Lower Glycemia Research Articles

Myo-inositol moderates maternal BMI and glycemia related variations in in-vitro placental 13C-DHA-metabolism, altering their relationships with birthweight

Transplacental docosahexaenoic-acid (DHA) supply for fetal development is regulated by placental DHA-lipid metabolism. Both maternal diabetes and obesity are linked to possible decreased fetal circulating DHA and increased placental DHA-lipids. Since myo-inositol is a promising intervention for gestational diabetes (GDM), we aimed to determine whether myo-inositol could rectify perturbations in placental DHA metabolism associated with maternal increasing glycemia and obesity and examine links with birthweight. Term placental villous explants from 17 women representing a range of BMIs and mid-gestational glycemia, were incubated with 13C-labeled-DHA for 48 h, in 0.3 µmol/L (control) or 60 µmol/L myo-inositol. Individual newly synthesized 13C-DHA-labeled lipid species were quantified by liquid-chromatography-mass-spectrometry. Compared with controls, incubation with myo-inositol decreased most 13C-DHA-lipids in placental explants from women with higher BMI or higher glycemia, but increased 13C-DHA-lipids with normal BMI or lower glycemia. Myo-inositol also increased 13C-DHA-labeled lipids in cases of lower birthweight centile, but induced decreases at higher centiles. Myo-inositol therefore lowered DHA-lipids in placenta with high basal placental DHA-lipid production (higher BMI and glycemia) but increased DHA-lipids where basal processing capacity is low. Myo-inositol thus moderates placental DHA metabolism towards a physiological mean which may in turn moderate birthweight.

Effect of Long-term Exercise Training on Physical Performance and Cardiorespiratory Function in Adults With CKD: A Randomized Controlled Trial

The safety and efficacy of long-term exercise training in reducing physical functional loss in older adults with advanced CKD and comorbidity is uncertain. Multicenter, parallel group, randomized controlled trial. Adults 55 years and older with estimated glomerular filtration rate (eGFR) of 15 to<45 mL/min/1.73 m2 enrolled from centers in Baltimore and Boston. Twelve months of in-center supervised exercise training incorporating majority aerobic but also muscle strengthening activities or a group health education control intervention, randomly assigned in 1:1 ratio. Primary outcomes were cardiorespiratory fitness and submaximal gait at 6 and 12 months quantified by peak oxygen consumption (Vo2peak) on graded exercise treadmill test and distance walked on the 6-minute walk test, respectively. Secondary outcomes were changes in lower extremity function, eGFR, albuminuria, glycemia, blood pressure, and body mass index. Among 99 participants, the mean age was 68 years, 62% were African American, and the mean eGFR was 33 mL/min/1.73 m2; 59% had diabetes, and 29% had coronary artery disease. Among those randomized to exercise, 59% of exercise sessions were attended in the initial 6 months. Exercise was well tolerated without excess occurrence of adverse events. At 6 months, aerobic capacity was higher among exercise participants (17.9 ± 5.5 vs 15.9 ± 7.0 mL/kg/min, P= 0.03), but the differences were not sustained at 12 months. The 6-minute walk distance improved more in the exercise group (adjusted difference: 98 feet [P= 0.02; P= 0.03 for treatment-by-time interaction]). The exercise group had greater improvements on the Timed Up and Go Test (P= 0.04) but not the Short Physical Performance Battery (P= 0.8). Planned sample size was not reached. Loss to follow-up and dropout were greater than anticipated. Among adults aged≥55 years with CKD stages 3b-4 and a high level of medical comorbidity, a 12-month program of in-center aerobic and resistance exercise training was safe and associated with improvements in physical functioning. Government grants (National Institutes of Health). Registered at ClinicalTrials.gov with study number NCT01462097.

Lower miR-21/ROS/HNE levels associate with lower glycemia after habit-intervention: Diapason study 1-year later

Background and Aims : The prevalence of prediabetes is increasing in the global population and its metabolic derangements may expose to a higher risk to develop type 2 diabetes (T2D) and its cardiovascular burden. Lifestyle modifications might have considerable benefits on ameliorating metabolic status. Alternative biomarkers, such as circulating miR-21, has been recently discovered associated with dysglycemia. Current evidences have demonstrated that miRs may predict the progression from pre-diabetic to diabetes state.

