Glucagon, With Insulin, Supports Postabsorptive Plasma Glucose
Glucagon, With Insulin, Supports Postabsorptive Plasma Glucose
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 · kg · min (lower than those used previously) provides basal insulin replacement and that a glucagon dose of 1.0 ng · kg · min underreplaces basal glucagon, we infused the somatostatin analog octreotide (30 ng · kg · min) (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 (± SE) plasma glucose decreased from 83 ± 1 to 63 ± 2 mg/dl at 60 min and then increased to 89 ± 3 mg/dl at 240 min. During isolated glucagon deficiency, plasma glucose decreased to hypoglycemic levels and was 55 ± 2 mg/dl at 240 min (P < 0.0001 vs. combined insulin and glucagon deficiency). Partial glucagon replacement raised plasma glucose to higher levels (P = 0.0469) during insulin deficiency and to higher levels (P = 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.
The prevalent view is that the postabsorptive plasma glucose concentration is maintained within the physiological range (˜70 mg/dl [3.9 mmol/l] to 110 mg/dl [6.1 mmol/l] in humans) by the interplay of the glucose-lowering action of insulin (specifically suppression of endogenous glucose production) and the glucose-raising action of glucagon (specifically stimulation of endogenous glucose production). It is supported, to varying degrees, by a body of evidence from studies of the effects of suppression of glucagon (and insulin among other actions) with somatostatin in experimental animals and humans, of immunoneutralization of glucagon, of defective glucagon biosynthesis, of diverse mutations and absent or reduced glucagon receptors in animals, and of glucagon antagonists in cells and animals. However, many of the studies interpreted to support a role for glucagon in maintenance of the postabsorptive plasma glucose concentration are open to alternative interpretations, and some lead to seemingly contradictory conclusions. Thus, the alternative view, postabsorptive glucoregulation predominantly or even exclusively by insulin, is plausible.
Studies of this issue in humans are limited and, in some instances, open to technical criticisms and are seemingly contradictory. 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 and the plasma glucose concentration, followed by an increase in glucose production and the plasma glucose concentration 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. Second, somatostatin infusion with putative insulin replacement was found to persistently reduce glucose production and the plasma glucose concentration in humans. That was interpreted to indicate that basal glucagon levels support postabsorptive endogenous glucose production and the plasma glucose concentration. However, that interpretation is predicated on the biological appropriateness of the putative basal insulin "replacement" dose used (0.20 mU · kg · min); 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. Third, administration of a glucagon antagonist did not reduce postabsorptive glucose production or the plasma glucose concentration in humans. Thus, a role of glucagon in maintenance of the postabsorptive plasma glucose concentration in humans has not been established convincingly.
In the current study, we used an updated version of the pancreatic (or islet) clamp technique to test the hypothesis that glucagon, in concert with insulin, supports the postabsorptive plasma glucose concentration in humans. We infused the potent somatostatin analog octreotide to suppress insulin and glucagon (and growth hormone) secretion and replaced growth hormone by infusion, over 4 h in healthy subjects on four occasions in random sequence: 1) with saline (combined insulin and glucagon deficiency), 2) with insulin replacement (isolated glucagon deficiency), 3) with partial glucagon replacement (insulin deficiency and partial glucagon deficiency), and 4) with insulin and partial glucagon replacement (partial glucagon deficiency).
Before initiating this study, we assessed putative insulin, glucagon, and growth hormone replacement doses in the absence of octreotide. Insulin has been infused peripherally in doses of 0.14, 0.15, 0.20, and 0.24 mU · kg · min to attempt to replace basal insulin levels during somatostatin infusion in human studies. However, we found these doses to be excessive. Insulin infusion in doses of 0.20 and 0.15 mU · kg · min (in the absence of somatostatin or octreotide) suppressed glucose production and caused hypoglycemia in healthy humans. A dose of 0.10 mU · kg · min raised peripheral insulin levels approximately twofold and, thus, likely approximated portal venous insulin concentrations and lowered glucose levels (and insulin secretion) only within the physiological range. It did not cause hypoglycemia. Indeed, it would likely have had less of a glucose-lowering effect in the absence of endogenous insulin secretion. Therefore, that insulin dose was used to replace insulin during octreotide infusion in the current study. Given the hypothesis we tested, it is critically important that glucagon not be overreplaced. We found that glucagon infused in a dose of 1.0 ng · kg · min (in the absence of somatostatin or octreotide) raised mean plasma glucagon concentrations by only 16% and did not alter glucose production or plasma glucose levels. Since that dose almost assuredly does not cause supraphysiological hepatic portal venous glucagon concentrations, it was used to intentionally underreplace glucagon during octreotide infusion in the current study.
