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Richard M Obrien - One of the best experts on this subject based on the ideXlab platform.
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the three Insulin Response sequences in the glucose 6 phosphatase catalytic subunit gene promoter are functionally distinct
Journal of Biological Chemistry, 2003Co-Authors: Beth Vander T Kooi, Ryan S Streeper, Christina A Svitek, David R Powell, James K Oeser, Richard M ObrienAbstract:Abstract Glucose-6-phosphatase catalyzes the terminal step in the gluconeogenic and glycogenolytic pathways. In HepG2 cells, the maximum repression of basal glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription by Insulin requires two distinct promoter regions, designated A (located between −231 and −199) and B (located between −198 and −159), that together form an Insulin Response unit. Region A binds hepatocyte nuclear factor-1, which acts as an accessory factor to enhance the effect of Insulin, mediated through region B, on G6Pase gene transcription. We have previously shown that region B binds the transcriptional activator FKHR (FOXO1a) in vitro. Chromatin immunoprecipitation assays demonstrate that FKHR also binds the G6Pase promoter in situ and that Insulin inhibits this binding. Region B contains three Insulin Response sequences (IRSs), designated IRS 1, 2, and 3, that share the core sequence T(G/A)TTTT. However, detailed analyses reveal that these three G6Pase IRSs are functionally distinct. Thus, FKHR binds IRS 1 with high affinity and IRS 2 with low affinity but it does not bind IRS 3. Moreover, in the context of the G6Pase promoter, IRS 1 and 2, but not IRS 3, are required for the Insulin Response. Surprisingly, IRS 3, as well as IRS 1 and IRS 2, can each confer an inhibitory effect of Insulin on the expression of a heterologous fusion gene, indicating that, in this context, a transcription factor other than FKHR, or its orthologs, can also mediate an Insulin Response through the T(G/A)TTTT motif.
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regulation of phosphoenolpyruvate carboxykinase and Insulin like growth factor binding protein 1 gene expression by Insulin the role of winged helix forkhead proteins
Journal of Biological Chemistry, 2000Co-Authors: Robert K Hall, Richard M Obrien, Tomoyuki Yamasaki, Tomas Kucera, Mary Waltnerlaw, Daryl K GrannerAbstract:Abstract Winged helix/forkhead (Fox) transcription factors have been implicated in the regulation of a number of Insulin-responsive genes. The Insulin Response elements (IREs) of the phosphoenolpyruvate carboxykinase (PEPCK) and Insulin-like growth factor-binding protein-1 (IGFBP-1) genes bind members of the FKHR and HNF3 subclasses of Fox proteins. Previous mutational analyses of the PEPCK and IGFBP-1 IREs revealed mutations which do not affect the binding of HNF3 proteins to these elements but do eliminate the ability of the IREs to mediate an Insulin Response. This dissociation of binding and function provided compelling evidence that HNF3 proteins,per se, are not Insulin Response proteins. The same approach was used here to determine if FKHRL1, a member of the FKHR subclass of Fox proteins, binds to the PEPCK and IGFBP-1 IREs in a manner that correlates with the ability of these elements to mediate an Insulin Response. Overexpression of FKHRL1 stimulates transcription from transfected reporter constructs that contain a multimerized PEPCK IRE or an IGFBP-1 IRE and this stimulation is repressed by Insulin. There is a direct correlation between the ability of mutant versions of the PEPCK and IGFBP-1 IREs to bind FKHRL1 and their ability to mediate FKHRL1-induced transcription when FKHRL1 is overexpressed. However, under conditions where FKHRL1 is not overexpressed, there is a lack of correlation between FKHRL1 binding to mutant versions of the PEPCK and IGFBP-1 IREs and the ability of these elements to mediate an Insulin Response. Therefore, the PEPCK and IGFBP-1 IREs mediate FKHRL1-induced transcription and its inhibition by Insulin when this protein is overexpressed, but at the normal cellular concentration of FKHRL1 the Insulin Response mediated by these elements must involve another protein.
