title: Insulin-mediated suppression of lipolysis in adipose tissue and skeletal muscle of obese type 2 diabetic men and men with normal glucose tolerance.
abstract: OBJECTIVE
  Impaired regulation of lipolysis and accumulation of lipid intermediates may contribute to obesity-related insulin resistance and type 2 diabetes mellitus. We investigated insulin-mediated suppression of lipolysis in abdominal subcutaneous adipose tissue (AT) and skeletal muscle (SM) of obese men with normal glucose tolerance (NGT) and obese type 2 diabetic men.
  
  
  METHODS
  Eleven NGT men and nine long-term diagnosed type 2 diabetic men (7 ± 1 years), matched for age (58 ± 2 vs 62 ± 2 years), BMI (31.4 ± 0.6 vs 30.5 ± 0.6 kg/m(2)) and [Formula: see text] (28.9 ± 1.5 vs 29.5 ± 2.4 ml kg(-1) min(-1)) participated in this study. Interstitial glycerol concentrations in AT and SM were assessed using microdialysis during a 1 h basal period and a 6 h stepwise hyperinsulinaemic-euglycaemic clamp (8, 20 and 40 mU m(-2) min(-1)). AT and SM biopsies were collected to investigate underlying mechanisms.
  
  
  RESULTS
  Hyperinsulinaemia suppressed interstitial SM glycerol concentrations less in men with type 2 diabetes (-7 ± 6%, -13 ± 9% and -27 ± 9%) compared with men with NGT (-21 ± 7%, -38 ± 8% and -53 ± 8%) (p = 0.014). This was accompanied by increased circulating fatty acid and glycerol concentrations, a lower glucose infusion rate (21.8 ± 3.1 vs 30.5 ± 2.0 μmol kg body weight(-1) min(-1); p < 0.05), higher hormone-sensitive lipase (HSL) serine 660 phosphorylation, increased saturated diacylglycerol (DAG) lipid species in the muscle membrane and increased protein kinase C (PKC) activation in type 2 diabetic men vs men with NGT. No significant differences in insulin-mediated reduction in AT interstitial glycerol were observed between groups.
  
