Increased Growth Differentiation Factor 15 in Patients with Hypoleptinemia-Associated Lipodystrophy
Abstract
:1. Introduction
2. Results
2.1. LD Patients Have a Significantly Impaired Metabolic Profile and Higher GDF15 Serum Concentrations than Controls
2.2. Univariate and Multivariate Analyses
2.3. GDF15 Serum Levels during Metreleptin Supplementation
2.4. GDF15 mRNA Expression in a Mouse Model of Congenital Generalized LD and Leptin-Deficient Obesity
3. Discussion
4. Material and Methods
4.1. Patients and Control Group
4.2. Anthropometric Measurements and Laboratory Assessment
4.3. Animal Care and Animal Experiments
4.4. Quantitative Real-Time RT-PCR Analysis
4.5. Statistical Analysis
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ALAT | alanine aminotransferase |
ASAT | aspartate aminotransferase |
iBAT | intrascapular brown adipose tissue |
BMI | body mass index |
CRP | C reactive protein |
eGFR, EpiAT | estimated glomerular filtration rate |
FFA | free fatty acids |
FG | fasting glucose |
FGF | fibroblast growth factor |
FI | fasting insulin |
GGT | gamma-glutamyl transferase |
H bA1c | glycosylated hemoglobin A1c |
HDL | high density lipoprotein |
HIV | human immunodeficiency virus |
HOMA-IR | homeostasis model assessment of insulin resistance |
LD | lipodystrophy |
LDL | low density lipoprotein |
sAT | subcutaneous adipose tissue |
TG | triglycerides |
VAT | visceral adipose tissue |
WHR | waist-to-hip ratio |
References
- Zhang, Y.; Liu, J.; Yao, J.; Ji, G.; Qian, L.; Wang, J.; Zhang, G.; Tian, J.; Nie, Y.; Zhang, Y.E.; et al. Obesity: Pathophysiology and intervention. Nutrients 2014, 6, 5153–5183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Garg, A. Clinical review#: Lipodystrophies: Genetic and acquired body fat disorders. J. Clin. Endocrinol. Metab. 2011, 96, 3313–3325. [Google Scholar] [CrossRef] [PubMed]
- Simha, V.; Garg, A. Inherited lipodystrophies and hypertriglyceridemia. Curr. Opin. Lipidol. 2009, 20, 300–308. [Google Scholar] [CrossRef] [PubMed]
- Fasshauer, M.; Blüher, M. Adipokines in health and disease. Trends Pharmacol. Sci. 2015, 36, 461–470. [Google Scholar] [CrossRef] [PubMed]
- Haque, W.A.; Shimomura, I.; Matsuzawa, Y.; Garg, A. Serum adiponectin and leptin levels in patients with lipodystrophies. J. Clin. Endocrinol. Metab. 2002, 87, 2395. [Google Scholar] [CrossRef]
- Shimomura, I.; Hammer, R.E.; Ikemoto, S.; Brown, M.S.; Goldstein, J.L. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999, 401, 73–76. [Google Scholar] [CrossRef]
- Oral, E.A.; Simha, V.; Ruiz, E.; Andewelt, A.; Premkumar, A.; Snell, P.; Wagner, A.J.; DePaoli, A.M.; Reitman, M.L.; Taylor, S.I.; et al. Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med. 2002, 346, 570–578. [Google Scholar] [CrossRef]
