Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PL002

Plenary Lecture

Sweetness and light: Impaired regulation of insulin secretion in diabetes

F. M. Ashcroft1

1. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.


Type 2 diabetes is a major global health problem that afflicts >450 million people worldwide. It is characterised by chronic hyperglycaemia that results from insufficient insulin release from pancreatic beta-cells. Both a genetic predisposition and lifestyle factors are involved, which explains why T2D develops with age and is associated with a progressive decline in beta-cell function. Rare genetic forms of diabetes that cause diabetes shortly after birth (neonatal diabetes) can offer insight into the aetiology of type 2 diabetes. We have studied neonatal diabetes caused by activating mutations in the genes encoding the subunits of the ATP-sensitive potassium (KATP) channel. This channel plays a critical role in insulin secretion by coupling changes in cell metabolism to membrane electrical activity, calcium influx and thereby insulin exocytosis. It consists of pore-forming Kir6.x subunits and regulatory sulphonylurea receptor (SURx) subunits, both of which participate in metabolic regulation by binding adenine nucleotides. ATP binding to Kir6.2 inhibits channel activity whereas Mg-nucleotide interaction with SUR1 stimulates channel activity. About 50% of cases of neonatal diabetes are caused by gain-of-function mutations in Kir6.2 or SUR1. We found that these mutations impair ATP inhibition, locking the channel open and preventing insulin secretion. Using a novel FRET-based method of measuring ATP binding we showed some mutations directly interfere with ATP binding; others act indirectly by increasing the intrinsic channel open probability. In many cases, anti-diabetic sulphonylurea drugs are able to close the mutant channels, thereby stimulating insulin secretion. This has enabled >90% of patients with neonatal diabetes caused by KATP channel mutations to transfer from insulin injections to oral tablet therapy, which greatly improves their clinical condition and quality of life. Transfer is less effective, however, in patients with diabetes of longer duration. To understand why this is the case, we generated a mouse model of neonatal diabetes. We found as little as two weeks of diabetes led to a dramatic metabolic rewiring of beta-cell metabolism. This was characterised by marked changes in gene expression, protein levels and glucose metabolite concentrations, which led to reduced glucose-stimulated ATP production and insulin release. It also caused substantial glycogen storage, impaired autophagy and beta-cell apoptosis. If the diabetes was of short duration, these effects were largely reversed following restoration of euglycaemia with sulphonylurea therapy. However, the ability to effect reversal declined with diabetes duration. These data may help explain why older neonatal diabetes patients find it more difficult to transfer to drug therapy, and why the drug dose decreases with time in many patients. Similar changes in gene expression and metabolism were found in insulin-secreting INS-1 cells exposed to 25mM glucose for 48 hours; and in a mouse model in which diabetes develops gradually with age (due to deletion of fumarate hydratase). Thus they appear to be a consequence of chronic hyperglycaemia, rather than hypoinsulinaemia or enhanced KATP channel activity. This suggests that by causing metabolic rewiring chronic hyperglycaemia may contribute to the progressive loss of beta-cell function in type 2 diabetes as well as neonatal diabetes. We propose that a small increase in plasma glucose (e.g. due to age, pregnancy or insulin resistance) may reduce mitochondrial metabolism and insulin secretion so increasing glycaemia further and producing a vicious cycle that drives the progression from impaired glucose tolerance to diabetes.

Where applicable, experiments conform with Society ethical requirements