Hypoglycemic effect of combined ghrelin and glucagon receptor blockade

Bharath K. Mani, Aki Uchida, Young Lee, Sherri Osborne-Lawrence, Maureen J. Charron, Roger H. Unger, Eric D. Berglund, Jeffrey M. Zigman

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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 beta;-cell toxin streptozotocin induced hyperglycemia and raised plasma ghrelin levels in wild-typemice, 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.

Original languageEnglish (US)
Pages (from-to)1847-1857
Number of pages11
JournalDiabetes
Volume66
Issue number7
DOIs
StatePublished - Jul 1 2017

Fingerprint

Glucagon Receptors
Ghrelin Receptor
Ghrelin
Hypoglycemic Agents
Blood Glucose
Streptozocin
Glucagon
Knockout Mice
Hyperglycemia
Type 1 Diabetes Mellitus
Hypoglycemia
Monoclonal Antibodies
Insulin
Hormones
Glucose

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Mani, B. K., Uchida, A., Lee, Y., Osborne-Lawrence, S., Charron, M. J., Unger, R. H., ... Zigman, J. M. (2017). Hypoglycemic effect of combined ghrelin and glucagon receptor blockade. Diabetes, 66(7), 1847-1857. https://doi.org/10.2337/db16-1303

Hypoglycemic effect of combined ghrelin and glucagon receptor blockade. / Mani, Bharath K.; Uchida, Aki; Lee, Young; Osborne-Lawrence, Sherri; Charron, Maureen J.; Unger, Roger H.; Berglund, Eric D.; Zigman, Jeffrey M.

In: Diabetes, Vol. 66, No. 7, 01.07.2017, p. 1847-1857.

Research output: Contribution to journalArticle

Mani, BK, Uchida, A, Lee, Y, Osborne-Lawrence, S, Charron, MJ, Unger, RH, Berglund, ED & Zigman, JM 2017, 'Hypoglycemic effect of combined ghrelin and glucagon receptor blockade', Diabetes, vol. 66, no. 7, pp. 1847-1857. https://doi.org/10.2337/db16-1303
Mani BK, Uchida A, Lee Y, Osborne-Lawrence S, Charron MJ, Unger RH et al. Hypoglycemic effect of combined ghrelin and glucagon receptor blockade. Diabetes. 2017 Jul 1;66(7):1847-1857. https://doi.org/10.2337/db16-1303
Mani, Bharath K. ; Uchida, Aki ; Lee, Young ; Osborne-Lawrence, Sherri ; Charron, Maureen J. ; Unger, Roger H. ; Berglund, Eric D. ; Zigman, Jeffrey M. / Hypoglycemic effect of combined ghrelin and glucagon receptor blockade. In: Diabetes. 2017 ; Vol. 66, No. 7. pp. 1847-1857.
@article{0100dfe26b674e63a06f4f2100cad5d2,
title = "Hypoglycemic effect of combined ghrelin and glucagon receptor blockade",
abstract = "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 beta;-cell toxin streptozotocin induced hyperglycemia and raised plasma ghrelin levels in wild-typemice, 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.",
author = "Mani, {Bharath K.} and Aki Uchida and Young Lee and Sherri Osborne-Lawrence and Charron, {Maureen J.} and Unger, {Roger H.} and Berglund, {Eric D.} and Zigman, {Jeffrey M.}",
year = "2017",
month = "7",
day = "1",
doi = "10.2337/db16-1303",
language = "English (US)",
volume = "66",
pages = "1847--1857",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "7",

}

TY - JOUR

T1 - Hypoglycemic effect of combined ghrelin and glucagon receptor blockade

AU - Mani, Bharath K.

AU - Uchida, Aki

AU - Lee, Young

AU - Osborne-Lawrence, Sherri

AU - Charron, Maureen J.

AU - Unger, Roger H.

AU - Berglund, Eric D.

AU - Zigman, Jeffrey M.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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 beta;-cell toxin streptozotocin induced hyperglycemia and raised plasma ghrelin levels in wild-typemice, 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.

AB - 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 beta;-cell toxin streptozotocin induced hyperglycemia and raised plasma ghrelin levels in wild-typemice, 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.

UR - http://www.scopus.com/inward/record.url?scp=85021134983&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021134983&partnerID=8YFLogxK

U2 - 10.2337/db16-1303

DO - 10.2337/db16-1303

M3 - Article

VL - 66

SP - 1847

EP - 1857

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 7

ER -