- Diker-Cohen, T.; Cochran, E.; Gorden, P.; Brown, R.J. Partial and generalized lipodystrophy: Comparison of baseline characteristics and response to metreleptin. J. Clin. Endocrinol. Metab. 2015, 100, 1802–1810. [Google Scholar] [CrossRef] [Green Version]
- Bootcov, M.R.; Bauskin, A.R.; Valenzuela, S.M.; Moore, A.G.; Bansal, M.; He, X.Y.; Zhang, H.P.; Donnellan, M.; Mahler, S.; Pryor, K.; et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc. Natl. Acad. Sci. USA 1997, 94, 11514–11519. [Google Scholar] [CrossRef] [Green Version]
- Hsu, J.-Y.; Crawley, S.; Chen, M.; Ayupova, D.A.; Lindhout, D.A.; Higbee, J.; Kutach, A.; Joo, W.; Gao, Z.; Fu, D.; et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 2017, 550, 255–259. [Google Scholar] [CrossRef]
- Mulligan, K.; Khatami, H.; Schwarz, J.-M.; Sakkas, G.K.; DePaoli, A.M.; Tai, V.W.; Wen, M.J.; Lee, G.A.; Grunfeld, C.; Schambelan, M. The effects of recombinant human leptin on visceral fat, dyslipidemia, and insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia. J. Clin. Endocrinol. Metab. 2009, 94, 1137–1144. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mullican, S.E.; Lin-Schmidt, X.; Chin, C.-N.; Chavez, J.A.; Furman, J.L.; Armstrong, A.A.; Beck, S.C.; South, V.J.; Dinh, T.Q.; Cash-Mason, T.D.; et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat. Med. 2017, 23, 1150–1157. [Google Scholar] [CrossRef] [PubMed]
- Emmerson, P.J.; Wang, F.; Du, Y.; Liu, Q.; Pickard, R.T.; Gonciarz, M.D.; Coskun, T.; Hamang, M.J.; Sindelar, D.K.; Ballman, K.K.; et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat. Med. 2017, 23, 1215–1219. [Google Scholar] [CrossRef]
- Xiong, Y.; Walker, K.; Min, X.; Hale, C.; Tran, T.; Komorowski, R.; Yang, J.; Davda, J.; Nuanmanee, N.; Kemp, D.; et al. Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys. Sci. Transl. Med. 2017, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yokoyama-Kobayashi, M.; Saeki, M.; Sekine, S.; Kato, S. Human cDNA encoding a novel TGF-beta superfamily protein highly expressed in placenta. J. Biochem. 1997, 122, 622–626. [Google Scholar] [CrossRef] [PubMed]
- Lawton, L.N.; Bonaldo, M.F.; Jelenc, P.C.; Qiu, L.; Baumes, S.A.; Marcelino, R.A.; de Jesus, G.M.; Wellington, S.; Knowles, J.A.; Warburton, D.; et al. Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta. Gene 1997, 203, 17–26. [Google Scholar] [CrossRef]
- Fairlie, W.D.; Moore, A.G.; Bauskin, A.R.; Russell, P.K.; Zhang, H.P.; Breit, S.N. MIC-1 is a novel TGF-beta superfamily cytokine associated with macrophage activation. J. Leukoc. Biol. 1999, 65, 2–5. [Google Scholar] [CrossRef]
- Johnen, H.; Lin, S.; Kuffner, T.; Brown, D.A.; Tsai, V.W.-W.; Bauskin, A.R.; Wu, L.; Pankhurst, G.; Jiang, L.; Junankar, S.; et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat. Med. 2007, 13, 1333–1340. [Google Scholar] [CrossRef]
