Mechanisms of Action of Liraglutide in Patients With Type 2 Diabetes Treated With High-Dose Insulin.

CONTEXT

The mechanisms of action of incretin mimetics in patients with long-standing type 2 diabetes (T2D) and high insulin requirements have not been studied.

OBJECTIVE

To evaluate changes in β-cell function, glucagon secretion, and fat distribution after addition of liraglutide to high-dose insulin.

DESIGN

A single-center, randomized, double-blind, placebo-controlled trial.

SETTING

University of Texas Southwestern and Parkland Memorial Hospital clinics.

PATIENTS

Seventy-one patients with long-standing (median, 17 years) T2D requiring high-dose insulin treatment (>1.5 U/kg/d; average, 2.2 ± 0.9 U/kg/d).

INTERVENTION

Patients were randomized to liraglutide 1.8 mg/d or matching placebo for 6 months.

MAIN OUTCOME MEASURES

We measured changes in insulin and glucagon secretion using a 4-hour mixed-meal challenge test. Magnetic resonance-based techniques were used to estimate sc and visceral fat in the abdomen and ectopic fat in the liver and pancreas.

RESULTS

Glycosylated hemoglobin improved significantly with liraglutide treatment, with an end-of-trial estimated treatment difference between groups of −0.9% (95% confidence interval, −1.5, −0.4%) (P = .002). Insulin secretion improved in the liraglutide group vs placebo, as measured by the area under the curve of C-peptide (P = .002) and the area under the curves ratio of C-peptide to glucose (P = .003). Insulin sensitivity (Matsuda index) and glucagon secretion did not change significantly between groups. Liver fat and sc fat decreased in the liraglutide group vs placebo (P = .0006 and P = .01, respectively), whereas neither visceral nor pancreatic fat changed significantly.

CONCLUSIONS

Treatment with liraglutide significantly improved insulin secretion, even in patients with long-standing T2D requiring high-dose insulin treatment. Liraglutide also decreased liver and sc fat, but it did not alter glucagon secretion.