted [DR] and 109 ad libitum-fed [AL] monkeys). During the study, 49 AL monkeys and 3 DR monkeys died. Compared with the DR monkeys, the AL monkeys had a 2.6-fold increased risk of death. Hyperinsulinemia led to a 3.7-fold increased risk of death (p <.05); concordantly, the risk of death decreased by 7%, per unit increase in insulin sensitivity (M). There was significant organ pathology in the AL at death. The age at median survival in the AL was approximately 25 years compared with 32 years in the DR. The oldest monkey was a diabetic female (AL) that lived to be 40 years of age. These results suggest that dietary restriction leads to an increased average age of death in primates, associated with the prevention of hyperinsulinemia and the mitigation of age-related disease.