- Bauskin, A.R.; Brown, D.A.; Kuffner, T.; Johnen, H.; Luo, X.W.; Hunter, M.; Breit, S.N. Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer. Cancer Res. 2006, 66, 4983–4986. [Google Scholar] [CrossRef] [Green Version]
- Brown, D.A.; Moore, J.; Johnen, H.; Smeets, T.J.; Bauskin, A.R.; Kuffner, T.; Weedon, H.; Milliken, S.T.; Tak, P.P.; Smith, M.D.; et al. Serum macrophage inhibitory cytokine 1 in rheumatoid arthritis: A potential marker of erosive joint destruction. Arthritis Rheum. 2007, 56, 753–764. [Google Scholar] [CrossRef]
- Brown, D.A.; Breit, S.N.; Buring, J.; Fairlie, W.D.; Bauskin, A.R.; Liu, T.; Ridker, P.M. Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: A nested case-control study. Lancet 2002, 359, 2159–2163. [Google Scholar] [CrossRef]
- Vila, G.; Riedl, M.; Anderwald, C.; Resl, M.; Handisurya, A.; Clodi, M.; Prager, G.; Ludvik, B.; Krebs, M.; Luger, A. The Relationship between Insulin Resistance and the Cardiovascular Biomarker Growth Differentiation Factor-15 in Obese Patients. Clin. Chem. 2011, 57, 309–316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dostálová, I.; Haluzíková, D.; Haluzík, M. Fibroblast growth factor 21: A novel metabolic regulator with potential therapeutic properties in obesity/type 2 diabetes mellitus. Physiol. Res. 2009, 58, 1–7. [Google Scholar] [PubMed]
- Tsai, V.W.-W.; Macia, L.; Johnen, H.; Kuffner, T.; Manadhar, R.; Jørgensen, S.B.; Lee-Ng, K.K.M.; Zhang, H.P.; Wu, L.; Marquis, C.P.; et al. TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PLoS ONE 2013, 8, e55174. [Google Scholar] [CrossRef] [Green Version]
- Tsai, V.W.-W.; Macia, L.; Feinle-Bisset, C.; Manandhar, R.; Astrup, A.; Raben, A.; Lorenzen, J.K.; Schmidt, P.T.; Wiklund, F.; Pedersen, N.L.; et al. Serum Levels of Human MIC-1/GDF15 Vary in a Diurnal Pattern, Do Not Display a Profile Suggestive of a Satiety Factor and Are Related to BMI. PLoS ONE 2015, 10, e0133362. [Google Scholar] [CrossRef] [Green Version]
- Coll, A.P.; Chen, M.; Taskar, P.; Rimmington, D.; Patel, S.; Tadross, J.A.; Cimino, I.; Yang, M.; Welsh, P.; Virtue, S.; et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 2020, 578, 444–448. [Google Scholar] [CrossRef]
- Wollert, K.C.; Kempf, T.; Peter, T.; Olofsson, S.; James, S.; Johnston, N.; Lindahl, B.; Horn-Wichmann, R.; Brabant, G.; Simoons, M.L.; et al. Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation 2007, 115. [Google Scholar] [CrossRef] [Green Version]
- Kempf, T.; Björklund, E.; Olofsson, S.; Lindahl, B.; Allhoff, T.; Peter, T.; Tongers, J.; Wollert, K.C.; Wallentin, L. Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction. Eur. Heart J. 2007, 28. [Google Scholar] [CrossRef] [Green Version]
- Hagström, E.; Held, C.; Stewart, R.A.; Aylward, P.E.; Budaj, A.; Cannon, C.P.; Koenig, W.; Krug-Gourley, S.; Mohler, E.R.; Steg, P.G.; et al. Growth Differentiation Factor 15 Predicts All-Cause Morbidity and Mortality in Stable Coronary Heart Disease. Clin. Chem. 2017, 63. [Google Scholar] [CrossRef]
