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. 2005 Dec;115(12):3554-63.
doi: 10.1172/JCI25764.

Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage

Claude Knauf  1 , Patrice D Cani, Christophe Perrin, Miguel A Iglesias, Jean François Maury, Elodie Bernard, Fadilha Benhamed, Thierry Grémeaux, Daniel J Drucker, C Ronald Kahn, Jean Girard, Jean François Tanti, Nathalie M Delzenne, Catherine Postic, Rémy Burcelin
Affiliations

Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage

Claude Knauf et al. J Clin Invest. 2005 Dec.

Abstract

Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.

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Figures

Figure 1
Figure 1
Central control by GLP-1 of whole-body GIR. GIR (mg/kg/min) was calculated in steady-state euglycemic hyperinsulinemic conditions (5.5 mM; A) and in hyperglycemic conditions (10 mM, B; and 20 mM, C) in C57BL/6 control mice with ACF, Ex4, or GLP-1 antagonist Ex9 infused into their brains and in GLP-1 receptor KO mice (KO). Values are shown above each bar; error bars indicate ± SEM. (D) Dose response to glucose in all sets of mice plotted against GIRs in order to calculate the r2 of each curve. The mean of 6–11 mice per group is shown. *P < 0.05 versus icv ACF-infused mice.
Figure 2
Figure 2
Central control by GLP-1 of individual tissue glucose utilization. Individual tissue glucose utilization (ng/mg/min) was assessed during 20-mM hyperglycemic hyperinsulinemic conditions in (A) white adipose tissue (WAT), vastus lateralis (VL), soleus, extensor digitorum longus (EDL), skin and in (B) interscapular brown adipose tissue (BAT) of C57BL/6 control mice with ACF, Ex4, or Ex9 infused into their brains. The mean of 4–8 mice per group is shown. *P < 0.05 versus icv ACF-infused mice; #P < 0.05 versus icv Ex4-infused mice.
Figure 3
Figure 3
Central control by GLP-1 of muscle and liver glycogen content. Glycogen content (mg/g wet tissue) was measured in ground hind limb muscles (A) and liver (B) from C57BL/6 control mice with ACF, Ex4, or Ex9 infused into their brains and GLP-1 receptor KO mice during 20-mM hyperglycemic hyperinsulinemic conditions. The mean of 6–11 mice per group is shown. *P < 0.05 versus icv ACF-infused mice.
Figure 4
Figure 4
Central control by GLP-1 of whole-body GIR and muscle glycogen content are independent of muscle insulin action. (A) GIR (mg/kg/min) and (B) muscle glycogen content (mg/g) were measured in MIRKO mice infused with ACF (black bars) or Ex9 (white bars) during 20-mM hyperglycemic hyperinsulinemic conditions. The mean of 5–6 mice per group is represented. (C) PI3K activity (AU) in hind limb muscles of C57BL/6 mice infused with ACF (black bars) or Ex9 (white bars). The mean of 4 mice per group is shown. *P < 0.05 versus icv ACF-infused mice.
Figure 5
Figure 5
Central control by GLP-1 of muscle GSK3β phosphorylation. Muscle content in 46-kDa GSK3β-P in C57BL/6 mice with ACF or Ex9 infused into their brains, GLP-1 receptor KO mice, and MIRKO mice infused with ACF or Ex9 into their brains during a 20-mM hyperglycemic hyperinsulinemic clamp. The mean of 4 mice per group is shown. *P < 0.05 versus ACF-infused WT mice.
Figure 6
Figure 6
Central control by central GLP-1 of ChREBP and HKII mRNA in muscles. (A) ChREBP and (B) HKII mRNA concentrations (AU) were assessed in muscles of C57BL/6 and MIRKO mice during hyperinsulinemic euglycemic (5.5 mM, G5) or hyperglycemic (20 mM, G20) clamps. Some hyperglycemic C57BL/6 and MIRKO mice had Ex9 simultaneously infused into their brains. The mean of 4 mice per group is shown. *P < 0.05 versus euglycemic WT mice.
Figure 7
Figure 7
Central control by GLP-1 of glycogen content in denervated muscles. Glycogen content (mg/g wet tissue) was measured in ground hind limb denervated (D) or normal (I) muscles from C57BL/6 control mice with ACF, Ex4, or Ex9 infused into their brains during 20-mM hyperglycemic hyperinsulinemic conditions. The mean of 5–6 mice per group is shown. *P < 0.05 versus icv ACF-infused mice; **P < 0.05 versus normal muscle.
Figure 8
Figure 8
Glucose tolerance test in mice with type 2 diabetes induced by a high-fat diet and infused with Ex9 for 4 weeks into the peritoneal cavity. (A) Plasma glucose (mM) during an i.p. glucose tolerance test in C57BL/6 mice fed a high-fat diet (HFD) and infused with Ex9 or saline (Sal) through an osmotic pump for 4 weeks and in mice fed normal chow (NC). (B) Index of area under curve (AUC), expressed in AU, in the 3 tested conditions. The mean of 9 mice per group is shown. *P < 0.05 versus saline-infused HFD mice.
Figure 9
Figure 9
Central control by GLP-1 of liver glycogen content and insulin secretion during hyperglycemic clamp. (A) Liver glycogen content (mg/g); (B) plasma insulin concentration (μU/ml); (C) GIR (mg/kg/min); and (D) the ratio of GIR (mg/ml) to insulin (kg/min/μU) during a 20-mM hyperglycemic clamp in C57BL/6 mice infused simultaneously with ACF, Ex4, or Ex9 and in GLP-1 receptor KO mice. The mean of 6–8 mice per group is shown. *P < 0.05 versus icv ACF-infused mice.
Figure 10
Figure 10
Central control by GLP-1 of liver glycogen content and insulin secretion during hyperglycemic clamp when glucose was infused into the stomach. (A) Liver glycogen content (mg/g), (B) plasma insulin concentration (μU/ml), (C) GIR (mg/kg min), and (D) the ratio of GIR (mg/ml) to insulin (kg/min/μU) during a 20-mM hyperglycemic clamp achieved by intragastric infusion of glucose was performed in C57BL/6 mice simultaneously infused with ACF, Ex4, or Ex9. The mean of 6–8 mice per group is shown. *P < 0.05 versus icv ACF-infused mice.
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