Summary
Non-insulin-dependent diabetes mellitus (NIDDM) is commonly associated with hypertrigly-ceridaemia, low serum HDL-cholesterol concentrations, hypertension, obesity and accelerated atherosclerosis (metabolic syndrome X). Since a similar dyslipidaemia occurs with the acute-phase response, we investigated whether elevated acute-phase/stress reactants (the innate immune system’s response to environmental stress) and their major cytokine mediator (interleukin-6, IL-6) are associated with NIDDM and syndrome X, and may thus provide a unifying pathophysiological mechanism for these conditions. Two groups of Caucasian subjects with NIDDM were studied. Those with any 4 or 5 features of syndrome X (n = 19) were compared with a group with 0 or 1 feature of syndrome X (n = 25) but similar age, sex distribution, diabetes duration, glycaemic control and diabetes treatment. Healthy non-diabetic subjects of comparable age and sex acted as controls. Overnight urinary albumin excretion rate, a risk factor for cardiovascular disease, was also assayed in subjects to assess its relationship to the acute-phase response. Serum sialic acid was confirmed as a marker of the acute-phase response since serum concentrations were significantly related to established acute-phase proteins such as α-1 acid glycoprotein (r = 0.82, p < 0.0001). There was a significant graded increase of serum sialic acid, α-1 acid glycoprotein, IL-6 and urinary albumin excretion rate amongst the three groups, with the lowest levels in non-diabetic subjects, intermediate levels in NIDDM patients without syndrome X and highest levels in NIDDM patients with syndrome X. C-reactive protein and cortisol levels were also higher in syndrome X-positive compared to -negative patients and serum amyloid A was higher in both diabetic groups than in the control group. We conclude that NIDDM is associated with an elevated acute-phase response, particularly in those with features of syndrome X. Abnormalities of the innate immune system may be a contributor to the hypertriglyceridaemia, low HDL cholesterol, hypertension, glucose intolerance, insulin resistance and accelerated atherosclerosis of NIDDM. Microalbuminuria may be a component of the acutephase response.
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Abbreviations
- VLDL:
-
Very low density lipoprotein
- HDL:
-
high density lipoprotein
- PAI-1:
-
plasma activator inhibitor-1
- NIDDM:
-
non-insulin-dependent diabetes mellitus
- CHD:
-
coronary heart disease
- IL-6:
-
interleukin-6
- TNF-α:
-
tumour necrosis factor-α
References
Kaplan NM (1989) The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia and hypertension. Arch Intern Med 149: 1514–1520
Wajchenberg BL, Malerbi DA, Rocha MS, Lerario AC, Santomauro ATMG (1994) Syndrome X: a syndrome of insulin resistance. Diabet Metab Rev 10: 19–29
Yudkin J (1995) Coronary heart disease in diabetes mellitus: three new risk factors and a unifying hypothesis. J Intern Med 238: 21–30
Reaven GM (1988) Role of insulin resistance in human disease. Diabetes 37: 1595–1607
Zavaroni I, Bonora E, Pagliara M et al. (1989) Risk factors for coronary heart disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med 320: 702–760
Ganda OM, Arkin CF (1992) Hyperfibrinogenemia: an important risk factor for vascular complications in diabetes. Diabetes Care 15: 1245–1250
Barrett-Connor E (1992) Lower endogenous androgen levels and dyslipidemia in men with non-insulin-dependent diabetes mellitus. Ann Intern Med 117: 807–811
Crook M, Tutt P, Pickup JC (1993) Elevated serum sialic acid concentration in non-insulin-dependent diabetes and its relationship to blood pressure and retinopathy. Diabetes Care 16: 57–60
Crook MA, Tutt P, Simpson H, Pickup JC (1993) Serum sialic acid and acute phase proteins in type 1 and 2 diabetes mellitus. Clin Chim Acta 219: 131–138
Taniuchi K, Chifu K, Hayashi N et al. (1981) A new enzymatic method for the determination of sialic acid in serum and its application as a marker of acute phase reactants. Kobe J Med Sci 27: 91–102
Rosenberg A, Schengrund C-L (1976) Circulating sialyl compounds. In: Rosenberg A, Schengrund S (eds) Biological roles of sialic acid. New York, Plenum pp 275–294
Pickup JC, Mattock MB, Crook MA, Chusney GD, Burt D, Fitzgerald AP (1995) Serum sialic acid concentration and coronary heart disease in NIDDM. Diabetes Care 18: 1100–1103
Cabana VG, Siegel JN, Sabesin SM (1989) Effects of the acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins. J Lipid Res 30: 39–49
Blackman JD, Cabana VG, Mazzone T(1993) The acutephase response and associated lipoprotein abnormalities accompanying lymphoma. J Intern Med 233: 201–204
Spiegel RJ, Schaefer EJ, Magrath IT, Edwards B (1982) Plasma lipid alterations in leukemia and lymphoma. Am J Med 72: 775–782
Olsson AG (1991) Non-atherosclerotic disease and lipoproteins. Curr Opin Lipidol 2: 206–210
Kushner I, Mackiewicz A (1993) The acute phase response: an overview. In: Mackiewicz A, Kushner I, Baumann H (eds) Acute phase proteins: molecular biology, biochemistry and clinical applications. CRC Press Boca Raton, pp 3–19
Steel DM, Whitehead AS (1994) The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A. Immunol Today 15: 81–87
