Brief twice-weekly episodes of hypoglycemia reduce detection of clinical hypoglycemia in type 1 diabetes mellitus.

Ovalle, Fernando; Fanelli, Carmine G.; Paramore, Deanna S.; Hershey, Tamara; Craft, Suzanne; Cryer, Philip E.

doi:10.2337/diabetes.47.9.1472

Cited by 109 publications

(75 citation statements)

References 20 publications

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“…However, severe hypoglycemia does induce HSP-72 in both neurons (35) and astrocytes (36). Interestingly, prior bouts of hypoglycemia may actually confer some degree of protection on certain aspects of cognitive function during subsequent hypoglycemic episodes (29). The lack of HSP-72 expression in the hypoglycemic brains here is in keeping with previous studies showing that such expression occurs only after severe bouts of hypoglycemia, which produce burst suppression and an isoelectric electroencephalogram (35).…”

Section: Hypoglycemia and Arcuate Nucleus Apoptosissupporting

confidence: 78%

Presumed apoptosis and reduced arcuate nucleus neuropeptide Y and pro-opiomelanocortin mRNA in non-coma hypoglycemia.

2000

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Hypoglycemia reduces sympathoadrenal responses to subsequent hypoglycemic bouts by an unknown mechanism. To assess whether such hypoglycemia-associated autonomic failure is due to actual brain damage, male Sprague-Dawley rats underwent 1-h bouts of insulininduced (5 U/kg i.v.) hypoglycemia (1.6-2.8 mmol/l) 1 or 3 times on alternate days. Rats remained alert and were rescued with intravenous glucose at 60-80 min. Plasma epinephrine and corticosterone responses were significantly reduced during the second and third bouts. Brains from these rats were processed by the terminal transferase-mediated deoxyuridine triphosphatebiotin nick end-labeling ( W ith the advent of intensive insulin therapy for type 1 diabetes, there has been an increasing incidence of hypoglycemic episodes (1). Some of these are severe, resulting in coma and subsequent permanent brain damage and/or death (2-5). Other less severe hypoglycemic episodes do not impair consciousness. Regardless of degree, hypoglycemia is associated with a robust counterregulatory response (CRR) (6-9). Low levels of plasma glucose are sensed by selective neurons in the brain (10-14) as well as by glucosensors in the hepatic portal vein (15). Signals from these sensors provoke activation of the sympathoadrenal system with preferential release of epinephrine. In addition, cortisol is released from the adrenal cortex and glucagon from the pancreatic ␣-cells (6-9,16). This response maximizes the mobilization of glucose in the body. In addition to this CRR, subjects develop an awareness of their hypoglycemic state (6,9). Both the CRR and the hypoglycemia awareness can become blunted after only a single bout of hypoglycemia (9,17). Hypoglycemia awareness recovers fairly rapidly but the diminished CRR is often prolonged (6), suggesting that different mechanisms are responsible for the two phenomena. However, the mechanism underlying either of these remains unclear.Here, we present a rat model of the dampened CRR and show that a single bout of moderate hypoglycemia produces highly site-specific apparent apoptotic response in cells of the hypothalamic arcuate nucleus (ARC). This apoptosis is associated with a significant reduction in the expression of both neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA in this same nucleus. RESEARCH DESIGN AND METHODSAnimals and hypoglycemia. Male Sprague-Dawley rats were used at 300-400 g. They were housed at 22-23°C on a 12-h light-dark schedule and fed Purina rat chow (#5001) (PMI Nutrition International, Brentwood, MO) ad libitum. One group of rats (n = 12) had right atrial silastic catheters implanted via the right jugular vein under ketamine (45 mg/kg)/xylazine (9 mg/kg i.p.) anesthesia with buprenorphine (0.2 mg/kg) analgesia. Catheters were filled with a polyvinylpyrrolidone/heparin mix, which was replaced daily. The rats were allowed 4-5 days to recover and then were fasted overnight. Additional rats without venous catheters were also used (n = 34) and fasted overnight before testing. Between 0800 and 1000, a blood sample (...

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Section: Hypoglycemia and Arcuate Nucleus Apoptosissupporting

confidence: 78%

Presumed apoptosis and reduced arcuate nucleus neuropeptide Y and pro-opiomelanocortin mRNA in non-coma hypoglycemia.

2000

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“…Recent antecedent hypoglycaemia has been shown to shift glycaemic thresholds for autonomic (including epinephrine), symptomatic and cognitive dysfunction responses to subsequent hypoglycaemia to lower plasma glucose concentrations [21,29] (Fig. 5, 6), to impair glycaemic defence against hyperinsulinaemia [21] and to reduce detection of hypoglycaemia in the clinical setting [30] in patients with Type I diabetes. Major support for the concept of HAAF is provided by the finding, from three independent laboratories [31,32,33], that as little as 2 to 3 weeks of scrupulous avoidance of iatrogenic hypoglycaemia reverses hypoglycaemia unawareness (Fig.…”

Section: Pathophysiology Of Glucose Counterregulation In Type I Diabetesmentioning

confidence: 99%

Hypoglycaemia: The limiting factor in the glycaemic management of Type I and Type II Diabetes*

