Genetic Reduction of Glucose Metabolism Preserves Functional β-Cell Mass in KATP-Induced Neonatal Diabetes

Abstract

Beta-cell failure and loss of β-cell mass are key events in diabetes progression. Although insulin hypersecretion in early stages has been implicated in β-cell exhaustion/failure, loss of β-cell mass still occurs in KATP-gain-of-function (GOF) mouse models of human neonatal diabetes, in the absence of insulin secretion. Thus, we hypothesize that hyperglycemia-induced increased β-cell metabolism is responsible for β-cell failure, and that reducing glucose metabolism will prevent loss of β-cell mass. To test this, KATP-GOF mice were crossed with mice carrying β-cell specific glucokinase haploinsuficincy (GCK+/−), to genetically reduce glucose metabolism. As expected, both KATP-GOF and KATP-GOF/GCK+/− mice showed lack of glucose-stimulated insulin secretion. However, KATP-GOF/GCK+/− mice demonstrated markedly reduced blood glucose, delayed diabetes progression, and improved glucose tolerance compared to KATP-GOF mice. In addition, decreased plasma insulin and content, increased proinsulin and augmented plasma glucagon observed in KATP-GOF mice were normalized to control levels in KATP-GOF/GCK+/− mice. Strikingly, KATP-GOF/GCK+/− mice demonstrated preserved β-cell mass and identity, compared to the marked decrease in β-cell identity and increased dedifferentiation observed in KATP-GOF mice. Moreover KATP-GOF/GCK+/− mice demonstrated restoration of body-weight, and liver and brown/white adipose tissue mass and function, and normalization of physical activity and metabolic efficiency compared to KATP-GOF mice. These results demonstrate that decreasing β-cell glucose signaling can prevent glucotoxicity-induced loss of insulin content and β-cell failure independently of compensatory insulin hypersecretion and β-cell exhaustion.

KATP Channels and the Metabolic Regulation of Insulin Secretion in Health and Disease: The 2022 Banting Medal for Scientific Achievement Award Lecture

“…However, many people find caloric restriction difficult, so alternative strategies are needed. Our studies, and those of others, suggest that one way to halt β-cell decline would be to reduce glycolytic flux by partial inhibition of glucokinase ( 53 , 56 , 71 – 74 ). This would prevent the buildup of downstream signaling metabolites that lead to the changes in gene expression that drive β-cell functional decline.…”

“…Indeed, partial inhibition of glucokinase with mannoheptulose prevents all the changes in INS-1 cells ( 56 ) and restores insulin secretion in diabetic mouse islets ( 75 ). There is also accumulating evidence that partial glucokinase knockdown both in vitro and in vivo can help preserve and restore β-cell function in diabetic mice ( 72 – 74 ). Most importantly, perhaps, patients with heterozygous inactivating glucokinase mutations require no therapy, their diabetes does not progress, and, despite lifelong mild hyperglycemia, their incidence of diabetes complications is similar to that of people without diabetes ( 76 , 77 ).…”

Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells

“…The ability of mannoheptulose to prevent the effects of chronic hyperglycaemia suggests partial inhibition of glucokinase might be a viable strategy. Indeed, there is accumulating evidence that partial glucokinase inhibition both in vitro and in vivo can help preserve β-cell function and mass in mouse models of diabetes [61][62][63] . Although at first sight, it may seem paradoxical to suggest reducing GCK activity may be therapeutic in T2D, evidence from people with a heterozygous inactivating mutation in GCK provides support for this idea.…”

Targeting Protein Kinases to Protect Beta-Cell Function and Survival in Diabetes

“…Paradoxically, reports suggested that decreasing glucose metabolism by inhibiting the activity of glucokinase within the beta-cells could be a successful approach to protect beta-cells against chronic hyperglycemia, and to preserve a functional beta-cell mass in diabetes [ 51 , 114 , 119 , 120 , 121 ]. Inhibition of glucokinase, by reducing glycolytic flux, was indeed reported to preserve beta-cell mass, reduce ER stress, preserve mitochondrial morphology and function, maintain a beta-cell phenotype, and insulin secretion in preclinical mouse models of monogenic diabetes and T2D [ 51 , 121 , 122 ]. Challenges facing the use of glucokinase inhibitors are finding inhibitors that specifically target glucokinase within the beta-cells, evaluating the degree to which glucokinase inhibition is relevant, and the positioning and timing of glucokinase inhibition treatment.…”