frank diabetes mellitus and correlate well with total units C-peptide secretion in type -2 diabetes subjects who had. increased SF concentration. …
JK SCIENCE
REVIEW ARTICLE
Serum Ferritin and Type-2 Diabetes Mellitus
Sumeet Smotra, VRTandon, Sanjay Sharma, R P Kudyar
Introduction Diabetes Mellitus is a predominant public health concern, affecting millions of people worldwide The disease causes substantial morbidity and mortality and long term complications Recently, it is recognized that, increased body iron stores are associated with the development of glucose intolerance, gestational diabetes Type-2 diabetes1 Increased Serum Ferritin SF have been reported to negatively correlate with insulin sensitivity2,3 and the presence of insulin resistance syndrome4 Furthermore insulin resistance, compensated by hyperinsulinemia, sets in early even before the onset of frank diabetes mellitus and correlate well with indicators of iron overload and SF5Frequent blood donation lead to decrease iron stores, which in turn reduces post-prandal hyperinsulinemia in healthy volunteers and improves insulin sensitivity6Insulin resistance, correlate well with total units of blood transfused, splenomegaly and SF in chronically transfused patients of thalassemia major5 Phlebotomy is followed by drop in serum glucose, serum cholesterol, serum
triglycerides and improvement in both beta cell secretion and peripheral insulin action in type-2 diabetes mellitus7,8 Epidemiological studies also suggest that high body iron stores are associated with insulin resistance and type 2 diabetes9,10In a trial of poorly controlled diabetic patients, hyperferritinemia co-related with diabetic retinopathy11 A similar influence of the increase body iron stores on diabetic nephropathy and vascular dysfunction have been suggested12,13The present review discusses how raised serum iron levels can influence the patients of type-2 diabetes SF and its Influence on Serum Insulin levels Wrede et al 4 reported a significant correlation between SF and the presence of IRS Insulin Resistance Syndrome
criteria in a large representative population Suvarna et al 5 from India reported similar results and suggested that insulin resistance, sets in early even before the onset of frank diabetes mellitus and correlate well with total units of blood transfused, splenomegaly and SF in chronically transfused patients of thalassemia major5 Fernandez et al 1 found that in general population increased body iron stores are possibly associated with occurrence of
glucose intolerance, type-2 diabetes and gestational diabetes Facchini, 8 found significant reduction in serum insulin concentration after performing a 550 ml phlebotomy in healthy volunteers Blood letting of 1500 ml has been demonstrated to improve insulin sensitivity and to decrease C-peptide secretion in type -2 diabetes subjects who had increased SF concentration Similarly Dmochowski et al 2 reported in a study on thalassemic patients that SF concentration correlated negatively with insulin sensitivity and the conclusion of the study showed a major significant insulin resistance which may be compensated for by an elevated circulating insulin level Dymock et al 7 reported significant reduction in total daily insulin dosage following phlebotomy and improvement in diabetic status of patients following venesection Further epidemiological studies also support these findings which suggest that high body iron stores are associated with insulin resistance and type 2 diabetes9,10 Mechanism Rai Jiang et al 14 have reported elaboration of Hydroxyl radical in iron overload which causes cell damage This leads to insulin resistance - hyperinuslinemia initially followed by decrease secretion
and diabetes Deferroxamine, a chelating agent with antioxidant properties improves fasting blood glucose in chronically transfused patients of thalassemia major, thus it supports
From the Department of G Medicine ASCOMS, Sidhra, Govt Medical College, Jammu, Health Services, Jammu JK Correspondence to : Dr VR Tandon, 5B, Bakshi Nagar, Jammu Vol 9 No 4, October-December 2007 164
