Diabetes

OBJECTIVE— Vaspin was identified as an adipokine with insulin-sensitizing effects, which is predominantly secreted from visceral adipose tissue in a rat model of type 2 diabetes. We have recently shown that vaspin mRNA expression in adipose tissue is related to parameters of obesity and glucose metabolism. However, the regulation of vaspin serum concentrations in human obesity and type 2 diabetes is unknown.

RESEARCH DESIGN AND METHODS— For the measurement of vaspin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this ELISA, we assessed circulating vaspin in a cross-sectional study of 187 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance and in 60 individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or type 2 diabetes before and after a 4-week physical training program.

RESULTS— Vaspin serum concentrations were significantly higher in female compared with male subjects. There was no difference in circulating vaspin between individuals with NGT and type 2 diabetes. In the normal glucose-tolerant group, circulating vaspin significantly correlated with BMI and insulin sensitivity. Moreover, physical training for 4 weeks resulted in significantly increased circulating vaspin levels.

CONCLUSIONS— We found a sexual dimorphism in circulating vaspin. Elevated vaspin serum concentrations are associated with obesity and impaired insulin sensitivity, whereas type 2 diabetes seems to abrogate the correlation between increased circulating vaspin, higher body weight, and decreased insulin sensitivity. Low circulating vaspin correlates with a high fitness level, whereas physical training in untrained individuals causes increased vaspin serum concentrations.

Ablation of the hypothalamic peptide, melanin-concentrating hormone (MCH), leads to a lean phenotype and resistance to diet-induced obesity. Observation of MCH−/− mice at older ages suggested that these effects persist in mice >1 year old. Leanness secondary to caloric restriction is known to be associated with improved glucose tolerance as well as an overall increase in life span. Because the MCH−/− model represents leanness secondary to increased energy expenditure rather than caloric restriction, we were interested in determining whether this model of leanness would be associated with beneficial metabolic effects at older ages. To assess the effects of MCH ablation over a more prolonged period, we monitored male and female MCH−/− mice up to 19 months. The lean phenotype of MCH−/− mice persisted over the duration of the study. At 19 months, MCH−/− male and female mice weighed 23.4 and 30.8% less than their wild-type counterparts, a result of reduced fat mass in MCH−/− mice. Aged MCH−/− mice exhibited better glucose tolerance and were more insulin sensitive compared with wild-type controls. Aging-associated decreases in locomotor activity were also attenuated in MCH−/− mice. We also evaluated two molecules implicated in the pathophysiology of aging, p53 and silent inflammatory regulator 2 (Sir2). We found that expression of the tumor suppressor protein p53 was higher in MCH−/− mice at 9 and 19 months of age. In contrast, expression of Sir2 was unchanged. In aggregate, these findings suggest that MCH ablation improves the long-term outcome for several indicators of the aging process.

p66Shc điều chỉnh cả sản xuất các loài oxy phản ứng (ROS) phụ thuộc vào trạng thái ổn định và căng thẳng môi trường. Việc loại bỏ nó đã được chứng minh là giúp kháng lại stress oxy hóa và bảo vệ chuột khỏi bệnh mạch máu liên quan đến lão hóa. Nghiên cứu này nhằm xác minh giả thuyết rằng việc loại bỏ p66Shc cũng bảo vệ khỏi bệnh cầu thận do tiểu đường bằng cách giảm stress oxy hóa. Chuột p66Shc knockout (KO) tiểu đường do streptozotocin gây ra cho thấy những thay đổi ít rõ rệt hơn trong chức năng và cấu trúc thận, như được chỉ ra bởi các mức độ protein niệu, albumin niệu, chỉ số xơ hóa cầu thận và diện tích cầu thận và tế bào kẽ thấp hơn một cách đáng kể. Nội dung fibronectin và collagen IV ở cầu thận cũng thấp hơn ở chuột KO tiểu đường so với chuột kiểu hoang dã, trong khi apoptosis chỉ được phát hiện ở chuột kiểu hoang dã tiểu đường. Các sản phẩm cuối glycosyl hóa tiên tiến trong huyết thanh và mô thận, cũng như mức isoprostane 8-epi-prostaglandin F2α và kích hoạt yếu tố nhân κB (NF-κB) cũng thấp hơn ở chuột KO tiểu đường so với chuột kiểu hoang dã. Các tế bào kẽ từ chuột KO phát triển dưới điều kiện glucose cao cho thấy tỷ lệ chết tế bào, sản xuất matri, mức ROS và kích hoạt NF-κB thấp hơn so với các tế bào từ chuột kiểu hoang dã. Những dữ liệu này hỗ trợ vai trò của stress oxy hóa trong bệnh sinh của bệnh cầu thận do tiểu đường và chỉ ra rằng p66Shc liên quan đến cơ chế phân tử liên quan đến stress oxy hóa do tiểu đường gây ra và tổn thương thận phụ thuộc vào oxy hóa.

