Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes.

BACKGROUND: Alpha-glucosidase inhibitors (AGIs) have been shown to reduce incident type 2 diabetes but their impact on cardiovascular (CV) disease remains controversial. We sought to identify the overall impact of AGIs with respect to incident type 2 diabetes in individuals with impaired glucose tolerance (IGT), and CV outcomes in those with IGT or type 2 diabetes. METHODS: We used PubMed and SCOPUS to identify randomized controlled trials reporting the incidence of type 2 diabetes and/or CV outcomes that had compared AGIs with placebo in populations with IGT or type 2 diabetes, with or without established CV disease. Eligible studies were required to have ≥ 500 participants and/or ≥ 100 endpoints of interest. Meta-analyses of available trial data were performed using random effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident type 2 diabetes and CV outcomes. RESULTS: Of ten trials identified, three met our inclusion criteria for incident type 2 diabetes and four were eligible for CV outcomes. The overall HR (95% CI) comparing AGI with placebo for incident type 2 diabetes was 0.77 (0.67-0.88), p < 0.0001, and for CV outcomes was 0.98 (0.89-1.10), p = 0.85. There was little to no heterogeneity between studies, with I2 values of 0.03% (p = 0.43) and 0% (p = 0.79) for the two outcomes respectively. CONCLUSIONS: Allocation of people with IGT to an AGI significantly reduced their risk of incident type 2 diabetes by 23%, whereas in those with IGT or type 2 diabetes the impact on CV outcomes was neutral.

11ß-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial.

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regenerates active glucocorticoid, we investigated whether 11ß-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn't met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.

Angiopoietin-like gene expression in the mouse uterus during implantation and in response to steroids.

The purpose of this work was to determine if and where Angiopoietin-like genes are expressed in the mouse uterus during the implantation period of pregnancy and to determine if uterine expression of such genes is controlled by estrogen or progesterone. We found that all six known murine angiopoietin-like genes were expressed in the mouse uterus during implantation. The expression of four genes was controlled by either estrogen or progesterone. Only the levels of angiopoietin-like 4 (Angptl4) mRNA dramatically increased in implantation segments of the uterus during decidualization and was conceptus-independent. Due to this increased expression and the fact that angiopoietin-like 4 protein plays a role in lipid metabolism and angiogenesis in other tissues, only the expression of Angptl4 was further examined in the uterus and developing placenta. Angptl4 mRNA was localized to subpopulations of the endometrial stromal fibroblast and endothelial cell populations during decidualization. It was also localized to the ectoplacental cone, trophoblast giant cells and parietal endoderm of the conceptus at this time. By mid-pregnancy, Angptl4 mRNA was localized mainly to the mesometrial lymphoid aggregate region plus mesometrial endothelial cells of the uterus, as well as in various cell types of the conceptus. Additional work showed that Angptl4 expression increases in mouse endometrial stromal cells as they undergo decidualization in vitro. As in other cell types, the expression of Angptl4 in endometrial stromal cells was increased in response to an agonist of the peroxisome proliferator activated receptors. Taken together, the results of this work support the hypothesis that locally expressed Angptl4 might play a role in local uterine/placental lipid metabolism and vascular changes during implantation and thus provide a basis for future research.

Analysis of uterine gene expression in interleukin-15 knockout mice reveals uterine natural killer cells do not play a major role in decidualization and associated angiogenesis.

During decidualization, uterine natural killer (uNK) cells are the most abundant immune cell types found in the uterus. Although it is well known that they play key roles in spiral arteriole modification and the maintenance of decidual integrity seen after mid-pregnancy, their roles in the differentiation of decidual cells and accompanying angiogenesis during the process of decidualization is less well characterized. To address this, we used whole-genome Illumina BeadChip analysis to compare the gene expression profiles in implantation segments of the uterus during decidualization on day 7.5 of pregnancy between wild-type and uNK cell-deficient (interleukin-15-knockout) mice. We found almost 300 differentially expressed genes and verified the differential expression of ~60 using quantitative RT-PCR. Notably, there was a lack of differential expression of genes involved in decidualization and angiogenesis and this was also verified by quantitative RT-PCR. Similar endothelial cell densities and proliferation indices were also found in the endometrium between the implantation site tissues of wild-type and knockout mice undergoing decidualization. Overall, the results of this study reveal that uNK cells likely do not play a major role in decidualization and accompanying angiogenesis during implantation. In addition, the study identifies a large number of genes whose expression in implantation-site uterine tissue during decidualization depends on interleukin-15 expression in mice.

Predicting the risk of developing type 2 diabetes in Chinese people who have coronary heart disease and impaired glucose tolerance.

AIMS: Robust diabetes risk estimates in Asian patients with impaired glucose tolerance (IGT) and coronary heart disease (CHD) are lacking. We developed a Chinese type 2 diabetes risk calculator using Acarbose Cardiovascular Evaluation (ACE) trial data. METHODS: There were 3105 placebo-treated ACE participants with requisite data for model development. Clinically relevant variables, and those showing nominal univariate association with new-onset diabetes (P < .10), were entered into BASIC (clinical variables only), EXTENDED (clinical variables plus routinely available laboratory results), and FULL (all candidate variables) logistic regression models. External validation was performed using the Luzhou prospective cohort of 1088 Chinese patients with IGT. RESULTS: Over median 5.0 years, 493 (15.9%) ACE participants developed diabetes. Lower age, higher body mass index, and use of corticosteroids or thiazide diuretics were associated with higher diabetes risk. C-statistics for the BASIC (using these variables), EXTENDED (adding male sex, fasting plasma glucose, 2-hour glucose, and HbA1c), and FULL models were 0.610, 0.757, and 0.761 respectively. The EXTENDED model predicted a lower 13.9% 5-year diabetes risk in the Luzhou cohort than observed (35.2%, 95% confidence interval 31.3%-39.5%, C-statistic 0.643). CONCLUSION: A risk prediction model using routinely available clinical variables can be used to estimate diabetes risk in Chinese people with CHD and IGT.

