Antidiabetogenic Effect of Glucagon-like Peptide-1 (7–36)amide in Normal Subjects and Patients with Diabetes Mellitus

Gutniak, M.; Ørskov, Cathrine; Holst, Jens J.; Åhrén, Bo; Efendić, Suad

doi:10.1056/nejm199205143262003

Cited by 852 publications

(547 citation statements)

References 38 publications

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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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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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“…Using complementary pharmacological, biochemical and molecular biology approaches, we provide evidence that GLP-1, a gluco-incretin hormone under consideration for diabetes treatment [25,26], prevents glucose-and palmitate-induced apoptosis in the beta cell by a mechanism involving PKB and its downstream target NF-κB.…”

Section: Discussionmentioning

confidence: 99%

“…Glucagon-like peptide-1-(7-36) amide (GLP-1), a potent gluco-incretin hormone [21,22,23] secreted by the intestinal L-cells in response to fat meals and carbohydrates [24], is a potentially important drug in the treatment of Type 2 diabetes in view of its ability to improve insulin secretion in subjects with impaired glucose tolerance and Type 2 diabetes mellitus [25,26]. Through its ability to stimulate insulin gene expression and proinsulin biosynthesis [27] GLP-1 is also an insulinotropic agent.…”

Section: Introductionmentioning

confidence: 99%

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

et al. 2004

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Aims/hypothesis. We have provided evidence that glucagon-like peptide-1, a potential therapeutic agent in the treatment of diabetes, activates phosphatidylinositol-3 kinase/protein kinase B signalling in the pancreatic beta cell. Since this pathway promotes cell survival in a variety of systems, we tested whether glucagon-like peptide-1 protects beta cells against cell death induced by elevated glucose and/or non-esterified fatty acids. Methods. Human islets and INS832/13 cells were cultured at glucose concentrations of 5 or 25 mmol/l in the presence or absence of palmitate. Apoptosis was evaluated by monitoring DNA fragmentation and chromatin condensation. Wild-type and protein kinase B mutants were overexpressed in INS832/13 cells using adenoviruses. Nuclear factor-κB DNA binding was assayed by electrophoretic mobility shift assay. Results. In human pancreatic beta cells and INS832/13 cells, glucagon-like peptide-1 prevented beta cell apoptosis induced by elevated concentrations of (i) glucose (glucotoxicity), (ii) palmitate (lipotoxicity) and (iii) both glucose and palmitate (glucolipotoxicity). Overexpression of a dominant-negative protein kinase B suppressed the anti-apoptotic action of glucagonlike peptide-1 in INS832/13 cells, whereas a constitutively active protein kinase B prevented beta cell apoptosis induced by elevated glucose and palmitate. Glucagon-like peptide-1 enhanced nuclear factor-κB DNA binding activity and stimulated the expression of inhibitor of apoptosis protein-2 and Bcl-2, two antiapoptotic genes under the control of nuclear factor-κB. Inhibition of nuclear factor-κB by BAY 11-7082 abolished the prevention of glucolipotoxicity by glucagon-like peptide-1. Conclusions/interpretation. The results demonstrate a potent protective effect of glucagon-like peptide-1 on beta cell gluco-, lipo-and glucolipotoxicity. This effect is mediated via protein kinase B activation and possibly its downstream target nuclear factor-κB.

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“…In contrast, results from in vivo studies have been less consistent. GLP-1 (7-36) has been reported to increase glucose uptake during hyperglycaemia and hyperinsulinaemia in diabetic rats [17], pancreatectomized dogs [18] and in Type I (insulin-dependent) diabetic patients [19,20]. In contrast, GLP-1 (7-36) has been reported to have no effect on the insulin action in non-diabetic human subjects [21] GLP-1 (7-36) is actively being evaluated as a therapy for diabetes mellitus.…”

mentioning

confidence: 99%

“…A positive but small effect on insulin action has most consistently been observed in severely insulin deficient animals or Type I diabetic patients [18,20]. The methods used to assess insulin action also have differed ranging from clamps, to frequently sampled intravenous glucose tolerance tests to prandial infusions of glucose [17,18,19,20,21,22,23]. We were intrigued by the possibility that the pattern of degradation of GLP-1 (7-36) also might have influenced the results of these studies.…”

mentioning

confidence: 99%

Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans

et al. 2003

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Aims/hypothesis. The aim of this study was to determine whether rapid conversion to inactive and potentially antagonistic peptides could alter the response to GLP-1. Methods. We evaluated the ability of exendin-4, a GLP-1 analogue resistant to degradation by dipeptidyl peptidase IV, to modulate insulin-induced stimulation of glucose uptake and suppression of glucose production in eight healthy subjects during infusion of GLP-1 (1.2 pmol·kg -1 ·min -1 ), exendin-4 (0.12 pmol·kg -1 · min -1 ), or saline. Glucose was clamped at 5.3 mmol/l and insulin was infused to progressively increase insulin concentrations to about 65, 190 and 700 pmol/l, respectively. Endogenous insulin secretion was inhibited with somatostatin to ensure comparable portal insulin concentrations while glucagon and growth hormone were maintained at basal concentrations. Results. Glucose, insulin, C-peptide, glucagon and growth hormone concentrations did not differ on the three occasions. In contrast, cortisol concentrations were greater during both exendin-4 (25.1±4.4 mmol/l per 7 h; p<0.01) and GLP-1, (17.0±2.0 mmol/l 7 h; p<0.05) than saline (13.5±1.5 mmol/l per 7 h). While insulin-induced stimulation of glucose disappearance at the highest insulin concentrations tended to be greater and insulin-induced suppression of glucose production lower in the presence of exendin-4 or GLP-1 than saline, the differences were not significant. Conclusion/interpretation. Exendin-4 and GLP-1 increase cortisol secretion in human subjects. However, neither alters insulin action in non-diabetic human subjects. These data also suggest that the lack of an effect of GLP-1 on insulin action is not likely to be explained by rapid degradation to inactive or antagonistic peptides. [Diabetologia (2002[Diabetologia ( ) 45:1410[Diabetologia ( -1415 Keywords GLP-1, exendin-4, insulin action, glucose production, cortisol secretion. [11,12] and the liver [13]. GLP-1 (7-36) can increase glucose uptake in each of these tissues with its effects being additive to those of insulin [12,14,15,16]. In contrast, results from in vivo studies have been less consistent. GLP-1 (7-36) has been reported to increase glucose uptake during hyperglycaemia and hyperinsulinaemia in diabetic rats [17], pancreatectomized dogs [18] and in Type I (insulin-dependent) diabetic patients [19,20]. In contrast, GLP-1 (7-36) has been reported to have no effect on the insulin action in non-diabetic human subjects [21] GLP-1 (7-36) is actively being evaluated as a therapy for diabetes mellitus. GLP-1 (7-36) increases insulin secretion, decreases glucagon secretion and delays gastric emptying [1,2,3,4,5,6,7]. In vitro data suggest it might also enhance insulin action. Although controversial, GLP-1 receptors, to which Exendin-4

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Antidiabetogenic Effect of Glucagon-like Peptide-1 (7–36)amide in Normal Subjects and Patients with Diabetes Mellitus

Abstract: GLIP has an antidiabetogenic effect, and it may therefore be useful in the treatment of patients with NIDDM:

Cited by 852 publications

References 38 publications

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

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

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans

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