Type 2 diabetes mellitus is a major health problem of increasing incidence. To better study the pathogenesis and potential therapeutic agents for this disease, appropriate animal models are needed. Old World nonhuman primates (NHPs) are a useful animal model of type 2 diabetes; like humans, the disease is most common in older, obese animals. Before developing overt diabetes, NHPs have a period of obesity-associated insulin resistance that is initially met with compensatory insulin secretion. When either a relative or absolute deficiency in pancreatic insulin production occurs, fasting glucose concentrations begin to increase and diabetic signs become apparent. Pathological changes in pancreatic islets are also similar to those seen in human diabetics. Initially there is hyperplasia of the islets with abundant insulin production typically followed by replacement of islets with islet-associated amyloid. Diabetic NHPs have detrimental changes in plasma lipid and lipoprotein concentrations, lipoprotein composition, and glycation, which may contribute to progression of atherosclerosis. As both the prediabetic condition (similar to metabolic syndrome in humans) and overt diabetes become better defined in monkeys, their use in pharmacological studies is increasing. Likely due to their genetic similarity to humans and the similar characteristics of the disease in NHPs, NHPs have been used to study recently developed agonists of the peroxisome proliferators-activated receptors. Importantly, agonists of the different receptor subclasses elicit similar responses in both humans and NHPs. Thus, Old World NHPs are a valuable animal model of type 2 diabetes to study disease progression, associated risk factors, and potential new treatments.

Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid and glucose metabolism. PPAR␥ agonists improve insulin sensitivity and hyperglycemia and are effective in treating type 2 diabetes mellitus (T2DM), whereas PPAR␣ agonists are used to treat dyslipidemia and atherosclerosis. The goal here was to examine the efficacy of a selective PPAR␣ agonist {(S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP-900691} on lipid, glycemic, and inflammation indices in 14 cynomolgus monkeys with spontaneous T2DM maintained on daily insulin therapy. Monkeys were dosed orally with either vehicle (n ϭ 7) or CP-900691 (3 mg/kg, n ϭ 7) daily for 6 weeks. CP-900691 treatment increased plasma high-density lipoprotein cholesterol (HDLC) (33 Ϯ 3 to 60 Ϯ 4 mg/dL, p Ͻ 0.001) and apolipoprotein A1 (96 Ϯ 5 to 157 Ϯ 5 mg/dL, p Ͻ 0.001), reduced plasma triglycerides (547 Ϯ 102 to 356 Ϯ 90 mg/dL, p Ͻ 0.01), and apolipoprotein B (62 Ϯ 3 to 45 Ϯ 3 mg/dL, p Ͻ 0.01), improved the lipoprotein index (HDL to non-HDLC ratio; 0.28 Ϯ 0.06 to 0.79 Ϯ 0.16, p Ͻ 0.001), decreased body weight (p Ͻ 0.01) and C-reactive protein (CRP) (1700 Ϯ 382 to 304 Ϯ 102 ng/ml, p Ͻ 0.01), and increased adiponectin (1697 Ϯ 542 to 4242 Ϯ 1070 ng/ml, p Ͻ 0.001) compared with baseline. CP-900691 treatment reduced exogenous insulin requirements by approximately 25% (p Ͻ 0.04) while lowering plasma fructosamine from 2.87 Ϯ 0.09 to 2.22 Ϯ 0.17 mM (p Ͻ 0.05), indicative of improved glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in glycemic control, body weight, and CRP, suggest that CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations.The peroxisome proliferator-activated receptors (PPAR␣, PPAR␤, and PPAR␥) are a family of distinct nuclear receptors that associate with key naturally occurring lipid molecules and function as transcription factors in the regulation of carbohydrate and lipid metabolism, among other biological processes (Harwood and Hamanaka, 1998;Corton et al., 2000;Willson et al., 2000;Winegar et al., 2001). The PPARs became recognized as important pharmaceutical targets for the treatment of dyslipidemia, diabetes, and the cardiovascular disorders associated with obesity and the metabolic syndrome, when it was discovered that PPAR␥ was the therapeutic target for the marketed glitazone class of antidiabetic agents (Willson et al., , 2001Picard and Auwerx, 2002) and PPAR␣ was the therapeutic target for the marketed fibrate class of antidyslipidemic agents (Harwood and Hamanaka, 1998;Willson et al., 2000;Winegar et al., 2001). Because the pharmacological actions of PPAR␣, PPAR␤, and PPAR␥ activators are distinct (Corton et al., 2000; Article, publication date, and citation information can be found at