The aim of this work was to study the mechanism of free radical formation in type 1 diabetes and its possible prevention. We have found oxidation of blood glutathione and an increase in plasma lipoperoxide levels in both human type 1 diabetes and experimental diabetes. Peroxide production by mitochondria does not increase in diabetes. On the contrary, the activity of xanthine oxidase, a superoxide-generating enzyme, increases in liver and plasma of diabetic animals. The increase in plasma xanthine oxidase activity may be explained by the increase in the hepatic release of this enzyme, which is not due to nonspecific membrane damage: release of other hepatic enzymes, such as the amino transferases, does not increase in diabetes. Superoxide formation by aortic rings of rabbits increases significantly in diabetes. This is completely inhibited by allopurinol, an inhibitor of xanthine oxidase. Heparin, which releases xanthine oxidase from the vessel wall, also decreases superoxide formation by aortic rings of diabetic animals. Treatment with allopurinol decreases oxidative stress in type 1 diabetic patients: hemoglobin glycation, glutathione oxidation, and the increase in lipid peroxidation are prevented. These results may have clinical significance in the prevention of late-onset vascular complications of diabetes.

Patients with type 2 diabetes mellitus (T2DM) are at increased risk of severe coronavirus disease 2019 (COVID-19) outcomes possibly because of dysregulated inflammatory responses. Glucose-regulating medications, such as glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and pioglitazone, are known to have anti-inflammatory effects that may improve outcomes in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In a multinational retrospective cohort study, we used the TriNetX COVID-19 Research Network of 56 large health care organizations to examine these medications in relation to the incidence of hospital admissions, respiratory complications, and mortality within 28 days after a COVID-19 diagnosis. After matching for age, sex, race, ethnicity, BMI, and significant comorbidities, use of GLP-1R agonists and/or pioglitazone was associated with significant reductions in hospital admissions (GLP-1R: 15.7% vs. 23.5%, risk ratio [RR] 0.67 [95% CI 0.57–0.79; P < 0.001]; pioglitazone: 20.0% vs. 28.2%; RR 0.71 [95% CI 0.54–0.93; P = 0.01]). Use of GLP-1R agonists was also associated with reductions in respiratory complications (15.3% vs. 24.9%, RR 0.62 [95% CI 0.52–0.73]; P < 0.001) and incidence of mortality (1.9% vs. 3.3%, RR 0.58 [95% CI 0.35–0.97]; P = 0.04). Use of DPP-4 inhibitors was associated with a reduction in respiratory complications (24.0% vs. 29.2%, RR 0.82 [95% CI 0.74–0.90]; P < 0.001), and continued use of DPP-4 inhibitors after hospitalization was associated with a decrease in mortality compared with those who discontinued use (9% vs. 19%, RR 0.45 [95% CI 0.28–0.72]; P < 0.001). In conclusion, use of glucose-regulating medications, such as GLP-1R agonists, DPP-4 inhibitors, or pioglitazone, may improve COVID-19 outcomes for patients with T2DM; randomized clinical trials are needed to further investigate this possibility.

OBJECTIVE—Regulation of phosphoenolpyruvate carboxykinase (PEPCK), the key gene in gluconeogenesis, is critical for glucose homeostasis in response to quick nutritional depletion and/or hormonal alteration.

RESEARCH DESIGN/METHODS AND RESULTS— Here, we identified the testicular orphan nuclear receptor 4 (TR4) as a key PEPCK regulator modulating PEPCK gene via a transcriptional mechanism. TR4 transactivates the 490-bp PEPCK promoter-containing luciferase reporter gene activity by direct binding to the TR4 responsive element (TR4RE) located at −451 to −439 in the promoter region. Binding to TR4RE was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Eliminating TR4 via knockout and RNA interference (RNAi) in hepatocytes significantly reduced the PEPCK gene expression and glucose production in response to glucose depletion. In contrast, ectopic expression of TR4 increased PEPCK gene expression and hepatic glucose production in human and mouse hepatoma cells. Mice lacking TR4 also display reduction of PEPCK expression with impaired gluconeogenesis.

CONCLUSIONS—Together, both in vitro and in vivo data demonstrate the identification of a new pathway, TR4 → PEPCK → gluconeogenesis → blood glucose, which may allow us to modulate metabolic programs via the control of a new key player, TR4, a member of the nuclear receptor superfamily.