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conservation of an Insulin Response unit between mouse and human glucose 6 phosphatase catalytic subunit gene promoters transcription factor fkhr binds the Insulin Response sequence
Diabetes, 1999Co-Authors: Julio E Ayala, Frederic G Barr, Ryan S Streeper, Jay S Desgrosellier, Susan K Durham, Adisak Suwanichkul, Christina A Svitek, Joshua K Goldman, David R Powell, Richard M ObrienAbstract:Because overexpression of the glucose-6-phosphatase catalytic subunit (G-6-Pase) in both type 1 and type 2 diabetes may contribute to the characteristic increased rate of hepatic glucose production, we have investigated whether the Insulin Response unit (IRU) identified in the mouse G-6-Pase promoter is conserved in the human promoter. A series of human G-6-Pase-chloramphenicol acetyltransferase (CAT) fusion genes was transiently transfected into human HepG2 hepatoma cells, and the effect of Insulin on basal CAT expression was analyzed. The results suggest that the IRU identified in the mouse promoter is conserved in the human promoter, but that an upstream multimerized Insulin Response sequence (IRS) motif that is only found in the human promoter appears to be functionally inactive. The G-6-Pase IRU comprises two distinct promoter regions, designated A and B. Region B contains an IRS, whereas region A acts as an accessory element to enhance the effect of Insulin, mediated through region B, on basal G-6-Pase gene transcription. We have previously shown that the accessory factor binding region A is hepatocyte nuclear factor-1, and we show here that the forkhead protein FKHR is a candidate for the Insulin-responsive transcription factor binding region B.
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a multicomponent Insulin Response sequence mediates a strong repression of mouse glucose 6 phosphatase gene transcription by Insulin
Journal of Biological Chemistry, 1997Co-Authors: Ryan S Streeper, Christina A Svitek, Stacey C Chapman, Linda E Greenbaum, Rebecca Taub, Richard M ObrienAbstract:Abstract Glucose-6-phosphatase (G6Pase) catalyzes the final step in the gluconeogenic and glycogenolytic pathways. The transcription of the gene encoding the catalytic subunit of G6Pase is stimulated by glucocorticoids, whereas Insulin strongly inhibits both basal G6Pase gene transcription and the stimulatory effect of glucocorticoids. To identify the Insulin Response sequence (IRS) in the G6Pase promoter through which Insulin mediates its action, we have analyzed the effect of Insulin on the basal expression of mouse G6Pase-chloramphenicol acetyltransferase (CAT) fusion genes transiently expressed in hepatoma cells. Deletion of the G6Pase promoter sequence between −271 and −199 partially reduces the inhibitory effect of Insulin, whereas deletion of additional sequence between −198 and −159 completely abolishes the Insulin Response. The presence of this multicomponent IRS may explain why Insulin potently inhibits basal G6Pase-CAT expression. The G6Pase promoter region between −198 and −159 contains an IRS, since it can confer an inhibitory effect of Insulin on the expression of a heterologous fusion gene. This region contains three copies of the T(G/A)TTTTG sequence, which is the core motif of the phosphoenolpyruvate carboxykinase (PEPCK) gene IRS. This suggests that a coordinate increase in both G6Pase and PEPCK gene transcription is likely to contribute to the increased hepatic glucose production characteristic of patients with non-Insulin-dependent diabetes mellitus.
Terry G Unterman - One of the best experts on this subject based on the ideXlab platform.
