The Hypothermia of Hypoglycemia

Freinkel, Norbert; Metzger, Boyd E.; Harris, Ethan; Robinson, Sarah; Mager, Milton

doi:10.1056/nejm197210262871702

Cited by 100 publications

(26 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, direct sensing of dwindling energy reserves, for example in the hypothalamus, could be the leptin-independent signal. In support of this hypothesis, 2-deoxyglucose, an inhibitor of glucose utilization, induces torpor, particularly when given intra- cerebrally (36). Both A-ZIP͞F-1 and control mice entered torpor after systemic injection of 2-deoxyglucose (unpublished observations).…”

Section: Discussionmentioning

confidence: 75%

Torpor in mice is induced by both leptin-dependent and -independent mechanisms

Гаврилова

Leon

Marcus‐Samuels

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

202

182

View full text Add to dashboard Cite

We tested the effect of chronic leptin treatment on fasting-induced torpor in leptin-deficient A-ZIP͞F-1 and ob͞ob mice. A-ZIP͞F-1 mice have virtually no white adipose tissue and low leptin levels, whereas ob͞ob mice have an abundance of fat but no leptin. These two models allowed us to examine the roles of adipose tissue and leptin in the regulation of entry into torpor. Torpor is a short-term hibernation-like state that allows conservation of metabolic fuels. We first characterized the A-ZIP͞F-1 animals, which have a 10-fold reduction in total body triglyceride stores. Upon fasting, A-ZIP͞F-1 mice develop a lower metabolic rate and decreased plasma glucose, insulin, and triglyceride levels, with no increase in free fatty acids or ␤-hydroxybutyrate. Unlike control mice, by 24 hr of fasting, they have nearly exhausted their triglycerides and are catabolizing protein. To conserve energy supplies during fasting, A-ZIP͞F-1 (but not control) mice entered deep torpor, with a minimum core body temperature of 24°C, 2°C above ambient. In ob͞ob mice, fasting-induced torpor was completely reversed by leptin treatment. In contrast, neither leptin nor thyroid hormone prevented torpor in A-ZIP͞F-1 mice. These data suggest that there are at least two signals for entry into torpor in mice, a low leptin level and another signal that is independent of leptin and thyroid hormone levels. Studying rodent torpor provides insight into human torpor-like states such as near drowning in cold water and induced hypothermia for surgery.fasting ͉ lipoatrophic diabetes ͉ body temperature ͉ hypothermia ͉ A-ZIP͞F-1 mice L iving organisms must cope with food scarcity. The capabilities to store excess fuel and regulate energy expenditure were thus crucial evolutionary adaptations. In higher organisms, white adipocytes store triglycerides that are burned during fasting and starvation (1, 2). These adipocyte triglycerides account for the vast majority of the body's fuel reserves (3).Adipose tissues also contribute to energy homeostasis in an endocrine͞paracrine manner. Leptin is secreted by adipocytes in direct proportion to body fat mass and regulates energy expenditure, metabolic efficiency, and food intake (4-6). Leptin binds to receptors in the hypothalamus and other sites and conveys the size of adipose tissue lipid stores. Adipocytes also make additional hormones, including tumor necrosis factor ␣, which affects insulin sensitivity (7,8). Thus it is clear that adipose tissues contribute to energy metabolism in two ways, as a metabolic regulator and fuel depot.To analyze the physiologic roles of fat, we generated a transgenic mouse, named A-ZIP͞F-1, which has virtually no white adipose tissue and a reduced amount of brown adipose tissue (9). These mice express, selectively in adipose tissue, a dominant negative protein that heterodimerizes with certain basic leucine zipper transcription factors. The A-ZIP͞F-1 phenotype strikingly resembles that of humans with severe lipoatrophic diabetes mellitus, a disease characterized by reduced amounts of...

show abstract

Section: Discussionmentioning

confidence: 75%

Torpor in mice is induced by both leptin-dependent and -independent mechanisms

Гаврилова

Leon

Marcus‐Samuels

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

202

182

View full text Add to dashboard Cite

show abstract

“…Earlier studies have indicated that insulin levels do not change (3), or increase only slighly (21), relative to the hyperglycemia observed after 2DG infusions. In the present study the gradual rise in insulin levels was less than what might be expected for the level of hyperglycemia (38).…”

Section: Resultsmentioning

confidence: 98%

“…This miiarked increase in xvater intake in the cervical cord-sectioned patieint occurred in the absence of significanit inereases in catecholamines, PRA, glucose, and sodiumll concenitration (Fig. 4) (a) hypothalamic-pituitary responses including increased levels of prolactin, growth hormone, and corticol (3, 4); (b) hypothermia (7,21); and c increased food and water intake (7). Cervical cord-sectioned patients have a similar but potentiated hormonal and behavioral response to 2DG (3,4,22).…”

