Resistance to Symptomatic Insulin Reactions after Fasting

Drenick, Ernst J.; Alvarez, Lia C.; Tamási, G; Brickman, Arnold S.

doi:10.1172/jci107095

Cited by 94 publications

(65 citation statements)

References 21 publications

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“…However, in a recent study [10] in which adrenal vein epinephrine levels were examined in response to insulin hypoglycemia, it was found that intracarotid infusion of /J-hydroxybutyrate inhibited the epinephrine response to hypoglycemia. Drenick and co-workers [6] have furthermore shown no increase in catecholamine excretion after insulin-induced hypoglycemia in prolonged fasted (and thus hyperketonemic) man. Such data suggest that the appropriate brain center responsive to hypoglycemia no longer "recognizes" this state when provided with an alternate energy substrate in the form of ketone bodies.…”

Section: Discussionmentioning

confidence: 94%

Response to 2-Deoxy-D-glucose and to Glucagon in “Ketotic Hypoglycemia” of Childhood: Evidence for Epinephrine Deficiency and Altered Alanine Availability

et al. 1973

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ExtractThe commonest clinical type of hypoglycemia in childhood presents as "ketotic hypoglycemia," a syndrome which typically remits spontaneously before adolescence. In young children with the severe form of this syndrome, deficient catecholamine secretion and, recently, decreased mobilization of gluconeogenic substrate (alanine) have been shown. The present study concerns five children with ketotic hypoglycemia, aged 2.5 to 9.5 years, and six control children, of similar ages. Each received (7) an infusion of 2-deoxy-D-glucose (2-DG) to test the catecholamine response and (2) intravenous glucagon before and after a 26-28-hr fast, to define possible difference in the response of substrates and hormones, with particular reference to alanine. In the control group, the infusion of 2-DG, 50 mg/kg body wt over 30 min, induced anxiety, hunger or thirst and sweating, as well as a sustained rise in plasma glucose from 78 ± 5 (mean ± SEM) to 156 ± 13.5 mg/100 ml from 1-3 hr after beginning the infusion. There was a transient rise in renin activity in plasma (PRA) from 2.0 ± 0.5 to a peak of 5.8 ± 1.2 ng/ml/hr. By contrast, in the children with hypoglycemia, no clinical response was observed, and there was no change in either glucose in plasma, which remained at 77 ± 6 mg/100 ml, or in PRA (1.3 ± 0.3 to 1.0 ± 0.5 ng/ml/hr). After a period of unrestricted diet, and after an overnight fast, values of plasma glucose, insulin, glucagon, /3-hydroxybutyrate, and alanine were the same in the two groups. In both groups intravenous glucagon, 30 yug/kg, was followed by a comparable rise in glucose in plasma and immunoreactive insulin and a comparable fall in alanine in plasma. During the subsequent fast, glucose and insulin in plasma declined similarly. Ketonuria appeared at the same time and /S-hydroxybutyrate in plasma rose to equivalent values. The response to a second glucagon infusion was smaller after fasting both as to glucose in blood and plasma insulin, but once again similar for control and hypoglycemia groups. However, the fall in alanine in plasma was significantly greater in the hypoglycemic group during fasting (to 200 ± 13 /*M for the control group compared with 151 ± 13 ^Mforthe hypoglycemia group, P < 0.05) and at five time points (10,30, 60, 90, and 120 min) after the second glucagon administration. Absence of hyperglycemic response to 2-DG in ketotic hypoglycemia suggests 983 984 SlZONENKO ET AL. impaired catecholamine response. Further, after provocation by fasting and subsequent glucagon administration, the hypoalaninemia which resulted was more marked. Because epinephrine has been shown to raise alanine levels in plasma in man, it is hypothesized that a connection may exist between defective catechol secretion and alanine mobilization in ketotic hypoglycemia. SpeculationDecreased availability of alanine in so-called ketotic hypoglycemia probably represents a defective metabolic system by which neoglucogenic substrates are not readily mobilized, rather than an absolute absence of substrate. One of the poss...