  
  CONCLUSIONS
  Our results suggest that a blunted insulin-mediated suppression of SM lipolysis may promote the accumulation of membrane saturated DAG, aggravating insulin resistance, at least partly mediated by PKC. This may represent an important mechanism involved in the progression of insulin resistance towards type 2 diabetes.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01680133.
authors.affiliation: Department of Human Biology, NUTRIM School for Nutrition, Toxicology, and Metabolism, Maastricht University Medical Centre+, PO Box 616, 6200 MD, Maastricht, the Netherlands. j.jocken@maastrichtuniversity.nl
authors.forename: Johan W E
authors.initials: JW
authors.lastname: Jocken
authors.forename: Gijs H
authors.initials: GH
authors.lastname: Goossens
authors.forename: Hanneke
authors.initials: H
authors.lastname: Boon
authors.forename: Rachael R
authors.initials: RR
authors.lastname: Mason
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Essers
authors.forename: Bas
authors.initials: B
authors.lastname: Havekes
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.forename: Luc J
authors.initials: LJ
authors.lastname: van Loon
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Blaak
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000627:therapeutic use*; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D007328:Insulin
references.citation: Physiol Behav. 2008 May 23;94(2):206-18
references.pmid: 18037457
references.citation: Metabolism. 1981 Sep;30(9):936-40
references.pmid: 7022111
references.citation: Diabetes. 1999 Jan;48(1):10-4
references.pmid: 9892216
references.citation: FEBS Lett. 1999 Jan 29;443(3):285-9
references.pmid: 10025949
references.citation: Diabetes. 1993 Oct;42(10):1469-73
references.pmid: 8375586
references.citation: Obesity (Silver Spring). 2012 Jan;20(1):57-64
references.pmid: 21959346
references.citation: Horm Metab Res. 1985 Sep;17(9):471-5
references.pmid: 3899892
references.citation: Physiol Behav. 2008 May 23;94(2):219-30
references.pmid: 18262211
references.citation: Diabetes. 1997 Feb;46(2):169-78
references.pmid: 9000691
references.citation: Diabetes. 2002 Jul;51(7):2005-11
references.pmid: 12086926
references.citation: J Clin Endocrinol Metab. 2000 Oct;85(10):3740-5
references.pmid: 11061533
references.citation: Diabetes. 2008 Jul;57(7):1834-41
references.pmid: 18398140
references.citation: Diabetologia. 2007 Jan;50(1):103-12
references.pmid: 17131144
references.citation: J Clin Endocrinol Metab. 1999 Nov;84(11):3886-95
references.pmid: 10566624
references.citation: Diabetes. 2011 Oct;60(10):2441-9
references.pmid: 21948998
references.citation: Trends Endocrinol Metab. 2012 Aug;23(8):391-8
references.pmid: 22721584
references.citation: J Appl Physiol (1985). 2009 May;106(5):1529-37
references.pmid: 19265063
references.citation: J Biol Chem. 2012 Nov 30;287(49):41446-57
references.pmid: 23066022
references.citation: Acta Med Scand. 1967 Jul;182(1):93-107
references.pmid: 6028956
references.citation: J Clin Endocrinol Metab. 2002 May;87(5):2206-11
references.pmid: 11994365
references.citation: Am J Physiol Endocrinol Metab. 2000 Nov;279(5):E1097-103
references.pmid: 11052965
references.citation: Diabetologia. 2012 Apr;55(4):1140-50
references.pmid: 22252470
references.citation: Am J Physiol Endocrinol Metab. 2001 Jun;280(6):E1000-6
references.pmid: 11350782
references.citation: Diabetes. 2000 Aug;49(8):1353-8
references.pmid: 10923637
references.citation: Diabetologia. 2008 Feb;51(2):320-7
references.pmid: 18060661
references.citation: J Biol Chem. 1999 Aug 20;274(34):23702-6
references.pmid: 10446128
references.citation: Diabetes. 2010 Jan;59(1):80-8
references.pmid: 19833891
references.citation: Obesity (Silver Spring). 2011 Jul;19(7):1350-9
references.pmid: 21331063
references.citation: J Clin Endocrinol Metab. 2004 Jun;89(6):2690-6
references.pmid: 15181043
references.citation: Diabetologia. 2001 May;44(5):614-20
references.pmid: 11380080
references.citation: J Biol Chem. 2006 Dec 29;281(52):40236-41
references.pmid: 17074755
references.citation: Am J Physiol. 1990 Jun;258(6 Pt 1):E918-22
references.pmid: 2193533
references.citation: Am J Physiol Endocrinol Metab. 2002 Aug;283(2):E295-301
references.pmid: 12110534
references.citation: Diabetes. 2000 May;49(5):797-802
references.pmid: 10905489
references.citation: Am J Physiol. 1999 Jan;276(1):E151-4
references.pmid: 9886961
references.citation: Diabetologia. 1998 May;41(5):560-8
references.pmid: 9628274
references.citation: Diabetes. 2002 Sep;51(9):2742-8
references.pmid: 12196467
references.citation: Am J Physiol Endocrinol Metab. 2012 Aug 15;303(4):E534-41
references.pmid: 22713505
references.citation: J Clin Endocrinol Metab. 2010 Dec;95(12):5449-53
references.pmid: 20843949
references.citation: J Biol Chem. 1990 Oct 5;265(28):16880-5
references.pmid: 2211599
references.citation: Diabetes. 2011 Jun;60(6):1734-42
references.pmid: 21498783
references.citation: Diabetes. 2002 Oct;51(10):2959-63
references.pmid: 12351433
references.citation: Nat Med. 2011 Aug 21;17(9):1076-85
references.pmid: 21857651
references.citation: Am J Physiol. 1998 Dec;275(6):E909-16
references.pmid: 9843731
references.citation: Am J Physiol. 1998 Apr;274(4):E737-43
references.pmid: 9575836
references.citation: Cell Metab. 2007 Mar;5(3):167-79
references.pmid: 17339025
references.citation: J Lipid Res. 2006 Aug;47(8):1643-50
references.pmid: 16685078
references.citation: J Clin Invest. 1992 May;89(5):1610-7
references.pmid: 1569199
references.citation: J Biol Chem. 1985 Sep 5;260(19):10819-25
references.pmid: 3161882
references.citation: Am J Physiol Endocrinol Metab. 2001 Feb;280(2):E229-37
references.pmid: 11158925