Exendin-4 reduces glycemia by increasing liver glucokinase activity: an insulin independent effect

Dhanesha, Nirav; Joharapurkar, Amit; Shah, Gaurang; Dhote, Vipin; Kshirsagar, Samadhan; Bahekar, Rajesh; Jain, Mukul

doi:10.1016/s1734-1140(12)70740-5

Cited by 31 publications

(31 citation statements)

References 37 publications

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“…Moreover, insulin secretions occurred in a similar manner in all medium concentrations of glucose (2.8, 5.6 and 16.7 mM). One of the effects of exendin-4 is an increase in glucokinase enzyme activity in the liver through a parallel and independent insulin-mediated mechanism [3]. It has been shown that glucokinase can initiate phosphorylation of glucose after it has diffused into liver cells.…”

Section: Resultsmentioning

confidence: 99%

“…A number of drugs are being studied for treatment and prevention of metabolic syndrome, but investigations into pharmaceutical intervention of pancreatic and hepatic function associated with metabolic disturbances have received less attention. Exendin-4 is an United States Food and Drug Administration (FDA) approved glucagon-like peptide-1 that increases insulin-dependent glycogen synthesis and the liver’s glucose uptake [3]. In one study, exendin-4 demonstrated a reduction in ROS generation and an enhancement effect on antioxidant enzyme activity, such as SOD, GPX, and CAT in rats [4].…”

Section: Introductionmentioning

confidence: 99%

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Exendin-4 protects mice from D-galactose-induced hepatic and pancreatic dysfunction

Ahangarpour

Oroojan

Badavi

2017

Pathobiology of Aging & Age-related Diseases

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Investigations into pharmaceutical intervention of pancreatic and hepatic dysfunction associated with metabolic disturbances have received relatively little attention. The aim of this study was to investigate the protective effects of exendin-4 in mice receiving D-galactose, a reducing sugar that triggers ROS production and inflammatory mediators affecting the pancreas and liver. Exendin-4 is an United States Food and Drug Administration (FDA) approved glucagon-like peptide that increases insulin dependent glycogen synthesis and glucose uptake. Male NMRI mice (20–25 g), 3 months of age, were randomly divided into 6 groups of 12 mice each: control, exendin-4 (1 nmol/kg), exendin-4 (10 nmol/kg), D-galactose, D-galactose + exendin-4 (1 nmol/kg) and D-galactose + exendin-4 (10 nmol/kg). D-galactose (500 mg/kg) was given daily by oral gavage for 6 weeks. During the last 10 days, exendin-4 (1 and 10 nmol/kg) was injected intraperitoneally daily. Glucose, insulin, insulin resistance, lipid profiles, and hepatic enzyme levels significantly increased in the D-galactose group (p < 0.05), along with a significant decrease in superoxide dismutase activity and pancreatic islet insulin secretion (p < 0.05). Exendin-4 decreased D-galactose-induced increases in serum glucose and insulin, insulin resistance, lipid profiles, and hepatic enzymes, and improved pancreatic islet insulin secretion and antioxidant defense status. The results show that exendin-4 can prevent complications in mice with compromised pancreatic and hepatic function. Long term administration of D-galactose in mice may be a useful model to study insulin resistance, metabolic syndrome, and aging.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exendin-4 protects mice from D-galactose-induced hepatic and pancreatic dysfunction

Ahangarpour

Oroojan

Badavi

2017

Pathobiology of Aging & Age-related Diseases

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“…Although there is little meaningful evidence indicating expression of the GLP-1R in the liver (24,31), there are several reports of GLP-1-mediated regulation of hepatic glucose production in a manner separate from its ability to suppress glucagon release and, intriguingly, independent of insulin (32)(33)(34)(35). We therefore measured EGP rates to investigate whether a GLP-1R-dependent mechanism accounts for regulating glycemia in Gcgr 2/2 animals.…”

Section: Glp-1r Ablation Increases Egp In Insulinopenic Gcgr-null Micementioning

confidence: 99%

Absence of Glucagon and Insulin Action Reveals a Role for the GLP-1 Receptor in Endogenous Glucose Production

et al. 2014

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The absence of insulin results in oscillating hyperglycemia and ketoacidosis in type 1 diabetes. Remarkably, mice genetically deficient in the glucagon receptor (Gcgr) are refractory to the pathophysiological symptoms of insulin deficiency, and therefore, studies interrogating this unique model may uncover metabolic regulatory mechanisms that are independent of insulin. A significant feature of Gcgr-null mice is the high circulating concentrations of GLP-1. Hence, the objective of this report was to investigate potential noninsulinotropic roles of GLP-1 in mice where GCGR signaling is inactivated. For these studies, pancreatic β-cells were chemically destroyed by streptozotocin (STZ) in Gcgr−/−:Glp-1r−/− mice and in Glp-1r−/− animals that were subsequently treated with a high-affinity GCGR antagonist antibody that recapitulates the physiological state of Gcgr ablation. Loss of GLP-1 action substantially worsened nonfasting glucose concentrations and glucose tolerance in mice deficient in, and undergoing pharmacological inhibition of, the GCGR. Further, lack of the Glp-1r in STZ-treated Gcgr−/− mice elevated rates of endogenous glucose production, likely accounting for the differences in glucose homeostasis. These results support the emerging hypothesis that non–β-cell actions of GLP-1 analogs may improve metabolic control in patients with insulinopenic diabetes.

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“…Most importantly, incretins are known to stimulate insulin secretion during hyperglycemia. In addition, glucagon secretion may be reduced, and some studies have suggested that incretins may have direct effects on tissues such as the liver, increasing insulin sensitivity (1,10,26) and modifying molecular regulators of hepatic glucose metabolism (3,14,15,45,54), thereby modifying liver glucose production and uptake independently from the effects of changes in insulin secretion. On the other hand, other studies have not observed a direct effect (1,10,26), and our data support the latter conclusion.…”

Section: Discussionmentioning

confidence: 99%

“…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 so across a wide range of species, including the mouse (65), rat (4,19), dog (55), and human (35,62,63). Ex-4 has been shown to increase liver glucokinase activity in hepatocytes isolated from diabetic mice in an insulin-independent manner (14,15). In addition, GLP-1 and Ex-4 have been reported to increase glycogen accumulation in rat hepatocytes, an effect associated with increased and decreased glycogen synthase and phosphorylase activities, respectively (3,45,54), although others were unable to reproduce those results (47).…”

mentioning

confidence: 99%

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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Exendin-4 reduces glycemia by increasing liver glucokinase activity: an insulin independent effect

Cited by 31 publications

References 37 publications

Exendin-4 protects mice from D-galactose-induced hepatic and pancreatic dysfunction

Exendin-4 protects mice from D-galactose-induced hepatic and pancreatic dysfunction

Absence of Glucagon and Insulin Action Reveals a Role for the GLP-1 Receptor in Endogenous Glucose Production

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

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