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

2009 ◽  
Vol 296 (3) ◽  
pp. E415-E421 ◽  
Author(s):  
Safina Ali ◽  
Daniel J. Drucker
Keyword(s):  
Type 2 Diabetes ◽  
Therapeutic Potential ◽  
Receptor Gene ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucagon Receptor ◽  
Hepatic Glucose ◽  
Extrahepatic Tissues ◽  
Glucagon Receptor Gene

Glucagon is secreted from the α-cells of the pancreatic islets and regulates glucose homeostasis through modulation of hepatic glucose production. As elevated glucagon levels contribute to the pathophysiology of hyperglycemia in subjects with type 2 diabetes, reduction of glucagon receptor gene (Gcgr) activity represents a potential target for the treatment of T2DM. Herein, we review current concepts of glucagon action in hepatic and extrahepatic tissues and evaluate the therapeutic potential, mechanisms of action, and safety of reducing Gcgr signaling for the treatment of T2DM.

scholarly journals Novel liver-specific TORC2 siRNA corrects hyperglycemia in rodent models of type 2 diabetes

2009 ◽  
Vol 297 (5) ◽  
pp. E1137-E1146 ◽  
Author(s):  
Maziyar Saberi ◽  
David Bjelica ◽  
Simon Schenk ◽  
Takeshi Imamura ◽  
Gautam Bandyopadhyay ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Primary Mouse Hepatocytes ◽  
Primary Mouse ◽  
Hepatic Glucose ◽  
Zdf Rats ◽  
Mouse Hepatocytes

The transcription factor TORC2 [transducer of regulated cAMP-responsive element-binding protein (CREB) activity 2] is a major regulator of hepatic gluconeogenesis and is increased in hyperglycemic rodent models. Because chronic hyperglycemia and increased hepatic glucose production, via increased gluconeogenesis, is a key feature of type 2 diabetes, an effective in vivo method to efficiently knock down TORC2 could provide a potential therapy for treating hyperglycemia and type 2 diabetes. To assess this, primary mouse hepatocytes, high-fat diet (HFD)-fed mice, and Zucker diabetic fatty (ZDF) rats were treated with a siRNA against TORC2 (siTORC2), which was delivered via a novel lipid nanoparticle system, or control siRNA (siCON). Compared with siCON, administration of siTORC2 resulted in highly efficient, sustained (1–3 wk) knockdown of TORC2 and its gluconeogenic target genes phospho enolpyruvate carboxykinase and glucose-6-phophatase in primary mouse hepatocytes and in the livers of HFD-fed mice. In mice, this knockdown was specific to the liver and did not occur in kidney, skeletal muscle, or adipose tissue. In HFD-fed mice, siTORC2 reduced in vivo gluconeogenic capacity, fasting hepatic glucose production, and hyperglycemia, and led to improved hepatic and skeletal muscle insulin sensitivity. siTORC2 treatment also improved systemic hyperglycemia in ZDF rats. In conclusion, these results demonstrate the importance of TORC2 in modulating HGP in vivo and highlight a novel, liver-specific siRNA approach for the potential treatment of hyperglycemia and type 2 diabetes.

scholarly journals Phenotypic and Molecular Evaluation of a Chromosome 1q Region with Linkage and Association to Type 2 Diabetes in Humans

2009 ◽  
Vol 94 (4) ◽  
pp. 1401-1408 ◽  
Author(s):  
Hua Wang ◽  
Nicholas P. Hays ◽  
Swapan K. Das ◽  
Rebekah L. Craig ◽  
Winston S. Chu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Hepatic Glucose Production ◽  
Linkage Disequilibrium Block ◽  
Glucose Production ◽  
Risk Haplotype ◽  
Expression Of Genes ◽  
Hepatic Glucose

Abstract Objective: Linkage to type 2 diabetes (T2D) is well replicated on chromosome 1q21-q23. Within this region, T2D was associated with common single nucleotide polymorphisms that marked an extended linkage disequilibrium block, including the liver pyruvate kinase gene (PKLR), in several European-derived populations. In this study we sought to determine the molecular basis for the association and the phenotypic consequences of the risk haplotype. Research Design and Methods: Genes surrounding PKLR were resequenced in European-American and African-American cases and controls, and association with T2D was tested. Copy number variants (CNVs) were tested for four regions with real-time PCR. Expression of genes in the region was tested in adipose and muscle from nondiabetic subjects with each genotype. Insulin secretion, insulin sensitivity, and hepatic glucose production were tested in nondiabetic individuals with each haplotype combination. Results: No coding variant in the region was associated with T2D. CNVs were rare and not associated with T2D. PKLR was not expressed in available tissues, but expression of genes HCN3, CLK2, SCAMP3, and FDPS was not associated with haplotype combinations in adipose or muscle. Haplotype combinations were not associated with insulin secretion or peripheral insulin sensitivity, but homozygous carriers of the risk haplotype had increased hepatic glucose production during hyperinsulinemia. Conclusions: Noncoding variants in the PKLR region likely alter gene expression of one or more genes. Our extensive physiological and molecular studies suggest increased hepatic glucose production and reduced hepatic insulin sensitivity, thus pointing to PKLR itself as the most likely candidate gene in this population.

Role of the Gly40Ser Mutation in the Glucagon Receptor Gene in Brazilian Patients With Type 2 Diabetes Mellitus

Pancreas ◽  
2002 ◽  
Vol 24 (4) ◽  
pp. 386-390 ◽  
Author(s):  
Debora Shiota ◽  
Teresa Kasamatsu ◽  
Sergio A. Dib ◽  
Antonio R. Chacra ◽  
Regina S. Moisés
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Receptor Gene ◽  
Glucagon Receptor ◽  
Glucagon Receptor Gene

scholarly journals Cell Autonomous Dysfunction and Insulin Resistance in Pancreatic α Cells

2019 ◽  
Vol 20 (15) ◽  
pp. 3699 ◽  
Author(s):  
Norikiyo Honzawa ◽  
Kei Fujimoto ◽  
Tadahiro Kitamura
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Current Knowledge ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Hepatic Glucose

To date, type 2 diabetes is considered to be a “bi-hormonal disorder” rather than an “insulin-centric disorder,” suggesting that glucagon is as important as insulin. Although glucagon increases hepatic glucose production and blood glucose levels, paradoxical glucagon hypersecretion is observed in diabetes. Recently, insulin resistance in pancreatic α cells has been proposed to be associated with glucagon dysregulation. Moreover, cell autonomous dysfunction of α cells is involved in the etiology of diabetes. In this review, we summarize the current knowledge about the physiological and pathological roles of glucagon.

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