The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes.
Our previous studies suggest that the SNARE protein synaptosomal-associated protein of 23 kDa (SNAP23) is involved in the link between increased lipid levels and insulin resistance in cardiomyocytes. The objective was to determine whether SNAP23 may also be involved in the known association between lipid accumulation in skeletal muscle and insulin resistance/type 2 diabetes in humans, as well as to identify a potential regulator of SNAP23.



We analyzed skeletal muscle biopsies from patients with type 2 diabetes and healthy, insulin-sensitive control subjects for expression (mRNA and protein) and intracellular localization (subcellular fractionation and immunohistochemistry) of SNAP23, and for expression of proteins known to interact with SNARE proteins. Insulin resistance was determined by a euglycemic hyperinsulinemic clamp. Potential mechanisms for regulation of SNAP23 were also investigated in the skeletal muscle cell line L6.



We showed increased SNAP23 levels in skeletal muscle from patients with type 2 diabetes compared with that from lean control subjects. Moreover, SNAP23 was redistributed from the plasma membrane to the microsomal/cytosolic compartment in the patients with the type 2 diabetes. Expression of the SNARE-interacting protein Munc18c was higher in skeletal muscle from patients with type 2 diabetes. Studies in L6 cells showed that Munc18c promoted the expression of SNAP23.



We have translated our previous in vitro results into humans by showing that there is a change in the distribution of SNAP23 to the interior of the cell in skeletal muscle from patients with type 2 diabetes. We also showed that Munc18c is a potential regulator of SNAP23.
Boström
Pontus
P
Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Sahlgrenska University Hospital, Göteborg, Sweden.
Andersson
Linda
L
Vind
Birgitte
B
Håversen
Liliana
L
Rutberg
Mikael
M
Wickström
Ylva
Y
Larsson
Erik
E
Jansson
Per-Anders
PA
Svensson
Maria K
MK
Brånemark
Richard
R
Ling
Charlotte
C
Beck-Nielsen
Henning
H
Borén
Jan
J
Højlund
Kurt
K
Olofsson
Sven-Olof
SO
D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D004777:Environment; D005786:Gene Expression Regulation; D015309:Glucose Clamp Technique; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008862:Microsomes, Liver / Q000378:metabolism; D051938:Munc18 Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050766:Qb-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D050767:Qc-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D012016:Reference Values; D014430:Twins, Monozygotic
D001786:Blood Glucose; D051938:Munc18 Proteins; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; C100493:SNAP23 protein, human; D051057:Proto-Oncogene Proteins c-akt
PLoS One. 2008;3(12):e4074
19116655
J Biol Chem. 2007 Jun 1;282(22):16553-66
17412693
Am J Physiol. 1999 May;276(5):C1108-14
10329959
Mol Cell. 1999 Jun;3(6):751-60
10394363
Nat Cell Biol. 2007 Nov;9(11):1286-93
17922004
Biochem J. 1996 Aug 15;318 ( Pt 1):163-72
8761467
Diabetes. 2010 Jan;59(1):80-8
19833891
Biochim Biophys Acta. 2009 Jun;1791(6):448-58
18775796
J Lipid Res. 2007 Dec;48(12):2547-59
17878492
J Biol Chem. 2000 Mar 17;275(11):8240-7
10713150
Diabetologia. 2001 Jul;44(7):824-33
11508266
Biochem J. 2009 May 1;419(3):655-60
19193195
Nat Rev Mol Cell Biol. 2006 May;7(5):373-8
16550215
Diabetologia. 2006 Jun;49(6):1283-91
16609880
J Biol Chem. 1998 Jul 31;273(31):19740-6
9677404
J Clin Invest. 2005 Feb;115(2):291-301
15690082
J Clin Invest. 1997 Sep 1;100(5):1166-73
9303923
J Biol Chem. 2004 Nov 5;279(45):46835-42
15337753
Biochem J. 2003 Oct 15;375(Pt 2):433-40
12877659
EMBO Rep. 2005 Dec;6(12):1137-42
16319959
Curr Opin Lipidol. 2009 Feb;20(1):50-6
19133412
J Lipid Res. 2003 Jun;44(6):1174-81
12700337
Curr Opin Lipidol. 2008 Oct;19(5):441-7
18769224
Traffic. 2006 Oct;7(10):1408-19
16899085
Trends Biochem Sci. 2006 Apr;31(4):215-22
16540333
Nutr Metab (Lond). 2008 Jul 24;5:21
18652694
Diabetes. 2003 Aug;52(8):1910-7
12882905
J Biol Chem. 1998 Dec 11;273(50):33876-83
9837979
Am J Med. 2006 May;119(5 Suppl 1):S10-6
16563942
Curr Opin Lipidol. 2008 Jun;19(3):235-41
18460913
J Cell Sci. 2006 Jun 1;119(Pt 11):2246-57
16723731