Search

Diabetes is associated with a plethora of metabolic changes which may underlie the propensity to development of stroke (Figure 1).1 Insulin resistance has multiple drivers, is inextricably linked to type 2 diabetes, and is associated with coronary artery2 and cerebrovascular3 atherosclerosis. The long-term degree of hyperglycemia correlates with stroke likelihood, although there is no evidence that intensive glycemic treatment reduces stroke. Similarly, it appears that acute hyperglycemia at the time of stroke is associated with worse outcome, although there is no evidence that intensive glycemic treatment at the time of stroke improves outcome. Diabetes treatment approaches with evidence of pre-stroke prevention might play roles in post-stroke protection. [Extracted from the article]

Background Glucagon-like peptide-1 receptor agonists provide effective hyperglycemia management in patients with type 2 diabetes. In a randomized head-to-head trial, liraglutide 1.8 mg q.d. led to greater reductions in HbA1c than exenatide 10 μg b.i.d. There are no direct comparisons of liraglutide 1.2 mg q.d. and exenatide b.i.d.; therefore, in the present study, an indirect comparison and meta-analysis were undertaken. Methods A systematic literature search was performed for randomized controlled trials of liraglutide 1.2 mg q.d. or exenatide b.i.d. with HbA1c as an outcome and ≥25 subjects. Key data were extracted and analyzed. A random-effects model was used to incorporate heterogeneity between studies. Results Three liraglutide 1.2 mg q.d. (n = 1060) and 10 exenatide b.i.d. (n = 2609) placebo-controlled studies were identified, allowing indirect comparison with placebo as the common arm. Baseline characteristics were mean age ~55 years, disease duration ~7 years, HbA1c ~8%, and body mass index ~32 kg/m2. Compared with exenatide b.i.d., liraglutide 1.2 mg was associated with significantly greater reductions from baseline in HbA1c (-0.29%; 95% confidence interval [CI] -0.53, -0.05) and fasting plasma glucose (-0.92 mmol/L; 95% CI -1.43, -0.41), with shorter duration of nausea (3 vs 14 days; P = 0.002) and fewer withdrawals (odds ratio 0.34; 95% CI 0.22, 0.52). The incidence of adverse events (including nausea) and withdrawals because of adverse events were similar between treatments. Conclusions Liraglutide 1.2 mg provided a significantly greater reduction in HbA1c than exenatide 10 μg b.i.d. The significantly shorter duration of nausea with liraglutide than exenatide may be appreciated by patients. [ABSTRACT FROM AUTHOR]

Background Toll-like receptor 4 ( TLR4) plays an important role in innate immunity. Activation of innate immune response and subsequent chronic low-grade inflammation are thought to be involved in the pathogenesis of type 2 diabetes. In this study, we aimed to investigate the association of TLR4 variants with type 2 diabetes in the Chinese population. Methods Seven tag single nucleotide polymorphisms ( SNPs) of TLR4 based on HapMap Chinese data were genotyped in the Shanghai Chinese, including 3404 type 2 diabetes patients and 3401 controls. The controls were extensively phenotyped for the traits related to glucose metabolism and insulin secretion. Results In total participants, we identified that rs10759932 and rs1927911 were associated with type 2 diabetes (odds ratio 1.106, P = 0.009 for rs10759532, odds ratio 1.092, P = 0.013 for rs1927911). rs11536889 showed a trend association with type 2 diabetes (odds ratio 0.957, P = 0.057). This SNP was also associated with 2-h plasma glucose ( P = 0.033) and high-density lipoprotein-cholesterol ( P = 0.031). In female participants, rs10759932, rs1927911 and rs11536889 were associated with type 2 diabetes (odds ratio 1.176, P = 0.002 for rs10759932, odds ratio 1.136, P = 0.009 for rs1927911, odds ratio 0.882, P = 0.024 for rs11536889). Besides, rs11536889 was significantly associated with 2-h plasma glucose ( P = 0.050) and HOMA- B ( P = 0.046) with adjusting for age and body mass index in female normal subjects. Conclusions We conclude that genetic variants of TLR4 are associated with type 2 diabetes in the Chinese population, especially in female subjects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Clinical and epidemiological findings point to an association between type 2 diabetes ( T2D) and low birth weight. However, the nature of the relationship is largely unknown. The aim of this study was to identify novel single nucleotide polymorphisms ( SNPs) in T2D and birth weight, and their pleiotropic loci. Methods A pleiotropy-informed conditional false discovery rate (c FDR) method was applied to two independent genome-wide association studies ( GWAS) summary statistics of T2D ( n = 149 821) and birth weight ( n = 26 836). Results A conditional Q- Q plot showed strong enrichment of genetic variants in T2D conditioned on different levels of association with birth weight. 133 T2D-associated SNPs, including 120 novel SNPs, were identified with a significance threshold of c FDR < 0.05; 13 significant birth weight-associated SNPs, including 12 novel SNPs (c FDR < 0.05) were identified. Conjunctional c FDR (cc FDR) analysis identified nine pleiotropic loci, including seven novel loci, shared by both T2D and birth weight (cc FDR < 0.05). Two novel SNPs located at the CDK5 regulatory subunit-associated protein 1-like 1 ( CDKAL1; rs1012635; c FDR < 0.05) and adenylate cyclase 5 ( ADCY5; rs4677887; c FDR < 0.05) genes are of note. These two genes increase the risk of T2D and low birth weight through the pathway of the 'fetal insulin hypothesis.' Conclusion Several pleiotropic loci were identified between T2D and birth weight by leveraging GWAS results. The results make it possible to explain a greater proportion of trait heritability and improve our understanding of the shared pathophysiology between T2D and birth weight. [ABSTRACT FROM AUTHOR]