Metformin Improves Peripheral Insulin Sensitivity in Youth With Type 1 Diabetes

Abstract

Context: Type 1 diabetes in adolescence is characterized by insulin deficiency and insulin resistance (IR), both thought to increase cardiovascular disease risk. We previously demonstrated that adolescents with type 1 diabetes have adipose, hepatic, and muscle IR, and that metformin lowers daily insulin dose, suggesting improved IR. However, whether metformin improves IR in muscle, hepatic, or adipose tissues in type 1 diabetes was unknown.

Objective: Measure peripheral, hepatic, and adipose insulin sensitivity before and after metformin or placebo therapy in youth with obesity with type 1 diabetes.

Design: Double-blind, placebo-controlled clinical trial.

Setting: Multi-center at eight sites of the T1D Exchange Clinic Network.

Participants: A subset of 12- to 19-year-olds with type 1 diabetes (inclusion criteria: body mass index ≥85th percentile, HbA1c 7.5% to 9.9%, insulin dosing ≥0.8 U/kg/d) from a larger trial (NCT02045290) were enrolled.

Intervention: Participants were randomized to 3 months of metformin (N = 19) or placebo (N = 18) and underwent a three-phase hyperinsulinemic euglycemic clamp with glucose and glycerol isotope tracers to assess tissue-specific IR before and after treatment.

Main outcome measures: Peripheral insulin sensitivity, endogenous glucose release, rate of lipolysis.

Results: Between-group differences in change in insulin sensitivity favored metformin regarding whole-body IR [change in glucose infusion rate 1.3 (0.1, 2.4) mg/kg/min, P = 0.03] and peripheral IR [change in metabolic clearance rate 0.923 (-0.002, 1.867) dL/kg/min, P = 0.05]. Metformin did not impact insulin suppression of endogenous glucose release (P = 0.12). Adipose IR was not assessable with traditional methods in this highly IR population.

Conclusions: Metformin appears to improve whole-body and peripheral IR in youth who are overweight/obese with type 1 diabetes.

Copyright © 2019 Endocrine Society.

Figures

Figure 1.

Consort diagram. Participant visit and call follow up after randomization is shown above.

Figure 2.

Glucose and insulin concentrations during each phase of the clamp. Glucose (A) and insulin (B) concentrations are shown. The placebo-treated groups are shown on the left, and the metformin treated-group is shown on the right, with pretreatment in gray and posttreatment in white. Data are shown from each phase of the clamp (basal, 16 mIU/m2/min, and 80 mIU/m2/min). Box plots are 25th to 75th percentile, with the group mean as the dark line and outliers shown as circles.

Figure 3.

Glucose-related measures during the clamp, before and after intervention. Rates of glucose Ra (A), glucose (B), and glucose nonoxidative disposal (NOD) (C) are shown. The placebo-treated groups are shown on the left, and the metformin-treated group is shown on the right, with pretreatment in gray and posttreatment in white. Data are shown from each phase of the clamp (basal, 16 mIU/m2/min, and 80 mIU/m2/min). Box plots are 25th to 75th percentile, with the group mean as the dark line and outliers shown as circles.

Figure 4.

Change in clamp measures of insulin sensitivity. The change in each measure of insulin sensitivity from baseline to 13 weeks for the placebo or metformin treatment group are shown above. GIR (A) and GIR per FFM (B) representing whole-body sensitivity were different between groups after treatment. Peripheral insulin sensitivity from the 80 mU/m2/min phase, represented as change in glucose Rd (C), was not different between groups, whereas glucose MCR (D), which controls for serum glucose, trended to be different. There was no difference in change in glucose Ra (E) during the 16 mU/m2/min phase, representing endogenous glucose production, nor glycerol Ra (F) during the 10 mU/m2/min phase, representing lipolysis. Data are means and standard errors of the means.

Figure 5.

Lipid-related measures during the clamp and before and after intervention. Serum glycerol concentrations (A), FFA concentrations (B), and glycerol Ra (C) are shown. The placebo-treated groups are shown on the left, and the metformin-treated group is shown on the right, with pretreatment in gray and posttreatment in white. Data are shown from each phase of the clamp (basal, 16 mIU/m2/min, and 80 mIU/m2/min). Box plots are 25th to 75th percentile, with the group mean as the dark line and outliers shown as circles.