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Publication Record


Counterregulatory responses to hypoglycemia differ between glimepiride and glyburide in non diabetic individuals.
Joy NG, Tate DB, Davis SN
(2015) Metabolism 64: 729-37
MeSH Terms: Adult, Blood Glucose, C-Peptide, Female, Glucagon, Glucose Clamp Technique, Glyburide, Humans, Hypoglycemia, Hypoglycemic Agents, Insulin, Leptin, Male, Pancreatic Polypeptide, Single-Blind Method, Sulfonylurea Compounds
Show Abstract · Added July 30, 2015
OBJECTIVE - Reported rates of hypoglycemia in patients with type 2 diabetes mellitus are lower with glimepiride as compared to glyburide. The aim of this study was to determine whether physiologic differences in counterregulatory neuroendocrine and metabolic mechanisms during hypoglycemia provide a basis for the observed clinical differences between glimepiride and glyburide.
RESEARCH DESIGN AND METHODS - Non-diabetic volunteers (age 38±2years, BMI 26±1kg/m(2)) were studied in a single-blind fashion during separate 2day randomized protocols consisting of 2h hyperinsulinemic (9pmol/kg/min) euglycemic (4.9±0.1mmol) and hypoglycemic (2.9±0.1mmol/L) clamps. Individuals received biologically equivalent doses of glimepiride (4mg) or glyburide (10mg) 1h prior to each glucose clamp (n=11) as well as a control group of placebo studies. Glucose kinetics were calculated using D-Glucose-6-6d2.
RESULTS - Insulin and C-peptide levels were increased (p<0.05) during euglycemia in both sulfonylurea groups as compared to placebo. However, despite equivalent hypoglycemia, insulin and C-peptide levels were higher (p<0.05) only after glyburide. Glucagon responses and endogenous glucose production (EGP) were decreased (p<0.05) during hypoglycemia following glyburide administration as compared to glimepiride. Glyburide reduced (p<0.05) norepinephrine responses during euglycemic clamps. In addition combined epinephrine and norepinephrine responses during hypoglycemia were reduced (p<0.05) following glyburide as compared to placebo. Leptin levels fell by a greater amount (p<0.05) during hypoglycemia with both sulfonylureas as compared to placebo.
CONCLUSIONS - In summary, glimepiride and glyburide can both similarly increase insulin and C-peptide levels during hyperinsulinemic euglycemia. However, during moderate hyperinsulinemic hypoglycemia (2.9mmol/L) glyburide resulted in increased C-peptide and insulin, but blunted glucagon, sympathetic nervous system and EGP responses. We conclude that glyburide can acutely reduce key neuroendocrine and metabolic counterregulatory defenses during hypoglycemia in healthy individuals.
Copyright © 2015. Published by Elsevier Inc.
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16 MeSH Terms
Effects of Acute and Antecedent Hypoglycemia on Endothelial Function and Markers of Atherothrombotic Balance in Healthy Humans.
Joy NG, Tate DB, Younk LM, Davis SN
(2015) Diabetes 64: 2571-80
MeSH Terms: Adult, Biomarkers, Blood Glucose, Endothelium, Vascular, Female, Fibrinolysis, Humans, Hypoglycemia, Inflammation, Male, Platelet Activation, Thrombosis
Show Abstract · Added July 30, 2015
The aim of this study was to determine the effects of single and repeated episodes of clamped hypoglycemia on fibrinolytic balance, proinflammatory biomarkers, proatherothrombotic mechanisms, and endothelial function. Twenty healthy individuals (12 male and 8 female) were studied during separate 2-day randomized protocols. Day 1 consisted of either two 2-h hyperinsulinemic (812 ± 50 pmol/L)-euglycemic (5 ± 0.1 mmol/L) or hyperinsulinemic (812 ± 50 pmol/L)-hypoglycemic (2.9 ± 0.1 mmol/L) clamps. Day 2 consisted of a single 2-h hyperinsulinemic-hypoglycemic clamp. Two-dimensional Doppler ultrasound was used to determine brachial arterial endothelial function. Plasminogen activator inhibitor 1, vascular cell adhesion molecule-1, intracellular adhesion molecule-1, E-selectin, P-selectin, TAT (thrombin/antithrombin complex), tumor necrosis factor-α, and interleukin-6 responses were increased (P < 0.05) during single or repeated hypoglycemia compared with euglycemia. Endogenous and exogenous nitric oxide (NO)-mediated vasodilation were both impaired by repeated hypoglycemia. Neuroendocrine and autonomic nervous system (ANS) responses were also blunted by repeated hypoglycemia (P < 0.05). In summary, acute moderate hypoglycemia impairs fibrinolytic balance; increases proinflammatory responses, platelet activation, and coagulation biomarkers; and reduces NO-mediated endothelial function in healthy individuals. Repeated episodes of hypoglycemia further impair vascular function by additionally reducing exogenously NO-mediated endothelial function and increasing coagulation biomarkers. We conclude that despite reduced neuroendocrine and ANS responses, antecedent hypoglycemia results in greater endothelial dysfunction and an increased proatherothrombotic state compared with a single acute episode of hypoglycemia.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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12 MeSH Terms
Interleukin-6 amplifies glucagon secretion: coordinated control via the brain and pancreas.
