Glucose Challenge Research Articles

Glucose-Responsive Injectable Thermogels via Dynamic-Covalent Cross-Linking of Pluronic Micelles.

Stimuli-responsive hydrogels are an area of active discovery for approaches to deliver therapeutics in response to disease-specific indicators. Glucose-responsive delivery of insulin is of particular interest in better managing diabetes. Accordingly, hydrogels have been explored as platforms that enable both a rate and dose of insulin release aligning with the real-time physiological disease state; materials often include glucose sensing by dynamic-covalent cross-linking between phenylboronic acids (PBAs) and diols, with competition from ambient glucose reducing cross-link density of the material and accelerating release of encapsulated insulin. Yet, these materials historically have challenges with insulin leakage, offer limited glucose-responsive release of the insulin payload, and require unreasonably high injection pressures for syringe administration. Here, a thermogel platform prepared from temperature-induced micelles formed into a network by PBA-Diol cross-linking is optimized using a formulation-centered approach to maximize glucose-responsive insulin delivery. Importantly, the dual-responsive nature of this platform enables a low-viscosity sol at ambient temperature for facile injection, solidifying into a stable viscoelastic hydrogel network once in the body. The final optimized formulation affords acceleration in insulin release in response to glucose and enables single dose blood glucose control in diabetic rodents when subjected to multiple glucose challenges.

Insulin Response to Oral Glucose and Cardiometabolic Disease: A Mendelian Randomization Study to Assess Potential Causality

Mendelian randomization (MR) suggests post-prandial hyperinsulinemia (unadjusted for plasma glucose) increases body mass index (BMI) but its impact on cardiometabolic disease (CMD), a leading cause for mortality and morbidity in people with obesity, is not established. Fat distribution, i.e. increased centripetal and/or reduced femoro-gluteal adiposity, is causally associated with and better predicts CMD than BMI. We therefore undertook bi-directional MR to assess the effect of corrected insulin response (CIR, insulin 30 minutes after a glucose challenge adjusted for plasma glucose) on BMI, waist–to-hip ratio (WHR), leg fat, type 2 diabetes (T2D), triglyceride (TG), high-density lipoprotein (HDL), liver fat, hypertension and CAD in people of European descent.

Effect of Aerobic Exercise Training on Circulating Fibroblast Growth Factor-21 Response to Glucose Challenge in Overweight and Obese Men: A Pilot Study

Fibroblast growth factor-21 (FGF21) is a liver-derived hormone that lowers blood glucose. Although aerobic exercise training also lowers blood glucose, its effect on circulating FGF21levels remains obscure. This study aimed to examine the effect of aerobic exercise training on serum FGF21 levels in overweight and obese men. A total of 14 overweight/obese men were included in the analyses. Participants attended supervised aerobic exercise training for 12 weeks (three times per week) and completed the standard oral glucose tolerance test pre- and post-exercise training. Plasma glucose, serum insulin, and serum FGF21 levels were measured at fasting and 60 and 120 min after glucose loading. The exercise training reduced plasma glucose and serum FGF21 levels during glucose loading (p<0.05). The change in the area under the curve of plasma glucose was positively correlated with that in the area under the curve of serum FGF21 (r s =0.569, p=0.034). Lowering postprandial circulating FGF21 levels may be associated with the improved glucose tolerance induced by habitual aerobic exercise in overweight and obese men.

3D-printed polyurethane immunoisolation bags with controlled pore architecture for macroencapsulation of islet clusters encapsulated in alginate gel.

Diabetes mellitus is a fast-growing chronic metabolic condition caused by insulin deficiency or resistance, leading to lifelong insulin use. It has become one of the world's most difficult non-communicable diseases. The goal of this study was to view the effectiveness of the combined method of macro- and microencapsulation for islet transplantation. The process of 3D printing is used to make macroencapsulation bags with regulated diffusion properties thanks to the emerging small pored channels. The ink used to manufacture 3D-printed bags with controlled specifications was polyurethane solution(13% w/v). Swelling experiments revealed that there was very little swelling and that the membrane maintained its structural stability. Alginate beads (made from 5% w/v solution) were used to microencapsulate islet cell clusters. Direct contact assay was used to confirm in vitro cytocompatibility. The insulin release from the encapsulated rabbit islets was confirmed using a glucose challenge assay. When challenged with 20mM glucose on day 7, the encapsulated islet cells released insulin at a rate of 9.72 ± 0.65mU/L, which was identical to the RIN-5F islet cell line control, confirming the functioning of the encapsulated islets. After 21days of culture, the islets were shown to be viable utilizing a live-dead assay. As a result, our work demonstrates that 3D printing for macroencapsulating cells, as well as microencapsulation with alginates, is a viable scale-up technology with great potential in the field of pancreatic islet transplantation.

