Effect of Intermittent Endogenous Hyperglucagonemia on Glucose Homeostasis in Normal and Diabetic Man

Rizza, Robert A.; Verdonk, Carlos A.; Miles, John M.; Service, F. John; Gerich, John E.

doi:10.1172/jci109404

Cited by 65 publications

(26 citation statements)

References 30 publications

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“…In light of this and of the augmented glucagon effect during profound hypoglycemia, one may have expected a shorter recovery time during exenatide treatment compared with placebo, but this was not observed. There may be several reasons: 1) the sensitivity of this experimental design was not sufficient to detect small differences in the recovery time, 2) the marked hyperinsulinemia was at a level that may have masked the opposing effects of differing levels of glucagon and potentially different amounts of releasable glycogen stores, and/or 3) dynamics in portal glucagon concentrations are apparently more important than actual peripheral concentrations (29). Serum FFA concentrations were almost identical during both exenatide and placebo arms during the whole study.…”

Section: Discussionmentioning

confidence: 99%

Effect of Intravenous Infusion of Exenatide (Synthetic Exendin-4) on Glucose-Dependent Insulin Secretion and Counterregulation During Hypoglycemia

et al. 2004

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This study assessed whether glucose-dependent insulin secretion and overall counterregulatory response are preserved during hypoglycemia in the presence of exenatide. Twelve healthy fasted volunteers were randomized in a triple-blind crossover study to receive either intravenous exenatide (0.066 pmol ⅐ kg ؊1 ⅐ min ؊1 ) or placebo during a 270-min stepwise hyperinsulinemichypoglycemic clamp (insulin infusion 0.8 mU ⅐ kg ؊1 ⅐ min ؊1 ). Plasma glucose was clamped sequentially at 5.0 (0 -120 min), 4.0 (120 -180 min), 3.2 (180 -240 min), and 2.7 mmol/l (240 -270 min). At 270 min, insulin infusion was terminated and plasma glucose increased to ϳ3.2 mmol/l. The time to achieve plasma glucose >4 mmol/l thereafter was recorded. Insulin secretory rates (ISRs) and counterregulatory hormones were measured throughout. Glucose profiles were superimposable between the exenatide and placebo arms. In the presence of euglycemic hyperinsulinemia, ISRs in the exenatide arm were ϳ3.5-fold higher than in the placebo arm (353 ؎ 29 vs. 100 ؎ 29 pmol/min [least-square means ؎ SE]). However, ISRs declined similarly and rapidly at all hypoglycemic steps (<4 mmol/l) in both groups. Glucagon was suppressed in the exenatide arm during euglycemia and higher than placebo during hypoglycemia. Plasma glucose recovery time was equivalent for both treatments. The areas under the concentration-time curve from 270 to 360 min for cortisol, epinephrine, norepinephrine, and growth hormone were similar between treatment arms. There were no differences in adverse events. In the presence of exenatide, there was a preserved, glucose-dependent insulin secretory response and counterregulatory response during hypoglycemia. Diabetes 53:2397-2403, 2004 T he pathogenesis of type 2 diabetes is characterized by peripheral insulin resistance and progressive failure of pancreatic ␤-cell function, ultimately resulting in deficient insulin secretion. Furthermore, an excessive glucagon secretion and an impaired incretin response to meals contribute to the metabolic derangement of the disease (1-4). Control of circulating glucose levels is rarely optimal, and many currently available therapies also have unfavorable side effects and restrictions, limiting the extent of their use (5-8). This emphasizes the need for novel antidiabetic agents.Glucagon-like peptide (GLP)-1 is an incretin hormone secreted from the intestinal mucosa in response to meal ingestion. Physiological GLP-1 exhibits several glucoregulatory functions, such as glucose-dependent enhancement of insulin secretion, suppression of glucagon secretion, delayed gastric emptying, and reduction of food intake. It may even promote ␤-cell preservation and improved neogenesis (9). GLP-1 has an extremely short half-life in plasma.Exenatide (synthetic exendin-4) is a 39 -amino acid peptide incretin mimetic that demonstrates the above glucoregulatory actions of GLP-1 (10,11), and it has been shown to be a potent agonist to the GLP-1 receptor in vitro (12). Clinical studies in humans have demonstrated markedly improved ...

