Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin

Ralph A DeFronzo, Curtis Triplitt, Yongming Qu, Michelle S Lewis, David Maggs, Leonard C Glass, Ralph A DeFronzo, Curtis Triplitt, Yongming Qu, Michelle S Lewis, David Maggs, Leonard C Glass

Abstract

Objective: Study the effects of exenatide (EXE) plus rosiglitazone (ROSI) on beta-cell function and insulin sensitivity using hyperglycemic and euglycemic insulin clamp techniques in participants with type 2 diabetes on metformin.

Research design and methods: In this 20-week, randomized, open-label, multicenter study, participants (mean age, 56 +/- 10 years; weight, 93 +/- 16 kg; A1C, 7.8 +/- 0.7%) continued their metformin regimen and received either EXE 10 microg b.i.d. (n = 45), ROSI 4 mg b.i.d. (n = 45), or EXE 10 microg b.i.d. + ROSI 4 mg b.i.d. (n = 47). Seventy-three participants underwent clamp procedures to quantitate insulin secretion and insulin sensitivity. RESULTS A1C declined in all groups (P < 0.05), but decreased most with EXE+ROSI (EXE+ROSI, -1.3 +/- 0.1%; ROSI, -1.0 +/- 0.1%, EXE, -0.9 +/- 0.1%; EXE+ROSI vs. EXE or ROSI, P < 0.05). ROSI resulted in weight gain, while EXE and EXE+ROSI resulted in weight loss (EXE, -2.8 +/- 0.5 kg; EXE+ROSI, -1.2 +/- 0.5 kg; ROSI, + 1.5 +/- 0.5 kg; P < 0.05 between and within all groups). At week 20, 1st and 2nd phase insulin secretion was significantly higher in EXE and EXE+ROSI versus ROSI (both P < 0.05). Insulin sensitivity (M value) was significantly higher in EXE+ROSI versus EXE (P = 0.014).

Conclusions: Therapy with EXE+ROSI offset the weight gain observed with ROSI and elicited an additive effect on glycemic control with significant improvements in beta-cell function and insulin sensitivity.

Trial registration: ClinicalTrials.gov NCT00135330.

Figures

Figure 1
Figure 1
Glucose and insulin concentrations during the meal challenge test and insulin concentrations during the hyperglycemic clamp before (■, broken line) and after (○, solid line) treatment with EXE, EXE+ROSI, or ROSI. Arrows indicate time of arginine stimulation (ARG) during the hyperglycemic clamp. Data are presented as LS means ± SE for the meal challenge test and LS means for the hyperglycemic clamp.
Figure 2
Figure 2
Disposition index, M value, and M/I index before (□) and after (■) treatment with EXE, EXE+ROSI, and ROSI. *P < 0.05 when compared with baseline, †P < 0.05 between EXE+ROSI and ROSI at baseline. Data are LS means ± SE. BL, baseline; E, exenatide; E+R, exenatide plus rosiglitazone; EP, end point; I, steady-state plasma insulin concentration during the euglycemic clamp; M, insulin-stimulated glucose disposal during the euglycemic clamp; R, rosiglitazone.

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