Counterregulatory Hormones Research Articles

216-LB: Hepatocyte N6-Methyladenosine mRNA Modification in Hepatic Gluconeogenesis and Diabetes

The liver produces endogenous glucose to support life during fasting. Counterregulatory hormones, including glucagon, catecholamines, and glucocorticoids, stimulate the expression of gluconeogenic enzymes in the liver, thus driving liver glucose production. In contrast, insulin suppresses hepatic gluconeogenesis, thereby restraining postprandial glucose levels. Hepatic gluconeogenesis aberrantly increases in type 2 diabetes due to an imbalance between insulin and counterregulatory hormone actions, contributing to hyperglycemia and glucose intolerance. N6-methyladenosine (m6A) RNA methylation has emerged as a critical paradigm shaping cell identities and functions. The Mettl3/Mettl14 complex catalyzes m6A on RNA and RNA-binding proteins bind to the m6A motifs and determine the fate of client mRNAs (splicing, trafficking, stability, and/or translation) . However, m6A RNA modification has not been explored in liver gluconeogenesis. Here, we identified Mettl14 as an important positive regulator of hepatic gluconeogenesis. Liver Mettl14 levels were increased in db/db mice and mice with high fat diet (HFD) -induced obesity. Hepatocyte-specific deletion of Mettl14 decreased hepatic glucose production and ameliorated HFD-induced glucose intolerance; conversely, liver-specific overexpression of Mettl14 increased liver glucose production and HFD-induced glucose intolerance. Of note, Mettl14 did not alter liver insulin actions under our experimental conditions. Remarkably, hepatic deficiency of Mettl14 profoundly blunted the ability of glucagon to stimulate gluconeogenesis in mice. Consistently, deletion of Mettl14 largely blocked glucagon-stimulated gluconeogenesis ex vivo in liver slices as well as in primary hepatocyte cultures. In contrast, overexpression of Mettl14 had the opposite effects. Collectively, these data unravel a previously unrecognized glucagon/Mettl14/gluconeogenesis axis that is involved in hyperglycemia and glucose intolerance in diabetes. Disclosure Q. Zheng: None. X. Zhong: None. D. Ren: None. L. Rui: None. Funding National Institutes of Health (RO1DK127568) , American Heart Association (831585)

216-OR: Hypoglycemia Frequency and Physiological Response to Double or Triple Doses of Once-Weekly Insulin Icodec vs. Once-Daily Insulin Glargine in T2D

Insulin icodec is a basal insulin in development for once-weekly (OW) dosing. The aim of this study was to compare the hypoglycemia frequency and response after icodec vs. insulin glargine U100 (IGlar) overdosing. In a randomized, open-label, two-period crossover trial, 43 individuals with T2D on basal insulin±metformin (mean±SD age 56±9 yrs, HbA1c 7.2±0.7%) received OW icodec for 6 weeks and once-daily IGlar for 12 days at equimolar total weekly doses based on the individual daily run-in IGlar dose (mean 30±14 U) titrated to a fasting SMPG target of 80-130 mg/dL. Once at steady state, double (DD) and triple (TD) doses of icodec and IGlar were followed by hypoglycemia induction 44 h (icodec) or 7 h (IGlar) post-dose (expected time of maximum glucose-lowering effect) : First, euglycemia was maintained at 100 mg/dL by variable i.v. glucose. Then, PG was allowed to decrease to a nadir of no less than 45 mg/dL maintained for 15 min. Euglycemia was restored by constant i.v. glucose. Hypoglycemic symptom score (HSS) and counterregulatory hormones were assessed at PG 100 mg/dL and at predefined PG levels until nadir PG. For DD, clinically significant hypoglycemia (PG<54 mg/dL) occurred in 40 vs. 36% of subjects for icodec vs. IGlar (odds ratio 1.28; p=0.63) . For TD, clinically significant hypoglycemia occurred in 53 vs. 70% of subjects (odds ratio 0.48; p=0.14) , mean nadir PG was 56 vs. 52 mg/dL (treatment ratio 1.07; p<0.001) , change in HSS at nadir PG was comparable for icodec vs. IGlar (treatment difference 0.46; p=0.77) , responses in adrenaline, noradrenaline and cortisol during hypoglycemia development were greater for icodec vs. IGlar, while glucagon and growth hormone levels increased similarly. In conclusion, a DD or TD of once-weekly insulin icodec does not lead to increased risk of hypoglycemia compared to once-daily IGlar. During hypoglycemia, a comparable symptomatic response and a moderately greater endocrine response were seen for icodec vs. IGlar. Disclosure E.Svehlikova: n/a. K.Niss arfelt: Employee; Novo Nordisk. R.Cailleteau: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. S.Deller: None. K.Thomsen: Employee; Novo Nordisk. M.Hart: None. I.Mursic: None. T.Pieber: Advisory Panel; Arecor, Novo Nordisk A/S, Research Support; AstraZeneca, European Union, JDRF, Novo Nordisk Foundation, Sanofi, Speaker's Bureau; Novo Nordisk A/S, Roche Diagnostics. H.Haahr: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. Funding Novo Nordisk

