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Cited by 71Adipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and MetabolismLipid metabolism and biosynthesis

Glucose-dependent insulinotropic polypeptide promotes lipid deposition in subcutaneous adipocytes in obese type 2 diabetes patients: a maladaptive response

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Thondam, Sravan K., Daousi, Christina, Wilding, John P. H., Holst, Jens J., Ameen, Gulizar I., Yang, Chenjing, Whitmore, Catherine, Mora, Silvia +1 more·2017·American Journal of Physiology-Endocrinology and Metabolism
DOI 10.1152/ajpendo.00347.2016
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Abstract

Glucose-dependent insulinotropic polypeptide (GIP) beyond its insulinotropic effects may regulate postprandial lipid metabolism. Whereas the insulinotropic action of GIP is known to be impaired in type 2 diabetes mellitus (T2DM), its adipogenic effect is unknown. We hypothesized that GIP is anabolic in human subcutaneous adipose tissue (SAT) promoting triacylglycerol (TAG) deposition through reesterification of nonesterified fatty acids (NEFA), and this effect may differ according to obesity status or glucose tolerance. Twenty-three subjects categorized into four groups, normoglycemic lean ( n = 6), normoglycemic obese ( n = 6), obese with impaired glucose regulation (IGR; n = 6), and obese T2DM ( n = 5), participated in a double-blind, randomized, crossover study involving a hyperglycemic clamp with a 240-min GIP infusion (2 pmol·kg −1 ·min −1 ) or normal saline. Insulin, NEFA, SAT-TAG content, and gene expression of key lipogenic enzymes were determined before and immediately after GIP/saline infusions. GIP lowered NEFA concentrations in the obese T2DM group despite diminished insulinotropic activity (mean NEFA AUC 0–4 h ± SE, 41,992 ± 9,843 µmol·l −1 ·min −1 vs. 71,468 ± 13,605 with placebo, P = 0.039, 95% CI: 0.31–0.95). Additionally, GIP increased SAT-TAG in obese T2DM (1.78 ± 0.4 vs 0.86 ± 0.1-fold with placebo, P = 0.043, 95% CI: 0.1–1.8). Such effect with GIP was not observed in other three groups despite greater insulinotropic activity. Reduction in NEFA concentration with GIP correlated with adipose tissue insulin resistance for all subjects (Pearson, r = 0.56, P = 0.005). There were no significant gene expression changes in key SAT lipid metabolism enzymes. In conclusion, GIP appears to promote fat accretion and thus may exacerbate obesity and insulin resistance in T2DM.

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  • In diet-induced obese rodents, GCGR agonist treatment causes weight loss by reducing food intake, increasing lipid use through brown fat thermogenesis, and raising whole-body energy expenditure, partly via FGF21 and FXR.

    “In diet-induced obese rodents, GCGR agonist administration drives weight loss through a reduction in food intake, an induction of lipid utilization via brown fat thermogenesis, along with an increase in whole-body energy expenditure; the latter effect in part attributed to the stimulation of liver-secreted FGF21, and transcriptional upregulation of the hepatic bile acid-activated nuclear receptor,”

    From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [72]

    The Introduction and Discussion address GIP and fat deposition, chiefly in human adipose tissue, not GCGR agonist treatment in diet-induced obese rodents. Searches for GCGR, FGF21, FXR, thermogenesis, food intake, and energy expenditure found no passage addressing the attributed mechanism. Page numbers were not available in our copy. (LLM, conf=0.76)

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  • GIP/GLP-1 co-agonists like tirzepatide show higher effect on glycemic control and weight loss.

    “Such an interest also stems from the higher effect on glycemic control and weigh loss showed with GIP/GLP-1 co-agonists like tirzepatide [135], as well as the intriguing effects of retatrutide, the first GIP/GLP-1/GCGR (glucagon receptor) co-agonist [136].”

    From Adipose Tissue: A Novel Target of the Incretin Axis? A Paradigm Shift in Obesity-Linked Insulin Resistance (2024) · cites this paper as [135]

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Research works printed but not linked: 1

  1. WHO. WHO Guidelines Approved by the Guidelines Review Committee. In: Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus: Abbreviated Report of a WHO Consultation. Geneva: World Health OrganizationCopyright (c) World Health Organization 2011.

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Authors
Thondam, S. K., Daousi, C., Wilding, J. P. H., Holst, J. J., Ameen, G. I., Yang, C., Whitmore, C., Mora, S., & Cuthbertson, D. J.
Affiliations
  • Aintree University Hospital (GB)
  • University of Liverpool (GB)
  • University of Copenhagen (DK)
  • Department of Cellular and Molecular Physiology University of Liverpool, Liverpool, United Kingdom; and
Corresponding author
Thondam, Sravan K.
ORCID
Venue
American Journal of Physiology-Endocrinology and Metabolism
Publisher
American Physiological Society
Published
2017-03-01
Volume
312
Issue
3
Pages
E224-E233
ISSN
  • 0193-1849 (ISSN-L)
  • 1522-1555
DOI
10.1152/ajpendo.00347.2016
OpenAlex
W2568114375
Cited by
71
References
41
Citations by year
2026: 8 · 2025: 9 · 2024: 8 · 2023: 6 · 2022: 9 · 2021: 4 · 2020: 9 · 2019: 8 · 2018: 5 · 2017: 5
FWCI
5.78
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
The NovoNordisk UK research Foundation, Broadfield park, Brighton Road, Crawley, West Sussex, United kingdom, RH11 9RT
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
type 2 diabetes, obesity, subcutaneous adipose tissue, lipid accumulation, triglycerides, free fatty acids, insulin resistance, insulinotropic effect, hyperglycemic clamp, lipogenic gene expression
MeSH terms
Adult, Blood Glucose, Diabetes Mellitus, Type 2, Double-Blind Method, Esterification, Fatty Acids, Nonesterified, Gastric Inhibitory Polypeptide, Humans, Insulin, Male, Middle Aged, Obesity, Triglycerides, Glucose Clamp Technique, Case-Control Studies, Adipocytes, Glucose Intolerance, Cross-Over Studies, Subcutaneous Fat, Lipogenesis, Adipogenesis, Lipid Metabolism, Incretins

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