Counterregulatory Hormones Research Articles

SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants With Type 1 Diabetes.

Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (n = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic-hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on α-cell function.

A Randomized Crossover Trial Comparing Glucose Control During Moderate-Intensity, High-Intensity, and Resistance Exercise With Hybrid Closed-Loop Insulin Delivery While Profiling Potential Additional Signals in Adults With Type 1 Diabetes.

To compare glucose control with hybrid closed-loop (HCL) when challenged by high intensity exercise (HIE), moderate intensity exercise (MIE), and resistance exercise (RE) while profiling counterregulatory hormones, lactate, ketones, and kinetic data in adults with type 1 diabetes. This study was an open-label multisite randomized crossover trial. Adults with type 1 diabetes undertook 40 min of HIE, MIE, and RE in random order while using HCL (Medtronic MiniMed 670G) with a temporary target set 2 h prior to and during exercise and 15 g carbohydrates if pre-exercise glucose was <126 mg/dL to prevent hypoglycemia. Primary outcome was median (interquartile range) continuous glucose monitoring time-in-range (TIR; 70-180 mg/dL) for 14 h post-exercise commencement. Accelerometer data and venous glucose, ketones, lactate, and counterregulatory hormones were measured for 280 min post-exercise commencement. Median TIR was 81% (67, 93%), 91% (80, 94%), and 80% (73, 89%) for 0-14 h post-exercise commencement for HIE, MIE, and RE, respectively (n = 30), with no difference between exercise types (MIE vs. HIE; P = 0.11, MIE vs. RE, P = 0.11; and HIE vs. RE, P = 0.90). Time-below-range was 0% for all exercise bouts. For HIE and RE compared with MIE, there were greater increases, respectively, in noradrenaline (P = 0.01 and P = 0.004), cortisol (P < 0.001 and P = 0.001), lactate (P ≤ 0.001 and P ≤ 0.001), and heart rate (P = 0.007 and P = 0.015). During HIE compared with MIE, there were greater increases in growth hormone (P = 0.024). Under controlled conditions, HCL provided satisfactory glucose control with no difference between exercise type. Lactate, counterregulatory hormones, and kinetic data differentiate type and intensity of exercise, and their measurement may help inform insulin needs during exercise. However, their potential utility as modulators of insulin dosing will be limited by the pharmacokinetics of subcutaneous insulin delivery.

EUGLYCEMIC DIABETIC KETOACIDOSIS MASQUERADING AS TOXIC ALCOHOL INGESTION

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: First reported in 1973, euglycemic diabetic ketoacidosis (euDKA) historically accounted for 0.8-1.1% of diabetic ketoacidosis (DKA) cases [1]. Without hyperglycemia, the anion gap metabolic acidosis (AGMA) of euDKA may be attributed to other causes. We present a case of euDKA that was mistaken for toxic alcohol poisoning. CASE PRESENTATION: A 53-year-old woman with type 2 diabetes (T2D), for which she reported taking metformin and glyburide, presented with abdominal pain and nausea. She also reported drinking "vodka" given by a stranger the day prior. Labs included bicarbonate 12 mEq/L, anion gap (AG) 18, lactate 1.7 mmol/L, lipase 735 U/L, and urinalysis with 2+ glucose and 3+ ketones. CT confirmed pancreatitis. Correctional insulin was ordered but not given due to blood sugar of 121-225 mg/dL. Repeat labs overnight revealed bicarbonate <5, AG >18, and arterial pH 7.09. After toxicology consult, she was given IV fomepizole and transferred to the ICU for urgent hemodialysis (HD) for possible toxic alcohol poisoning. Just prior to placing HD access, records obtained revealed that she was prescribed empagliflozin. Ultimately, a toxic alcohol panel was negative and beta-hydroxybutyrate was elevated at 0.86 mmol/L. She was treated with infusions of crystalloid, insulin, and dextrose. Her ketosis resolved in 9 days, and she was discharged on insulin and metformin. DISCUSSION: Previously seen with low caloric intake, alcohol or cocaine use, liver disease, or pregnancy, euDKA has recently been linked to sodium glucose cotransporter 2 inhibitor (SGLT2I) use [2]. Since FDA approval in 2013, SGLT2I use has steadily risen as data on cardiovascular and renal benefits accumulate. SGLT2Is act independent of insulin by blocking proximal tubule reabsorption of glucose. This can lead to euglycemia despite insulin deficiency and the potential for an acute insult, like pancreatitis, to trigger euDKA. Along with lack of insulin, SGLT2I-related euDKA may be mediated by volume depletion, counterregulatory hormones, and enhanced lipolysis and fatty acid oxidation [3]. Notably, pancreatitis can trigger euDKA without SGLT2I use [2]. Though the initial ketonuria and lack of inebriation were, in retrospect, clues to the presence of DKA in this case, the report of a suspicious ingestion led to a presumptive diagnosis of toxic alcohol poisoning. Indeed, untreated toxic alcohol poisoning can lead to major disability or death, and prompt empiric treatment is vital if clinical suspicion exists. CONCLUSIONS: The rapid diagnosis of AGMA remains a challenge in intensive care. As SGLT2I use continues to grow, providers will increasingly encounter euDKA. Importantly, euglycemia does not exclude DKA, and euDKA must be routinely considered in the differential of unexplained severe AGMA to prevent adverse outcomes from delays in treatment. REFERENCE #1: Jenkins et al. Euglycaemic diabetic ketoacidosis: does it exist? Acta Diabetol 1993;30:251-3. REFERENCE #2: Bonora et al. Euglycemic Ketoacidosis. Review Curr Diab Rep 2020 May 19;20:25. REFERENCE #3: Qiu et al. Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: Basic mechanisms and therapeutic perspectives. Diabetes Metab Res Rev 2017 Jul;33(5). DISCLOSURES: No relevant relationships by Christos Argyropoulos, source=Web Response No relevant relationships by Matt Bouchonville, source=Web Response No relevant relationships by Mitchell Byrd, source=Web Response No relevant relationships by Melissa Fang, source=Web Response No relevant relationships by Umair Khan, source=Web Response No relevant relationships by Joao Teixeira, source=Web Response

