ESPE Yearbook of Paediatric Endocrinology

PLoS One. 2022 Feb 18;17(2):e0258054. doi: 10.1371/journal.pone.0258054. PMID: 35180212.

Brief Summary: This mouse model of diabetes describes how early administration of sodium glucose transporter 2 (SGLT2) inhibitors can protect pancreatic beta-cells from glucotoxicity damage. Early use of SGLT2 inhibitors can revert/prevent beta-cell failure in mice with diabetes due to KATP channel defects.

Chronic hyperglycemia in type 1 and type 2 diabetes induces beta-cell membrane hyperexcitability, persistently elevated intracellular calcium concentrations and insulin hypersecretion as well as oxidative and endoplasmic reticulum (ER) stress. This all leads to beta-cell exhaustion, loss of beta cell function and mass. Loss of beta-cell mass also occurs in KATP-gain-of-function (KATP-GOF) mouse model of human neonatal diabetes mellitus (NDM) but in this case there is no insulin hypersecretion. Little is known about the underlying mechanisms and temporal progression of loss of functional beta-cell mass in monogenic diabetes, in the absence of compensatory increase in insulin secretion.

SGLT2 inhibitors are a new class of antidiabetic drugs that inhibit glucose reabsorption in the kidneys and increase glucose excretion in the urine. Because their mechanism of action is independent of insulin secretion or action, SGLT2 inhibitors can be used in combination with other therapies. Individuals with Type 2 diabetes treated with SGLT2 inhibitors demonstrate improved glycemic control, increased glucose- and incretin-stimulated insulin secretion and enhanced insulin sensitivity as well as reduced blood pressure, decreased plasma lipids and reduced risk for cardiovascular events (1).

Although improved beta-cell function by SGLT2 inhibitors has been suggested in humans and rodents, the underlying mechanisms and timeframe of this effect remain unclear, with most studies performed in the setting of obesity and type 2 diabetes (2). KATP-GOF mice model show an unexpected loss of insulin content, decreased proinsulin processing and increased proinsulin at 2-weeks of diabetes accompanied marked increase in beta-cell oxidative and ER stress, without changes in islet cell identity. Administration of the SGLT2 inhibitor dapagliflozin restored insulin content, decreased proinsulin: insulin ratio and reduced oxidative and ER stress but this was only effective if given before 40 days from the onset of the diabetes (when loss of beta-cell mass and identity had already occurred).

Thus, it is the hyperglycemia per se, and not insulin hypersecretion that drives beta-cell failure in diabetes and recovery of beta-cell function by SGLT2 inhibitors is potentially through reduction of oxidative and ER stress. SGLT2 inhibitors revert/prevent beta-cell failure when used in early stages of diabetes, but not when loss of beta-cell mass/identity already occurred. This has important clinical implications for the early use of SGLT2 inhibitor therapy for diabetes mellitus.

References: 1. Kaneto H, Obata A, Kimura T, Shimoda M, Okauchi S, Shimo N, et al. Beneficial effects of sodium-glucose cotransporter 2 inhibitors for preservation of pancreatic beta-cell function and reduction of insulin resistance. J Diabetes. 2017; 9(3):219–25.2. Al Jobori H, Daniele G, Adams J, Cersosimo E, Solis-Herrera C, Triplitt C, et al. Empagliflozin Treatment Is Associated With Improved beta-Cell Function in Type 2 Diabetes Mellitus. J Clin Endocrinol Metab. 2018; 103(4):1402–7. Epub 2018/01/18.