Abstract
Background: Some studies suggest that IL-6 is connected with glucose metabolism and insulin action,
so like IGF-IGFBPs system it could play the role in diabetes etiopathogenesis.
Aim: The aim of the study was therefore to test the hypothesis that in children and adolescents
IL-6 is of importance for the etiopathogenesis of diabetes mellitus type 1 and that
IL-6 is connected with carbohydrate metabolism and IGF-IGFBPs action.
Methods: There were 49 patients with type 1 diabetes: 10 persons at onset diabetes and 39
with disease lasted at least 1 year and 33 age-matched healthy children included into
the study. Serum IGF-I concentrations were measured by RIA; IGFBP-1 and IGFBP-2 by
IRMA and IL-6 concentrations using quantitative ELISA immunoassays. HbA1c was measured
by HPLC method. Multiple regression, ANOVA, and Student's t-test were used for statistical analysis.
Results: IL-6 and IGF-I, IGFBP-1 and IGFBP-2 levels did not differ statistically significant
between diabetic patients and controls. IL-6 concentrations were statistically higher
at onset diabetes than in diabetic patients with long-term disease. IL-6 did not correlate
with IGF-I and its binding proteins - 1 and - 2 in examined groups. At onset of disease
IL-6 correlated with insulin requirement. There were not found correlations between
IL-6 and HbA1c in diabetic groups. IGF-I positively correlated with age and growth
in both groups and with IGFBP-2 in diabetic patients. IGFBP-2 correlated negatively
with BMI in all examined groups.
Conclusions: IL-6 might play a significant role in type 1 diabetes mellitus etiopathogenesis.
It seems that IL-6 does not regulate IGF-IGFBP system in diabetic children and adolescents
or IL-6 maybe cooperate with IGF-I, but their significant dependence on insulin action
influences their mutual relationships.
Key words
Type 1 diabetes mellitus - diabetes onset - IL-6 - IGF-I - IGFBPs
References
- 1
Bendtzen K, Buschard K, Diamant M, Horn T, Svenson M.
Possible role of IL-1, TNF-alpha, and IL-6 in insulin-dependent diabetes mellitus
and autoimmune thyroid disease.
Lymphokine Res.
1989;
8
335-340
- 2
Boyne M S, Thame M, Bennett F I, Osmaond C, Miel J P, Forrester T E.
The relationship among circulating insulin-like growth factor (IGF)-I, IGF-binding
proteins-1 and -2, and birth anthropometry: a prospective study.
J Clin Endocrinol Metab.
2003;
88
1687-1691
- 3
Cavallo M G, Pozzilli P, Bird C, Wadhwa M, Meager A, Visalli N, Gearing A J, Andreani D,
Thorpe R.
Cytokines in sera from insulin-dependent diabetic patients at diagnosis.
Clin Exp Immunol.
1991;
86
256-259
- 4
Cole T J, Donnet M L, Stanfield J P.
Weight-for-height indices to assess nutritional status-a new index on a slide-rule.
Am J Clin Nutr.
1981;
34
1935-1943
- 5
De Benedetti F.
Cytokines and Growth Impairment Associated with Chronic Inflammation.
Horm Res.
2000;
53
6
- 6
De Benedetti F, Meazza C, Martini A.
Role of interleukin-6 in growth failure: an animal model.
Horm Res.
2002;
58
24-27
- 7
De Benedetti F, Meazza C, Oliveri M, Pignatti P, Vivarelli M, Alonzi T, Fattori E,
Garrone S, Barreca A, Martini A.
Effect of IL-6 on IGF binding protein-3: a study in IL-6 transgenic mice and in patients
with systemic juvenile idiopathic arthritis.
Endocrinology.
2001;
142
4818-4826
- 8
de Martino M, Galli L, Chiarelli F, Verrotti A, Rossi M E, Bindi G, Galluzzi F, Salti R,
Vierucci A.
Interleukin-6 release by cultured peripheral blood mononuclear cells inversely correlates
with height velocity, bone age, insulin-like growth-factor-I, and insulin-like growth
factor binding protein-3 serum levels in children with perinatal HIV-1 infection.
