Vedrana Stojanovic-Susulic

GLP-1 receptor activation inhibits VLDL production and reverses hepatic steatosis by decreasing hepatic lipogenesis in high-fat-fed APOE*3-Leiden mice.

Objective In addition to improve glucose intolerance, recent studies suggest that glucagon-like peptide-1 (GLP-1) receptor agonism also decreases triglyceride (TG) levels. The aim of this study was to evaluate the effect of GLP-1 receptor agonism on very-low-density lipoprotein (VLDL)-TG production and liver TG metabolism. Experimental Approach The GLP-1 peptide analogues CNTO3649 and exendin-4 were continuously administered subcutaneously to high fat diet-fed APOE*3-Leiden transgenic mice. After 4 weeks, hepatic VLDL production, lipid content, and expression profiles of selected genes involved in lipid metabolism were determined. Results CNTO3649 and exendin-4 reduced fasting plasma glucose (up to −30% and −28% respectively) and insulin (−43% and −65% respectively). In addition, these agents reduced VLDL-TG production (−36% and −54% respectively) and VLDL-apoB production (−36% and −43% respectively), indicating reduced production of VLDL particles rather than reduced lipidation of apoB. Moreover, they markedly decreased hepatic content of TG (−39% and −55% respectively), cholesterol (−30% and −55% respectively), and phospholipids (−23% and −36% respectively), accompanied by down-regulation of expression of genes involved in hepatic lipogenesis (Srebp-1c, Fasn, Dgat1) and apoB synthesis (Apob). Conclusion GLP-1 receptor agonism reduces VLDL production and hepatic steatosis in addition to an improvement of glycemic control. These data suggest that GLP-receptor agonists could reduce hepatic steatosis and ameliorate dyslipidemia in patients with type 2 diabetes mellitus.

Protein Engineering Strategies for Sustained Glucagon-Like Peptide-1 Receptor–Dependent Control of Glucose Homeostasis

OBJECTIVE—We have developed a novel platform for display and delivery of bioactive peptides that links the biological properties of the peptide to the pharmacokinetic properties of an antibody. Peptides engineered in the MIMETIBODY platform have improved biochemical and biophysical properties that are quite distinct from those of Fc-fusion proteins. CNTO736 is a glucagon-like peptide 1 (GLP-1) receptor agonist engineered in our MIMETIBODY platform. It retains many activities of native GLP-1 yet has a significantly enhanced pharmacokinetic profile. Our goal was to develop a long-acting GLP-1 receptor agonist with sustained efficacy. RESEARCH DESIGN AND METHODS—In vitro and in vivo activity of CNTO736 was evaluated using a variety of rodent cell lines and diabetic animal models. RESULTS—Acute pharmacodynamic studies in diabetic rodents demonstrate that CNTO736 reduces fasting and postprandial glucose, decreases gastric emptying, and inhibits food intake in a GLP-1 receptor–specific manner. Reduction of food intake following CNTO736 dosing is coincident with detection of the molecule in the circumventricular organs of the brain and activation of c-fos in regions protected by the blood-brain barrier. Diabetic rodents dosed chronically with CNTO736 have lower fasting and postprandial glucose and reduced body weight. CONCLUSIONS—Taken together, our data demonstrate that CNTO736 produces a spectrum of GLP-1 receptor–dependent actions while exhibiting significantly improved pharmacokinetics relative to the native GLP-1 peptide.

CNTO736, a Novel Glucagon-Like Peptide-1 Receptor Agonist, Ameliorates Insulin Resistance and Inhibits Very Low-Density Lipoprotein Production in High-Fat-Fed Mice

CNTO736 is a glucagon-like peptide (GLP) 1 receptor agonist that incorporates a GLP-1 peptide analog linked to the Mimetibody platform. We evaluate the potential of acute and chronic CNTO736 treatment on insulin sensitivity and very low-density lipoprotein (VLDL) metabolism. For acute studies, diet-induced insulin-resistant C57BL/6 mice received a single intraperitoneal injection of CNTO736 or vehicle. Chronic effects were studied after 4 weeks of daily intraperitoneal administration. A hyperinsulinemic-euglycemic clamp monitored insulin sensitivity. A single dose of CNTO736 reduced fasting plasma glucose levels (CNTO736, 4.4 ± 1.0; control, 6.3 ± 2.4 mM) and endogenous glucose production (EGP) (CNTO736, 39 ± 11; control, 53 ± 13 μmol/min/kg) and increased insulin-mediated glucose uptake (CNTO736, 76 ± 25; control, 54 ± 13 μmol/min/kg). Chronic administration of CNTO736 reduced fasting glucose levels (CNTO736, 4.1 ± 0.8; control 6.0 ± 1.0 mM), improved insulin-dependent glucose uptake (CNTO736, 84 ± 19; control, 61 ± 15 μmol/min/kg), and enhanced inhibition of EGP (CNTO736, 91 ± 18; control, 80 ± 10% inhibition). In addition, chronic dosing with CNTO736 reduced fasting EGP (CNTO736, 39 ± 9; control, 50 ± 8 μmol/min/kg) and VLDL production (CNTO736, 157 ± 23; control, 216 ± 36 μmol/h/kg). These results indicate that CNTO736 reinforces insulins action on glucose disposal and production in diet-induced insulin-resistant mice. In addition, CNTO736 reduces basal hepatic glucose and VLDL output in these animals. The data suggest that CNTO736 may be a useful tool in the treatment of type 2 diabetes.