Attenuation of metabolic stress response during spinal surgery under general anaesthesia - A comparison between preoperative carbohydrate drink or no carbohydrate load

Background: Surgery is a stress which stimulates the increase of counter regulatory hormones. Pre-operative prolonged fasting increases stress further. Although a pre-operative carbohydrate (CHO) drink has been variably reported to yield benefit in reducing the perioperative stress and is being used frequently for elective surgeries, some recent reports also reports that preoperative CHO loading did not result in increase or decrease in the post-operative complication rates when compared with placebo or fasting group. Aims and Objectives: The present study was designed to determine the stress response in the postoperative period at 24 h in terms of changes in the levels of cortisol and other biomarkers. Materials and Methods: This randomized, parallel group, and double-blind study was conducted in 75 patients aged 18–65 years, of American Society of Anesthesiologists Physical Status Classes I and II, scheduled for elective lumbar spine surgery under general anesthesia. The patients were randomly allocated to receive 300 ml plain water at 9 pm on the day before surgery and 2 h before operation (Group C, control, n=25), or 300 ml plain water at 9 pm on the day before surgery and solution containing 75 grams of glucose dissolved in 300 ml water in the morning 2 h before surgery (Group CHO-1, n=25), or to receive 75 grams of glucose dissolved in 300 ml water at 9 pm in the night before the surgery and again in the morning at 2 h before surgery (Group CHO-2, n=25). In all the three groups, the levels of insulin (C-peptide), lactate, glucose, and cortisol were determined preoperatively (before the induction of anesthesia) and 24 h postoperatively. Results: There was considerable difference between post-operative blood cortisol level among the three groups (583.9 vs. 462.3 vs. 389.6 nMol/L, Control vs., CHO load once or twice, respectively, P<0.0001). A significant difference in post-operative values was also seen with other parameters such as serum lactate, glucose, and C-peptide. Considerable differences were seen in both preoperative and postoperative period in case of cortisol and lactate whereas it was limited to postoperative values in case of glucose and C-peptide. Conclusion: Pre-operative glucose loading showed better efficacy in suppressing perioperative stress response in terms of less rise of serum cortisol and lactate as compared to no CHO load.

Diabetic Ketoacidosis: A Review Article

Type 1 Diabetes Mellitus is the most common chronic disease in childhood and one of its complications is diabetic ketoacidosis. Diabetic ketoacidosis is considered one of the most common causes of death in a patient with type 1 diabetes. Diabetic ketoacidosis is characterized by hyperglycemia, hyperosmolarity, ketosis, and acidosis. The incidence rate of diabetic ketoacidosis has increased globally, annually. Diabetic ketoacidosis may be life-threatening and lead to diabetic coma or death. Diabetic ketoacidosis is defined as metabolic decompensation caused by increasing ketones in the blood. Diabetic ketoacidosis occurs when the body doesn’t have enough insulin to allow blood sugar into the cells for use as energy potentiated by glucose counter-regulatory hormone excess. Diabetic ketoacidosis presents with vague symptoms such as nausea, vomiting, and pain in the abdomen. A characteristic symptom of diabetic ketoacidosis, such as Kussmaul breathing, is present in limited patients. Early diagnosis and management are effective to improve patient outcomes. Infections in diabetic patients should be carefully monitored as they are the most common precipitating factors for diabetic ketoacidosis. The diagnosis of diabetic ketoacidosis is based on three major signs which are hyperglycemia, metabolic acidosis, and ketosis. The treatment of diabetic ketoacidosis includes fluid resuscitation, electrolyte replacement, insulin administration, and monitoring of the signs of cerebral edema and fluid overdose. This review article will mainly focus on the epidemiology, pathogenesis, diagnosis, management, and morbidity of diabetic ketoacidosis. Keywords: Diabetic Ketoacidosis, Review Article, Insulin Therapy, Type one Diabetes mellitus. Type Two Diabetes Mellitus

