title: Glucose-dependent insulinotropic polypeptide promotes lipid deposition in subcutaneous adipocytes in obese type 2 diabetes patients: a maladaptive response.
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 AUC0-4 h± SE, 41,992 ± 9,843 µmol·l-1·min-1vs. 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.
authors.affiliation: Obesity and Endocrinology Research Group, University Hospital Aintree, Liverpool, United Kingdom s.thondam@liverpool.ac.uk.
authors.forename: Sravan K
authors.identifier: 0000-0002-3675-4168
authors.initials: SK
authors.lastname: Thondam
authors.affiliation: Obesity and Endocrinology Research Group, University Hospital Aintree, Liverpool, United Kingdom.
authors.forename: Christina
authors.initials: C
authors.lastname: Daousi
authors.affiliation: Obesity and Endocrinology Research Group, University Hospital Aintree, Liverpool, United Kingdom.|Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors.forename: John P H
authors.initials: JP
authors.lastname: Wilding
authors.affiliation: NovoNordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Department of Cellular and Molecular Physiology University of Liverpool, Liverpool, United Kingdom; and.
authors.forename: Gulizar I
authors.initials: GI
authors.lastname: Ameen
authors.affiliation: Department of Cellular and Molecular Physiology University of Liverpool, Liverpool, United Kingdom; and.
authors.forename: Chenjing
authors.initials: C
authors.lastname: Yang
authors.affiliation: Obesity and Endocrinology Research Group, University Hospital Aintree, Liverpool, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Whitmore
authors.affiliation: Department of Cellular and Molecular Physiology University of Liverpool, Liverpool, United Kingdom; and.
authors.forename: Silvia
authors.initials: S
authors.lastname: Mora
authors.affiliation: Obesity and Endocrinology Research Group, University Hospital Aintree, Liverpool, United Kingdom.|Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cuthbertson
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D004311:Double-Blind Method; D004951:Esterification / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000150:complications / Q000378:metabolism*; D006801:Humans; D054795:Incretins / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D050151:Subcutaneous Fat / Q000166:cytology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D054795:Incretins; D007328:Insulin; D014280:Triglycerides; D005749:Gastric Inhibitory Polypeptide
keywords: adipose tissue; glucose-dependent insulinotropic polypeptide; lipid metabolism; nonesterified fatty acids; type 2 diabetes