Correlation between serum SUMO1 level and hypertriglyceridemia in type 2 diabetes mellitus patients

doi:10.3969/j.issn.1674-8115.2024.10.008

Abstract

Abstract:

Objective ·To explore the correlation between serum small ubiquitin-like modifier 1 (SUMO1) levels and hypertriglyceridemia in patients with type 2 diabetes mellitus (T2DM). Methods ·A total of 239 newly diagnosed T2DM patients were recruited from the endocrinology clinic of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, between September 2020 and March 2021. Among them, 92 patients had hypertriglyceridemia, and 147 patients did not. Basic information and laboratory parameters were collected. The differences in serum SUMO1 levels between the two groups were analyzed. Factors influencing hypertriglyceridemia in patients with T2DM were analyzed, and the impact of serum SUMO1 levels on the risk of hypertriglyceridemia in T2DM patients was investigated. Results ·Patients with T2DM and hypertriglyceridemia had significantly higher serum SUMO1 levels compared to those without hypertriglyceridemia (1 114.99 pg/mL vs 902.43 pg/mL, P<0.001). Binary Logistic regression analysis suggested that serum SUMO1 levels (OR=1.527, 95%CI 1.200?1.943), glycated hemoglobin (OR=1.202, 95%CI 1.038?1.391), and blood uric acid (OR=1.006, 95%CI 1.003?1.010) were independent risk factors for hypertriglyceridemia in patients with T2DM. After adjusting for various confounding factors and stratifying serum SUMO1 levels into quartiles, the risk of hypertriglyceridemia in T2DM patients with the highest quartile (Q4) of serum SUMO1 levels was 2.707 times higher compared to those in the lowest quartile (Q1) (95%CI 1.231?5.951). Multiple linear stepwise regression analysis revealed that female gender, waist-to-hip ratio, triglycerides and serum creatinine were independent risk factors for elevated serum SUMO1 levels. Conclusion ·Serum SUMO1 level in patients with T2DM complicated with HTG is significantly higher than that in patients without HTG, and the serum SUMO1 level is an independent risk factor for T2DM complicated with HTG.

Key words: small ubiquitin-like modifier (SUMO1), SUMOylation, hypertriglyceridemia, type 2 diabetes mellitus (T2DM)

CLC Number:

R587.1

ZHANG Xinyan, LI Han, RAN Hui, SU Qing, ZHANG Hongmei. Correlation between serum SUMO1 level and hypertriglyceridemia in type 2 diabetes mellitus patients[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(10): 1266-1272.