- Hagström, E.; James, S.K.; Bertilsson, M.; Becker, R.C.; Himmelmann, A.; Husted, S.; Katus, H.A.; Steg, P.G.; Storey, R.F.; Siegbahn, A.; et al. Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: Results from the PLATO study. Eur. Heart J. 2016, 37. [Google Scholar] [CrossRef] [Green Version]
- Dostálová, I.; Roubícek, T.; Bártlová, M.; Mráz, M.; Lacinová, Z.; Haluzíková, D.; Kaválková, P.; Matoulek, M.; Kasalicky, M.; Haluzík, M. Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: The influence of very low calorie diet. Eur. J. Endocrinol. 2009, 161. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sugulle, M.; Dechend, R.; Herse, F.; Weedon-Fekjaer, M.S.; Johnsen, G.M.; Brosnihan, K.B.; Anton, L.; Luft, F.C.; Wollert, K.C.; Kempf, T.; et al. Circulating and placental growth-differentiation factor 15 in preeclampsia and in pregnancy complicated by diabetes mellitus. Hypertension 2009, 54, 106–112. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wiklund, F.E.; Bennet, A.; Magnusson, P.K.; Eriksson, U.K.; Lindmark, F.; Wu, L.; Yaghoutyfam, N.; Marquis, C.P.; Stattin, P.; Pedersen, N.L.; et al. Macrophage inhibitory cytokine-1 (MIC-1/GDF15): A new marker of all-cause mortality. Aging Cell 2010, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Daniels, L.B.; Clopton, P.; Laughlin, G.A.; Maisel, A.S.; Barrett-Connor, E. Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: The Rancho Bernardo Study. Circulation 2011, 123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brown, R.J.; Araujo-Vilar, D.; Cheung, P.T.; Dunger, D.; Garg, A.; Jack, M.; Mungai, L.; Oral, E.A.; Patni, N.; Rother, K.I.; et al. The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline. J. Clin. Endocrinol. Metab. 2016, 101, 4500–4511. [Google Scholar] [CrossRef] [PubMed]
- Patel, S.; Alvarez-Guaita, A.; Melvin, A.; Rimmington, D.; Dattilo, A.; Miedzybrodzka, E.L.; Cimino, I.; Maurin, A.-C.; Roberts, G.P.; Meek, C.L.; et al. GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans. Cell Metab. 2019, 29, 707–718. [Google Scholar] [CrossRef] [Green Version]
- McDuffie, J.R.; Riggs, P.A.; Calis, K.A.; Freedman, R.J.; Oral, E.A.; DePaoli, A.; Yanovski, J.A. Effects of exogenous leptin on satiety and satiation in patients with lipodystrophy and leptin insufficiency. J. Clin. Endocrinol. Metab. 2004, 89. [Google Scholar] [CrossRef] [Green Version]
- Hoffmann, A.; Ebert, T.; Klöting, N.; Dokas, J.; Jeromin, F.; Jessnitzer, B.; Burkhardt, R.; Fasshauer, M.; Kralisch, S. Leptin dose-dependently decreases atherosclerosis by attenuation of hypercholesterolemia and induction of adiponectin. Biochim. Biophys. Acta 2016, 1862, 113–120. [Google Scholar] [CrossRef] [Green Version]
