AimsTo characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon‐like peptide‐1 (GLP‐1) and glucagon receptors.Materials and methods MEDI0382 was evaluated in vitro for its ability to stimulate cAMP accumulation in cell lines expressing transfected recombinant or endogenous GLP‐1 or glucagon receptors, to potentiate glucose‐stimulated insulin secretion (GSIS) in pancreatic β‐cell lines and stimulate hepatic glucose output (HGO) by primary hepatocytes. The ability of MEDI0382 to reduce body weight and improve energy balance (i.e. food intake and energy expenditure), as well as control blood glucose, was evaluated in mouse models of obesity and healthy cynomolgus monkeys following single and repeated daily subcutaneous administration for up to 2 months.Results MEDI0382 potently activated rodent, cynomolgus and human GLP‐1 and glucagon receptors and exhibited a fivefold bias for activation of GLP‐1 receptor versus the glucagon receptor. MEDI0382 produced superior weight loss and comparable glucose lowering to the GLP‐1 peptide analogue liraglutide when administered daily at comparable doses in DIO mice. The additional fat mass reduction elicited by MEDI0382 probably results from a glucagon receptor‐mediated increase in energy expenditure, whereas food intake suppression results from activation of the GLP‐1 receptor. Notably, the significant weight loss elicited by MEDI0382 in DIO mice was recapitulated in cynomolgus monkeys.ConclusionsRepeated administration of MEDI0382 elicits profound weight loss in DIO mice and non‐human primates, produces robust glucose control and reduces hepatic fat content and fasting insulin and glucose levels. The balance of activities at the GLP‐1 and glucagon receptors is considered to be optimal for achieving weight and glucose control in overweight or obese Type 2 diabetic patients.

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In a search for more effective anti-diabetic treatment, we used a process coupling low-affinity biochemical screening with highthroughput co-crystallography in the design of a series of compounds that selectively modulate the activities of all three peroxisome proliferator-activated receptors (PPARs), PPAR␣, PPAR␥, and PPAR␦. Transcriptional transactivation assays were used to select compounds from this chemical series with a bias toward partial agonism toward PPAR␥, to circumvent the clinically observed side effects of full PPAR␥ agonists. Co-crystallographic characterization of the lead molecule, indeglitazar, in complex with each of the 3 PPARs revealed the structural basis for its PPAR pan-activity and its partial agonistic response toward PPAR␥. Compared with full PPAR␥-agonists, indeglitazar is less potent in promoting adipocyte differentiation and only partially effective in stimulating adiponectin gene expression. Evaluation of the compound in vivo confirmed the reduced adiponectin response in animal models of obesity and diabetes while revealing strong beneficial effects on glucose, triglycerides, cholesterol, body weight, and other metabolic parameters. Indeglitazar has now progressed to Phase II clinical evaluations for Type 2 diabetes mellitus (T2DM).adiponectin ͉ diabetes ͉ partial agonist ͉ PPAR pan-agonist ͉ Scaffold-based drug discovery T herapeutic approaches to Type 2 diabetes mellitus (T2DM), which currently affects Ϸ6% of adults in the United States (US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA; 2005), are generally polypharmaceutical in nature, targeting effects on insulin sensitivity and elements of the coincident dyslipidemia and cardiovascular diseases (1). However, polypharmacy in these treatment regimens has been cited as a potential additional risk factor (2), with many patients on 4 or more concomitant medications. A more effective strategy would be to use a single agent that possesses combined benefits from simultaneous inhibition or stimulation of several related targets, without the risks associated with combination therapy. However, optimizing activities against several targets is a complex design problem that necessitates judicious choice of targets and requires new ways in which therapeutic agents are generated.Two classes of marketed therapeutics, the fibrates (as lipidlowering agents) and the glitazones (as insulin-sensitizing drugs) target related receptors known as PPAR␣ and PPAR␥, respectively, whereas a third member of the subfamily, PPAR␦, has been the target of intense preclinical interest as an avenue for treatment of dyslipidemia (3). A pan-agonist, capable of stimulating the 3 peroxisome proliferator-activated receptors (PPARs) as a group, would be expected to be particularly useful in the treatment of T2DM from the standpoints of both efficacy and reduction in the additional risk factors associated with polypharmacy. Despite the close structural relationship between these 3 receptors, the search for compounds whi...

GPR39 is a G protein-coupled receptor expressed in liver, gastrointestinal tract, adipose tissue, and pancreas. We have recently shown that young GPR39(-/-) mice have normal body weight, food intake, and fasting glucose and insulin levels. In this study, we examined the role of GPR39 in aging and diet-induced obese mice. Body weight and food intake were similar in wild-type and GPR39(-/-) mice as they aged from 12 to 52 wk or when fed a low-fat/high-sucrose or high-fat/high-sucrose diet. Fifty-two-week-old GPR39(-/-) mice showed a trend toward decreased insulin levels after oral glucose challenge. When fed either a low-fat/high-sucrose or high-fat/high-sucrose diet, GPR39(-/-) mice had increased fed glucose levels and showed decreased serum insulin levels during an oral glucose tolerance test in the face of unchanged insulin tolerance. Pancreas morphology and glucose-stimulated insulin secretion in isolated islets from wild-type and GPR39(-/-) mice were comparable, suggesting that GPR39 is not required for pancreas development or ex vivo insulin secretion. Small interfering RNA-mediated knockdown of GPR39 in clonal NIT-1 beta-cells revealed that GPR39 regulates the expression of insulin receptor substrate-2 and pancreatic and duodenal homeobox-1 in a cell-autonomous manner; insulin receptor substrate-2 mRNA was also significantly decreased in the pancreas of GPR39(-/-) mice. Taken together, our data indicate that GPR39 is required for the increased insulin secretion in vivo under conditions of increased demand, i.e. on development of age-dependent and diet-induced insulin resistance. Thus, GPR39 agonists may have potential for the treatment of type 2 diabetes.

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