ESPE Yearbook of Paediatric Endocrinology

Diabetes. 2022 1;71(6):1233-1245. doi: 10.2337/db21-0992. PMID: 35294000.

Brief Summary: This mouse model of diabetes tested the hypothesis that reducing the metabolic flux (rate of metabolism) in the beta cell can prevent beta-cell failure and preserve beta-cell mass. Reducing glucose metabolism may be a mechanism for preventing glucotoxicity-induced loss of functional beta-cell mass in diabetes.

Beta-cell exhaustion, loss of mass and function are thought to occur due to insulin hypersecretion in both type 1 and type 2 diabetes. However, beta-cell exhaustion, loss of mass and function also occur in a monogenic form of neonatal diabetes mellitus to gain of function mutations in the KATP channel where there is no insulin hypersecretion (1). To test the hypothesis that it is the beta-cell hyperglycemia induced metabolism that leads to beta-cell failure, the authors crossed KATP-GOF (Gain of function)–induced neonatal diabetic mice with beta-cell–specific GCK haplo-insufficient mice (GCK1/, Glucokinase 1)). GCK is a key enzyme which allows the entry of glucose into the beta-cells.

The beta-cell specific GCK haplo-insufficient mice (GCK1/) allows less glucose to enter the beta-cell and thus reduces the metabolic flux in the beta-cell. The double-mutant KATP-GOF/GCK1/ mice had slower progression of diabetes development and the rate of metabolism was reduced in the beta-cell. In addition, the insulin content of the beta-cells was preserved as was the beta-cell mass and identity. The double mutant mice also showed increased insulin sensitivity and restoration of body weight and liver and brown/white adipose tissue mass and function and normalization of physical activity and metabolic efficiency thus suggesting that the other tissues are also impacted by the reduction in the metabolic flux in the beta-cell. Therefore, a reduction in the beta-cell glucose metabolism seems to be protective for insulin preservation and beta-cell identity.

Thus, paradoxically, reducing glucose metabolism may be a mechanism to prevent glucotoxicity-induced loss of functional beta-cell mass in diabetes and to maintain adipose tissue and liver function. However, these observations need to be tested in human pancreatic beta-cells which have many differences to rodents.

Reference: 1. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–110.