SGLT2 knockout prevents hyperglycemia and is associated with reduced pancreatic ß-cell death in genetically obese mice.

Inhibition of the sodium-glucose co-transporter type 2 (SGLT2) has received growing acceptance as a novel, safe and effective means to improve glycemic control in patients with type 2 diabetes. Inhibition of SGLT2 lowers the renal glucose threshold and reduces plasma glucose by promoting glucose excretion in urine. Both animal studies and clinical trials in man suggest that SGLT2 inhibition has the potential to improve pancreatic ß-cell function by reducing glucose toxicity. However, there is limited data exploring how reducing glucotoxicity via SGLT2 inhibition affects rates of ß-cell proliferation and death throughout life in the context of insulin resistance and type 2 diabetes. SGLT2-/- mice were backcrossed to the db/db strain to produce littermate control db/db-SGLT2+/+ and experimental db/db-SGLT2-/- mice. Mice were euthanized at 5, 12 and 20 weeks of age to collect plasma for glucose, insulin, lipid and cytokine measures, and pancreata for histological analysis including determination of ß-cell mass and rates of proliferation and death. SGLT2 deletion in db/db mice reduced plasma glucose as early as 5 weeks of age and continued throughout life without changes in plasma lipids or cytokines. Reduced plasma glucose levels occurred in parallel with an increase in the relative ß-cell volume and reduced frequency of ß-cell death, and no apparent change in rates of ß-cell proliferation. These data add to a growing body of evidence demonstrating that improved glycemic control achieved through SGLT2 inhibition can preserve ß-cell function and endogenous insulin secretion by reducing glucose toxicity and rates of ß-cell death.

Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice.

Mitochondrial dysfunction is associated with many human diseases and results from mismatch of damage and repair over the life of the organelle. PARK2 is a ubiquitin E3 ligase that regulates mitophagy, a repair mechanism that selectively degrades damaged mitochondria. Deletion of PARK2 in multiple in vivo models results in susceptibility to stress-induced mitochondrial and cellular dysfunction. Surprisingly, Park2 knockout (KO) mice are protected from nutritional stress and do not develop obesity, hepatic steatosis or insulin resistance when fed a high-fat diet (HFD). However, these phenomena are casually related and the physiological basis for this phenotype is unknown. We therefore undertook a series of acute HFD studies to more completely understand the physiology of Park2 KO during nutritional stress. We find that intestinal lipid absorption is impaired in Park2 KO mice as evidenced by increased fecal lipids and reduced plasma triglycerides after intragastric fat challenge. Park2 KO mice developed hepatic steatosis in response to intravenous lipid infusion as well as during incubation of primary hepatocytes with fatty acids, suggesting that hepatic protection from nutritional stress was secondary to changes in energy balance due to altered intestinal triglyceride absorption. Park2 KO mice showed reduced adiposity after 1-wk HFD, as well as improved hepatic and peripheral insulin sensitivity. These studies suggest that changes in intestinal lipid absorption may play a primary role in protection from nutritional stress in Park2 KO mice by preventing HFD-induced weight gain and highlight the need for tissue-specific models to address the role of PARK2 during metabolic stress.