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
Open accessAbstract
In type-2 diabetes, the overall incretin effect is reduced. The present investigation was designed to compare insulinotropic actions of exogenous incretin hormones (gastric inhibitory peptide [GIP] and glucagon-like peptide 1 [GLP-1] [7-36 amide]) in nine type-2 diabetic patients (fasting plasma glucose 7.8 mmol/liter; hemoglobin A1c 6.3 +/- 0.6%) and in nine age- and weight-matched normal subjects. Synthetic human GIP (0.8 and 2.4 pmol/kg.min over 1 h each), GLP-1 [7-36 amide] (0.4 and 1.2 pmol/kg.min over 1 h each), and placebo were administered under hyperglycemic clamp conditions (8.75 mmol/liter) in separate experiments. Plasma GIP and GLP-1 [7-36 amide] concentrations (radioimmunoassay) were comparable to those after oral glucose with the low, and clearly supraphysiological with the high infusion rates. Both GIP and GLP-1 [7-36 amide] dose-dependently augmented insulin secretion (insulin, C-peptide) in both groups (P < 0.05). With GIP, the maximum effect in type-2 diabetic patients was significantly lower (by 54%; P < 0.05) than in normal subjects. With GLP-1 [7-36 amide] type-2 diabetic patients reached 71% of the increments in C-peptide of normal subjects (difference not significant). Glucagon was lowered during hyperglycemic clamps in normal subjects, but not in type-2 diabetic patients, and further by GLP-1 [7-36 amide] in both groups (P < 0.05), but not by GIP. In conclusion, in mild type-2 diabetes, GLP-1 [7-36 amide], in contrast to GIP, retains much of its insulinotropic activity. It also lowers glucagon concentrations.
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In individuals with T2DM, there is a decrease in the incretin effect primarily attributed to the diminished effects of gastric inhibitory polypeptide (GIP).
“In individuals with T2DM, there is a decrease in the incretin effect which primarily attributed to the diminished effects of gastric inhibitory polypeptide (GIP).9”
From GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review (2024) · cites this paper as [9]
The Discussion (page not available) reports a reduced or absent incretin effect in type-2 diabetes and substantially reduced insulin-secretory responsiveness to GIP. It says GIP probably contributes little in these patients, but the study did not quantify the overall incretin effect or establish that diminished GIP action is its primary cause; it also notes that the GLP-1 response may be insufficient. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGLP-1 has therapeutic potential for reducing elevated plasma glucose and body weight, while GIP is unable to stimulate insulin secretion or lower plasma glucose effectively in T2D.
“Among the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), the latter has been established as having therapeutic potential for reducing elevated plasma glucose (1, 2) and body weight (3), while the former has been unable to either stimulate insulin secretion (1) or lower plasma glucose effectively in type 2 diabetes (T2D) (4).”
From The science of safety: adverse effects of GLP-1 receptor agonists as glucose-lowering and obesity medications (2026) · cites this paper as [1]
The Discussion supports GLP-1’s potential to lower plasma glucose in type 2 diabetes and describes GIP’s insulinotropic activity as greatly reduced. But the paper also reports that GIP significantly increased insulin secretion in the patients, so saying it was unable to stimulate insulin secretion overstates the result. The body-weight and GIP glucose-lowering claims are attached to other citations in the citing sentence. (LLM, conf=0.90)
Experimental — accuracy not yet measuredDespite differences in populations and treatment length, the amount of weight loss with tirzepatide was largely consistent with the SURPASS trials.
“Despite the slight differences based on the subject cohort and the duration of treatment, this magnitude of weight loss was largely consistent with the SURPASS trials132-140.”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [137]
The Methods and Results describe short infusions of GIP and GLP-1 [7-36 amide] and measure insulin-related responses, not weight loss. Searches for tirzepatide, SURPASS trials, and weight-loss outcomes found no passage in our copy addressing the claimed comparison. (LLM, conf=0.79)
Experimental — accuracy not yet measuredIn T2D, the endocrine pancreas ceases responsiveness to GIP but remains responsive to GLP-1, explaining the reduced or absent incretin effect of GIP in T2D.