Barnes TM, Otero YF, Elliott AD, Locke AD, Malabanan CM, Coldren AG, Brissova M, Piston DW, McGuinness OP
(2014) Am J Physiol Endocrinol Metab 307: E896-905
MeSH Terms: Animals, Brain, Epinephrine, Glucagon, Glucagon-Secreting Cells, Glucose Clamp Technique, Hypoglycemia, Interleukin-6, Islets of Langerhans, Lipopolysaccharides, Mice, Mice, Inbred C57BL, Mice, Knockout, Stress, Physiological, Sympathomimetics
Show Abstract · Added October 7, 2014
Inappropriate glucagon secretion contributes to hyperglycemia in inflammatory disease. Previous work implicates the proinflammatory cytokine interleukin-6 (IL-6) in glucagon secretion. IL-6-KO mice have a blunted glucagon response to lipopolysaccharide (LPS) that is restored by intravenous replacement of IL-6. Given that IL-6 has previously been demonstrated to have a transcriptional (i.e., slow) effect on glucagon secretion from islets, we hypothesized that the rapid increase in glucagon following LPS occurred by a faster mechanism, such as by action within the brain. Using chronically catheterized conscious mice, we have demonstrated that central IL-6 stimulates glucagon secretion uniquely in the presence of an accompanying stressor (hypoglycemia or LPS). Contrary to our hypothesis, however, we found that IL-6 amplifies glucagon secretion in two ways; IL-6 not only stimulates glucagon secretion via the brain but also by direct action on islets. Interestingly, IL-6 augments glucagon secretion from both sites only in the presence of an accompanying stressor (such as epinephrine). Given that both adrenergic tone and plasma IL-6 are elevated in multiple inflammatory diseases, the interactions of the IL-6 and catecholaminergic signaling pathways in regulating GCG secretion may contribute to our present understanding of these diseases.
Copyright © 2014 the American Physiological Society.
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15 MeSH Terms
Hypoglycemia-associated autonomic failure in healthy humans: comparison of two vs three periods of hypoglycemia on hypoglycemia-induced counterregulatory and symptom response 5 days later.
Moheet A, Kumar A, Eberly LE, Kim J, Roberts R, Seaquist ER
(2014) J Clin Endocrinol Metab 99: 664-70
MeSH Terms: Adult, Blood Glucose, Female, Humans, Hypoglycemia, Male, Middle Aged, Pure Autonomic Failure
Show Abstract · Added July 30, 2015
CONTEXT - Hypoglycemia-associated autonomic failure (HAAF) limits the ability of patients with diabetes to achieve target glycemia. Animal models have provided insights into the pathogenesis of HAAF, but a robust human model of HAAF in which recurrent hypoglycemia impacts the counterregulatory responses to hypoglycemia days later is lacking.
OBJECTIVE - The aim of this study was to determine the impact of two or three episodes of moderate hypoglycemia on counterregulatory responses to subsequent hypoglycemia induced 5 days later.
DESIGN AND SUBJECTS - Six healthy subjects participated in each of the two study protocols. In both protocol 1 and 2, subjects underwent two 2-hour hypoglycemic clamp studies during the morning and afternoon of day 1. In protocol 2, subjects underwent an additional third hypoglycemic clamp during the morning of day 2. All subjects in both protocols underwent a final hypoglycemic clamp on the morning of day 5.
