Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus

Abstract

Glucagon-Like Peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7–36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1 mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.

Gliptin and GLP‐1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide‐induced endotoxemia

“…Most interestingly, Chang et al [6] found that exendin-4 decreases iNOS expression in Raw264.7 macrophages. Of note, there is recent evidence indicating that in obesity and T2DM the cardio-metabolic effects of GLP-1 are attenuated, via impaired p38-MAPK signaling [31].…”

Cardiovascular effects of Glucagon-like peptide 1 (GLP-1) receptor agonists

“…Studies in dogs demonstrated an increased myocardial glucose uptake during a hyperinsulinemic-euglycemic clamp [46]. …”

Glucagon-like peptide-1 (7–36) but not (9–36) augments cardiac output during myocardial ischemia via a Frank–Starling mechanism

“…Administration of GLP-1 (7–36) results in proportional increases in circulating GLP-1 (9–36) levels [21;40]. Data on cardiovascular effects of these peptides are mixed: Infusion of the (7–36) or (9–36) peptide have produced increased [3;31], decreased [24;26;36;41], or no change [19;28;35] in cardiac contractile function in normal hearts in rats, dogs and pigs. Effects of GLP-1 (7–36) or (9–36) to augment preload-dependent indices of cardiac function in ischemic and failing hearts [2;27–29;41] have been more clearly demonstrated, although again this effect is not consistently observed [30;38].…”