Bioengineered Pancreas-Liver Crosstalk in a Microfluidic Coculture Chip Identifies Human Metabolic Response Signatures in Prediabetic Hyperglycemia.

Aberrant glucose homeostasis is the most common metabolic disturbance affecting one in ten adults worldwide. Prediabetic hyperglycemia due to dysfunctional interactions between different human tissues, including pancreas and liver, constitutes the largest risk factor for the development of type 2 diabetes. However, this early stage of metabolic disease has received relatively little attention. Microphysiological tissue models that emulate tissue crosstalk offer emerging opportunities to study metabolic interactions. Here, a novel modular multitissue organ-on-a-chip device is presented that allows for integrated and reciprocal communication between different 3D primary human tissue cultures. Precisely controlled heterologous perfusion of each tissue chamber is achieved through a microfluidic single "synthetic heart" pneumatic actuation unit connected to multiple tissue chambers via specific configuration of microchannel resistances. On-chip coculture experiments of organotypic primary human liver spheroids and intact primary human islets demonstrate insulin secretion and hepatic insulin response dynamics at physiological timescales upon glucose challenge. Integration of transcriptomic analyses with promoter motif activity data of 503 transcription factors reveals tissue-specific interacting molecular networks that underlie β-cell stress in prediabetic hyperglycemia. Interestingly, liver and islet cultures show surprising counter-regulation of transcriptional programs, emphasizing the power of microphysiological coculture to elucidate the systems biology of metabolic crosstalk.

Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function

Diabetes is a multifactorial disorder characterized by loss or dysfunction of pancreatic β-cells. β-cells are heterogeneous, exhibiting different glucose sensing, insulin secretion and gene expression. They communicate with other endocrine cell types via paracrine signals and between β-cells via gap junctions. Here, we identify the importance of signaling between β-cells via the extracellular signal WNT4. We show heterogeneity in Wnt4 expression, most strikingly in the postnatal maturation period, Wnt4-positive cells, being more mature while Wnt4-negative cells are more proliferative. Knock-out in adult β-cells shows that WNT4 controls the activation of calcium signaling in response to a glucose challenge, as well as metabolic pathways converging to lower ATP/ADP ratios, thereby reducing insulin secretion. These results reveal that paracrine signaling between β-cells is important in addition to gap junctions in controling insulin secretion. Together with previous reports of WNT4 up-regulation in obesity our observations suggest an adaptive insulin response coordinating β-cells.

Acute Low Force Electrically Induced Exercise Modulates Post Prandial Glycemic Markers in People with Spinal Cord Injury.

Regular exercise involves daily muscle contractions helping metabolize up to 70% of daily ingested glucose. Skeletal muscle increases glucose uptake through two distinct pathways: insulin signaling pathway and muscle contraction mediated AMPK pathway. People with paralysis are unable to contract their muscles which atrophy, transform into insulin resistant glycolytic muscle, and develop osteoporosis. Our goal is to determine if low force electrically induced exercise (LFE) will modulate the post prandial insulin and glucose response in people with and without spinal cord injury (SCI). 18 people with SCI and 23 without SCI (Non-SCI) participated in an assessment of metabolic biomarkers during passive sitting (CTL) and a bout of LFE delivered to the quadriceps/hamstring muscle groups after a glucose challenge. Baseline fasting insulin (p = 0.003) and lactate (p = 0.033) levels were higher in people with SCI, but glucose levels (p = 0.888) were similar compared to the non-SCI population. After 1-h of muscle contractions using LFE, heart rate increased (p &lt; 0.001), capillary glucose decreased (p = 0.004), insulin decreased (p &lt; 0.001), and lactate increased (p = 0.001) in the SCI population. These findings support that LFE attenuates certain metabolic blood biomarkers during a glucose challenge and may offer a lifestyle strategy to regulate metabolic responses after eating among people with SCI.