Figures/Tables 4

TrendMD

References 44

1	LI Y, TENG D, SHI X, et al. Prevalence of diabetes recorded in mainland China using 2018 diagnostic criteria from the American Diabetes Association: national cross sectional study[J]. BMJ, 2020, 369: m997.
2	ZHENG Y, LEY S H, HU F B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications[J]. Nat Rev Endocrinol, 2018, 14: 88-98.
3	AL-SULAITI H, DIBOUN I, AGHA M V, et al. Metabolic signature of obesity-associated insulin resistance and type 2 diabetes[J]. J Transl Med, 2019, 17(1): 348.
4	POPKIN B M. Synthesis and implications: China's nutrition transition in the context of changes across other low- and middle-income countries[J]. Obes Rev, 2014, 15(Suppl 1): 60-67.
5	GORDON-LARSEN P, WANG H, POPKIN B M. Overweight dynamics in Chinese children and adults[J]. Obes Rev, 2014, 15(Suppl 1): 37-48.
6	SUBRAMANIAN S, CHAIT A. Hypertriglyceridemia secondary to obesity and diabetes[J]. Biochim Biophys Acta, 2012, 1821(5): 819-825.
7	REINER Ž. Hypertriglyceridaemia and risk of coronary artery disease[J]. Nat Rev Cardiol, 2017, 14: 401-411.
8	YANG A L, MCNABB-BALTAR J. Hypertriglyceridemia and acute pancreatitis[J]. Pancreatology, 2020, 20(5): 795-800.
9	ALEXOPOULOS A S, QAMAR A, HUTCHINS K, et al. Triglycerides: emerging targets in diabetes care? review of moderate hypertriglyceridemia in diabetes[J]. Curr Diabetes Rep, 2019, 19(4): 13.
10	GEISS-FRIEDLANDER R, MELCHIOR F. Concepts in sumoylation: a decade on[J]. Nat Rev Mol Cell Biol, 2007, 8: 947-956.
11	FLOTHO A, MELCHIOR F. Sumoylation: a regulatory protein modification in health and disease[J]. Annu Rev Biochem, 2013, 82: 357-385.
12	GAREAU J R, LIMA C D. The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition[J]. Nat Rev Mol Cell Biol, 2010, 11: 861-871.
13	LIANG Y C, LEE C C, YAO Y L, et al. SUMO5, a novel poly-SUMO isoform, regulates PML nuclear bodies[J]. Sci Rep, 2016, 6: 26509.
14	FAGERBERG L, HALLSTRÖM B M, OKSVOLD P, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics[J]. Mol Cell Proteom, 2014, 13(2): 397-406.
15	CHANG H M, YEH E T H. SUMO: from bench to bedside[J]. Physiol Rev, 2020, 100(4): 1599-1619.
16	BARRY J, LOCK R B. Small ubiquitin-related modifier-1: wrestling with protein regulation[J]. Int J Biochem Cell Biol, 2011, 43(1): 37-40.
17	ZHENG Q, CAO Y, CHEN Y L, et al. Senp2 regulates adipose lipid storage by de-SUMOylation of Setdb1[J]. J Mol Cell Biol, 2018, 10(3): 258-266.
18	MOORADIAN A D. Dyslipidemia in type 2 diabetes mellitus[J]. Nat Rev Endocrinol, 2009, 5: 150-159.
19	COCATE P G, NATALI A J, DE OLIVEIRA A, et al. Red but not white meat consumption is associated with metabolic syndrome, insulin resistance and lipid peroxidation in Brazilian middle-aged men[J]. Eur J Prev Cardiol, 2015, 22(2): 223-230.
20	KELLEY D E, GOODPASTER B H. Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance[J]. Diabetes Care, 2001, 24(5): 933-941.
21	YANG Y, HE Y, WANG X, et al. Protein SUMOylation modification and its associations with disease[J]. Open Biol, 2017, 7(10): 170167.
22	BOHREN K M, NADKARNI V, SONG J H, et al. A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus[J]. J Biol Chem, 2004, 279(26): 27233-27238.
23	WOO C H, ABE J. SUMO: a post-translational modification with therapeutic potential?[J]. Curr Opin Pharmacol, 2010, 10(2): 146-155.
24	YEH E T. SUMOylation and De-SUMOylation: wrestling with life's processes[J]. J Biol Chem, 2009, 284(13): 8223-8227.
25	SEGERSTOLPE Å, PALASANTZA A, ELIASSON P, et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes[J]. Cell Metab, 2016, 24(4): 593-607.
26	DAI X Q, PLUMMER G, CASIMIR M, et al. SUMOylation regulates insulin exocytosis downstream of secretory granule docking in rodents and humans[J]. Diabetes, 2011, 60(3): 838-847.
27	HE X Y, LAI Q H, CHEN C, et al. Both conditional ablation and overexpression of E2 SUMO-conjugating enzyme (UBC9) in mouse pancreatic beta cells result in impaired beta cell function[J]. Diabetologia, 2018, 61(4): 881-895.
28	SAPIR A. Not so slim anymore-evidence for the role of SUMO in the regulation of lipid metabolism[J]. Biomolecules, 2020, 10(8): E1154.
29	CARIOU B, CHARBONNEL B, STAELS B. Thiazolidinediones and PPARγ agonists: time for a reassessment[J]. Trends Endocrinol Metab, 2012, 23(5): 205-215.
30	TONTONOZ P, SPIEGELMAN B M. Fat and beyond: the diverse biology of PPARgamma[J]. Annu Rev Biochem, 2008, 77: 289-312.
31	MIKKONEN L, HIRVONEN J, JÄNNE O A. SUMO-1 regulates body weight and adipogenesis via PPARγ in male and female mice[J]. Endocrinology, 2013, 154(2): 698-708.
32	AHMADIAN M, SUH J M, HAH N, et al. PPARγ signaling and metabolism: the good, the bad and the future[J]. Nat Med, 2013, 19: 557-566.
33	WADOSKY K M, WILLIS M S. The story so far: post-translational regulation of peroxisome proliferator-activated receptors by ubiquitination and SUMOylation[J]. Am J Physiol Heart Circ Physiol, 2012, 302(3): H515-H526.
34	KERSHAW E E, SCHUPP M, GUAN H P, et al. PPARgamma regulates adipose triglyceride lipase in adipocytes in vitro and in vivo[J]. Am J Physiol Endocrinol Metab, 2007, 293(6): E1736-E1745.
35	WOLFRUM C, STOFFEL M. Coactivation of Foxa2 through Pgc-1beta promotes liver fatty acid oxidation and triglyceride/VLDL secretion[J]. Cell Metab, 2006, 3(2): 99-110.
36	BELAGULI N S, ZHANG M, BRUNICARDI F C, et al. Forkhead box protein A2 (FOXA2) protein stability and activity are regulated by sumoylation[J]. PLoS One, 2012, 7(10): e48019.
37	LIU Y, DOU X, ZHOU W Y, et al. Hepatic small ubiquitin-related modifier (SUMO)-specific protease 2 controls systemic metabolism through SUMOylation-dependent regulation of liver-adipose tissue crosstalk [J]. Hepatology, 2021, 74(4): 1864-1883.
38	HIRANO Y, MURATA S, TANAKA K, et al. Sterol regulatory element-binding proteins are negatively regulated through SUMO-1 modification independent of the ubiquitin/26 S proteasome pathway[J]. J Biol Chem, 2003, 278(19): 16809-16819.
39	ARITO M, HORIBA T, HACHIMURA S, et al. Growth factor-induced phosphorylation of sterol regulatory element-binding proteins inhibits sumoylation, thereby stimulating the expression of their target genes, low density lipoprotein uptake, and lipid synthesis[J]. J Biol Chem, 2008, 283(22): 15224-15231.
40	LIU B, WANG T, MEI W, et al. Small ubiquitin-like modifier (SUMO) protein-specific protease 1 de-SUMOylates Sharp-1 protein and controls adipocyte differentiation[J]. J Biol Chem, 2014, 289(32): 22358-22364.
41	SHIMANO H, SATO R. SREBP-regulated lipid metabolism: convergent physiology—divergent pathophysiology[J]. Nat Rev Endocrinol, 2017, 13: 710-730.
42	SOYAL S M, NOFZIGER C, DOSSENA S, et al. Targeting SREBPs for treatment of the metabolic syndrome[J]. Trends Pharmacol Sci, 2015, 36(6): 406-416.
43	WANG Q, ZHANG N, YANG X, et al. ERα promotes SUMO1 transcription by binding with the ERE and enhances SUMO1-mediated protein SUMOylation in breast cancer[J]. Gland Surg, 2023, 12(7): 963-973.
44	CHO S J, YUN S M, LEE D H, et al. Plasma SUMO1 protein is elevated in Alzheimer's disease[J]. J Alzheimers Dis, 2015, 47(3): 639-643.