JK SCIENCE above hypothesis5 Recently, it has been suggested that transferrin and iron induce insulin resistance of glucose transport in adipocytes is through a mechanism independent of fatty acids15 However, further studies are required to investigate the pathophysiological mechanism and consequences of increased SF levels in patients with Insulin resistance syndrome SF and its Influence on Various Biochemical parameters In the diabetic patients, a positive correlation between increased SF and poor glycemic control reflected by higher HbAIC, has been suggested by Eschwege et al 16 They reported that haemoglobin AIc values measured in diabetic patients with idiopathic haemochromatosis tended to be lower than in diabetics without haemochromatosis which may be ascribed to the venesection therapy, which
induces an increased turnover of red cells, and consequently a decrease time available for their glycosylation Metabolic syndrome17 or syndrome X are terms used to describe constellation of metabolic divulgements that include insulin resistance, hyper tension, dislipidemia with low HDL-C and elevated triglycerides, central or visceral obesity, type-2 diabetes mellitus or IGT/IFT and accelerated cardiovascular disease Iron stores expressed as SF concentration, have been proposed as component of insulin resistance syndrome SF concentration is also directly associated with serum uric acid another component of the insulin resistance syndrome and inversely related with HDL concentration Phlebotomy is followed by drop in serum glucose, serum cholesterol, serum triglycerides and improvement in both beta cell secretion and peripheral insulin action in type-2 diabetes mellitus7,8 Wrede et al 4 suggested that SF values are significantly increased in men and women with high BMI 25 kg/m2, increased cholesterol 200 mg/ dl, and increased systolic 160 mmHg blood pressure, in women with diabetes, and in men with increased diastolic 95 mmHg blood pressure4 SF and its Influence on Diabetic
Complications DyMock et al 7 reported influence of the increase body iron stores on diabetic nephropathy and vascular dysfunction Diabetic nephropathy is currently single commonest indication for renal replacement therapy world wide and patients developing end stage renal disease in
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diabetes is increasing 18 Tight blood glucose control reduces the risk of developing nephropathy In patients with increased SF, glycemic control is poor and there is vascular damage Insulin resistance has been documented by Ralpha A, 19 They found impaired tissue sensitivity in uraemic patient In diabetic nephropathy, there is decrease in the GFR albuminuria Once proteinuria has occurred, it is treated by ACE inhibitor or Angiotensin receptor biockers, but it is a progressive condition and it leads to end stage renal disease In a trial by Cantur KZ et al 11 poorly controlled patients of diabetes had hyperferritinemia This confirmed that SF was increased in diabetes as long as glycemic control was not achieved They also found correlation between ferritin level and diabetic retinopathy Whereas persistent hyperglycemia appears to be the primary factor in the pathogenesis of neuropathy, several
functional disturbances are found in the microvasculature of the nerves of diabetic patients Vinik et al 20 These include decreased neural blood flow, increase in vascular resistance and altered vascular permeability This dysfunctional phase in the nerves as in the small vessels, is also associated with elements of metabolic syndrome such as insulin resistance, elevated systolic blood pressure and diabetic dyslipidemics Vinik et al 20 Supporting evidence also comes from animal models and analysis of atherosclerotic lesion in men The evidence from prospective human studies is inconsistent; some patients with increased levels have shown risk of coronary heart disease while others have not Discrepancy may be due to environmental bias and variability in response Studies by Beyar 21 and Ascherio 6 showed inconsistent effect on coronary heart disease So, nothing conclusively could be established about the relationship between SF level and cerebrovascular disease Conclusion It is abundantly clear from the review of studies that increased SF levels are associated with increased S Insulin levels reflecting insulin resistance, poor glycemic control and increased TC, S Triglyceride and Uric
