Hyperglycemic Response Research Articles

Assessment of laparotomy-induced stress response in opium- and morphine-addicted rats by measuring serum glucose and corticosterone levels: an animal experiment

Background: Surgical procedures induce stress responses similar to severe illnesses, activating the metabolic and neuroendocrine systems, especially the hypothalamic-pituitary-adrenal (HPA) axis. The resulting cortisol surge maintains homeostasis but can adversely affect recovery by elevating blood glucose levels and increasing the risk of complications. Given the high prevalence of opium use, especially in the Middle East and southwestern Asia, and its suspected impact on HPA axis function, this study assesses corticosterone (CS) and glucose as indicators of impaired neuroendocrine responses to surgical stress in an animal model with chronic opioid use. Materials and methods: Thirty-six male Wistar rats were randomly assigned to three groups: morphine-addicted, opium-addicted, and control. Addiction was induced by administering increasing doses of morphine or opium in drinking water, as verified by naloxone injections. Laparotomy was performed under ketamine and xylazine anesthesia. Blood samples were collected post-surgery and post-recovery to measure the CS and glucose levels. Results: This study included 30 rats, with ten rats per group. Post-surgery, mean CS levels were higher in the control group compared to the addicted groups, although not significantly higher. Thirty minutes post-recovery, CS levels remained elevated in the addicted groups. Mean glucose levels were significantly higher in the control group both immediately and thirty minutes post-recovery, indicating a sustained hyperglycemic response. No significant differences were observed between addicted groups in glucose levels. Conclusion: Our study suggests that chronic opioid use may reduce the neuroendocrine response to surgical stress, as shown by lower CS levels in addicted rats. This aligns with existing research on opioids and stress responses. However, the small sample size and lack of baseline measurements limit the findings. Future studies should use larger, more diverse samples and additional biomarkers. This pilot study highlights the need for further research on altered stress responses in opioid-addicted patients undergoing surgery, emphasizing the importance of tailored postoperative care.

Mode of Action of Retinoic Acid in the Regulation of Glucose Metabolism in Mud Crab, Scylla serrata: Evidence for the Involvement of Crustacean Hyperglycemic Hormone

In the current study, we evaluated the effect of retinoids, 9-Cis retinoic acid (9CRA) and all-trans retinoic acid (ATRA) on carbohydrate metabolism in the mud crab, Scylla serrata. Intact and eyestalk ablated male crabs (n=10 crabs per group) were selected and retinoic acid isomers, 9CRA and ATRA were injected into the crabs. Parallel controls were maintained. Significant reduction in the hemolymph sugar levels was observed in crabs subjected to eyestalk ablation (ESX) over intact crabs. Injection of 9CRA into intact but not in ESX crabs exhibited a dose- and time-dependent manner hyperglycemic response. ATRA administration did not induce hyperglycemia either in intact or ESX crabs. Injection of 9CRA showed a significant decrease in total carbohydrate content and glycogen levels in hepatopancreas and muscle tissues of intact crabs over their respective controls. Further, the activity levels of glycogen phosphorylase were also elevated in selected tissues of intact crabs administered with 9CRA. In addition, intact crabs which received 9CRA resulted in up regulation of expression of CHH mRNA from the eyestalks. Taken together, we postulate that 9CRA-induced hyperglycemia might be ascribed to neurotransmitter effects mediating the release of CHH from the eyestalk. The release of CHH eventually caused glycogenolysis in the selected hepatopancreas and muscle tissues of the mud crab Scylla serrata thereby hyperglycemia.

Divergent hypoglycemic and hyperglycemic responses to the components of evening meals. A general adult population study in individuals without diabetes (AEGIS study)