157-LB: Scanning Frequency and Glucose Variability in the First Trimester of T1DM Pregnancies Predict Time Spent in Very Low Glucose Range in the Last One—Analysis of Intermittently Scanned Continuous Glucose Monitoring

Scanning frequency and glucose variability in the first trimester of T1DM pregnancies predict time spent in very low glucose range in the last one: analysis of intermittently scanned continuous glucose monitoring Hypoglycemia is inevitable side effect of tight glycemic control in type 1 diabetes mellitus (T1DM) pregnancies. Using technology novel risk factors are revealed. Total of 34 patients (mean age 29.8 ± 6.1 yrs, BMI 23.6± 3.6 kg/m2, disease duration 15.2± 8.9 yrs) having very low glycemia in third trimester (&amp;lt; 3 mmol/L or 55 mg/dL) were included in the study. Patients used intermittently scanned continuous glucose monitoring (isCGM) FreeStyle Libre, Abott for a minimum of 3 months before conception and had glucose data availability &amp;gt; 80% of the time. Data from first trimester showed mean scanning frequency 12.17 ± 6.5 scans/day, estimated average glucose 7.2 ± 1.4 mmol/L, CV% 41.9 ± 6.5, GMI 6.4 ± 0.5, time below range &amp;lt;3.5 mmol/L or 64 mg/dL 10.7 ± 8.0 % and time spent in very low glucose range &amp;lt;3mmol/L or 55 mg/dL 5.4 ± 4.9 %. In last trimester mean scanning frequency was 16.3 ± 7.6 scans/day, estimated average glucose 6.1 ± 0.9 mmol/L, CV% 34.6 ±6.0 , GMI 5.9 ± 0.4 , time below range 11.0 ±9.3 %, time spent in very low glucose range 5.2 ± 4.8 %. Parameters from the first trimester of pregnancy significantly correlating with time spent in very low glucose range in the third trimester were scanning frequency (r −0.365, p 0.37) and CV % (r 0.465, p 0.006) . Linear regression analysis performed for CV% and scanning frequency showed R square 0.434 and p 0.002 in ANOVA. Two isCGM parameters from first trimester of pregnancy that influence on very low glucose rate in the third one are low scanning frequency and higher %CV. Combined they add to 43% of very low glucose occurrence. Patients who scan frequently in the first trimester of pregnancy and have low glucose variability spend less time in very low glucose range in the third trimester. For the others continuous glucose monitoring with hypo alerts should be offered. Disclosure M. Baretic: None. G. Leksic: None. M. Ivanisevic: None.

990-P: Prebiotics and Metformin: A Pilot Randomized Controlled Trial in Youth-Onset Type 2 Diabetes

Metformin is the only first-line oral agent for youth with type 2 diabetes mellitus (Y-T2D) , but efficacy and adherence is complicated by gastrointestinal (GI) side effects. Prebiotic microbiome modulators (MM) may reduce side effects by shifting the microbial flora and promoting metabolism of short-chain fatty acid producing bacteria. The feasibility and tolerability of prebiotic use in Y-T2D is unknown. We hypothesized that a prebiotic MM would be safe, tolerable, and decrease GI symptoms in youth. We compared lower GI symptoms and glycemia in Y-T2D at initiation of daily metformin therapy in a 1-week, randomized, double-blind, crossover trial of a daily prebiotic MM versus placebo shake (Phase 1) followed by a 1 month open-labeled extension (Phase 2) . We assessed stool frequency, stool consistency (King’s Stool Chart) , and used principal component analysis to create a composite GI symptom score (urgency, bloating, flatulence, consistency) . Mixed effects models were used to compare continuous glucose monitor profiles and quality of life metrics (Pediatric Quality of Life Inventory™) . In six Y-T2D (17.2±1.7y (mean±SD) , 66% female, BMI 42±9 kg/m2, HbA1c 6.4±0.6%) stool frequency was assessed every 1-2 days. Stool frequency, stool composition, GI symptom score, and quality of life scores were not different by group or study phase. There were no severe adverse effects during the trial. One youth had increased bloating and discontinued the prebiotic in Phase 2. During phase 1, prebiotic MM tended to have lower average glucose (122±26 vs. 135±23 mg/dL, P=0.07) but this was not sustained in phase 2 (136±31 vs.135±23, P=0.8) . Time in range, standard deviation, and coefficient of variation of glucose were similar during the study. In summary, the prebiotic MM was well tolerated during short-term metformin therapy in Y-T2D, but was not associated with GI symptom, quality of life, or metabolic changes. Future studies should explore localized gut and systemic metabolic effects of prebiotics in youth. Disclosure K. Tuttle: None. L. Mabundo: None. M.S. Stagliano: None. K.B. Dietsche: None. A.B. Courville: None. D.E. Estrada: None. S.T. Chung: None. Funding NIDDK/NIH Intramural Research Program

1513-PUB: HMGB1 Knockdown Increases Glucose Sensitivity, Decreases Hyperglycemia and Insulin Resistance in Type 2 Diabetes