2002

Diabetologia

733

574

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Hypoglycaemia is the limiting factor in the glycaemic management of diabetes. Iatrogenic hypoglycaemia is typically the result of the interplay of insulin excess and compromised glucose counterregulation in Type I (insulin-dependent) diabetes mellitus. Insulin concentrations do not decrease and glucagon and epinephrine concentrations do not increase normally as glucose concentrations decrease. The concept of hypoglycaemia-associated autonomic failure (HAAF) in Type I diabetes posits that recent antecedent iatrogenic hypoglycaemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycaemia unawareness (by reducing the autonomic and the resulting neurogenic symptom responses). Perhaps the most compelling support for HAAF is the finding that as little as 2 to 3 weeks of scrupulous avoidance of hypoglycaemia reverses hypoglycaemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients. The mediator and mechanism of HAAF are not known but are under active investigation. The glucagon response to hypoglycaemia is also reduced in patients approaching the insulin deficient end of the spectrum of Type II (non-insulin-dependent) diabetes mellitus, and glycaemic thresholds for autonomic (including epinephrine) and symptomatic responses to hypoglycaemia are shifted to lower plasma glucose concentrations after hypoglycaemia in Type II diabetes. Thus, patients with advanced Type II diabetes are also at risk for HAAF. While it is possible to minimise the risk of hypoglycaemia by reducing risks -including a 2 to 3 week period of scrupulous avoidance of hypoglycaemia in patients with hypoglycaemia unawareness -methods that provide glucose-regulated insulin replacement or secretion are needed to eliminate hypoglycaemia and maintain euglycaemia over a lifetime of diabetes. [Diabetologia (2002) 45:937-948] Keywords Hypoglycaemia, glucagon, epinephrine, adrenal medulla, sympathetic nervous system, hypoglycaemia-associated autonomic failure.

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“…Recently, a clinical syndrome known as hypoglycemiaassociated autonomic failure (HAAF) has drawn attention to the fact that glucoregulatory mechanisms are impaired by prior exposure to glucoprivation (1)(2)(3). HAAF occurs in diabetic patients as a consequence of prior inadvertent hypoglycemic bouts associated with intensive insulin therapy.…”

mentioning

confidence: 99%

“…In HAAF, plasma epinephrine, norepinephrine (NE), and glucagon responses to a hypoglycemic challenge are severely diminished. In addition, increased appetite and autonomic signs, such as sweating and cardiac palpitations, that normally occur during hypoglycemia are reduced (1,2,4). Consequently, affected individuals are not able to detect an ongoing or developing hypoglycemic emergency.…”

mentioning

confidence: 99%

Repeated 2-deoxy-D-glucose-induced glucoprivation attenuates Fos expression and glucoregulatory responses during subsequent glucoprivation.

Sanders

Ritter

2000

Diabetes

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A condition of reduced responsiveness to hypoglycemia, known as hypoglycemia-associated autonomic failure (HAAF), occurs in diabetic patients in the wake of a prior hypoglycemic episode. This condition suggests that hypoglycemia alters central glucose-sensing mechanisms. This experiment examined the effects of repeated 2-deoxy-D-glucose (2DG)-induced glucoprivation on subsequent 2DG-induced feeding and hyperglycemic responses in rats. Fos immunoreactivity (ir) in adrenal medulla and brain sites involved in these responses was also examined. Rats were injected daily for 10 days with 2DG (200 mg/kg) or saline (0.9%) or were handled. On day 11, rats were injected with 2DG (200 mg/kg). After injection, food intake was measured in one group. In another group, food was withheld, and multiple blood samples were collected for glucose determination. In a third group, food was withheld, and rats were killed after 2 h for evaluation of Fos-ir. Prior repeated glucoprivation reduced subsequent feeding and hyperglycemia responses to 2DG to baseline levels. Double-label immunohistochemistry showed that Fos-ir was reduced or abolished in catecholamine cell groups A1, A1/C1, C1, C3, and A6 and in the paraventricular nucleus of the hypothalamus and adrenal medulla. In other brain sites, 2DG-induced Fos-ir was diminished or unaffected by prior glucoprivation. Sites in which Fos-ir was abolished have been implicated previously in glucoprivic control of feeding and adrenal medullary secretion. Therefore, the present findings may identify crucial neuroanatomical sites that are altered by prior glucoprivation and that mediate some of the physiological deficits observed in HAAF.

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Brief twice-weekly episodes of hypoglycemia reduce detection of clinical hypoglycemia in type 1 diabetes mellitus.

Cited by 109 publications

References 20 publications

Presumed apoptosis and reduced arcuate nucleus neuropeptide Y and pro-opiomelanocortin mRNA in non-coma hypoglycemia.

Presumed apoptosis and reduced arcuate nucleus neuropeptide Y and pro-opiomelanocortin mRNA in non-coma hypoglycemia.

Hypoglycaemia: The limiting factor in the glycaemic management of Type I and Type II Diabetes*

Repeated 2-deoxy-D-glucose-induced glucoprivation attenuates Fos expression and glucoregulatory responses during subsequent glucoprivation.

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