Index	T2DM with HTG (n=92)	T2DM without HTG (n=147)	P value
Age/year	52.43±11.84	58.29±12.66	<0.001
Male/n (%)	64 (69.56)	84 (57.14)	0.054
BMI/(kg·m^-2)	26.34±4.00	25.04±3.20	0.006
WHR	0.94±0.06	0.92±0.05	0.024
SBP/mmHg	139.42±17.71	137.32±16.18	0.349
DBP/mmHg	87.83±11.89	83.53±11.48	0.006
HbA1c/n(%)	8.74±2.13	8.11±2.14	0.029
FBG/(mmol·L^-1)	9.36±3.07	8.33±2.61	0.006
HDL/(mmol·L^-1)	1.11±0.21	1.31±0.34	<0.001
LDL/(mmol·L^-1)	3.43±1.02	3.17±0.99	0.055
TC/(mmol·L^-1)	5.62±1.13	5.05±1.17	<0.001
TAG/(mmol·L^-1)	2.37 (2.00, 3.48)	1.25 (0.88, 1.48)	<0.001
Insulin/(pmol·L^-1)	57.00 (42.45, 94.45)	50.88 (34.52, 78.73)	0.028
Scr/(μmol·L^-1)	64.09±15.16	61.63±16.03	0.243
ALT/(U·L^-1)	32.00 (20.00, 50.25)	24.00 (17.00, 34.25)	0.100
AST/(U·L^-1)	24.50 (20.00, 33.00)	21.50 (17.75, 26.00)	0.327
UA/(μmol·L^-1)	375.76±94.36	325.33±87.76	<0.001
Smoking/n(%)	31 (33.69)	33 (22.45)	0.060
Drinking/n(%)	26 (28.26)	33 (22.45)	0.325