- Fu, Y.; Taniguchi, Y.; Shinkai, S.; Tanaka, M.; Ito, M. Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders. Geriatr. Gerontol. Int. 2016, 16, 17–29. [Google Scholar] [CrossRef]
- Kempf, T.; Guba-Quint, A.; Torgerson, J.; Magnone, M.C.; Haefliger, C.; Bobadilla, M.; Wollert, K.C. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: Results from the XENDOS trial. Eur. J. Endocrinol. 2012, 167. [Google Scholar] [CrossRef]
- Carstensen, M.; Herder, C.; Brunner, E.J.; Strassburger, K.; Tabak, A.G.; Roden, M.; Witte, D.R. Macrophage inhibitory cytokine-1 is increased in individuals before type 2 diabetes diagnosis but is not an independent predictor of type 2 diabetes: The Whitehall II study. Eur. J. Endocrinol. 2010, 162. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tsai, V.W.; Zhang, H.P.; Manandhar, R.; Lee-Ng, K.K.M.; Lebhar, H.; Marquis, C.P.; Husaini, Y.; Sainsbury, A.; Brown, D.A.; Breit, S.N. Treatment with the TGF-b superfamily cytokine MIC-1/GDF15 reduces the adiposity and corrects the metabolic dysfunction of mice with diet-induced obesity. Int. J. Obes. (Lond.) 2018, 42, 561–571. [Google Scholar] [CrossRef] [PubMed]
- Breit, S.N.; Carrero, J.J.; Tsai, V.W.; Yagoutifam, N.; Luo, W.; Kuffner, T.; Bauskin, A.R.; Wu, L.; Jiang, L.; Barany, P.; et al. Macrophage inhibitory cytokine-1 (MIC-1/GDF15) and mortality in end-stage renal disease. Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc.—Eur. Ren. Assoc. 2012, 27. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hoffmann, A.; Ebert, T.; Klöting, N.; Kolb, M.; Gericke, M.; Jeromin, F.; Jessnitzer, B.; Lössner, U.; Burkhardt, R.; Stumvoll, M.; et al. Leptin decreases circulating inflammatory IL-6 and MCP-1 in mice. Biofactors 2019, 45, 43–48. [Google Scholar] [CrossRef] [Green Version]
- Herrero, L.; Shapiro, H.; Nayer, A.; Lee, J.; Shoelson, S.E. Inflammation and adipose tissue macrophages in lipodystrophic mice. Proc. Natl. Acad. Sci. USA 2010, 107, 240–245. [Google Scholar] [CrossRef] [Green Version]
- Javor, E.D.; Ghany, M.G.; Cochran, E.K.; Oral, E.A.; DePaoli, A.; Premkumar, A.; Kleiner, D.E.; Gorden, P. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology (Baltim. Md.) 2005, 41. [Google Scholar] [CrossRef]
- Koo, B.K.; Um, S.H.; Seo, D.S.; Joo, S.K.; Bae, J.M.; Park, J.H.; Chang, M.S.; Kim, J.H.; Lee, J.; Jeong, W.-I.; et al. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease. Liver Int. 2018, 38, 695–705. [Google Scholar] [CrossRef]
- Lee, E.S.; Kim, S.H.; Kim, H.J.; Kim, K.H.; Lee, B.S.; Ku, B.J. Growth Differentiation Factor 15 Predicts Chronic Liver Disease Severity. Gut Liver 2017, 11, 276–282. [Google Scholar] [CrossRef]
- Kim, K.H.; Kim, S.H.; Han, D.H.; Jo, Y.S.; Lee, Y.-H.; Lee, M.-S. Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice. Sci. Rep. 2018, 8, 6789. [Google Scholar] [CrossRef]
