Plasma IL-1Ra: linking hyperapoB to risk factors for type 2 diabetes independent of obesity in humans

S Bissonnette, N Saint-Pierre, V Lamantia, Y Cyr, H Wassef, M Faraj, S Bissonnette, N Saint-Pierre, V Lamantia, Y Cyr, H Wassef, M Faraj

Abstract

Background/objective: Plasma apoB predicts the incidence of type 2 diabetes (T2D); however, the link between apoB-linpoproteins and risks for T2D remain unclear. Insulin resistance (IR) and compensatory hyperinsulinemia characterize prediabetes, and the involvement of an activated interleukin-1 (IL-1) family, mainly IL-1β and its receptor antagonist (IL-Ra), is well documented. ApoB-lipoproteins were reported to promote IL-1β secretion in immune cells; however, in vivo evidence is lacking. We hypothesized that obese subjects with hyperapoB have an activated IL-1 system that explains hyperinsulinemia and IR in these subjects.

Subjects/methods: We examined 81 well-characterized normoglycemic men and postmenopausal women (⩾27 kg m(-2), 45-74 years, non-smokers, sedentary, free of chronic disease). Insulin secretion and sensitivity were measured by the gold-standard Botnia clamp, which is a combination of a 1-h intravenous glucose tolerance test (IVGTT) followed by 3-h hyperinsulinemic euglycemic clamp.

Results: Plasma IL-1β was near detection limit (0.071-0.216 pg ml(-1)), while IL-1Ra accumulated at 1000-folds higher (77-1068 pg ml(-1)). Plasma apoB (0.34-1.80 g l(-1)) associated significantly with hypersinsulinemia (totalIVGTT: C-peptide r=0.27, insulin r=0.22), IR (M/I=-0.29) and plasma IL-1Ra (r=0.26) but not with IL-1β. Plasma IL-1Ra associated with plasma IL-1β (r=0.40), and more strongly with hyperinsulinemia and IR than apoB, while the association of plasma IL-1β was limited to second phase and total insulin secretion (r=0.23). Adjusting the association of plasma apoB to hyperinsulinemia and IR for IL-1Ra eliminated these associations. Furthermore, despite equivalent body composition, subjects with hyperapoB (⩾80th percentile, 1.14 g l(-1)) had higher C-peptide secretion and lower insulin sensitivity than those with low plasma apoB (⩽20th percentile, 0.78 g l(-1)). Adjustment for plasma IL-1 Ra eliminated all group differences.

Conclusion: Plasma apoB is associated with hyperinsulinemia and IR in normoglycemic obese subjects, which is eliminated upon adjustment for plasma IL-1Ra. This may implicate the IL-1 family in elevated risks for T2D in obese subjects with hyperapoB.

Figures

Figure 1
Figure 1
Plasma glucose, insulin and C-peptide and glucose infusion rates (GIR) during the IVGTT in women (a) and men (b) and the hyperinsulinemia euglycemia clamp (HIEG) in women (c) and men (d), the two-component test of the Botnia clamp. Sex difference at *P⩽0.05 and **P⩽0.01.
Figure 2
Figure 2
Hyperbolic relation (one phase decay) of insulin sensitivity with total insulin secretion (a), total C-peptide secretion (b), first-phase insulin secretion (c) and second-phase insulin secretion (d) in women (open circles) and men (closed circles).
Figure 3
Figure 3
Correlation of plasma apoB with plasma IL-1β (a), IL-1Ra (b), total insulin secretion (c), total C-peptide secretion (d), second-phase insulin secretion (e) and insulin sensitivity (f) in women (open circles, dotted slope line) and men (solid circles, dashed slope line). Solid slope line represents pooled men and women data.
Figure 4
Figure 4
Correlation of plasma IL-1β with total (a) and second-phase insulin secretion (b) and IL-1Ra with total insulin secretion (c), total C-peptide (d), first-phase insulin secretion (e), second-phase insulin secretion (f), insulin sensitivity (g) and plasma IL-1β (h), in women (open circles, dotted slope line) and men (solid circles, dashed slope line). Solid slope line represents pooled men and women data.

