Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog

Abstract

-Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n ϭ 8) or exenatide was infused at low (0.3 pmol·kg Ϫ1 ·min Ϫ1 , Ex-4-low; n ϭ 5) or high (0.9 pmol·kg Ϫ1 ·min Ϫ1 , Ex-4-high; n ϭ 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 Ϯ 0.4, 2.0 Ϯ 0.7, and 3.7 Ϯ 0.7 mg·kg Ϫ1 ·min Ϫ1 between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 Ϯ 428, 5,710 Ϯ 355, and 7,262 Ϯ 1,053 U/ml; hepatic sinusoidal: 14,679 Ϯ 1,700, 15,341 Ϯ 2,208, and 20,445 Ϯ 4,020 U/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 Ϯ 0.53, 6.41 Ϯ 0.57, and 8.12 Ϯ 0.54 mg·kg Ϫ1 ·min Ϫ1 ), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver. exenatide; exendin-4; incretin; hepatic glucose metabolism; hepatic glucose uptake; hepatic glucose production GLUCAGON-LIKE PEPTIDE-1 (GLP-1) receptor agonists represent a new class of antidiabetic agent that has gained popularity in recent years. Exenatide [exendin-4 (Ex-4)] is a long-acting mimetic of GLP-1 that has been shown to increase glucosedependent insulin secretion, restore the first-phase insulin response, and reduce inappropriately high glucagon secretion in patients with type 2 diabetes mellitus (17,30,37). It has also been demonstrated to slow gastric emptying and reduce food intake in humans and to increase pancreatic ␤-cell proliferation and neogenesis in rodents (17,30). Compared with GLP-1, Ex-4 is a more potent stimulator of glucose-dependent insulin release, and it has greater potency for glucose lowering in vivo (23,30,52,66). This is due at least partly to Ex-4 resistance to degradation by dipeptidyl peptidase-4, which extends its plasma half-life and thereby increases its therapeutic potential (30).Although the effects of GLP-1 and Ex-4 are known to be related to their ability to alter pancreatic ␣-and ␤-cell hormone secretion (7, 9, 29), their direct effects on the liver are less clear (1,10,26). Although several groups have detected GLP-1 receptor expression in the liver of mice (6), rats (61, 64), and humans (24, 56), others have been unable to do...

A computer model simulating human glucose absorption and metabolism in health and metabolic disease states

“…The improvements in patient glycaemic responses elicited by GLP-1 agonists, or dipeptidyl peptidase inhibitors that retard GLP-1 degradation, within the circulation, or AMPK activators, e.g. metformin or other biguanides 40 , 64 , 98 and reversal of the pathological effects of NAFLD and NASH by GLP-1 agonists 85 , 99 tend to corroborate the view that GLP-1 deficiency is a cause of metabolic disease. GLP-1 agonists, such as exenatide, used in treatment of 2TDM, have been shown to be effective in reducing hyperglycaemia and hyperinsulinaemia namely 100 .…”

“…Two important effects of hepatic and portal endothelial dysfunction are increased hepatic vascular resistance resulting in reduced hepatic sinus blood flow and raised portal blood pressure 81 – 83 . Additionally, reduction in hepatic glucokinase activity, associated with NASH and T2DM, reduces hepatic insulin-and GLP-1-dependent glucose uptake and metabolism 84 , 85 .…”