Loss of Slc12a2 specifically in pancreatic β-cells drives metabolic syndrome in mice.
Rana AbdelgawadYakshkumar Dilipbhai RathodModhi AlshammariLisa KellyChristian A HübnerLydia Aguilar-BryanMauricio Di FulvioPublished in: PloS one (2022)
The risk of type-2 diabetes and cardiovascular disease is higher in subjects with metabolic syndrome, a cluster of clinical conditions characterized by obesity, impaired glucose metabolism, hyperinsulinemia, hyperlipidemia and hypertension. Diuretics are frequently used to treat hypertension in these patients, however, their use has long been associated with poor metabolic outcomes which cannot be fully explained by their diuretic effects. Here, we show that mice lacking the diuretic-sensitive Na+K+2Cl-cotransporter-1 Nkcc1 (Slc12a2) in insulin-secreting β-cells of the pancreatic islet (Nkcc1βKO) have reduced in vitro insulin responses to glucose. This is associated with islet hypoplasia at the expense of fewer and smaller β-cells. Remarkably, Nkcc1βKO mice excessively gain weight and progressive metabolic syndrome when fed a standard chow diet ad libitum. This is characterized by impaired hepatic insulin receptor activation and altered lipid metabolism. Indeed, overweight Nkcc1βKO but not lean mice had fasting and fed hyperglycemia, hypertriglyceridemia and non-alcoholic steatohepatitis. Notably, fasting hyperinsulinemia was detected earlier than hyperglycemia, insulin resistance, glucose intolerance and increased hepatic de novo gluconeogenesis. Therefore, our data provide evidence supporting the novel hypothesis that primary β-cell defects related to Nkcc1-regulated intracellular Cl-homeostasis and β-cell growth can result in the development of metabolic syndrome shedding light into additional potential mechanisms whereby chronic diuretic use may have adverse effects on metabolic homeostasis in susceptible individuals.
Keyphrases
- insulin resistance
- high fat diet induced
- metabolic syndrome
- type diabetes
- glycemic control
- induced apoptosis
- high fat diet
- cardiovascular disease
- adipose tissue
- blood glucose
- skeletal muscle
- weight loss
- cell cycle arrest
- polycystic ovary syndrome
- cardiovascular risk factors
- endoplasmic reticulum stress
- weight gain
- physical activity
- risk assessment
- body mass index
- end stage renal disease
- ejection fraction
- signaling pathway
- newly diagnosed
- machine learning
- cell proliferation
- cell therapy
- liver injury
- single cell
- prognostic factors
- wild type
- coronary artery disease
- cardiovascular events
- peritoneal dialysis
- chronic kidney disease
- acute heart failure
- mesenchymal stem cells