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 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.

Ghrelin as a Survival Hormone

“…Although the ghrelin system contributes to hyperglycemia and/or hyperphagia in various pathological states linked to diabetes, including leptin deficiency, MODY3, and streptozotocin (STZ) administration [76–78], the blood glucose-raising actions of ghrelin seems more likely to have developed as a defensive strategy, to protect against life-threatening hypoglycemia and to prolong survival (Figure 2, Box 1). Following their initial report on the discovery of GOAT, Drs.…”

“…For instance, hypoglycemia is induced in 24 h-fasted 3 week-old mice, but not in 24 h-fasted adult mice upon blockade of ghrelin secretion with a β-blocker, suggesting that neonates and infants may be more dependent on the blood glucose protective actions of ghrelin than adults [32]. Regarding the availability of other counterregulatory hormones, whereas glucagon receptor genetic deletion prevents the hyperglycemia induced by STZ, the concomitant increase in plasma ghrelin acts in that setting to block the development of hypoglycemia, as administration of a GHSR antagonist further reduces blood glucose levels into the markedly hypoglycemic range in overnight-fasted, STZ-treated glucagon receptor-knockout mice [78]. …”

LEAP2 changes with body mass and food intake in humans and mice

“…Plasma acyl-ghrelin is regulated at least in part by metabolic status. In both humans and rodents, plasma acyl-ghrelin increases during short-term fasting and declines during obese states (1,(10)(11)(12)(13)(14)(15). Plasma acyl-ghrelin also increases in chronic energy-restricted states in rodents, although in humans, prolonged fasting results in a decline in plasma acyl-ghrelin (13,(15)(16)(17).…”

Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemia

“…Reduced GCGR signaling also leads to altered levels of multiple humoral factors important in the control of glucose. Hence, Gcgr −/− mice have increased ghrelin levels even during insulinopenic conditions due to STZ treatment [19] , and this may contribute to the prevention of hypoglycemia. On the other hand, loss of Gcgr results in supraphysiological increases in Fibroblast Growth factor 21 (FGF21) [6] and GLP-1 [2] , hormones that each have glucose-lowering properties.…”