Overview of counterregulation and its abnormalities in diabetes mellitus and other conditions

Gerich, John E.; Campbell, Peter J.

doi:10.1002/dmr.5610040202

Cited by 66 publications

(27 citation statements)

References 146 publications

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“…A comparison of the current findings with our earlier reports suggests that hepatic glucosensors are quantitatively more important for hypoglycemic detection as the rate of fall in glycemia decreases. Given the clinical prevalence of slowly developing (i.e., graded) hypoglycemia (28), hepatic glucosensors appear critical for hypoglycemic detection.…”

Section: Discussionmentioning

confidence: 99%

Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia.

Donovan

Hamilton-Wessler

Halter

et al. 1994

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

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The impact of hepatic glucose concentration on the sympathetic response to progressive hypoglycemia was examined in chronically cannulated conscious male dogs (n = 6). Graded hypoglycemia was induced via peripheral insulin infusion (30 pmol kg-1-min-1) with either peripheral (PER) or portal (POR) glucose infusion. Over the 260-min experimental period, arterial glycemia was adjusted from 5.2 ± 0.1 to 2.5 ± 0.1 mM in decrements of %0.5 mM every 40 min. Arterial glycemias were not sigfntly different between PER and POR at any measured level. However, hepatic glycemia was signiicantly elevated at all times during POR (8.4 ± 0.8 to 3.4 ± 0.2 mM) when compared to PER (5.2 ± 0.2 to 2.5 ± 0.1 mM). Plasma epinephrine values were significantly greater during PER vs. POR at all arterial glycemias below 4.0 mM. At the lowest level of arterial glycemia studied (2.5 ± 0.2 mM) the epinephrine response above basal was 3-fold greater for PER (8.7 ± 1.7 nM) when compared to POR (2.6 ± 0.6 nM) (P < 0.01). Plasma norepinephrine results were similar for the two protocols, with PER demonstrating a 3-fold greater response above basal when compared to POR at 2.5 mM arterial glycemia (P < 0.05). While the sympathetic response was markedly different between protocols when expressed as a function of arterial glycemia, when expressed as a function of hepatic glycemia this discrepancy was largely eliminated. This latter observation supports the liver as the primary locus for glycemic detection relevant to the sympathoadrenal response when hypoglycemia develops slowly-i.e., over a period of 2-3 h. A comparison of the current findings with our previous observations suggests that the hepatic glucosensors may play a greater role in hypoglycemic counterregulation as the rate of fall in glycemia is less.In 1924 Walter B. Cannon and coworkers (1) provided the first convincing evidence that insulin-induced hypoglycemia resulted in increased sympathetic output. At that time, they proposed that the enhanced sympathetic activity was likely due to glucopenia "local" to the autonomic nervous system. This position was supported by the earlier work of Claude Bernard (2) and others (3, 4), demonstrating that lesions to specific aspects ofthe brain had a profound impact on glucose metabolism. The existence of specific "glucoreceptors" within the hypothalamus was later proposed by Mayer and Marshall (5). Subsequent studies in which direct microinjections were used have now clearly identified glucosensitive neurons within the ventromedial and lateral hypothalamus (6). In addition, substantial evidence has accumulated over the years delineating the efferent capacity of the central nervous system (CNS) to impact upon glucoregulation (6,7). This has led to the prevailing concept that the brain "senses" ambient glycemia and effects the requisite glucoregulatory mechanisms.Evidence for the role of the CNS in glycemic detection has relied largely on nonphysiological stimuli, such as brain lesions, electrical stimulation, glucose analogues, and direct (in th...

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Section: Discussionmentioning

confidence: 99%

Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia.

Donovan

Hamilton-Wessler

Halter

et al. 1994

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

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“…Deficient secretion of glucagon and catecholamines plays a major role in the morbidity associated with iatrogenic hypoglycemia in patients with type 1 diabetes (7,27,28). The glucagon response to hypoglycemia is commonly diminished after some years of treatment of type 1 diabetes (29,30).…”

