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
Open accessAbstract
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) x (110 min)(-1) (p < 0.05) and during GLP-1 infusion from 48.7 +/- 11.8 to 126.6 +/- 32.5 (nmol/l) x (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] x [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.
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Patients with obesity have impaired incretin secretion.
“Patients with obesity have impaired incretin secretion (Højberg et al, 2009).”
From Emerging pharmacotherapies for obesity: A systematic review (2025) · cites this paper as Højberg et al, 2009
The Introduction (page unavailable) reports reduced incretin-hormone secretion in patients with type 2 diabetes, not in patients with obesity generally. The Discussion (page unavailable) addresses impaired insulin responses to infused incretins, which is distinct from impaired incretin secretion. The claim extends the reported secretion finding to a different population. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn a meta-analysis of more than 41,000 people, after 1 year, at least 10% weight loss occurred in 62.1% on tirzepatide and 38.0% on semaglutide.
“After 1 year of treatment, weight loss of ≥10% was achieved in 62.1% of subjects receiving tirzepatide, and in 38.0% of subjects receiving semaglutide149.”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [149]
The Methods describe a study of eight patients with type 2 diabetes, and the Insulin treatment section reports outcomes after four weeks. Searches for tirzepatide, semaglutide, the stated percentages, and a one-year meta-analysis found no passage addressing the claimed weight-loss results. Page numbers were not available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredEarly evidence indicated that tirzepatide caused additional weight loss of 4.3% at 6 months and 7.2% at 12 months, with no difference in gastrointestinal side effects.
“Preliminary evidence further suggested that treatment with tirzepatide led to additional weight loss of −4.3% after 6 months, and −7.2% after 12 months, without differences in the occurrence of gastrointestinal adverse effects149.”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [149]
The Methods describe four weeks of insulin treatment, and the Discussion addresses changes in responses to GLP-1 and GIP. Searches for tirzepatide, the 6- and 12-month weight-loss figures, and gastrointestinal adverse effects found no passage addressing the attributed claim (page numbers unavailable). (LLM, conf=0.78)
Experimental — accuracy not yet measuredIntensive insulin administration treatment results in improved insulin secretion from islet beta-cells after GIP infusion.
“Studies have demonstrated that intensive insulin administration treatment results in improved insulin secretion from islet beta-cells after GIP infusion.161,162”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [161]
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- Authors
- Højberg, P. V., Vilsbøll, T., Rabøl, R., Knop, F. K., Bache, M., Krarup, T., Holst, J. J., & Madsbad, S.
- Affiliations
- Hvidovre Hospital (DK)
- Gentofte Hospital (DK)
- University of Copenhagen (DK)
- Corresponding author
- Højberg, P. V.
- Venue
- Diabetologia
- Published
- 2008-11-27
- Volume
- 52
- Issue
- 2
- Pages
- 199-207
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W1967295307
- Cited by
- 414
- References
- 47
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 32 · 2023: 29 · 2022: 27 · 2021: 20 · 2020: 26 · 2019: 31 · 2018: 22 · 2017: 13 · 2016: 33 · 2015: 30 · 2014: 22 · 2013: 31 · 2012: 16
- FWCI
- 13.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Novo Nordisk
- Novo Nordisk Fonden
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- type 2 diabetes, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, incretin effect, insulin secretion, C-peptide response, hyperglycaemic clamp, insulin therapy, obesity, glycemic control, first-phase insulin secretion
- MeSH terms
- Adult, Blood Glucose, C-Peptide, Diabetes Mellitus, Type 2, Fasting, Gastric Inhibitory Polypeptide, Glycated Hemoglobin, Humans, Infusions, Intravenous, Insulin, Male, Middle Aged, Reference Values, Fructosamine, Glucagon-Like Peptide 1
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