Glucagon-like peptide-1 has no insulin-like effects in insulin-dependent diabetic dogs maintained normoglycemic and normoinsulinemic

Freyse, Ernst‐Joachim; Knospe, S; Becher, Tobias; Hag, O. El; Göke, Burkhard; Fischer, Uwe

doi:10.1016/s0026-0495(99)90023-9

Cited by 14 publications

(17 citation statements)

References 23 publications

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“…In vitro studies have suggested that GLP-1 alone or in combination with insulin can enhance liver, muscle, and fat glucose uptake (8 -10,14 -16). We (21) and others (19,20,(41)(42)(43) have been unable to detect an effect of GLP-1 on insulin action or glucose effectiveness in either nondiabetic subjects or subjects with type 2 diabetes. However, all these experiments involved intravenous infusion of insulin and glucose.…”

Section: Discussionmentioning

confidence: 58%

“…GLP-1 has been reported to increase glucose uptake during hyperglycemia and hyperinsulinemia in diabetic rats (16) and pancreatectomized dogs (17) and during euglycemia and hyperinsulinemia in humans with type 1 diabetes (18). On the other hand, GLP-1 has been reported to have no effect on insulin action during euglycemia and hyperinsulinemia in nondiabetic humans (19) and dogs (20) or during "prandial" insulin and glucose infusions in humans with type 2 diabetes (21).…”

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confidence: 99%

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Effect of Glucagon-Like Peptide-1(7-36)-Amide on Initial Splanchnic Glucose Uptake and Insulin Action in Humans With Type 1 Diabetes

Vella¹,

Shah²,

Basu³

et al. 2001

Diabetes

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In vitro studies indicate that glucagon-like peptide-1(7-36)-amide (GLP-1) can enhance hepatic glucose uptake. To determine whether GLP-1 increases splanchnic glucose uptake in humans, we studied seven subjects with type 1 diabetes on two occasions. On both occasions, glucose was maintained at ϳ5.5 mmol/l during the night using a variable insulin infusion. On the morning of the study, a somatostatin, glucagon, and growth hormone infusion was started to maintain basal hormone levels. Glucose (containing [3 H]glucose) was infused via an intraduodenal tube at a rate of 20 mol ⅐ kg ؊1 ⅐ min ؊1 . Insulin concentrations were increased to ϳ500 pmol/l while glucose was clamped at ϳ8.8 mmol/l for the next 4 h by means of a variable intravenous glucose infusion labeled with [6,6-2 H 2 ]glucose. Surprisingly, the systemic appearance of intraduodenally infused glucose was higher (P ‫؍‬ 0.01) during GLP-1 infusion than saline infusion, indicating a lower (P < 0.05) rate of initial splanchnic glucose uptake (1.4 ؎ 1.5 vs. 4.8 ؎ 0.8 mol ⅐ kg ؊1 ⅐ min ؊1 ). On the other hand, flux through the hepatic uridine-diphosphate-glucose pool did not differ between study days (14.2 ؎ 5.5 vs. 13.0 ؎ 4.2 mol ⅐ kg ؊1 ⅐ min ؊1 ), implying equivalent rates of glycogen synthesis. GLP-1 also impaired (P < 0.05) insulin-induced suppression of endogenous glucose production (6.9 ؎ 2.9 vs. 1.3 ؎ 1.4 mol ⅐ kg ؊1 ⅐ min ؊1 ), but caused a time-dependent increase (P < 0.01) in glucose disappearance (93.7 ؎ 10.0 vs. 69.3 ؎ 6.3 mol ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.01) that was evident only during the final hour of study. We conclude that in the presence of hyperglycemia, hyperinsulinemia, and enterally delivered glucose, GLP-1 increases total body but not splanchnic glucose uptake in humans with type 1 diabetes. Diabetes 50: 565-572, 2001 G lucagon-like peptide-1(7-36)-amide (GLP-1) and its analogues are being actively evaluated as a potential therapy for humans with type 1 diabetes (1-5). GLP-1 enhances insulin secretion, decreases glucagon secretion, and delays gastric emptying (6,7). In vitro studies also suggest that GLP-1 may have extrapancreatic effects (8,9). GLP-1 receptors are present in muscle (10,11), fat (8,12), and liver (13). In vitro studies have shown that GLP-1 can increase glucose uptake in each of these tissues and that its effects are additive to those of insulin (14,15). In contrast, results from in vivo studies have been less consistent. GLP-1 has been reported to increase glucose uptake during hyperglycemia and hyperinsulinemia in diabetic rats (16) and pancreatectomized dogs (17) and during euglycemia and hyperinsulinemia in humans with type 1 diabetes (18). On the other hand, GLP-1 has been reported to have no effect on insulin action during euglycemia and hyperinsulinemia in nondiabetic humans (19) and dogs (20) or during "prandial" insulin and glucose infusions in humans with type 2 diabetes (21).All of these studies evaluated insulin action during intravenous glucose infusion. This approach contrasts with the situation that occurs und...