Section: Diabetes Vol 52 March 2003mentioning

confidence: 99%

Role of Corticotrophin-Releasing Hormone in the Impairment of Counterregulatory Responses to Hypoglycemia

et al. 2003

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We have explored the role of individual elements of the hypothalamic pituitary adrenal axis on the pathogenesis of hypoglycemia-associated autonomic failure. Five groups of male Sprague-Dawley rats were used. Control animals had 3 days of sham treatment followed by a hyperinsulinemic/hypoglycemic glucose clamp on day 4. A second group underwent 3 days of antecedent insulininduced hypoglycemia then a subsequent clamp. Three more groups underwent pretreatment with corticosterone, adrenocorticotrophic hormone (ACTH), or corticotrophin-releasing hormone (CRH) mirroring the glucocorticoid response of the hypoglycemic group. Subsequent counterregulatory responses showed marked differences. CRH-(and insulin-treated) animals showed markedly reduced epinephrine responses (CRH 1,276 ؎ 404 pg/ml, controls 3,559 ؎ 563 pg/ml; P < 0.05). In contrast, ACTH pretreatment augmented epinephrine responses (6,681 ؎ 814 pg/ml; P ‫؍‬ 0.007 versus controls); corticosterone pretreatment caused a similar but nonsignificant enhancement. The same pattern was seen for norepinephrine. CRH pretreatment also suppressed glucagon responses to hypoglycemia (control 157 ؎ 21, CRH 68 ؎ 10 pg/ml; P ‫؍‬ 0.004). The addition of a CRH receptor 1 (CRHr1) antagonist to the antecedent CRH reversed the subsequent suppression of epinephrine. These findings suggest that CRH acting via CRHr1 plays an important role in the sympathoadrenal downregulation seen in this rodent model of antecedent hypoglycemia; this action is not mediated via activation of the hypothalamic-pituitary-adrenal axis. Diabetes 52: 605-613, 2003

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“…Although hypoglycemia in IDDM is mediated in part by overinsulinization, it is now appreciated that a deficient hormonal counterregulatory response to hypoglycemia is a key pathogenic factor (8)(9)(10)(11)(12). IDDM patients lose their capacity to release glucagon during hypoglycemia relatively early in the course of the disease ( 13), and as a result, are dependent on epinephrine to reverse hypoglycemia (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Impaired hormonal responses to hypoglycemia in spontaneously diabetic and recurrently hypoglycemic rats. Reversibility and stimulus specificity of the deficits.

Powell¹,

Sherwin²,

Shulman³

1993

J. Clin. Invest.

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To evaluate the roles of iatrogenic hypoglycemia and diabetes per se in the pathogenesis of defective hormonal counterregulation against hypoglycemia in insulin-dependent diabetes mellitus (IDDM), nondiabetic, and spontaneously diabetic BB/ Wor rats were studied using a euglycemic/hypoglycemic clamp. In nondiabetic rats, recurrent (4 wk) insulin-induced hypoglycemia (mean daily glucose, MDG, 59 mg/dl) dramatically reduced glucagon and epinephrine responses by 84 and 94%, respectively, to a standardized glucose fall from 110 to 50 mg/dl. These deficits persisted for > 4 d after restoring normoglycemia, and were specific for hypoglycemia, with normal glucagon and epinephrine responses to arginine and hypovolemia, respectively. After 4 wk of normoglycemia, hormonal counterregulation increased, with the epinephrine, but not the glucagon response reaching control values. In diabetic BB rats (MDG 245 mg/dl with intermittent hypoglycemia), glucagon and epinephrine counterregulation were reduced by 86 and 90%, respectively. Chronic iatrogenic hypoglycemia (MDG 52 mg / dl) further suppressed counterregulation. Prospective elimination of hypoglycemia (MDG 432 mg/dl) improved, but did not normalize hormonal counterregulation. In diabetic rats, the glucagon defect appeared to be specific for hypoglycemia, whereas deficient epinephrine secretion also occurred during hypovolemia. We concluded that both recurrent hypoglycemia and the diabetic state independently lead to defective hormonal counterregulation. These data suggest that in IDDM iatrogenic hypoglycemia magnifies preexisting counterregulatory defects, thereby increasing the risk of severe hypoglycemia. (J. Clin. Invest. 1993. 92:2667-2674

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Overview of counterregulation and its abnormalities in diabetes mellitus and other conditions

Cited by 66 publications

References 146 publications

Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia.

Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia.

Role of Corticotrophin-Releasing Hormone in the Impairment of Counterregulatory Responses to Hypoglycemia

Impaired hormonal responses to hypoglycemia in spontaneously diabetic and recurrently hypoglycemic rats. Reversibility and stimulus specificity of the deficits.

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