Adults receiving conventional replacement therapy for hypopituitarism are known to have increased cardiovascular mortality. The aim of this study was to assess the lipid profiles of 30 hypopituitary adults compared with 2 case control groups, 1 matched for age, sex, and body mass index (BMI) and the second matched for age and sex only with a BMI representative of the general population. Fasting lipids, lipoproteins, and apoproteins (Apo) were determined by routine methods. Low density lipoprotein (LDL) particle size was determined by nondenaturing gradient gel electrophoresis. LDL size was significantly smaller in the hypopituitary group (25.9 +/- 0.1 nm) than in the BMI-matched (26.2 +/- 0.1 nm; P < 0.05) and standard control (26.3 +/- 0.1 nm; P < 0.01) groups. High density lipoprotein cholesterol levels in the hypopituitary group were significantly lower than those in the BMI-matched control group (1.13 +/- 0.06 vs. 1.34 +/- 0.06 mmol/L; P < 0.05) and the standard control group (1.38 +/- 0.06 mmol/L; P < 0.005). Apo A1 levels were also lower compared with those in the BMI-matched (122 +/- 6 vs. 137 +/- 4 mg/dL; P < 0.05) and the standard (143 +/- 4 mg/dL; P < 0.005) control groups. There was a trend toward higher triglyceride levels when the hypopituitary subjects were compared with the standard control group [1.4 (95% CI, 1.3-2.2) vs. 1.0 (95% CI, 0.9-1.4) mmol/L; P = 0.06]. These differences were more marked in the female subjects studied. No significant differences were noted in total cholesterol, LDL cholesterol, or Apo B levels. We conclude that hypopituitary patients receiving conventional replacement therapy have an atherogenic lipid profile characterized by small dense LDL, decreased high density lipoprotein cholesterol, and increased triglyceride levels, which may contribute to the excess cardiovascular mortality in this group.

Cannabinoid-1 (CB 1 ) receptor antagonists exhibit pharmacological properties favorable to treatment of obesity, caused by both centrally mediated effects on appetite and peripherally mediated effects on energy metabolism. However, the relative contribution of these effects to the weight loss produced by CB 1 receptor antagonists remains unclear. Here, we compare food intake-related and independent effects of the CB 1 -selective antagonist 1-azetidine-3-carboxamide (PF-95453) in obese cynomolgus monkeys. Monkeys were divided into three study groups (n ϭ 10 each) and treated once daily for 8 weeks with either vehicle or PF-95453 as follows: 1, fed ad libitum and dosed orally with vehicle; 2, fed ad libitum and dosed orally with PF-95453 (0.5 mg/kg weeks 1-3, 1.0 mg/kg weeks 4 -8); and 3, fed an amount equal to the amount consumed by the drug-treated group and dosed orally with vehicle (pair-fed). PF-95453 treatment significantly reduced food consumption by 23%, body weight by 10%, body fat by 39%, and leptin by 34% while increasing adiponectin by 78% relative to vehicle-treated controls. Pairfed animals did not exhibit reductions in body weight or leptin but did show significantly reduced body fat (11%) and increased adiponectin (15%) relative to vehicle-treated controls but markedly less than after PF-95453 treatment. Indeed, significant differences were noted between the drug-treated and pair-fed groups with respect to body weight reduction, body fat reduction, increased adiponectin, and leptin reduction. Similar to humans, monkeys treated with the CB 1 receptor antagonist exhibited decreased body weight and body fat, a substantial portion of which seemed to be independent of the effects on food intake.