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gene and activation specific mechanisms for Insulin inhibition of basal and glucocorticoid induced Insulin like growth factor binding protein 1 and phosphoenolpyruvate carboxykinase transcription roles of forkhead and Insulin Response sequences
Journal of Biological Chemistry, 2001Co-Authors: David Yeagley, Terry G Unterman, Patrick G QuinnAbstract:Abstract The Insulin Response sequence (IRS) of the phosphoenolpyruvate carboxykinase (PEPCK) promoter, located within the glucocorticoid Response unit, was first characterized by its ability to mediate Insulin inhibition when inserted into a thymidine kinase promoter. The IRSs of the PEPCK and Insulin-like growth factor binding protein-1 (IGFBP-1) promoters have been proposed to contribute to regulation by glucocorticoids and Insulin. Forkhead (FKHR) recognizes IRS sequences, is phosphorylated in Response to Insulin, and mediates Insulin inhibition of basal IGFBP-1 transcription in an IRS-dependent manner. Here, we investigate the contributions of FKHR and IRSs to Insulin inhibition of basal and glucocorticoid-induced transcription of PEPCK and IGFBP-1. Expression of T/S/S, in which three putative protein kinase B (PKB) sites in FKHR are mutated, reduced Insulin inhibition of basal expression of IGFBP-1 but not PEPCK. Mutation of the IGFBP-1 IRSs abolished Insulin inhibition in the presence of T/S/S. Mutation of the PEPCK IRS had no effect on Insulin inhibition in the presence of T/S/S, indicating that Insulin inhibits PEPCK transcription independently of the IRS or of the putative PKB phosphorylation sites in FKHR. Mutations in the IRS or FKHR had no effect on Insulin inhibition of glucocorticoid-induced transcription of either the PEPCK or IGFBP-1 gene. Thus, Insulin uses gene- and activation-specific mechanisms to regulate the basal and glucocorticoid-induced activity of these genes.
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regulation of glucose 6 phosphatase gene expression by protein kinase bα and the forkhead transcription factor fkhr evidence for Insulin Response unit dependent and independent effects of Insulin on promoter activity
Journal of Biological Chemistry, 2000Co-Authors: Dieter Schmoll, Kay S Walker, Dario R Alessi, Rolf Grempler, Ann N Burchell, Shaodong Guo, Reinhard Walther, Terry G UntermanAbstract:Glucose-6-phosphatase plays an important role in the regulation of hepatic glucose production, and Insulin suppresses glucose-6-phosphatase gene expression. Recent studies indicate that protein kinase B and Forkhead proteins contribute to Insulin-regulated gene expression in the liver. Here, we examined the role of protein kinase B and Forkhead proteins in mediating effects of Insulin on glucose-6-phosphatase promoter activity. Transient transfection studies with reporter gene constructs demonstrate that Insulin suppresses both basal and dexamethasone/cAMP-induced activity of the glucose-6-phosphatase promoter in H4IIE hepatoma cells. Both effects are partially mimicked by coexpression of protein kinase Balpha. Coexpression of the Forkhead transcription factor FKHR stimulates the glucose-6-phosphatase promoter activity via interaction with an Insulin Response unit (IRU), and this activation is suppressed by protein kinase B. Coexpression of a mutated form of FKHR that cannot be phosphorylated by protein kinase B abolishes the regulation of the glucose-6-phosphatase promoter by protein kinase B and disrupts the ability of Insulin to regulate the glucose-6-phosphatase promoter via the IRU. Mutation of the Insulin Response unit of the glucose-6-phosphatase promoter also prevents the regulation of promoter activity by FKHR and protein kinase B but only partially impairs the ability of Insulin to suppress both basal and dexamethasone/cAMP-stimulated promoter function. Taken together, these results indicate that signaling by protein kinase B to Forkhead proteins can account for the ability of Insulin to regulate glucose-6-phosphatase promoter activity via the IRU and that other mechanisms that are independent of the IRU, protein kinase B, and Forkhead proteins also are important in mediating effects of in Insulin on glucose-6-phosphatase gene expression.
