Impact of Metformin on Glucose Metabolism in Nondiabetic, Obese African Americans

A placebo-controlled, 24-month randomized study

Pharmacological therapy using antidiabetic drugs can delay the onset of type 2 diabetes in individuals with impaired glucose tolerance (IGT) (1–3). These drugs lower blood glucose, but each drug class impacts glucose dysregulation by a different mechanism (4). It is unclear whether simply lowering mean blood glucose can reduce the risk of type 2 diabetes or whether it is the drug effect on particular targets of glucose dysregulation or other unknown drug effects that allow for the decreased incidence of type 2 diabetes in IGT.

Metformin decreases the incidence of type 2 diabetes in IGT (3). But whether metformin treatment earlier in the disease process might further delay progression to IGT/type 2 diabetes is unknown. We performed a double-blind placebo-controlled study of metformin in first-degree relatives of African Americans with type 2 diabetes for 24 months. The aim of the present study is to examine the effect of metformin on glucose metabolism in normal glucose tolerant (NGT) African Americans at risk for type 2 diabetes.

The study included 126 NGT African Americans. The MET group (n = 45) received 500 mg/day metformin and the PLA group (n = 81) received placebo for 24 months. Yearly oral glucose tolerance tests and frequently sampled intravenous glucose tolerance tests were performed.

Baseline clinical characteristics were similar between groups. There were no sex differences. The MET group demonstrated a reduction in weight (−1.4 ± 1 kg) and BMI (−0.53 ± 0.4 kg/m²). Weight (1.4 ± 0.8 kg, P < 0.02) and BMI (0.5 ± 0.34 kg/m², P < 0.01) increased in PLA. Following metformin therapy, acute first- and second-phase glucose, insulin, and C-peptide area under the curve did not change. However, hepatic insulin extraction (HIE) was increased 21% in the MET group vs. 5% in the PLA group.

As increased hepatic glucose production and decreased HIE is commonly seen as a component of glucose dysregulation in type 2 diabetes and other high-risk populations (5–7), improvement in HIE could potentially lead to overall improvement in glucose metabolism. In this study, the MET group was associated with modest weight reduction and enhanced HIE. The reason for the improved HIE is unclear but may reflect a mechanistic change at the level of the liver in response to metformin. Our findings of increased HIE could partly be responsible for the hepatic effect on glucose regulation previously reported (4). This finding is of great interest, demonstrating a “resetting” of the hepatic response to insulin resistance and a return to a more physiologic glucoregulation with even small doses of metformin in nondiabetic at-risk individuals.

Although other glucose-lowering drugs have been found to both improve (8) and worsen (9) HIE, to the best of our knowledge, the current findings represent a unique response not previously reported with metformin usage in an NGT population. Whether this restoration of HIE translates to a reduced occurrence of IGT/type 2 diabetes in our at-risk African-American population is not known. The drug was well tolerated for the 2-year duration without significant adverse events. Further studies are needed to determine the optimal dose of metformin for maximum benefit on early abnormalities in glucose dysregulation while minimizing side effects. Based on our current data, the treatment of at-risk African Americans with metformin is safe and may be beneficial in preventing conversion to IGT/type 2 diabetes.