Abstract and Introduction
Abstract
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 · kg · min (lower than those used previously) provides basal insulin replacement and that a glucagon dose of 1.0 ng · kg · min underreplaces basal glucagon, we infused the somatostatin analog octreotide (30 ng · kg · min) (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 (± SE) plasma glucose decreased from 83 ± 1 to 63 ± 2 mg/dl at 60 min and then increased to 89 ± 3 mg/dl at 240 min. During isolated glucagon deficiency, plasma glucose decreased to hypoglycemic levels and was 55 ± 2 mg/dl at 240 min (P < 0.0001 vs. combined insulin and glucagon deficiency). Partial glucagon replacement raised plasma glucose to higher levels (P = 0.0469) during insulin deficiency and to higher levels (P = 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.
Introduction
The prevalent view is that the postabsorptive plasma glucose concentration is maintained within the physiological range (˜70 mg/dl [3.9 mmol/l] to 110 mg/dl [6.1 mmol/l] in humans) by the interplay of the glucose-lowering action of insulin (specifically suppression of endogenous glucose production) and the glucose-raising action of glucagon (specifically stimulation of endogenous glucose production). It is supported, to varying degrees, by a body of evidence from studies of the effects of suppression of glucagon (and insulin among other actions) with somatostatin in experimental animals and humans, of immunoneutralization of glucagon, of defective glucagon biosynthesis, of diverse mutations and absent or reduced glucagon receptors in animals, and of glucagon antagonists in cells and animals. However, many of the studies interpreted to support a role for glucagon in maintenance of the postabsorptive plasma glucose concentration are open to alternative interpretations, and some lead to seemingly contradictory conclusions. Thus, the alternative view, postabsorptive glucoregulation predominantly or even exclusively by insulin, is plausible.
Studies of this issue in humans are limited and, in some instances, open to technical criticisms and are seemingly contradictory. 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 and the plasma glucose concentration, followed by an increase in glucose production and the plasma glucose concentration 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. Second, somatostatin infusion with putative insulin replacement was found to persistently reduce glucose production and the plasma glucose concentration in humans. That was interpreted to indicate that basal glucagon levels support postabsorptive endogenous glucose production and the plasma glucose concentration. However, that interpretation is predicated on the biological appropriateness of the putative basal insulin "replacement" dose used (0.20 mU · kg · min); 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. Third, administration of a glucagon antagonist did not reduce postabsorptive glucose production or the plasma glucose concentration in humans. Thus, a role of glucagon in maintenance of the postabsorptive plasma glucose concentration in humans has not been established convincingly.
In the current study, we used an updated version of the pancreatic (or islet) clamp technique to test the hypothesis that glucagon, in concert with insulin, supports the postabsorptive plasma glucose concentration in humans. We infused the potent somatostatin analog octreotide to suppress insulin and glucagon (and growth hormone) secretion and replaced growth hormone by infusion, over 4 h in healthy subjects on four occasions in random sequence: 1) with saline (combined insulin and glucagon deficiency), 2) with insulin replacement (isolated glucagon deficiency), 3) with partial glucagon replacement (insulin deficiency and partial glucagon deficiency), and 4) with insulin and partial glucagon replacement (partial glucagon deficiency).
Before initiating this study, we assessed putative insulin, glucagon, and growth hormone replacement doses in the absence of octreotide. Insulin has been infused peripherally in doses of 0.14, 0.15, 0.20, and 0.24 mU · kg · min to attempt to replace basal insulin levels during somatostatin infusion in human studies. However, we found these doses to be excessive. Insulin infusion in doses of 0.20 and 0.15 mU · kg · min (in the absence of somatostatin or octreotide) suppressed glucose production and caused hypoglycemia in healthy humans. A dose of 0.10 mU · kg · min raised peripheral insulin levels approximately twofold and, thus, likely approximated portal venous insulin concentrations and lowered glucose levels (and insulin secretion) only within the physiological range. It did not cause hypoglycemia. Indeed, it would likely have had less of a glucose-lowering effect in the absence of endogenous insulin secretion. Therefore, that insulin dose was used to replace insulin during octreotide infusion in the current study. Given the hypothesis we tested, it is critically important that glucagon not be overreplaced. We found that glucagon infused in a dose of 1.0 ng · kg · min (in the absence of somatostatin or octreotide) raised mean plasma glucagon concentrations by only 16% and did not alter glucose production or plasma glucose levels. Since that dose almost assuredly does not cause supraphysiological hepatic portal venous glucagon concentrations, it was used to intentionally underreplace glucagon during octreotide infusion in the current study.
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