Clinical Spectrum of Sulfonylurea Overdose and Experience With Diazoxide Therapy

Palatnick, Wes; Meatherall, Robert; Tenenbein, Milton

doi:10.1001/archinte.1991.00400090133023

Cited by 45 publications

(14 citation statements)

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“…Thus selective suppression of insulin secretion, without stimulation of glucagon secretion, raised plasma glucose and serum nonesterified fatty acid concentrations. These findings define the temporal patterns and magnitudes of the metabolic responses to diazoxide and underscore the primacy of regulated insulin secretion in the physiological regulation of postabsorptive carbohydrate and lipid metabolism.glucose; insulin; glucagon; epinephrine; norepinephrine; adenosine 5Ј-triphosphate-dependent potassium channel DIAZOXIDE IS AN ATP-dependent potassium (K ATP ) channel agonist that is used clinically to treat hyperinsulinemic hypoglycemia (2,8,10,11,13,21,25,34). It opens potassium channels and hyperpolarizes plasma membranes, including those of pancreatic ␤-cells and thus decreases insulin secretion (1,2,6,7,8,10,11,13,21,23,25,34).…”

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confidence: 82%

“…After rapid intravenous injection, the onset of the effect to reduce vascular resistance is rapid (minutes) but, because the drug is Ͼ90% protein bound, prolonged (hours). Despite the initial studies in humans decades ago (8,10,11,21) and the use of the drug clinically (1,2,3,8,10,11,13,21,25,34), the precise mechanism, temporal patterns, and magnitudes of the metabolic responses to diazoxide have not been defined systematically. To do so, we measured neuroendocrine and metabolic responses to intravenous and oral diazoxide in healthy young adults and thus tested the hypothesis that suppression of insulin secretion, without stimulation of glucagon secretion, raises the postabsorptive plasma glucose concentration.…”

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confidence: 99%

“…It opens potassium channels and hyperpolarizes plasma membranes, including those of pancreatic ␤-cells and thus decreases insulin secretion (1,2,6,7,8,10,11,13,21,23,25,34). However, diazoxide is a nonselective K ATP channel agonist (6, 23), K ATP channels are expressed widely (1, 6, 7), and alternative mechanisms of its plasma glucose-raising action have been proposed (10, 11).…”

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Mechanism, temporal patterns, and magnitudes of the metabolic responses to the K_ATPchannel agonist diazoxide

Raju¹,

Cryer²

2005

American Journal of Physiology-Endocrinology and Metabolism

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Raju, Bharathi, and Philip E. Cryer. Mechanism, temporal patterns, and magnitudes of the metabolic responses to the KATP channel agonist diazoxide. Am J Physiol Endocrinol Metab 288: E80 -E85, 2005. First published August 31, 2004; doi:10.1152/ ajpendo.00188.2004.-To assess the mechanism, temporal patterns, and magnitudes of the metabolic responses to the ATP-dependent potassium channel agonist diazoxide, neuroendocrine and metabolic responses to intravenous diazoxide (saline, 1.0 and 2.0 mg/kg) and oral diazoxide (placebo, 4.0 and 6.0 mg/kg) were assessed in healthy young adults. Intravenous diazoxide produced rapid, but transient, decrements (P ϭ 0.0023) in plasma insulin (e.g., nadirs of 2.8 Ϯ 0.5 and 1.8 Ϯ 0.3 U/ml compared with 7.0 Ϯ 1.0 U/ml after saline at 4.0 -7.5 min) and C-peptide (P ϭ 0.0228) associated with dose-related increments in plasma glucose (P ϭ 0.0044) and serum nonesterified fatty acids (P Ͻ 0.0001). After oral diazoxide, plasma insulin appeared to decline, as did C-peptide, again associated with dose-related increments in plasma glucose (P Ͻ 0.0001) and serum nonesterified fatty acids (P ϭ 0.0141). Plasma glucagon, as well as cortisol and growth hormone, was not altered. Plasma epinephrine increased (P ϭ 0.0215) slightly only after intravenous diazoxide. There were doserelated increments in plasma norepinephrine (P ϭ 0.0038 and P ϭ 0.0005, respectively), undoubtedly reflecting a compensatory sympathetic neural response to vasodilation produced by diazoxide, but these would not raise plasma glucose or serum nonesterified fatty acid levels. Thus selective suppression of insulin secretion, without stimulation of glucagon secretion, raised plasma glucose and serum nonesterified fatty acid concentrations. These findings define the temporal patterns and magnitudes of the metabolic responses to diazoxide and underscore the primacy of regulated insulin secretion in the physiological regulation of postabsorptive carbohydrate and lipid metabolism.glucose; insulin; glucagon; epinephrine; norepinephrine; adenosine 5Ј-triphosphate-dependent potassium channel DIAZOXIDE IS AN ATP-dependent potassium (K ATP ) channel agonist that is used clinically to treat hyperinsulinemic hypoglycemia (2,8,10,11,13,21,25,34). It opens potassium channels and hyperpolarizes plasma membranes, including those of pancreatic ␤-cells and thus decreases insulin secretion (1,2,6,7,8,10,11,13,21,23,25,34). However, diazoxide is a nonselective K ATP channel agonist (6, 23), K ATP channels are expressed widely (1, 6, 7), and alternative mechanisms of its plasma glucose-raising action have been proposed (10, 11). One example of the widespread actions of diazoxide is its vasodilating effect (3,22). Indeed, the drug has been used clinically for the urgent treatment of hypertension (3,22). After rapid intravenous injection, the onset of the effect to reduce vascular resistance is rapid (minutes) but, because the drug is Ͼ90% protein bound, prolonged (hours). Despite the initial studies in humans decades ago (8,10,11,21) and the use of...