Acid levels in diabetic patients and complications of type-2 diabetes like nephropathy, retinopathy, neuropathy and hypertension except for which data is insufficient vascular disease and
Vol 9 No 4, October-December 2007
JK SCIENCE ischemic heart disease Many measures are taken for prevention, treatment of anemia, but it is important to realize that raised levels of iron above physiological requirement serve no useful purpose in Diabetes Mellitus patients Anemia is very prevalent in Indian population and continuous efforts are being made to prevent and treat anemia at physician, Government and community levels which can influence the coexisting diabetic state
References 1 Fernandez-Real JM, Lopez B A and Ricart W Cross talk between iron metabolism and diabetes Diabetes Care 2002 Aug 51; 2345-48 2 Dmochowski K, Finegood DT, Fran Combe W, Tyler B Z B Factors determining glucose tolerance in patients with thalassemia Major J Clin Endocrinal Metab1993; 77:478-83 3 Cavallo-P, Giovanni P, Franco C, et al Insulin resistance and hyperinsulinemia in homozygous B- Thalassemia Metabolism 44;1996; 281-86 4 Wrede CE, Buettner R, Bollheimer LC,Scholmerich J, Palitzsch KD, Hellerbrand C
Association between SF and the insulin resistance syndrome in a representative population Eur J Endocrinol 2006;154:333-40 5 Suvarna J,Ingle H, Deshmukh CT Insulin resistance and beta cell function in chronically transfused patients of thalassemia major Indian Pediatr 2006;43:393-400 6 Ascherio A, Millett WC, Rimm EB, Giovannucci El Stampfer MJ: Blood Donation and risk of coronary heart disease in men Circulation 2001; 103: 52-7 7 Dymock MW J C, Payke D A, Oakley W G, Roger William Observations as the pathogenesis, complications and treatment of Diabetes, 115 cases of Hemochromatosis American J Medicine 1972; 203-09 8 Facchini FS Effect of Phlebotomy on Plasma Glucose and Insulin Concentrations Diabetes care 1988: 21:2190 9 Rajpathak S, Ma J,Manson J,Willett WC,Hu FB Iron intake and the risk of type 2 diabetes in women: a prospective cohort study Diabetes Care 2006;29:1370-6 10 Jiang R,Ma J, Ascherio A, et al Dietary iron intake and blood donations in relation to risk of type 2 diabetes in men: a prospective cohort study Am J Clin Nutr 2004;79:70-5 11 Canturk Z, Cetinarslay B, Tarkun I, Canturk NZ SF Levels in poorly and well-controlled diabetes mellitus endocr Res 2003;29:299-306
12 Loebstein R, Lehotay DC, Luo X et al Diabetic nephropathy in hypertransfused patients with beta-thalassemia The role of oxidative stress Diabetes Care 1998;21:1306-9 13 Dymock MW J Cassar, DAPayke, WG Oakley, Roger William: Observations as the pathogenesis, complications and treatment of Diabetes, 115 cases of Hemochromatosis American J Medicine 1972; 203-09 14 Rui J, Joann E M, James B M et al Body iron stores in relation of type-2 diabetes in apparently healthy women JAMA, 2004; 291:711-17 15 Green A, Basile R,Rumberger JM Transferrin and iron induce insulin resistance of glucose transport in adipocytes Metabolism 2006;55:1042-5 16 Eschwege E, Saddi R, Wacjman H, Levy R, Thibult N, Duchateau A Haemoglobin AIc in patients on venesection therapy for haemochromatosis Diabete Metab 1982;8:137-40 17 Eroglu D, Zeyneloglu HB Metabolic disorders in patients with recent gestational diabetes mellitus J Obstet Gynaecol Res 2006;32:408-15 18 Marshall S M: Recent advances in diabetic nephropathy Post graduate Medical Journal 2004;80;620-33 19 Ralph A, De Fronze, Anders Alvestrand, Douglas Smith, R Hendler, E Hendler, John Wahren: Insulin resistance in uraemia J Clin Invest 198167;563-68 20
Vinik , Erbas A I , Stansberry T, et al Small fiber neuropathy and neurovascular disturbances in diabetes mellitus Experimental Clinical Endocrinology Diabetes, 2001:S451S473 21 Baer DM, Tekawa IS, Hurley LB Iron stores are not associated with acute myocardial infarction Circulation 1994;89;2915-18
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