Few real-life studies have analyzed the glycemic response to nutrients in individuals without diabetes. We investigated the glycemic response to evening meals in relation to individual characteristics, nutrient components, and preprandial and postprandial routines. A cross-sectional study of 489 individuals without diabetes from a randomly selected general adult population (310 women, median age 46 years, range 18-84 years) was conducted using a continuous glucose monitoring device for 7 days. The study recorded the participants' glycemic profile at 6h after dinner, the food consumed at dinner, the fasting duration before dinner, and the duration between the end of dinner and going to bed. Principal component analysis and multilevel functional data analysis were used to interpret the data. On average, a postprandial glycemic peak was observed at 45min, followed by a decline to baseline levels from 90min onwards. Older age, higher body mass index, and large meals (especially those high in starch and dairy products) were all significantly associated with higher glucose levels throughout the 6h after dinner. The fruit component was associated with a higher initial glycemic peak, followed by a lowering glycemic effect thereafter (p<0.001). The alcohol component was associated with an initial hypoglycemic effect (p=0.006). The participants who fasted longer before dinner had higher postprandial glycemic peaks (p=0.001), and those who went to bed later had higher postprandial glucose levels than those who went to bed earlier (p=0.003). The participants' characteristics, nutrient components, and pre- and post-dinner routines have divergent effects on post-dinner glycemic response.

6567 Novel Indication of GLP-1 Receptor Agonists Beyond Weight Loss: Addressing Post-Gastric Bypass Late Dumping Syndrome

Abstract Disclosure: G. Arevalo: None. S. Gra Menendez: None. D. Soliman: None. R.J. Galindo: Consulting Fee; Self; Novo Nordisk, Eli Lilly &amp; Company, Sanofi, Bayer, Inc., Boehringer Ingelheim, Pfizer, Inc., Abbott Laboratories. Grant Recipient; Self; National Institute of Diabetes and Digestive and Kidney Diseases (2P30DK111024), National Institute of Diabetes and Digestive and Kidney Diseases (K23DK123384). Other; Self; Novo Nordisk, Eli Lilly &amp; Company, Dexcom. Background: Late dumping syndrome, characterized by postprandial hyperinsulinemic hypoglycemia (PHH), represents a complex clinical challenge in post-bariatric patients. GLP-1 receptor agonists are being explored as an effective therapeutic option. Clinical Case: A 47-year-old overweight (BMI of 29.86 kg/m²) woman, with a medical history of scleroderma and esophageal dysmotility, underwent a gastric sleeve gastrectomy later requiring conversion to Roux-en-Y gastric bypass to improve esophageal motility. Eleven months post-bypass, she began experiencing recurrent episodes of hypoglycemia (venous glucose 49-70 mg/dL, n &amp;gt;70 mg/dL) accompanied by sweating, palpitations, drowsiness, and weakness. Initial tests were consistent with postprandial hyperinsulinemic hypoglycemia: serum insulin (13.5 µIU/mL, n &amp;lt; 3 µIU/mL), and c-peptide (4.1 ng/mL, n &amp;lt; 0.6 ng/mL). The Sigstad score and the Arts dumping severity score were positive for late dumping syndrome with a score of 26 and 14, respectively. During glucagon administration, the patient's blood glucose level increased by up to 50 mg/dL within 10 minutes of administration. Both sulfonylurea screening and insulin antibody tests were negative. Real-time CGM measurements showed patterns of postprandial hyperglycemic peaks, up to 160-180 mg/dL (n &amp;lt;140 mg/dL), approximately 30 to 60 min after meals, followed by rapidly declining glucose (1-2 hours later), resulting in hypoglycemic events as low as 49 mg/dL. Initial management with dietary changes and pharmacological treatment was unsuccessful due to poor medication tolerability of acarbose and diazoxide, and low adherence to the prescribed diet due to her esophageal dysmotility. The CGM patterns and symptom presentation raised suspicion that late dumping syndrome was triggered by rapid hyperglycemic responses after oral ingestions of typical meals, resulting in the desynchronization of hormonal responses (insulin and GLP-1), and post-prandial hypoglycemia. Hence, the consideration for a GLP-1 receptor agonist emerged. A weekly subcutaneous injection of a long-acting GLP-1 receptor agonist, semaglutide 0.25 mg exhibited marked improvement in her glycemic profile: fewer episodes of postprandial hyperglycemia, and the subsequent descents in blood glucose were less pronounced. The patient demonstrated a favorable response with no severe hypoglycemic episodes reported during a follow-up period of three months. Conclusion: This is the first case to demonstrate semaglutide's efficacy as a standalone treatment for PHH in post-bariatric patients. In this case, semaglutide effectively controlled glycemia and improved the patient's quality of life, presenting a promising therapeutic option for such complex cases. Presentation: 6/1/2024

Assessing the Hypertension Risk: A Deep Dive into Cereal Consumption and Cooking Methods-Insights from China.

