Exenatide Sensitizes Insulin-Mediated Whole-Body Glucose Disposal and Promotes Uptake of Exogenous Glucose by the Liver

Zheng, Dan; Ionut, Viorica; Mooradian, Vahe; Stefanovski, Darko; Bergman, Richard N.

doi:10.2337/db08-0875

Cited by 42 publications

(36 citation statements)

References 52 publications

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“…In another study in dogs, net hepatic glucose uptake was increased marginally by Ex-4 under hyperglycemic hyperinsulinemic conditions during a somatostatin clamp (67). A possi- ble explanation for the discrepancy between that study and the present study is that in the former study insulin was infused into a peripheral vein during somatostatin infusion.…”

contrasting

confidence: 51%

“…In contrast, when insulin is infused into a peripheral vein, portal levels are slightly lower than arterial levels (53). Thus, although arterial insulin levels increased from basal almost fivefold during the clamp in the study by Zheng et al (67), portal vein insulin concentrations would have increased less than twofold. Therefore, it is possible that Ex-4 may potentiate the effects of insulin action on liver glucose uptake during a smaller rise in hepatic insulin levels, whereas the physiological liver insulin levels generated by mild hyperglycemia in the present study may have been saturating in regard to an insulinEx-4 interaction.…”

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confidence: 58%

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

Edgerton

Johnson

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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-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...

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confidence: 51%

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confidence: 58%

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

Edgerton

Johnson

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…For instance, increased microvascular perfusion in muscle could lead to increased glucose uptake, a beneficial phenomenon which was shown in rodents and dogs. 3,29 In our study, we observed insulin-independent reductions in glucose levels after exenatide infusion, which could be explained by increased muscle glucose disposal rate. However, in this study, we did not assess this by using labeltracer techniques.…”

mentioning

confidence: 56%

GLP-1 Receptor Agonist Exenatide Increases Capillary Perfusion Independent of Nitric Oxide in Healthy Overweight Men

Smits

Muskiet

Tonneijck

et al. 2015

ATVB

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Objective-The insulinotropic gut-derived hormone glucagon-like peptide-1 (GLP-1) increases capillary perfusion via a nitric oxide-dependent mechanism in rodents. This improves skeletal muscle glucose use and cardiac function. In humans, the effect of clinically used GLP-1 receptor agonists (GLP-1RAs) on capillary density is unknown. We aimed to assess the effects of the GLP-1RA exenatide on capillary density as well as the involvement of nitric oxide in humans. Approach and Results-We included 10 healthy overweight men (age, 20-27 years; body mass index, 26-31 kg/m 2 ). Measurements were performed during intravenous infusion of placebo (saline 0.9%), exenatide, and a combination of exenatide and the nonselective nitric oxide-synthase inhibitor l-N G -monomethyl arginine. Capillary videomicroscopy was performed, and baseline and postocclusive (peak) capillary densities were counted. Compared with placebo, exenatide increased baseline and peak capillary density by 20.1% and 8.3%, respectively (both P=0.016). Concomitant l-N G -monomethyl arginine infusion did not alter the effects of exenatide. Vasomotion was assessed using laser Doppler fluxmetry. Exenatide nonsignificantly reduced the neurogenic domain of vasomotion measurements (R=−5.6%; P=0.092), which was strongly and inversely associated with capillary perfusion (R=−0.928; P=0.036). Glucose levels were reduced during exenatide infusion, whereas levels of insulin were unchanged. Conclusions-Acute exenatide infusion increases capillary perfusion via nitric oxide-independent pathways in Materials and MethodsIn this mechanistic cross-over study, healthy overweight participants were subjected to continuous intravenous infusion of placebo (isotonic saline), GLP-1RA exenatide, l-NMMA or a combination of l-NMMA and exenatide. During these conditions, microvascular perfusion was assessed using intravital videomicroscopy and laser Doppler fluxmetry. A complete description of Materials and Methods are available in the Online-only Data Supplement. Results Patient CharacteristicsTen healthy overweight men were included in this analysis. Full characteristics of the subjects can be found in the Table. Capillary VideomicroscopyCompared with placebo, exenatide increased baseline capillary density with 8.0 (5.3-10.5) cap/mm 2 (P=0.016) and peak postarterial occlusion capillary density with 6.5 (4.8-7.8) cap/ mm 2 (P=0.016). This corresponds with an increase of 20.1% and 8.3%, respectively. When exenatide was coinfused with l-NMMA, no significant differences compared with exenatide infused alone were observed (Figure 1).Tests were performed during 2 study days. Day-to-day variation for baseline capillary density and postocclusive peak density were 4.7% and 1.7%, respectively. We conducted sensitivity analyses to assess potential interference of day-to-day variation by including unstimulated measurements (before any intervention) in the statistical model. These sensitivity analyses showed no different results compared with the original analyses. Laser Doppler FluxmetryDuring p...

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“…Thus, the function of GLP-1 is not limited to the islets. The extrapancreatic actions of GLP-1 include inhibition of gastric emptying, regulation of appetite and satiety, suppression of glucose production, and promotion of hepatic glucose uptake (2,4,20,23,25,27).…”

Section: Discussionmentioning

confidence: 99%

Glucagon receptor antagonist-mediated improvements in glycemic control are dependent on functional pancreatic GLP-1 receptor

Gu¹,

Winters²,

Motani³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Exenatide Sensitizes Insulin-Mediated Whole-Body Glucose Disposal and Promotes Uptake of Exogenous Glucose by the Liver

Cited by 42 publications

References 52 publications

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

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

GLP-1 Receptor Agonist Exenatide Increases Capillary Perfusion Independent of Nitric Oxide in Healthy Overweight Men

Glucagon receptor antagonist-mediated improvements in glycemic control are dependent on functional pancreatic GLP-1 receptor

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