Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.

Chronic hyperglycaemia causes a dramatic decrease in mitochondrial metabolism and insulin content in pancreatic β-cells. This underlies the progressive decline in β-cell function in diabetes. However, the molecular mechanisms by which hyperglycaemia produces these effects remain unresolved. Using isolated islets and INS-1 cells, we show here that one or more glycolytic metabolites downstream of phosphofructokinase and upstream of GAPDH mediates the effects of chronic hyperglycemia. This metabolite stimulates marked upregulation of mTORC1 and concomitant downregulation of AMPK. Increased mTORC1 activity causes inhibition of pyruvate dehydrogenase which reduces pyruvate entry into the tricarboxylic acid cycle and partially accounts for the hyperglycaemia-induced reduction in oxidative phosphorylation and insulin secretion. In addition, hyperglycaemia (or diabetes) dramatically inhibits GAPDH activity, thereby impairing glucose metabolism. Our data also reveal that restricting glucose metabolism during hyperglycaemia prevents these changes and thus may be of therapeutic benefit. In summary, we have identified a pathway by which chronic hyperglycaemia reduces β-cell function.

Diabetes mellitus involves both insufficient insulin secretion and dysregulation of glucagon secretion¹. In healthy people, a fall in plasma glucose stimulates glucagon release and thereby increases counter-regulatory hepatic glucose production. This response is absent in many patients with type-1 diabetes (T1D)², which predisposes to severe hypoglycaemia that may be fatal and accounts for up to 10% of the mortality in patients with T1D³. In rats with chemically induced or autoimmune diabetes, counter-regulatory glucagon secretion can be restored by SSTR antagonists^4–7 but both the underlying cellular mechanism and whether it can be extended to humans remain unestablished. Here, we show that glucagon secretion is not stimulated by low glucose in isolated human islets from donors with T1D, a defect recapitulated in non-obese diabetic mice with T1D. This occurs because of hypersecretion of somatostatin, leading to aberrant paracrine inhibition of glucagon secretion. Normally, K_ATP channel-dependent hyperpolarization of β-cells at low glucose extends into the δ-cells through gap junctions, culminating in suppression of action potential firing and inhibition of somatostatin secretion. This ‘electric brake’ is lost following autoimmune destruction of the β-cells, resulting in impaired counter-regulation. This scenario accounts for the clinical observation that residual β-cell function correlates with reduced hypoglycaemia risk⁸.

Risk alleles for type 2 diabetes at the STARD10 locus are associated with lowered STARD10 expression in the β-cell, impaired glucose-induced insulin secretion, and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids and thus the pathways through which STARD10 regulates β-cell function are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the β-cell and the role of the protein in controlling proinsulin processing and insulin granule biogenesis and maturation. We used isolated islets from mice deleted selectively in the β-cell for Stard10 (βStard10KO) and performed electron microscopy, pulse-chase, RNA sequencing, and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in the INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay was performed on purified STARD10 protein. βStard10KO islets had a sharply altered dense core granule appearance, with a dramatic increase in the number of "rod-like" dense cores. Correspondingly, basal secretion of proinsulin was increased versus wild-type islets. The solution of the crystal structure of STARD10 to 2.3 Å resolution revealed a binding pocket capable of accommodating polyphosphoinositides, and STARD10 was shown to bind to inositides phosphorylated at the 3' position. Lipidomic analysis of âStard10KO islets demonstrated changes in phosphatidylinositol levels, and the inositol lipid kinase PIP4K2C was identified as a STARD10 binding partner. Also consistent with roles for STARD10 in phosphoinositide signalling, the phosphoinositide-binding proteins Pirt and Synaptotagmin 1 were amongst the differentially expressed genes in βStard10KO islets. Our data indicate that STARD10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis, and insulin processing.

Despite the current media focus, Covid-19 is not the only current pandemic. There is also a global pandemic of diabetes. It is caused by an insufficiency of the hormone insulin, which lowers blood glucose levels. Here we highlight recent work that addresses the question of how insulin is normally secreted from the β-cells of the pancreas and what goes wrong with this process in diabetes. We focus on the metabolic regulation of the ATP-sensitive potassium channel, an ATP-gated membrane pore that regulates insulin secretion. We show that when this pore is shut, insulin is released, and when it is open, insulin release is prevented. As may be expected, genetic mutations that impair the ability of ATP to close the channel cause neonatal diabetes. We also consider if a failure of β-cell metabolism to generate enough ATP to close the channel may lead to the progressive decline in β-cell function in type 2 diabetes.

Chronic hyperglycaemia impairs insulin secretion by disrupting beta‐cell metabolism and reducing expression of insulin. These changes are mediated by glucose metabolites downstream of glucokinase. We hypothesized that chronically enhancing glucokinase activity at low glucose would mimic the effects of glucotoxicity and, conversely, that reducing glucokinase activity would prevent the deleterious effects of chronic hyperglycaemia. Human islet microtissues or INS‐1 cells were cultured at low or high glucose for 2 weeks (islets) or 48 h (INS‐1 cells) in the presence or absence of either a glucokinase activator (MK‐0941 or dorzagliatin) or a glucokinase inhibitor (mannoheptulose). We measured changes in glucose‐stimulated insulin secretion, insulin content, glycogen content, gene expression, and oxygen consumption. Chronic glucokinase activation in low‐glucose‐cultured islet microtissues and INS‐1 cells downregulated insulin secretion and content, impaired mitochondrial metabolism, and altered metabolic gene expression, to the same extent as high‐glucose culture. Conversely, reduction of glucokinase activity in high‐glucose‐cultured islet microtissues by mannoheptulose prevented the changes produced by chronic hyperglycaemia. Moreover, the effects of chronic hyperglycaemia on insulin secretion and metabolic gene expression (but not insulin content) were largely reversed by subsequent inhibition of glucokinase. Chronic glucokinase activation in euglycaemia thus mimics the effects of chronic hyperglycaemia, whereas partial inhibition of glucokinase in hyperglycaemia restores normal beta‐cell function. This explains why, in the long term, glucokinase activators are ineffective at controlling glycaemia in type 2 diabetes, and demonstrates that normalizing glucokinase activity can prevent and reverse chronic glucose toxicity.