RESULTS - In protocol 1, there were no significant differences in the hypoglycemia-induced hormone response or in symptoms scores between the mornings of days 1 and 5. In protocol 2, hypoglycemia-induced epinephrine (P = .02) and cortisol (P = .04) secretions were significantly lower on day 5 compared with day 1, whereas glucagon (P = .08) and norepinephrine (P = .59) were not different. Also in protocol 2, neurogenic (P = .02) and neuroglycopenic (P = .04) symptoms during hypoglycemia were decreased on day 5 compared with day 1.
CONCLUSION - These results demonstrate that exposure of healthy humans to three 2-hour hypoglycemic episodes over 30 hours leads to significant blunting in counterregulatory and symptom response to subsequent hypoglycemia on day 5.
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8 MeSH Terms
Pregnancy augments hepatic glucose storage in response to a mixed meal.
Moore MC, Smith MS, Connolly CC
(2012) Br J Nutr 107: 493-503
MeSH Terms: Animals, Biological Transport, Blood Glucose, Dogs, Female, Glucose, Glycogen, Glycolysis, Hindlimb, Hyperglycemia, Hypoglycemia, Insulin, Intestinal Absorption, Kinetics, Liver, Liver Glycogen, Models, Animal, Muscle, Skeletal, Oxidation-Reduction, Postprandial Period, Pregnancy
Show Abstract · Added December 5, 2013
Studies were carried out on conscious female non-pregnant (NP) and pregnant (P; third-trimester) dogs (n 16; eight animals per group) to define the role of the liver in mixed meal disposition with arteriovenous difference and tracer techniques. Hepatic and hindlimb substrate disposal was assessed for 390 min during and after an intragastric mixed meal infusion labelled with [¹⁴C]glucose. The P dogs exhibited postprandial hyperglycaemia compared with NP dogs (area under the curve (AUC; change from basal over 390 min) of arterial plasma glucose: 86 680 (sem 12 140) and 187 990 (sem 33 990) mg/l in NP and P dogs, respectively; P < 0·05). Plasma insulin concentrations did not differ significantly between the groups (AUC: 88 230 (sem 16 314) and 69 750 (sem 19 512) pmol/l in NP and P dogs, respectively). Net hepatic glucose uptake totalled 3691 (sem 508) v. 5081 (sem 1145) mg/100 g liver in NP and P dogs, respectively (P = 0·38). The AUC of glucose oxidation by the gut and hindlimb were not different in NP and P dogs, but hepatic glucose oxidation (84 (sem 13) v. 206 (sem 30) mg/100 g liver) and glycogen synthesis (0·4 (sem 0·5) v. 26 (sem 0·7) g/100 g liver) were greater in P dogs (P < 0·05). The proportion of hepatic glycogen deposited via the direct pathway did not differ between the groups. Hindlimb glucose uptake and skeletal muscle glycogen synthesis was similar between the groups, although final glycogen concentrations were higher in NP dogs (9·6 (sem 0·6) v. 70 (sem 0·6) mg/g muscle; P < 0·05). Thus, hepatic glucose oxidation and glycogen storage were augmented in late pregnancy. Enhanced hepatic glycogen storage following a meal probably facilitates the maintenance of an adequate glucose supply to maternal and fetal tissues during the post-absorptive period.
1 Communities
1 Members
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21 MeSH Terms
Characteristics and effects of nurse dosing over-rides on computer-based intensive insulin therapy protocol performance.
Campion TR, May AK, Waitman LR, Ozdas A, Lorenzi NM, Gadd CS
(2011) J Am Med Inform Assoc 18: 251-8
MeSH Terms: Adult, Attitude to Computers, Decision Support Systems, Clinical, Drug Dosage Calculations, Drug Therapy, Computer-Assisted, Female, Guideline Adherence, Humans, Hypoglycemia, Insulin, Intensive Care Units, Male, Middle Aged, Practice Patterns, Nurses', Retrospective Studies, Tennessee
Show Abstract · Added January 20, 2015
OBJECTIVE - To determine characteristics and effects of nurse dosing over-rides of a clinical decision support system (CDSS) for intensive insulin therapy (IIT) in critical care units.
DESIGN - Retrospective analysis of patient database records and ethnographic study of nurses using IIT CDSS.
MEASUREMENTS - The authors determined the frequency, direction-greater than recommended (GTR) and less than recommended (LTR)- and magnitude of over-rides, and then compared recommended and over-ride doses' blood glucose (BG) variability and insulin resistance, two measures of IIT CDSS associated with mortality. The authors hypothesized that rates of hypoglycemia and hyperglycemia would be greater for recommended than over-ride doses. Finally, the authors observed and interviewed nurse users.
