GIP Affects Hepatic Fat and Brown Adipose Tissue Thermogenesis but Not White Adipose Tissue Transcriptome in Type 1 Diabetes

Sebastian Møller Nguyen Heimbürger; Bjørn Hoe; Chris Neumann Nielsen; Natasha Chidekel Bergman; Kirsa Skov-Jeppesen; Bolette Hartmann; Jens Juul Holst; Flemming Dela; Julie Overgaard; Joachim Størling; Tina Vilsbøll; Thomas Fremming Dejgaard; Jesper Foged Havelund; Vladimir Gorshkov; Frank Kjeldsen; Nils Joakim Færgeman; Martin Rønn Madsen; Mikkel B Christensen; Filip Krag Knop

doi:10.1210/clinem/dgac542

GIP Affects Hepatic Fat and Brown Adipose Tissue Thermogenesis but Not White Adipose Tissue Transcriptome in Type 1 Diabetes

J Clin Endocrinol Metab. 2022 Nov 25;107(12):3261-3274. doi: 10.1210/clinem/dgac542.

Authors

Sebastian Møller Nguyen Heimbürger^{1

2

3

4}, Bjørn Hoe^{1

5}, Chris Neumann Nielsen¹, Natasha Chidekel Bergman¹, Kirsa Skov-Jeppesen^{3

6}, Bolette Hartmann^{3

6}, Jens Juul Holst^{3

6}, Flemming Dela^{7

8}, Julie Overgaard², Joachim Størling^{2

6}, Tina Vilsbøll^{1

2

5}, Thomas Fremming Dejgaard^{1

2}, Jesper Foged Havelund⁹, Vladimir Gorshkov⁹, Frank Kjeldsen⁹, Nils Joakim Færgeman⁹, Martin Rønn Madsen¹⁰, Mikkel B Christensen^{1

5

11

12}, Filip Krag Knop^{1

2

3

5}

Affiliations

¹ Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark.
² Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark.
³ Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
⁴ Department of Translational Pharmacology, Zealand Pharma A/S, 2860 Søborg, Denmark.
⁵ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
⁶ Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
⁷ Xlab, Center for Healthy Ageing, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
⁸ Department of Geriatrics, Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark.
⁹ Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark.
¹⁰ Department of Computational Biology, Gubra A/S, 2970 Hørsholm, Denmark.
¹¹ Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark.
¹² Copenhagen Center for Translational Research, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark.

PMID: 36111559
DOI: 10.1210/clinem/dgac542

Abstract

Context: Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to exert insulin-independent effects on lipid and bone metabolism.

Objective: We investigated the effects of a 6-day subcutaneous GIP infusion on circulating lipids, white adipose tissue (WAT), brown adipose tissue (BAT), hepatic fat content, inflammatory markers, respiratory exchange ratio (RER), and bone homeostasis in patients with type 1 diabetes.

Methods: In a randomized, placebo-controlled, double-blind, crossover study, 20 men with type 1 diabetes underwent a 6-day continuous subcutaneous infusion with GIP (6 pmol/kg/min) and placebo (saline), with an interposed 7-day washout period.

Results: During GIP infusion, participants (26 ± 8 years [mean ± SD]; BMI 23.8 ± 1.8 kg/m2; glycated hemoglobin A1c 51 ± 10 mmol/mol [6.8 ± 3.1%]) experienced transiently increased circulating concentrations of nonesterified fatty acid (NEFA) (P = 0.0005), decreased RER (P = 0.009), indication of increased fatty acid β-oxidation, and decreased levels of the bone resorption marker C-terminal telopeptide (P = 0.000072) compared with placebo. After 6 days of GIP infusion, hepatic fat content was increased by 12.6% (P = 0.007) and supraclavicular skin temperature, a surrogate indicator of BAT activity, was increased by 0.29 °C (P < 0.000001) compared with placebo infusion. WAT transcriptomic profile as well as circulating lipid species, proteome, markers of inflammation, and bone homeostasis were unaffected.

Conclusion: Six days of subcutaneous GIP infusion in men with type 1 diabetes transiently decreased bone resorption and increased NEFA and β-oxidation. Further, hepatic fat content, and supraclavicular skin temperature were increased without affecting WAT transcriptomics, the circulating proteome, lipids, or inflammatory markers.

Trial registration: ClinicalTrials.gov NCT03734718.

Keywords: GIP; brown adipose tissue; cardiovascular disease; hepatic steatosis; type 1 diabetes; white adipose tissue.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue, Brown / metabolism
Adipose Tissue, White
Bone Resorption* / metabolism
Cross-Over Studies
Diabetes Mellitus, Type 1* / drug therapy
Diabetes Mellitus, Type 1* / metabolism
Fatty Acids, Nonesterified / metabolism
Gastric Inhibitory Polypeptide / pharmacology
Humans
Male
Proteome / metabolism
Thermogenesis
Transcriptome

GIP Affects Hepatic Fat and Brown Adipose Tissue Thermogenesis but Not White Adipose Tissue Transcriptome in Type 1 Diabetes

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