Caloric Restriction Substantially Improves Glucose Regulation in Mice With Hnf1a-Deficient Beta-Cells

HNF1A-MODY, the most prevalent form of monogenic diabetes, displays incomplete penetrance, indicating the involvement of other environmental and genetic factors in the disease etiology. Currently, it is largely unknown what the influence of environmental factors, such as toxins or diet, is on HNF1A-MODY onset and progression. Here we address this issue by exploring the impact of diet on islet and insulin-secreting beta-cells in the context of HNF1A mutation.

Transgenic mice allowing the specific Hnf1a mutation in insulin-secreting beta-cells were exposed to four distinct dietary regimens including combinations of high-fat diet and caloric restriction. In vitro stem cell islets bearing the HNF1A^P291fsinsC heterozygous mutation and their isogenic controls were used for validation in humans. The readouts included physiological tests, immunofluorescence, proteomics, bulk, and single-cell transcriptomics.

Hnf1a-deficient beta-cells exhibited high sensitivity to dietary cues. Exposure to a high-fat diet exacerbated the glucose regulation defects, while caloric restriction significantly improved blood glucose levels in vivo, without perturbing islet architecture. The high-throughput methods identified changes in the Hnf1a-deficient beta-cells proteome landscape, involving conserved critical regulators of metabolic and growth processes, such as the Carbohydrate Response Element Binding Protein (Chrebp/Mlxipl) and ATP citrate lyase (Acly) among others.

This study hallmarks the important impact of diet on Hnf1a-deficient beta-cells, stemming new therapeutic perspectives, such as future diet management approaches.