Epinephrine supports the postabsorptive plasma glucose concentration and prevents hypoglycemia when glucagon secretion is deficient in man.

Rosen, S. G.; Clutter, William E.; Berk, Michael; Shah, Suresh D.; Cryer, Philip E.

doi:10.1172/jci111226

Cited by 40 publications

(19 citation statements)

References 40 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These include studies of the impacts of suppression of endogenous glucagon secretion in experimental animals (5) and humans (40), immunoneutralization of glucagon (3), defective synthesis of biologically active glucagon (12, 49), diverse mutations (1, 17, 25, 26), and absent (13, 32) or reduced (21, 45) glucagon receptors in experimental animals and of glucagon antagonists in experimental animals (19), cells (33), and humans (35).…”

Section: Evidence For the Prevalent Viewmentioning

confidence: 99%

Maintenance of the postabsorptive plasma glucose concentration: insulin or insulin plus glucagon?

Raju

Cryer

2005

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

The prevalent view is that the postabsorptive plasma glucose concentration is maintained within the physiological range by the interplay of the glucose-lowering action of insulin and the glucose-raising action of glucagon. It is supported by a body of evidence derived from studies of suppression of glucagon (and insulin, among other effects) with somatostatin in animals and humans, immunoneutralization of glucagon, defective glucagon synthesis, diverse mutations, and absent or reduced glucagon receptors in animals and glucagon antagonists in cells, animals, and humans. Many of these studies are open to alternative interpretations, and some lead to seemingly contradictory conclusions. For example, immunoneutralization of glucagon lowered plasma glucose concentrations in rabbits, but administration of a glucagon antagonist did not lower plasma glucose concentrations in healthy humans. Evidence that the glycemic threshold for glucagon secretion, unlike that for insulin secretion, lies below the physiological range, and the finding that selective suppression of insulin secretion without stimulation of glucagon secretion raises fasting plasma glucose concentrations in humans underscore the primacy of insulin in the regulation of the postabsorptive plasma glucose concentration and challenge the prevalent view. The alternative view is that the postabsorptive plasma glucose concentration is maintained within the physiological range by insulin alone, specifically regulated increments and decrements in insulin, and the resulting decrements and increments in endogenous glucose production, respectively, and glucagon becomes relevant only when glucose levels drift below the physiological range. Although the balance of evidence suggests that glucagon is involved in the maintenance of euglycemia, more definitive evidence is needed, particularly in humans. glucose metabolism; hypoglycemia; diabetes GIVEN EVIDENCE of absolute or relative hyperglucagonemia in patients with type 1 and type 2 diabetes (27,29,37,38), Unger and Orci (48) first proposed that glucagon, in the setting of absolute or relative insulin deficiency, plays a role in the pathogenesis of diabetes. Their bihormonal hypothesis was based on three lines of evidence: 1) endogenous hyperglycemia had never been observed in the absence of glucagon; 2) when both insulin and glucagon were suppressed with somatostatin, hyperglycemia did not occur; and 3) somatostatin-induced suppression of glucagon reduced glycemia in humans with diabetes. With respect to the last, somatostatin has been shown to reduce, but not normalize, fasting and postprandial hyperglycemia (15) and to delay increments in plasma glucose (as well as in plasma nonesterified fatty acids, glycerol, and ␤-hydroxybutyrate) concentrations following withdrawal of insulin in patients with type 1 diabetes (14). Although these findings are entirely consistent with a role of glucagon in the pathogenesis of hyperglycemia (and ketosis) in type 1 diabetes, control studies with somatostatin administration and replacem...

show abstract

Section: Evidence For the Prevalent Viewmentioning

confidence: 99%

Maintenance of the postabsorptive plasma glucose concentration: insulin or insulin plus glucagon?