RESULTS - 5.1% (9075) of 179,452 IIT CDSS doses were over-rides. 83.4% of over-ride doses were LTR, and 45.5% of these were ≥ 50% lower than recommended. In contrast, 78.9% of GTR doses were ≤ 25% higher than recommended. When recommended doses were administered, the rate of hypoglycemia was higher than the rate for GTR (p = 0.257) and LTR (p = 0.033) doses. When recommended doses were administered, the rate of hyperglycemia was lower than the rate for GTR (p = 0.003) and LTR (p < 0.001) doses. Estimates of patients' insulin requirements were higher for LTR doses than recommended and GTR doses. Nurses reported trusting IIT CDSS overall but appeared concerned about recommendations when administering LTR doses.
CONCLUSION - When over-riding IIT CDSS recommendations, nurses overwhelmingly administered LTR doses, which emphasized prevention of hypoglycemia but interfered with hyperglycemia control, especially when BG was >150 mg/dl. Nurses appeared to consider the amount of a recommended insulin dose, not a patient's trend of insulin resistance, when administering LTR doses overall. Over-rides affected IIT CDSS protocol performance.
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16 MeSH Terms
Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs.
Rivera N, Ramnanan CJ, An Z, Farmer T, Smith M, Farmer B, Irimia JM, Snead W, Lautz M, Roach PJ, Cherrington AD
(2010) J Clin Invest 120: 4425-35
MeSH Terms: 3-Hydroxybutyric Acid, AMP-Activated Protein Kinases, Animals, Diabetes Mellitus, Type 1, Disease Models, Animal, Dogs, Enzyme Activation, Fatty Acids, Nonesterified, Female, Glucagon, Gluconeogenesis, Glycogenolysis, Humans, Hypoglycemia, Insulin, Liver, Liver Glycogen, Male, Signal Transduction
Show Abstract · Added February 13, 2015
In individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. Under conditions of insulin-induced hypoglycemia, glucagon is the most important stimulus for hepatic glucose production. In contrast, during euglycemia, insulin potently inhibits glucagon's effect on the liver. The first aim of the present study was to determine whether low blood sugar augments glucagon's ability to increase glucose production. Using a conscious catheterized dog model, we found that hypoglycemia increased glucagon's ability to overcome the inhibitory effect of insulin on hepatic glucose production by almost 3-fold, an effect exclusively attributable to marked enhancement of the effect of glucagon on net glycogen breakdown. To investigate the molecular mechanism by which this effect comes about, we analyzed hepatic biopsies from the same animals, and found that hypoglycemia resulted in a decrease in insulin signaling. Furthermore, hypoglycemia and glucagon had an additive effect on the activation of AMPK, which was associated with altered activity of the enzymes of glycogen metabolism.
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2 Members
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19 MeSH Terms
Psychological problems in adolescents with diabetes.
Jaser SS
(2010) Adolesc Med State Art Rev 21: 138-51, x-xi
MeSH Terms: Adaptation, Psychological, Adolescent, Depression, Diabetes Mellitus, Type 1, Family Relations, Feeding and Eating Disorders, Humans, Hypoglycemia, Mass Screening, Personal Autonomy
Show Abstract · Added March 11, 2015
For youth with type 1 diabetes (T1DM), the transition into adolescence is often associated with poorer adherence to treatment, deteriorating metabolic control, and increased risk for psychological disorders. The current article summarizes recent findings on psychological problems for adolescents with diabetes, including depression, eating disorders, fear of hypoglycemia, and problems specific to adolescents with T2DM. The impact of family functioning on adolescent adjustment and the importance of parent-child collaboration on treatment management is emphasized. By using the strategies described in this article, primary care providers have the potential to support adolescents with diabetes, while screening for problems that may be better treated by other professionals.
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10 MeSH Terms
Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo.