References

    1. 1Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999; 104: 787–794.
    1. 2Stumvoll M. Control of glycaemia: from molecules to men. Minkowski Lecture 2003. Diabetologia 2004; 47: 770–781.
    1. 3Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 1990; 113: 909–915.
    1. 4Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005; 365: 1333–1346.
    1. 5Sniderman AD, Lamarche B, Tilley J, Seccombe D, Frohlich J. Hypertriglyceridemic hyperapoB in type 2 diabetes. Diabetes Care 2002; 25: 579–582.
    1. 6Faraj M, Messier L, Bastard JP, Tardif A, Godbout A, Prud'homme D et al. Apolipoprotein B: a predictor of inflammatory status in postmenopausal overweight and obese women. Diabetologia 2006; 49: 1637–1646.
    1. 7Bissonnette S, Salem H, Wassef H, Saint-Pierre N, Tardif A, Baass A et al. Low density lipoprotein delays clearance of triglyceride-rich lipoprotein by human subcutaneous adipose tissue. J Lipid Res 2013; 54: 1466–1476.
    1. 8Masella R, Vari R, D'Archivio M, Santangelo C, Scazzocchio B, Maggiorella MT et al. Oxidised LDL modulate adipogenesis in 3T3-L1 preadipocytes by affecting the balance between cell proliferation and differentiation. FEBS Lett 2006; 580: 2421–2429.
    1. 9Pedrini MT, Kranebitter M, Niederwanger A, Kaser S, Engl J, Debbage P et al. Human triglyceride-rich lipoproteins impair glucose metabolism and insulin signalling in L6 skeletal muscle cells independently of non-esterified fatty acid levels. Diabetologia 2005; 48: 756–766.
    1. 10Cnop M, Hannaert JC, Grupping AY, Pipeleers DG. Low density lipoprotein can cause death of islet beta-cells by its cellular uptake and oxidative modification. Endocrinology 2002; 143: 3449–3453.
    1. 11Roehrich ME, Mooser V, Lenain V, Herz J, Nimpf J, Azhar S et al. Insulin-secreting beta-cell dysfunction induced by human lipoproteins. J Biol Chem 2003; 278: 18368–18375.
    1. 12Rutti S, Ehses JA, Sibler RA, Prazak R, Rohrer L, Georgopoulos S et al. Low- and high-density lipoproteins modulate function, apoptosis, and proliferation of primary human and murine pancreatic beta-cells. Endocrinology 2009; 150: 4521–4530.
    1. 13Boon J, Hoy AJ, Stark R, Brown RD, Meex RC, Henstridge DC et al. Ceramides contained in LDL are elevated in type 2 diabetes and promote inflammation and skeletal muscle insulin resistance. Diabetes 2013; 62: 401–410.
    1. 14Onat A, Can G, Hergenc G, Yazici M, Karabulut A, Albayrak S. Serum apolipoprotein B predicts dyslipidemia, metabolic syndrome and, in women, hypertension and diabetes, independent of markers of central obesity and inflammation. Int J Obes (Lond) 2007; 31: 1119–1125.
    1. 15Ley SH, Harris SB, Connelly PW, Mamakeesick M, Gittelsohn J, Wolever TM et al. Association of apolipoprotein B with incident type 2 diabetes in an Aboriginal Canadian population. Clin Chem 2010; 56: 666–670.
    1. 16Salomaa V, Havulinna A, Saarela O, Zeller T, Jousilahti P, Jula A et al. Thirty-one novel biomarkers as predictors for clinically incident diabetes. PLoS One 2010; 5: e10100.
    1. 17Hwang YC, Ahn HY, Park SW, Park CY. Apolipoprotein B and non-HDL cholesterol are more powerful predictors for incident type 2 diabetes than fasting glucose or glycated hemoglobin in subjects with normal glucose tolerance: a 3.3-year retrospective longitudinal study. Acta Diabetol 2014; 51: 941–946.
    1. 18Donath MY, Schumann DM, Faulenbach M, Ellingsgaard H, Perren A, Ehses JA. Islet inflammation in type 2 diabetes: from metabolic stress to therapy. Diabetes Care 2008; 31: S161–S164.
    1. 19Skeldon AM, Faraj M, Saleh M. Caspases and inflammasomes in metabolic inflammation. Immunol Cell Biol 2014; 92: 304–313.
    1. 20Masters SL, Latz E, O'Neill LA. The inflammasome in atherosclerosis and type 2 diabetes. Sci Transl Med 2011; 3: 81ps17.
    1. 21Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol 2013; 25: 469–484.
    1. 22Osborn O, Brownell SE, Sanchez-Alavez M, Salomon D, Gram H, Bartfai T. Treatment with an Interleukin 1 beta antibody improves glycemic control in diet-induced obesity. Cytokine 2008; 44: 141–148.