Cereal grains are rich in carbohydrates and could trigger a hyperglycemic response which is closely linked to blood pressure status. We aim to examine the associations between the consumption of cereals with different cooking methods and hypertension risk. We conducted a prospective analysis utilizing the nationwide data of 11,080 adult participants who were free of hypertension at baseline. Cereal intake was assessed using 3-day 24 h dietary recalls with a weighing technique. Hypertension incidence was identified in adherence with the Seventh Joint National Commission guidelines during the follow-up. Cox proportional hazards regression models were used to extrapolate hazard ratios associated with hypertension risk. Over an average follow-up span of 7 years (77,560 person-years), we identified 3643 new hypertension cases. The intake of total, fried, and baked cereals was associated with 15%, 20%, and 20% higher risk of hypertension, respectively. Whole grain consumers had an 8% lower risk of hypertension compared with non-consumers, while total refined grain consumers showed no significant association. Replacing one daily serving of fried or baked cereals with an equivalent serving of boiled cereals was related to a 28% or 14% lower risk, respectively. Total, fried, and baked cereal consumption was positively associated with hypertension risk, while consuming whole grains was related to a lower risk. Modifying cooking methods from frying or baking to boiling for cereals may be beneficial to lower risk. The current study underscores the significance of considering both the degree of processing and cooking methods applied to cereals in addressing hypertension prevention and management.

Polyphenols in foods: a potential strategy for preventing and managing the postprandial hyperglycemic response.

Type 2 diabetes mellitus (T2DM) is a significant health risk worldwide, and effective management strategies are needed. Polyphenols exhibit diverse biological functions, are abundant in various plants, and influence carbohydrate digestion and absorption. This review provides a comprehensive overview of clinical evidence regarding the relationship between dietary polyphenols and the postprandial hyperglycemic response. Human intervention studies have demonstrated the benefits of polyphenol-rich foods in improving glucose and insulin metabolism, underscoring their role in preventing T2DM. These findings highlight the potential of polyphenol-rich foods for managing hyperglycemia and mitigating T2DM risk and provide insight into effective dietary strategies for glycemic control and overall health.

Comparison of Hyperglycemic Effects of Antenatal Administration of Dexamethasone in Gestational Diabetes: A Study of Recommended Versus Predicted Split Doses Regimens

Objective: To compare three consecutive days of hyperglycemic response following antenatal Dexamethasone regimens of 12mg or 6mg in diet-controlled gestational diabetes, administered for fetal lung maturity. Study Design: Quasi-experimental study Place and Duration of Study: Department of Obstetrics and Gynaecology, Combined Military Hospital, Kharian Pakistan, from Oct 2020 to Mar 2021. Methodology: Forty women who met inclusion criteria were selected and assigned to two Groups. Group-A was administered quartered 24 mg steroids 6 hours daily, and Group-B was administered halved 24mg 12 hours daily. Blood sugar levels (BSL) were recorded before and after meals, thrice a day for three consecutive days, and on proforma. Results: Among the selected patients, the mean age was 25.5±2.9 years, and the mean gestational age (duration of pregnancy) was 30.3±2.0 weeks. Out of six blood sugar levels recorded daily for three consecutive days, the episodes of hyperglycemia in the (Group-B) 12-hourly steroid dose were found to be less significant than those in the (Group-A) split 6-hourly dose. Conclusion: The recommended 12 mg, twice-a-day regimen of antenatal corticosteroids was better than the proposed 6mg, four times a day regimen as it caused fewer hyperglycemic episodes in gestational diabetics.

