Diabetologia. 2021 May;64(5):1133-1143. doi: 10.1007/s00125-021-05390-x. PMID: 33558985.
In order to gain some insight into the potential mechanism/s of diminished beta cell function over time, this mouse model of CHI was developed with an activating GCK (Glucokinase) mutation. In the short term, the mice developed mild fasting hypoglycaemia (this was very mild with fasting blood glucose 3.6mmol/L) associated with increased beta-cell proliferation and mass. However, in the long-term, impaired glucose tolerance developed associated with decreased beta cell mass but with preserved beta cell function. At a cellular level there was evidence of beta-cell DNA damage.
Hyperglycaemia (as in type 2 diabetes) elicits both short term and long-term changes in beta-cell function and mass. In the short-term beta-cells respond to hyperglycaemia by increasing insulin secretion thus lowering the blood glucose and maintaining normoglycaemia. However, long-term exposure to hyperglycaemia is thought to lead to exhaustion of beta-cells with diminished insulin secretion leading to persistence of the hyperglycaemia. Similarly, some forms of congenital hyperinsulinism (CHI) also improve over time and can develop diabetes in the long-term. The underlying mechanisms that potentially lead to beta-cell exhaustion are not clear.
The key question addressed in this manuscript was whether increased workload of the beta cell per se is responsible for the beta cell toxicity. GCK is a key enzyme regulating beta-cell flux; it converts glucose into glucose-6-phosphate and is termed the beta-cell glucose sensor. Activating GCK mutations lead to a rare form CHI and can be thought of as a model of increased beta cell workload. Thus, these observations suggest that increased beta cell workload induces a reduction in beta cell mass in the long-term. Whether this also applies to the situation with type 2 diabetes will need further investigations.