    1. 23Meier CA, Bobbioni E, Gabay C, Assimacopoulos-Jeannet F, Golay A, Dayer JM. IL-1 receptor antagonist serum levels are increased in human obesity: a possible link to the resistance to leptin? J Clin Endocrinol Metab 2002; 87: 1184–1188.
    1. 24Maedler K, Dharmadhikari G, Schumann DM, Storling J. Interleukin-1 beta targeted therapy for type 2 diabetes. Expert Opin Biol Ther 2009; 9: 1177–1188.
    1. 25Ruotsalainen E, Salmenniemi U, Vauhkonen I, Pihlajamaki J, Punnonen K, Kainulainen S et al. Changes in inflammatory cytokines are related to impaired glucose tolerance in offspring of type 2 diabetic subjects. Diabetes Care 2006; 29: 2714–2720.
    1. 26Salmenniemi U, Ruotsalainen E, Pihlajamaki J, Vauhkonen I, Kainulainen S, Punnonen K et al. Multiple abnormalities in glucose and energy metabolism and coordinated changes in levels of adiponectin, cytokines, and adhesion molecules in subjects with metabolic syndrome. Circulation 2004; 110: 3842–3848.
    1. 27Grossmann V, Schmitt VH, Zeller T, Panova-Noeva M, Schulz A, Laubert-Reh D et al. Profile of the immune and inflammatory response in individuals with prediabetes and type 2 diabetes. Diabetes Care 2015; 38: 1356–1364.
    1. 28Luotola K, Pietila A, Zeller T, Moilanen L, Kahonen M, Nieminen MS et al. Associations between interleukin-1 (IL-1) gene variations or IL-1 receptor antagonist levels and the development of type 2 diabetes. J Intern Med 2011; 269: 322–332.
    1. 29Herder C, Brunner EJ, Rathmann W, Strassburger K, Tabak AG, Schloot NC et al. Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist precede the onset of type 2 diabetes: the Whitehall II study. Diabetes Care 2009; 32: 421–423.
    1. 30Marculescu R, Endler G, Schillinger M, Iordanova N, Exner M, Hayden E et al. Interleukin-1 receptor antagonist genotype is associated with coronary atherosclerosis in patients with type 2 diabetes. Diabetes 2002; 51: 3582–3585.
    1. 31Stollenwerk MM, Lindholm MW, Porn-Ares MI, Larsson A, Nilsson J, Ares MP. Very low-density lipoprotein induces interleukin-1beta expression in macrophages. Biochem Biophys Res Commun 2005; 335: 603–608.
    1. 32Thomas CE, Jackson RL, Ohlweiler DF, Ku G. Multiple lipid oxidation products in low density lipoproteins induce interleukin-1 beta release from human blood mononuclear cells. J Lipid Res 1994; 35: 417–427.
    1. 33Wassef H, Bissonnette S, Saint-Pierre N, Lamantia V, Cyr Y, Chrétien M et al. The apoB/PCSK9 ratio: a new index for metabolic risk in humans. J Clin Lipidol 2015. (in press).
    1. 34Wassef H, Salem H, Bissonnette S, Baass A, Dufour R, Davignon J et al. White adipose tissue apolipoprotein CI secretion in relation to delayed plasma clearance of dietary fat in humans. Arterioscler Thromb Vasc Biol 2012; 32: 2785–2793.
    1. 35Tripathy D, Wessman Y, Gullstrom M, Tuomi T, Groop L. Importance of obtaining independent measures of insulin secretion and insulin sensitivity during the same test: results with the Botnia clamp. Diabetes Care 2003; 26: 1395–1401.
    1. 36Faraj M, Beauregard G, Loizon E, Moldes M, Clement K, Tahiri Y et al. Insulin regulation of gene expression and concentrations of white adipose tissue-derived proteins in vivo in healthy men: relation to adiponutrin. J Endocrinol 2006; 191: 427–435.
    1. 37Bastard JP, Vandernotte JM, Faraj M, Karelis AD, Messier L, Malita FM et al. Relationship between the hyperinsulinemic-euglycaemic clamp and a new simple index assessing insulin sensitivity in overweight and obese postmenopausal women. Diabetes Metab 2007; 33: 261–268.
    1. 38Faraj M, Lavoie ME, Messier L, Bastard JP, Prud'homme D. Reduction in serum apoB is associated with reduced inflammation and insulin resistance in post-menopausal women: A MONET study. Atherosclerosis 2010; 211: 682–688.
    1. 39Bergman RN. Orchestration of glucose homeostasis: from a small acorn to the California oak. Diabetes 2007; 56: 1489–1501.
    1. 40Jones A, Hattersley A. The clinical utility of C-peptide measurement in the care of patients with diabetes. Diabet Med 2013; 30: 803–817.