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phosphorylation of serine 256 by protein kinase b disrupts transactivation by fkhr and mediates effects of Insulin on Insulin like growth factor binding protein 1 promoter activity through a conserved Insulin Response sequence
Journal of Biological Chemistry, 1999Co-Authors: Shaodong Guo, Stephen B Cichy, Graham Rena, Philip Cohen, Terry G UntermanAbstract:Insulin inhibits the expression of multiple genes in the liver containing an Insulin Response sequence (IRS) (CAAAA(C/T)AA), and we have reported that protein kinase B (PKB) mediates this effect of Insulin. Genetic studies in Caenorhabditis elegans indicate that daf-16, a forkhead/winged-helix transcription factor, is a major target of the Insulin receptor-PKB signaling pathway. FKHR, a human homologue of daf-16, contains three PKB sites and is expressed in the liver. Reporter gene studies in HepG2 hepatoma cells show that FKHR stimulates Insulin-like growth factor-binding protein-1 promoter activity through an IRS, and introduction of IRSs confers this effect on a heterologous promoter. Insulin disrupts IRS-dependent transactivation by FKHR, and phosphorylation of Ser-256 by PKB is necessary and sufficient to mediate this effect. Antisense studies indicate that FKHR contributes to basal promoter function and is required to mediate effects of Insulin and PKB on promoter activity via an IRS. To our knowledge, these results provide the first report that FKHR stimulates promoter activity through an IRS and that phosphorylation of FKHR by PKB mediates effects of Insulin on gene expression. Signaling to FKHR-related forkhead proteins via PKB may provide an evolutionarily conserved mechanism by which Insulin and related factors regulate gene expression.
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protein kinase b akt mediates effects of Insulin on hepatic Insulin like growth factor binding protein 1 gene expression through a conserved Insulin Response sequence
Journal of Biological Chemistry, 1998Co-Authors: Stephen B Cichy, Shaodong Guo, Shahab Uddin, A V Danilkovich, Anke Klippel, Terry G UntermanAbstract:Insulin regulates the expression of multiple hepatic genes through a conserved Insulin Response sequence (IRS) (CAAAAC/TAA) by an as yet undetermined mechanism. Protein kinase B/Akt (PKB/Akt), a member of the PKA/PKC serine/threonine kinase family, functions downstream from phosphatidylinositol 3'-kinase (PI3K) in mediating effects of Insulin on glucose transport and glycogen synthesis. We asked whether PKB/Akt mediates sequence-specific effects of Insulin on hepatic gene expression using the model of the Insulin-like growth factor binding protein-1 (IGFBP-1) promoter. Insulin lowers IGFBP-1 mRNA levels, inhibits IGFBP-1 promoter activity, and activates PKB/Akt in HepG2 hepatoma cells through a PI3K-dependent, rapamycin-insensitive mechanism. Constitutively active PI3K and PKB/Akt are each sufficient to mediate effects of Insulin on the IGFBP-1 promoter in a nonadditive fashion. Dominant negative K179 PKB/Akt disrupts the ability of Insulin and PI3K to activate PKB/Akt and to inhibit promoter activity. The IGFBP-1 promoter contains two IRSs each of which is sufficient to mediate sequence-specific effects of Insulin, PI3K, and PKB/Akt on promoter activity. Highly related IRSs from the phosphoenolpyruvate carboxykinase and apolipoprotein CIII genes also are effective in this setting. These results indicate that PKB/Akt functions downstream from PI3K in mediating sequence-specific effects of Insulin on the expression of IGFBP-1 and perhaps multiple hepatic genes through a conserved IRS.
David R Powell - One of the best experts on this subject based on the ideXlab platform.
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the three Insulin Response sequences in the glucose 6 phosphatase catalytic subunit gene promoter are functionally distinct
Journal of Biological Chemistry, 2003Co-Authors: Beth Vander T Kooi, Ryan S Streeper, Christina A Svitek, David R Powell, James K Oeser, Richard M ObrienAbstract:Abstract Glucose-6-phosphatase catalyzes the terminal step in the gluconeogenic and glycogenolytic pathways. In HepG2 cells, the maximum repression of basal glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription by Insulin requires two distinct promoter regions, designated A (located between −231 and −199) and B (located between −198 and −159), that together form an Insulin Response unit. Region A binds hepatocyte nuclear factor-1, which acts as an accessory factor to enhance the effect of Insulin, mediated through region B, on G6Pase gene transcription. We have previously shown that region B binds the transcriptional activator FKHR (FOXO1a) in vitro. Chromatin immunoprecipitation assays demonstrate that FKHR also binds the G6Pase promoter in situ and that Insulin inhibits this binding. Region B contains three Insulin Response sequences (IRSs), designated IRS 1, 2, and 3, that share the core sequence T(G/A)TTTT. However, detailed analyses reveal that these three G6Pase IRSs are functionally distinct. Thus, FKHR binds IRS 1 with high affinity and IRS 2 with low affinity but it does not bind IRS 3. Moreover, in the context of the G6Pase promoter, IRS 1 and 2, but not IRS 3, are required for the Insulin Response. Surprisingly, IRS 3, as well as IRS 1 and IRS 2, can each confer an inhibitory effect of Insulin on the expression of a heterologous fusion gene, indicating that, in this context, a transcription factor other than FKHR, or its orthologs, can also mediate an Insulin Response through the T(G/A)TTTT motif.