Response of circulating metabolites to an oral glucose challenge and risk of cardiovascular disease and mortality in the community

BackgroundNew biomarkers to identify cardiovascular disease (CVD) risk earlier in its course are needed to enable targeted approaches for primordial prevention. We evaluated whether intraindividual changes in blood metabolites in response to an oral glucose tolerance test (OGTT) may provide incremental information regarding the risk of future CVD and mortality in the community.MethodsAn OGTT (75 g glucose) was administered to a subsample of Framingham Heart Study participants free from diabetes (n = 361). Profiling of 211 plasma metabolites was performed from blood samples drawn before and 2 h after OGTT. The log2(post/pre) metabolite levels (Δmetabolites) were related to incident CVD and mortality in Cox regression models adjusted for age, sex, baseline metabolite level, systolic blood pressure, hypertension treatment, body mass index, smoking, and total/high-density lipoprotein cholesterol. Select metabolites were related to subclinical cardiometabolic phenotypes using Spearman correlations adjusted for age, sex, and fasting metabolite level.ResultsOur sample included 42% women, with a mean age of 56 ± 9 years and a body mass index of 30.2 ± 5.3 kg/m2. The pre- to post-OGTT changes (Δmetabolite) were non-zero for 168 metabolites (at FDR ≤ 5%). A total of 132 CVD events and 144 deaths occurred during median follow-up of 24.9 years. In Cox models adjusted for clinical risk factors, four Δmetabolites were associated with incident CVD (higher glutamate and deoxycholate, lower inosine and lysophosphatidylcholine 18:2) and six Δmetabolites (higher hydroxyphenylacetate, triacylglycerol 56:5, alpha-ketogluturate, and lower phosphatidylcholine 32:0, glucuronate, N-monomethyl-arginine) were associated with death (P < 0.05). Notably, baseline metabolite levels were not associated with either outcome in models excluding Δmetabolites. The Δmetabolites exhibited varying cross-sectional correlation with subclinical risk factors such as visceral adiposity, insulin resistance, and vascular stiffness, but overall relations were modest. Significant Δmetabolites included those with established roles in cardiometabolic disease (e.g., glutamate, alpha-ketoglutarate) and metabolites with less defined roles (e.g., glucuronate, lipid species).ConclusionsDynamic changes in metabolite levels with an OGTT are associated with incident CVD and mortality and have potential relevance for identifying CVD risk earlier in its development and for discovering new potential therapeutic targets.

The Relationship Between Subclinical Hypothyroidism and Gestational Diabetes Mellitus

The most common metabolic disorder during pregnancy is gestational diabetes mellitus (GDM). GDM can occur in anywhere between 1.7 and 11.6 percent of people. In hypothyroidism, the rates of glucose oxidation and glycogen synthesis are reduced, and the peripheral tissues' consumption of glucose is also delayed. Patients with subclinical and overt hypothyroidism develop insulin resistance because insulin is unable to adequately maintain the muscles' use of glucose. According to the literature, hypothyroidism is linked to 6–15 percent of GDM pregnancies. Additionally, the chance of having GDM is 4.3 times higher in pregnant women who have hypothyroidism. This study aimed to reveal the relationship between first-trimester thyroid function tests and GDM. This retrospective cohort study was conducted between May 2021 and May 2022. 100 pregnant patients diagnosed with GDM and 500 healthy controls were included in the study. Using a 75 g glucose challenge test, GDM was identified. The trimester-specific recognized normal limits were used to evaluate the TSH and fT4 readings. There was a statistically significant difference in terms of SCH between patients with and without GDM (p=0.04). TSH's performance in predicting GDM was evaluated using AUC and ROC (AUC=0.586 and p=0.006). To forecast GDM, the TSH level cut-off value was discovered to be 1.58. The AUC was found to be 0.586 (0.521-0.652). Furthermore, the selectivity is 58% and the sensitivity is 41%. There are many studies in the literature investigating thyroid functions and the development of gestational diabetes mellitus. Our study also found a correlation between the diagnosis of subclinical hypothyroidism in the first trimester and GDM. The study adds to the literature the importance of being cautious and vigilant in terms of the development of gestational diabetes mellitus based on the results of the thyroid function test in the first trimester.

