Dose-response effects of insulin glargine in type 2 diabetes

Zhihui Wang, Maka S Hedrington, Nino Gogitidze Joy, Vanessa J Briscoe, M Antoinette Richardson, Lisa Younk, Wendell Nicholson, Donna B Tate, Stephen N Davis, Zhihui Wang, Maka S Hedrington, Nino Gogitidze Joy, Vanessa J Briscoe, M Antoinette Richardson, Lisa Younk, Wendell Nicholson, Donna B Tate, Stephen N Davis

Abstract

Objective: To determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes.

Research design and methods: Twenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 +/- 3 years, with BMI 36 +/- 2 kg/m(2) and A1C 8.3 +/- 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique. RESULTS Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and beta-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 mumol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal.

Conclusion: A single subcutaneous injection of glargine at a dose of >or=0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00574912.

Figures

Figure 1
Figure 1
Effects of single injections of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) on plasma glucose. Insulin and C-peptide levels in overnight fasted type 2 diabetic individuals. Plasma glucose levels at 24 h are significantly increased (P < 0.05) in the placebo and 0.5 units/kg dose groups. Plasma insulin levels are significantly increased (P < 0.05) compared with that for placebo after all doses of glargine; 1.0, 1.5, and 2.0 units/kg doses of glargine are increased (P < 0.05) compared with the 0.5 units/kg dose. Plasma C-peptide levels are significantly decreased (P < 0.05) compared with that for placebo. Incremental AUC values after 1.0, 1.5, and 2.0 units/kg doses are also significantly lower (P < 0.05) than after the 0.5 units/kg dose.
Figure 2
Figure 2
Effects of single injections of insulin glargine (0.0.5, 1.0, 1.5, and 2.0 units/kg) on endogenous glucose production, glucose rate of disappearance, and glucose infusion rates in overnight fasted type 2 diabetic individuals. Rates of endogenous glucose production are significantly suppressed by a greater amount (P < 0.05) after 1.0, 1.5, and 2.0 units/kg compared with that for placebo. Rates of glucose disposal are similar after placebo and all doses of glargine. Glucose infusion rates are significantly increased (P < 0.05) after all doses of glargine compared with that for placebo. Incremental AUC values for 1.0, 1.5, and 2.0 units/kg doses were also significantly increased compared with that for 0.5 units/kg dose.

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