Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .).

Amylin Pharmaceuticals (AstraZeneca).

Arteriovenous difference and tracer ([3-(3)H]glucose) techniques were used in 42-h-fasted conscious dogs to identify any insulin-like effects of intraportally administered glucagon-like peptide 1-(7-36)amide (GLP-1). Each study consisted of an equilibration, a basal, and three 90-min test periods (P1, P2, and P3) during which somatostatin, intraportal insulin (3-fold basal) and glucagon (basal), and peripheral glucose were infused. Saline was infused intraportally in P1. During P2 and P3, GLP-1 was infused intraportally at 0.9 and 5.1 pmol. kg(-1). min(-1) in eight dogs, at 10 and 20 pmol. kg(-1). min(-1) in seven dogs, and at 0 pmol. kg(-1). min(-1) in eight dogs (control group). Net hepatic glucose uptake was significantly enhanced during GLP-1 infusion at 20 pmol. kg(-1). min(-1) [21.8 vs. 13.4 micromol. kg(-1). min(-1) (control), P < 0.05]. Glucose utilization was significantly increased during infusion at 10 and 20 pmol. kg(-1). min(-1) [87.3 +/- 8.3 and 105.3 +/- 12.8, respectively, vs. 62.2 +/- 5.3 and 74.7 +/- 7.4 micromol. kg(-1). min(-1) (control), P < 0.05]. The glucose infusion rate required to maintain hyperglycemia was increased (P < 0.05) during infusion of GLP-1 at 5.1, 10, and 20 pmol. kg(-1). min(-1) (22, 36, and 32%, respectively, greater than control). Nonhepatic glucose uptake increased significantly during delivery of GLP-1 at 5.1 and 10 pmol. kg(-1). min(-1) (25 and 46% greater than control) and tended (P = 0.1) to increase during GLP-1 infusion at 20 pmol. kg(-1). min(-1) (24% greater than control). Intraportal infusion of GLP-1 at high physiological and pharmacological rates increased glucose disposal primarily in nonhepatic tissues.

rington. Interaction of glucagon and epinephrine in the control of hepatic glucose production in the conscious dog. Am J Physiol Endocrinol Metab 284: E695-E707, 2003. First published December 27, 2002 10.1152/ajpendo.00308.2002Epinephrine increases net hepatic glucose output (NHGO) mainly via increased gluconeogenesis, whereas glucagon increases NHGO mainly via increased glycogenolysis. The aim of the present study was to determine how the two hormones interact in controlling glucose production. In 18-h-fasted conscious dogs, a pancreatic clamp initially fixed insulin and glucagon at basal levels, following which one of four protocols was instituted. In G ϩ E, glucagon (1.5 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ; portally) and epinephrine (50 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ; peripherally) were increased; in G, glucagon was increased alone; in E, epinephrine was increased alone; and in C, neither was increased. In G, E, and C, glucose was infused to match the hyperglycemia seen in G ϩ E (ϳ250 mg/dl). The areas under the curve for the increase in NHGO, after the change in C was subtracted, were as follows: G ϭ 661 Ϯ 185, E ϭ 424 Ϯ 158, G ϩ E ϭ 1,178 Ϯ 57 mg/kg. Therefore, the overall effects of the two hormones on NHGO were additive. Additionally, glucagon exerted its full glycogenolytic effect, whereas epinephrine exerted its full gluconeogenic effect, such that both processes increased significantly during concurrent hormone administration.canine; gluconeogenesis; glycogenolysis; counterregulatory hormones GLUCAGON AND EPINEPHRINE, the two primary counterregulatory hormones, are secreted in response to physiological stresses such as hypoglycemia, exercise, and infection. The individual actions of these two hormones on glucose production have been well defined, yet it remains unclear how they interact acutely in a physiological setting to stimulate glucose production. Glucagon has been shown to have rapid effects on hepatic glucose production, with half-maximal activation occurring in ϳ4.5 min (19). In conscious dogs, administration of glucagon at a fourfold basal rate in the presence of a pancreatic clamp and fixed basal insulin resulted in a rapid increase (180%) in glucose production that waned with time, such that after 3 h it was increased by only 41% (7). This effect of glucagon on glucose production has been shown to result primarily from a rapid, potent, time-dependent effect on glycogenolysis and to a lesser extent from a less potent, slower effect on gluconeogenesis (7). Studies in humans have also shown that glucagon can increase glucose production in a rapid, time-dependent manner primarily by increasing glycogenolysis (8,41).The mild effect of glucagon on gluconeogenesis is somewhat surprising when it is considered that the hormone is known to stimulate both transcription and activation of hepatic gluconeogenic enzymes (22,39,49,50). In fact, glucagon has been shown to increase hepatic gluconeogenic efficiency in vivo both acutely (67) and chronically (43), yet the contribution of the rise in gluconeogenesis to the increase in...