IL-1RA, Acute Exercise, and Beta-cell Function (ANEX)

Subjects (N=48) with poorly-controlled type 2 diabetes (HbA1c>7%) will be assigned to one of the 4 following interventions in a randomised, parallel group design: [I] Control (placebo injection; no exercise), [II] Anakinra (100 mg subcutaneous injection of human recombinant interleukin-1 receptor antagonist), [III] Exercise (1 h cycle ergometry at 75% VO2max), [IV] Anakinra + Exercise. Pancreatic beta-cell function (plasma insulin responses) will be measured before and after each intervention using a hyperglycemic clamp (5.4 mM above basal glucose) combined with GLP-1 infusion (0.5 pmol/kg/min) and arginine injection (5 g bolus).

Placebo will be administered as a subcutaneous injectable bolus, the day prior to the repeated measurement of beta-cell function.

100 mg of Kineret (Anakinra) will be administered as a subcutaneous injectable bolus, the day prior to the repeated measurement of beta-cell function.

1 hour of cycling exercise will be performed at 75% VO2max, the day prior to the repeated measurement of beta-cell function.

100 mg of Kineret (Anakinra) will be administered as a subcutaneous injectable bolus followed by 1 hour of cycling exercise at 75% VO2max, the day prior to the repeated measurement of beta-cell function.

A hyperglycemic clamp will be performed combined with glucagon-like peptide(GLP)-1 infusion and arginine injection. The primary outcome is the insulin secretory response to glucose, GLP-1, and arginine.

Inclusion Criteria: Type 2 diabetes with HbA1c >7% Exclusion Criteria: HbA1c >7% Age <30 or >80 y BMI <25 or >40 kg/m2 Pregnancy Evidence of chronic haematological/renal/hepatic/pulmonary/heart disease >2kg weight change in prior 6 months Alcohol consumption (men: >14 drinks/week; women: >7 drinks/week) Smoking Physical activity of >150 min/week Contraindication to exercise Contraindication to use of anakinra