Raju

Cryer

2005

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…During isolated glucagon deficiency (octreotide with growth hormone plus insulin replacement), plasma glucose concentrations decreased to hypoglycemic levels, as evidenced not only by the glucose levels but also by activation of adrenomedullary epinephrine secretion. Indeed, glucose levels would have undoubtedly fallen to lower levels were it not for activation of glucose counterregulatory systems, specifically increased epinephrine secretion (7). Since this dose of insulin, in the absence of octreotide, does not cause hypoglycemia (10), this finding provides direct evidence that glucagon supports the postabsorptive plasma glucose concentration in humans.…”

Section: Discussionmentioning

confidence: 84%

“…While these findings suggest an initial tonic effect of basal glucagon secretion to support the postabsorptive plasma glucose concentration, they suggest that suppression of insulin secretion is the dominant glycemic effect of somatostatin and, therefore, that insulin is the primary determinant of the postabsorptive plasma glucose concentration. Second, somatostatin infusion with putative insulin replacement was found to persistently reduce glucose production and the plasma glucose concentration in humans (7). That was interpreted to indicate that basal glucagon levels support postabsorptive endogenous glucose production and the plasma glucose concentration.…”

Section: Conclusion-thesementioning

confidence: 99%

“…However, that interpretation is predicated on the biological appropriateness of the putative basal insulin "replacement" dose used (0.20 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ); given the potency of the hormone, even slight insulin overreplacement alone (see below) could have caused the observed decrements in glucose production and plasma glucose. Furthermore, glucagon replacement, during somatostatin infusion without or with insulin replacement, was not studied to document a role for glucagon per se (7). Third, administration of a glucagon antagonist did not reduce postabsorptive glucose production or the plasma glucose concentration in humans (8).…”

Section: Conclusion-thesementioning

confidence: 99%

“…Insulin has been infused peripherally in doses of 0.14 (11), 0.15 (3), 0.20 (7,12), and 0.24 (13) mU ⅐ kg Ϫ1 ⅐ min Ϫ1 to attempt to replace basal insulin levels during somatostatin infusion in human studies. However, we found these doses to be excessive.…”

Section: Conclusion-thesementioning

confidence: 99%

See 2 more Smart Citations

Glucagon, in Concert With Insulin, Supports the Postabsorptive Plasma Glucose Concentration in Humans

et al. 2007

View full text Add to dashboard Cite

OBJECTIVE-Given the interest in glucagon antagonism as a potential treatment of diabetes, we tested the hypothesis that glucagon, in concert with insulin, supports the postabsorptive plasma glucose concentration in humans.RESEARCH DESIGN AND METHODS-Following preliminary studies that indicated that a peripheral intravenous insulin dose of 0.1 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 (lower than those used previously) provides basal insulin replacement and that a glucagon dose of 1.0 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 underreplaces basal glucagon, we infused the somatostatin analog octreotide (30 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) (with growth hormone replacement) over 4 h in 14 healthy adults on four separate occasions to produce endogenous insulin and glucagon deficiency with 1) saline (combined insulin and glucagon deficiency), 2) insulin replacement (isolated glucagon deficiency), 3) partial glucagon replacement (insulin and partial glucagon deficiency), and 4) insulin and partial glucagon replacement (partial glucagon deficiency).RESULTS-During combined insulin and glucagon deficiency, glucose production decreased and then increased, and mean (ϮSE) plasma glucose decreased from 83 Ϯ 1 to 63 Ϯ 2 mg/dl at 60 min and then increased to 89 Ϯ 3 mg/dl at 240 min. During isolated glucagon deficiency, plasma glucose decreased to hypoglycemic levels and was 55 Ϯ 2 mg/dl at 240 min (P Ͻ 0.0001 vs. combined insulin and glucagon deficiency). Partial glucagon replacement raised plasma glucose to higher levels (P ϭ 0.0469) during insulin deficiency and to higher levels (P ϭ 0.0090) during insulin replacement.CONCLUSIONS-These three findings provide direct evidence that glucagon, in concert with insulin, supports the postabsorptive plasma glucose concentration in humans.

