Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man.

Liljenquist, John E.; Mueller, Guenter; Cherrington, Alan D.; Keller, Ulrich; Chiasson, J. L.; Perry, James M.; Lacy, William W.; Rabinowitz, D.

doi:10.1172/jci108649

Cited by 154 publications

(66 citation statements)

References 22 publications

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“…Not only is the liver very sensitive to changes in plasma glucagon, it also responds rapidly, with a half-maximal activation time of only 8 minutes (27). Human studies, although less well controlled, confirmed that the observations made in the dog extend to man (22)(23)(24)(25)(28)(29)(30). Thus, it is evident that after an overnight fast, basal levels of glucagon drive resting glucose production, thereby allowing insulin to link hepatic glucose output to the body's need for glucose.…”

Section: Metabolic Credentialsmentioning

confidence: 95%

“…It is worth noting that glucose tolerance is not altered in muscle-specific insulin receptor KO mice (83) or in whole-body Glut4-null mice (84). In the normal dog and human, on the other hand, when insulin and glucagon secretion were simultaneously made deficient using somatostatin (30,85), insulin lack resulted in a significant decrease in glucose clearance and a consequent doubling of the plasma glucose level. Thus, in large mammals, the effect of insulin deficiency on muscle glucose uptake - at least acutely - is apparent even in the face of glucagon lack.…”

Section: Glucagonocentrism: Insulin Actions Are Mediated By Glucagonsmentioning

confidence: 99%

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Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

2012

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The hormone glucagon has long been dismissed as a minor contributor to metabolic disease. Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence: (a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency; (b) hyperglucagonemia is present in every form of poorly controlled diabetes; (c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency; (d) total β cell destruction in glucagon receptor-null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia. From this and other evidence, we conclude that glucose-responsive β cells normally regulate juxtaposed α cells and that without intraislet insulin, unregulated α cells hypersecrete glucagon, which directly causes the symptoms of diabetes. This indicates that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy.Conflict of interest: Alan D.

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Section: Metabolic Credentialsmentioning

confidence: 95%

Section: Glucagonocentrism: Insulin Actions Are Mediated By Glucagonsmentioning

confidence: 99%

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

2012

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“…Glucagon is the primary controller of hepatic glucose production in the sedentary state (Liljenquist et al, 1977). Exercise is a robust challenge of the processes involved because of the high rates of glucose production necessary to maintain blood glucose (Wasserman, 2009).…”

Section: Control Of Muscle Glucose Influx During Exercisementioning

confidence: 99%

The physiological regulation of glucose flux into musclein vivo

Wasserman

Ayala

et al. 2011

Journal of Experimental Biology

137

106

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Summary Skeletal muscle glucose uptake increases dramatically in response to physical exercise. Moreover, skeletal muscle comprises the vast majority of insulin-sensitive tissue and is a site of dysregulation in the insulin-resistant state. The biochemical and histological composition of the muscle is well defined in a variety of species. However, the functional consequences of muscle biochemical and histological adaptations to physiological and pathophysiological conditions are not well understood. The physiological regulation of muscle glucose uptake is complex. Sites involved in the regulation of muscle glucose uptake are defined by a three-step process consisting of: (1) delivery of glucose to muscle, (2) transport of glucose into the muscle by GLUT4 and (3) phosphorylation of glucose within the muscle by a hexokinase (HK). Muscle blood flow, capillary recruitment and extracellular matrix characteristics determine glucose movement from the blood to the interstitium. Plasma membrane GLUT4 content determines glucose transport into the cell. Muscle HK activity, cellular HK compartmentalization and the concentration of the HK inhibitor glucose 6-phosphate determine the capacity to phosphorylate glucose. Phosphorylation of glucose is irreversible in muscle; therefore, with this reaction, glucose is trapped and the uptake process is complete. Emphasis has been placed on the role of the glucose transport step for glucose influx into muscle with the past assertion that membrane transport is rate limiting. More recent research definitively shows that the distributed control paradigm more accurately defines the regulation of muscle glucose uptake as each of the three steps that define this process are important sites of flux control.

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“…First, the glycemic response to suppression of both endogenous insulin and glucagon (among other effects) with somatostatin is biphasic, with an initial transient decrease in glucose production (3)(4)(5) and the plasma glucose concentration (4 -6), followed by an increase in glucose production (3)(4)(5) and the plasma glucose concentration (4 -6) in healthy humans. 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.…”

Section: Conclusion-thesementioning

confidence: 99%

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

et al. 2007

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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.

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Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man.

Cited by 154 publications

References 22 publications

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

The physiological regulation of glucose flux into musclein vivo

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

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