Effects of Type 2 Diabetes on the Regulation of Hepatic Glucose Metabolism

Basu, Ananda; Shah, Pankaj; Nielsen, Michael Festersen; Basu, Rita; Rizza, Robert A.

doi:10.1136/jim-52-06-30

Cited by 21 publications

(19 citation statements)

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“…An increase in the glucagon/insulin ratio is likely an important determinant of the hyperglycemia seen in type 2 diabetes patients (6,7,19). Consistent with the importance of glucagon for fasting hyperglycemia, infusion of low doses of glucagon leads to the development of hyperglycemia (44), whereas suppression of glucagon secretion in the fasting state by somatostatin infusion significantly reduces hepatic glucose production (6).…”

Section: Glucagon and The Pathophysiology Of Type 2 Diabetesmentioning

confidence: 79%

Benefits and limitations of reducing glucagon action for the treatment of type 2 diabetes

Ali¹,

Drucker²

2009

American Journal of Physiology-Endocrinology and Metabolism

114

136

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Section: Glucagon and The Pathophysiology Of Type 2 Diabetesmentioning

confidence: 79%

Benefits and limitations of reducing glucagon action for the treatment of type 2 diabetes

Ali¹,

Drucker²

2009

American Journal of Physiology-Endocrinology and Metabolism

114

136

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“…In addition, we found that SITA treatment reduced the increased glucagon/insulin ratio that ensued rapidly after STZ injections, and, undoubtedly, this contributed to the glucose-lowering action of SITA in this model of diabetes. In diabetes, inappropriate glucagon secretion in fasting and postprandial states contributes to hyperglycaemia [16][17][18][19][20][21][22][23], besides impaired insulin secretion attributed to beta cell failure. Although we could not clarify the precise mechanism of how SITA reduced the relative glucagon secretion, we assume that SITA-mediated enhanced levels of endogenous active GLP-1 may have suppressed glucagon secretion from alpha cells, as previously reported [24].…”

Section: Dpp-4 Inhibition Alleviated the Reduction In Insulin Contentmentioning

confidence: 99%

Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice

et al. 2011

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Aims/hypothesis Incretins stimulate insulin secretion in a glucose-dependent manner but also promote pancreatic beta cell protection. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new glucose-lowering treatment that blocks incretin degradation by DPP-4. We assessed whether DPP-4 inhibition suppresses the progression to hyperglycaemia in a low-dose streptozotocin (STZ)-induced diabetic mouse model, and then investigated how DPP-4 inhibition affects islet function and morphology. Methods The DPP-4 inhibitor, des-fluoro-sitagliptin (SITA), was administered to mice during and after STZ injections, and in some mice also before STZ. Results In control mice, STZ resulted in hyperglycaemia associated with impaired insulin secretion and excess glucagon secretion. In SITA-treated STZ mice, these metabolic abnormalities were improved, particularly when SITA administration was initiated before STZ injections. We observed beta cell loss and dramatic alpha cell expansion associated with decreased insulin content and increased glucagon content after STZ administration. In SITA-treated mice, islet architecture and insulin content were preserved, and no significant increase in glucagon content was observed. After STZ exposure, beta cell apoptosis increased before hyperglycaemia, and SITA treatment reduced the number of apoptotic beta cells. Interestingly, alpha cell proliferation was observed in nontreated mice after STZ injection, but the proliferation was not observed in SITA-treated mice. Conclusions/interpretation Our results suggest that the ability of DPP-4 inhibition to suppress the progression to STZ-induced hyperglycaemia involves both alleviation of beta cell death and alpha cell proliferation.