GABA induces a hormonal counter-regulatory response in subjects with long-standing type 1 diabetes

IntroductionExperimentally, gamma-aminobutyric acid (GABA) has been found to exert immune-modulatory effects and induce beta-cell regeneration, which make it a highly interesting substance candidate for the treatment of type 1 diabetes...

New Options to Simplify the Treatment of Severe Hypoglycemia in Long-Term Care

New Options to Simplify the Treatment of Severe Hypoglycemia in Long-Term Care

Глікемічний скринінг і вторинні порушення вуглеводного обміну при ендокринній патології

Причиною поганого глікемічного контролю при цукровому діабеті може бути надлишкова секреція контрінсулярних гормонів при різних ендокринопатіях. А отже, глікемічний скринінг і скринінг ендокринних захворювань, які супроводжуються порушеннями вуглеводного обміну, повинні проводитися паралельно.

SGLT2 Inhibition by Dapagliflozin Attenuates Diabetic Ketoacidosis in Mice with Type-1 Diabetes

SGLT2 inhibitors increase plasma ketone concentrations. It has been suggested that insulinopenia, along with an increase in the counter-regulatory hormones epinephrine, corticosterone, glucagon and growth hormone, can induce ketoacidosis, especially in type-1 diabetes (T1DM). Dehydration precipitates SGLT2 inhibitor-induced ketoacidosis in type-2 diabetes. We studied the effects of dapagliflozin and water deprivation on the development of ketoacidosis and the associated signaling pathways in T1DM mice. C57BL/6 mice were fed a high-fat diet. After 7days, some mice received intraperitoneal injection of streptozocin + alloxan (STZ/ALX). The treatment groups were control + water at lib; control + dapagloflozin + water at lib; control + dapagloflozin + water deprivation; STZ/ALX + water at lib; STZ/ALX + water deprivation; STZ/ALX + dapagloflozin + water at lib; STZ/ALX + dapagloflozin + water deprivation. Dapagliflozin was given for 7days. In the morning of day 18, food was removed, and water was removed in the water deprivation groups. ELISA, rt-PCR, and immunoblotting were used to assess blood, heart, liver, white and brown adipose tissues. The T1DM mice had ketoacidosis even without water deprivation. Water deprivation increased plasma levels of β-hydroxybutyrate, acetoacetate, corticosterone, and epinephrine and reduced the levels of adiponectin in T1DM mice. Interleukin (IL) 1β, IL-6, IL-8, and TNFα were also increased in the T1DM mice with water deprivation. Dapagliflozin attenuated the changes in the T1DM mice without and with water deprivation. Likewise, water deprivation increased the activation of the inflammasome in the heart, liver, and white fat of the T1DM mice and dapagliflozin attenuated these changes. Dapagliflozin reduced the mRNA levels of glucagon receptors in the liver and the increase in GPR109a in white and brown fat. In the liver, dapagliflozin increased AMPK phosphorylation, and attenuated the phosphorylation of TBK1 and the activation of NFκB. Dapagliflozin reduced ketone body levels and attenuated the activation of NFκB and the activation of the inflammasome in T1DM mice with ketoacidosis.

Role of High Voltage-Gated Ca2+ Channel Subunits in Pancreatic β-Cell Insulin Release. From Structure to Function.