Subklinik Hipotiroidizm ile Gestasyonel Diabetes Mellitus Arasındaki İlişki

Aim: The most common metabolic disorder during pregnancy is gestational diabetes mellitus (GDM). GDM can occur in anywhere between 1.7 and 11.6 percent of people. In hypothyroidism, the rates of glucose oxidation and glycogen synthesis are reduced, and the peripheral tissues' consumption of glucose is also delayed. Patients with subclinical and overt hypothyroidism develop insulin resistance because insulin is unable to adequately maintain the muscles' use of glucose. According to the literature, hypothyroidism is linked to 6–15 percent of GDM pregnancies. Additionally, the chance of having GDM is 4.3 times higher in pregnant women who have hypothyroidism. This study aimed to reveal the relationship between first-trimester thyroid function tests and GDM. &#x0D; Material and Method: This retrospective cohort study was conducted between May 2021 and May 2022. 100 pregnant patients diagnosed with GDM and 500 healthy controls were included in the study. Using a 75 g glucose challenge test, GDM was identified. The trimester-specific recognized normal limits were used to evaluate the TSH and fT4 readings.&#x0D; Results: There was a statistically significant difference in terms of SCH between patients with and without GDM (p=0.04). TSH's performance in predicting GDM was evaluated using AUC and ROC (AUC=0.586 and p=0.006). To forecast GDM, the TSH level cut-off value was discovered to be 1.58. The AUC was found to be 0.586 (0.521-0.652). Furthermore, the selectivity is 58% and the sensitivity is 41%&#x0D; Conclusion: There are many studies in the literature investigating thyroid functions and the development of gestational diabetes mellitus. Our study also found a correlation between the diagnosis of subclinical hypothyroidism in the first trimester and GDM. The study adds to the literature the importance of being cautious and vigilant in terms of the development of gestational diabetes mellitus based on the results of the thyroid function test in the first trimester.

Risk of obstetric and neonatal morbidity in gestational diabetes in a single institution: A retrospective, observational study.

Gestational diabetes mellitus (GDM) is defined as a carbohydrate intolerance with onset or first recognition occurring during pregnancy and GDM could be risk factor for various maternal fetal complications. This study aimed to investigate risks of maternal and neonatal outcomes according to GDM and normal glucose tolerance. This retrospective, observational study included singleton pregnant women who had received a 50-g oral glucose challenge test in 2nd trimester of gestation and gave birth at National Health Insurance Service Ilsan Hospital. Maternal and neonatal complications were compared between GDM and non-GDM groups. Among the 682 women, 56 were diagnosed with GDM and 626 were non-GDM group. Maternal age was older and prepregnant body mass index was higher in GDM. The rate of cesarean delivery, preeclampsia, and transfusion was similar; however, the incidence of preterm birth was higher in GDM. Multivariate analysis, however, showed that GDM was independent risk factor only for preterm birth in <37 weeks (adjusted odds ratio, 2.25; 95% confidence interval, 1.16–4.36). Regarding neonatal morbidities, APGAR score <7 at 5 minutes and the rate of macrosomia were similar; however, the rates of neonatal intensive care unit (NICU) admission, large for gestational age (LGA), and intubation were higher in GDM. Multivariate analysis, however, showed that GDM was not independent risk factor for LGA, NICU admission, and intubation rate. Compared with the non-GDM group, GDM was associated with an increased likelihood of preterm birth <37 weeks, however, did not increase cesarean delivery, postpartum hemorrhage, LGA, and NICU admission rate. This study showed that the majority of women with GDM delivered with similar maternal and neonatal outcomes in non-GDM women.

A comparative study of prevalence of Gestational Diabetes Mellitus between urban and rural women in kut city

This study was carried out to show the prevalence of gestational diabetes mellitus(GDM) between urban and rural pregnant women in kut city of Iraq .A total of one thousand pregnant women (divided into 500 from urban areas and 500 rural areas),who had attended various antenatal clinics were screened for GDM by (one hour post 50 gm glucose load) oral glucose challenge test. Women who had an abnormal screening test proceeded to oral glucose tolerance testing by had a 3 hr. 100 gram oral glucose tolerance test (OGTT) and National diabetes data group criteria applied for diagnosis of GDM. This study showed the overall prevalence of GDM to be 3.2% (3.8% in urban women versus 2.6% in suburban women)

Visceral Adiposity Index as an Indicator for Menstrual Disturbance, Hormonal and Metabolic Dysfunction in Polycystic Ovarian Syndrome.

