Exercise plus liraglutide improves glucose tolerance, glucagon response, beta cell function

Liraglutide therapy combined with aerobic exercise results in better glucose tolerance, beta cell function, and glucagon responses after losing weight, a study has shown.

“[I]n adults with obesity without diabetes, who initially lost at least 5 percent of body weight, only the combination of an aerobic exercise program and liraglutide improved postprandial glucose and glucagon responses and beta cell function compared with placebo,” the researchers said.

“Thus, the combination treatment after weight loss seems more beneficial to glucose regulation than either treatment alone and the combination of exercise and glucagon-like peptide-1 receptor agonist (GLP-1 RA) may therefore offer additional risk reduction,” they added.

This randomized placebo-controlled trial included 195 adults with obesity (body mass index, 32‒43 kg/m²) without diabetes who underwent an 8-week low-calorie diet (800 kcal/d). Participants were randomly assigned to 52 weeks of aerobic exercise, liraglutide 3.0 mg/d, exercise and liraglutide combined, or placebo.

The researchers then assessed the changes in glucose and glucagon response to a 3-hour mixed meal test and disposition index, as a measure of beta cell function.

After 1 year, participants in the combination group showed reduced postprandial glucose response (‒9 percent, 95 percent confidence interval [CI], ‒14 to ‒3; p=0.002), improved beta cell function (49 percent, 95 percent CI, 16‒93; p=0.001), and lower glucagon response (‒18 percent, 95 percent CI, ‒34 to ‒3; p=0.024) compared with those in the placebo group. [Obesity 2023;31:977-989]

Liraglutide alone also led to improvements in postprandial glucose response (‒7 percent, 95 percent CI, ‒12 to ‒1; p=0.018), but neither in beta cell function nor glucagon, when compared to placebo. Exercise alone, on the other hand, resulted in similar postprandial glucose response, beta cell function, and glucagon response as placebo.

Clinical implications

Improvements in the combination group may have clinical implications for the prevention of type 2 diabetes (T2D) in adults with obesity, according to the researchers.

“First, elevated fasting and postprandial glucose strongly predict T2D. Second, insulin resistance and progressive beta cell dysfunction are key etiological factors in T2D that seem to be potentiated by obesity,” they said. [Lancet Diabetes Endocrinol 2016;4:27-34; JAMA 2001;285:2109-2113; JAMA 2001;285:2109-2113]

“Finally, glucagon plays an essential role in the pathogenesis of T2D, where hyperglucagonemia contributes to elevated glucose levels due to increased hepatic glucose production,” the researchers added. [Curr Diab Rep 2014;14:555]

Notably, the addition of exercise to liraglutide resulted in decreased postprandial insulin response relative to placebo. An earlier study reported a reduced insulin response to meal intake after exercise interventions. [Br J Sports Med 2019;53:1183-1192]

“Reasons for this may be that the combination group maintained the improved insulin sensitivity induced by the low-calorie diet together with increased insulin clearance. The disposition index was calculated to assess changes in beta cell function, whereby insulin secretion is adjusted for changes in insulin sensitivity,” the researchers said.

“This is essential because insulin secretion normally adapts to changes in insulin sensitivity. Only the combination treatment significantly improved this measure of beta cell function compared with placebo and by an improvement of 49 percent,” they added.