The pancreatic islets of Langerhans secrete several hormones critical for glucose homeostasis. The β-cells, the major cellular component of the pancreatic islets, secrete insulin, the only hormone capable of lowering the plasma glucose concentration. The counter-regulatory hormone glucagon is secreted by the α-cells while δ-cells secrete somatostatin that via paracrine mechanisms regulates the α- and β-cell activity. These three peptide hormones are packed into secretory granules that are released through exocytosis following a local increase in intracellular Ca2+ concentration. The high voltage-gated Ca2+ channels (HVCCs) occupy a central role in pancreatic hormone release both as a source of Ca2+ required for excitation-secretion coupling as well as a scaffold for the release machinery. HVCCs are multi-protein complexes composed of the main pore-forming transmembrane α1 and the auxiliary intracellular β, extracellular α2δ, and transmembrane γ subunits. Here, we review the current understanding regarding the role of all HVCC subunits expressed in pancreatic β-cell on electrical activity, excitation-secretion coupling, and β-cell mass. The evidence we review was obtained from many seminal studies employing pharmacological approaches as well as genetically modified mouse models. The significance for diabetes in humans is discussed in the context of genetic variations in the genes encoding for the HVCC subunits.

Specific Naturopathic Modalities Ameliorate Glucose Homeostasis and Other Physiological Parameters in Human Diabetics

Background: Diabetes Mellitus is now becoming a serious medical and socio-economic issue all over the world. Early initiation of combination therapy has been suggested as a way to achieve glycemic control, postpone the complications and possibly restore β-cell function. Naturopathy and yoga is one of the upcoming medical systems which had showed a promising result for many lifestyle disorders and hence, this study was aimed to evaluate the effect of 10 days Integrated Naturopathy and Yoga (INY) treatment especially Abdomen Massage and Neutral Hip Bath on glycemic control and anthropometric measures.&#x0D; Methods: 100 subjects with diabetes were selected and randomly allocated into Case group (naturopathy &amp; yoga intervention with Abdomen Massage and Neutral Hip Bath) and Control group (naturopathy &amp; yoga intervention). The subjects were assessed for blood glucose levels and anthropometric measures at baseline and after the intervention of 10 days.&#x0D; Results: The result of this study showed a significant reduction in Fasting Glucose (FG) and Post Prandial Glucose (PPG) after 10 days of intervention where Body Mass Index (BMI) and Waist Hip Ratio (WHR) have not shown significant changes in the groups. The case group has a larger mean difference between pre and post values of FG, PPG, BMI, and WHR as compared to the control group.&#x0D; Conclusion: Abdomen massage with neutral hip bath is relatively better for lowering the FG, PPG along with BMI and WHR, by the activation of adiponectin, Brown Adipose Tissue, Atrial natriuretic peptide and counter-regulatory stress hormones, which control hormonal activity, glucose absorption, metabolism and excretion.

Acute hypoglycemia and risk of cardiac arrhythmias in insulin-treated type 2 diabetes and controls.

ObjectiveHypoglycemia is associated with an increased risk of cardiovascular disease including cardiac arrhythmias. We investigated the effect of hypoglycemia in the setting of acute glycemic fluctuations on cardiac rhythm and cardiac repolarization in insulin-treated patients with type 2 diabetes compared with matched controls without diabetes.DesignA non-randomized, mechanistic intervention study.MethodsInsulin-treated patients with type 2 diabetes (n = 21, age (mean ± s.d.): 62.8 ± 6.5 years, BMI: 29.0 ± 4.2 kg/m2, HbA1c: 6.8 ± 0.5% (51.0 ± 5.4 mmol/mol)) and matched controls (n = 21, age: 62.2 ± 8.3 years, BMI 29.2 ± 3.5 kg/m2, HbA1c: 5.3 ± 0.3% (34.3 ± 3.3 mmol/mol)) underwent a sequential hyperglycemic and hypoglycemic clamp with three steady-states of plasma glucose: (i) fasting plasma glucose, (ii) hyperglycemia (fasting plasma glucose +10 mmol/L) and (iii) hyperinsulinemic hypoglycemia (plasma glucose < 3.0 mmol/L). Participants underwent continuous ECG monitoring and blood samples for counterregulatory hormones and plasma potassium were obtained.ResultsBoth groups experienced progressively increasing heart rate corrected QT (Fridericia’s formula) interval prolongations during hypoglycemia ((∆mean (95% CI): 31 ms (16, 45) and 39 ms (24, 53) in the group of patients with type 2 diabetes and controls, respectively) with similar increases from baseline at the end of the hypoglycemic phase (P = 0.43). The incidence of ventricular premature beats increased significantly in both groups during hypoglycemia (P = 0.033 and P < 0.0001, respectively). One patient with type 2 diabetes developed atrial fibrillation during recovery from hypoglycemia.ConclusionsIn insulin-treated patients with type 2 diabetes and controls without diabetes, hypoglycemia causes clinically significant and similar increases in cardiac repolarization that might increase vulnerability for serious cardiac arrhythmias and sudden cardiac death.

