BACKGROUND: This study aimed to investigate the potential differences in the influence of impaired glucose tolerance (IGT) with and without metabolic syndrome (MetS) on cardiovascular (CV) events and mortality.
METHODS: Participants having IGT with MetS (IGT_MetS), those having IGT without MetS (IGT_non_MetS), and those having normal glucose tolerance (NGT) without MetS (NGT_non_MetS) (N = 246, N = 294, and N = 471, respectively) were included in this study. Cox proportional hazards regression was used to examine the relationship among these three groups and CV events and mortality.
RESULTS: Over the 30-year follow-up period, 57 (12.1%) participants having NGT_non_MetS, 55 (18.71%) with IGT_non_MetS, and 74 (30.08%) with IGT_MetS experienced CV mortality. After adjusting for risk factors, the hazard ratios for CV mortality were 2 (95% confidence interval [CI], 1.38-2.91) for the IGT_non_MetS group and 2.96 (95% CI, 2.09-4.19) for the IGT_MetS group, compared with the NGT_non_MetS group. Similar patterns were observed for CV events, with hazard ratios of 1.49 (95% CI, 1.19-1.88) for the IGT_non_MetS group and 1.97 (95% CI, 1.58-2.47) for the IGT_MetS group. Sensitivity analysis revealed that the hazard ratios of the IGT_non_MetS and IGT_MetS groups indicated a higher risk of all-cause mortality, myocardial infarction events or myocardial infarction mortality, and stroke events or stroke mortality compared with that of the NGT_non_MetS group.
CONCLUSIONS: IGT_non_MetS increased the risk of CV mortality and events. Furthermore, when it occurred in conjunction with MetS, it further increased the risk of CV mortality and events. This suggested that active intervention is required.

The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.

OBJECTIVE: Myo-inositol (MI) is an insulin-sensitizing dietary supplement, enhancing the transfer of glucose into the cell. Gestational diabetes mellitus (GDM) is characterized by abnormal glucose tolerance, which is associated with elevated insulin resistance. The present study aimed to assess the effect of MI supplementation during pregnancy on the incidence of GDM.
METHODS: We performed a single-center, open-label, randomized controlled trial. A cohort of 200 pregnant women at 11-13+6 weeks of gestation were randomly assigned in two groups: MI group (n = 100) and control group (n = 100). The MI group received MI and folic acid (4000 mg MI and 400 mcg folic acid daily), while the control group received folic acid alone (400 mcg folic acid daily) until 26-28 weeks of gestation, when the 75 g Oral Glucose Tolerance Test (OGTT) was performed for the diagnosis of GDM. Clinical and metabolic outcomes were assessed.
RESULTS: The incidence of GDM was significantly higher in the MI group (14.9%) compared to the control group (28.5%) (P = 0.024). Women treated with MI had significantly lower OGTT glucose values, than those not treated with MI (P < 0.001). The insulin resistance as assessed by HOMA-IR was significantly lower in the MI group versus control (P = 0.045). Furthermore, MI group had significantly higher insulin sensitivity as measured by the Matsuda Index, compared to the control group (P = 0.037).
CONCLUSIONS: MI supplementation seems to be an effective option to improve the glycemic control of pregnant women and prevent the onset of GDM.
BACKGROUND: ISRCTN registry: ISRCTN16142533. Registered 09 March 2017.

BACKGROUND: A compromised cardiac autonomic function has been found in subjects with insulin resistance related disorders such as obesity, impaired glucose tolerance (IGT) and type 2 diabetes and confers an increased risk of adverse cardiovascular outcomes. Growing evidence indicate that 1 h plasma glucose levels (1hPG) during an oral glucose tolerance test (OGTT) ≥ 155 mg/dl identify amongst subjects with normal glucose tolerance (NGT) a new category of prediabetes (NGT 1 h-high), harboring an increased risk of cardiovascular organ damage. In this study we explored the relationship between 1 h post-load hyperglycemia and cardiac autonomic dysfunction.
METHODS: Presence of cardiac autonomic neuropathy (CAN) defined by cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV), assessed by 24-h electrocardiography were evaluated in 88 non-diabetic subjects subdivided on the basis of OGTT data in: NGT with 1 h PG < 155 mg/dl (NGT 1 h-low), NGT 1 h-high and IGT.
RESULTS: As compared to subjects with NGT 1 h-low, those with NGT 1 h-high and IGT were more likely to have CARTs defined CAN and reduced values of the 24 h time domain HVR parameters including standard deviation of all normal heart cycles (SDNN), standard deviation of the average RR interval for each 5 min segment (SDANN), square root of the differences between adjacent RR intervals (RMSSD), percentage of beats with a consecutive RR interval difference > 50 ms (PNN50) and Triangular index. Univariate analyses showed that 1hPG, but not fasting and 2hPG, was inversely associated with all the explored HVR parameters and positively with CARTs determined presence of CAN. In multivariate regression analysis models including several confounders we found that 1hPG was an independent contributor of HRV and presence of CAN.
CONCLUSIONS: Subjects with 1hPG ≥ 155 mg/dl have an impaired cardiac autonomic function.