Dietary fibre from seeds of Australia native Plantago species as modulators of quality and glycaemic response in starch gels

Dietary fibre (DF) is a non-digestible nutrient which has important roles in the digestive system including mantaining regularity, and reducing the risk of certain cancers and non-communicable diseases, such as metabolic syndrome. Even though the positive health effects of DF have long been established, it has been shown that DF intake for children and adults in Australia is below the recommended range – less than 20% of adults met the suggested intake for reducing risk of chronic diseases(1). Plantago ovata, also known as psyllium, is widely used as DF supplement with evidence showing positive effects on weight control, hyperglycaemic response, cholesterol levels, and irritable bowel syndrome(2). P. ovata seed husk produces a highly viscous gel called mucilage when seeds are exposed to moisture. This mucilage is nearly pure DF and has an intricately layered structure which can be further fractionated and studied as a proxy for different gelling systems. Interestingly, Australia is home to many mucilage-producing Plantago species, most of which are underexplored and underutilised, but show remarkable gelling properties and hypoglycaemic potential(3). In this work, we compare structural and functional properties of fractionated DF from P. ovata, and two promising Australian native relatives, P. turrifera and P. drummondii, and their effect on enzymatic hydrolysis in potato starch gels. Using a 3-step fractionation method, we have separated distinct fractions and explored their individual properties(4). P. turrifera and P. drummondii have higher water absorbing capacity, DF yield, and viscosity compared to P. ovata. Monosaccharide composition of all three species is similar – they are highly substituted heteroxylans with minor pectic component. Notably, arabinose to xylose ratio in all species increases with further extraction steps, which is different from cereal arabinoxylans. In an attempt to explore impact of DF in starch-rich systems, we have fabricated DF-potato starch gels and measured enzymatic hydrolysis (with porcine pancreatic α-amylase), freeze-thaw stability, and colour change. Addition of DF reduced syneresis (water separation) during 15 day freeze-thaw cycle measurement, which can lead to prolonged storage stability and has positive implications for shelf life. Colour change was most noticeable when P. drumondii DF were added, while colour of P. ovata and P. turiferra DF gels was similar to control potato starch gel. Effects on α-amylase starch hydrolysis were significant as well, and depended on species and fractions. Certain DFs had impacts on constant k (speed of hydrolysis), while effects on the extent of hydrolysis are still being explored. In conclusion, utility of Australia native P. turrifera and P. drumondii DFs are evident when applied to starch gels, and should be further explored in food products such as bread to increase DF intake and possibly lower glycaemic index.

Effect of Acute Caffeine Exposure on Blood Glucose and Hepatic Glycogen Content in Normal and Thyroidectomized Male Wistar Rats.

Acute caffeine exposure had been shown to induce hyperglycemia however; the influence of thyroid hormones on the caffeine-induced hyperglycemia is yet to be established. The present study was therefore designed to investigate the effect of caffeine exposure on blood glucose and hepatic glycogen content in thyroidectomized rats. Sixty adult male Wistar rats were randomly divided into 10 groups as I-X (n=6). Rats in groups I, III, V, VII and IX were given normal saline, caffeine, prazosin + caffeine, propranolol +caffeine, combined prazosin+ propranolol+caffeine injections respectively while rats in groups II, IV, VI, VIII and X were thyroidectomized and treated in similar manner as the normal rats respectively. Surgical removal of the thyroid gland was done in the thyroidectomised groups while sham-operation was done in Normal group to serve as control. After healing and following an overnight fast, the rats were anaesthetized and the femoral vein and carotid artery were cannulated for drug administration and blood glucose measurement respectively. After stabilization, following basal measurements, rats from each group were injected normal saline or caffeine (6mg/kg) while another sets were pre-treated prazosin (0.2 mg/kg), propanolol (0.5 mg/kg) or their combination before caffeine administration. Blood glucose was then monitored for 60 minutes post-injection of caffeine at 5 minutes interval. Liver samples were collected at the end of the observation period for glycogen content determination. Caffeine caused significant increased blood glucose levels in both normal and thyroidectomized rats which were up to 210% and 180% respectively at the peak of their responses. Liver glycogen content of the thyroidectomized rats (3.11 ± 0.20 mg/100g tissue weight) was significantly higher than the normal rats (1.91 ± 0.43 mg/100g tissue weight). These glycogen contents were significantly reduced by caffeine in both normal (0.25 ± 0.04 mg/100g tissue weight) and thyroidectomized rats (1.65 ± 0.16 mg/100g tissue weight) when compared with their controls. The caffeine effects on blood glucose and hepatic glycogen content were abolished by pretreatment with propanolol or a combination of prazosin and propanolol in both normal and thyroidectomized rats but pretreatment with prazosin caused only significant reduction in hyperglycemic response to caffeine. The findings of this study suggest that caffeine-induced hyperglycemia in both normal and thyroidectomized rats are mediated through both alpha and beta adrenoceptors.