Introduction: Type-2 diabetes (T2D) characterizes by chronic hyperglycemia and insulin resistance. Hyperglycemia causes tissue damage and serious complications. High Mobility Group Box-1 (HMGB1) mediates the onset and progression of T2D, but the exact mechanism of HMGB1 glucose regulation in T2D is poorly understood. Global knockout of HMGB1 is fatal in neonatal mice primarily due to hypoglycemia. Therefore, using an inducible HMGB1 Knockout (iHMGB1 KO) model we evaluated the role of HMGB1 in adult mice progression of T2D (3) . We hypothesize that iHMGB1 KO mice will have decreased longitudinal hyperglycemia with decreased insulin resistance in a Streptozotocin (STZ) induced model of T2D. Methods: Male 8-week adult iHMGB1 KO mice were injected with Tamoxifen IP for days (1mg/kg) to induce HMGB1 knockdown. HMGB1 Flox (wildtype) were used as control. Then, mice were injected with STZ IP for 5 days (25mg/kg) , diabetic phenotype developed for weeks. HMGB1 knockdown was characterized via immunoblot and RT-PCR. Mice were placed on normal or high fat diet to evaluate T2D progression via metabolic cage analysis (MCA) . Glucose and insulin tolerance tests (GTT and ITT) were performed. Results: HMGB1 was significantly knocked down in iHMGB1 KO mice. MCA showed that STZ + normal diet had the appropriate respiratory quotient for translational T2D. GTT and ITT demonstrated higher glucose sensitivity and insulin tolerance in iHMGB1 KO T2D mice. Longitudinal glycemia measurement showed that iHMGB1 KO T2D mice have a progressively lower glycemia. Conclusion: With an effective knockdown of HMGB1, we evidenced increased glucose sensitivity, decreased hyperglycemia and insulin resistance in STZ induced T2D mice. Findings show that decreasing HMGB1 allows T2D adult mice to regulate glucose metabolism and insulin sensitivity better. Further studies will be directed to investigate the mechanisms that govern the role of HMGB1 in T2D. Disclosure Z.Liu: None. R.I.Mota alvidrez: None. Funding This work was funded by department of surgery support for RIMA

Characterization of the metabolic differences between male and female C57BL/6 mice

AimsThe present study aims to compare the responses between male and female C57BL/6 mice to multiple metabolic challenges to understand the importance of sex in the control of energy homeostasis. Main methodsMale and female C57BL/6 mice were subjected to nutritional and hormonal challenges, such as food restriction and refeeding, diet-induced obesity, feeding response to ghrelin and leptin, ghrelin-induced growth hormone secretion, and central responsiveness to ghrelin and leptin. The hypothalamic expression of transcripts that control energy homeostasis was also evaluated. Key findingsMale mice lost more weight and lean body mass in response to food restriction, compared to females. During refeeding, males accumulated more body fat and exhibited lower energy expenditure and glycemia, as compared to females. Additionally, female mice exhibited a higher protection against diet-induced obesity and related metabolic imbalances in comparison to males. Low dose ghrelin injection elicited higher food intake and growth hormone secretion in male mice, whereas the acute anorexigenic effect of leptin was more robust in females. However, the sex differences in the feeding responses to ghrelin and leptin were not explained by variations in the central responsiveness to these hormones nor by differences in the fiber density from arcuate nucleus neurons. Female, but not male, mice exhibited compensatory increases in hypothalamic Pomc mRNA levels in response to diet-induced obesity. SignificanceOur findings revealed several sexually differentiated responses to metabolic challenges in C57BL/6 mice, highlighting the importance of taking into account sex differences in metabolic studies.

Metabolic effect of orchidectomy on C57BL6/J mice exposed to intermittent hypoxia