show abstract

Hypoglycemia

Cryer¹,

Frier²

2003

International Textbook of Diabetes Mellitus

View full text Add to dashboard Cite

Iatrogenic hypoglycemia often causes recurrent morbidity and precludes maintenance of lifelong euglycemia in people with diabetes mellitus. It causes an array of neurogenic (autonomic) and neuroglycopenic symptoms, cardiovascular responses, neurophysiological changes and cognitive impairments, and, if severe and prolonged, death. It is the result of the interplay of exogenous or endogenous insulin excess and compromised physiological and behavioral defenses against falling glucose levels in type 1 diabetes and advanced type 2 diabetes. Absolute or relative insulin excess occurs when (1) insulin (or insulin secretagogue) doses are excessive, ill‐timed, or of the wrong type; (2) the intake of exogenous carbohydrate is decreased as following a missed meal or snack or during an overnight fast; (3) endogenous glucose production is decreased as following alcohol ingestion; (4) insulin‐independent glucose utilization is increased as during exercise; (5) sensitivity to insulin is increased as following exercise, in the middle of the night, during effective glycemic therapy, or following weight loss; (6) insulin clearance is decreased as with progressive renal insufficiency. However, insulin excess alone explains only a minority of episodes of severe hypoglycemia. Compromised defenses include defective glucose counterregulation (absent glucagon responses and reduced adrenaline responses) and impaired awareness of hypoglycemia (partial or complete loss of the warning symptoms of developing hypoglycemia that previously prompted the patient to eat and abort the episode). The concept of hypoglycemia‐associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation (by reducing the adrenaline response, in the setting of an absent glucagon response, to subsequent hypoglycemia) and impaired awareness of hypoglycemia (by reducing the autonomic response and the resultant symptomatic responses to subsequent hypoglycemia) and thus a vicious cycle of recurrent iatrogenic hypoglycemia. It has been supported by the discovery that as little as 2–3 weeks of scrupulous avoidance of hypoglycemia reverses impaired awareness and improves the adrenaline response in most affected patients. Risk factors for hypoglycemia‐associated autonomic failure include more marked insulin deficiency, a history of severe hypoglycemia, impaired awareness of hypoglycemia, or both and aggressive glycemic therapy per se as evidenced by lower mean glycemia (HbA 1c ), lower glycemic goals, or both. Prevention of iatrogenic hypoglycemia includes thorough patient education, partnership and ongoing professional support, regular self‐monitoring of blood glucose, individualized glycemic goals, and rational and flexible drug regimens. The latter include use of newer long‐acting and rapid‐acting insulin analogues in insulin‐deficient diabetes and perhaps of insulin sensitizers or relatively glucose‐dependent insulin secretagogues in those with sufficient residual endogenous insulin secretion. Oral carbohydrate or glucose is sufficient to treat most episodes, but parenteral glucagon or intravenous glucose is often necessary for severe episodes. Such short‐term treatments must be followed by regimen adjustments designed to prevent recurrent hypoglycemia, often including a period of scrupulous avoidance of iatrogenic hypoglycemia. Ultimately we need to learn to replace insulin in a much more physiological fashion, to prevent, correct, or compensate for compromised glucose counterregulation, or both if we are to achieve euglycemia safely over a lifetime of diabetes.

show abstract

Epinephrine supports the postabsorptive plasma glucose concentration and prevents hypoglycemia when glucagon secretion is deficient in man.

Cited by 40 publications

References 40 publications

Maintenance of the postabsorptive plasma glucose concentration: insulin or insulin plus glucagon?

Maintenance of the postabsorptive plasma glucose concentration: insulin or insulin plus glucagon?

Glucagon, in Concert With Insulin, Supports the Postabsorptive Plasma Glucose Concentration in Humans

Hypoglycemia

Contact Info

Product

Resources

About