Ceramide enhanced the hepatic glucagon response through regulation of CREB activity

Background & aimsHyperglycemia is associated with lipid disorders in patients with diabetes. Ceramides are metabolites involved in sphingolipid metabolism that accumulate during lipid disorders and exert deleterious effects on glucose and lipid metabolism. However, the effects of ceramide on glucagon-mediated hepatic gluconeogenesis remain largely unknown. This study was designed to investigate the impact of ceramides on gluconeogenesis in the context of the hepatic glucagon response, with the aim of finding new pharmacological interventions for hyperglycemia in diabetes. MethodsLiquid chromatography-mass spectrometry was used to quantify ceramide content in the serum of patients with diabetes. Primary hepatocytes were isolated from male C57BL/6J mice to study the effects of ceramide on hepatic glucose production. Immunofluorescence staining was performed to view cAMP-responsive element-binding protein (CREB)- regulated transcription co-activator 2 (CRTC2) nuclear translocation in hepatocytes. Serine palmitoyl-transferase, long chain base subunit 2 (Sptlc2) knockdown mice were generated using an adeno-associated virus containing shRNA, and hepatic glucose production was assessed glucagon tolerance and pyruvate tolerance tests in mice fed a normal chow diet and high-fat diet. ResultsIncreased ceramide levels were observed in the serum of patients newly diagnosed with type 2 diabetes. De novo ceramide synthesis was activated in mice with metabolic disorders. Ceramide enhanced hepatic glucose production in primary hepatocytes. In contrast, genetic silencing of Sptlc2 prevented this process. Mechanistically, ceramides de-phosphorylate CRTC2 (Ser 171) and facilitate its translocation into the nucleus for CREB activation, thereby augmenting the hepatic glucagon response. Hepatic Sptlc2 silencing blocked ceramide generation in the liver and thus restrained the hepatic glucagon response in mice fed a normal chow diet and high-fat diet. ConclusionsThese data indicate that ceramide serves as an intracellular messenger that augments hepatic glucose production by regulating CRTC2/CREB activity in the context of the hepatic glucagon response, suggesting that CRTC2 phosphorylation might be a potential node for pharmacological interventions to restrain the hyperglycemic response during fasting in diabetes.

Statin treatment is associated with greater hyperglycaemic response to a glucagon challenge

Statin treatment is associated with greater hyperglycaemic response to a glucagon challenge

Gene deletion of the PACAP/VIP receptor, VPAC2R, alters glycemic responses during metabolic and psychogenic stress in adult female mice.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and the homologous peptide, vasoactive intestinal peptide (VIP), participate in glucose homeostasis using insulinotropic and counterregulatory processes. The role of VIP receptor 2 (VPAC2R) in these opposing actions needs further characterization. In this study, we examined the participation of VPAC2R on basal glycemia, fasted levels of glucoregulatory hormones and on glycemia responses during metabolic and psychogenic stress using gene-deleted (Vipr2-/- ) female mice. The mean basal glycemia was significantly greater in Vipr2-/- in the fed state and after an 8-h overnight fast as compared to wild-type (WT) mice. Insulin tolerance testing following a 5-h fast (morning fast, 0.38 U/kg insulin) indicated no effect of genotype. However, during a more intense metabolic challenge (8 h, ON fast, 0.25 U/kg insulin), Vipr2-/- females displayed significantly impaired insulin hypoglycemia. During immobilization stress, the hyperglycemic response and plasma epinephrine levels were significantly elevated above basal in Vipr2-/- , but not WT mice, in spite of similar stress levels of plasma corticosterone. Together, these results implicate participation of VPAC2R in upregulated counterregulatory processes influenced by enhanced sympathoexcitation. Moreover, the suppression of plasma GLP-1 levels in Vipr2-/- mice may have removed the inhibition on hepatic glucose production and the promotion of glucose disposal by GLP-1. qPCR analysis indicated deregulation of central gene markers of PACAP/VIP signaling in Vipr2-/- , upregulated medulla tyrosine hydroxylase (Th) and downregulated hypothalamic Vip transcripts. These results demonstrate a physiological role for VPAC2R in glucose metabolism, especially during insulin challenge and psychogenic stress, likely involving the participation of sympathoadrenal activity and/or metabolic hormones.