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confidence: 82%

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confidence: 99%

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confidence: 99%

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Mechanism, temporal patterns, and magnitudes of the metabolic responses to the K_ATPchannel agonist diazoxide

Raju¹,

Cryer²

2005

American Journal of Physiology-Endocrinology and Metabolism

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“…Diazoxide has traditionally been used when there is a significant sulfonylurea overdose, utilizing its ability to inhibit insulin release through opening islet ␤-cell ATP-dependent K ϩ channels. 4 However, hypotension and reflex tachycardia may preclude the use of diazoxide in elderly patients with coronary artery disease. More recently, octreotide has emerged as a viable therapeutic alternative.…”

Section: Discussionmentioning

confidence: 99%

Octreotide for relapsing sulfonylurea‐induced hypoglycemia in a dialysis patient

Yavari

Ostermann

MacLean

et al. 2007

Dialysis & Transplantation

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With the predicted epidemic of type 2 diabetes mellitus and the clear link between glycemic control and longterm outcomes, the use of oral hypoglycemic agents is likely to increase. The major adverse effect of sulfonylurea agents is hypoglycemia, which traditionally is treated with hypertonic dextrose. Our case illustrates the challenges and pitfalls of the management of relapsing hypoglycemia in a hemodialysis patient on regular gliclazide. Case ReportA 47-year old hemodialysis patient with type 2 diabetes mellitus was admitted to the hospital because of vascular access problems. He usually took 80 mg of gliclazide once a day, with a capillary blood glucose measurement (BM) of 6-10 mmol/L. Other medications that he took included omeprazole, amlodipine, fluoxetine, ramipril, amitriptyline, atorvastatin, aspirin, and darbepoetin alfa.One week into his admission, the patient became septic and was started on empirical treatment with vancomycin for a presumed catheter-related infection. During the night, his BM gradually fell to 1.9 mmol/L despite regular snacks. In the morning he was confused, hypotensive, and sweating profusely. He was resuscitated with 50 mL of 50% dextrose given intravenously (IV), 1 mg of glucagon given subcutaneously (SC), and IV fluids.His condition improved temporarily. However, during the course of the day, he had 4 additional episodes of symptomatic hypoglycemia requiring intervention with boluses of 50% dextrose. A second dose of glucagon was given, mainly in an attempt to reduce the amount of IV dextrose necessary (Figure 1). A clear decrease in the response to hypertonic dextrose was noted, both in peak BM attained and in the time before a repeat bolus was needed. On the fifth occasion, his BM fell to 2.2 mmol/L, and he was given a single dose of 50 g of octreotide SC in addition to 50 mL of 50% dextrose IV and 100 mg of hydrocortisone IV. Within 20 minutes his BM was 8.6 mmol/L, and it remained above 5.5 mmol/L for the next 6 hours. Subsequent BMs ranged from 10 to 14 mmol/L.His serum cortisol level measured at 4 PM, prior to administration of hydrocortisone, was 501 nmol/L (9 AM reference range 120-500 nmol/L), with an insulin level of 1098 pmol/L (normal range 0-75 pmol/L). Blood cultures yielded methicillin-sensitive Staphylococcus aureus. His dialysis catheter was removed, and gliclazide was permanently discontinued. He had no further episodes of hypoglycemia and made a full recovery. DiscussionSulfonylureas act predominately by stimulating the release of preformed insulin from pancreatic ␤-cells. They also enhance insulin activity by reducing extrahepatic clearance of insulin. Sulfonylureas are hepatically metabolized and differ predominately in their duration of action and in the degree of renal excretion of the parent compound or active metabolite. In the UKPDS study, the incidence of major sulfonylurea-associated hypoglycemia was 1.0%-1.4%, compared with an incidence of 1.8% with insulin. 1 In general, this risk is increased in older patients; with renal impairment, liver disea...