IntroductionSleep apnea (SA) is characterized by obstructions of the airways or cessation of breathing during sleep leading to intermittent hypoxia (IH). IH is a source of oxidative stress and inflammation altering the functions of pancreas, liver, muscles and adipose tissue. As a consequence, sleep apnea patients have a high prevalence of insulin resistance and glucose intolerance which can lead to type 2 diabetes. In mice, exposures to IH induce adipose tissue inflammation, liver injury and worsen the pancreatic β‐cell injury in a model of diabetes. While these effects are associated with insulin resistance, glucose tolerance is improved, notably via an enhanced glucose uptake by skeletal muscles. In men, sleep apnea and diabetes are also characterized by low testosterone levels. Interestingly, testosterone levels are positively corelated with insulin sensitivity in human, and low testosterone levels can be associated with inflammation, oxidative stress and insulin resistance. Therefore, we tested the hypothesis that testosterone modulates the metabolic alterations induced by IH in male mice.MethodWe used intact (Sham) or orchidectomized (ORX) C57BL/6J male mice exposed for 14 days to IH (12h / day, 10 cycles / h, 6% nadir oxygen) or normoxia (Nx). The animals were weighed, and we assessed body composition in terms of lean and fat mass, as well as fluid content by using a small animal MRI scanner before the surgery, before IH or Nx exposures and at the end of the protocol. The day after the last IH session, mice were fasted for 6h, we measured fasting glycaemia and insulinemia then we performed a glucose tolerance test.ResultsIn Sham mice, IH decreased bodyweight and fat mass. This was associated with a decrease of fasting glycaemia, insulinemia and HOMA‐IR (index of insulin resistance), and improved glucose sensitivity. ORX decreased bodyweight and lean tissue mass, associated with lower fasting glycemia, insulinemia, HOMA‐IR and improved whole body glucose sensitivity. ORX mice exposed to IH had a decrease of both fat and lean tissue mass leading to further reduction of body weight. However, there was no additive effects of ORX and ORX IH for fasting glycaemia, insulinemia, HOMA‐IR and glucose sensitivity.ConclusionIH and ORX respectively reduce fat and lean tissue mass, and these effects are additive when both stimuli are applied simultaneously. Contrastingly, there are no additive effects of IH and ORX on the metabolic parameters reported here.

Pasta Structure Affects Mastication, Bolus Properties, and Postprandial Glucose and Insulin Metabolism in Healthy Adults

ABSTRACTBackgroundStructure and protein–starch interactions in pasta products can be responsible for lower postprandial glycemic responses compared with other cereal foods.ObjectivesWe tested the effect on postprandial glucose metabolism induced by 2 pasta products, couscous, and bread, through their structural changes during mastication and simulated gastric digestion.MethodsTwo randomized controlled trials (n = 30/trial) in healthy, normal-weight adults (mean BMI of 23.9 kg/m2 (study 1) and 23.0 kg/m2 (study 2)) evaluated postprandial glucose metabolism modulation to portions of durum wheat semolina spaghetti, penne, couscous, and bread each containing 50 g available carbohydrate. A mastication trial involving 26 normal-weight adults was conducted to investigate mastication processes and changes in particle size distribution and microstructure (light microscopy) of boluses after mastication and in vitro gastric digestion.ResultsBoth pasta products resulted in lower areas under the 2-h curve for blood glucose (−40% for spaghetti and −22% for penne compared with couscous; −41% for spaghetti and −30% for penne compared with bread), compared with the other grain products (P < 0.05). Pasta products required more chews (spaghetti: 34 ± 18; penne: 38 ± 20; bread: 27 ± 13; couscous: 24 ± 17) and longer oral processing (spaghetti: 21 ± 13 s; penne: 23 ± 14 s; bread: 18 ± 9 s; couscous: 14 ± 10 s) compared with bread or couscous (P < 0.01). Pastas contained more large particles (46–67% of total particle area) compared with bread (0–30%) and couscous (1%) after mastication and in vitro gastric digestion. After in vitro gastric digestion, pasta samples still contained large areas of nonhydrolyzed starch embedded within the protein network; the protein in bread and couscous was almost entirely digested, and the starch was hydrolyzed.ConclusionsPreservation of the pasta structure during mastication and gastric digestion explains slower starch hydrolysis and, consequently, lower postprandial glycemia compared with bread or couscous prepared from the same durum wheat semolina flour in healthy adults.The postprandial in vivo trials were registered at clinicaltrials.gov as NCT03098017 and NCT03104686.

Matched whole grain wheat and refined wheat milled products do not differ in glycemic response or gastric emptying in a randomized, crossover trial

Epidemiologic and some clinical studies support the view that whole grain foods have lower glycemic response than refined grain foods. However, from the perspective of food material properties, it is not clear why whole grain cereals containing mostly insoluble and nonviscous dietary fibers (e.g., wheat) would reduce postprandial glycemia. We hypothesized that glycemic response for whole grain wheat milled products would not differ from that of refined wheat when potentially confounding variables (wheat source, food form, particle size, viscosity) were matched. Our objective was to study the effect of whole grain wheat compared with refined wheat milled products on postprandial glycemia, gastric emptying, and subjective appetite. Using a randomized crossover design, healthy participants (n=16) consumed 6 different medium-viscosity porridges made from whole grain wheat or refined wheat milled products, all from the same grain source and mill: whole wheat flour, refined wheat flour, cracked wheat, semolina, reconstituted wheat flour with fine bran, and reconstituted wheat flour with coarse bran. Postprandial glycemia, gastric emptying, and appetitive response were measured using continuous glucose monitors, the 13C-octanoic acid (8:0) breath test, and visual analog scale (VAS) ratings. Bayes factors were implemented to draw inferences about null effects. Little-to-no differences were observed in glycemic responses, with lower incremental AUC between 0 and 120min glycemic responses only for semolina [mean difference (MD): -966mg min/dL; 95% CI: -1775, -156mg min/dL; P = 0.02) and cracked wheat (MD: -721mg min/dL; 95% CI: -1426, -16mg min/dL; P = 0.04) than for whole wheat flour porridge. Bayes factors suggested weak to strong evidence for a null effect (i.e., no effect of treatment type) in glycemic response, gastric emptying, and VAS ratings. Although whole grain wheat foods provide other health benefits, they did not in their natural composition confer lower postprandial glycemia or gastric emptying than their refined wheat counterparts.This trial was registered at clinicaltrials.gov as NCT03467659.