235-OR: Sustained QTc Prolongation during Recovery from Hypoglycemia in Patients with Type 1 Diabetes

Hypoglycemia and increased glycemic variability have been associated with cardiac arrhythmias and sudden cardiac death. We investigated cardiac repolarization during acute hypoglycemia followed by recovery to hyperglycemia or euglycemia in patients with type 1 diabetes. In a randomized crossover study, patients with type 1 diabetes (N=24, (mean±SD) age 53±years, HbA1c 7.5±0.8% [57.6±8.9 mmol/mol], diabetes duration 23±14 years, BMI 25.7± 3.1 kg/m2) underwent two clamps with three steady-state phases: 1) a hyperinsulinemic-euglycemic phase for 45 minutes, 2) a hyperinsulinemic-hypoglycemic phase for 60 minutes, and 3) a recovery phase in hyperglycemia (clamp A) or euglycemia (clamp B) for 60 minutes. Continuous ECG (Holter) monitoring and blood samples for counterregulatory hormones and plasma potassium were obtained. Linear mixed models were used to assess the impact of hypoglycemia and recovery to hyperglycemia vs. euglycemia on cardiac repolarization. Heart rate-corrected QT (QTc) (Fridericia’s formula) progressively increased from baseline (mean (95% CI) , clamp A: 415 msec (409;421) ; clamp B: 418 msec (412;424)) during hypoglycemia on both clamp days (∆mean (95% CI) , clamp A: 21 msec (11;31) ; clamp B: 22 msec (12;31)) . In the recovery phase, QTc remained increased during hyperglycemia and euglycemia (17 msec (11;21) vs. 14 msec (10;20)) with no difference in change between recovery to hyperglycemia compared to euglycemia (3 msec (-6;11) , P=0.5442) . No significant changes from baseline were observed in QTc dispersion (heterogeneity of myocardial repolarization) during hypoglycemia or in the recovery phases. We conclude that clinically significant QTc prolongations during insulin-induced hypoglycemia remain during a 60-minute recovery period independently of recovery to hyperglycemia or euglycemia in patients with type 1 diabetes. Thus, vulnerability for serious cardiac arrhythmias and sudden cardiac death may extend beyond a hypoglycemic event itself. Disclosure C.R.Andreasen: None. A.Andersen: n/a. P.G.Hagelqvist: None. J.V.Lauritsen: None. S.Engberg: Employee; Novo Nordisk A/S. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd. Funding Danish Diabetes Academy (NNF17SA0031406)

Impact of Polymorphism in the β2-Receptor Gene on Metabolic Responses to Repeated Hypoglycemia in Healthy Humans.

The Arg16 variant in the β2-receptor gene is associated with increased risk of severe hypoglycemia in subjects with type 1 diabetes mellitus. We hypothesized that the Arg16 variant is associated with decreased metabolic and symptomatic responses to recurrent hypoglycemia. Twenty-five healthy male subjects selected according to ADRB2 genotype and being homozygous for either Arg16 (AA; n = 13) or Gly16 (GG; n = 12) participated in 2 consecutive trial days with 3 periods of hypoglycemia (H1-H3) induced by a hyperinsulinemic hypoglycemic clamp. The main outcome measure was mean glucose infusion rate (GIR) during H1-H3. During H1-H3, there was no difference between AA or GG subjects in GIR, counter-regulatory hormones (glucagon, epinephrine, cortisol, growth hormone), or substrate levels of lactate, glycerol, and free fatty acids (FFAs), and no differences in symptom response score or cognitive performance (trail making test, Stroop test). At H3, lactate response was reduced in both genotype groups, but AA subjects had decreased response (mean ± standard error of the mean of area under the curve) of glycerol (-13.1 ± 3.8 μmol L-1 hours; P = .0052), FFA (-30.2 ± 11.1 μmol L-1 hours; P = .021), and β-hydroxybutyrate (-0.008 ± 0.003 mmol L-1 hour; P = .027), while in GG subjects alanine response was increased (negative response values) (-53.9 ± 20.6 μmol L-1 hour; P = .024). There was no difference in GIR between genotype groups, but secondary outcomes suggest a downregulation of the lipolytic and β-hydroxybutyrate responses to recurrent hypoglycemia in AA subjects, in contrast to the responses in GG subjects.

