More than one-third of the worldwide population is overweight or obese and therefore at risk of developing type 2 diabetes mellitus. In order to mitigate this pandemic, safer and more potent therapeutics are urgently required. This necessitates the continued use of animal models to discover, validate and optimize novel therapeutics for their safe use in humans. In order to improve the transition from bench to bedside, researchers must not only carefully select the appropriate model but also draw the right conclusions. In this Review, we consolidate the key information on the currently available animal models of obesity and diabetes and highlight the advantages, limitations and important caveats of each of these models.

In the postprandial state, the liver takes up and stores glucose to minimize the fluctuation of glycemia. Elevated insulin concentrations, an increase in the load of glucose reaching the liver, and the oral/enteral/portal vein route of glucose delivery (compared with the peripheral intravenous route) are factors that increase the rate of net hepatic glucose uptake (NHGU). The entry of glucose into the portal vein stimulates a portal glucose signal that not only enhances NHGU but concomitantly reduces muscle glucose uptake to ensure appropriate partitioning of a glucose load. This coordinated regulation of glucose uptake is likely neurally mediated, at least in part, because it is not observed after total hepatic denervation. Moreover, there is evidence that both the sympathetic and the nitrergic innervation of the liver exert a tonic repression of NHGU that is relieved under feeding conditions. Further, the energy sensor 5'AMP-activated protein kinase appears to be involved in regulation of NHGU and glycogen storage. Consumption of a high-fat and high-fructose diet impairs NHGU and glycogen storage in association with a reduction in glucokinase protein and activity. An understanding of the impact of nutrients themselves and the route of nutrient delivery on liver carbohydrate metabolism is fundamental to the development of therapies for impaired postprandial glucoregulation.

To investigate the temporal response of the liver to insulin and portal glucose delivery, somatostatin was infused into four groups of 42-h-fasted, conscious dogs ( n ϭ 6/group), basal insulin and glucagon were replaced intraportally, and hyperglycemia was created via a peripheral glucose infusion for 90 min (period 1). This was followed by a 240-min experimental period (period 2) in which hyperglycemia was matched to period 1 and either no changes were made (CON), a fourfold rise in insulin was created (

Recent findings have shown an inverse association between circulating C15:0/C17:0 fatty acids with disease risk, therefore, their origin needs to be determined to understanding their role in these pathologies. Through combinations of both animal and human intervention studies, we comprehensively investigated all possible contributions of these fatty acids from the gut-microbiota, the diet, and novel endogenous biosynthesis. Investigations included an intestinal germ-free study and a C15:0/C17:0 diet dose response study. Endogenous production was assessed through: a stearic acid infusion, phytol supplementation, and a Hacl1 −/− mouse model. Two human dietary intervention studies were used to translate the results. Finally, a study comparing baseline C15:0/C17:0 with the prognosis of glucose intolerance. We found that circulating C15:0/C17:0 levels were not influenced by the gut-microbiota. The dose response study showed C15:0 had a linear response, however C17:0 was not directly correlated. The phytol supplementation only decreased C17:0. Stearic acid infusion only increased C17:0. Hacl1 −/− only decreased C17:0. The glucose intolerance study showed only C17:0

The impact of the novel basal insulin LY2605541 (LY) on hepatic and nonhepatic glucose uptake (non-HGU) was evaluated. Conscious dogs underwent euglycemic clamps with tracer and hepatic balance measurements. Clamp period infusions were peripheral venous regular insulin (0.1 nmol ⋅ kg−1 ⋅ h−1 [control], n = 6) or LY (bolus [nmol/kg], continuous [nmol ⋅ kg−1 ⋅ h−1]: 0.5, 0.5 [n = 6]; 0.375, 0.375 [n = 5]; 0.25, 0.25 [n = 4]), somatostatin, and glucose, as well as intraportal glucagon (basal). During the clamp, the dogs switched from net hepatic glucose output to uptake (rates reached 2.1 ± 1.2, 0.9 ± 2.1, 8.6 ± 2.3, and 6.0 ± 1.1 µmol ⋅ kg−1 ⋅ min−1 within 5 h in control, LY0.25, LY0.375, and LY0.5, respectively). Non-HGU in LY increased less than in control; the ratio of change from basal in non-HGU to change in net hepatic glucose balance, calculated when glucose infusion rates (GIRs) were ~20 µmol ⋅ kg-1 ⋅ min−1 in all groups, was higher in control (1.17 ± 0.38) versus LY0.25 (0.39 ± 0.33), LY0.375 (−0.01 ± 0.13), and LY0.5 (−0.09 ± 0.07). Likewise, the change from baseline in glucose Rd-to-Ra ratio was greatest in control (1.4 ± 0.3 vs. 0.6 ± 0.4, 0.5 ± 0.2, and 0.6 ± 0.2 in LY0.25, LY0.375, and LY0.5, respectively). In contrast to exogenously administered human insulin, LY demonstrated preferential hepatic effects, similar to endogenously secreted insulin. Therefore, the analog might reduce complications associated with current insulin therapy.