Corticosterone induces discrete epigenetic signatures in the dorsal and ventral hippocampus that depend upon sex and genotype: focus on methylated Nr3c1 gene

The genomic effects of circulating glucocorticoids are particularly relevant in cortico-limbic structures, which express a high concentration of steroid hormone receptors. To date, no studies have investigated genomic differences in hippocampal subregions, namely the dorsal (dHPC) and ventral (vHPC) hippocampus, in preclinical models treated with exogenous glucocorticoids. Chronic oral corticosterone (CORT) in mouse is a pharmacological approach that disrupts the activity of the hypothalamic-pituitary-adrenal axis, increases affective behavior, and induces genomic changes after stress in the HPC of wildtype (WT) mice and mice heterozygous for the gene coding for brain-derived neurotrophic factor Val66Met (hMet), a variant associated with genetic susceptibility to stress. Using RNA-sequencing, we investigated the genomic signatures of oral CORT in the dHPC and vHPC of WT and hMet male and female mice, and examined sex and genotype differences in response to oral CORT. Males under CORT showed lower glycemia and increased anxiety- and depression-like behavior compared to females that showed instead opposite affective behavior in response to CORT. Rank–rank-hypergeometric overlap (RRHO) was used to identify genes from a continuous gradient of significancy that were concordant across groups. RRHO showed that CORT-induced differentially expressed genes (DEGs) in WT mice and hMet mice converged in the dHPC of males and females, while in the vHPC, DEGs converged in males and diverged in females. The vHPC showed a higher number of DEGs compared to the dHPC and exhibited sex differences related to glucocorticoid receptor (GR)-binding genes and epigenetic modifiers. Methyl-DNA-immunoprecipitation in the vHPC revealed differential methylation of the exons 1C and 1F of the GR gene (Nr3c1) in hMet females. Together, we report behavioral and endocrinological sex differences in response to CORT, as well as epigenetic signatures that i) differ in the dHPC and vHPC,ii) are distinct in males and females, and iii) implicate differential methylation of Nr3c1 selectively in hMet females.

PalatinoseTM (Isomaltulose) and Prebiotic Inulin-Type Fructans Have Beneficial Effects on Glycemic Response and Gut Microbiota Composition in Healthy Volunteers-A Real-Life, Retrospective Study of a Cohort That Participated in a Digital Nutrition Program.

It is well-appreciated that the diet is a crucial tool to counteract cardiometabolic disturbances due to its impact on blood glucose concentration and gut microbiome. This retrospective analysis aimed to examine whether the inclusion of isomaltulose and prebiotic inulin-type fructans (ITF) into the habitual diet has an impact on glycemic control and gut microbiota. Furthermore, we examined interindividual differences in glycemic response to sugar replacement with isomaltulose. We retrospectively analyzed data of 117 individuals who participated in a digital nutrition program including a 14-day continuous glucose measurement. Participants underwent six test days with sweetened drinks (isomaltulose vs. sucrose) consumed with their usual breakfasts and lunches. Dinner was supplemented with ITF for 11 days. Postprandial glycemia and 24 h-glycemic variability were determined following test meals and days, respectively. Fecal microbiota was analyzed by 16S rRNA sequencing before and after test phase. Meals with isomaltulose-sweetened drinks compared to meals with sucrose-sweetened drinks induced lower postprandial glycemia. Moreover, glucose oscillations over 24 h were lower on isomaltulose when compared to sucrose test days and improved further during ITF supplementation. Furthermore, ITF modulated gut microbiota composition beneficially. Responder analysis revealed that 72% of participants benefited from the sugar replacement with isomaltulose and that their gut microbiota differed from the low responders. Taken together, the incorporation of isomaltulose and ITF into the habitual diet was shown to be an effective strategy to improve glucose control and beneficially modulate gut microbiota, and thereby aid to maintain metabolic health. Data indicate interindividual differences in glycemic response to ingredients and suggest that gut microbiota might be somehow related to it.