The features of liver glycogen fractions in streptozotocin-induced type-I diabetic rats

The ratio of counter-regulatory hormones to insulin is increased in diabetes. This causes a change in the activities of the enzymes involved in glycogen metabolism. Thus, it is expected that the structure of glycogen will be changed reversibly in diabetes mellitus. The current research was done to study whether the fractions of glycogen have been changed in streptozotocin (STZ)-induced diabetes in rats. To this end, one group of 10 male rats received a single injection with STZ and were compared with the control group. Liver glycogen fractions were analyzed for the content of carbohydrates, protein, and organic phosphate. Hyperglycemia and clinical signs of diabetes appeared after two days of STZ- injection and continued up to two weeks. In diabetic rats relative to controls, total glycogen decreased by about 39% (24.4 ± 3.0 mg/g wet weight of liver vs. 39.7 ± 2.2, p = 0.001), and the change happened entirely in acid-soluble glycogen (ASG) fraction (19.1 ± 1.7 vs. 33.4 ± 2.2, p = 0.001), while acid-insoluble glycogen (AIG) increased slightly but not significantly (5.5 ± 1.1, vs. 4.5 ± 0.8, p = 0.5). Diabetes was also associated with the change in the content of glycogen protein and the ratio of ASG to AIG. The content of organic phosphate was 181.4 ± 26.3 and 39.2 ± 7.9 µg/g wet weight of liver for ASG and AIG fractions in control rats and had no significant change in diabetes. In conclusion, diabetes is accompanied by the reduction in liver glycogen carbohydrate and protein of total and soluble fraction but the content of organic phosphate has not been affected.

Clinical Decision‐Making in Endocrine Physiology: Induced Hypoglycemia in Dogs

Clinical endocrinology cases present unique challenges to veterinary students, as assessment and management encompasses various shades of grey. In order to process nuances and make clinical decisions, students must have a firm grasp of the basic tenets of endocrine physiology, such as the relationship between various hormones and negative feedback loops. We hypothesized that incorporating current diabetes monitoring technology into a hands‐on first‐year veterinary physiology laboratory would improve their understanding of glucose homeostasis. Students receive didactic instruction in foundational endocrine physiology concepts during their physiology lecture class. The laboratory applies the concept of glucose homeostasis and the role of insulin and counterregulatory hormones, as well as the impetus for clinical decision‐making in hypoglycemic patients. Before entering the laboratory, students complete a pre‐laboratory questionnaire assessing medical math, glucose homeostasis concepts, and overall predictions for decision‐making as a team (approximately six students per laboratory group). Each group is assigned a dog from the Veterinary Physiology and Pharmacology (VTPP) teaching colony. The dogs are non‐diabetic and fasted the night before the laboratory takes place. A flash glucose monitoring system (FGMS), which measures interstitial glucose concentration, is applied to each dog before the start of that day’s laboratory. The students must weigh their dog and calculate a dose of regular insulin at 0.3 U/kg; one of the abstract’s authors double checks each dose for accuracy. Students administer regular insulin intravenously and use various methods to check the blood glucose with a portable blood glucose meter (PBGM) and the interstitial glucose concentration with the FGMS every 10 minutes. Based on the glucose concentration and the dog’s clinical signs, students are empowered to make corrections using a single dose of dexamethasone, intravenous dextrose, and/or food. Once the dog is normoglycemic and they have completed at least 90 minutes’ worth of readings, the exercise is complete. Students complete a post‐laboratory survey assessing the same concepts as the pre‐laboratory survey. In the pre‐laboratory survey, students frequently commented that they expected to gain a better understanding of glucose homeostasis and the effects of insulin on dogs. They discussed delegating work and the impact of various communication styles on the overall flow of the laboratory session. In the post‐laboratory survey, students frequently commented on their newfound respect for how rapidly insulin acts within the body, as well as treating the clinical signs of hypoglycemia quickly. The students identified communication obstacles and various techniques and solutions developed in a short time period. Our endocrine physiology laboratory cements key concepts introduced in lecture, as 94% (164/174) of students reported that the laboratory improved their understanding of glucose homeostasis. When asked if their group communicated well, 97% (168/174) of students agreed. The laboratory is uniquely situated to blend conceptual physiology knowledge with critical thinking and clinical decision‐making skills.