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Section: Discussionmentioning

confidence: 94%

Response to 2-Deoxy-D-glucose and to Glucagon in “Ketotic Hypoglycemia” of Childhood: Evidence for Epinephrine Deficiency and Altered Alanine Availability

et al. 1973

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“…However, after 3-7 days of starvation, ketone-body utilization increases substantially, accounting for 50-85% of total oxidative metabolism in skeletal muscle (2,6). With continuing starvation, a decline in ketone-body utilization by skeletal muscle has been observed, so that after 24 days of fasting, the net uptake of AcAc plus fi-OHB accounts for 0-16% of muscle oxidative metabolism (2,7,8). The circulating arterial concentration of total ketone bodies in obese subjects increases from 2-3 mmol/liter after 3 days of starvation to 7-8 mmol/liter after 24-42 days of continuous starvation (1, 2).…”

Section: Resultsmentioning

confidence: 99%

“…It was reported that after 3-7 days of starvation, ketone bodies were the preferred fuels for skeletal muscle, accounting for 50-85% of muscle oxidative metabolism in obese and lean subjects (2,6). However, it was observed in obese subjects that after more prolonged periods of starvation, free fatty acids (FFA) were preferentially utilized by muscle, and only a small net uptake of ketone bodies occurred (2,7,8).…”

Section: Introductionmentioning

confidence: 99%

Hepatic Ketogenesis and Gluconeogenesis in Humans

Garber¹,

Menzel²,

Boden³

et al. 1974

J. Clin. Invest.

210

106

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A B S T R A C T Splanchnic arterio-hepatic venous differences for a variety of substrates associated with carbohydrate and lipid metabolism were determined simultaneously with hepatic blood flow in five patients after 3 days of starvation.Despite the relative predominance of circulating Phydroxybutyrate, the splanchnic productions of both fhydroxybutyrate and acetoacetate were approximately equal, totaling 115 g/24 h. This rate of hepatic ketogenesis was as great as that noted previously after 5-6 wk of starvation. Since the degree of hyperketonemia was about threefold greater after 5-6 wk of starvation, it seems likely that the rate of ketone-body removal by peripheral tissues is as important in the development of the increased ketone-body concentrations observed after prolonged starvation as increased hepatic ketonebody production rate.

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“…These data were interpreted to suggest that after a period of adaptation the human brain could convert to the use of ketones as a metabolic fuel. These observations received support from clinical observations that hypoglycaemia appeared to be better tolerated in persons after prolonged fast [28] but the idea remained that a period (unspecified) of adaptation was required for the brain to switch on the necessary enzyme systems. This was despite an elegant study in rodents [29] that demonstrated equal evidence of brain ketone utilisation in rats made acutely hyperketonaemic by ketone infusion as in animals made subacutely ketonaemic by prolonged fasting.…”

Section: Brain Metabolism and Hypoglycaemiamentioning

confidence: 99%

Hypoglycaemia in diabetes mellitus - protecting the brain

Amiel

1997

Diabetologia

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The principal danger of hypoglycaemia is the associated loss of brain function. Under normal circumstances, the brain is almost exclusively dependent on glucose to fuel its metabolism and function and, since its glucose stores are negligible, normal brain function relies upon an adequate supply of glucose from its blood supply.In animal models, prolonged very profound hypoglycaemia eventually results in neurone death (compared with ischaemia, which results in non-selective loss of all brain cell types) [1]. In clinical practice, apparent full recovery is the rule even from severe episodes of hypoglycaemia. Permanent impairment of brain function is seen only after the most severe episodes, usually associated with massive insulin overdose, often either deliberate or malicious [2]. In general, the loss of brain function due to hypoglycaemia presents in any degree from mild confusion or disinhibition to coma and full recovery apparently occurs within an hour of restoration of normoglycaemia [3]. There are concerns that recurrent episodes of hypoglycaemia-associated coma may result in permanent damage to cortical (intellectual) function although in adults the data are inconclusive, with some studies suggesting an acceleration of the age-related decline in performance on IQ testing [4], while others relate this to associated diabetic neuropathy [5]. Prospective studies of people who have been at particular risk for recurrent severe hypoglycaemia show no effect on long-term cognitive function [6,7]. There is evidence of permanent impairment of IQ after recurrent hypoglycaemic episodes occurring before the age of 5 years (i. e. affecting the developing brain) [8]. (For a review of the possible long-term effects of recurrent hypoglycaemia, see [9]). Protective mechanisms against severe hypoglycaemiaIn health, severe hypoglycaemia (now defined as the state in which the patient is unable to self-treat because of impaired function and has to be treated by someone else [10]), does not occur because of the efficient systems the body has to detect and deal with

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Resistance to Symptomatic Insulin Reactions after Fasting

Cited by 94 publications

References 21 publications

Response to 2-Deoxy-D-glucose and to Glucagon in “Ketotic Hypoglycemia” of Childhood: Evidence for Epinephrine Deficiency and Altered Alanine Availability

Response to 2-Deoxy-D-glucose and to Glucagon in “Ketotic Hypoglycemia” of Childhood: Evidence for Epinephrine Deficiency and Altered Alanine Availability

Hepatic Ketogenesis and Gluconeogenesis in Humans

Hypoglycaemia in diabetes mellitus - protecting the brain

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