Glucagon: Role in the Hyperglycemia of Diabetes Mellitus

Dobbs, R. E.; Sasaki, Hideo; Sasaki, Haruka; Faloona, Gerald R.; Valverde, Isabel; Baetens, D.; Orci, Lelio; Unger, Roger H

doi:10.1126/science.1089999

Cited by 226 publications

(108 citation statements)

References 18 publications

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“…Lack of insulin increases production of the glycemia-increasing hormone glucagon, an effect thought to underlie uncontrolled hy- perglycemia in T1D rodents (26) and humans (37). Pancreatic preproglucagon mRNA and glucagon levels as well as plasma glucagon levels were elevated in T1D-icv-PBS mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Fujikawa

Chuang

Sakata

et al. 2010

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

182

222

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Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulindeficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.brain | leptin monotherapy | glucose homeostasis | glucagon suppression A ccording to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million people in the United States alone. Regrettably, for reasons yet to be understood, the incidence of T1D has been increasing at an alarming annual rate of ∼3%, thus indicating that the number of patients with T1D is predicted to rise significantly in the future (1). T1D occurs as a consequence of pancreatic β-cell destruction leading to insulin deficiency, a defect that causes hyperglycemia, hyperglucagonemia, cachexia, ketoacidosis, and other abnormalities (2, 3). T1D is a deadly condition if not treated. Current life-saving interventions include daily insulin administration; insulin therapy reduces hyperglycemia, glycosylated hemoglobin, and cachexia and prevents or delays some T1D-associated morbidities (3, 4). However, even with insulin therapy, T1D secondary complications include debilitating and long-lasting conditions, such as heart disease, neuropathy, and hypertension (5-7). Moreover, probably because of insulin's lipogenic and cholesterologenic actions, longterm insulin treatment is suspected to underlie the increased ectopic lipid deposition (i.e., in nonadipose tissues) (8) and incidence of coronary artery disease (>90% after the age of 55 y) (9, 10) seen in patients with T1D. Furthermore, in part attributable to insulin's potent, fast-acting, glycemia-lowering effects, intensive insulin therapy significantly increases the risk for hypoglycemia, an event that is disabling and can even be fatal (3,(11...

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Section: Resultsmentioning

confidence: 99%

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Fujikawa

Chuang

Sakata

et al. 2010

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

182

222

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“…We had previously shown that hepatic overproduction of glucose, ketones, and other catabolic manifestations of insulin deficiency cannot occur in the absence of hyperglucagonemia (16). To determine if the antidiabetic effects of leptin might be mediated by glucagon suppression, which was suggested by Tuduri et al (17), we compared plasma glucagon in the four groups of diabetic mice.…”

Section: Resultsmentioning

confidence: 99%

Leptin therapy in insulin-deficient type I diabetes

Wang

Chen

Clark

et al. 2010

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

310

335

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In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, like insulin, normalizes the levels of a wide array of hepatic intermediary metabolites in multiple chemical classes, including acylcarnitines, organic acids (tricarboxylic acid cycle intermediates), amino acids, and acyl CoAs. In contrast to insulin monotherapy, however, leptin lowers both lipogenic and cholesterologenic transcription factors and enzymes and reduces plasma and tissue lipids. The results imply that leptin administration may have multiple short-and long-term advantages over insulin monotherapy for type 1 diabetes.glucagon suppression | lipid-lowering | metabolomics | cholesterol regulation | glucose regulation

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“…This indicates that the dosage may have been relatively low. Others (De Vane et al 1974;Dobbs et al 1975) have obtained greater depressions of glucagon concentrations with larger doses in other species. Furthermore, some of the remaining plasma IRG may represent intestinal glucagon.…”

Section: Discussionmentioning

confidence: 99%

Rates of Removal of Exogenous and Endogenous Glucagon From the Plasma of Sheep in Vivo

Brockman¹

1980

Aust. Jnl. Of Bio. Sci.

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The removal of exogenous and endogenous glucagon from plasma was determined in vivo in sheep weighing 53±1 (mean±s.e.) kg. Porcine glucagon was infused intravenously for 90 min. The metabolic clearance rates (MCR) were determined from plateau immunoreactive glucagon (IRG) concentrations in plasma and infusion rates of glucagon. The mean clearance rate (±s.e.) was 16·7±1·6 litres per hour (n = 20). Upon termination of the infusion, the decrease in IRG concentrations in plasma was determined. Least-squares regression analysis of non-linear functions indicated the data fit a two-component exponential function. The time constant for the rapid component of the plasma IRG disappearance function was -0·32±0·04 min-1 (mean±s.e.). The time constant for the slow component was -0·022±0·008 min-'. The rate of removal of endogenous glucagon was estimated during the infusion of somatostatin when glucagon secretion was inhibited. The time constants (mean±s.e., n = 8) for the decrease in IRG during somatostatin infusion were -0·42±0·08 and -0·003±0·002 min-' for fast and slow components, respectively. The time constants for the rapid components of exogenous and endogenous glucagon were not significantly different. This suggests that endogenous and exogenous glucagon are similarly removed from plasma.

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Glucagon: Role in the Hyperglycemia of Diabetes Mellitus

Cited by 226 publications

References 18 publications

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Leptin therapy in insulin-deficient type I diabetes

Rates of Removal of Exogenous and Endogenous Glucagon From the Plasma of Sheep in Vivo

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