Effect of Medical and Surgical Interventions on α-Cell Function in Dysglycemic Youth and Adults in the RISE Study

Abstract

Objective: To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols.

Research design and methods: Glucagon was measured in three randomized, parallel, clinical studies: 1) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; 2) 267 adults studied at the same time points and treated with MET, G/M, or liraglutide plus metformin (L+M) or given placebo (PLAC); and 3) 88 adults studied at baseline and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose, and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs).

Results: No change in fasting glucagon, steady-state glucagon, or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all P ≤ 0.005), which was maintained 3 months after treatment withdrawal (all P < 0.01). LB in adults also reduced fasting glucagon, steady-state glucagon, and AGR at 12 and 24 months (P < 0.05 for all, except AGR at 12 months [P = 0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss.

Conclusions: Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributable to weight loss in both interventions.

Trial registration: ClinicalTrials.gov NCT01779362 NCT01779375 NCT01763346.

Figure 1

Plasma glucagon concentrations during the hyperglycemic clamps in youth and adults in the three RISE protocols. Pediatric Medication Study: G/M (A) and MET (B) at baseline (red), after 12 months of intervention (blue), and after 3 months of intervention withdrawal (green). Adult Medication Study: G/M (C), MET (D), L+M (E), and PLAC (F) at baseline (red), after 12 months of intervention (blue), and after 3 months of intervention withdrawal (green). Adult Surgery Study: LB (G) and MET (H) at baseline (red) and after 12 months of intervention (blue) and 24 months of intervention (green). Data are displayed as means ± SEM.

Figure 2

Plasma glucagon concentrations during the OGTTs in youth and adults in the three RISE protocols. Pediatric Medication Study: G/M (A) and MET (B) at baseline (red), after 12 months of intervention (blue), and after 3 months of intervention withdrawal (green). Adult Medication Study: G/M (C), MET (D), L+M (E), and PLAC (F) at baseline (red), after 12 months of intervention (blue), and after 3 months of intervention withdrawal (green). Adult Surgery Study: lap band surgery (G) and MET (H) at baseline (red) and after 12 months of intervention (blue) and 24 months of intervention (green). Data are displayed as mean ± SEM.