Lower miR-21/ROS/HNE levels associate with lower glycemia after habit-intervention: DIAPASON study 1-year later

BackgroundThe prevalence of prediabetes is increasing in the global population and its metabolic derangements may expose to a higher risk to develop type 2 diabetes (T2D) and its cardiovascular burden. Lifestyle modifications might have considerable benefits on ameliorating metabolic status. Alternative biomarkers, such as circulating miR-21, has been recently discovered associated with dysglycemia. Here we evaluated, in a longitudinal cohort of dysglycemic population the relation between the circulating miR-21/ROS/HNE levels and the habit-intervention (HI) after 1 year of follow-up.Methods1506 subjects from DIAPASON study were screened based on the Findrisc score. Of them, 531 subjects with Findrisc ≥ 9 were selected for dysglycemia (ADA criteria) and tested for circulating miR-21, ROS and HNE levels, as damaging-axis. 207 subjects with dysglycemia were re-evaluated after 1-year of habit intervention (HI). Repeated measures tests were used to evaluate changes from baseline to 1-year of follow-up. The associations between glycemic parameters and miR-21/ROS/HNE were implemented by linear regression and logistic regression models.ResultsAfter HI, we observed a significant reduction of miR-21/ROS/HNE axis in dysglycemic subjects, concomitantly with ameliorating of metabolic parameters, including insulin resistance, BMI, microalbuminuria, reactive hyperemia index and skin fluorescence. Significant positive interaction was observed between miR-21 axis with glycaemic parameters after HI. Lower miR-21 levels after HI, strongly associated with a reduction of glycemic damaging-axis, in particular, within-subjects with values of 2hPG < 200 mg/dL.ConclusionsOur findings demonstrated that HI influenced the epigenetic changes related to miR-21 axis, and sustain the concept of reversibility from dysglycemia. These data support the usefulness of novel biological approaches for monitoring glycemia as well as provide a screening tool for preventive programmes.

Ischemic stroke and reperfusion therapies in diabetic patients.

The study aimed to identify the main prognostic factors in diabetic patients with ischemic stroke undergoing reperfusion therapies (RT). This retrospective study included 170 diabetic patients: 62 treated with intravenous thrombolysis (IVT) alone and 108 with mechanical thrombectomy (MT). Among MT patients, 29 underwent IVT. We collected clinical, laboratory, and radiological data. The outcomes were 3-month functional impairment (measured by modified Rankin scale, mRs), discharge neurological severity (measured by National Institutes of Health Stroke Scale score, NIHSS), 3-month mortality, intracranial hemorrhage (ICH), and symptomatic intracranial hemorrhage (SICH). We performed a general analysis for all RT and sub-group analyses for IVT and MT. A lower mRs was associated with lower glycemia and admission NIHSS (aNIHSS) in all RT and MT; lower aNIHSS and younger age in IVT. Mortality increased with hyperglycemia, aNIHSS, and age in all RT; age and aNIHSS in IVT; hyperglycemia and systolic pressure in MT. A lower discharge NIHSS was related with lower aNIHSS, thrombolysis, and no thrombectomy in all RT; lower aNIHSS in IVT; lower aNIHSS and thrombolysis in MT. ICH was associated with elevated aNIHSS, older age, and lower platelets in all RT; lower platelets and older age in IVT; higher aNIHSS in MT. SICH depended on longer thrombectomy duration in all RT; no metformin use in IVT; higher weight in MT. The study shed light on diabetic patients and stroke RT highlighting the protective effect of metformin in IVT and the role of glycemia, weight, and combined treatment in MT.

Metabolic phenotypes explain the relationship between dysglycaemia and frailty in older people with type 2 diabetes

BackgroundDysglycaemia (hyperglycaemia and hypoglycaemia) increase the risk of frailty in older people with diabetes, which appears contradictory. However, the characteristics of patients included in these studies are different and may reflect different metabolic phenotypes of frailty that may explain this apparent contradiction. AimsTo review the characteristics of frail patients included in clinical studies that reported an association between dysglycaemia and frailty in order to explore whether there is any metabolic differences in the profile of these patients. MethodsA systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Key words around older people, type 2 diabetes mellitus, frailty, hyperglycaemia and low glycaemia were used in the literature search. ResultsOnly 8 studies met the inclusion criteria. Four studies investigated the risk of frailty associated with low glycaemia. Two studies showed that hypoglycaemia increased the risk of frailty by 44% (HR 1.60, 95% CI 1.14 to 2.42) and predicted greater level of dependency (p < 0.001), respectively. The other two studies reported that HbA1c inversely correlated with clinical frailty scale (r = −0.31, p < 0.01) and HbA1c < 6.0% was associated with increased risk of disability (3.45, 1.02 to 11.6), respectively. Compared with non-frail patients, those with frailty tended to have lower body weight or body mass index (BMI), have features of malnutrition such as low serum albumin or low total cholesterol and suffer from more comorbidities including dementia. Four studies explored the association of high glycaemia with frailty. Higher HbA1c predicted frailty (OR 1.43, 95% CI 1.045 to 1.97) and positively correlated with Edmonton frail score (r = 0.44, p < 0.001), respectively in two studies. The other two studies found that subjects with HbA1c ≥ 6.5% had the greatest prevalence of frailty (70.3%) and subjects with higher HbA1c at baseline to have a higher frailty level throughout later life, respectively. Compared with non-frail patients, those with frailty tended to have higher body weight, waist circumference and BMI. They also have less physical activity, higher cholesterol level and have more comorbidities. ConclusionsDysglycaemia increases the risk of frailty but the characteristics of patients in these studies suggest different metabolic phenotypes of frailty. Therefore, these metabolic differences in frailty should be taken into consideration in the management of older people with diabetes.