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Section: Discussionmentioning

confidence: 99%

Effect of Intravenous Infusion of Exenatide (Synthetic Exendin-4) on Glucose-Dependent Insulin Secretion and Counterregulation During Hypoglycemia

et al. 2004

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“…Plasma [3-3H]glucose specific activity was determined as previouslycdescribed (16); in brief, triplicate 0.3-ml aliquots of deproteinized plasma were evaporated to dryness at 37°C unlder compressed air to remonve tritiated water. The residue was resuspended in 0.5 ml distilled water, and after the addition of 10 ml Aquasol (New England Nuclear), its radioactivity w%as counited in a refrigerated li(quid scintillation spectrometer.…”

Section: Methodsmentioning

confidence: 99%

Adrenergic Mechanisms for the Effects of Epinephrine on Glucose Production and Clearance in Man

Rizza¹,

Cryer²,

Haymond³

et al. 1980

J. Clin. Invest.

338

140

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A B S T R A C T The present studies were undertaken to assess the adrenergic mechanisms by which epinephrine stimulates glucose production and suppresses glucose clearance in man: epinephrine (50 ng/kg per min) was infused for 180 min alone and during either alpha (phentolamine) or beta (propranolol)-adrenergic blockade in normal subjects under conditions in which plasma insulin, glucagon, and glucose were maintained at comparable levels by infusion of somatostatin (100 ,ug/h), insulin (0.2 mU/kg per min), and variable amounts of glucose. In additional experiments, to control for the effects of the hyperglycemia caused by epinephrine, variable amounts of glucose without epinephrine were infused along with somatostatin and insulin to produce hyperglycemia comparable with that observed during infusion of epinephrine. This glucose infusion suppressed glucose production from basal rates of 1.8+0.1 to 0.0±0.1 mg/kg per min (P < 0.01), but did not alter glucose clearance. During infusion of epinephrine, glucose production increased transiently from a basal rate of 1.8+0.1 to a maximum of 3.0±0.2 mg/kg per min (P < 0.01) at min 30, and returned to near basal rates at min 180 (1.9±0.1 mg/kg per min). Glucose clearance decreased from a basal rate of 2.0±0.1 to 1.5±0.2 ml/kg per min at the end of the epinephrine infusion (P < 0.01). Infusion of phentolamine did not alter these effects ofepinephrine on glucose production and clearance. In contrast, infusion of propranolol completely prevented the suppression ofglucose clearance by epinephrine, and inhibited the stimulation of glucose production by epinephrine by 80±6% (P < 0.001). These results indicate that, under conditions Dr. Rizza is a recipient of a Clinical Investigator Award

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“…40 It is also well known that glucagon and insulin are both responsible for the regulation and maintenance of normal glucose homeostasis. 34,[41][42][43][44] Following a meal, rising glucose concentrations stimulate insulin secretion, which suppresses hepatic glucose production from glycogen. 45,46 As absorption decreases and glucose concentrations fall (even below baseline values), an incremental increase in glucagon stimulates glycogenolysis to maintain blood glucose concentrations within a narrow and defined range.…”

Section: Glucagon Discovery and Actionmentioning

confidence: 99%

Minimizing Morbidity of Hypoglycemia in Diabetes

Chung

Haymond

2014

J Diabetes Sci Technol

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Type 1 diabetes is a common chronic disease of childhood and one of the most difficult conditions to manage. Advances in insulin formulations and insulin delivery devices have markedly improved the ability to achieve normal glucose homeostasis. However, hypoglycemia remains the primary limiting factor in achieving normoglycemia and is a frequent complication in children with acute gastroenteritis and/or poor oral intake. In situations of impaired carbohydrate intake or absorption, glucagon therapy is the only out-of-hospital treatment option available to families and caregivers. Glucagon is recommended for the treatment of severe hypoglycemia and rapidly increases blood glucose by increasing hepatic glucose production from glycogenolysis. Mini-dose glucagon is a widely utilized off-label treatment for managing mild or impending hypoglycemia and is administered as a small subcutaneous injection. It was initially described for use in children who were unable to tolerate or absorb oral carbohydrates but not in need of advanced medical care. Yet, mini-dose glucagon may be useful in any individual with relative insulin excess. The regimen aims to prevent severe hypoglycemic episodes and is safe, effective, and easily administered by patients and caregivers in the out-of-hospital setting. By empowering patients and their families, this important tool could help to alleviate the physical, psychosocial, and financial burden evolving from impending hypoglycemia.

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Effect of Intermittent Endogenous Hyperglucagonemia on Glucose Homeostasis in Normal and Diabetic Man

Cited by 65 publications

References 30 publications

Effect of Intravenous Infusion of Exenatide (Synthetic Exendin-4) on Glucose-Dependent Insulin Secretion and Counterregulation During Hypoglycemia

Effect of Intravenous Infusion of Exenatide (Synthetic Exendin-4) on Glucose-Dependent Insulin Secretion and Counterregulation During Hypoglycemia

Adrenergic Mechanisms for the Effects of Epinephrine on Glucose Production and Clearance in Man

Minimizing Morbidity of Hypoglycemia in Diabetes

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