Study investigates preservation or improvement of B-cell function using metformin in youth with type 2 diabetes, with or without short-term insulin.
Type 2 diabetes in youth is continuously increasing. It is primarily caused by the B-cell dysfunction. The RISE trial investigated whether treatment with metformin in youth, using metformin alone or insulin followed by metformin, would preserve or improve B-cell function. In the TODAY study, it was found that glycemic management is worse and there are more treatment failures when B-cell function is low or impaired from baseline . Metformin and insulin each alone have been found to improve the function of B-cells and to improve glucose tolerance in type 2 diabetes. The RISE trial was done to test whether a short-term treatment of insulin for 3 months followed by 9 months of metformin would improve B-cell function of youth with type 2 diabetes.
The study participants were youth ages 10 -19 years with a BMI < 50 kg/m2 but in the 85th percentile or higher for their age and gender. The participants had impaired glucose tolerance or were recently diagnosed with type 2 diabetes. The insulin provided was glargine and it was titrated twice a week to achieve a glucose of 4.4 to 5 mmol/L. Glucose was self-monitored and then followed up with metformin treatment. The metformin treatment was titrated to reach 1000 mg twice daily. Participants who were already taking metformin discontinued metformin and then randomized to take insulin glargine. The metformin group of participants took metformin twice daily for 12 months. Each group of participants took their medication regimen for 12 months and then were followed for 3 months while off the medications. HbA1c, safety, and body dimensions were evaluated every 3 months. Oral glucose tests and hyperglycemic clamps were repeated at 12 months and 15 months. Adherence, adverse effects, hyper- and hypoglycemia were assessed at each study visit. Participants were withdrawn from the study and treated with additional treatment if their HbA1c exceeded the safety thresholds.
The hyperglycemic clamp was done to assess three beta cell measures, including steady state, acute C-peptide response to arginine at maximum glycemic potentiation, and acute C-peptide response to glucose. C-peptide levels were not found to be different between the two treatment groups when evaluated at baseline, 12 months, and 15 months. Beta cell function decreased and worsened over the course of treatment. HbA1c did not differ between either group at any point in time. However, the HbA1c did decrease significantly at 3 months in the insulin/metformin group and in both groups at 6 months. At 9 and 12 months, both groups went back to their baseline HbA1c measures while still taking metformin. No significant changes in post-prandial and fasting glucose were found in the metformin only group. In the glargine and metformin group, post-prandial levels were significantly lower than baseline at 12 months (p<0.02), but by 15 months, they rebound to baseline values.
In conclusion, B-cell function in patients who have type 2 diabetes, youth and adults, will continue to decline, regardless of insulin and metformin treatment. Because B-cell dysfunction is the main reason for the pathogenesis of type 2 diabetes, another solution to this problem should be investigated.
- B-cell dysfunction is the primary route of pathogenesis of type 2 diabetes.
- Both metformin and insulin have shown to improve B-cell function on their own.
- Metformin and insulin together do not prevent the progression of B-cell dysfunction.
“Impact of Insulin and Metformin Versus Metformin Alone on β-Cell Function in Youth With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes.” Diabetes Care, 2018, p. dc180787., doi:10.2337/dc18-0787.
TODAY Study Group. Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and b-cell function in TODAY. Diabetes Care 2013;36:1749–1757
See more information on the RISE study and metformin in youth here.