198-OR: The Stimulatory Effect of Glucagon on Insulin Secretion Is Glucose Dependent in Healthy Human Subjects

Glucagon is generally considered to be a counter-regulatory hormone with a primary role to raise blood glucose concentrations by increasing endogenous glucose production (EGP). However, recent preclinical findings support a paracrine action of glucagon to act directly on pancreatic beta cells to promote nutrient-stimulated insulin secretion. In mice, the divergent actions of glucagon are dependent on glycemic status: during fasting glucagon acts predominantly at the liver to raise blood glucose, whereas in the fed state when glycemia is elevated, the insulinotropic effects predominate to lower glucose. These mechanistic findings have not been extended to human physiology. Therefore, we designed a study to test the hypothesis that in healthy humans glucagon actions are also dependent on ambient glycemia. Subjects received glucagon (100 ng/kg) during fasting euglyemia or experimental hyperglycemia (~150 mg/dl) on separate days. On both days, glycemia was maintained for 60 min prior to a glucagon infusion for an additional 60 min. Blood glucose was monitored at bedside and plasma samples were analyzed for C-peptide and di-deuterated glucose enrichment to calculate HGP. During fasting euglycemia, blood glucose was 85 mg/dl and glucagon elicited an increase to a 60 minute average of 132 mg/dl with a peak at ~156 mg/dl at the end of the infusion. Concordant with increased glycemia was an immediate increase in HGP (1.8x) and a delayed increase in C-peptide AUC (1.5x). For the hyperglycemia studies, blood glucose was maintained at 150 mg/dl before and during glucagon administration. Here, glucagon caused a rapid and robust increase in C-peptide AUC (4x) and a more gradual increase in HGP (2x). This glycemic-dependent behavior of glucagon suggests a physiologic role to promote prandial insulin secretion in healthy subjects. This raises the possibility that this incretin function of glucagon plays a role in β-cell function in diabetic subjects. Disclosure S. M. Gray: None. G. Zhang: None. W. Bennett: None. J. Tong: None. J. Campbell: None. D. A. D’alessio: Advisory Panel; Self; Eli Lilly and Company, Sun Pharmaceutical Industries Ltd., Research Support; Self; Eli Lilly and Company, Merck &amp; Co., Inc. Funding National Institutes of Health (F32DK121420, R01DK101991)

342-P: Effects of Sitagliptin on Hypoglycemic Episodes and Counterregulation in Type 2 Diabetic Patients Tightly Titrated with Insulin Glargine

DPP-4 inhibitors may prevent hypoglycemic episodes in insulin-treated type 2 diabetes (T2D), but mechanisms are unclear. 20 T2D patients treated with basal insulin and metformin (± other agents) were recruited for two randomized treatments (placebo or 100 mg/d sitagliptin) in addition to insulin glargine/metformin; 17 completed (3 women, 14 men; age 57 ± 7 yrs.; BMI 28.8 ± 3.9 kg/m2; HbA1c 7.4 ± 0.7 %). After titrating fasting plasma glucose (PG) to 90-110 mg/dl, patients were observed during a 3-day (d) inpatient period with exposure to oral glucose or lipid loads, strenuous exercise and fasting, while increasing insulin doses to 110, and 120 % of the titrated dose before d 2 and 3, respectively. Hypoglycemic episodes (PG &amp;lt; 70 mg/dl) were identified by measuring venous plasma glucose or symptoms, and prompted the determination of counter-regulatory hormones at the glucose nadir and 30 and 60 min later. After titrating insulin glargine, fasting PG was 112 ± 5 and 107 ± 5 mg/dl with placebo and sitagliptin treatment, respectively. Concentrations of insulin, C-peptide and counterregulatory hormones were similar during both treatments. Hypoglycemic episodes were mainly nocturnal (10 p.m. to 7 a.m.), with a similar PG nadir (65 ± 4 mg/dl) and incidence with placebo and sitagliptin (4.5 ± 3.2 vs. 4.6 ± 3.6 episodes per patient, respectively, p = 0.96). With a similar incidence of daytime (7 a.m. to 10 p.m.) chemical hypoglycemia, the incidence of symptomatic episodes was higher with sitagliptin (0.2 ± 0.4 vs. 0.0 ± 0.0, p = 0.028). Counter-regulatory responses were suppressed by sitagliptin for cortisol (p = 0.022), unchanged for glucagon, HGH, noradrenaline and prolactin, and accentuated for adrenaline (p = 0.022). Our results suggest that sitagliptin treatment augments counter-regulatory responses of adrenaline at minimal degrees of hypoglycemia. This may increase symptoms, in particular during daytime, and may offer opportunities for earlier treatment. Disclosure M. A. Nauck: Advisory Panel; Self; Berlin-Chemie AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Consultant; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Speaker’s Bureau; Self; Berlin-Chemie AG, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk. A. Feldmann: None. J. J. Meier: Advisory Panel; Self; AstraZeneca, MSD Corporation, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, MSD Corporation, Novo Nordisk, Sanofi. M. Nauck: None. C. Kapitza: Research Support; Self; ADOCIA, Afon Technology, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gan &amp; Lee Pharmaceuticals, Johnson &amp; Johnson, Julphar, Mylan N. V., Nestlé, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Funding Merck Sharp &amp; Dohme Corp