Clin Immunol.
2000;
94
212-218
- 9
Eckstein F, Pavicic T, Nedbal S, Schmidt C, Wehr U, Rambeck W, Wolf E, Hoeflich A.
Insulin-like growth factor-binding protein-2 (IGFBP-2) overexpression negatively regulates
bone size and mass, but not density in the absence and presence of growth hormone/IGF-I
excess in transgenic mice.
Anat Embryol (Berl).
2002;
206
139-148
- 10
Fernandez-Celemin l, Thissen J P.
Interleukin-6 stimulates hepatic insulin-like growth factor binding protein-4 messenger
ribonucleic acid and protein.
Endocrinology.
2001;
142
241-248
- 11
Froesch E R, Mehboob A, Hussain A, Zapf J.
Insulin growth factor I: Physiology, metabolic effects and clinical uses.
Diab Met Rev.
1996;
12
195-215
- 12
Frystyk J, Bek T, Flyvbjerg A, Skjaerbaek C, Orskov H.
The relationship between the circulating IGF system and the presence of retinopathy
in type 1 diabetic patients.
Diabet Med.
2003;
20
269-276
- 13
Geerlings S E, Brouwer E C, Van Kessel K C, Gaastra W, Stolk R P, Hoepelman A I.
Cytokine secretion is impaired in women with diabetes mellitus.
Eur J Clin Invest.
2000;
30
995-1001
- 14
Granot D, Synder M.
Glucose induces cAMP-independent growth-related changes in stationary cells of Saccharomyces
cerevisiae.
Proc Natl Acad Sci USA.
1991;
88
5724-5728
- 15
Jeschke M G, Barrow R E, Herndon D N.
Insulin-like growth factor I plus insulin-like growth factor binding protein 3 attenuates
the proinflammatory acute phase response in severely burned children.
Ann Surg.
2000;
231
246-252
- 16
Juul A, Bang P, Hertel N T.
Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults:
relation to age, sex, stage of puberty, testicular size, and body mass index.
J Clin Endocrinol Metab.
1994;
78
744-752
- 17
Kado S, Nagase T, Nagata N.
Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6
receptor complexes in patients with type 2 diabetes mellitus.
Acta Diabetol.
1999;
36
67-72
- 18
Katsanos K H, Tsatsoulis A, Christodoulou D, Challa A, Katsaraki A, Tsianos E V.
Reduced serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 levels
in adults with inflammatory bowel disease.
Growth Horm IGF Res.
2001;
11
364-367
- 19
Kołaczyński J W, Caro J F.
Insulin-like growth factor-1 therapy in diabetes: physiologic basis, clinical benefits,
and risks.
Ann Intern Med.
1994;
120
47-55
- 20 Kopczyńska-Sikorska J. Normy w pediatrii. 1st ed. Warszawa; PZWL 1996: 11-64
- 21
Krsek M, Skrha J, Sucharda P, Justova V, Lacinova Z.
Changes in IGF-I levels and its binding proteins in diabetes mellitus and obesity.
Cas Lek Ces.
2003;
142
216-219
- 22
Lelbach A, Scharf J G, Ramadori G.
Regulation of insulin-like growth factor-I and insulin-like growth factor binding
protein-1, -3, -4 in cocultures of rat hepatocytes and Kupffer cells by interleukin-6.
J Hepatol.
2001;
35
558-567
- 23
Le Roith D.
Insulin-like growth factors.
N Engl J Med.
1997;
336
633-640
- 24
Lewitt M S, Denyer G S, Cooney G J, Baxter R C.
Insulin-like growth factor-binding protein-1 modulates blood glucose levels.
Endocrinology.
1991;
129
2254-2257
- 25
McCarty M F.
Interleukin-6 as a central mediator of cardiovascular risk associated with chronic
inflammation, smoking, diabetes, and visceral obesity: down-regulation with essential
fatty acids, ethanol, and pentoxifylline.
Med Hypotheses.
1999;
52
465-477
- 26
Niedźwiedzka A, Dziatkowiak H, Sztefko K.