Urotensin II receptor knockout alleviates streptozotocin‐induced hyperglucagonemia and diabetic kidney disease

Plasma and urinary levels of UII, a potent vasoactive peptide, are elevated in diabetes mellitus (DM) patients. UII receptor (UT) expression levels are also increased in the kidneys of humans and animals with DM. Palosuran, an orally active UT antagonist, increased insulin levels and improved renal function in uninephrectomized streptozotocin (STZ)‐treated rats. However, human studies on the potential use of palosuran for kidney protection in diabetes were inconclusive. In addition to UT antagonism, palosuran can activate somatostatin receptors. Also, the reduced affinity of palosuran for UT in intact cells and tissues suggests that it may not be an optimal UT antagonist. Thus, using non‐selective and less potent UT antagonists constitutes a weakness in the scientific rigor of the prior attempts to dissect UT as a potential therapeutic target in DKD. Hence, studies using genetic animal models and highly selective and potent pharmacological antagonists are needed to fill the gaps of understanding on the pathophysiological significance of the UII system in DM. In the present study, we examine the development of hyperglycemia and DKD in the wild‐type (WT) and UT knockout (KO) mouse model of type 1 DM.STZ‐treated mice showed increased blood glucose levels, glucosuria, decreased plasma insulin levels, and diabetic kidney disease (DKD), which UT KO attenuated. However, UT KO failed to reverse STZ‐induced insulin deficiency. To understand the underlying mechanism for alleviating hyperglycemia and DKD in UT KO despite the uncorrected insulin deficiency, we tested the role of the primary insulin counterregulatory hormone, glucagon. We found that STZ treatment increased plasma glucagon levels in WT mice but not in UT KO mice. This finding was supported by double immunohistochemistry of pancreatic islet sections, where STZ treatment reduced insulin and increased glucagon staining. UT KO reversed only the effect of STZ on glucagon staining. These findings suggest that UT KO protects the glucagon‐producing alpha cells but not the insulin‐producing beta cells.UII increased glucagon secretion in a cultured pancreatic alpha cell line, which UT inhibition reversed. Next, to determine how UII triggers glucagon secretion, we performed membrane potential recordings in alpha cells using the perforated‐patch clamp technique. UII produced depolarization of alpha cells. This effect was abolished by UT inhibition. Calcium (Ca2+) imaging demonstrated that UII stimulates intracellular Ca2+ ([Ca2+]i) elevation in alpha cells, which T‐ and L‐type Ca2+ channel blockers attenuated.Taken together, the results of this study suggest that: (1) STZ‐treatment causes insulin deficiency, hyperglycemia, glucosuria, DKD, and hyperglucagonemia. (2) UT KO reverses STZ effects, except insulin deficiency. (3) UII increases glucagon secretion by alpha cells, mediated by UII‐induced membrane depolarization and Ca2+ influx via T‐ and L‐type Ca2+ channels. Therefore, the reversal of hyperglycemia, glucosuria, and DKD in UT KO might be linked to the reversal of hyperglucagonemia.

Use of Continuous Glucose Monitoring in the Assessment and Management of Patients With Diabetes and Chronic Kidney Disease.

In developed countries, diabetes is the leading cause of chronic kidney disease (CKD) and accounts for 50% of incidence of end stage kidney disease. Despite declining prevalence of micro- and macrovascular complications, there are rising trends in renal replacement therapy in diabetes. Optimal glycemic control may reduce risk of progression of CKD and related death. However, assessing glycemic control in patients with advanced CKD and on dialysis (G4-5) can be challenging. Laboratory biomarkers, such as glycated haemoglobin (HbA1c), may be biased by abnormalities in blood haemoglobin, use of iron therapy and erythropoiesis-stimulating agents and chronic inflammation due to uraemia. Similarly, glycated albumin and fructosamine may be biased by abnormal protein turnover. Patients with advanced CKD exhibited heterogeneity in glycemic control ranging from severe insulin resistance to ‘burnt-out’ beta-cell function. They also had high risk of hypoglycaemia due to reduced renal gluconeogenesis, frequent use of insulin and dysregulation of counterregulatory hormones. Continuous glucose monitoring (CGM) systems measure glucose in interstitial fluid every few minutes and provide an alternative and more reliable method of glycemic assessment, including asymptomatic hypoglycaemia and hyperglycaemic excursions. Recent international guidelines recommended use of CGM-derived Glucose Management Index (GMI) in patients with advanced CKD although data are scarce in this population. Using CGM, patients with CKD were found to experience marked glycemic fluctuations with hypoglycemia due to loss of glucose and insulin during haemodialysis (HD) followed by hyperglycemia in the post-HD period. On the other hand, during peritoneal dialysis, patients may experience glycemic excursions with influx of glucose from dialysate solutions. These undesirable glucose exposure and variability may accelerate decline of residual renal function. Although CGM may improve the quality of glycemic monitoring and control in populations with CKD, further studies are needed to confirm the accuracy, optimal mode and frequency of CGM as well as their cost-effectiveness and user-acceptability in patients with advanced CKD and dialysis.