Metabolomics Profiling of Patients With A−β+ Ketosis-Prone Diabetes During Diabetic Ketoacidosis

When stable and near-normoglycemic, patients with "A-β+" ketosis-prone diabetes (KPD) manifest accelerated leucine catabolism and blunted ketone oxidation, which may underlie their proclivity to develop diabetic ketoacidosis (DKA). To understand metabolic derangements in A-β+ KPD patients during DKA, we compared serum metabolomics profiles of adults during acute hyperglycemic crises, without (n = 21) or with (n = 74) DKA, and healthy control subjects (n = 17). Based on 65 kDa GAD islet autoantibody status, C-peptide, and clinical features, 53 DKA patients were categorized as having KPD and 21 type 1 diabetes (T1D); 21 nonketotic patients were categorized as having type 2 diabetes (T2D). Patients with KPD and patients with T1D had higher counterregulatory hormones and lower insulin-to-glucagon ratio than patients with T2D and control subjects. Compared with patients withT2D and control subjects, patients with KPD and patients with T1D had lower free carnitine and higher long-chain acylcarnitines and acetylcarnitine (C2) but lower palmitoylcarnitine (C16)-to-C2 ratio; a positive relationship between C16 and C2 but negative relationship between carnitine and β-hydroxybutyrate (BOHB); higher branched-chain amino acids (BCAAs) and their ketoacids but lower ketoisocaproate (KIC)-to-Leu, ketomethylvalerate (KMV)-to-Ile, ketoisovalerate (KIV)-to-Val, isovalerylcarnitine-to-KIC+KMV, propionylcarnitine-to-KIV+KMV, KIC+KMV-to-C2, and KIC-to-BOHB ratios; and lower glutamate and 3-methylhistidine. These data suggest that during DKA, patients with KPD resemble patients with T1D in having impaired BCAA catabolism and accelerated fatty acid flux to ketones-a reversal of their distinctive BCAA metabolic defect when stable. The natural history of A-β+ KPD is marked by chronic but varying dysregulation of BCAA metabolism.

Extreme High Insulin Requirements in Two Non-Diabetic Patients Following Cardiac Transplantation

Introduction: Blood glucose (BG) management is challenging following cardiac transplantation (CT) due to insulin resistance (IR) induced by post-operative stress and inflammation, intravenous pressors, and high-dose steroids. Severe IR manifested by extreme insulin requirements is rare. We report 2 such patients without prior history of diabetes (DM) requiring massive doses of IV insulin in the immediate post-op period. Patient 1: A 59 y/o male with hypertrophic cardiomyopathy (CM) presented with symptoms of acute decompensated heart failure and ultimately underwent orthotopic CT. At baseline, HbA1c was 5.8% and BMI 23 kg/m2. Exam was significant for acanthosis nigricans. He received 1g IV methylprednisolone (MP) during surgery and 125 mg IV Q 8 hours subsequently. His blood glucose (BG) immediately post-op was 312 mg/dL and was started on IV insulin. Despite doses up to 93 U/hr, BG remained >300mg/dl. With steroid taper, insulin requirements declined rapidly. He was transitioned to small dose of insulin glargine and was discharged on metformin monotherapy with near-normal BGs. Patient 2: 49 y/o male with a genetic CM was admitted for elective orthotopic CT. At baseline, HbA1c was 5.8% and BMI 32 kg/m2. Exam was significant for central obesity. He received similar doses of IV MP as patient 1 but also required inotropes (dobutamine, epinephrine, milrinone mixed in 5% dextrose containing fluids.) His BG immediately post-op was 284 mg/dL and was started on IV insulin. Despite doses up to 85 U/hr, BG remained >250 mg/dl. With steroid taper, insulin requirements resolved rapidly and he was discharged with normal BGs off all DM agents. Pseudo insulin resistance (i.e. line occlusion or erroneous IV insulin solution concentration) was excluded in both cases. Conclusion: Although many patients require high insulin doses after CT, rarely are infusion rates as high as in our patients achieved, particularly in non-diabetic individuals. We propose that it was the combination of underlying IR/prediabetes, counter-regulatory hormones, proinflammatory cytokines, increased lipolysis, with exogenous steroids and catecholamine-based inotropic agents that resulted in extreme inhibition of insulin action. However, because this combination of factors is not necessarily rare in post-CT patients, other factors must have been at play and will remain to be elucidated. From a pragmatic standpoint, because of rapid decrease in BG levels as steroids were tapered, we recommend very close follow-up of such patients with rapid decreases in insulin infusion rates as necessitated by trends in prevailing glycemia to prevent hypoglycemia. It would also be helpful to target a slightly higher glucose goal in such patients to prevent subsequent hypoglycemia.