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conservation of an Insulin Response unit between mouse and human glucose 6 phosphatase catalytic subunit gene promoters transcription factor fkhr binds the Insulin Response sequence
Diabetes, 1999Co-Authors: Julio E Ayala, Frederic G Barr, Ryan S Streeper, Jay S Desgrosellier, Susan K Durham, Adisak Suwanichkul, Christina A Svitek, Joshua K Goldman, David R Powell, Richard M ObrienAbstract:Because overexpression of the glucose-6-phosphatase catalytic subunit (G-6-Pase) in both type 1 and type 2 diabetes may contribute to the characteristic increased rate of hepatic glucose production, we have investigated whether the Insulin Response unit (IRU) identified in the mouse G-6-Pase promoter is conserved in the human promoter. A series of human G-6-Pase-chloramphenicol acetyltransferase (CAT) fusion genes was transiently transfected into human HepG2 hepatoma cells, and the effect of Insulin on basal CAT expression was analyzed. The results suggest that the IRU identified in the mouse promoter is conserved in the human promoter, but that an upstream multimerized Insulin Response sequence (IRS) motif that is only found in the human promoter appears to be functionally inactive. The G-6-Pase IRU comprises two distinct promoter regions, designated A and B. Region B contains an IRS, whereas region A acts as an accessory element to enhance the effect of Insulin, mediated through region B, on basal G-6-Pase gene transcription. We have previously shown that the accessory factor binding region A is hepatocyte nuclear factor-1, and we show here that the forkhead protein FKHR is a candidate for the Insulin-responsive transcription factor binding region B.
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hepatic nuclear factor 3 and high mobility group i y proteins bind the Insulin Response element of the Insulin like growth factor binding protein 1 promoter
Endocrinology, 1997Co-Authors: Susanne V Allander, Susan K Durham, Adisak Suwanichkul, Ann O Scheimann, Richard M Wasserman, David R PowellAbstract:The Insulin Response element (IRE) of the human Insulin-like growth factor-binding protein-1 (IGFBP-1) promoter contains a palindrome of the T(A/G)TTT sequence crucial to hormonal regulation of many genes. In initial studies of how this IRE participates in hormonal regulation, the electromobility shift assay was used under a variety of conditions to identify IRE-binding proteins. An exhaustive search identified five proteins that specifically bind this IRE; purified proteins were used to show that all five are related to either the high mobility group I/Y (HMGI/Y) or hepatic nuclear factor 3 (HNF3) protein families. Further studies used purified HNF3 and HMGI proteins to show: 1) each protects the IGFBP-1 IRE from deoxyribonuclease I (DNaseI) digestion; and 2) HNF3 but not HMGI/Y binds to the related phosphoenolpyruvate carboxykinase and Apo CIII IREs. A series of IRE mutants with variable responsiveness to Insulin were used to show that the presence of a TGTTT sequence in the mutants did parallel, but HM...
Mohammad F Saad - One of the best experts on this subject based on the ideXlab platform.