Neuroglycopenia: common etiologies, clinical characteristics, and management

Glucose is primary source of energy substrate for the brain, however, during physiological stresses or other situations with low blood glucose, ketone bodies are another important source of energy for brain. Hypoglycemia has significant impact on the brain and symptomatic hypoglycemia is referred as Neuroglycopenia. Since the brain has minimal endogenous glycogen stores and does not generate glucose intrinsically, it requires a constant supply of glucose from the circulation. Impairment in glucose supply leads to activation of counter regulatory hormone mainly the neuroendocrine response in order to restore the energy requirement. If this response fails to secure the energy demand hypoglycemia can present clinically as headache, stroke, seizure, cognitive impairment or coma. A prompt and accurate diagnosis would allow for more precise treatment and less neuronal damage. This article focuses on common etiology, counter regulatory responses to hypoglycemia, clinical features and management of hypoglycemia.

Effect of lactate administration on cerebral blood flow during hypoglycemia in people with type 1 diabetes

IntroductionImpaired awareness of hypoglycemia, clinically reflected by the inability to timely detect hypoglycemia, affects approximately 25% of the people with type 1 diabetes. Both altered brain lactate handling and increased...

Altered functional connectivity during hypoglycaemia in type 1 diabetes

Behavioural responses to hypoglycaemia require coordinated recruitment of broadly distributed networks of interacting brain regions. We investigated hypoglycaemia-related changes in brain connectivity in people without diabetes (ND) and with type 1 diabetes with normal (NAH) or impaired (IAH) hypoglycaemia awareness. Two-step hyperinsulinaemic hypoglycaemic clamps were performed in 14 ND, 15 NAH and 22 IAH participants. BOLD timeseries were acquired at euglycaemia (5.0 mmol/L) and hypoglycaemia (2.6 mmol/L), with symptom and counter-regulatory hormone measurements. We investigated hypoglycaemia-related connectivity changes using established seed regions for the default mode (DMN), salience (SN) and central executive (CEN) networks and regions whose activity is modulated by hypoglycaemia: the thalamus and right inferior frontal gyrus (RIFG). Hypoglycaemia-induced changes in the DMN, SN and CEN were evident in NAH (all p < 0.05), with no changes in ND or IAH. However, in IAH there was a reduction in connectivity between regions within the RIFG (p = 0.001), not evident in the ND or NAH groups. We conclude that hypoglycaemia induces coordinated recruitment of the DMN and SN in diabetes with preserved hypoglycaemia awareness which is absent in IAH and ND. Changes in connectivity in the RIFG, a region associated with attentional modulation, may be key in impaired hypoglycaemia awareness.

Neural control of pancreatic peptide hormone secretion

Pancreatic peptide hormone secretion is inextricably linked to maintenance of normal levels of blood glucose. In animals and man, pancreatic peptide hormone secretion is controlled, at least in part, by input from parasympathetic (vagal) premotor neurons that are found principally in the dorsal motor nucleus of the vagus (DMV). Iatrogenic (insulin-induced) hypoglycaemia evokes a homeostatic response commonly referred to as the glucose counter-regulatory response. This homeostatic response is of particular importance in Type 1 diabetes in which episodes of hypoglycaemia are common, debilitating and lead to suboptimal control of blood glucose. Glucagon is the principal counterregulatory hormone but for reasons unknown, its secretion during insulin-induced hypoglycaemia is impaired. Pancreatic parasympathetic neurons are distinguishable electrophysiologically from those that control other (e.g. gastric) functions and are controlled by supramedullary inputs from hypothalamic structures such as the perifornical region. During hypoglycaemia, glucose-sensitive, GABAergic neurons in the ventromedial hypothalamus are inhibited leading to disinhibition of perifornical orexin neurons with projections to the DMV which, in turn, leads to increased secretion of glucagon.

High Plasma Oxytocin Levels in Men With Hypersexual Disorder.