A Unique Presentation of a Paraganglioma and Its Consequences

Introduction: Paragangliomas (PGL) are extremely rare tumors arising from extra-adrenal neural crest cells with an incidence of 0.8 per 100,000 person-years. Sympathetic chain PGLs usually arise in the abdomen, with about 75% of them arising intra-abdominally [2]. On CT or MRI, PGLs are usually have homogenous enhancement or central areas of low attenuation. The consequences of PGLs are many, and one complication that is rarely noted is glycemic disturbances with catecholamine excess. Here, we present a case of a radiographically unique appearing PGL that resulted in dramatic improvement of diabetes after resection.Case: 41 year old male with a past medical history of diabetes, CKD and developmental delay presented with hyperglycemia. Patient’s home regimen of Glargine 15 units qHS and Humalog 5 units TID AC had run out a few days prior. Patient had Hemoglobin A1c of 11.8% mg/dL and a C-peptide of 0.4 ng/ml. Endocrine was initially consulted for glucose management. Hospital course was complicated by abdominal pain and CT imaging showed low attenuation splenic masses, retroperitoneal lymphadenopathy and a large, necrotic appearing mesenteric mass consistent with lymphoma. MRI reaffirmed mass with peripheral enhancement and central necrosis consistent with neoplasm.Patient underwent biopsy of lymphadenopathy, which came back benign and then went for biopsy of mass. As the needle entered the mass, the patient became acutely hypertensive and tachycardic. He received phentolamine with good response and labs were drawn for catecholamine producing tumor. Plasma norepinephrine level was 6048 pg/ml and a chromogranin level of 4788 ng/ml. An MIBG scan revealed focal uptake at the lesion without evidence of metastasis. In the subsequent weeks, he was alpha- and then beta-blocked and underwent resection of mass that was complicated by transient hypotension and hypoglycemia. Eventually, patient’s blood pressure was controlled and insulin requirements dropped precipitously to just requiring 4 units of glargine by discharge.Discussion: This patient had a mass on CT scan that appeared to be consistent with lymphoma as opposed to PGL that led to biopsy and subsequent catecholamine crisis. Fortunately, this was controlled and subsequent resection led to improvement in the patient’s glycemic control. It has been thought that glucose intolerance in PGL patients is due to impaired insulin release through desensitization of the beta-adrenergic receptor. Furthermore, Catecholamines, as counter-regulatory hormones, have been well documented to raise blood sugar on this basis as well. Fortunately for our patient, he survived an initial biopsy and post-operatively, was able to actually have an improvement in his glycemic control. It also is a reminder to always do a screen for PGL before doing a needle biopsy of a compatible abdominal mass.

Hypoglycemia Impairs Baroreflex Sensitivity: Implications for Autonomic Control of Cardiovascular Function in Diabetes