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Section: Discussionmentioning

confidence: 58%

mentioning

confidence: 99%

Effect of Glucagon-Like Peptide-1(7-36)-Amide on Initial Splanchnic Glucose Uptake and Insulin Action in Humans With Type 1 Diabetes

Vella¹,

Shah²,

Basu³

et al. 2001

Diabetes

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“…Several studies have indicated that GLP-1 might have an insulin-independent effect on glucose homeostasis [26][27][28][29][30][31][32], while other researchers suggested that GLP-1 did not acutely affect glucose metabolism independently of insulin [33][34][35][36][37]. These conflicting results may be a consequence of the large variability in the model and methods used: healthy vs diabetic, diabetic hyperglycaemic vs diabetic maintained euglycaemic, clamp vs IVGTT etc.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones

et al. 2005

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“…Gutniak et al (19) and Sandhu et al (20) have reported that GLP-1 increases glucose uptake during a hyperinsulinemic-euglycemic clamp in people with t y p e 1 diabetes and in pancreatectomized dogs, respectively. On the other hand, other investigators using the same technique failed to detect an effect of GLP-1 on insulin action in healthy volunteers, pancreatectomized dogs, and people with t y p e 2 diabetes (21)(22)(23)(24). In contrast, D'Alessio and colleagues (25,26), using the cold minimal model, has reported that G L P-1 increases both insulin action and glucose effectiveness in healthy volunteers.…”

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confidence: 96%

Effect of glucagon-like peptide 1(7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes.

et al. 2000

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Although it is well established that glucagon-like peptide 1(7-36) amide (GLP-1) is a potent stimulator of insulin secretion, its effects on insulin action and glucose effectiveness are less clear. To determine whether GLP-1 increases insulin action and glucose eff e c t i v eness, subjects with type 2 diabetes were studied on two occasions. Insulin was infused during the night on both occasions to ensure that baseline glucose concentrations were comparable. On the morning of study, either GLP-1 (1.2 p m o l · k g -1 · min -1 ) or saline were infused along with somatostatin and replacement amounts of glucagon. Glucose also was infused in a pattern mimicking that typically observed after a carbohydrate meal. Insulin concentrations were either kept constant at basal levels (n = 6) or varied so as to create a prandial insulin profile (n = 6). The increase in glucose concentration was virtually identical on the GLP-1 and saline study days during both the basal (1.21 ± 0.15 vs. 1.32 ± 0 . 1 9 mol/l per 6 h) and prandial (0.56 ± 0.14 vs. 0.56 ± 0 . 1 0 mol/l per 6 h) insulin infusions. During both the basal and prandial insulin infusions, glucose disappearance promptly increased after initiation of the glucose infusion to rates that did not differ on the GLP-1 and saline study days. Suppression of endogenous glucose production also was comparable on the GLP-1 and saline study days during both the basal (-2.7 ± 0.3 vs. -3.1 ± 0.2 µmol/kg) and prandial (-3.1 ± 0.4 vs. -3.0 ± 0.6 µmol/kg) insulin infusions. We conclude that when insulin and glucagon concentrations are matched, G L P-1 has negligible effects on either insulin action or glucose effectiveness in people with type 2 diabetes. These data strongly support the concept that GLP-1 improves glycemic control in people with type 2 diabetes by increasing insulin secretion, by inhibiting glucagon secretion, and by delaying gastric emptying rather than by altering extrapancreatic glucose metabolism. D i a b e t e s 4 9 :6 1 1-617, 2000 P eople with type 2 diabetes have defects in insulin secretion, insulin action, and glucose effectiveness ( d e fined as the ability of glucose to stimulate its own uptake and suppress its own release at basal insulin). Numerous studies have established that glucagon-like peptide 1(7-36) amide (GLP-1) is a potent stimulus for insulin secretion in both people with type 2 diabetes and healthy volunteers (1-5). It also inhibits glucagon secretion and delays gastric emptying (3,6,7). However, GLP-1's effects on insulin action and glucose effectiveness are more controversial (8,9). GLP-1 receptors have been reported to be present in fat, muscle, and liver (10-13). Some (14-17), but not all (18), in vitro studies have shown that GLP-1 can stimulate glucose uptake and enhance insulin action in these tissues. In vivo studies have been even more contradictory. Gutniak et al. (19) and Sandhu et al. (20) have reported that GLP-1 increases glucose uptake during a hyperinsulinemic-euglycemic clamp in people with t y p e 1 diabetes and in pancreatec...

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Glucagon-like peptide-1 has no insulin-like effects in insulin-dependent diabetic dogs maintained normoglycemic and normoinsulinemic

Cited by 14 publications

References 23 publications

Effect of Glucagon-Like Peptide-1(7-36)-Amide on Initial Splanchnic Glucose Uptake and Insulin Action in Humans With Type 1 Diabetes

Effect of Glucagon-Like Peptide-1(7-36)-Amide on Initial Splanchnic Glucose Uptake and Insulin Action in Humans With Type 1 Diabetes

Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones

Effect of glucagon-like peptide 1(7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes.

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