Jarrett RJ, Viberti GC, Argyropoulos A, Hill RD, Mahmud U, Murreis TJ (1984) Microalbuminuria predicts mortality in non-insulin-dependent diabetes. Diabet Med 1: 17–19
Mogensen CE (1984) Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310: 356–360
Groop L, Ekstrand A, Forsblom C et al. (1993) Insulin resistance, hypertension and microalbuminuria in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 36: 642–647
Mattock MB, Keen H, Viberti GC et al. (1988) Coronary heart disease and urinary albumin excretion in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 31: 82–87
Rose G, Blackburn H, Gillum RF, Prineas RJ (1982) Cardiovascular survey methods. WHO Mongr Series 56 pp 162–165
Simpson H, Chusney GD, Crook MA, Pickup JC (1993) Serum sialic acid enzymatic assay based on microtitre plates. Br J Biomed Sci 50: 164–167
Keen H, Clouverakis C (1963) An immunoassay for urinary albumin at low concentration. Lancet ii: 913–916
Havel RJ, Eden HA, Bragdon JH (1955) The distribution and chemical composition of ultracentrifugationally separated lipoproteins in human serum. J Clin Invest 34: 1345–1353
Jonsson A, Wales JK (1976) Blood glycoprotein levels in diabetes mellitus. Diabetologia 12: 245–250
McMillan DE (1989) Increased levels of acute-phase serum proteins in diabetes. Metabolism 38: 1042–1046
Feingold KR, Staprans I, Memon RA et al. (1992) Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance. J Lipid Res 33: 1765–1776
Kisilevsky R (1991) Serum amyloid A (SAA), a protein without a function: some suggestions with reference to cholesterol metabolism. Med Hypoth 35: 337–341
Baumann H, Gauldie J (1994) The acute phase response. Immunol Today 15: 74–80
Dinarello CA (1991) Interleukin-1. In: Thomson AW (ed) The cytokine handbook. Academic Press London, pp 47–82
Akira S, Taga T, Kishimoto T (1993) Interleukin-6 in biology and medicine. Adv Immunol 54: 1–78
Jaattela M (1991) Biological activities and mechanisms of action of tumor necrosis factor α/cachectin. Lab Invest 64: 724–742
Rivier C, Vale W (1984) Influence of corticotrophin-releasing factor on reproductive functions in the rat. Endocrinology 114: 914–921
Brindley DN (1992) Neuroendocrine regulation and obesity. Int J Obes 16 [Suppl 3]: 73–79
Björntorp P (1992) Biochemistry of obesity in relation to diabetes. In: Alberti KGMM, DeFronzo RA, Keen H, Zimmet P (eds) International textbook of diabetes. John Wiley Chichester pp 551–568
Jeanrenaud B (1995) Insulin, corticosterone and the autonomic nervous system in animal obesities: a viewpoint. Diabetologia 38: 998–1002
Figueredo A, Ibarra JL, Bagazgoitia J et al. (1993) Plasma C3d levels and ischemic heart disease in type II diabetes. Diabetes Care 16: 445–449
Feingold KR, Grunfeld C (1992) Role of cytokines in inducing hyperlipidemia. Diabetes 41: [Suppl 2] 97–101
Yokota T, Hansson GK (1995) Immunological mechanisms in atherosclerosis. J Intern Med 238: 479–489
Hotamisligil GS, Spiegelman BM (1994) Tumor necrosis factor a: a key component of the obesity-diabetes link. Diabetes 43: 1271–1278
Bendtzen K, Buschard K, Diamant M, Horn T, Svenson M (1989) Possible role of IL-1, TNFα and IL-6 in insulin-dependent diabetes mellitus and autoimmune thyroid disease. Lymphokine Res 8: 335–341
Rabinovitch A (1994) Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Diabetes 43: 613–621
Pickup JC, Day CD, Bailey C et al. (1995) Plasma sialic acid in animal models of diabetes mellitus: evidence for modulation of sialic acid concentrations by insulin deficiency. Life Sci 57: 1383–1391
Thompson D, Harrison SP, Evans SW, Whicher JT (1991) Insulin modulation of acute-phase protein production in a human hepatoma cell line. Cytokine 3: 619–626
Campos SP, Baumann H (1992) Insulin is a prominent modulator of the cytokine-stimulated expression of acutephase plasma protein genes. Mol Cell Biol 12: 1789–1797
Stuart J, George AJ, Davies AJ, Aukland A, Hurlow RA (1981) Haematological stress syndrome in atherosclerosis. J Clin Pathol 34: 464–467
Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC (1996) C-reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. Br Med J 312: 1061–1065
Vlassara H, Brownlee M, Manogue KR, Dinarello C, Pasagian A (1988) Cachectin/TNF and IL-1 induced by glucose modified proteins: role in normal tissue modelling. Science 240: 1546–1548
Imani F, Horii Y, Suthanthiran M et al. (1993) Advanced glycosylation endproduct-specific receptors on human and rat T-lymphocytes mediate synthesis of interferon y: role in tissue remodelling. J Exp Med 178: 2165–2172
Barker DJP, Hales CN, Fall CHD, Osmond C, Phipps K, Clark PMS (1993) Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36: 62–67
Caswell M, Pike LA, Bull BS, Stuart J (1993) Effect of age on tests of the acute-phase response. Arch Pathol Lab Med 117: 906–910
Fagiolo U, Cossarizza A, Scala E et al. (1993) Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 23: 2375–2378
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Pickup, J.C., Mattock, M.B., Chusney, G.D. et al. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 40, 1286–1292 (1997). https://doi.org/10.1007/s001250050822
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DOI: https://doi.org/10.1007/s001250050822