- Li, D.; Zhang, H.; Zhong, Y. Hepatic GDF15 is regulated by CHOP of the unfolded protein response and alleviates NAFLD progression in obese mice. Biochem. Biophys. Res. Commun. 2018, 498, 388–394. [Google Scholar] [CrossRef]
- Akinci, B.; Unlu, S.M.; Celik, A.; Simsir, I.Y.; Sen, S.; Nur, B.; Keskin, F.E.; Ozgen, S.B.; Kutbay, O.N.; Sarer, Y.B.; et al. Renal complications of lipodystrophy: A closer look at the natural history of kidney disease. Clin. Endocrinol. 2018, 89. [Google Scholar] [CrossRef] [PubMed]
- Chong, A.Y.; Lupsa, B.C.; Cochran, E.K.; Gorden, P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia 2010, 53, 27–35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, X.; Chrysovergis, K.; Kosak, J.; Kissling, G.; Streicker, M.; Moser, G.; Li, R.; Eling, T.E. hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling. Aging (Albany N. Y.) 2014, 6, 690–704. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Miehle, K.; Ebert, T.; Kralisch, S.; Hoffmann, A.; Kratzsch, J.; Schlögl, H.; Stumvoll, M.; Fasshauer, M. Circulating serum chemerin levels are elevated in lipodystrophy. Clin. Endocrinol. (Oxf.) 2016, 84, 932–938. [Google Scholar] [CrossRef]
- Matthews, D.R.; Hosker, J.P.; Rudenski, A.S.; Naylor, B.A.; Treacher, D.F.; Turner, R.C. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28, 412–419. [Google Scholar] [CrossRef] [Green Version]
- Levey, A.S.; Stevens, L.A.; Schmid, C.H.; Zhang, Y.L.; Castro, A.F.; Feldman, H.I.; Kusek, J.W.; Eggers, P.; van Lente, F.; Greene, T.; et al. A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 2009, 150, 604–612. [Google Scholar] [CrossRef]
- Shimomura, I.; Hammer, R.E.; Richardson, J.A.; Ikemoto, S.; Bashmakov, Y.; Goldstein, J.L.; Brown, M.S. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: Model for congenital generalized lipodystrophy. Genes Dev. 1998, 12, 3182–3194. [Google Scholar] [CrossRef] [Green Version]
Parameter | Controls | LD | p |
---|---|---|---|
n | 60 | 60 | |
GDF15 (ng/L) | 414.9 (257.6) | 818.9 (881.6) | <0.001 * |
Age (years) | 39 (22) | 42 (24) | 0.591 |
Gender (male/female) | 12/48 | 12/48 | - |
BMI (kg/m2) | 24.6 (4.9) | 25.2 (4.6) | 0.193 |
WHR | 0.81 (0.11) | 0.97 (0.11) | <0.001 * |
SBP (mmHg) | 122 (22) | 131 (19) | <0.001 * |
DBP (mmHg) | 78 (15) | 81 (14) | 0.183 |
HbA1c (%) | 5.2 (0.6) | 6.0 (2.1) | <0.001 * |
HbA1c (mmol/mol) | 33.3 (6.3) | 42.4 (23.0) | <0.001 * |
FG (mmol/L) | 5.2 (0.8) | 5.6 (3.8) | 0.020 * |
FI (pmol/L) | 51.8 (45.8) | 114.9 (113.6) | <0.001 * |
HOMA-IR | 1.7 (1.7) | 4.9 (5.8) | <0.001 * |
Cholesterol (mmol/L) | 5.36 (1.35) | 5.29 (2.05) | 0.258 |
HDL cholesterol (mmol/L) | 1.54 (0.59) | 0.85 (0.52) | <0.001 * |
LDL cholesterol (mmol/L) | 3.56 (1.39) | 2.74 (1.76) | <0.001 * |
TG (mmol/L) | 0.98 (0.60) | 2.92 (5.82) | <0.001 * |