Background: Iatrogenic hypoglycemia is an unintended, though common, occurrence in individuals with diabetes. There is a clear association between hypoglycemia exposure and an increase in mortality in individuals with type 2 diabetes (T2DM). It is well-established that recurrent hypoglycemic episodes impair the counterregulatory hormone responses; however, it is yet to be determined if in T2DM there are more global effects of hypoglycemia on autonomic control of cardiovascular function (baroreflex sensitivity, BRS), as has been shown in healthy individuals. This is a clinically relevant knowledge gap as decreases in BRS are pro-arrhythmogenic and associated with decreases in mortality in individuals with diabetes. Objective: We tested the hypothesis that in individuals with T2DM, hypoglycemia impairs baroreflex sensitivity (BRS), a robust measure of cardiovascular autonomic control. Methods: Individuals with well-controlled T2DM and without known cardiovascular disease were exposed to two 90-minute episodes of experimental hypoglycemia (50 mg/dl) in the same day. All individuals experienced a hypoglycemic-hyperinsulinemic clamp in the morning (AM clamp) and again in the afternoon (PM clamp). BRS was assessed using the modified Oxford method (sequential administration of nitroprusside and phenylephrine) before the initiation of each hypoglycemic-hyperinsulinemic clamp, during the last 30 minutes of hypoglycemia, and the following day. Results: The study included 16 individuals with a diagnosis of T2DM (6 men and 10 women) with the following characteristics (mean ± SD): age 45 ± 11 years, BMI 32 ± 6 kg/m2, hemoglobin A1c 6.4 ± 0.9%, and diabetes duration 8 ± 5 years. At baseline, individuals with T2DM had a BRS of 7.7 ± 3.6 ms/mmHg, which is reduced compared to a BRS of 21.3 ± 13.8 ms/mmHg in a historical healthy control group of 54 subjects (p<0.001). A mixed effects model adjusting for sex, age, BMI, and insulin level, demonstrated a significant effect of hypoglycemia on BRS (p=0.008). Pairwise comparisons revealed a significant decrease in BRS during the PM clamp as compared with BRS assessed at baseline (5.5 ± 5.0 vs 7.7 ± 3.6 ms/mmHg, p=0.045), during the AM clamp (5.5 ± 5.0 vs 10.5 ± 5.6 ms/mmHg, p=0.43), and the following day (5.5 ± 5.0 vs 8.6 ± 3.8 ms/mmHg, p=0.33). Of note, there was no significant difference between BRS at baseline and during the AM clamp (p=0.44). Additionally, insulin levels positively and strongly correlated with BRS at baseline (R2 0.52) and during the AM clamp (R2 0.67). Discussion: Insulin may have a stimulatory effect on BRS during a hyperinsulinemic hypoglycemic clamp that counters the inhibitory effect of hypoglycemia during the first episode of hypoglycemia. However, with exposure to a second hypoglycemic clamp, BRS decreases. Conclusion: Individuals with T2DM have low BRS at baseline, which is further reduced after 2 episodes of hypoglycemia.

A Case of Euglycemic Diabetic Ketoacidosis Following Canagliflozin Therapy

Introduction: Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes mellitus (DM). In general, DKA characterized by blood sugar over 250 mg/dL, anion-gap metabolic acidosis, and increased plasma or urine ketones. Approximately 2–3% of DKA patients can present with normal blood glucose levels (less than 250 mg/dl) which called euglycemic DKA. Some of the etiologies of euglycemic DKA include recent use of insulin, low caloric intake, alcoholism, chronic liver disease, and pregnancy. Very rarely, SGLT2 inhibitor use may be responsible for euglycemic DKA. Case Presentation: Here we present a case of 44 years old female with a past medical history of DM type 2 who presented with acute onset of nausea and vomiting. Initial laboratory findings were remarkable for anion gap metabolic acidosis with a blood glucose level of 201 mg/dl. The patient was on long-acting insulin along with Canagliflozin and Metformin therapy over years and reported being compliant with medications. She was treated with intravenous insulin therapy which resolved acidosis as well as symptoms. The patient was discharged with recommendations of discontinuation of Canagliflozin. Discussion: SGLT2 inhibitors are the novel class of oral antidiabetic drugs which widely used due to their favorable cardiovascular and renal outcomes independent of glycemic control. However, their side effects remain a concern. DKA is a rare but serious side effect of SGLT2 inhibitors with an incidence rate of 9.4% in type 1 DM and less than 0.2% in type 2 DM. Patients typically present with euglycemia or low-grade hyperglycemia which results in a diagnostic challenge for treating physicians. SGLT2 inhibitors increase urinary glucose excretion with a subsequent decrease in circulating insulin and an increase in glucagon, rendering a metabolic shift from glucose to fatty acid utilization. During times of intercurrent illness (decreased oral intake, sepsis) or metabolic stress (surgery), decreased carbohydrate intake coupled with the aforementioned changes will result in decreased insulin secretion and increased counter-regulatory hormones including adrenaline and cortisol, promoting lipolysis, fatty acid oxidation, and ketone production by the liver which ultimately leading to euglycemic DKA. Conclusion: SGLT2 inhibitors induced euglycemic DKA treatment is identical to classic DKA with consideration of the lack of hyperglycemia. Appropriate patient counseling to ensure safe SGLT2 inhibitor therapy is crucial, including appropriate holding parameters during concomitant volume-depleting illnesses and decreased oral intake. Timely diagnosis of euglycemic DKA, and recognitions of other rare but lethal side effects to decrease overall morbidity and mortality.

Maximal Fat Oxidation During Exercise Is Already Impaired in Pre-pubescent Children With Type 1 Diabetes Mellitus.

