Glucose-dependent insulinotropic polypeptide promotes lipid deposition in subcutaneous adipocytes in obese type 2 diabetes patients: a maladaptive response

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) beyond its insulinotropic effects may regulate postprandial lipid metabolism. Whereas the insulinotropic action of GIP is known to be impaired in type 2 diabetes mellitus (T2DM), its adipogenic effect is unknown. We hypothesized that GIP is anabolic in human subcutaneous adipose tissue (SAT) promoting triacylglycerol (TAG) deposition through reesterification of nonesterified fatty acids (NEFA), and this effect may differ according to obesity status or glucose tolerance. Twenty-three subjects categorized into four groups, normoglycemic lean ( = 6), normoglycemic obese ( = 6), obese with impaired glucose regulation (IGR; = 6), and obese T2DM ( = 5), participated in a double-blind, randomized, crossover study involving a hyperglycemic clamp with a 240-min GIP infusion (2 pmol·kg·min) or normal saline. Insulin, NEFA, SAT-TAG content, and gene expression of key lipogenic enzymes were determined before and immediately after GIP/saline infusions. GIP lowered NEFA concentrations in the obese T2DM group despite diminished insulinotropic activity (mean NEFA AUC ± SE, 41,992 ± 9,843 µmol·l·min vs. 71,468 ± 13,605 with placebo, = 0.039, 95% CI: 0.31-0.95). Additionally, GIP increased SAT-TAG in obese T2DM (1.78 ± 0.4 vs 0.86 ± 0.1-fold with placebo, = 0.043, 95% CI: 0.1-1.8). Such effect with GIP was not observed in other three groups despite greater insulinotropic activity. Reduction in NEFA concentration with GIP correlated with adipose tissue insulin resistance for all subjects (Pearson, = 0.56, = 0.005). There were no significant gene expression changes in key SAT lipid metabolism enzymes. In conclusion, GIP appears to promote fat accretion and thus may exacerbate obesity and insulin resistance in T2DM.

GIP(3-30)NH2 is an efficacious GIP receptor antagonist in humans: a randomised, double-blinded, placebo-controlled, crossover study

“…This confirmed that GIP(1-42) increases adipose tissue blood flow and triacylglycerol deposition via the GIP receptor and demonstrated that GIP(3-30)NH 2 can inhibit these processes. Under the present study conditions, infusion of GIP(3-30)NH 2 was not associated with any changes in peripheral plasma lipid concentrations consistent with the lack of acute effects of GIP on these variables, as previously reported [49]. Importantly, the antagonist did not elicit any side effects or discomfort.…”

Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/FFAR3 pathway

“…Since GIP has been shown to exert pro-adipogenic action in adipose tissues (Miyawaki et al 2002, Thondam et al 2017, excessive secretion of GIP is undesirable in diabetes patients with obesity (Reimann & Gribble 2016). As α-GIs suppress an adipogenic hormone, GIP, but potentiate an anorexigenic hormone, GLP-1, the treatment of diabetes mellitus with α-GIs might be beneficial for obese diabetic patients to prevent further increase in their body weight.…”

Diabetes and dyslipidemia: characterizing lipoprotein metabolism

“…Reduction in NEFA concentration with GIP correlated with a reduction in adipose tissue insulin resistance. 50 …”