Metformin action over gut microbiota is related to weight and glycemic control in gestational diabetes mellitus: A randomized trial.

Metformin, which is known to produce profound changes in gut microbiota, is being increasingly used in gestational diabetes mellitus (GDM). The aim of this study was to elucidate the differences in gut microbiota composition and function in women with GDM treated with metformin compared to those treated with insulin. From May to December 2018, 58 women with GDM were randomized to receive insulin (INS; n=28) or metformin (MET; n=30) at the University Hospital Virgen de la Victoria, Málaga, Spain. Basal visits, with at least 1 follow-up visit and prepartum visit, were performed. At the basal and prepartum visits, blood and stool samples were collected. The gut microbiota profile was determined through 16S rRNA analysis. Compared to INS, women on MET presented a lower mean postprandial glycemia and a lower increase in weight and body mass index (BMI). Firmicutes and Peptostreptococcaceae abundance declined, while Proteobacteria and Enterobacteriaceae abundance increased in the MET group. We found inverse correlations between changes in the abundance of Proteobacteria and mean postprandial glycemia (p=0.023), as well as between Enterobacteriaceae and a rise in BMI and weight gain (p=0.031 and p=0.036, respectively). Regarding the metabolic profile of gut microbiota, predicted metabolic pathways related to propionate degradation and ubiquinol biosynthesis predominated in the MET group. Metformin in GDM affects the composition and metabolic profile of gut microbiota. These changes could mediate, at least in part, its clinical effects. Studies designed to assess how these changes influence metabolic control during and after pregnancy are necessary.

ASSOCIATIONS OF ENOS GLU298ASP (G894T) ENDOTHELIAL DYSFUNCTION GENE POLYMORPHISMS WITH METABOLIC DISORDERS IN PATHOLOGICAL PREGNANCY.

The aim: To determine the association between the Glu298Asp (G894T) polymorphisms of the eNOS gene with metabolic disorders in excessive gestational weight gain (GWG) pregnancy. Materials and methods: 97 pregnant women in 9-12, and 37-39 weeks of gestation were examined. The recommended GWG was diagnosed in 33 (34.0 %), insufficient in 19 (19.6 %), and excessive in 45 (46.4 %) patients. Genetic variants of eNOS were analyzed by real-time polymerase chain reaction, lipid profile, and carbohydrate status were performed. The results were statistically analyzed using Statistica 6.0 program pack (StatSoft Inc., USA) and Microsoft Excel statistical analysis package. Results: GWG in the group of patients with gene eNOS TT polymorphism was significantly higher (1.5-fold) compared to pregnant with GG - genotype (р<0.05). Pregnant, inherited the TT allele of the eNOS gene, associated with higher levels of hypertriglyceridemia, hypercholesterolemia, of lipoprotein low density, glycemia, hyperinsulinemia, and higher HOMA-IR compared to carriers of GG and GT alleles (р<0.05) in the third trimester, which is especially manifested in excessive GWG. Conclusions: Decreased activity of the eNOS gene in the presence of pathological alleles is the initiator of impaired lipid and carbohydrate metabolisms and, as a consequence, excessive GWG. A high risk of excessive GWG was found in pregnant women with TT polymorphism Glu298Asp (G894T) (OR=4.52; 95%CI: 1.18-17.32; р<0.05) (frequency distribution of 73.7 %). Endothelial dysfunction is a pathogenetic link of excessive body weigh in pregnancy.

BACH2 inhibition reverses β cell failure in type 2 diabetes models.

Type 2 diabetes (T2D) is associated with defective insulin secretion and reduced β cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of β cell failure is a key translational question. Here, we reverse engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic inflexibility and endocrine progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca2+ flux analyses of top candidate master regulatory (MR) proteins in islet cells validated transcription factor BACH2 and associated epigenetic effectors as key drivers of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a nondiabetic phenotype. BACH2-immunoreactive islet cells increased approximately 4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing β cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.