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“…Patients who have type I diabetes will eventually require administration of exogenous insulin to prevent ketoacidosis, as did the patient described in this case report. In patients with type II diabetes and/or residual pancreatic function, glucose must be administered with attention to the possibility of endogenous insulin release in response to rapid elevation in plasma glucose concentrations [55,56].…”

Section: What Adverse Events Are Associated With Insulin Overdose?mentioning

confidence: 99%

Case Files of the Harvard Medical Toxicology Fellowship at Children’s Hospital Boston: An Insulin Overdose

Skolnik

Ewald

2010

J. Med. Toxicol.

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A 16-year-old boy with a history of type I diabetes mellitus being managed with an insulin pump presented to the emergency department in cardiac arrest. Per report from the patient's mother, the patient had noticed that his insulin cartridge, containing insulin lispro, was empty the night prior to admission so he had replaced it at approximately 7:00 PM. He had used his glucometer through the night with recorded values of 225-389 mg/dL and had administered a total of 14.5 units of insulin via his pump. At around 6:30 AM, the morning of admission, his mother attempted to wake him for school and found him cyanotic and motionless. She attempted to obtain a fingerstick glucose measurement but was unable to do so and administered glucagon, as well as activating Emergency Medical Services (EMS). When EMS arrived, the patient was pulseless. Cardiopulmonary resuscitation was initiated, and the patient was endotracheally intubated. Point-of-care glucose determination was 81 mg/dL. He received epinephrine, atropine, naloxone, and an ampule of 50% dextrose (25 g) during his prehospital care. He was defibrillated twice at 200 J for ventricular fibrillation. He was transferred to the emergency department with cardiopulmonary resuscitation in progress. EMS reported that an empty insulin syringe had been seen underneath the patient's bed. After approximately 1 h of resuscitative efforts, during which the patient received additional epinephrine, sodium bicarbonate, and hydrocortisone, he had return of spontaneous circulation. His initial arterial blood gas revealed a pH of 6.8, PaCO 2 of 70 mmHg, and PaO 2 of 335 mmHg. His serum glucose at that time was 377 mg/dL, and the anion gap was 39 mEq/L with urine negative for ketones. He underwent computed tomography scan of the head, chest, abdomen, and pelvis that demonstrated left upper lobe consolidation and gastric distention but was otherwise normal. He was transferred to a tertiary-care children's hospital where his serum glucose on arrival was 50 mg/dL. He received 25 g of intravenous dextrose, and an infusion of 10% dextrose in normal saline was started. A toxicology consult was obtained.

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Clinical Spectrum of Sulfonylurea Overdose and Experience With Diazoxide Therapy

Cited by 45 publications

References 13 publications

Mechanism, temporal patterns, and magnitudes of the metabolic responses to the K_ATPchannel agonist diazoxide

Mechanism, temporal patterns, and magnitudes of the metabolic responses to the K_ATPchannel agonist diazoxide

Octreotide for relapsing sulfonylurea‐induced hypoglycemia in a dialysis patient

Case Files of the Harvard Medical Toxicology Fellowship at Children’s Hospital Boston: An Insulin Overdose

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Clinical Spectrum of Sulfonylurea Overdose and Experience With Diazoxide Therapy

Cited by 45 publications

References 13 publications

Mechanism, temporal patterns, and magnitudes of the metabolic responses to the KATPchannel agonist diazoxide

Mechanism, temporal patterns, and magnitudes of the metabolic responses to the KATPchannel agonist diazoxide

Octreotide for relapsing sulfonylurea‐induced hypoglycemia in a dialysis patient

Case Files of the Harvard Medical Toxicology Fellowship at Children’s Hospital Boston: An Insulin Overdose

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Mechanism, temporal patterns, and magnitudes of the metabolic responses to the K_ATPchannel agonist diazoxide

Mechanism, temporal patterns, and magnitudes of the metabolic responses to the K_ATPchannel agonist diazoxide