Impact of Acarbose on Incident Diabetes and Regression to Normoglycemia in People With Coronary Heart Disease and Impaired Glucose Tolerance: Insights From the ACE Trial.

OBJECTIVE: We examined the impact of acarbose, an α-glucosidase inhibitor, on incident diabetes and regression to normoglycemia in 6,522 Acarbose Cardiovascular Evaluation (ACE) trial participants in China who had impaired glucose tolerance (IGT) and coronary heart disease (CHD). RESEARCH DESIGN AND METHODS: Participants were randomly assigned to acarbose or placebo and followed with four monthly fasting plasma glucose (FPG) tests and annual oral glucose tolerance tests. Incident diabetes was defined as two successive diagnostic FPG levels ≥7 mmol/L or 2-h plasma glucose (PG) levels ≥11.1 mmol/L while taking study medication or a masked adjudicated confirmation of this diagnosis. Regression to normoglycemia was defined as FPG <6.1 mmol/L and 2-h PG <7.8 mmol/L. Intention-to-treat and on-treatment analyses were conducted using Poisson regression models, overall and for subgroups (age, sex, CHD type, HbA1c, FPG, 2-h PG, BMI, estimated glomerular filtration rate, for IGT alone, for IGT + impaired fasting glucose, and for use of thiazides, ACE inhibitors [ACEis]/angiotensin receptor blockers [ARBs], ß-blockers, calcium channel blockers, or statins). RESULTS: Incident diabetes was less frequent with acarbose compared with placebo (3.2 and 3.8 per 100 person-years, respectively; rate ratio 0.82 [95% CI 0.71, 0.94], P = 0.005), with no evidence of differential effects within the predefined subgroups after accounting for multiple testing. Regression to normoglycemia occurred more frequently in those randomized to acarbose compared with placebo (16.3 and 14.1 per 100 person-years, respectively; 1.16 [1.08, 1.25], P < 0.0001). This effect was greater in participants not taking an ACEi or ARB (1.36 [1.21, 1.53], P interaction = 0.0006). The likelihood of remaining in normoglycemic regression did not differ between the acarbose and placebo groups (P = 0.41). CONCLUSIONS: Acarbose reduced the incidence of diabetes and promoted regression to normoglycemia in Chinese people with IGT and CHD.

Predicting heart failure events in patients with coronary heart disease and impaired glucose tolerance: Insights from the Acarbose Cardiovascular Evaluation (ACE) trial.

AIMS: Heart failure is a fatal complication of type 2 diabetes but little is known about its incidence in people with impaired glucose tolerance (IGT). We used Acarbose Cardiovascular Evaluation (ACE) trial data to identify predictors of hospitalisation for heart failure (hHF) or cardiovascular (CV) death in patients with coronary heart disease (CHD) and IGT randomised to acarbose or placebo. METHODS: Independent hHF/CV death risk factors were determined using Cox proportional hazards models, with participants censored at first hHF event, CV death, or end of follow-up. RESULTS: During median 5-year follow-up, the composite outcome of hHF/CV death occurred in 393 (6.0%) participants. Significant hHF/CV death multivariate predictors were higher age and plasma creatinine, and prior heart failure (HF), myocardial infarction (MI), atrial fibrillation (AF) and stroke. Acarbose, compared with placebo, did not reduce hHF/CV death (hazard ratio [HR] 0.89, 95% CI 0.64-1.24, P = 0.48) or hHF (HR 0.90, 95% CI 0.74-1.10, P = 0.32). CONCLUSIONS: Patients with CHD and IGT at greater risk of hHF/CV death were older with higher plasma creatinine, prior HF, MI, AF or stroke. Addition of acarbose to optimised CV therapy to reduce post-prandial glucose excursions did not reduce the risk of hHF/CV death or hHF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513.

Localization of C-Fos-Induced Growth Factor (Figf) mRNA Expression in the Mouse Uterus during Implantation.

The purpose of this study was to characterize the localization of Figf mRNA in the mouse uterus during embryo implantation. Strong Figf mRNA hybridization signals were seen in the primary decidual zone just after the onset of implantation from Days 4.5-6.5. On Day 7.5, this expression continued around the concept us, but in addition we observed high expression of Figf mRNA in the endothelial cells that line the forming vascular sinusoids in the lateral me some trial decidua. Interestingly, on Days 8.5 this high expression continued in the endothelial cells of sinusoids in the lateral me some trial decidual tissue but not in the decidual cells surrounding the concept us. As implantation and placental development finished, Figf mRNA expression remained in the endothelial cells of the sinusoids and spiral arterioles of the decidua basalis. Interestingly, Flt4 mRNA was localized to the endothelial cells lining the sinusoids that form during implantation. Since the endothelial cells of the me some trial sinusoids exhibit a high level of proliferation, we speculate that FIGF-FLT4 signaling may play a role in their formation and function during implantation. This work will provide a basis for further research on the potential role of FIGF-FLT4 signaling in endometrial angiogenesis during implantation in mice.