    1. 41Cartier A, Bergeron J, Poirier P, Almeras N, Tremblay A, Lemieux I et al. Increased plasma interleukin-1 receptor antagonist levels in men with visceral obesity. Ann Med 2009; 41: 471–478.
    1. 42Juge-Aubry CE, Somm E, Giusti V, Pernin A, Chicheportiche R, Verdumo C et al. Adipose tissue is a major source of interleukin-1 receptor antagonist: upregulation in obesity and inflammation. Diabetes 2003; 52: 1104–1110.
    1. 43Connelly PW, Poapst M, Davignon J, Lussier-Cacan S, Reeder B, Lessard R et al. Reference values of plasma apolipoproteins A-I and B, and association with nonlipid risk factors in the populations of two Canadian provinces: Quebec and Saskatchewan. Canadian Heart Health Surveys Research Group. Can J Cardiol 1999; 15: 409–418.
    1. 44Retnakaran R, Shen S, Hanley AJ, Vuksan V, Hamilton JK, Zinman B. Hyperbolic relationship between insulin secretion and sensitivity on oral glucose tolerance test. Obesity (Silver Spring) 2008; 16: 1901–1907.
    1. 45Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest 2006; 116: 1802–1812.
    1. 46Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 2004; 53: S16–S21.
    1. 47Barg S, Eliasson L, Renstrom E, Rorsman P. A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells. Diabetes 2002; 51: S74–S82.
    1. 48Seino S, Shibasaki T, Minami K. Dynamics of insulin secretion and the clinical implications for obesity and diabetes. J Clin Invest 2011; 121: 2118–2125.
    1. 49Cerasi E, Ktorza A. Anatomical and functional plasticity of pancreatic beta-cells and type 2 diabetes. Med Sci 2007; 23: 885–894.
    1. 50Ferrara CM, Goldberg AP, Nicklas BJ, Sorkin JD, Ryan AS. Sex differences in insulin action and body fat distribution in overweight and obese middle-aged and older men and women. Appl Physiol Nutr Metab 2008; 33: 784–790.
    1. 51Ryan AS, Hurlbut DE, Lott ME, Ivey FM, Fleg J, Hurley BF et al. Insulin action after resistive training in insulin resistant older men and women. J Am Geriatr Soc 2001; 49: 247–253.
    1. 52Kim SH, Reaven G. Sex differences in insulin resistance and cardiovascular disease risk. J Clin Endocrinol Metab 2013; 98: E1716–E1721.
    1. 53Jensen MD, Nielsen S, Gupta N, Basu R, Rizza RA. Insulin clearance is different in men and women. Metabolism 2012; 61: 525–530.
    1. 54Kuniyasu A, Hayashi S, Nakayama H. Adipocytes recognize and degrade oxidized low density lipoprotein through CD36. Biochem Biophys Res Commun 2002; 295: 319–323.
    1. 55D'Archivio M, Scazzocchio B, Filesi C, Vari R, Maggiorella MT, Sernicola L et al. Oxidised LDL up-regulate CD36 expression by the Nrf2 pathway in 3T3-L1 preadipocytes. FEBS Lett 2008; 582: 2291–2298.
    1. 56Grupping AY, Cnop M, Van Schravendijk CF, Hannaert JC, Van Berkel TJ, Pipeleers DG. Low density lipoprotein binding and uptake by human and rat islet beta cells. Endocrinology 1997; 138: 4064–4068.
    1. 57Feingold KR, Marshall M, Gulli R, Moser AH, Grunfeld C. Effect of endotoxin and cytokines on lipoprotein lipase activity in mice. Arterioscler Thromb Vasc Biol 1994; 14: 1866–1872.
    1. 58Stienstra R, Joosten LA, Koenen T, van Tits B, van Diepen JA, van den Berg SA et al. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab 2010; 12: 593–605.
    1. 59Schumann DM, Maedler K, Franklin I, Konrad D, Storling J, Boni-Schnetzler M et al. The Fas pathway is involved in pancreatic beta cell secretory function. Proc Natl Acad Sci USA 2007; 104: 2861–2866.
    1. 60Donath MY, Dalmas E, Sauter NS, Boni-Schnetzler M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab 2013; 17: 860–872.
    1. 61Boni-Schnetzler M, Thorne J, Parnaud G, Marselli L, Ehses JA, Kerr-Conte J et al. Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta -cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation. J Clin Endocrinol Metab 2008; 93: 4065–4074.
    1. 62van Poppel PC, van Asseldonk EJ, Holst JJ, Vilsboll T, Netea MG, Tack CJ. The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance. Diabetes Obes Metab 2014; 16: 1269–1273.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa