Is Type 2 Diabetes a Glycogen Storage Disease of Pancreatic β Cells?

Abstract

Elevated plasma glucose leads to pancreatic β cell dysfunction and death in type 2 diabetes. Glycogen accumulation, due to impaired metabolism, contributes to this "glucotoxicity" via dysregulated biochemical pathways promoting β cell dysfunction. Here, we review emerging data, and re-examine published findings, on the role of glycogen in β cells in normoglycemia and in diabetes.

Keywords: diabetes; glycogen; insulin; pancreatic β cell.

Figure 1. Glycogen is present in human β-cells in diabetes

Representative electron micrograph showing glycogen in a β-cell of a type-2 diabetic organ donor with diet-controlled diabetes (HbA1c, 6.6) for 10 years. Sample prepared and stained for glycogen (Brereton et al 2016). Glycogen particles (gly, electron dense material) were distributed throughout the cytoplasm in most β-cells. Autophagic bodies and lysosomes (inset, lys) also contained glycogen. Insulin granules (Ins) contained either dark crystalline cores (mature) or less electron dense material (immature). Scale bar, 1µM. Scale bar of inset 0.5µM.

Figure 2. Pathways for glycogen accumulation and its effects in β-cells

A. Key pathways for glycogen synthesis and degradation. GCK, glucokinase. G6PC2, gucose-6-phosphatase. PGM1, phosphoglucomutase. GYG1, glycogenin. GYS1 GYS2, glycogen synthase. PTG protein targetting to glycogen (a subunit of PKA). GBE1, glycogen branching enzyme. PYLL.M, glycogen phosphorylase muscle (PYGM) and liver (PYGL) types. AGL (amylo-α-1,6-glucosidase, 4-α-glucanotransferase), glycogen debranching enzyme. B,C. Diagrammatic representation of the effects of glycogen accumulation in β-cells. (B) In chronic hyperglycaemia (as in type 2 diabetes) oxidative metabolism of glucose is reduced, leading to decreased insulin release. Glucose continues to enter the cell and is converted to glucose-6-phosphate (G-6-P) by glucokinase. Elevation of G-6-P leads to allosteric activation of glycogen synthase (GS) and increased expression of Protein Targeting to Glycogen (PTG), resulting in glycogen accumulation. Continued glycogen accumulation can lead to activation of apoptotic mechanisms and cell death. Pathways amplified in chronic hyperglycaemia are indicated in red. (C) When extracellular glucose is reduced, glycogen is metabolised via glycogen phosphorylase (GP) to G-6-P, which, via restored oxidative metabolism, leads to enhanced ATP production, resulting in inappropriately elevated insulin secretion. Pathways amplified on restoration of blood glucose are indicated in red.