Work

The Downregulation of Type 1 Diabetes Susceptibility Gene PGM1 Induces Metabolic Imbalance and Stress in Pancreatic β-Cells

Year: 2026

Type: article

Abstract: Phosphoglucomutase 1 (PGM1) is a type 1 diabetes susceptibility gene that potentially plays a key role in regulating central carbon metabolism in β-cells. Previous work suggested that β-cell PGM1 transcription is lowered after coxsackievirus B4 infection. Thus, we hypothesized that decreased PGM1 levels disrupt β-cell metabolic homeostasis and result in β-cell fragility and type 1 diabetes. First, we showed that the synthetic double-stranded RNA polyinosinic:polycytidylic acid, or Poly(I:C) attenuated PGM1 transcription both in human islets and EndoC-βH1 cell line. At 5.5 mmol/L glucose, PGM1 deficiency enhanced the rate of glycolysis, tricarboxylic acid cycle, hexosamine, and pentose phosphate pathway. However, at 20 mmol/L glucose, PGM1-deficient cells showed impaired mitochondrial respiration. Moreover, truncated N-glycans were enriched in PGM1-deficient cells, suggesting aberrant protein glycosylation. Autophagic flux, which was dependent on the lysosomal glycosylated protein function, was impaired in PGM1-deficient cells. Increased endoplasmic reticulum stress was evident in PGM1-deficient cells. Our results suggest that PGM1 is a metabolic regulator of pancreatic β-cells. Its deficiency leads to metabolic imbalance and cellular stress, potentially augmenting type 1 diabetes development. ARTICLE HIGHLIGHTS: In the β-cell, the expression of phosphoglucomutase 1 (PGM1), a type 1 diabetes risk gene, is reduced by double-stranded RNA exposure, modeled by polyinosinic:polycytidylic acid transfection. Deficient PGM1 expression disrupts central carbon metabolism, protein glycosylation, and autophagic flux. These changes precipitate endoplasmic reticulum stress and mitochondrial dysfunction, potentially augmenting type 1 diabetes development.

Source: Diabetes

DOI: 10.2337/db25-0191