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Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes.

Chia CW, Carlson OD, Kim W, Shin YK, Charles CP, Kim HS, Melvin DL, Egan JM - Diabetes (2009)

Bottom Line: Intriguingly, GIP also induced an early postprandial augmentation in glucagon, a significant elevation in late postprandial glucose, and a decrease in late postprandial GLP-1 levels.However, with a concomitant increase in glucagon, the glucose-lowering effect was lost.GIP infusion further worsened hyperglycemia postprandially, most likely through its suppressive effect on GLP-1.

View Article: PubMed Central - PubMed

Affiliation: National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA.

ABSTRACT

Objective: Glucose-dependent insulinotropic polypeptide (GIP), unlike glucagon-like peptide (GLP)-1, lacks glucose-lowering properties in patients with type 2 diabetes. We designed this study to elucidate the underlying pathophysiology.

Research design and methods: Twenty-two insulin-naïve subjects with type 2 diabetes were given either synthetic human GIP (20 ng x kg(-1) x min(-1)) or placebo (normal saline) over 180 min, starting with the first bite of a mixed meal (plus 1 g of acetaminophen) on two separate occasions. Frequent blood samples were obtained over 6 h to determine plasma GIP, GLP-1, glucose, insulin, glucagon, resistin, and acetaminophen levels.

Results: Compared with placebo, GIP induced an early postprandial increase in insulin levels. Intriguingly, GIP also induced an early postprandial augmentation in glucagon, a significant elevation in late postprandial glucose, and a decrease in late postprandial GLP-1 levels. Resistin and acetaminophen levels were comparable in both interventions. By immunocytochemistry, GIP receptors were present on human and mouse alpha-cells. In alphaTC1 cell line, GIP induced an increase in intracellular cAMP and glucagon secretion. CONCLUSIONS; GIP, given to achieve supraphysiological plasma levels, still had an early, short-lived insulinotropic effect in type 2 diabetes. However, with a concomitant increase in glucagon, the glucose-lowering effect was lost. GIP infusion further worsened hyperglycemia postprandially, most likely through its suppressive effect on GLP-1. These findings make it unlikely that GIP or GIP receptor agonists will be useful in treating the hyperglycemia of patients with type 2 diabetes.

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AUCALL (t = 0–360 min) for GIP (A-1), insulin (B-1), glucose (C-1), glucagon (D-1), and GLP-1 (E-1) during placebo (blue) and GIP infusion (orange). With fasting values (t = 0) serving as baseline levels, positive AUC and negative AUC corresponded to area above and below baseline levels, respectively. The AUC for each curve, AUCALL (t = 0–360 min), was further divided into different time periods: AUC0–60 (t = 0–60 min), AUC60–120 (t = 60–120 min), AUC120–220 (t = 120–220 min), and AUC220–360 (t = 220–360 min) to better quantify the changes in response to placebo versus GIP infusion for GIP (A-2), insulin (B-2), glucose (C-2), glucagon (D-2), and GLP-1 (E-2). ***P < 0.001; **P < 0.01; *P < 0.05.
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Figure 3: AUCALL (t = 0–360 min) for GIP (A-1), insulin (B-1), glucose (C-1), glucagon (D-1), and GLP-1 (E-1) during placebo (blue) and GIP infusion (orange). With fasting values (t = 0) serving as baseline levels, positive AUC and negative AUC corresponded to area above and below baseline levels, respectively. The AUC for each curve, AUCALL (t = 0–360 min), was further divided into different time periods: AUC0–60 (t = 0–60 min), AUC60–120 (t = 60–120 min), AUC120–220 (t = 120–220 min), and AUC220–360 (t = 220–360 min) to better quantify the changes in response to placebo versus GIP infusion for GIP (A-2), insulin (B-2), glucose (C-2), glucagon (D-2), and GLP-1 (E-2). ***P < 0.001; **P < 0.01; *P < 0.05.

Mentions: The average fasting values (t = 0) for all plasma glucose and hormones were not statistically different between placebo and GIP intervention: GIPplacebo = 43.3 ± 6.5 pmol/l, GIPGIP = 47.9 ± 10.0 pmol/l, P = 0.408; insulinplacebo = 12.7 ± 1.5 μU/ml, insulinGIP = 11.5 ± 1.1 μU/ml, P = 0.220; glucoseplacebo = 159.3 ± 11.0 mg/dl, glucoseGIP = 155.0 ± 10.0 mg/dl, P = 0.431; glucagonplacebo = 99.1 ± 8.4 ρg/ml, glucagonGIP = 107.7 ± 9.7 ρg/ml, P = 0.054; and GLP-1placebo = 5.1 ± 0.9 pmol/l, GLP-1GIP = 5.4 ± 1.0 pmol/l, P = 0.205. Mixed meal alone induced an increase in fasting GIP levels in placebo from ∼43 ± 6 to 91 ± 10 pmol/l (average from 60 to 180 min). When GIP was infused from 0 to 180 min with a meal, mean GIP levels went from 48 ± 10 pmol/l at baseline to 495 ± 44 pmol/l (average from 60 to 180 min) (Fig. 2A). Upon termination of infusion, GIP levels rapidly decreased and approached fasting levels by the end of the study. As expected, the difference in plasma GIP levels between placebo and GIP infusion was statistically significant (P < 0.001) at all time periods, as calculated by both single time point comparisons and AUC analyses (Fig. 2A andFig. 3A-1– A-2).


Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes.