Introduction: Obesity is a major risk factor associated with multiple pathological conditions including diabetes and cardiovascular disease. Endothelial dysfunction is an early predictor of obesity. However, little is known regarding how early endothelial changes trigger obesity. In the present work we report a novel endothelial-mediated mechanism essential for regulation of metabolic homeostasis, driven by c-Myc. Methods: We used conditional knockout (EC-Myc KO) and overexpression (EC-Myc OE) mouse models to investigate the endothelial-specific role of c-Myc in metabolic homeostasis during aging and high-fat diet exposure. Body weight and metabolic parameters were collected over time and tissue samples collected at endpoint for biochemical, pathology and RNA-sequencing analysis. Animals exposed to high-fat diet were also evaluated for cardiac dysfunction. Results: In the present study we demonstrate that EC-Myc KO triggers endothelial dysfunction, which precedes progressive increase in body weight during aging, under normal dietary conditions. At endpoint, EC-Myc KO animals showed significant increase in white adipose tissue mass relative to control littermates, which was associated with sex-specific changes in whole body metabolism and increase in systemic leptin. Overexpression of endothelial c-Myc attenuated diet-induced obesity and visceral fat accumulation and prevented the development of glucose intolerance and cardiac dysfunction. Transcriptome analysis of skeletal muscle suggests that the protective effects promoted by endothelial c-Myc overexpression are associated with the expression of genes known to increase weight loss, energy expenditure and glucose tolerance. Conclusion: Our results show a novel important role for endothelial c-Myc in regulating metabolic homeostasis and suggests its potential targeting in preventing obesity and associated complications such as diabetes type-2 and cardiovascular dysfunction.

Periodontitis is independently associated with numerous lifestyle diseases. Diabetic patients have approximately threefold increased odds of periodontitis, which in turn increases the risk of systemic inflammation. The study by Thazhe Poyil et al is an effort to establish the inflammatory link between diabetic re-tinopathy (DR) and periodontitis based on the periodontal inflamed surface area in diabetic patients with and without DR. To further advance the study, we suggest refining the eligibility criteria to explicitly state the clinical correlates of periodontitis and DR, larger sample size and improved sampling methodology, matching of baseline characteristics of the two groups, as well as improved statistical approach and interpretation of the study findings. Measurement of hemoglobin A1c (HbA1c) in studies comparing type 2 diabetes mellitus patients with DR of matched severity with and without periodontitis could provide a clearer picture of whether HbA1c level is indeed influenced by periodontitis.

UNASSIGNED: To account for the heterogeneity of gestational diabetes (GDM), this study investigated tailored predictors during pregnancy and at 6-8 weeks postpartum of glucose intolerance (GI) at 1-year postpartum. We identified predictors according to data-driven clusters, analogous to the newly proposed diabetes classification, and for clinical ease also based on BMI-categories.
UNASSIGNED: This is a secondary analysis of the MySweetheart trial. It included 179 women with GDM who underwent a 75g oral glucose tolerance test and HbA1c measurement at 1-year postpartum. Predictors were determined according to: a) cluster analysis based on age, BMI, HOMA-IR and HOMA-B; and b) BMI-categories (normal weight [NW], and overweight/obesity [OW/OB]).
UNASSIGNED: We identified two clusters during pregnancy and at 6-8 weeks postpartum (for both time points an \"insulin-resistant\", and an \"insulin-deficient\" cluster). The \"insulin-resistant\" cluster was associated with a 2.9-fold (CI: 1.46-5.87; pregnancy) and 3.5-fold (CI: 1.63-7.52; at 6-8 weeks postpartum) increased risk of GI at 1-year postpartum. During pregnancy, the most relevant predictors of GI were history of previous GDM and fasting glucose for the \"insulin-deficient\" and NW category and HOMA-IR for the \"insulin-resistant\" and OW/OB category (all p ≤0.035). In the postpartum, predictors were more heterogenous and included the insulin-sensitivity-adjusted-secretion index and 1-h glucose in the \"insulin-deficient\" and NW women.
UNASSIGNED: In women with GDM, we identified \"insulin-resistant\" and \"insulin-deficient\" clusters with distinct risks of future GI. Predictors varied according to clusters or BMI-categories emphasizing the need for tailored risk assessments.

