Acute administration of glucagon-like peptide 1 (GLP-1) and its agonists slows gastric emptying, which represents the major mechanism underlying their attenuation of postprandial glycemic excursions. However, this effect may diminish during prolonged use. We compared the effects of prolonged and intermittent stimulation of the GLP-1 receptor on gastric emptying and glycemia. Ten healthy men received intravenous saline (placebo) or GLP-1 (0.8 pmol/kg ⋅ min), as a continuous 24-h infusion (“prolonged”), two 4.5-h infusions separated by 20 h (“intermittent”), and a 4.5-h infusion (“acute”) in a randomized, double-blind, crossover fashion. Gastric emptying of a radiolabeled mashed potato meal was measured using scintigraphy. Acute GLP-1 markedly slowed gastric emptying. The magnitude of the slowing was attenuated with prolonged but maintained with intermittent infusions. GLP-1 potently diminished postprandial glycemia during acute and intermittent regimens. These observations suggest that short-acting GLP-1 agonists may be superior to long-acting agonists when aiming specifically to reduce postprandial glycemic excursions in the treatment of type 2 diabetes.

The molecular mechanisms underpinning susceptibility loci for type 2 diabetes (T2D) remain poorly understood. Coding variants in peptidylglycine α-amidating monooxygenase (PAM) are associated with both T2D risk and insulinogenic index. Here, we demonstrate that the T2D risk alleles impact negatively on overall PAM activity via defects in expression and catalytic function. PAM deficiency results in reduced insulin content and altered dynamics of insulin secretion in a human β-cell model and primary islets from cadaveric donors. Thus, our results demonstrate a role for PAM in β-cell function, and establish molecular mechanisms for T2D risk alleles at this locus.

OBJECTIVEGlucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have additive insulinotropic effects when coadministered in health. We aimed to determine whether GIP confers additional glucose lowering to that of GLP-1 in the critically ill.RESEARCH DESIGN AND METHODSTwenty mechanically ventilated critically ill patients without known diabetes were studied in a prospective, randomized, double-blind, crossover fashion on 2 consecutive days. Between T0 and T420 minutes, GLP-1 (1.2 pmol/kg · min−1) was infused intravenously with either GIP (2 pmol/kg · min−1) or 0.9% saline. Between T60 and T420 minutes, nutrient liquid was infused into the small intestine at 1.5 kcal/min.RESULTSAdding GIP did not alter blood glucose or insulin responses to small intestinal nutrient. GIP increased glucagon concentrations slightly before nutrient delivery (P = 0.03), but not thereafter.CONCLUSIONSThe addition of GIP to GLP-1 does not result in additional glucose-lowering or insulinotropic effects in critically ill patients with acute-onset hyperglycemia.

Dahl et al. 1 report the first evaluation of the effect of the oral glucagon-like peptide-1 (GLP-1) receptor agonist (RA), semaglutide, on gastric emptying in type 2 diabetes. We consider that their study is compromised by substantial methodological flaws and that interpretation of the outcomes is both incorrect and misleading.In brief, in a crossover design, Dahl et al. 1 studied 15 patients with well-controlled type 2 diabetes who received oral semaglutide, escalated to a dose of 14 mg over 12 weeks and 3 days, or placebo; the two treatment periods were separated by 5 to 9 weeks. Gastric emptying was assessed at 12 weeks and 3 days (i.e. at steady state