ContextHypersexual disorder (HD) involves excessive, persistent sexual behaviors related to various mood states and the diagnosis compulsive sexual behavior disorder is included as an impulse control disorder in the 11th revision of the International Classification of Diseases. Although the neurobiology behind the disorder is not clear, some studies suggest dysregulated hypothalamic-pituitary-adrenal axis. Oxytocin acts as counterregulatory neuroendocrine hormone to cortisol and is also involved in sexual behavior.ObjectiveWe hypothesized that oxytocin may play a role in the pathophysiology of HD with compensatory actions to cortisol.DesignLongitudinal.SettingANOVA clinic (Karolinska University Hospital).Patients or other participants64 males with HD and 38 age-matched healthy volunteers.Main Outcome MeasuresPlasma oxytocin levels, measured with radioimmunoassay; Hypersexual Disorder Screening Inventory; and Hypersexual Disorder: Current Assessment Scale for assessing hypersexual symptoms.InterventionsA patient subgroup (n = 30) completed the manual-based group-administered cognitive-behavioral therapy (CBT) program for HD, and posttreatment oxytocin levels were measured.ResultsHypersexual men (n = 64) exhibited significantly higher oxytocin plasma levels (mean ± SD: 31.0 ± 9.9 pM) compared with healthy volunteers (16.9 ± 3.9 pM; P < 0.001). There were significant positive correlations between oxytocin levels and the rating scales measuring hypersexual behavior. Patients who completed CBT treatment (n = 30) had a significant reduction of oxytocin plasma levels from pretreatment (30.5 ± 10.1 pM) to posttreatment (20.2 ± 8.0 pM; P < 0.001).ConclusionsThe results suggest that the hyperactive oxytocinergic system in hypersexual men may be a compensatory mechanism to attenuate hyperactive stress.

Fetomaternal Acid-Base Balance and Electrolytes during Pregnancy.

A pregnant mother undergoes significant changes in acid-base status as well as sodium and calcium metabolism to combat her physiological needs of pregnancy. Pregnant patients experience mild respiratory alkalosis due to the stimulation of the respiratory center by progesterone. This is associated with a corresponding increase in bicarbonate excretion by kidneys; as a result, the pH remains slightly high (7.40–7.45) but within the normal range. Pregnant women are predisposed to starvation ketosis as compared to nonpregnant states due to relative insulin resistance and increased production of the counter-regulatory hormone. Physiological mild hyponatremia occurs during pregnancy due to increased AVP secretion caused by resetting of osmoreceptors in the hypothalamus at a lower osmolality, but values below 130 mEq/L require a diagnostic workup and intervention. Gestational diabetes insipidus can occur due to increased production or decreased destruction of enzyme vasopressinase. Secretion of parathyroid hormone-related peptide by the placenta and breasts and two- to three-fold increased calcium and phosphate absorption in the maternal gut are the key changes in calcium metabolism during pregnancy. Though rare, both hypo- and hypercalcemia in pregnancy are associated with significant maternofetal morbidity and mortality.How to cite this articleAhmed A. Fetomaternal Acid–Base Balance and Electrolytes during Pregnancy. Indian J Crit Care Med 2021; 25(Suppl 3):S193–S199.

Stress Hyperglycemia: A Problem that Cannot be Ignored

Stress hyperglycemia is a strong neuroendocrine reaction in thehypothalamic pituitary adrenal cortex under severe infection, trauma, burns,hemorrhage, surgery and other harmful stimulated, resulting in increasedsecretion of counter-regulatory hormones. These hormones promotedthe production of sugar and cause glucose metabolism disorders withcytokines and insulin resistance. In this condition, the production of sugarexceeds the utilization of sugar by the tissues, which eventually leads to anincrease in blood glucose levels in plasma. In the intensive care unit, stresshyperglycemia is very common and can occur in patients with or withoutdiabetes. The incidence is as high as 96%, and it is an independent factorin the death of critically ill patients. Hyperglycemia not only prolongsthe hospitalization time, mechanical ventilation time and increased theincidence of serious infections in critically ill patients, but can also leadto the occurrence of type 2 diabetes. Therefore, it is very important tolearn the pathological mechanism of stress hyperglycemia, the harm ofhyperglycemia and blood sugar management.

