Effects Of Iron Overload On Glucose Metabolism And Its Related Mechanism

PART I THE STUDY ABOUT THE RELATED MECHANISM OF IRON OVERLOAD-INDUCED DIABETES MELLITUSObjective To observe the effects of iron overload on apoptosis of pancreatic islet cells and its function by iron-overloaded gerbil model. In order to explore possible pathogenesis of iron overload-induced glucose metabolic disorders, and provide the necessary scientific basis for the prevention and treatment of iron overload-induced diabetes.Method 20 healthy adult female Mongolia gerbils with 8-10 week old were purchased from Zhejiang University School of Medicine experimentalanimal Centre. The gerbils Were randomly divided into the iron overload group (10) and the normol control group(NC).The 10 group received 200mg·kg-1·week-1 dextran iron by intraperitoneal injection over a period of 18 weeks, While age-matched control group did not undergo iron loading or treatment and was similarly injected with the same dose of sterile saline during the same period.In addition to intervention measures in both groups, other conditions were consistent. Weight and random blood glucose of each gerbil were monitored every week at a fixed time. The changes of Gerbils, mental state, weight, hair color and appetite were observed every day during the modeling. After treatment, All pretreatment gerbils were fasted for 12 hours before the determination of weight, and all gerbils were sacrificed after anesthesia.removal of the eye, the inner canthus blood were collected for detection of serum ferritin, fasting glucose. Quickly took out each gerbil of pancreatic tissue, and made into paraffin sections.Hematoxylin-Eosin and Prussian blue iron stain were used to observe morphological changes of the pancreas and pancreatic iron deposition conditions. Furthermore, immunohistochemical methods were used to detect expression of insulin in the pancreas in each group of gerbils.Results1. At the end of the modeling, the growth delayed and Weight loss in iron overload group than the control group(P<0.01). But serum ferritin significantly higher than the control group (P<0.01),which suggested that iron overload animal model was successful.2. In iron-overload group, there were Prussian blue particles obviously deposition in pancreatic exocrine gland and pancreatic islet cells through Prussian blue iron stain, while the control group was not found.3. In iron-overload group, areas of gerbil islet cell were significantly less than the control group (P<0.05), and a small amount of cell degeneration, hemorrhage, necrosis or changes before necrosis were visible in the exocrine glands, while there was no abnormal morphological changes in the control group.4. In iron-overload group, fasting blood glucose was significantly higher than before the intervention and control group (P<0.05). Immunohistochemical staining showed that insulin expression in β cell cytoplasm, and insulin staining in iron-overload group was obviously pale, Insulin-positive signal was significantly weaker than the control group (P<0.05).Conclusion1.At the end of modeling, Fasting Blood Glucose in Iron-overload group was significantly higher than in the control group, which suggested iron overload could lead to disorders of glucose metabolism in the organism.2.It could be found some iron deposited in the pancreas of Iron-overloaded gerbil through pathological tissue iron staining.3. Apoptosis of pancreatic beta cells, reduction of insulin secretion function may be the main mechanism of iron overload-induced diabetes in later stages, and reduction or elimination of iron overload in the body,to some extent, was expected to improve glucose metabolism disorder.PART Ⅱ THE STUDY ABOUT THE CORRELATION BETWEEN DIABETES MELLITUS AND BETA THALASSEMIA MAJORObjective This study aimed at evaluating the prevalence of diabetes and Exploring the relationship between iron overload and diabetes mellitus in the young Chinese population with β-TM. So as to provide the basis for clinical treatment of thalassemia patients with diabetes mellitus.Methods A total of 277 β-TM patients (male 178, female 99, aged 2-25 years, median age 10 years) and 80 healthy age-matched controls were interviewed(male 50, female 30, aged 3-20 years, median age 10 years). Fasting serum insulin(FINS) and glucose(IFG), insulin resistance index(HOMA-IR) and sensitivity index(ISI) were evaluated, and indicators of iron overload (serum ferritin(SF), total units of blood transfused were recorded in our study. And those study results were compared and analyzed.Results1、Compared with the controls,the cases had higher FPG、FINS and HOMA-IR(P<0.05,respectively),but lower ISI(P<0.01).2、There were 7 diabetes (2.53%), and 82(29.60%) patients were impaired fasting glucose.103(37.18%)patients were short stature in our study.and the median values of SF was 3977.5ng / ml (range,558.6-14724ng/ml), severe iron-overload (SF> 2500ng/ml) patients was as high as 69%.3、The patients, age, total units of blood transfused were correlated well with FPG、FINS and HOMA-IR(r=0.424,r=0.3575，r=0.413;r=0.382, r= 0.396, r=0.450,P<0.05 respectively). The incidence of diabetes and IFG patients with ≥10 years old were significantly higher than those of patients with<10 years old(7.07% vs 0%,P=0.000; 49.5% vs 18.5%,P=0.000, respectively).4、The SF in β-TM patients was correlated well with FPG、FINS and HOMA-IR (r=0.364,r=0.134,r=0.189,P<0.05 respectively).the incidence of diabetes and IFG patients with serum ferritin levels>2500 ng/ml were significantly higher than those of patients with serum ferritin levels≤2500 ng/ml (3.64% vs 0%,P=0.000; 36.1% vs 11.7%,p=0.000, respectively.Conclusions1、Iron overload in patients with β--TM in Guangxi was serious, and iron overload was closely related to development of diabetes.2、Age, blood transfusion and the degree of iron overload were closely associated with Thalassemia patients complicated with diabetes.More severe iron overload, and a higher risk of developing diabetes.Especially patients over 10 years old should be more wary of high risk of sugar metabolism disease.3、Insulin resistance and pancreatic β-cell dysfunction may be the main mechanisms of disorders of glucose metabolism induced by iron overload in an early stage.