Correcting Postprandial Hyperglycemia in Zucker Diabetic Fatty Rats With an SGLT2 Inhibitor Restores Glucose Effectiveness in the Liver and Reduces Insulin Resistance in Skeletal Muscle

Abstract

Ten-week-old Zucker diabetic fatty (ZDF) rats at an early stage of diabetes embody metabolic characteristics of obese human patients with type 2 diabetes, such as severe insulin and glucose intolerance in muscle and the liver, excessive postprandial excursion of plasma glucose and insulin, and a loss of metabolic flexibility with decreased lipid oxidation. Metabolic flexibility and glucose flux were examined in ZDF rats during fasting and near-normal postprandial insulinemia and glycemia after correcting excessive postprandial hyperglycemia using treatment with a sodium–glucose cotransporter 2 inhibitor (SGLT2-I) for 7 days. Preprandial lipid oxidation was normalized, and with fasting, endogenous glucose production (EGP) increased by 30% and endogenous glucose disposal (E-Rd) decreased by 40%. During a postprandial hyperglycemic-hyperinsulinemic clamp after SGLT2-I treatment, E-Rd increased by normalizing glucose effectiveness to suppress EGP and stimulate hepatic glucose uptake; activation of glucokinase was restored and insulin action was improved, stimulating muscle glucose uptake in association with decreased intracellular triglyceride content. In conclusion, SGLT2-I treatment improves impaired glucose effectiveness in the liver and insulin sensitivity in muscle by eliminating glucotoxicity, which reinstates metabolic flexibility with restored preprandial lipid oxidation and postprandial glucose flux in ZDF rats.

Sustained fasting glucose oxidation and postprandial lipid oxidation associated with reduced insulin dose in type 2 diabetes with sodium–glucose cotransporter 2 inhibitor: A randomized, open‐label, prospective study

“…However, a previous rat model of early type 2 diabetes showed that SGLT2 inhibitor reduces RQ. In the present study, the participants were well past early diabetes and lacked metabolic control, which might have contributed to the higher fasting RQ that was different from the animal study. Furthermore, the postprandial RQ elevation (postprandial 30 and 90 min, compared with the fasting), which represents postprandial metabolic flexibility, was abolished in the insulin + dapagliflozin group relative to the elevation observed in the insulin group.…”

“…Hyperglycemia is known to impair energy substrate oxidation in fasting and postprandial states, through impaired utilization of the intracellular energy source. Insofar as increased elimination of glucose into the urine is expected to reduce glucose availability, which can be used as an intracellular energy source.…”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…SGLT2Is have been shown to increase skeletal muscle glucose uptake 520 and reduce insulin resistance at the skeletal muscle. 521 In an animal model of high fat, diet-induced obesity, canagliflozin was shown to induce expression of IGF-1, protect against muscle mass loss, and restore the contractile force of muscle, 522 suggestive of a protective role for SGLT2Is on skeletal muscle.…”

Spontaneous regression of hepatocellular carcinoma with reduction in angiogenesis‐related cytokines after treatment with sodium‐glucose cotransporter 2 inhibitor in a cirrhotic patient with diabetes mellitus

“…In our case, spontaneous regression of HCC was observed after SGLT2i treatment; no other clinical report has shown an association between SGLT2i treatment and spontaneous regression of HCC. However, SGLT2i is known to reduce insulin resistance in skeletal muscle of Zucker diabetic fatty rats . As insulin resistance is a potent risk factor for HCC proliferation, SGLT2i might suppress HCC through an improvement of insulin resistance.…”