Abstract
Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes mellitus (T2DM), plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis and hyperglycemia. Therefore, glucagon receptor (GCGR) antagonism has been proposed as a pharmacologic approach to treat T2DM. In support of this concept, a potent small-molecule GCGR antagonist (GRA), MK-0893, demonstrated dose-dependent efficacy to reduce hyperglycemia, with an HbA1c reduction of 1.5% at the 80 mg dose for 12 weeks in T2DM. However, GRA treatment was associated with dose-dependent elevation of plasma LDL-cholesterol (LDL-c). The current studies investigated the cause for increased LDL-c. We report findings that link MK-0893 with increased glucagon-like peptide 2 and cholesterol absorption. There was not, however, a GRA-related modulation of cholesterol synthesis. These findings were replicated using structurally diverse GRAs. To examine potential pharmacologic mitigation, coadministration of ezetimibe (a potent inhibitor of cholesterol absorption) in mice abrogated the GRA-associated increase of LDL-c. Although the molecular mechanism is unknown, our results provide a novel finding by which glucagon and, hence, GCGR antagonism govern cholesterol metabolism.
Highlights
Glucagon and insulin have opposing action in governing glucose homeostasis
Ezetimibe alone and in combination with MK-0893 and GRA2 significantly and reduced plasma campesterol and sitosterol, and in the coadministration arms, maintained plasma cholesterol at normal levels (Fig. 6E). The impetus for these investigations of the effect of GCGR antagonist (GRA) on cholesterol homeostasis in humanized GCGR (hGCGR) mice arose from clinical observations that dose-dependent increases in LDL-c occur in type 2 diabetes mellitus (T2DM) patients treated with the GRA, MK-0893
Because our data supported that the effect was mechanism based, we sought to determine among cholesterol synthesis, excretion, absorption, or plasma clearance of LDL-c, which mechanism was primarily responsible
Summary
Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes mellitus (T2DM), plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis and hyperglycemia. Glucagon receptor (GCGR) antagonism has been proposed as a pharmacologic approach to treat T2DM. In type 2 diabetes mellitus (T2DM), as well as in type 1 diabetes mellitus, fasting plasma glucagon is generally elevated, inappropriate to prevailing hyperglycemia, and there is less suppression during prandial metabolism [1]. This imbalance in secretion of islet hormones is considered to be a key aspect of the pathophysiology causing hyperglycemia [1, 2]. In a 12 week placebo-controlled dose-ranging clinical study in T2DM using the GRA, MK-0893, dose-response improvement of hyperglycemia was observed, with a reduction of HbA1c of 1.5% at 80 mg per day, the top dose
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