Increase in visceral adiposity is characteristic of polycystic ovarian syndrome (PCOS) and is the main cause of insulin resistance and hyperandrogenism. This study tried to compare the visceral adiposity index (VAI) in PCOS women and control population, thereby exploring its correlation with ovarian morphology, hormonal and metabolic dysfunction. Reproductive-age women who fulfilled the Rotterdam criteria for PCOS constituted the cases. Control population consisted of the same number of non-PCOS women. History of menstrual irregularity and features of hyperandrogenism were noted. Overnight fasting serum hormonal profile on second day of the cycle, oral glucose tolerance test (OGTT) and serum fasting insulin and lipid profile were obtained. Ultrasound evaluation was done simultaneously. Free androgen index (FAI), homeostatic model assessment of insulin resistance (HOMA-IR) and VAI were calculated. Serum androgen levels and OGTT were greater in PCOS women. No significant difference was noted in serum fasting glucose, fasting insulin and lipid profile between cases and controls. Both systolic and diastolic blood pressures were significantly higher among women with PCOS. Mean ovarian volume, antral follicle count, FAI and HOMA-IR were higher in PCOS women. VAI was significantly higher in cases compared to controls. VAI demonstrated a strong negative correlation with number of menstrual cycles per year. Increasing VAI was associated with longer menstrual cycles and correlated positively with greater severity of anovulation. VAI also showed highly significant correlation with fasting blood glucose and statistically significant moderately strong positive correlation with OGTT values at two hours post glucose challenge, systolic blood pressure and mean ovarian volume.There was no demonstrable correlation between androgen levels or HOMA-IR values. VAI is higher in women with PCOS. It correlates positively with features of disease severity and ovarian morphology. An assessment of VAI in PCOS women could be predictive of a greater propensity for development of classical metabolic risk factors.

Vertical sleeve gastrectomy normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice.

ObjectivesGlucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis. Glucocorticoid activation is catalysed by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). Excess glucocorticoids are associated with insulin resistance and hyperglycaemia. A small number of studies have demonstrated effects on glucocorticoid metabolism of bariatric surgery, a group of gastrointestinal procedures known to improve insulin sensitivity and secretion, which were assumed to result from weight loss. In this study, we hypothesize that a reduction in glucocorticoid action following bariatric surgery contributes to the widely observed euglycemic effects of the treatment.MethodsGlucose and insulin tolerance tests were performed at ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvested from fed mice and 11β-HSD1 levels were measured by quantitative RT-PCR or Western (immuno-) blotting, respectively. 11β-HSD1 null mice (Hsd11b1 -/-) were generated using CRISPR/Cas9 genome editing. Wild type and littermate Hsd11b1 -/- mice underwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. ResultsUnder the conditions used, no differences in weight loss were observed between VSG treated and sham operated mice. However, both lean and obese WT VSG mice displayed significantly improved glucose clearance and insulin sensitivity. Remarkably, VSG restored physiological corticosterone production in HFD mice and reduced 11β-HSD1 expression in liver and adipose tissue post-surgery. Elimination of the 11β-HSD1/Hsd11b1 gene by CRISPR/Cas9 mimicked the effects of VSG on body weight and tolerance to 1g/kg glucose challenge. However, at higher glucose loads, the euglycemic effect of VSG was superior to Hsd11b1 elimination.ConclusionsBariatric surgery improves insulin sensitivity and reduces glucocorticoid activation at the tissular level, under physiological and pathophysiological (obesity) conditions, irrespective of weight loss. These findings point towards a physiologically relevant gut-glucocorticoid axis, and suggest that lowered glucocorticoid exposure may represent an additional contribution to the health benefits of bariatric surgery.

A dual Keap1 and p47phox inhibitor Ginsenoside Rb1 ameliorates high glucose/ox-LDL-induced endothelial cell injury and atherosclerosis.

