Glucose‐dependent insulinotropic polypeptide induces lipolysis during stable basal insulin substitution and hyperglycaemia in men with type 1 diabetes: A randomized, double‐blind, placebo‐controlled, crossover clinical trial

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) plays an important role in the glucose and lipid metabolism. We investigated the effects of exogenous GIP on lipid metabolism during time of stable insulin levels. Ten male patients with type 1 diabetes without endogenous insulin secretion (C-peptide-negative, mean [±SD] age 26 ± 4years, body mass index 24 [±2] kg/m 2 , glycated haemoglobin 56 [±8] mmol/mol or 7.3 [±0.8]%) were studied in a randomized, double-blind, placebo-controlled, crossover study with continuous intravenous infusions of GIP (4 pmol/kg/min) or placebo (saline), during two separate 90-minute hyperglycaemic (12 mmol/L) clamps with basal insulin substitution (0.1-0.2 mU/kg/min). Plasma glycerol concentrations increased from baseline during GIP infusion and decreased during placebo infusion (baselinesubtracted area under the curve [bsAUC] 703 ± 407 vs. À262 ± 240 μmol/L Â min, respectively; P < 0.001). Free fatty acids (FFAs) increased during GIP infusions (bsAUC 5505 ± 2170 μEq/L Â min) and remained unchanged during placebo infusion (bsAUC À74 ± 2363 μEq/L Â min), resulting in a significant difference between GIP and placebo infusions (P < 0.001). Plasma concentrations of glucose, insulin, glucagon-like peptide-1 and glucagon were similar during GIP and placebo infusions. GIP increased plasma glycerol and FFAs in patients with type 1 diabetes during hyperglycaemia and stable basal insulin levels. This supports a direct lipolytic effect of GIP at high glucose and low levels of plasma insulin.

Glucose-Dependent Insulinotropic Polypeptide Plasma Level Influences the Effect of n-3 PUFA Supplementation

“…Other studies reported either lipolytic or lipogenic action of GIP, depending on the obesity status or glucose tolerance [ 2 , 3 , 4 , 26 , 27 ]. GIP infusion was found to induce lipolysis, shown as increased plasma NEFA and glycerol concentrations, during stable basal insulin substitution and hyperglycemia in men with type 1 diabetes [ 28 ]. The results are consistent with the NEFA changes observed in high GIP group after reducing plasma GIP level in our trial.…”

GIP und GLP-1-Rezeptoragonismus in der Therapie des Typ 2 Diabetes mit Fokus auf Tirzepatid

“…Es wird diskutiert, dass der GIP-Agonismus, indem er die Lipidpufferkapazität des wATs verbessert, die Fettansammlung in anderen Organen (ektope Lipidspeicherung) reduzieren kann [57,58]. Erst kürzlich wurde in Clamp-Versuchen gezeigt, dass GIP bei Patienten/Patientinnen mit Typ-1-Diabetes und bei niedrigen Insulinspiegeln Plasmaglyceride und freie Fettsäuren erhöht, was auf eine direkte lipolytische Wirkung von GIP bei hohen Glukosespiegeln und niedrigen Plasmainsulinspiegeln hinweist [69]. Zusätzlich wird daher angenommen, dass GIP eine wichtige Rolle bei der Adipositas spielt, auch wenn die biologische Wirkung von GIP noch nicht ausreichend verstanden ist.…”

Tirzepatide: A Novel, Once-weekly Dual GIP and GLP-1 Receptor Agonist for the Treatment of Type 2 Diabetes

“…36,37 GIP plays an important role in the regulation of food intake, lipoprotein lipase activity and fat decomposition during carbohydrate/fat degradation in adipose tissue; it produces a direct lipolytic effect during hyperglycaemia and low levels of insulin. 38 Elimination of GIPR activity by various mechanisms, including genetic ablation blockage, GIPR antagonist or neutralization of GIPR, has a favourable effect on glucose tolerance and obesity. [39][40][41][42] GIPR antagonists have been developed as treatments for T2D and obesity.…”

“… 36 , 37 GIP plays an important role in the regulation of food intake, lipoprotein lipase activity and fat decomposition during carbohydrate/fat degradation in adipose tissue; it produces a direct lipolytic effect during hyperglycaemia and low levels of insulin. 38 …”