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GPR120 (Ffar4) has been postulated to represent an important receptor mediating the improved metabolic profile seen upon ingestion of a diet enriched in polyunsaturated fatty acids (PUFAs). GPR120 is highly expressed in the digestive system, adipose tissue, lung and macrophages and also present in the endocrine pancreas. A new Gpr120 deficient mouse model on pure C57bl/6N background was developed to investigate the importance of the receptor for long-term feeding with a diet enriched with fish oil. Male Gpr120 deficient mice were fed two different high fat diets (HFDs) for 18 weeks. The diets contained lipids that were mainly saturated (SAT) or mainly n-3 polyunsaturated fatty acids (PUFA). Body composition, as well as glucose, lipid and energy metabolism, was studied. As expected, wild type mice fed the PUFA HFD gained less body weight and had lower body fat mass, hepatic lipid levels, plasma cholesterol and insulin levels and better glucose tolerance as compared to those fed the SAT HFD. Gpr120 deficient mice showed a similar improvement on the PUFA HFD as was observed for wild type mice. If anything, the Gpr120 deficient mice responded better to the PUFA HFD as compared to wild type mice with respect to liver fat content, plasma glucose levels and islet morphology. Gpr120 deficient animals were found to have similar energy, glucose and lipid metabolism when fed HFD PUFA compared to wild type mice. Therefore, GPR120 appears to be dispensable for the improved metabolic profile associated with intake of a diet enriched in n-3 PUFA fatty acids. [ABSTRACT FROM AUTHOR]

Glucokinase (GK) plays a key role in maintaining glucose homeostasis by stimulating insulin secretion from pancreatic β-cells and increasing hepatic glucose uptake. In this study we have investigated the effects of a novel, orally active glucokinase activator (GKA71) on insulin secretion and glucose tolerance in mice with high-fat diet (HFD) induced glucose intolerance. Mice were fed the HFD (58% fat by energy) for 8 weeks prior to administration of GKA71, which was provided in the diet (150 mg GKA71/kg food) giving a daily dose of ∼300 µg GKA71/mouse. Control mice were fed HFD or a normal diet (ND, 11% fat by energy). After 1 and 4 weeks with GKA71, glucose tolerance was studied in intravenous glucose tolerance test (IVGTT). Blood samples were taken just before and 1, 5, 10, 20, 50 and 75 min after the glucose injection (0.75g/kg). After 4-weeks treatment islets and liver were isolated. The GKA treatment significantly reduced basal plasma glucose level (5.3±0.3 vs. 8.3±0.3 mM in HFD, P<0.001, and 7.4±0.3 mM in ND, P<0.001). Basal insulin levels were also reduced by GKA71 (210±20 vs. 520±100 pM in HFD, P<0.01). The IVGTTs showed that GKA71 significantly improved glucose tolerance compared to HFD control mice (K[sub G] 4.0±0.5 vs. 2.5±0.2 %/min in HFD, P<0.01) being similar to ND fed mice (K[sub G] 3.8±0.2 %/min), although without increasing insulin secretion (AIR 485±120 vs. 670±85 pM in HFD, P>0.05). The AIR was 890±74 pM in the ND fed mice. There was no difference between the IVGTT results after 1 or 4 weeks with GKA71, suggesting full effect already after l-weeks treatment. Isolated islets from GKA treated mice demonstrated augmented glucose stimulated insulin secretion. Liver glycogen and triglyceride levels were similar in HFD control and HFD-GKA mice. In conclusion, activation of GK in HFD-fed mice potently reduces glycemia and normalizes glucose tolerance, demonstrating GKA as a potential therapeutic agent for treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]