Aerobic Physical Exercise Improves Exercise Tolerance and Fasting Glycemia Independent of Body Weight Change in Obese Females.

Obesity is associated with increased risk of several chronic diseases and the loss of disease-free years, which has increased the focus of much research for the discovery of therapy to combat it. Under healthy conditions, women tend to store more fat in subcutaneous deposits. However, this sexual dimorphism tends to be lost in the presence of comorbidities, such as type 2 diabetes mellitus (T2DM). Aerobic physical exercise (APE) has been applied in the management of obesity, however, is still necessary to better understand the effects of APE in obese female. Thus, we investigated the effect of APE on body weight, adiposity, exercise tolerance and glucose metabolism in female ob/ob mice. Eight-weeks-old female wild-type C57BL/6J and leptin-deficient ob/ob mice (Lepob) were distributed into three groups: wild-type sedentary group (Wt; n = 6), leptin-deficient sedentary group (LepobS; n = 5) and leptin-deficient trained group (LepobT; n = 8). The LepobT mice were subjected to 8 weeks of aerobic physical exercise (APE) at 60% of the maximum velocity achieved in the running capacity test. The APE had no effect in attenuating body weight gain, and did not reduce subcutaneous and retroperitoneal white adipose tissue (SC-WAT and RP-WAT, respectively) and interscapular brown adipose tissue (iBAT) weights. The APE neither improved glucose intolerance nor insulin resistance in the LepobT group. Also, the APE did not reduce the diameter or the area of RP-WAT adipocytes, but the APE reduced the diameter and the area of SC-WAT adipocytes, which was associated with lower fasting glycemia and islet/pancreas area ratio in the LepobT group. In addition, the APE increased exercise tolerance and this response was also associated with lower fasting glycemia in the LepobT group. In conclusion, starting APE at a later age with a more severe degree of obesity did not attenuate the excessive body weight gain, however the APE promoted benefits that can improve the female health, and for this reason it should be recommended as a non-pharmacological therapy for obesity.

L-Glutamine supplementation enhances glutathione peroxidase and paraoxonase-1 activities in HDL of exercising older individuals.

Oxidative stress is an important factor in the formation of atherosclerotic plaques. High-density lipoprotein (HDL) harbors paraoxonase-1 (PON-1) and glutathione peroxidase (GPx), key enzymes in the protection against the harmful effects of oxidative stress. Although exercise training can increase both HDL-c content and its antioxidant action, and glutamine (Gln) intake also promotes GPx-based defenses, the association between exercise training and Gln in the regulation of PON-1 activity was not explored. Therefore, the objective of this study was to investigate the effects of Gln supplementation on the redox balance and on the total HDL antioxidant capacity by evaluation of the activity of PON-1 and GPx enzymes in physically exercised elderly individuals compared to non-exercised ones. Fifty-one practitioners of a combined exercise training program (CET, age: 71.9±5.7years) and 32 non-practitioners (NP, age: 73±6.3years) participated in the study. CET and NP groups were separated into 2 subgroups according to the supplementation: Gln, 0.3g/kg/day + 10g maltodextrin (CET-Gln, n=26; and NP-Gln, n=16) or placebo, 10g maltodextrin (CET-PL, n=25; and NP-PL, n=16). Blood samples were drawn at baseline and after 30days after commencement of the supplementation for biochemical and enzyme activity analyses. Increased HDL-c, total peroxidase (PRx), and GPx activities were found in both CET-Gln and NP-Gln after the supplementation period, compared to baseline, in opposition to CET-PL and NP-PL groups. PON-1 activity increased only in CET-Gln. In both CET-Gln and NP-Gln groups, there was a reduction of the total peroxides/PRx, iron/PRx, and total peroxides/GPX ratios after supplementation. In CET-Gln, thiobarbituric acid-reactive substances (TBARS)/PRx and TBARS/GPx ratios were also lower after supplementation. CET-Gln and CET-PL subgroups had lower glycemia than NP-Gln and NP-PL, either at baseline or after the supplementation periods. The other parameters were unchanged after supplementation [total cholesterol, LDL-c, triglycerides, non-HDL cholesterol, total peroxides, TBARS, iron serum, Trolox-equivalent antioxidant capacity (TEAC), and uric acid]. Gln supplementation can increase glutathione peroxidase activity regardless the individuals were physically active or sedentary, but the PON-1 activity only increased in physically active individuals. These results show the potential of Gln supplementation in the maintenance of the vascular redox balance, with potential implications for atherogenesis protection.