Diabetes and cancer relationships (糖尿病与肿瘤的关联性)

Diabetes and cancer are both heterogeneous and multifactorial diseases with tremendous impact on health worldwide. Epidemiologic evidence suggests that certain malignancies may be associated with diabetes, as well as with diabetes risk factors and, perhaps, with certain diabetes treatments. Numerous biological mechanisms could account for these relationships. Insulin‐like growth factor (IGF)‐1, IGF‐2, IGF‐1 receptors, insulin, and the insulin receptor play roles in the development and progression of cancers. Although evidence from randomized controlled trials does not support or refute associations of diabetes and its treatments with either increased or reduced risk of cancer incidence or prognosis, consideration of malignancy incidence rates and the magnitude of the trials that would be required to address these issues explains why such studies may not be readily undertaken.     

Vitamin D and Type 2 diabetes mellitus (维生素D与2型糖尿病)

Based on increasing evidence from animal and human studies, vitamin D deficiency is now regarded as a potential risk factor for Type 2 diabetes mellitus (T2DM). Vitamin D is involved in the pathogenesis of pancreatic β‐cell dysfunction, insulin resistance, and systemic inflammation, conditions that contribute to the development of T2DM. Vitamin D can affect the progress of this disease directly through the activation of its own receptor, and indirectly via the regulation of calcium homeostasis. Observational studies have revealed the association between vitamin D deficiency and incident T2DM. More double‐blind randomized control studies that investigate the effects of vitamin D supplementation on insulin sensitivity, insulin secretion, and the occurrence of T2DM are needed.     

Omeprazole improves the anti‐obesity and antidiabetic effects of exendin‐4 in db/db mice (奥美拉唑改善唾液素‐4 对db/db小鼠的减肥与降糖作用)*

Background: In addition to its glucoregulatory actions, exendin‐4, a stable glucagon‐like peptide‐1 receptor agonist, exhibits protective effects in the pancreas and anti‐obesity effects. Suitable combination treatment with other anti‐obesity or pancreas protective agents would be an effective approach to optimize these additional effects. In the present study, we investigated the effects of the addition of omeprazole, a proton pump inhibitor, to exendin‐4 in db/db mice, an experimental model of obesity and type 2 diabetes. Methods: The effects repeated dose treatment for 14 days with exendin‐4 (8 μg/kg, s.c.) and omeprazole (30 mg/kg, s.c.) on glycemic control, food intake, and body weight were determined in obese and hyperglycemic db/db mice. The effects of these treatments on plasma gastrin, ghrelin, and leptin levels were determined, along with effects on nausea‐like symptoms. The pancreatic effects of the repeated dose treatment were assessed by measuring %HbA1c in the circulation as well as pancreatic insulin and glucagon content and glucokinase activity. Results: Combination treatment resulted in significant decreases in plasma leptin and ghrelin levels after repeated dosing. Omeprazole improved the anorectic and body weight‐lowering effects and reversed the inhibitory effect of exendin‐4 on gastrin levels after repeated dose treatment. The 14‐day combination treatment significantly reduced glucose excursion and improved insulin levels, with a concomitant decrease in %HbA1c levels. It also improved glucokinase activity and pancreatic insulin content, with a significant decrease in glucagon content. Conclusions: Combined treatment with omeprazole with exendin‐4 reduces food intake and body weight gain, most likely through changes in plasma ghrelin and leptin levels, and improves pancreatic insulin and glucagon content by improving glucokinase activity.     

Empagliflozin for the treatment of type 2 diabetes mellitus: An overview of safety and efficacy based on Phase 3 trials 艾格列净治疗2型糖尿病：基于3期试验的安全性与有效性概述

In the treatment of type 2 diabetes mellitus (T2DM), a relatively new class of oral agents inhibits sodium–glucose cotransporter 2 (SGLT2), reducing reabsorption of filtered glucose and increasing urinary glucose excretion. Numerous SGLT2 inhibitors have been approved for the treatment of T2DM in adults, most recently empagliflozin, which was approved in Europe and the US in 2014. The Phase 3 program has enrolled >14 000 patients and has assessed the efficacy and safety of empagliflozin as monotherapy and in combination. These studies have demonstrated improvements in glycemic control, and modest reductions in body weight and blood pressure. Empagliflozin was generally well tolerated, with no increased risk of hypoglycemia versus placebo as monotherapy or as add‐on therapy, except when given with sulfonylurea. The studies showed an increased risk of urinary tract and genital infections with empagliflozin, although most infections were mild to moderate in intensity. Furthermore, small (but clinically insignificant) increases in hematocrit and lipid levels have been observed for empagliflozin. Due to the mode of action of empagliflozin, care should be exercised when treating patients at risk of volume depletion. The risks and benefits must be weighed for each patient, but the data reviewed herein show promise for empagliflozin as a treatment for patients with T2DM.     

FoxO6 in glucose metabolism (FoxO6在葡萄糖代谢中的作用)

The forkhead box O (FoxO) subfamily has four members, namely FoxO1, FoxO3, FoxO4, and FoxO6. Unlike the other three members of the FoxO family, FoxO6 has garnered considerably less attention because of earlier reports that FoxO6 expression was limited to the brain. Recent data indicate that FoxO6 is produced in the liver of both rodents and humans. Hepatic FoxO6 activity, which remains at low basal levels in fed states, is markedly induced in fasted mice. FoxO6 activity becomes abnormally higher in the liver of mice with dietary obesity or type 2 diabetes (T2D). Genetically engineered mice with elevated FoxO6 activity in the liver exhibit prediabetes, culminating in the development of glucose intolerance, fasting hyperglycemia, and hyperinsulinemia. Conversely, inhibition of FoxO6 activity in the insulin‐resistant liver results in a reduction in fasting hyperglycemia, contributing to the amelioration of hyperinsulinemia in T2D mice. These new data suggest that FoxO6 is an important regulator of hepatic glucose metabolism in response to insulin or physiological cues. Insulin inhibits FoxO6 activity by promoting its phosphorylation and disabling its activity in the nucleus without altering its subcellular distribution via a mechanism that is distinct from other members of the FoxO subfamily. In this article, we comprehensively review the role of FoxO6 in glucose metabolism in health and disease. We also address whether FoxO6 dysregulation is a contributing factor for the pathogenesis of fasting hyperglycemia and discuss whether FoxO6 is a potential therapeutic target for improving fasting hyperglycemia in T2D.