Section: Resultsmentioning

confidence: 98%

Increased Thirst and Plasma Arginine Vasopressin Levels during 2-Deoxy-d-glucose-induced Glucoprivation in Humans

Thompson¹,

Campbell²,

Lilavivat³

et al. 1981

J. Clin. Invest.

View full text Add to dashboard Cite

A B S T R A C T Insulin-induced hypoglycemia by unknown mechanism(s) increases plasma arginine vasopressin (AVP) levels in humans. Mechanisms for increased AVP levels during central nervous system glucoprivation were investigated by administering 20-min i.v. infusions of 2-deoxy-D-glucose (50 mg/kg), a competitive inhibitor of glucose utilization, or normal saline (sham), to 24 normal volunteers. Some of the infusions were administered in combination with neuropharmacological blocking agents (placebo). The behavioral, physiological, metabolic, and hormonal correlates of 2-deoxy-D-glucose (2DG)-induced glucoprivation and AVP secretion were studied in a group (n = 5) pretreated for 1 wk with either mazindol (1 mg per os three times per day), a potent norepinephrine and dopamine-reuptake blocker, or placebo. A second group (n = 5) received either propranolol (3 mg/3 min followed by 80 ,tg/min) or normal saline infusion before and during 2DG administration. With 2DG alone, plasma AVP levels increased from 1.3 + 0.3 pg/ml at base line to a peak of 4.5+1.4 pg/ml at 60 min and remained elevated for 150 min. From 30 to 180 min after 2DG administration, the 2DG-infused volunteers increased their water intake in comparison with shaminfused volunteers. Marked increases in epinephrine and slight increases in norepinephrine were associated with increases in plasma glucose and renin activity and decreases in plasma potassium. Plasma sodium and osmolality increased transiently and mean arterial pressure (MAP) fell. These changes, however, were small and inconstant and could not account for the observed increases in thirst and AVP levels. Pretreatment with mazindol prevented the decrease in MAP and the increase in plasma renin activity (PRA) following 2DG infusions without modifying increased thirst, water intake, or AVP responses to glucoprivation. Pretreatment with propranolol effectively blocked ,3-adrenoreceptors as evidenced by increased MAP and plasma epinephrine, and abolition ofthe RPA increases during 2DG-induced glycoprivation, but did not suppress AVP and thirst responses. A cervical cordsectioned patient lacking descending sympathetic outflow had a potentiated thirst response to 2DG-induced glucoprivation in the absence of increases in sodium, catecholamines, and PRA. Thus 2DG administration activates mechanisms for increased thirst and AVP which are unrelated to changes in peripheral catecholamines, MAP, PRA, and osmolality.

show abstract

“…However, we cannot exclude the possibility that maternal counterregulatory responses to hypoglycemia may have been involved as well. Nonetheless, since each of the latter is part ofthe normal physiological response to intracellular glucopenia in mammals (25)(26)(27)(28), the maternal hypoglycemia must be deemed the initiating event and hence a real risk factor during early organogenesis.…”

Section: Discussionmentioning

confidence: 99%

Embryotoxic effects of brief maternal insulin-hypoglycemia during organogenesis in the rat.

Buchanan¹,

Schemmer²,

Freinkel³

1986

J. Clin. Invest.

View full text Add to dashboard Cite

To test whether maternal hypoglycemia can impair organogenesis, we induced brief glucopenia with insulin in conscious pregnant rats during either the headfold stage or the early neural tube closure stage of embryogenesis. At each time, 10 pairs of animals received identical insulin infusions for 1 h. Half the animals were maintained at euglycemia during the infusions, while the others were allowed to become hypoglycemic. Euglycemia was maintained or restored in all animals immediately after the insulin was stopped. Spontaneous activity was diminished during the hypoglycemia but consciousness was preserved. Embryos were removed from mothers and examined 2 d later. This examination revealed that embryos from the hypoglycemic mothers were growth-retarded and displayed a small but significant incidence of gross developmental anomalies compared with embryos from the insulin-infused euglycemic mothers. Thus, brief, mild maternal hypoglycemia during early organogenesis can disrupt normal embryo development in the rat. The effect is due to the hypoglycemia per se rather than to the insulin employed for its induction.

show abstract

The Hypothermia of Hypoglycemia

Cited by 100 publications

References 20 publications

Torpor in mice is induced by both leptin-dependent and -independent mechanisms

Torpor in mice is induced by both leptin-dependent and -independent mechanisms

Increased Thirst and Plasma Arginine Vasopressin Levels during 2-Deoxy-d-glucose-induced Glucoprivation in Humans

Embryotoxic effects of brief maternal insulin-hypoglycemia during organogenesis in the rat.

Contact Info

Product

Resources

About