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Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level
Metabolism-clinical and Experimental, 2000Co-Authors: Ken C Chiu, Leeming Chuang, Jennifer L Mcgullam, George P Tsai, Mohammad F SaadAbstract:Abnormal glucose metabolism and a high prevalence of diabetes have been reported in patients with primary and secondary hyperparathyroidism. We hypothesize that plasma intact parathyroid hormone (iPTH) level is a determinant of either Insulin sensitivity or β-cell function. The study included 52 normotensive, healthy subjects with glucose tolerance. Insulin sensitivity and β-cell function were assessed using a hyperglycemic clamp. Fasting plasma iPTH was determined. The relationships between its level and Insulin sensitivity index and β-cell function were examined. Insulin sensitivity index was inversely correlated with plasma iPTH level (r2 = .104, P = .020). The first phase Insulin Response was positively correlated with plasma iPTH level (r2 = .098, P = .023), but no correlation existed with the second phase Insulin Response. After adjusting for age, gender, ethnicity, and waist-to-hip ratio, plasma iPTH level was an independent determinant of Insulin sensitivity index (P = .019). However, no independent relationship between plasma iPTH level and β-cell function (the first phase and second phase Insulin Response) was found. In normotensive, glucose-tolerant, and healthy subjects, plasma iPTH level accounts for 10.4% of the variation in Insulin sensitivity index. For each pg/mL increment in plasma iPTH level, there is a decrease of 0.247 μmol/L/m2/min/pmol/L in Insulin sensitivity index. Although the molecular basis of this relationship is not clear, our results indicate that plasma iPTH level is inversely correlated with Insulin sensitivity index. Copyright © 2000 by W.B. Saunders Company
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Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level
Metabolism-clinical and Experimental, 2000Co-Authors: Ken C Chiu, Leeming Chuang, Jennifer L Mcgullam, George P Tsai, Nancy P Lee, Jennifer M Ryu, Mohammad F SaadAbstract:Abnormal glucose metabolism and a high prevalence of diabetes have been reported in patients with primary and secondary hyperparathyroidism. We hypothesize that plasma intact parathyroid hormone (iPTH) level is a determinant of either Insulin sensitivity or beta-cell function. The study included 52 normotensive, healthy subjects with glucose tolerance. Insulin sensitivity and beta-cell function were assessed using a hyperglycemic clamp. Fasting plasma iPTH was determined. The relationships between its level and Insulin sensitivity index and beta-cell function were examined. Insulin sensitivity index was inversely correlated with plasma iPTH level (r2 = .104, P = .020). The first phase Insulin Response was positively correlated with plasma iPTH level (r2 = .098, P = .023), but no correlation existed with the second phase Insulin Response. After adjusting for age, gender, ethnicity, and waist-to-hip ratio, plasma iPTH level was an independent determinant of Insulin sensitivity index (P = .019). However, no independent relationship between plasma iPTH level and beta-cell function (the first phase and second phase Insulin Response) was found. In normotensive, glucose-tolerant, and healthy subjects, plasma iPTH level accounts for 10.4% of the variation in Insulin sensitivity index. For each pg/mL increment in plasma iPTH level, there is a decrease of 0.247 micromol/L/m2/min/pmol/L in Insulin sensitivity index. Although the molecular basis of this relationship is not clear, our results indicate that plasma iPTH level is inversely correlated with Insulin sensitivity index.
Tina Vilsboll - One of the best experts on this subject based on the ideXlab platform.
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the pathophysiology of diabetes involves a defective amplification of the late phase Insulin Response to glucose by glucose dependent Insulinotropic polypeptide regardless of etiology and phenotype
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Sten Madsbad, Tina Vilsboll, Filip K Knop, Thure Krarup, A Johansen, Steen Larsen, T Hansen, Oluf Pedersen, J J HolstAbstract:The effect of the Insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1), is preserved in typical middle-aged, obese, Insulin-resistant type 2 diabetic patients, whereas a defective amplification of the so-called late-phase plasma Insulin Response (20–120 min) to glucose by the other incretin hormone, glucose-dependent Insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma Insulin and C-peptide Responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2 diabetic patients. We studied (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis; 2) lean type 2 diabetic patients (body mass index < 25 kg/m2); 3) patients with latent autoimmune diabetes in adults; 4) diabetic patients with mutations in the HNF-1α gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three ...
