Metformin reverses metabolic memory in a diabetes model

Patients with diabetes struggle to maintain a normal balance of glucose levels. Complications emerge when there is an excess of blood glucose or when insulin is not responsive to elevated blood glucose levels. While improved diet and increased physical activity have been proved to mitigate disease onset and symptoms in those already diagnosed with the disease, the effects of prolonged periods of mismanaged glycemic control can be more challenging to reverse at a cellular level in the kidneys and liver.

"Metabolic memory" refers to the notion that glucose-sensing cells function as though glucose levels are high even when they are not. Recent evidence from the Diabetes Complications and Control Trial suggested that even after normal glycemic levels are maintained, the liver and kidney cells remain in a sensitized state because of the metabolic memory of glucose-sensing cells. In this JBC paper, Kulbhushan Tikoo and colleagues at the National Institute of Pharmaceutical Education and Research S.A.S. Nagar in India investigated the effects of metformin, a drug used to treat type 2 diabetes, on metabolic memory in conjunction with diet reversal in a rat model for diabetes.

The researchers fed rats a normal or high-fat diet for 16 weeks. The high-fat diet simulated prolonged hyperglycemia. The rats on the high-fat diet were then divided into three groups with different diets: a prolonged high-fat diet, a normal diet to simulate diet reversal and a normal diet with metformin treatment. They were kept on their diets for eight weeks. Tikoo and colleagues then measured body weight of the rats as well as their biomarkers such as glucose levels, lipid profile and kidney function at the eight- and 16-week time points and at the end of the study at 24 weeks.

The authors concluded that the 16-week high-fat diet rendered the rats insulin resistant, a hallmark of type 2 diabetes. After the 16-week high-fat diet, the animals undergoing diet reversal had indications of metabolic memory. However, the rats undergoing diet reversal with metformin treatment had improved outcomes compared to the animals on diet reversal alone. This suggests that metformin treatment can mitigate the negative effects of metabolic memory associated with diabetes.