IGF-I and its binding proteins in children and adolescents with IDDM.
Horm Res.
1999;
51
95
- 27
Niedźwiedzka A, Dziatkowiak H.
IGF-I and its binding proteins 1 and 3 in adolescents with IDDM and diabetic complications.
Horm Res.
2000;
53
61
- 28
Nishimura F, Takahashi K, Kurihara M, Takashiba S, Murayama Y.
Peridontal disease as a complication of diabetes mellitus.
Ann Peridontol.
1998;
3
20-29
- 29
Ono S, Ichikura T, Mochizuki H.
The pathogenesis of the systemic response syndrome and compensatory response syndrome
following surgical stress.
Nippen Gela Galkoi Zasshi.
2003;
104
499-505
- 30
Pickup J C, Chusney G D, Thomas S M, Burt D.
Plasma interleukin-6, tumor necrosis factor alpha, and blood cytokine production in
type 2 diabetes.
Life Sci.
2000;
67
291-300
- 31 Reiter E O, Rosenfeld R G.
IGFs and its binding proteins. Greenspan F, Strewler G Basic and Clinical Endocrinology. Stanford, CT; Appleton
and Lange 1997: 1437-1453
- 32
Rieu M, Binoux M.
Serum levels of insulin-like growth factor (IGF) and IGF binding protein in insulin-dependent
diabetics during an episode of severe metabolic decompensation and recovery phase.
J Clin Endocrinol Metab.
1985;
60
781-785
- 33
Sandler S, Bendtzen K, Eizirik D L, Welsh M.
Inerleukin-6 affects insulin secretion and glucose metabolism of rat pancreatic islets
in vitro.
Endocrinology.
1990;
126
1288-1294
- 34
Soop M, Duxbury H, Agwunobi A O, Gibson J M, Hopkins S J, Childs Ch, Cooper R G, Maycock P,
Little R A, Carlson G L.
Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin
in humans.
Am J Physiol Endocrinol Metab.
2002;
282
1278-1285
- 35
Strasser-Vogel B, Blum W F, Past R.
Insulin-like growth factor (IGF)-I and -II and IGF-binding proteins-1, -2, and -3
in children and adolescents with diabetes mellitus: correlation with metabolic control
and height attainment.
J Clin Endocrinol Metab.
1995;
80
1207-1213
- 36
Street M E, de'Angelis G L, Camacho-Huebner C, Savage M O, Fornaroli F, Bernasconi S,
Giovannelli G.
Interleukin-6 (IL-6) levels and the IGF-IGFBP system in chronic inflammatory bowel
disease (CIBD) in childhood.
Horm Res.
2000;
53
64
- 37
Street M E, Miraki-Mound F, Sanderson I R, Savage M O, Giovannelli G, Bernasconi S,
Camacho-Huebner C.
Interleukin (IL)-1 b and IL-6 modulate insulin-like growth factor binding protein
(IGFBP) secretion in Caco-2 Cells.
Horm Res.
2000;
53
64
- 38
Suikkari A M, Koivisto V A, Rutanen E M, Yki-Jarivinen H, Karonen S L, Seppala M.
Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding
protein.
J Clin Endocrinol Metab.
1988;
66
266-272
- 39
van den Beld A W, Blum W F, Pols H A, Grobbee D E, Lamberts S W.
Serum insulin-like growth factor binding protein-2 levels as an indicator of functional
ability in elderly men.
Eur J Endocrinol.
2003;
148
627-634
- 40
Wędrychowicz A, Stopyrowa J, Fyderek K, Mieżyński W.
Serum and stool interleukin 6 in active and inactive ulcerative colitis in children.
Pediatria Współczesna.
2000;
3
165-169
1 A preliminary version of this study was presented at ISPAD 2001, Sienna, Italy
M. D., Ph.D. Anna Wędrychowicz
Polish-American Children's Hospital
ul. Wielicka 265
30-663 Kraków
Poland
Telefon: + 48126581277
Fax: + 48 1 26 58 10 05
eMail: miniedzw@cyf-kr.edu.pl