The role of adrenergic mechanisms in the substrate and hormonal response to insulin-induced hypoglycemia in man.

Garber, Alan J.; Cryer, Philip E.; Santiago, Julio V.; Haymond, Morey W.; Pagliara, Anthony S.; Kipnis, David

doi:10.1172/jci108460

Cited by 362 publications

(161 citation statements)

References 71 publications

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“…On the basis of the present results, it would seem that only catecholamines possess the potency to normalize rapidly blood glucose concentration after insulin-induced hypoglycaemia, whereas glucagon, cortisol, and growth hormone seem to be of no major relevance to the acute restoration of glucose homeostasis. This impact of adrenergic mechanisms in the initiation of the counter-regulatory response to insulin-induced hypoglycaemia in man has also been underlined by the observation that of all the hormones studied only the increment in plasma catecholamines preceded the increase in hepatic glucose production [42].…”

Section: Discussionmentioning

confidence: 90%

The role of ?diabetogenic? hormones on carbohydrate and lipid metabolism following oral glucose loading in insulin dependent diabetics: Effects of acute hormone administration

et al. 1981

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Summary. To evaluate the relative role of "diabetogenic" hormones as insulin antagonists in severe derangements of diabetic control, glucagon, cortisol, growth hormone and adrenaline were administered by continuous intravenous infusion, separately and in combination, to ketosis-prone insulin-dependent diabetics (n = 11). The amount of insulin required for the assimilation of a 50 g glucose load during the various hormone infusions was determined by means of an automated glucose-controlled insulin infusion system and used as an index of insulin effectiveness. Raising plasma hormone concentrations acutely into the range seen in severe diabetic states (glucagon 517+_70pg/ml; cortisol 32-+3gg/dl; growth hormone 14+3ng/ml) did not alter significantly blood glucose profile and insulin requirement (control ll.3_l.lU; glucagon 11.6-+2.0U; cortisol 11.1_+0.4 U; growth hormone 12.9___1.4 U), except for adrenaline (plasma level 550_+ 192 pg/ml), which caused a marked rise in blood glucose levels and a threefold increase in insulin demand (31.1_+ 3.7 U). Combined infusion of all hormones did not potentiate significantly the latter effect (38.3___4.7 U). The effectiveness of metabolic control by insulin was assessed by a marked decrease in plasma nonesterified free fatty acids and ketone bodies upon its administration after glucose ingestion in all groups studied. It is concluded that from the hormones investigated within this study adrenaline exerts the strongest diabetogenic action during its short term administration followed by that of growth hormone. Whereas it may well be that over-insulinization of the patients by the glucose controlled insulin infusion system has overcome and disguised the smaller diabetogenic effects of cortisol and glucagon.Key words: Diabetes mellitus, counter-regulatory hormones, glucagon, cortisol, growth hormone, adrenaline, insulin, non-esterified fatty acids, ketone bodies.Excess secretion of insulin-counteracting hormones is claimed to be important in the metabolic changes and insulin resistance in diabetic ketoacidosis [1,2]. The observations in severe derangements of diabetic control include elevated plasma levels of glucagon [3], cortisol [4], growth hormone [5,6], and catecholamines [7,8]. The hierachy of their pathogenetic significance, however, remains to be established. Hyperglycaemia, decreased glucose tolerance and insulin resistance have been demonstrated under certain circumstances after exogenous administration of these hormones [9][10][11][12]. Furthermore, the above mentioned counter-regulatory hormones are known to exert lipolytic and ketogenic activity when elevated to high physiological concentrations in insulin deficient diabetic man [12][13][14][15][16]. The delay in the development of ketoacidosis in insulin-withdrawn diabetics by either somatostatin-induced suppression of growth hormone and glucagon [17] or following pituitary ablation [1] serves as further support for implicating these hormones as pathogenic factors of deranged metabolic control. In addition, circulator...