Effects of intraoperative hypothermia on stress hormon response in surgical patients

Background/Aim. Surgical stress itself, as well as hypothermia induced by general anesthesia and low ambient temperature, activates stress hormone response with changes in catecholamines and counter-regulatory hormones. The aim of this study was to investigate the acute hormone stress response in patients who underwent major surgical procedures and the efficiency of external and internal warming methods in alleviating these changes. Methods. The study included a total of 60 patients who underwent major open abdominal surgical procedures and were randomly divided into 4 groups: control non-warmed (C), externally warmed using forced-air warming mattress (W), internally warmed using intravenous amino acids (A), and warmed with a combination of external and internal method (A+W). Esophageal temperature was used as a measure of core temperature. Concentrations of epinephrine, norepinephrine, cortisol, prolactin, and testosterone were measured. Blood samples for hormone measurement were obtained at two time points for catecholamines ? 90 min before and 120 min after finishing the surgery, and at additional two-time points for cortisol, prolactin, and testosterone (24 and 48 hrs after surgery). Results. In the W and A+W groups, the temperatures did not significantly differ between time points but constantly decreased in the C and A groups, with a statistically significant difference between the anesthesia induction and the 120th min (35.61 ? 042 vs. 33.86 ? 0.71?C; p &lt; 0.000 and 35.81 ? 0.54 vs. 34.45 ? 0.41?C; p &lt; 0.000, respectively). Catecholamine concentrations in all groups showed a significant increase during surgery, with the highest values recorded in the non-warmed group (777.07 ? 800.08 after vs. 106.13 ? 89.63 pg/mL before surgery for epinephrine and 1,349.67 ? 984.16 vs. 580.53 ? 465.38 for norepinephrine, p &lt; 0.000). Concentrations of cortisol and prolactin also showed a significant increase at the same time point, with a tendency to normalize after 48 hrs. On the contrary, testosterone concentrations showed a decrease after 120 min without normalization throughout the entire period of observation. Except for testosterone, changes in all stress hormones were attenuated in warmed groups compared to controls. Conclusions. Regarding both features of surgical stress investigated in this study (hypothermia and stress hormone response), the combination of endogenous amino acid-induced thermogenesis and external air warming mattress is most effective in its prevention.

A Case of SGLT-2i Induced Euglycemic Diabetic Ketoacidosis in the Setting of Gastrointestinal Stress

Euglycemic DKA (euDKA) is a rare, uncommon variant of DKA, characterized by the imbalance between insulin and counterregulatory hormones. Lately, the use of SGLT2 inhibitors is known to incite euDKA, which is often missed on initial presentation. In this case, we present a scenario of a 61-year-old African American male with a history of hypertension, CAD s/p CABG, and type 2 diabetes mellitus on SGLT2i (empagliflozin) with a clinical picture of normoglycemic DKA process. With a pH of 7.14, bicarbonate of 8 mEq/L, anion gap (AG) of 17mEq/L, ketoacidosis, and glucosuria, the patient met criteria for euDKA; however, the initial clinical diagnosis of euDKA was overlooked by the possibility of an underlying infectious gastroenteritis, given his recent history of travel with passengers with similar presentation, causing a delay in euDKA management. The management of euDKA is like that of a typical DKA, inculcating aggressive fluid resuscitation and insulin, followed by a permanent discontinuation of SGLT2i. Thus, this case highlights the importance of understanding SGLT2i induced euDKA and its early diagnostic and timely management to prevent further complications.

Diabetic Ketoasidosis

Diabetic ketoacidosis (DKA) is one of the acute complications for diabetics that usually occurs in type 1 DM, but it is possible in type 2 DM. DKA is caused by a decrease in effective insulin circulation associated with an increase in counter-regulatory hormones. The incidence of DKA ranges from 0 to 56 per 1000 people each year. In Indonesia, it is known that 71% of pediatric patients have DKA as the initial clinical presentation of type-1 DM in 2017. To know more about diabetic ketoacidosis. Knowing the characteristics of patients with diabetic ketoacidosis. Know how to treat patients with diabetic ketoacidosis. This reserch use Literatur-review method. DKA is a complication of uncontrolled type 1 diabetes mellitus and has a high risk of being life-threatening. The incidence of DKA in Indonesia is not known for certain, but it is estimated at 76.9% based on data from Riskesdas in 2007. DKA occurs due to insulin deficiency which will result in increased lipolysis and usually occurs due to metabolic stress conditions. Symptoms of DKA are symptoms of hyperglycemia and classic symptoms of hyperglycemia. The key to the diagnosis of DKA is an increase in total circulating ketone bodies. The initial management of DKA is to monitor and secure the airway, breathing, circulation.