Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival

Neumann, Ursula; Ho, Jessica S.S.; Mahdavi, Majid; Covey, Scott D.; Charron, Maureen J.; Kieffer, Timothy J.

doi:10.1016/j.molmet.2016.05.014

Cited by 25 publications

(20 citation statements)

References 18 publications

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Section: Discussionmentioning

confidence: 66%

“…Studies in glucagon receptor knockout mice rendered insulin deficient by streptozotocin have firmly demonstrated the metabolic benefits of absence of glucagon action without insulin administration. [18][19][20] In addition, we have shown in mice with near absence of insulin receptor signaling that REGN1193 treatment is able to lower glucose to near normal ranges. 21 Thus, patients with insulin receptor loss of function mutations, manifested as severe insulin resistance and diabetes, ie, Rabson-Mendenhall syndrome and other related diseases, may benefit from anti-glucagon receptor therapy.…”

Section: Discussionmentioning

confidence: 83%

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A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

Kostić

King

Yang

et al. 2017

Diabetes Obesity Metabolism

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AimsGlucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first‐in‐human healthy volunteer randomized double‐blinded trial.MethodsHealthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose‐lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges.ResultsREGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose‐dependent increases in hepatic aminotransferases. No increase in LDL‐C was observed. Hypoglycaemia, assessed as laboratory blood glucose ≤70 mg/dL, occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration‐time profiles suggest a 2‐compartment disposition and marked nonlinearity, consistent with target‐mediated clearance. REGN1193 inhibited the glucagon‐stimulated glucose increase in a dose‐dependent manner. The 0.6 mg/kg dose inhibited the glucagon‐induced glucose area under the curve for 0 to 90 minutes (AUC0‐90 minutes) by 80% to 90% on days 3 and 15, while blunting the increase in C‐peptide. REGN1193 dose‐dependently increased total GLP‐1, GLP‐2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups.ConclusionREGN1193, a GCGR‐blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggests an on‐target effect of glucagon receptor blockade. The underlying mechanism is unknown.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 83%

A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

Kostić

King

Yang

et al. 2017

Diabetes Obesity Metabolism

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“…In particular, genetic deletion of insulin (49) or the use of diphtheria toxin to induce near complete ablation of β-cells (50) in Gcgr −/− mice nonetheless induced full-blown diabetes. Thus, it has been suggested that a retained low level of insulin, as occurs in the STZ type 1 diabetes model, may be permissive for the blood glucose–lowering effect observed with GcgR antagonism.…”

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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“…Plasma levels of glucagon are aberrantly increased in individuals with T2DM 171–174 . In addition, animal models of reduced or ablated glucagon action show improvements in T2DM 96,175,176 (FIG. 4a,b).…”

Section: Targeting Hepatic Glucose Productionmentioning

confidence: 99%

Regulation of hepatic glucose metabolism in health and disease

2017

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The liver is crucial for the maintenance of normal glucose homeostasis — it produces glucose during fasting and stores glucose postprandially. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Net hepatic glucose production is the summation of glucose fluxes from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis and other pathways. In this Review, we discuss the in vivo regulation of these hepatic glucose fluxes. In particular, we highlight the importance of indirect (extrahepatic) control of hepatic gluconeogenesis and direct (hepatic) control of hepatic glycogen metabolism. We also propose a mechanism for the progression of subclinical hepatic insulin resistance to overt fasting hyperglycaemia in type 2 diabetes mellitus. Insights into the control of hepatic gluconeogenesis by metformin and insulin and into the role of lipid-induced hepatic insulin resistance in modifying gluconeogenic and net hepatic glycogen synthetic flux are also discussed. Finally, we consider the therapeutic potential of strategies that target hepatosteatosis, hyperglucagonaemia and adipose lipolysis.

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Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival

Cited by 25 publications

References 18 publications

A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

Hypoglycemic Effect of Combined Ghrelin and Glucagon Receptor Blockade

Regulation of hepatic glucose metabolism in health and disease

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