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“…In addition, it has been shown that a lack of suppression of glucagon secretion contributes to postprandial hyperglycemia in subjects with type 2 diabetes, at least in part by altering glycogen metabolism (Shah et al, 2000). Although there are many potential factors responsible for the high rate of glucose production seen in the individual with diabetes, an increased portal vein concentration of glucagon is clearly a factor (Shah et al, 2000;Jiang and Zhang, 2003;Basu et al, 2004b). Therefore, new therapeutic agents capable of blocking the effect of glucagon on glucose production could be effective in lowering fasting hyperglycemia and reducing postprandial glucose excursions in people with type 2 diabetes.…”

mentioning

confidence: 99%

A Novel Glucagon Receptor Antagonist, NNC 25-0926, Blunts Hepatic Glucose Production in the Conscious Dog

Rivera¹,

Grueter²,

Edgerton³

et al. 2007

J Pharmacol Exp Ther

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Elevated glucagon is associated with fasting hyperglycemia in type 2 diabetes. We assessed the effects of the glucagon receptor antagonist (2R)-N- [4-({4-(1-cyclohexen-1-yl) [(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-2-hydroxy-balanine (NNC 25-0926) on hepatic glucose production (HPG) in vivo, using arteriovenous difference and tracer techniques in conscious dogs. The experiments consisted of equilibration (Ϫ140 to Ϫ40 min), control (40 -0 min), and experimental [0 -180 min, divided into P1 (0 -60 min) and P2 (60 -180 min)] periods. In P1, NNC 25-0926 was given intragastrically at 0 (veh), 10, 20, 40, or 100 mg/kg, and euglycemia was maintained. In P2, somatostatin, basal intraportal insulin, and 5-fold basal intraportal glucagon (2.5 ng/kg/min) were infused. Arterial plasma insulin levels remained basal throughout the study in all groups. Arterial plasma glucagon levels remained basal during the control period and P1 and then increased to ϳ70 pg/ml in P2 in all groups. Arterial plasma glucose levels were basal in the control period and P1 in all groups. In P2, the arterial glucose level increased to 245 Ϯ 22 and 172 Ϯ 15 mg/dl in the veh and 10 mg/kg groups, respectively, whereas in the 20, 40, and 100 mg/kg groups, there was no rise in glucose. Net hepatic glucose output was ϳ2 mg/kg/min in all groups during the control period. In P2, it increased by 9.4 Ϯ 2 mg/kg/min in the veh group. In the 10, 20, 40, and 100 mg/kg groups, the rise was only 4.1 Ϯ 0.9, 1.6 Ϯ 0.6, 2.4 Ϯ 0.7, and 1.5 Ϯ 0.3 mg/kg/min, respectively, due to inhibition of glycogenolysis. In conclusion, NNC 25-0926 effectively blocked the ability of glucagon to increase HGP in the dog.Glucagon is secreted by the ␣ cells of the pancreas into the hepatic portal vein, thus exposing the liver to higher levels of the hormone than nonhepatic tissues. Plasma glucagon levels decrease in response to hyperglycemia, hyperinsulinemia, elevated plasma nonesterified fatty acid levels, and somatostatin (Ravier and Rutter, 2005;Young, 2005). Glucagon secretion is increased in response to hypoglycemia and elevated plasma amino acid levels (Burcelin et al., 1996;Cherrington, 1999;Jiang and Zhang, 2003;Young, 2005). The main physiological role of glucagon is to stimulate hepatic glucose production by activating glycogenolysis and gluconeogenesis, although its effect on the latter process is limited by its inability to increase gluconeogenic substrate delivery to the liver (Cherrington, 1999).Diabetes is characterized by fasting hyperglycemia and/or abnormal postprandial glycemia (Basu et al., 2004a,b). These abnormalities are associated with increased glucose production, which is the result of both glycogenolysis and gluconeogenesis. Several studies have shown that gluconeogenesis is increased in diabetes due to an increase in the availability of gluconeogenic amino acids, a rise in lipolysis, and the resulting elevation in free fatty acids and glycerol levels (Consoli et al., 1990;Puhakainen et al., 1992;Gastaldelli et al., 2000). Another contrib...

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Effects of Type 2 Diabetes on the Regulation of Hepatic Glucose Metabolism

Cited by 21 publications

References 0 publications

Benefits and limitations of reducing glucagon action for the treatment of type 2 diabetes

Benefits and limitations of reducing glucagon action for the treatment of type 2 diabetes

Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice

A Novel Glucagon Receptor Antagonist, NNC 25-0926, Blunts Hepatic Glucose Production in the Conscious Dog

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