Perioperative hyperglycemic response to single-dose dexamethasone in patients undergoing surgery under spinal anesthesia

BackgroundDexamethasone is a potent corticosteroid when comes to effectively preventing postoperative nausea and vomiting (PONV). However, some studies have documented its association with hyperglycemia. In our study, we compared the effect of single-dose dexamethasone (8 mg) on blood glucose concentrations among diabetics and non-diabetic patients who received spinal anesthesia for elective lower abdominal and lower limb surgeries.ResultsWe recruited 80 patients and divided them into two groups of 40 patients each. After dexamethasone administration, diabetic patients had an early peak rise of blood glucose levels at 3 h, (157.85 ± 12.19) compared to 6 h, (125.30 ± 14.95) in non-diabetics. In diabetic patients, blood glucose levels remained consistently over the baseline and maximum rise was seen at 12 h (188.25 ± 41.33), which obviated the need or administration of injection insulin. Hyperglycemia can lead to a variety of physiological derangements.ConclusionsAlthough dexamethasone is a useful means of successful prevention and treatment of PONV, the clinician should use his clinical judgment before administering dexamethasone.Trial registrationCTRI, CTRI/2020/06/025765, Registered 02 June 2020, prospectively registered, http://ctri.nic.in/Clinicaltrials/login.php.

Generating slow digestibility in cooked potatoes by modulating starch accessibility to α-amylase and mucosal α-glucosidase to different levels

Health issues associated with overconsuming rapidly digestible glycemic carbohydrates continue to be prevalent globally. Transforming starch digestion from a hyperglycemic response to a sustained dietary glucose profile is an ideal digestion scenario. Digesting starch to glucose requires α-amylase (AMY) and mucosal α-glucosidase (m-AG). AMY can quickly break down starch molecules, and m-AG functions as the gatekeeper of dietary glucose production. In this study of cooked potatoes, we hypothesize that slow glucogenesis from starch can be achieved by modulating the accessibility of AMY and m-AG to starch to different levels by modifying cell wall permeability by promoting cross-linking of calcium with endogenous pectins. Raw potato cubes were blanched with 0–500 mg/L calcium solution, followed by steaming. Fully cooked potatoes with the pre-treatment had up to 41% and 99% reduction of the permeability for dextran probes of 20 kDa and 70 kDa, respectively, and a non-detectable permeability of 150 kDa dextran. Permeability data indicated a decrease in the accessibility of AMY and a complete restriction of m-AG to access starch in cells supported by data on starch susceptibility to both AMY and m-AG separately. In vitro stimulated gastrointestinal digestion data demonstrated a blunt glucose profile with a reduction of RDS from 80% to 46% and an increase of SDS from 12% to 37%. By modulating starch accessibility to AMY and m-AG to different extents, cooked potatoes were fully digested with a slow glucose-released profile. The modification was a pre-treatment, and modified potatoes can be processed into potato foods, such as french fries, mashed potatoes, and others.

Heparin and calreticulin interact on the surface of early G0/G1 dividing rat mesangial cells to regulate hyperglycemic glucose-induced responses

Heparin can block pathological responses associated with diabetic nephropathy in animal models and human patients. Our previous studies showed that the interaction of heparin on the surface of rat mesangial cells (RMCs) entering G1 of cell division in hyperglycemic glucose: 1) blocked glucose uptake by glucose transporter 4; 2) inhibited cytosolic uridine diphosphate-glucose elevation that would occur within 6h from G0/G1; and 3) prevented subsequent activation of hyaluronan synthesis in intracellular compartments and subsequent inflammatory responses. However, specific proteins that interact with heparin are unresolved. Here, we showed by live cell imaging that fluorescent heparin was rapidly internalized into the cytoplasm and then into the endoplasmic reticulum, Golgi, and nuclei compartments. Biotinylated-heparin was applied onto the surface of growth arrested G0/G1 RMCs in order to extract heparin-binding protein(s). SDS-PAGE gels showed two bands at ∼70kDa in the extract that were absent when unlabeled heparin was used to compete. Trypsin digests of the bands were analyzed by MS and identified as calreticulin and prelamin A/C. Immunostaining with their antibodies identified the presence of calreticulin on the G0/G1 RMC cell surface. Previous studies have shown that calreticulin can be on the cell surface and can interact with the LDL receptor-related protein, which has been implicated in glucose transport by interaction with glucose transporter 4. Thus, cell surface calreticulin can act as a heparin receptor through a mechanism involving LRP1, which prevents the intracellular responses in high glucose and reprograms the cells to synthesize an extracellular hyaluronan matrix after division.