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the pathophysiology of diabetes involves a defective amplification of the late phase Insulin Response to glucose by glucose dependent Insulinotropic polypeptide regardless of etiology and phenotype
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Sten Madsbad, Tina Vilsboll, Filip K Knop, Thure Krarup, A Johansen, Steen Larsen, T Hansen, Oluf Pedersen, J J HolstAbstract:The effect of the Insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1), is preserved in typical middle-aged, obese, Insulin-resistant type 2 diabetic patients, whereas a defective amplification of the so-called late-phase plasma Insulin Response (20-120 min) to glucose by the other incretin hormone, glucose-dependent Insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma Insulin and C-peptide Responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2 diabetic patients. We studied (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis; 2) lean type 2 diabetic patients (body mass index < 25 kg/m(2)); 3) patients with latent autoimmune diabetes in adults; 4) diabetic patients with mutations in the HNF-1alpha gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three hyperglycemic clamps (2 h, 15 mM) with continuous infusion of saline, 1 pmol GLP-1 (7-36)amide/kg body weight.min or 4 pmol GIP pmol/kg body weight.min. The early-phase (0-20 min) plasma Insulin Response tended to be enhanced by both GIP and GLP-1, compared with glucose alone, in all five groups. In contrast, the late-phase (20-120 min) plasma Insulin Response to GIP was attenuated, compared with the plasma Insulin Response to GLP-1, in all five groups. Significantly higher glucose infusion rates were required during the late phase of the GLP-1 stimulation, compared with the GIP stimulation. In conclusion, lack of GIP amplification of the late-phase plasma Insulin Response to glucose seems to be a consequence of diabetes mellitus, characterizing most, if not all, forms of diabetes.
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defective amplification of the late phase Insulin Response to glucose by gip in obese type ii diabetic patients
Diabetologia, 2002Co-Authors: Tina Vilsboll, Sten Madsbad, Thure Krarup, Jens Moller HolstAbstract:Abstract Aims/hypothesis. Glucagon-like-peptide-1 (GLP-1) is strongly Insulinotropic in patients with Type II (non-Insulin-dependent) diabetes mellitus, whereas glucose-dependent Insulinotropic polypeptide (GIP) is less effective. Our investigation evaluated "early" (protocol 1) – and "late phase" (protocol 2) Insulin and C-peptide Responses to GLP-1 and GIP stimulation in patients with Type II diabetes. Methods. Protocol 1: eight Type II diabetic patients and eight matched healthy subjects received i.v. bolus injections of GLP-1(2.5 nmol) or GIP(7.5 nmol) concomitant with an increase of plasma glucose to 15 mmol/l. Protocol 2: eight Type II diabetic patients underwent a hyperglycaemic clamp (15 mmol/l) with infusion (per kg body weight/min) of either: 1 pmol GLP-1 (7–36) amide (n=8), 4 pmol GIP (n=8), 16 pmol GIP (n=4) or no incretin hormone (n=5). For comparison, six matched healthy subjects were examined. Results. Protocol 1: Type II diabetic patients were characterised by a decreased "early phase" Response to both stimuli, but their relative Response to GIP versus GLP-1 stimulation was exactly the same as in healthy subjects [Insulin (C-peptide): patients 59±9% (74±6%) and healthy subjects 62±5% (71±9%)]. Protocol 2, "Early phase" (0–20 min) Insulin Response to glucose was delayed and reduced in the patients, but enhanced slightly and similarly by GIP and GLP-1. GLP-1 augmented the "late phase" (20–120 min) Insulin secretion to levels similar to those observed in healthy subjects. In contrast, the "late phase" Responses to both doses of GIP were not different from those obtained with glucose alone. Accordingly, glucose infusion rates required to maintain the hyperglycaemic clamp in the "late phase" period (20–120 min) were similar with glucose alone and glucose plus GIP, whereas a doubling of the infusion rate was required during GLP-1 stimulation. Conclusion/interpretation. Lack of GIP amplification of the late phase Insulin Response to glucose, which contrasts markedly to the normalising effect of GLP-1, could be a key defect in Insulin secretion in Type II diabetic patients.