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.
. Insulin-independent effects of GLP-1 on canine liver glucose metabolism: duration of infusion and involvement of hepatoportal region. Am J Physiol Endocrinol Metab 287: E75-E81, 2004. First published March 16, 2004 10.1152/ ajpendo.00035.2004.-Whether glucagon-like peptide-1 (GLP-1) has insulin-independent effects on glucose disposal in vivo was assessed in conscious dogs by use of tracer and arteriovenous difference techniques. After a basal period, each experiment consisted of three periods (P1, P2, P3) during which somatostatin, glucagon, insulin, and glucose were infused. The control group (C) received saline in P1, P2, and P3, the PePe group received saline in P1 and GLP-1 (7.5 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) peripherally (Pe; iv) in P2 and P3, and the PePo group received saline in P1 and GLP-1 peripherally (iv) (P2) and then into the portal vein (Po; P3). Glucose and insulin concentrations increased to two-and fourfold basal, respectively, and glucagon remained basal. GLP-1 levels increased similarly in the PePe and PePo groups during P2 (ϳ200 pM), whereas portal GLP-1 levels were significantly increased (3-fold) in PePo vs. PePe during P3. In all groups, net hepatic glucose uptake (NHGU) occurred during P1. During P2, NHGU increased slightly but not significantly in all groups. During P3, NHGU increased in PePe and PePo groups to a greater extent than in C, but no significant effect of the route of infusion of GLP-1 was demonstrated (16.61 Ϯ 2.91 and 14.67 Ϯ 2.09 vs. 4.22 Ϯ 1.57 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , respectively). In conclusion: GLP-1 increased glucose disposal in the liver independently of insulin secretion; its full action required long-term infusion. The route of infusion did not modify the hepatic response.glucagon-like peptide-1; glucose uptake; portal infusion; dog GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is synthesized from proglucagon in the L cells of the duodenum, distal ileum, and colon in response to meal absorption, after which it is rapidly released into the portal vein (22, 37). The main and active form of GLP-1, GLP-1-(7-36), is rapidly degraded by dipeptidyl peptidase IV (DPP-IV) into GLP-1-(9 -36) in the intestinal tissues as well as in the blood (23, 27). The consequence is a rapid elimination of GLP-1 from plasma with a half-life estimated at 1-2 min in several species (22). The earliest biological effect of GLP-1 discovered was its ability to increase glucose-dependent insulin secretion (18, 28) as well as the transcription of the proinsulin gene and biosynthesis of insulin (12). The glucose-dependent effect of GLP-1 on insulin secretion has suggested a potential use of this agent in the treatment of diabetes without deleterious hypoglycemia. Indeed, it lowers postprandial glucose levels in both healthy and human subjects with type 2 diabetes by stimulating insulin secretion but also by inhibiting glucagon secretion from the ␣-cell and delaying gastric emptying (1,17,40).GLP-1 receptors are present on -cells (38), and there are numerous reports of GLP-1 receptors on glucose-consuming tissues suc...
Whether glucagon-like peptide (GLP)-1 requires the hepatic portal vein to elicit its insulin secretion-independent effects on glucose disposal in vivo was assessed in conscious dogs using tracer and arteriovenous difference techniques. In study 1, six conscious overnight-fasted dogs underwent oral glucose tolerance testing (OGTT) to determine target GLP-1 concentrations during clamp studies. Peak arterial and portal values during OGTT ranged from 23 to 65 pM and from 46 to 113 pM, respectively. In study 2, we conducted hyperinsulinemic-hyperglycemic clamp experiments consisting of three periods (P1, P2, and P3) during which somatostatin, glucagon, insulin and glucose were infused. The control group received saline, the PePe group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally, the PePo group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally (P2) and then intraportally (P3), and the PeHa group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally (P2) and then through the hepatic artery (P3) to increase the hepatic GLP-1 load to the same extent as in P3 in the PePo group (n = 8 dogs/group). Arterial GLP-1 levels increased similarly in all groups during P2 ( approximately 50 pM), whereas portal GLP-1 levels were significantly increased (2-fold) in the PePo vs. PePe and PeHa groups during P3. During P2, net hepatic glucose uptake (NHGU) increased slightly but not significantly (vs. P1) in all groups. During P3, GLP-1 increased NHGU in the PePo and PeHa groups more than in the control and PePe groups (change of 10.8 +/- 1.3 and 10.6 +/- 1.0 vs. 5.7 +/- 1.0 and 5.4 +/- 0.8 micromol.kg(-1).min(-1), respectively, P < 0.05). In conclusion, physiological GLP-1 levels increase glucose disposal in the liver, and this effect does not involve GLP-1 receptors located in the portal vein.
In individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. Under conditions of insulin-induced hypoglycemia, glucagon is the most important stimulus for hepatic glucose production. In contrast, during euglycemia, insulin potently inhibits glucagon's effect on the liver. The first aim of the present study was to determine whether low blood sugar augments glucagon's ability to increase glucose production. Using a conscious catheterized dog model, we found that hypoglycemia increased glucagon's ability to overcome the inhibitory effect of insulin on hepatic glucose production by almost 3-fold, an effect exclusively attributable to marked enhancement of the effect of glucagon on net glycogen breakdown. To investigate the molecular mechanism by which this effect comes about, we analyzed hepatic biopsies from the same animals, and found that hypoglycemia resulted in a decrease in insulin signaling. Furthermore, hypoglycemia and glucagon had an additive effect on the activation of AMPK, which was associated with altered activity of the enzymes of glycogen metabolism. IntroductionIn individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. The incidence of hypoglycemia is less frequent in individuals with type 2 diabetes, but as the disease progresses and patients begin to use insulin, it once again becomes a limiting factor in glycemic control (1). The counterregulatory response to hypoglycemia in the normal individual involves the release of glucagon, epinephrine, norepinephrine, cortisol, and growth hormone, which together increase glucose production and limit glucose utilization (2). Glucagon has been shown to provide the primary stimulus for the counterregulatory increase in glucose production in response to insulin-induced hypoglycemia in the normal individual (2). Furthermore, abnormalities in the response of the α cell to hypoglycemia make individuals with diabetes more prone to low blood sugar (1, 2).We have previously examined the interaction between insulin and glucagon in controlling glucose production in the conscious dog (3). Intraportal replacement of basal amounts of insulin and glucagon in the presence of somatostatin infusion was associated with sustained basal glucose production. A selective 4-fold rise in glucagon resulted in an increment in glucose production of approximately 4.5 mg/kg/min at 30 minutes. In contrast, a selective 4-fold rise in insulin resulted in a decrement in glucose production of approximately 1.3 mg/kg/min at 30 minutes. When both hormones were simultaneously increased 4-fold, the decrement in glucose production at 30 minutes was only approximately 0.6 mg/kg/min. Therefore, glucagon's effect was 4.5 mg/kg/min in the presence of basal insulin -despite the accompanying hyperglycemia - and only 0.7 mg/kg/min in the presence of high insulin and euglycemia, a reduction of almost 85%. These data indicate that, in the absence of hypoglycemia, insulin dominates glucagon's action on the liver even when equimolar in...
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