Is β-Cell Dysfunction Present in Adult Autoantibody Negative Relatives of Individuals with Type 1 Diabetes Mellitus?

Background/Objective: Individuals with a family history of type 1 diabetes mellitus (T1D) are at increased genetic risk for T1D. Previous studies identified the presence of β-cell dysfunction before clinical onset and diagnosis of T1D. However, it is unclear if β-cell dysfunction predates islet autoimmunity in individuals at high genetic risk. Our objective was to test β-cell function in islet antibody negative adults who have a first-degree relative with T1D. We hypothesized that individuals at genetic risk for T1D would exhibit β-cell dysfunction even without detectable islet autoimmunity.Methods: We used ordinary one-way and Brown-Forsythe ANOVA to compare the repeated mixed meal tolerance test (MMTT) and hyperglycemic clamp glucose-stimulated β-cell response and function measures between three groups of individuals: normoglycemic adults without T1D family history age, sex, and BMI-matched islet antibody negative first-degree relatives of individuals with T1D, and islet antibody positive first-degree relatives of individuals with T1D.Results: Neither the MMTT first-phase insulin secretion measures (c-peptide0-15 minutes, c-peptide0-30 minutes, insulin0-15 minutes, insulin0-30 minutes), nor second-phase measures (c-peptide0-120 minutes, insulin0-120 minutes, and glucose0-120 minutes) showed a statistically significant difference between groups. The clamp acute c-peptide response to glucose, insulin sensitivity, c-peptide steady state, first-phase β-cell function, and second-phase β-cell function were similar between subject groups in both visits. Fasting proinsulin:c-peptide ratios, a biomarker of β-cell stress, were also similar between participant groups.Conclusion and Impact: Our data suggest that genetically at-risk autoantibody negative adult relatives of individuals with T1D do not demonstrate β-cell dysfunction compared to controls. Studies show that β-cell ER dysfunction preceding T1D onset is more striking in younger children. Thus, our findings may reflect the use of an adult study population. Alternatively, β-cell dysfunction in T1D may require initial autoimmune activation. This study will contribute to the growing understanding of risk factors contributing to T1D development.This project was funded, in part, with support from the Research Training Program in Diabetes and Obesity funded, in part by grant 3T32DK064466 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding also provided by JDRF grant 2-SRA-2017-498-M-B.

The role of preproglucagon peptides in regulating β-cell morphology and responses to streptozotocin-induced diabetes.

Insulin secretion from β-cells is tightly regulated by local signaling from preproglucagon (Gcg) products from neighboring α-cells. Physiological paracrine signaling within the microenvironment of the β-cell is altered after metabolic stress, such as high-fat diet or the β-cell toxin, streptozotocin (STZ). Here, we examined the role and source of Gcg peptides in β-cell function and in response to STZ-induced hyperglycemia. We used whole body Gcg null (GcgNull) mice and mice with Gcg expression either specifically within the pancreas (GcgΔPanc) or the intestine (GcgΔIntest). With lower doses of STZ exposure, insulin levels were greater and glucose levels were lower in GcgNull mice compared with wild-type mice. When Gcg was functional only in the intestine, plasma glucagon-like peptide-1 (GLP-1) levels were fully restored but these mice did not have any additional protection from STZ-induced diabetes. Pancreatic Gcg reactivation normalized the hyperglycemic response to STZ. In animals not treated with STZ, GcgNull mice had increased pancreas mass via both α- and β-cell hyperplasia and reactivation of Gcg in the intestine normalized β- but not α-cell mass, whereas pancreatic reactivation normalized both β- and α-cell mass. GcgNull and GcgΔIntest mice maintained higher β-cell mass after treatment with STZ compared with control and GcgΔPanc mice. Although in vivo insulin response to glucose was normal, global lack of Gcg impaired glucose-stimulated insulin secretion in isolated islets. Congenital replacement of Gcg either in the pancreas or intestine normalized glucose-stimulated insulin secretion. Interestingly, mice that had intestinal Gcg reactivated in adulthood had impaired insulin response to KCl. We surmise that the expansion of β-cell mass in the GcgNull mice compensated for decreased individual β-cell insulin secretion, which is sufficient to normalize glucose under physiological conditions and conferred some protection after STZ-induced diabetes.NEW & NOTEWORTHY We examined the role of Gcg on β-cell function under normal and high glucose conditions. GcgNull mice had decreased glucose-stimulated insulin secretion, increased β-cell mass, and partial protection against STZ-induced hyperglycemia. Expression of Gcg within the pancreas normalized these endpoints. Intestinal expression of Gcg only normalized β-cell mass and glucose-stimulated insulin secretion. Increased β-cell mass in GcgNull mice likely compensated for decreased insulin secretion normalizing physiological glucose levels and conferring some protection after STZ-induced diabetes.