Oxidative stress is a vital contributor to the development and progression of diabetes-accelerated atherosclerosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known molecule that participates in cellular defense against oxidative stress. Utilizing luciferase reporter assay from 379 natural products, we reported here that Ginsenoside Rb1 played a dual role in inhibiting Kelch-like ECH-associated protein 1 (Keap1) and p47phox luciferase reporter activities. In endothelial cells (ECs), Rb1 pretreatment enhanced cell viability, reduced oxidative stress, inflammation, endothelial-mesenchymal transition (EndMT), and apoptosis, as well as ameliorated mitochondrial quality following oxidized low-density lipoprotein (ox-LDL) plus high glucose (HG) challenge. Rb1 directly bound to Keap1 and promoted its ubiquitination and proteasomal degradation dependent on lysine residues (K108, K323, and K551) by recruiting the E3 ligase synovial apoptosis inhibitor 1 (SYVN1), leading to Nrf2 dissociation from Keap1, Nrf2 nuclear translocation, Nrf2/PGC-1α complex formation. We further identified that Rb1 could bind to p47phox and reduce its phosphorylation and membrane translocation, thereby disrupting the assembly of the NOX2 complex. Importantly, Rb1-mediated preservation of cytoplasmic p47phox stabilized and contributed to Nrf2 activation. Additionally, we revealed that Rb1 reduced aortic atherosclerotic plaque formation along with reductions in oxidative stress and inflammatory response in streptozotocin (STZ)-induced ApoE−/− mice, but not in ApoE−/− mice with deficiency of Nrf2 and PGC-1α. Collectively, we demonstrated that Rb1, which directly targeted Keap1 and p47phox in ECs, may be an attractive candidate for the treatment of atherosclerosis in diabetes.

Journal-related Activities and Other Special Activities at the 2022 American Society of Anesthesiologists Meeting

Journal-related Activities and Other Special Activities at the 2022 American Society of Anesthesiologists Meeting

Dynamic patterns of postprandial metabolic responses to three dietary challenges.

Food intake triggers extensive changes in the blood metabolome. The kinetics of these changes depend on meal composition and on intrinsic, health-related characteristics of each individual, making the assessment of changes in the postprandial metabolome an opportunity to assess someone's metabolic status. To enable the usage of dietary challenges as diagnostic tools, profound knowledge about changes that occur in the postprandial period in healthy individuals is needed. In this study, we characterize the time-resolved changes in plasma levels of 634 metabolites in response to an oral glucose tolerance test (OGTT), an oral lipid tolerance test (OLTT), and a mixed meal (SLD) in healthy young males (n = 15). Metabolite levels for samples taken at different time points (20 per individual) during the challenges were available from targeted (132 metabolites) and non-targeted (502 metabolites) metabolomics. Almost half of the profiled metabolites (n = 308) showed a significant change in at least one challenge, thereof 111 metabolites responded exclusively to one particular challenge. Examples include azelate, which is linked to ω-oxidation and increased only in OLTT, and a fibrinogen cleavage peptide that has been linked to a higher risk of cardiovascular events in diabetes patients and increased only in OGTT, making its postprandial dynamics a potential target for risk management. A pool of 89 metabolites changed their plasma levels during all three challenges and represents the core postprandial response to food intake regardless of macronutrient composition. We used fuzzy c-means clustering to group these metabolites into eight clusters based on commonalities of their dynamic response patterns, with each cluster following one of four primary response patterns: (i) “decrease-increase” (valley-like) with fatty acids and acylcarnitines indicating the suppression of lipolysis, (ii) “increase-decrease” (mountain-like) including a cluster of conjugated bile acids and the glucose/insulin cluster, (iii) “steady decrease” with metabolites reflecting a carryover from meals prior to the study, and (iv) “mixed” decreasing after the glucose challenge and increasing otherwise. Despite the small number of subjects, the diversity of the challenges and the wealth of metabolomic data make this study an important step toward the characterization of postprandial responses and the identification of markers of metabolic processes regulated by food intake.

Nicotinamide riboside kinase 1 protects against diet and age-induced pancreatic β-cell failure

ObjectiveDisturbances in NAD+ metabolism have been described as a hallmark for multiple metabolic and age-related diseases, including type 2 diabetes. While alterations in pancreatic β-cell function are critical determinants of whole-body glucose homeostasis, the role of NAD+ metabolism in the endocrine pancreas remains poorly explored. Here, we aimed to evaluate the role of nicotinamide riboside (NR) metabolism in maintaining NAD+ levels and pancreatic β-cell function in pathophysiological conditions. MethodsWhole body and pancreatic β-cell-specific NRK1 knockout (KO) mice were metabolically phenotyped in situations of high-fat feeding and aging. We also analyzed pancreatic β-cell function, β-cell mass and gene expression. ResultsWe first demonstrate that NRK1, the essential enzyme for the utilization of NR, is abundantly expressed in pancreatic β-cells. While NR treatment did not alter glucose-stimulated insulin secretion in pancreatic islets from young healthy mice, NRK1 knockout mice displayed glucose intolerance and compromised β-cells response to a glucose challenge upon high-fat feeding or aging. Interestingly, β cell dysfunction stemmed from the functional failure of other organs, such as liver and kidney, and the associated changes in circulating peptides and hormones, as mice lacking NRK1 exclusively in β-cells did not show altered glucose homeostasis. ConclusionsThis work unveils a new physiological role for NR metabolism in the maintenance of glucose tolerance and pancreatic β-cell function in high-fat feeding or aging conditions.

