A Low-Carbohydrate DietImproves Glucose Metabolism in Lean Insulinopenic Akita Mice Along With Sodium-Glucose Cotransporter 2 Inhibitor.

Yukihiro Fujita,Masakazu Haneda,Yuichi Makino,Kuralay K Atageldiyeva,Yasutaka Takeda,Tsuyoshi Yanagimachi

doi:10.3389/fendo.2020.601594

Abstract

ObjectiveA low-carbohydrate diet (LC) can be beneficial to obese subjects with type2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 inhibitor (SGLT2i) presents prompt glucose-lowering effects in subjects with T2DM. We investigated how LC and SGLT2i could similarly or differently influence on the metabolic changes, including glucose, lipid, and ketone metabolism in lean insulinopenic Akita mice. We also examined the impacts of the combination.MethodsMale Akita mice were fed ad libitum normal-carbohydrate diet (NC) as a control or low-carbohydrate diet (LC) as an intervention for 8 weeks with or without SGLT2i treatment. Body weight and casual bold glucose levels were monitored during the study, in addition to measuring TG, NEFA, and ketone levels. We quantified gene expressions involved in gluconeogenesis, lipid metabolism and ketogenesis in the liver and the kidney. We also investigated the immunostaining analysis of pancreatic islets to assess the effect of islet protection.ResultsBoth LC and SGLT2i treatment reduced chronic hyperglycemia. Moreover, the combination therapy additionally ameliorated glycemic levels and preserved the islet morphology in part. LC but not SGLT2i increased body weight accompanied by epididymal fat accumulation. In contrast, SGLT2i, not LC potentiated four-fold ketone production with higher ketogenic gene expression, in comparison with the non-treated Akita mice. Besides, the combination did not enhance further ketone production compared to the SGLT2i alone.ConclusionsOur results indicated that both LC and SGLT2i reduced chronic hyperglycemia, and the combination presented synergistic favorable effects concomitantly with amelioration of islet morphology, while the combination did not enhance further ketosis in Akita mice.

Highlights

It is widely appreciated that nutritional intervention is a major approach as the treatment for diabetes to maintain adequate body weight, especially for obese subjects with insulin resistance
Our results indicated that both low-carbohydrate diet (LC) and Sodium-glucose cotransporter 2 inhibitor (SGLT2i) reduced chronic hyperglycemia, and the combination presented synergistic favorable effects
Akita mice were randomized into four groups: the LC group was fed with LC alone, the normal-carbohydrate diet (NC)+Ipra group was treated with an SGLT2i ipragliflozin alone and fed with NC, the LC+Ipra combined group was fed with LC and treated with Ipragliflozin, and the NC group was a nontreated control, respectively

Summary

Introduction

It is widely appreciated that nutritional intervention is a major approach as the treatment for diabetes to maintain adequate body weight, especially for obese subjects with insulin resistance. Total calorie restriction is conventionally practiced, but nutrition-oriented restrictions such as a low-carbohydrate diet (LC), a low-fat diet or Mediterranean diet are alternatively preferred, especially for obese type 2 diabetes mellitus (T2DM) with insulin resistance [1, 2]. Some reports indicated that LC induced life-threatening ketoacidosis in subjects with T1DM, who intentionally reduced daily dosage of insulin injection or developed to euglycemic diabetic ketoacidosis [3, 4]. Clinical trials revealed that SGLT2i could improve glycemic control and reduced the dosage of insulin, even in subjects with type 1 diabetes mellitus (T1DM) [10]. SGLT2i is a potential tool to treat T1DM with insulin injection, adversely with a slightly higher risk of ketoacidosis [10]

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Conclusion