FFA (mmol/L) | 0.44 (0.21) | 0.61 (0.28) | 0.002 * |
Creatinine (µmol/L) | 76 (20) | 67 (21) | 0.011 * |
eGFR (mL/min/1.73 m2) | 94.0 (19.0) | 100.2 (31.7) | 0.043 * |
CRP (mg/L) | 0.7 (1.5) | 1.7 (2.5) | 0.016 * |
Adiponectin (mg/L) | 9.3 (7.7) | 2.7 (3.7) | <0.001 * |
Leptin (µg/L) | 12.0 (13.9) | 4.3 (4.7) | <0.001 * |
FGF21 (pg/mL) # | 184.4 (236.8) | 381.8 (530.0) | 0.002 * |
Smoking (n) | 7/60 | 18/59 | 0.014 * |
Metformin (n) | 0/60 | 28/60 | <0.001 * |
ALAT (µkat/L) | 0.34 (0.20) | 0.49 (0.42) | <0.001 * |
ASAT (µkat/L) | 0.33 (0.08) | 0.48 (0.28) | <0.001 * |
GGT (µkat/L) | 0.28 (0.20) | 0.65 (0.60) | <0.001 * |
Parameter | Univariate Correlations | Multivariate Regression Analysis | |
---|---|---|---|
r/p | β | p | |
Age (years) | 0.494/<0.001 * | 0.177 | 0.043 † |
Group (LD vs. Non-LD) | - | 0.228 | 0.017 † |
Gender | - | 0.005 | 0.943 |
BMI (kg/m2) | 0.275/0.002 * | - | - |
WHR | 0.573/<0.001 * | 0.079 | 0.404 |
SBP (mmHg) | 0.265/0.003 * | -0.099 | 0.143 |
DBP (mmHg) | 0.153/0.095 | - | - |
HbA1c (%) | 0.588/<0.001 * | - | - |
HbA1c (mmol/mol) | 0.599/<0.001 * | 0.225 | 0.005 † |
FG (mmol/L) | 0.381/<0.001 * | - | - |
FI (pmol/L) | 0.389/<0.001 * | - | - |
HOMA-IR | 0.451/<0.001 * | - | - |
Cholesterol (mmol/L) | 0.003/0.974 | - | - |
HDL cholesterol (mmol/L) | −0.408/<0.001 * | 0.085 | 0.450 |
LDL cholesterol (mmol/L) | −0.392/<0.001 * | ||
TG (mmol/L) | 0.572/<0.001 * | 0.323 | 0.004 † |
FFA (mmol/L) | 0.179/0.056 | - | - |
Creatinine (µmol/L) | 0.034/0.715 | - | - |
eGFR (mL/min/1.73 m2) | −0.277/0.002 * | −0.345 | <0.001 † |
CRP (mg/L) | 0.291/0.001 * | 0.152 | 0.023 † |
Adiponectin (mg/L) | −0.263/0.004 * | - | - |
Leptin (µg/L) | −0.198/0.030 * | - | - |
FGF21 (pg/mL) | 0.560/<0.001 * | - | - |
Smoking | 0.245/0.007 * | - | - |
Metformin | 0.493/<0.001 * | - | - |
Parameter | Baseline Characteristics | ||
---|---|---|---|
n | 16 | ||
Age (years) | 42 (18) | ||
Gender (male/female) | 3/13 | ||
Before treatment | 6 months treatment | p | |
GDF15 (ng/L) | 1312.0 (1277.1) | 1157.6 (888.0) | 0.715 |
BMI (kg/m2) | 27.4 (5.6) | 27.3 (7.1) | 0.035 * |
WHR | 0.97 (0.11) | 0.96 (0.09) | 0.331 |
SBP (mmHg) | 128 (16) | 128 (9) | 0.754 |
DBP (mmHg) | 80 (16) | 74 (14) | 0.510 |
HbA1c (%) | 8.0 (2.2) | 7.2 (1.3) | 0.081 |
HbA1c (mmol/mol) | 63.9 (23.8) | 55.3 (14.5) | 0.119 |
FG (mmol/L) | 9.6 (2.9) | 7.9 (4.2) | 0.808 |
FI (pmol/L) | 144.2 (280.0) | 238.1 (374.4) | 0.542 |
HOMA-IR | 12.4 (11.0) | 10.6 (22.2) | 0.583 |
Cholesterol (mmol/L) | 5.85 (4.94) | 5.11 (4.32) | 0.502 |
HDL cholesterol (mmol/L) | 0.62 (0.48) | 0.62 (0.42) | 0.659 |
LDL cholesterol (mmol/L) | 1.65 (2.09) | 1.66 (1.79) | 0.318 |
TG (mmol/L) | 8.64 (14.78) | 3.97 (6.18) | 0.020 * |
FFA (mmol/L) | 0.70 (0.30) | 0.63 (0.42) | 0.594 |
Creatinine (µmol/L) | 63 (20) | 62 (25) | 1.000 |
