The role of Glucose dependent Insulinotropic Polypeptide (GIP) and other gut hormones in glucose regulation and adipose tissue metabolism in obesity and type 2 diabetes

Aims and hypothesis: Beyond the insulinotropic effects, glucose-dependent insulinotropic polypeptide (GIP) may regulate post-prandial lipid metabolism by promoting fat deposition and inflammation in adipose tissue after high fat diets. We hypothesised that GIP would have an anabolic action in subcutaneous adipose tissue (SAT) promoting non-esterified fatty acid (NEFA) re-esterification. We speculated these effects may be mediated by changes to the expression of key lipid metabolism enzymes and that GIP may promote inflammation by affecting the expression of key adipokines in SAT. We postulated that these effects may be different according to obesity status or glucose tolerance. Incretins and other gut hormones are affected by medications used in the treatment of T2DM. We hypothesised that metformin, a commonly used drug in T2DM, may influence the secretion of incretin and other gut hormones which may contribute to its pleotropic effects in glucose metabolism. Subjects/Methods: We recruited 31 participants, for 2 different studies. In the first study, 23 men in four categories, normoglycaemic lean (n=6), normoglycaemic obese, (n=6), obese with impaired glucose regulation (IGR) (n=6) and obese, T2DM (n=5) participated in a double-blind, randomised, crossover study involving a hyperglycaemic clamp with a 4-hour infusion of GIP or placebo (normal saline). Serum insulin, plasma NEFA concentrations, SAT triacylglycerol (TAG) content and gene expression of key lipid metabolism enzymes, lipoprotein lipase (LPL), adipose tissue triglyceride lipase (ATGL) and hormone sensitive lipase (HSL) and adipokine gene expression (TNF-α, MCP-1, osteopontin and adiponectin) in SAT were determined before and after the GIP/placebo infusions. In the second study, eight subjects (6 male and 2 female) were studied on two occasions for 6 hours following a standard mixed meal, before and after metformin monotherapy for at least 3 months. Blood samples were taken in the fasted state and at multiple time points after the mixed meal for measuring incretin hormone, glucagon like peptide (GLP-1), ghrelin (appetite regulatory gut hormone) and dipeptidyl peptidase –IV (DPP-IV) activity. Results: Study-1 The insulinotropic effect of GIP vs. placebo was greater in lean, obese and obese IGR groups with no significant effect in obese T2DM. In contrast, GIP lowered NEFA concentrations in obese T2DM concomitantly increasing the SAT-TAG content. Such effects were not observed in other groups. There was no change in gene expression of LPL, ATGL and HSL with GIP or placebo infusions. The gene expression of TNF-α was significantly higher in obese T2DM group and the expression of MCP-1 was higher in lean and obese subjects. Study-2 Metformin monotherapy in obese patients with T2DM was associated with significantly increased postprandial active GLP-1 concentrations. Conclusion: In T2DM, although the insulinotropic effect of GIP is impaired, the ability of GIP to promote fat storage seems intact lowering NEFA concentrations and increasing SAT lipid deposition which may further exacerbate obesity and insulin resistance. Oral hypoglycaemic agent metformin influences the incretin system by increasing GLP-1 concentrations and this may represent another important mechanism of its glucose-lowering effect

Metformin and the gastrointestinal tract

Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognised as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a number of actions within the gut. It increases intestinal glucose uptake and lactate production, increases GLP-1 concentrations and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release preparation of metformin has recently been shown to improve glycaemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects associated with metformin intolerance

Unacylated ghrelin modulates circulating angiogenic cell number in insulin-resistant states

Abstract Background Type 2 diabetes (T2D) is associated with reduced numbers and impaired function of circulating angiogenic cells (CAC) which contributes to the progression of atherosclerosis and microvascular disease. Previous studies suggest that short-term infusion of unacylated ghrelin (UAG) normalizes CAC number in patients with T2D. To determine dose-dependent effects of short-term infusion of UAG in T2D patients using a cross-over model, and of long-term infusion of UAG in obese mice, on differentiation of monocyte progenitors into CAC. Methods Eight overweight T2D patients were infused overnight with 3 and 10 µg/kg/h of UAG in a double-blind, placebo-controlled cross-over study. To assess the effects of long-term UAG treatment, obese mice were infused with UAG for 4 weeks. Monocyte progenitors were assessed for their ability to differentiate into CAC in vitro. Results In T2D patients, UAG treatment caused a reduction in differentiation of CAC, dependent on UAG dose and differentiation method. However, mice treated with UAG showed a significant increase in differentiation of bone marrow progenitors into CAC. Conclusion UAG causes a minor suppressive effect on CAC development after short-term treatment in humans, but experiments in mice suggest that long-term treatment has beneficial effects on CAC formation. The Netherlands Trial Register: TC=248