Objective: We evaluated substrate utilization during submaximal exercise, together with glycemic responses and hormonal counter-regulation to exercise, in children with type 1 diabetes mellitus (T1DM).Methods: Twelve pre-pubescent children with T1DM and 12 healthy children were matched by sex and age. Participants completed a submaximal incremental exercise test to determine their fat and carbohydrate oxidation rates by indirect calorimetry. Levels of glycemia, glucagon, cortisol, growth hormone, noradrenaline, adrenaline, and insulin were monitored until 120 min post-exercise.Results: Absolute peak oxygen uptake (VO2 peak) was significantly lower in the children with T1DM than in the healthy controls (1131.4 ± 102.5 vs. 1383.0 ± 316.6 ml.min−1, p = 0.03). Overall carbohydrate and lipid oxidation rates were the same in the two groups, but for exercise intensities, higher than 50% of VO2 peak, fat oxidation rate was significantly lower in the children with T1DM. The absolute maximal lipid oxidation rate was significantly lower in the T1DM children (158.1 ± 31.6 vs. 205.4 ± 42.1 mg.min−1, p = 0.005), and they reached a significantly lower exercise power than the healthy controls (26.4 ± 1.2 vs. 35.4 ± 3.3 W, p = 0.03). Blood glucose responses to exercise were negatively correlated with pre-exercise blood glucose concentrations (r = −0.67; p = 0.03).Conclusion: Metabolic and hormonal responses during sub-maximal exercise are impaired in young children with T1DM.

Ventromedial hypothalamic nucleus glycogen regulation of metabolic-sensory neuron AMPK and neurotransmitter expression: role of lactate.

Astrocyte glycogen is dynamically remodeled during metabolic stability and provides oxidizable l-lactate equivalents during neuroglucopenia. Current research investigated the hypothesis that ventromedial hypothalamic nucleus (VMN) glycogen metabolism controls glucostimulatory nitric oxide (NO) and/or glucoinhibitory gamma-aminobutyric acid (GABA) neuron 5'-AMP-activated protein kinase (AMPK) and transmitter marker, e.g., neuronal nitric oxide synthase (nNOS), and glutamate decarboxylase65/67 (GAD) protein expression. Adult ovariectomized estradiol-implanted female rats were injected into the VMN with the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) before vehicle or l-lactate infusion. Western blot analysis of laser-catapult-microdissected nitrergic and GABAergic neurons showed that DAB caused lactate-reversible upregulation of nNOS and GAD proteins. DAB suppressed or increased total AMPK content of NO and GABA neurons, respectively, by lactate-independent mechanisms, but lactate prevented drug enhancement of pAMPK expression in nitrergic neurons. Inhibition of VMN glycogen disassembly caused divergent changes in counter-regulatory hormone, e.g. corticosterone (increased) and glucagon (decreased) secretion. Outcomes show that VMN glycogen metabolism controls local glucoregulatory transmission by means of lactate signal volume. Results implicate glycogen-derived lactate deficiency as a physiological stimulus of corticosterone release. Concurrent normalization of nitrergic neuron nNOS and pAMPK protein and corticosterone secretory response to DAB by lactate infers that the hypothalamic-pituitary-adrenal axis may be activated by VMN NO-mediated signals of cellular energy imbalance.

Endogenous Glucose Production in Critical Illness.

Regulation of endogenous glucose production (EGP) by hormonal, neuronal, and metabolic signaling pathways contributes to the maintenance of euglycemia under normal physiologic conditions. EGP is defined by the generation of glucose from substrates through glycogenolysis and gluconeogenesis, usually in fasted states, for local and systemic use. Abnormal increases in EGP are noted in patients with diabetes mellitus type 2, and elevated EGP may also impact the pathogenesis of nonalcoholic fatty liver disease and congestive heart failure. In this narrative review, we performed a literature search in PubMed to identify recently published English language articles characterizing EGP in critical illness. Evidence from preclinical and clinical studies demonstrates that critical illness can disrupt EGP through multiple mechanisms including increased systemic inflammation, counterregulatory hormone and catecholamine release, alterations in the hypothalamic-pituitary axis, insulin resistance, lactic acidosis, and iatrogenic insults such as vasopressors and glucocorticoids administered as part of clinical care. EGP contributes to hyperglycemia in critical illness when abnormally elevated and to hypoglycemia when abnormally depressed, each of which has been independently associated with increased mortality. Increased EGP may also promote protein catabolism that could worsen critical illness myopathy and impede recovery. Better understanding of the mechanisms and factors contributing to dysregulated EGP in critical illness may help in the development of therapeutic strategies that promote euglycemia, reduce intensive care unit-associated catabolism, and improve patient outcomes.