eGFR (mL/min/1.73 m2) | 101.3 (41.1) | 109.3 (33.4) | 0.893 |
CRP (mg/L) | 3.1 (5.4) | 4.5 (4.5) | 0.094 |
Adiponectin (mg/L) | 2.2 (1.8) | 2.0 (2.1) | 0.382 |
Leptin (µg/L) | 5.1 (4.6) | 11.8 (20.6) | 0.023 * |
ALAT (µkat/L) | 0.54 (0.46) | 0.52 (0.33) | 0.055 |
ASAT (µkat/L) | 0.57 (0.57) | 0.47 (0.52) | 0.680 |
GGT (µkat/L) | 1.04 (2.53) | 0.91 (0.74) | 0.194 |
Parameter | Control | Tg(SREBP-1c) | p | |
---|---|---|---|---|
Saline | Leptin | |||
n | 8 | 8 | 8 | |
Age (years) | ||||
Gender (male/female) | 8/0 | 8/0 | 8/0 | |
BW (g) | 23.3 (0.6) | 22.1 (0.8) a | 17.8 (0.9) b | 0.0001 * |
iBAT weight (mg) | 57.5 (3.2) | 193.8 (17.1) a | 121.1 (14.7) a;b | <0.0001 * |
sAT weight (mg) | 348.4 (40.0) | 80.2 (4.3) a | 53.1 (4.2) a | <0.0001 * |
epiAT weight (mg) | 435.6 (30.3) | 97.8 (6.0) a | 57.1 (6.0) a | <0.0001 * |
WHR | n.d. | n.d. | n.d. | |
SBP (mmHg) | n.d. | n.d. | n.d. | |
DBP (mmHg) | n.d. | n.d. | n.d. | |
HbA1c (%) | n.d. | n.d. | n.d. | |
HbA1c (mmol/mol) | n.d. | n.d. | n.d. | |
FG (mmol/L) | 6.3 (0.6) | 7.8 (0.7) | 7.7 (1.8) | 0.526 |
FI (pmol/L) | n.d. | n.d. | n.d. | |
HOMA-IR | n.d. | n.d. | n.d. | |
Cholesterol (mmol/L) | 31.1 (4.7) | 42.7 (2.4) | 35.0 (7.8) | 0.325 |
HDL cholesterol (mmol/L) | n.d. | n.d. | n.d. | |
LDL cholesterol (mmol/L) | n.d. | n.d. | n.d. | |
TG (mmol/L) | 2.0 (0.1) | 7.4 (1.2) a | 3.5 (1.1) b | 0.0017 * |
FFA (mmol/L) | 0.5 (0.02) | 0.7 (0.03) a | 0.6 (0.06) | 0.0248 * |
Creatinine (µmol/L) | n.d. | n.d. | n.d. | |
eGFR (mL/min/1.73 m2) | n.d. | n.d. | n.d. | |
CRP (mg/L) | n.d. | n.d. | n.d. | |
Adiponectin (mg/L) | n.d. | n.d. | n.d. | |
Leptin (µg/L) | n.d. | n.d. | n.d. | |
FGF21 (pg/mL) | n.d. | n.d. | n.d. | |
Smoking (n) | - | - | - | |
Metformin (n) | - | - | - | |
ALAT (µkat/L) | 0.9 (0.13) | 6.0 (0.69) a | 2.6 (0.58) b | <0.0001 * |
ASAT (µkat/L) | 3.5 (0.6) | 8.1 (0.9) a | 4.5 (0.8) b | 0.0013 * |
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Kralisch, S.; Hoffmann, A.; Estrada-Kunz, J.; Stumvoll, M.; Fasshauer, M.; Tönjes, A.; Miehle, K. Increased Growth Differentiation Factor 15 in Patients with Hypoleptinemia-Associated Lipodystrophy. Int. J. Mol. Sci. 2020, 21, 7214. https://doi.org/10.3390/ijms21197214
Kralisch S, Hoffmann A, Estrada-Kunz J, Stumvoll M, Fasshauer M, Tönjes A, Miehle K. Increased Growth Differentiation Factor 15 in Patients with Hypoleptinemia-Associated Lipodystrophy. International Journal of Molecular Sciences. 2020; 21(19):7214. https://doi.org/10.3390/ijms21197214
Chicago/Turabian StyleKralisch, Susan, Annett Hoffmann, Juliane Estrada-Kunz, Michael Stumvoll, Mathias Fasshauer, Anke Tönjes, and Konstanze Miehle. 2020. "Increased Growth Differentiation Factor 15 in Patients with Hypoleptinemia-Associated Lipodystrophy" International Journal of Molecular Sciences 21, no. 19: 7214. https://doi.org/10.3390/ijms21197214