Lee-Young RS, Ayala JE, Hunley CF, James FD, Bracy DP, Kang L, Wasserman DH
(2010) Am J Physiol Regul Integr Comp Physiol 298: R1399-408
MeSH Terms: AMP-Activated Protein Kinases, Animals, Body Composition, Body Weight, Calorimetry, Indirect, Energy Metabolism, Female, Gluconeogenesis, Glycogen, Hypoglycemia, Insulin, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mitochondria, Muscle, Skeletal, Nitric Oxide Synthase Type III, Oxidative Phosphorylation, Photoperiod, Physical Conditioning, Animal, Physical Exertion, Pregnancy, Regional Blood Flow, Signal Transduction
Show Abstract · Added March 18, 2013
Endothelial nitric oxide synthase (eNOS) is associated with a number of physiological functions involved in the regulation of metabolism; however, the functional role of eNOS is poorly understood. We tested the hypothesis that eNOS is critical to muscle cell signaling and fuel usage during exercise in vivo, using 16-wk-old catheterized (carotid artery and jugular vein) C57BL/6J mice with wild-type (WT), partial (+/-), or no expression (-/-) of eNOS. Quantitative reductions in eNOS expression ( approximately 40%) elicited many of the phenotypic effects observed in enos(-/-) mice under fasted, sedentary conditions, with expression of oxidative phosphorylation complexes I to V and ATP levels being decreased, and total NOS activity and Ca(2+)/CaM kinase II Thr(286) phosphorylation being increased in skeletal muscle. Despite these alterations, exercise tolerance was markedly impaired in enos(-/-) mice during an acute 30-min bout of exercise. An eNOS-dependent effect was observed with regard to AMP-activated protein kinase signaling and muscle perfusion. Muscle glucose and long-chain fatty acid uptake, and hepatic and skeletal muscle glycogenolysis during the exercise bout was markedly accelerated in enos(-/-) mice compared with enos(+/-) and WT mice. Correspondingly, enos(-/-) mice exhibited hypoglycemia during exercise. Thus, the ablation of eNOS alters a number of physiological processes that result in impaired exercise capacity in vivo. The finding that a partial reduction in eNOS expression is sufficient to induce many of the changes associated with ablation of eNOS has implications for chronic metabolic diseases, such as obesity and insulin resistance, which are associated with reduced eNOS expression.
1 Communities
3 Members
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25 MeSH Terms
Impaired glucose tolerance and predisposition to the fasted state in liver glycogen synthase knock-out mice.
Irimia JM, Meyer CM, Peper CL, Zhai L, Bock CB, Previs SF, McGuinness OP, DePaoli-Roach A, Roach PJ
(2010) J Biol Chem 285: 12851-61
MeSH Terms: Animals, Blood Glucose, Crosses, Genetic, Fasting, Gluconeogenesis, Glucose Clamp Technique, Glucose Tolerance Test, Glycogen, Glycogen Storage Disease, Glycogen Synthase, Hypoglycemia, Liver, Mice, Mice, Knockout, Organ Specificity, Time Factors
Show Abstract · Added July 21, 2014
Conversion to glycogen is a major fate of ingested glucose in the body. A rate-limiting enzyme in the synthesis of glycogen is glycogen synthase encoded by two genes, GYS1, expressed in muscle and other tissues, and GYS2, primarily expressed in liver (liver glycogen synthase). Defects in GYS2 cause the inherited monogenic disease glycogen storage disease 0. We have generated mice with a liver-specific disruption of the Gys2 gene (liver glycogen synthase knock-out (LGSKO) mice), using Lox-P/Cre technology. Conditional mice carrying floxed Gys2 were crossed with mice expressing Cre recombinase under the albumin promoter. The resulting LGSKO mice are viable, develop liver glycogen synthase deficiency, and have a 95% reduction in fed liver glycogen content. They have mild hypoglycemia but dispose glucose less well in a glucose tolerance test. Fed, LGSKO mice also have a reduced capacity for exhaustive exercise compared with mice carrying floxed alleles, but the difference disappears after an overnight fast. Upon fasting, LGSKO mice reach within 4 h decreased blood glucose levels attained by control floxed mice only after 24 h of food deprivation. The LGSKO mice maintain this low blood glucose for at least 24 h. Basal gluconeogenesis is increased in LGSKO mice, and insulin suppression of endogenous glucose production is impaired as assessed by euglycemic-hyperinsulinemic clamp. This observation correlates with an increase in the liver gluconeogenic enzyme phosphoenolpyruvate carboxykinase expression and activity. This mouse model mimics the pathophysiology of glycogen storage disease 0 patients and highlights the importance of liver glycogen stores in whole body glucose homeostasis.
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16 MeSH Terms