Top

Diabetologia

Published in:

01-02-2009 | Article

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Authors: P. V. Højberg, T. Vilsbøll, R. Rabøl, F. K. Knop, M. Bache, T. Krarup, J. J. Holst, S. Madsbad

Published in: Diabetologia | Issue 2/2009

Abstract

Objective

The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes.

Methods

Eight obese patients with type 2 diabetes with poor glycaemic control (HbA_1c 8.6 ± 1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4 ± 1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve.

Results

Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0–10 min). The late phase C-peptide response (10–120 min) increased during GIP infusion from 33.0 ± 8.5 to 103.9 ± 24.2 (nmol/l) × (110 min)⁻¹ (p < 0.05) and during GLP-1 infusion from 48.7 ± 11.8 to 126.6 ± 32.5 (nmol/l) × (110 min)⁻¹ (p < 0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2 ± 11.2 vs 46.5 ± 12.7 [nmol/l] × [110 min]⁻¹).

Conclusions

Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone.

ClinicalTrials.gov ID no.: NCT 00612950

Funding: This study was supported by The Novo Nordisk Foundation, The Medical Science Research Foundation for Copenhagen.

Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110PubMedCrossRef

Porte D Jr (1991) Banting lecture 1990. Beta-cells in type II diabetes mellitus. Diabetes 40:166–180PubMedCrossRef

Turner R, Cull C, Holman R (1996) United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med 124:136–145PubMed

Creutzfeldt W, Nauck M (1992) Gut hormones and diabetes mellitus. Diabetes Metab Rev 8:149–177PubMed

Nauck M, Stockmann F, Ebert R, Creutzfeldt W (1986) Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29:46–52PubMedCrossRef

Tronier B, Dejgaard A, Madsbad S (1985) Absence of incretin effect in obese type 2 and diminished effect in lean type 2 and obese subjects. Diab Res Clin Pract (Suppl 1):S568

Vilsboll T, Krarup T, Madsbad S, Holst JJ (2002) Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia 45:1111–1119PubMedCrossRef

Vilsboll T, Knop FK, Krarup T et al (2003) 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. J Clin Endocrinol Metab 88:4897–4903PubMedCrossRef

Toft-Nielsen MB, Damholt MB, Madsbad S et al (2001) Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 86:3717–3723PubMedCrossRef

10.

Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ (2001) Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 50:609–613PubMedCrossRef

11.

Dube PE, Brubaker PL (2004) Nutrient, neural and endocrine control of glucagon-like peptide secretion. Horm Metab Res 36:755–760PubMedCrossRef

12.

Holst JJ (2004) On the physiology of GIP and GLP-1. Horm Metab Res 36:747–754PubMedCrossRef

13.

Deacon CF, Johnsen AH, Holst JJ (1995) Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 80:952–957PubMedCrossRef

14.

Vilsboll T, Agerso H, Krarup T, Holst JJ (2003) Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. J Clin Endocrinol Metab 88:220–224PubMedCrossRef

15.

Vilsboll T, Agerso H, Lauritsen T et al (2006) The elimination rates of intact GIP as well as its primary metabolite, GIP 3-42, are similar in type 2 diabetic patients and healthy subjects. Regulatory Pept 137:168–172CrossRef

16.

Anonymous (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:837–853CrossRef

17.

Anonymous (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:854–865CrossRef

18.

Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG (1985) The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 34:222–234PubMedCrossRef

19.

Gutniak M, Orskov C, Holst JJ, Ahren B, Efendic S (1992) Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med. 326:1316–1322PubMed

20.

Hidaka H, Nagulesparan M, Klimes I et al (1982) Improvement of insulin secretion but not insulin resistance after short term control of plasma glucose in obese type II diabetics. J Clin Endocrinol Metab 54:217–222PubMed

21.

Poitout V, Robertson RP (2002) Minireview: Secondary beta-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity. Endocrinology 143:339–342PubMedCrossRef

22.

Schmeltz R, Wendorff HJ, Field JB (1978) Effect of control of blood glucose on plasma insulin responses to various stimuli in secondary failures to oral hypoglycemic agents and in newly diagnosed, maturity onset, ketosis-resistant diabetics. J Clin Endocrinol Metab 46:519–527PubMed

23.

Turner RC, McCarthy ST, Holman RR, Harris E (1976) Beta-cell function improved by supplementing basal insulin secretion in mild diabetes. Br Med J 1:1252–1254PubMed

24.

Vague P, Moulin JP (1982) The defective glucose sensitivity of the B cell in non insulin dependent diabetes. Improvement after twenty hours of normoglycaemia. Metabolism 31:139–142PubMedCrossRef

25.

Orskov C, Rabenhoj L, Wettergren A, Kofod H, Holst JJ (1994) Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes 43:535–539PubMedCrossRef

26.