TXNIP shuttling - a key molecular link in regulating inflammation and mitochondrial dysfunction in freeze tolerant wood frogs

Amphibians such as the wood frogs,Rana sylvatica, are a primary example of a freeze-tolerant vertebrate that undergoes whole body freezing. Multiple adaptations including sequestering 65–70% of total body water as extracellular/extra organ ice and producing massive amounts of glucose as a cryoprotectant support this. Interestingly, the high glucose levels induced in response to freezing can amplify oxidative stress's effects (reactive oxygen species, ROS) and induce inflammation and mitochondrial dysfunction. Since both freezing and dehydration stress (independent of freezing) can render wood frogs hyperglycemic, this study focussed on these two stresses to elucidate the role of a scaffold protein thioredoxin interacting protein (TXNIP), which localizes in multiple compartments inside the cell under hyperglycemic conditions and mediate diverse stress responses. The results from this study suggest a stress-specific response of TXNIP in inducing the cell-damaging pathway of inflammasome activation via its cytoplasmic localization during freezing. Interestingly, mitochondrial localization of TXNIP did not leads to increase in its binding to thioredoxin 2 (TRX-2) and activating the dysfunction of this organelle by releasing a mitochondrial protein cytochrome c (Cyt c) in cytoplasm under both freezing and dehydration stresses. Post-translational modifications of TXNIP hinted on changes in the regulating proteins involved in the inflammasome and mitochondrial dysfunction pathways, whereas sequential differences (cytosine residues) of amphibian TXNIP (compared to mammalian) assessed via 3D-modeling attributed to its weak binding to TRX-2. Overall, this study summarizes differential role of proteins activated under freeze and dehydration induced hyperglycemic response in freeze tolerant wood frogs.

Haematological alterations in a fresh water fish Anabas testudineus under cypermethrin exposure

Cypermethrin, a synthetic pyrethroid is a broad spectrum insecticide used extensively in households and agriculture fields to control the pests. Use of insecticides in agriculture to prevent the crop damage from pests come with a significant cost as they reach to the aquatic systems through irrigation and rain and deteriorates the water quality. It adversely affects the non-target organisms including fishes of the fresh water ecosystem. Pyrethroid insecticide cypermethrin was used for this investigation to study the alterations in blood biochemical of a fresh water fish Anabas testudineus. Acute toxicity of cypermethrin to the fish was determined for 24, 48, 72 and 96 hours. The LC50 value was measured 0.15 ppm, 0.20 ppm, 0.2 ppm and 0.30 ppm respectively by the regression equation. The sublethal concentration determined was 0.106 ppm. After exposure period of 30 days significant changes in the blood biochemical level was reported during the present study. Blood glucose, serum protein and serum cholesterol of cypermethrin treated fish exhibited hyperglycaemic, hypoproteinemic and hypercholesterolemic response. The present investigation come to a conclusion that cypermethrin alters the blood biochemistry of Anabas testudineus and hence, affects the fish health.

Evaluation of hyperglycaemic response to anti-emetic dose of dexamethasone in diabetic patients undergoing cholecystectomy

Evaluation of hyperglycaemic response to anti-emetic dose of dexamethasone in diabetic patients undergoing cholecystectomy