Peri-conceptional exposure to ambient air pollution increases risk of gestational diabetes among pregnant participants in the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) study

Background: Exposures to air pollution potentially disrupt maternal metabolic adaptation during pregnancy. However, influences of preconception and prenatal exposures to ambient air pollution on gestational diabetes mellitus (GDM) remain unclear, and even less is known about sensitive windows for these exposures’ effect on GDM. Methods: In 617 pregnant participants enrolled the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) study, we estimated daily levels of ambient particulate matter (PM₁₀; PM₂.₅), nitrogen dioxide (NO₂), ozone (O₃) using spatial interpolation. GDM was ascertained from medical records by physician diagnosis or defined as abnormally high glucose challenge and tolerance test results. We used distributed lag models (DLM) with Poisson regression to identify sensitive exposure windows by estimating weekly associations of exposures from pre-conception week (PcW) 12 to gestational week (GW) 24 with GDM risk, adjusting for maternal and meteorological factors. Analyses were additionally stratified by median prenatal Perceived Stress Scale (PSS, 14), median pre-pregnancy body mass index (BMI, 27.5 kg/m²), median age (28 years), and newborn sex to explore differential susceptibility to exposure effects. Results: Sixty (9.7%) participants were diagnosed with GDM. We identified sensitive peri-conceptional exposure windows for PM₂.₅, PM₁₀, and NO₂ ranging from PcW5 to GW3 associated with increased GDM risk. An IQR increase in each pollutant was associated with 5% (95%CI: 3.3-6.7%), 6% (5.9-7.4%), and 11% (9.3-12.2%) increased GDM risk, respectively. In stratified analyses, effects of PM₁₀ and NO₂ in the identified sensitive windows were greater among those &amp;#x2265;28 years old, with BMI&amp;#x2265;27.5 kg/m², or with PSS&amp;#x2265;14. Conclusions: Peri-conception exposures to ambient air pollutants were associated with increased risk of GDM. Stronger effects in the identified sensitive windows were seen in participants who were older, had higher BMI, or higher perceived stress. Keywords: air pollution, gestational diabetes, sensitive window, susceptibility, perceived stress, preconception

Selective protein kinase C inhibition switches time-dependent glucose cardiotoxicity to cardioprotection.

Hyperglycaemia at the time of myocardial infarction has an adverse effect on prognosis irrespective of a prior diagnosis of diabetes, suggesting glucose is the damaging factor. In ex vivo models of ischaemia, we demonstrated that deleterious effects of acutely elevated glucose are PKCα/β-dependent, and providing PKCα/β are inhibited, elevated glucose confers cardioprotection. Short pre-treatments with high glucose were used to investigate time-dependent glucose cardiotoxicity, with PKCα/β inhibition investigated as a potential mechanism to reverse the toxicity. Freshly isolated non-diabetic rat cardiomyocytes were exposed to elevated glucose to investigate the time-dependence toxic effects. High glucose challenge for >7.5 min was cardiotoxic, proarrhythmic and lead to contractile failure, whilst cardiomyocytes exposed to metabolic inhibition following 5-min high glucose, displayed a time-dependent protection lasting ∼15 min. This protection was further enhanced with PKCα/β inhibition. Cardioprotection was measured as a delay in contractile failure and KATP channel activation, improved contractile and Ca2+ transient recovery and increased cell survival. Finally, the effects of pre-ischaemic treatment with high glucose in a whole-heart coronary ligation protocol, where protection was evident with PKCα/β inhibition. Selective PKCα/β inhibition enhances protection suggesting glycaemic control with PKC inhibition as a potential cardioprotective therapeutics in myocardial infarction and elective cardiac surgery.