Krarup T, Holst JJ (1984) The heterogeneity of gastric inhibitory polypeptide in porcine and human gastrointestinal mucosa evaluated with five different antisera. Regulatory Pept 9:35–46CrossRef

27.

Krarup T, Madsbad S, Moody AJ et al (1983) Diminished immunoreactive gastric inhibitory polypeptide response to a meal in newly diagnosed type I (insulin-dependent) diabetics. J Clin Endocrinol Metab 56:1306–1312PubMedCrossRef

28.

Orskov C, Jeppesen J, Madsbad S, Holst JJ (1991) Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine. J Clin Invest 87:415–423PubMedCrossRef

29.

Knop FK, Vilsboll T, Hojberg PV et al (2007) The insulinotropic effect of GIP is impaired in patients with chronic pancreatitis and secondary diabetes mellitus as compared to patients with chronic pancreatitis and normal glucose tolerance. Regul Pept 144:123–130PubMedCrossRef

30.

Piteau S, Olver A, Kim SJ et al (2007) Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat. Biochem Biophys Res Commun 362:1007–1012PubMedCrossRef

31.

Orskov C, Wettergren A, Holst JJ (1996) Secretion of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day. Scand J Gastroenterol 31:665–670PubMedCrossRef

32.

Fehse F, Trautmann M, Holst JJ et al (2005) Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 90:5991–5997PubMedCrossRef

33.

Zander M, Madsbad S, Madsen JL, Holst JJ (2002) Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 359:824–830PubMedCrossRef

34.

Bratusch-Marrain PR, Waldhausl WK (1985) Suppression of basal, but not of glucose-stimulated insulin secretion by human insulin in healthy and obese hyperinsulinemic subjects. Metabolism 34:188–193PubMedCrossRef

35.

Murayama Y, Kawai K, Watanabe Y, Yoshikawa H, Yamashita K (1989) Insulin and glucagon secretion are suppressed equally during both hyper- and euglycemia by moderate hyperinsulinemia in patients with diabetes mellitus. J Clin Endocrinol Metab 68:925–931PubMed

36.

Vilsboll T, Krarup T, Madsbad S, Holst JJ (2003) Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regulatory Pept 114:115–121CrossRef

37.

Kjems LL, Holst JJ, Volund A, Madsbad S (2003) The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52:380–386PubMedCrossRef

38.

Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W (1993) Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 91:301–307PubMedCrossRef

39.

Meier JJ, Gallwitz B, Askenas M et al (2005) Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes. Diabetologia 48:1872–1881PubMedCrossRef

40.

Meier JJ, Hucking K, Holst JJ, Deacon CF, Schmiegel WH, Nauck MA (2001) Reduced insulinotropic effect of gastric inhibitory polypeptide in first-degree relatives of patients with type 2 diabetes. Diabetes 50:2497–2504PubMedCrossRef

41.

Nauck MA, El Ouaghlidi A, Gabrys B et al (2004) Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes. Regul Pept 122:209–217PubMedCrossRef

42.

Hojberg PV, Zander M, Vilsboll T et al (2008) Near normalisation of blood glucose improves the potentiating effect of GLP-1 on glucose-induced insulin secretion in patients with type 2 diabetes. Diabetologia 51:632–640PubMedCrossRef

43.

Hojberg PV, Vilsboll T, Zander M et al (2006) 4-weeks of near-normalisation of blood glucose has no effect on postprandial GLP-1 secretion but enhances beta cell responsivenes during a meal in patients with type 2 diabetes. Diabetologia 49(Suppl. 1):403–404

44.

Kosaka K, Kuzuya T, Akanuma Y, Hagura R (1980) Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatment. Diabetologia 18:23–28PubMedCrossRef

45.

Ryskjaer J, Deacon CF, Carr RD et al (2006) Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbA1c levels, but is not acutely affected by food intake. Eur J Endocrinol 155:485–493PubMedCrossRef

46.

Ahren B, Gomis R, Standl E, Mills D, Schweizer A (2004) Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 27:2874–2880PubMedCrossRef

47.

Nauck MA, El-Ouaghlidi A (2005) The therapeutic actions of DPP-IV inhibition are not mediated by glucagon-like peptide-1. Diabetologia 48:608–611PubMedCrossRef

Title: Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes
Authors: P. V. Højberg
T. Vilsbøll
R. Rabøl
F. K. Knop
M. Bache
T. Krarup
J. J. Holst
S. Madsbad
Publication date: 01-02-2009
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 2/2009
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-008-1195-5

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Abstract

Objective

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Objective

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2009

Metabolic consequences of a 50% partial pancreatectomy in humans

Ramadan-focused education and awareness in type 2 diabetes

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area

FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians

Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors

Secular trend for mortality from breast cancer and the association between diabetes and breast cancer in Taiwan between 1995 and 2006

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page