Glucagon receptor antagonism induces increased cholesterol absorption

Guan, Hong-Ping; Yang, Xiaodong; Lu, Ku; Wang, Shengping; Castro-Perez, José; Previs, Stephen F.; Wright, Michael; Shah, Vinit; Herath, Kithsiri; Xie, Dan; Szeto, Daphne; Forrest, Gail; Xiao, Jing; Palyha, Oksana; Sun, Liping; Andryuk, Paula J.; Engel, Samuel S.; Xiong, Yusheng; Lin, Songnian; Kelley, David E.; Erion, Mark D.; Davis, Harry R.; Wang, Liangsu

doi:10.1194/jlr.m060897

Cited by 67 publications

(57 citation statements)

References 55 publications

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“…However, although this drug exhibited little risk of hypoglycemia, it was associated with a small increase in LDL cholesterol and aminotransferase levels. A similar increase in LDL cholesterol levels was observed in clinical trials of MK-0893, resulting in discontinuation of this agent 38,39 . While an initial short-term clinical study with LY2409021 (Eli Lilly) showed encouraging decreases in fasting and postprandial glucose levels, they also raised concerns due to a rise in aminotransferases 40 .…”

Section: Strategies To Modulate Liver Glucose and Glycogen Metabolismsupporting

confidence: 67%

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Rines

Sharabi

Tavares

et al. 2016

Nat Rev Drug Discov

295

244

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Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis resulting in hyperglycemia. Although current diabetes treatments have exhibited some success in lowering blood glucose, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycemia. Novel diabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver in order to normalize blood glucose levels has not been fully exploited. Here, we review the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, and assess the prospect of therapeutically targeting associated pathways to treat type 2 diabetes.

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Section: Strategies To Modulate Liver Glucose and Glycogen Metabolismsupporting

confidence: 67%

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Rines

Sharabi

Tavares

et al. 2016

Nat Rev Drug Discov

295

244

View full text Add to dashboard Cite

show abstract

“…There are many studies showing the efficacy of inhibitory glucagon receptor antibodies to improve glucose tolerance in preclinical models and in some clinical studies (12,(53)(54)(55). Thus, the concept of targeting glucagon action to achieve hepatic insulin sensitivity and glucose lowering is well accepted (14), even though current methods of glucagon receptor inhibition may have unwanted side effects (56). Using hyperinsulinemic-euglycemic clamp studies, we determined that chronic FKN-Fc treatment specifically improves hepatic improve glucose tolerance without changing body weight.…”

Section: Discussionmentioning

confidence: 99%

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function

Riopel

Seo

Bandyopadhyay

et al. 2018

Journal of Clinical Investigation

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“…In addition, Gcgr −/− mice exhibit both high plasma GLP-1 and fibroblast growth factor 21 levels, both of which have been implicated in protecting STZ-treated Gcgr −/− mice from developing hyperglycemia (3,24,48). Rodent models and humans in which GcgR mAb or GcgR antagonists have been administered also exhibit high plasma GLP-1 levels (5,27,51,52). Although GLP-1 has been shown to suppress ghrelin secretion in human subjects indirectly via stimulating insulin secretion (53), the higher ghrelin levels found within Gcgr −/− mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Hypoglycemic Effect of Combined Ghrelin and Glucagon Receptor Blockade

et al. 2017

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Glucagon receptor (GcgR) blockade has been proposed as an alternative to insulin monotherapy for treating type 1 diabetes since deletion or inhibition of GcgRs corrects hyperglycemia in models of diabetes. The factors regulating glycemia in a setting devoid of insulin and glucagon function remain unclear but may include the hormone ghrelin. Not only is ghrelin release controlled by glucose but also ghrelin has many actions that can raise or reduce falls in blood glucose level. Here, we tested the hypothesis that ghrelin rises to prevent hypoglycemia in the absence of glucagon function. Both GcgR knockout (Gcgr−/−) mice and db/db mice that were administered GcgR monoclonal antibody displayed lower blood glucose levels accompanied by elevated plasma ghrelin levels. Although treatment with the pancreatic β-cell toxin streptozotocin induced hyperglycemia and raised plasma ghrelin levels in wild-type mice, hyperglycemia was averted in similarly treated Gcgr−/− mice and the plasma ghrelin level was further increased. Notably, administration of a ghrelin receptor antagonist further reduced blood glucose levels into the markedly hypoglycemic range in overnight-fasted, streptozotocin-treated Gcgr−/− mice. A lowered blood glucose level also was observed in overnight-fasted, streptozotocin-treated ghrelin receptor–null mice that were administered GcgR monoclonal antibody. These data suggest that when glucagon activity is blocked in the setting of type 1 diabetes, the plasma ghrelin level rises, preventing hypoglycemia.

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Glucagon receptor antagonism induces increased cholesterol absorption

Cited by 67 publications

References 55 publications

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function

Hypoglycemic Effect of Combined Ghrelin and Glucagon Receptor Blockade

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