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Section: Discussionmentioning

confidence: 90%

The role of ?diabetogenic? hormones on carbohydrate and lipid metabolism following oral glucose loading in insulin dependent diabetics: Effects of acute hormone administration

et al. 1981

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“…Although insulin inhibits key enzymes of gluconeogenesis (1) and the mobilization of gluconeogenic substrates to the liver (2)(3)(4)(5), it is well established that insulin-induced hypoglycemia (IIH) provokes the release of hormones (6)(7)(8)(9)(10)(11), which stimulate hepatic gluconeogenesis (11)(12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Rat liver responsiveness to gluconeogenic substrates during insulin-induced hypoglycemia

Souza

Borba-Murad

Ceddia

et al. 2001

Braz J Med Biol Res

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Hepatic responsiveness to gluconeogenic substrates during insulininduced hypoglycemia was investigated. For this purpose, livers were perfused with a saturating concentration of 2 mM glycerol, 5 mM Lalanine or 5 mM L-glutamine as gluconeogenic substrates. All experiments were performed 1 h after an ip injection of saline (CN group) or 1 IU/kg of insulin (IN group). The IN group showed higher (P<0.05) hepatic glucose production from glycerol, L-alanine and L-glutamine and higher (P<0.05) production of L-lactate, pyruvate and urea from L-alanine and L-glutamine. In addition, ip injection of 100 mg/kg glycerol, L-alanine and L-glutamine promoted glucose recovery. The results indicate that the hepatic capacity to produce glucose from gluconeogenic precursors was increased during insulin-induced hypoglycemia.

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“…Patients with type 1 diabetes suffer from an altered counterregulatory hormonal response to hypoglycemia characterized by severe blunting or absence of the glucagon response and both a lowered glucose threshold for and a reduced magnitude of epinephrine secretion (5,6). As a consequence, these patients have an increased risk of developing severe hypoglycemia (7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Fructose Amplifies Counterregulatory Responses to Hypoglycemia in Humans

et al. 2002

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Glucokinase (GK) is required for cellular glucose sensing, although there is a paucity of data regarding its role in the counterregulatory response to hypoglycemia in humans. Because fructose has been shown to modulate GK activity, we examined the effects of an acute infusion of fructose on hypoglycemia counterregulation in seven lean nondiabetic subjects. Using stepped hypoglycemia clamp studies (5.0, 4.4, 3.9, and 3.3 mmol/l target plasma glucose steps, 50 min each), subjects were studied on two separate occasions, without (control) or with co-infusion of fructose (1.2 mg ⅐ kg ؊1 ⅐ min ؊1 ). Fructose induced a resetting of the glycemic thresholds for secretion of epinephrine (3.8 ؎ 0.1 mmol/l) and glucagon (3.9 ؎ 0.2 mmol/l) to higher plasma glucose concentrations (4.0 ؎ 0.1 mmol/l [P ‫؍‬ 0.006] and 4.1 ؎ 0.1 mmol/l [P ‫؍‬ 0.03], respectively). In addition, the magnitude of increase in epinephrine and glucagon concentrations was higher after administration of fructose (48 and 39%, respectively, P < 0.05 for both). The amplification of these hormonal responses was specific because plasma norepinephrine, growth hormone, and cortisol were comparable in both sets of studies. Endogenous glucose production, measured with [3-3 H]glucose, increased by 47% (P < 0.05) in the fructose infusion studies compared with 14% (P ‫؍‬ NS) in the control studies. In addition, glucose uptake was more suppressed with fructose infusion (by 33%, P < 0.05). In concert with these effects of fructose on glucose kinetics, average glucose infusion rate was markedly reduced in the fructose infusion studies during the 3.9-mmol/l glucose step (4.6 ؎ 0.9 vs. 7.4 ؎ 1.1 mol ⅐ kg ؊1 ⅐ min ؊1 , respectively, P ‫؍‬ 0.03) and during the 3.3-mmol/l glucose step (0.5 ؎ 0.1 vs. 5.2 ؎ 1.2 mol ⅐ kg ؊1 ⅐ min ؊1 , respectively, P < 0.001), suggesting more potent glucose counterregulation and improved recovery from hypoglycemia with fructose infusion. We conclude that infusion of a catalytic dose of fructose amplifies the counterregulatory response to hypoglycemia by both increases in hormonal activation and augmentation of glucose counterregulation in humans. Diabetes 51: 893-900, 2002

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The role of adrenergic mechanisms in the substrate and hormonal response to insulin-induced hypoglycemia in man.

Cited by 362 publications

References 71 publications

The role of ?diabetogenic? hormones on carbohydrate and lipid metabolism following oral glucose loading in insulin dependent diabetics: Effects of acute hormone administration

The role of ?diabetogenic? hormones on carbohydrate and lipid metabolism following oral glucose loading in insulin dependent diabetics: Effects of acute hormone administration

Rat liver responsiveness to gluconeogenic substrates during insulin-induced hypoglycemia

Fructose Amplifies Counterregulatory Responses to Hypoglycemia in Humans

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