Index	T2DM with HTG (n=92)	T2DM without HTG (n=147)	P value
Age/year	52.43±11.84	58.29±12.66	<0.001
Male/n (%)	64 (69.56)	84 (57.14)	0.054
BMI/(kg·m^-2)	26.34±4.00	25.04±3.20	0.006
WHR	0.94±0.06	0.92±0.05	0.024
SBP/mmHg	139.42±17.71	137.32±16.18	0.349
DBP/mmHg	87.83±11.89	83.53±11.48	0.006
HbA1c/n(%)	8.74±2.13	8.11±2.14	0.029
FBG/(mmol·L^-1)	9.36±3.07	8.33±2.61	0.006
HDL/(mmol·L^-1)	1.11±0.21	1.31±0.34	<0.001
LDL/(mmol·L^-1)	3.43±1.02	3.17±0.99	0.055
TC/(mmol·L^-1)	5.62±1.13	5.05±1.17	<0.001
TAG/(mmol·L^-1)	2.37 (2.00, 3.48)	1.25 (0.88, 1.48)	<0.001
Insulin/(pmol·L^-1)	57.00 (42.45, 94.45)	50.88 (34.52, 78.73)	0.028
Scr/(μmol·L^-1)	64.09±15.16	61.63±16.03	0.243
ALT/(U·L^-1)	32.00 (20.00, 50.25)	24.00 (17.00, 34.25)	0.100
AST/(U·L^-1)	24.50 (20.00, 33.00)	21.50 (17.75, 26.00)	0.327
UA/(μmol·L^-1)	375.76±94.36	325.33±87.76	<0.001
Smoking/n(%)	31 (33.69)	33 (22.45)	0.060
Drinking/n(%)	26 (28.26)	33 (22.45)	0.325

Independent variable	β	Exp (β)	95%CI	P value
SUMO1	0.423	1.527	1.200-1.943	<0.001
HbA1c	0.184	1.202	1.038-1.391	0.010
UA	0.006	1.006	1.003-1.010	<0.001

Independent variable	β	Exp (β)	95%CI	P value
SUMO1	0.423	1.527	1.200-1.943	<0.001
HbA1c	0.184	1.202	1.038-1.391	0.010
UA	0.006	1.006	1.003-1.010	<0.001

SUMO1 quartile	n/total	Crude OR OR (95%CI)	Model 1 OR (95%CI)	Model 2 OR (95%CI)
Q1 (<691 pg·mL^-1)	15/59	1.000	1.000	1.000
Q2 (692-887 pg·mL^-1)	18/60	1.257 (0.562~2.812)	1.270 (0.566~2.850)	1.319 (0.584~2.976)
Q3 (888-1 187 pg·mL^-1)	27/58	2.550^① (1.170~5.578)	2.440^① (1.112~5.355)	2.419^① (1.097~5.332)
Q4 (≥1 188 pg·mL^-1)	32/62	3.129^① (1.450~6.752)	2.886^① (1.322~6.298)	2.707^① (1.231~5.951)
P value for trend		0.008	0.010	0.010