In this study, the antidiabetic activities of Lepionurus sylvestris Blume extract (LSB) in rats was investigated. The in vitro antidiabetic properties of LSB was evaluated using α-amylase, α-glucosidase and DPP-IV inhibitory assays, while the antioxidant assay was analysed using DPPH, ABTS and FRAP assays. Type 2 diabetes was with high-fructose/streptozotocin, and the diabetic animals were treated with LSB for 5 weeks. At the end of the experiment, the effects of LSB were evaluated via insulin level, lipid profile and hepatorenal function biomarkers. The level of oxido-inflammatory parameters, histopathology and insulin immunohistochemical staining in the pancreas was evaluated. Diabetic rats manifested significant increases in the blood glucose level, food/water intake, lipid profiles, hepatorenal function biomarkers, as well as a marked decreases in the body weight and serum insulin levels. Histopathological and insulin immunohistochemical examination also revealed decreased pancreatic beta cells and insulin positive cells, respectively. These alterations were associated with significant increases in malondialdehyde, TNF-α and IL-1β, in addition to significant declines in GSH, SOD and CAT activities. LSB significantly reduced blood glucose level, glucose intolerance, serum lipids, restored altered hepatorenal and pancreatic functions in the treated diabetic rats. Further, LSB showed antioxidant and anti-inflammatory activities by reducing malondialdehyde, TNF-α, IL-1β, and increasing antioxidant enzymes activities in the pancreatic tissues. A total of 77 secondary metabolites were tentatively identified in the UPLC-Q-TOF-MS analysis of LSB. Overall, these findings provides insight into the potentials of LSB as an antidiabetic agent which may be associated to the plethora bioactive compounds in the plant.

Circadian disruption causes glucose intolerance, cardiac fibrosis, and adipocyte dysfunction in sand rats (Psammomys obesus). Exercise intervention can improve glucose metabolism, insulin sensitivity, adipose tissue function and protect against inflammation. We investigated the influence of exercise on male P. obesus exposed to a short photoperiod (5 h light:19 h dark) and high-energy diet. Exercise reduced glucose intolerance. Exercise reduced cardiac expression of inflammatory marker Ccl2 and Bax:Bcl2 apoptosis ratio. Exercise increased heart:body weight ratio and hypertrophy marker Myh7:Myh6, yet reduced Gata4 expression. No phenotypic changes were observed in perivascular fibrosis and myocyte area. Exercise reduced visceral adipose expression of inflammatory transcription factor Rela, adipogenesis marker Ppard and browning marker Ppargc1a, but visceral adipocyte size was unaffected. Conversely, exercise reduced subcutaneous adipocyte size but did not affect any molecular mediators. Exercise increased ZT7 Bmal1 and Per2 in the suprachiasmatic nucleus and subcutaneous Per2. Our study provides new molecular insights and histological assessments on the effect of exercise on cardiac inflammation, adipose tissue dysfunction and circadian gene expression in P. obesus exposed to short photoperiod and high-energy diet. These findings have implications for the protective benefits of exercise for shift workers in order to reduce the risk of diabetes and cardiovascular disease.

From a forward mutagenetic screen to discover mutations associated with obesity, we identified mutations in the Spag7 gene linked to metabolic dysfunction in mice. Here, we show that SPAG7 KO mice are born smaller and develop obesity and glucose intolerance in adulthood. This obesity does not stem from hyperphagia, but a decrease in energy expenditure. The KO animals also display reduced exercise tolerance and muscle function due to impaired mitochondrial function. Furthermore, SPAG7-deficiency in developing embryos leads to intrauterine growth restriction, brought on by placental insufficiency, likely due to abnormal development of the placental junctional zone. This insufficiency leads to loss of SPAG7-deficient fetuses in utero and reduced birth weights of those that survive. We hypothesize that a \'thrifty phenotype\' is ingrained in SPAG7 KO animals during development that leads to adult obesity. Collectively, these results indicate that SPAG7 is essential for embryonic development and energy homeostasis later in life.
Obesity rates are climbing worldwide, leading to an increase in associated conditions such as type 2 diabetes. While new pharmaceutical approaches are available to help individuals manage their weight, many patients do not respond to them or experience prohibitive side effects. Identifying alternative treatments will likely require pinpointing the genes and molecular actors involved in the biological processes that control weight regulation. Previous research suggests that a protein known as SPAG7 could help shape how mice use and store the energy they extract from food. Flaherty et al. therefore set out to investigate the role this protein plays in the body. To do so, they created a line of mice born without SPAG7, which they monitored closely throughout life. These animals were underweight at birth and did not eat more than other mice, yet they were obese as adults. Their ability to exercise was reduced, their muscles were weaker and contained fibers with functional defects. The mice also exhibited biological changes associated with the onset of diabetes. Yet deleting SPAG7 during adulthood led to no such changes; these mice maintained normal muscle function and body weight. Closely examining how SPAG7-deficient mice developed in the womb revealed placental defects which likely caused these animals to receive fewer nutrients from their mother. Such early-life deprivation is known to be associated with the body shifting towards maximizing its use of resources and privileging fat storage, even into and throughout adulthood. By shedding light on the biological role of SPAG7, the work by Flaherty et al. helps to better understand how developmental events can increase the likelihood of obesity later in life. Further investigations are now needed to explore whether this knowledge could help design interventions relevant to human health.