Chia CW, Carlson OD, Kim W, Shin YK, Charles CP, Kim HS, Melvin DL, Egan JM - Diabetes (2009)

AUCALL (t = 0–360 min) for GIP (A-1), insulin (B-1), glucose (C-1), glucagon (D-1), and GLP-1 (E-1) during placebo (blue) and GIP infusion (orange). With fasting values (t = 0) serving as baseline levels, positive AUC and negative AUC corresponded to area above and below baseline levels, respectively. The AUC for each curve, AUCALL (t = 0–360 min), was further divided into different time periods: AUC0–60 (t = 0–60 min), AUC60–120 (t = 60–120 min), AUC120–220 (t = 120–220 min), and AUC220–360 (t = 220–360 min) to better quantify the changes in response to placebo versus GIP infusion for GIP (A-2), insulin (B-2), glucose (C-2), glucagon (D-2), and GLP-1 (E-2). ***P < 0.001; **P < 0.01; *P < 0.05.
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Related In: Results  -  Collection

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Figure 3: AUCALL (t = 0–360 min) for GIP (A-1), insulin (B-1), glucose (C-1), glucagon (D-1), and GLP-1 (E-1) during placebo (blue) and GIP infusion (orange). With fasting values (t = 0) serving as baseline levels, positive AUC and negative AUC corresponded to area above and below baseline levels, respectively. The AUC for each curve, AUCALL (t = 0–360 min), was further divided into different time periods: AUC0–60 (t = 0–60 min), AUC60–120 (t = 60–120 min), AUC120–220 (t = 120–220 min), and AUC220–360 (t = 220–360 min) to better quantify the changes in response to placebo versus GIP infusion for GIP (A-2), insulin (B-2), glucose (C-2), glucagon (D-2), and GLP-1 (E-2). ***P < 0.001; **P < 0.01; *P < 0.05.
Mentions: The average fasting values (t = 0) for all plasma glucose and hormones were not statistically different between placebo and GIP intervention: GIPplacebo = 43.3 ± 6.5 pmol/l, GIPGIP = 47.9 ± 10.0 pmol/l, P = 0.408; insulinplacebo = 12.7 ± 1.5 μU/ml, insulinGIP = 11.5 ± 1.1 μU/ml, P = 0.220; glucoseplacebo = 159.3 ± 11.0 mg/dl, glucoseGIP = 155.0 ± 10.0 mg/dl, P = 0.431; glucagonplacebo = 99.1 ± 8.4 ρg/ml, glucagonGIP = 107.7 ± 9.7 ρg/ml, P = 0.054; and GLP-1placebo = 5.1 ± 0.9 pmol/l, GLP-1GIP = 5.4 ± 1.0 pmol/l, P = 0.205. Mixed meal alone induced an increase in fasting GIP levels in placebo from ∼43 ± 6 to 91 ± 10 pmol/l (average from 60 to 180 min). When GIP was infused from 0 to 180 min with a meal, mean GIP levels went from 48 ± 10 pmol/l at baseline to 495 ± 44 pmol/l (average from 60 to 180 min) (Fig. 2A). Upon termination of infusion, GIP levels rapidly decreased and approached fasting levels by the end of the study. As expected, the difference in plasma GIP levels between placebo and GIP infusion was statistically significant (P < 0.001) at all time periods, as calculated by both single time point comparisons and AUC analyses (Fig. 2A andFig. 3A-1– A-2).

Bottom Line: Intriguingly, GIP also induced an early postprandial augmentation in glucagon, a significant elevation in late postprandial glucose, and a decrease in late postprandial GLP-1 levels.However, with a concomitant increase in glucagon, the glucose-lowering effect was lost.GIP infusion further worsened hyperglycemia postprandially, most likely through its suppressive effect on GLP-1.

View Article: PubMed Central - PubMed

Affiliation: National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA.

ABSTRACT

Objective: Glucose-dependent insulinotropic polypeptide (GIP), unlike glucagon-like peptide (GLP)-1, lacks glucose-lowering properties in patients with type 2 diabetes. We designed this study to elucidate the underlying pathophysiology.

Research design and methods: Twenty-two insulin-naïve subjects with type 2 diabetes were given either synthetic human GIP (20 ng x kg(-1) x min(-1)) or placebo (normal saline) over 180 min, starting with the first bite of a mixed meal (plus 1 g of acetaminophen) on two separate occasions. Frequent blood samples were obtained over 6 h to determine plasma GIP, GLP-1, glucose, insulin, glucagon, resistin, and acetaminophen levels.

Results: Compared with placebo, GIP induced an early postprandial increase in insulin levels. Intriguingly, GIP also induced an early postprandial augmentation in glucagon, a significant elevation in late postprandial glucose, and a decrease in late postprandial GLP-1 levels. Resistin and acetaminophen levels were comparable in both interventions. By immunocytochemistry, GIP receptors were present on human and mouse alpha-cells. In alphaTC1 cell line, GIP induced an increase in intracellular cAMP and glucagon secretion. CONCLUSIONS; GIP, given to achieve supraphysiological plasma levels, still had an early, short-lived insulinotropic effect in type 2 diabetes. However, with a concomitant increase in glucagon, the glucose-lowering effect was lost. GIP infusion further worsened hyperglycemia postprandially, most likely through its suppressive effect on GLP-1. These findings make it unlikely that GIP or GIP receptor agonists will be useful in treating the hyperglycemia of patients with type 2 diabetes.

Show MeSH
Related in: MedlinePlus