“which is not observed in the set of T2D where the endocrine pancreas ceases responsiveness to GIP but remains responsive to GLP-1, explaining the reduced/absent incretin effect of GIP in T2D [22,23].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [23]
GIP action is lost in T2D and even infusions of GIP that result in supraphysiological concentrations fail to elicit a significant insulin secretory response in T2D patients.
“However, GIP action is lost in T2D and even infusions of GIP that result in supraphysiological concentrations fail to elicit a significant insulin secretory response in T2D patients.160”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [160]
In type 2 diabetes, attenuated insulinotropic action of GIP and sometimes attenuated GLP-1 secretion contribute to impaired postprandial insulin secretion insufficient to maintain euglycaemia.
“in type 2 diabetes, a markedly attenuated insulinotropic action of GIP (66) and, in some cases, attenuated secretion of GLP-1 (67), contribute to an impairment of postprandial insulin secretion, so that the latter is insufficient to maintain euglycaemia.”
From Gut mechanisms linking intestinal sweet sensing to glycemic control (2018) · cites this paper as [66]
In GIP/GLP-1 dual agonism, GLP-1 quells the potential glucagon-stimulatory effects of GIP and also (re)sensitizes beta cells to GIP's incretin effects, while potentially enhancing GIP's beneficial effects on weight regulation mechanisms.
“In the setting of GIP/GLP-1 receptor agonist (dual agonism), GLP-1 quells the potential glucagon-stimulatory effects of GIP (64) and also (re)sensitizes beta cells to GIP's incretin effects (57), all while potentially enhancing GIP's beneficial effects on weight regulation mechanisms.”
From New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics (2023) · cites this paper as [57]
GIP-stimulated insulin secretion is significantly blunted in individuals with T2D, but responsiveness can be restored by mitigating hyperglycemia.
“It remained in the shadow of GLP-1, partly because GIP-stimulated insulin secretion is significantly blunted in individuals with T2D (56); notably, responsiveness can be restored by mitigating hyperglycemia (57).”
From New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics (2023) · cites this paper as [57]
GLP-1 suppresses glucagon release and reduces hepatic glucose production.
“GIP has been found to stimulate glucagon secretion, particularly at lower glucose values [14], whereas GLP-1 suppresses glucagon release and, consequently, reduces hepatic glucose production [15].”
From Adipose Tissue: A Novel Target of the Incretin Axis? A Paradigm Shift in Obesity-Linked Insulin Resistance (2024) · cites this paper as [15]
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Self-citation
- Authors
- Nauck, M. A., Heimesaat, M. M., Orskov, C., Holst, J. J., Ebert, R., & Creutzfeldt, W.
- Affiliations
- University of Göttingen (DE)
- University of Copenhagen (DK)
- Rigshospitalet (DK)
- Venue
- Journal of Clinical Investigation
- Published
- 1993-01-01
- Volume
- 91
- Issue
- 1
- Pages
- 301-307
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC330027
- OpenAlex
- W1969932276
- Cited by
- 1,651
- References
- 41
- Citations by year
- 2026: 45 · 2025: 51 · 2024: 63 · 2023: 63 · 2022: 57 · 2021: 57 · 2020: 50 · 2019: 70 · 2018: 50 · 2017: 49 · 2016: 71 · 2015: 62 · 2014: 75 · 2013: 84 · 2012: 59
- FWCI
- 16.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (203/2-1)
- 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
- glucagon-like peptide-1, GLP-1(7-36)amide, glucose-dependent insulinotropic polypeptide, type 2 diabetes, insulin secretion, C-peptide, glucagon, hyperglycemic clamp, incretin resistance
- MeSH terms
- Insulin Secretion, Blood Glucose, C-Peptide, Diabetes Mellitus, Type 2, Glucagon-Like Peptides, Female, Gastric Inhibitory Polypeptide, Glucagon, Glycated Hemoglobin, Humans, Insulin, Kinetics, Male, Middle Aged, Peptide Fragments, Protein Precursors, Reference Values, Time Factors, Glucose Clamp Technique, Glucagon-Like Peptide 1
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