مجله دیابت و متابولیسم ایران
سال پنجم شماره 2 (پیاپی 15، زمستان 1384)

All contemporary methods of insulin administration are non-physiological. The euglycemia that is achieved in at the expense of the adverse effects of systemic hyper-insulinemia, emphasize the importance of devising methods to deliver insulin physiologically and directly into the portal circulation. The aim of the present study was to evaluate the oral absorption of insulin from gastrointestinal tract, using novel oral drug delivery system delivery based on superporouse hydrogel (SPH) and SPH composite (SPHC) in combination with insulin. This study has been done based on interventional clinical trial in healthy volunteers. Capsules containing insulin and SPH &SPHC in various combination were administered orally, to 15 non-diabetics subjects in order to assess this biological effects and safety. Serum glucose, insulin and C - peptide levels were determined, at predetermined timed intervals up to 4 h. An increase in serum insulin level was demonstrated in all subjects that used polymer plus insulin. The nadir of serum glucose level appeared after 60 - 120 min following the ingestion of polymer plus insulin. Serum C - peptide levels were suppressed while exogenous insulin was absorbed at the same time. No adverse effects were detected during the trial and several weeks following the trial using SPH based drug delivery system. Insulin in combination with novel delivery agents, SPH & SPHC, given orally was partially absorbed through the GI tract in a biologically active form. This was demonstrated by serum glucose lowering effect of the delivery system as well as a suppression of plasma C-peptide which also represented a decrease in endogenous insulin secretion.

Glucokinase serves as a glucose sensor in pancreatic β-cells and plays a key role in glucose homeostasis and glucose-stimulated insulin secretion (GSIS). In the present study we examined the effect of glucosamine, a glucokinase inhibitor, on the pancreatic glucokinase and hexokinase activities and on insulin secretion from freshly rat pancreatic islets of Langerhans. Insulin concentration was measured by rat insulin ELISA kit. The pancreatic islets from normal and type 2 diabetic (nSTZ) rats were isolated by collagenase digestion method. Glucose phosphorylation was quantitated by measuring the rate of glucose-6-phosphate formation in the fluorometric assay. Insulin secretion from hand-picked islets was evaluated in static incubation system. Insulin concentration was measured by rat insulin ELISA kit. Our findings demonstrate that glucosamine in a dose dependent manner, reduced glucokinase activity in islet extract, but had no effect on hexokinase activity. The glucose-stimulated insulin secretion, was inhibited by glucosamine but it had no effect on the basal insulin secretion. In diabetic rats glucokinase was decreased while the basal insulin secretion and the activity of hexokinase were higher than normals. Based on results obtained from the present study, the assumption could be made that the decrease in the activity of glucokinase of pancreatic islets could be related to the impaired glucose stimulated insulin secretion. The increase in basal insulin secretion of diabetic rats may be due to an increase in pancreatic hexokinase activity.

Type 1 diabetes or insulin dependent diabetes mellitus is an autoimmune disease probably caused by various factors such genetics, environmental stresses, viral infections and diet. The disease is associated with damage to pancreatic insulin-producing β cells. Many researches have been performed to study the therapeutic effects of herbal medications on diabetes mellitus. The protective effects of some plants such as Cuminum cyminum, Trigonella foenum-graecum, Saliva sclarea, Allium ampeloprasum etc in diabetes induced rats were reported. Dill with the scientific name of Anethum graveolens, is a plant from umbellifera. This family which contains flavonoid compounds. In this research, effects of hydroalchoholic extract of this plant on blood glucose level, lipids and lipoproteins in Alloxan-induced diabetic rats was investigated. Fifteen adult male rats, weighing 200-250 gr, were used in three five member groups. Rats in the control group, received physiological serum. as intraperitoneal (IP). In diabetic control group (DCG), diabetes was induced using Alloxan monohydrate at a dose of 120 mg/kgbw. In addition to diabetes induction just like DCG, the treated diabetic control group (TDCG) rats were dosed with 300 mg/kgbw hydroalcoholic Anethum graveolens extract. All rats received all materials via intraperitoneal injection (IP). 48 hours after the last IP, blood sample was taken from each animal via cardiac puncture to measure blood factors. The results indicated significant reduction in glucose, total cholesterol, triglyceride, LDL and VLDL levels in TDCG rats compared to DCG rats. Due to the use of dill extract, HDL level was significantly increased. Effect of Anethum graveolens is related to antioxidant compounds. This compounds affect glucose absorbtion and beta cells regeneration. The results of this research indicate that using hydroalcoholic extract of Anethum graveolens could effectively decrease blood sugar levels.

Vascular factors in conjunction with metabolic issues are involved in both etiopathogenesis of diabetic neuropathy (DNU), and more remarkably in "repair" phase, when the net balance between neuroregenerative/degenerative reactions is dictated to some extent by these factors. The ischemic nature of DNU indicates the importance of re-establishment of blood vessels. VEGF, a growth factor which, in addition to its hemodynamic effects, possesses an "angiogenic" capacity has been the subject of extensive investigations in DNU, especially, interventional therapies. The impacts of racial and inherited backgrounds in the development of DNU suggest that the genetic issues partially govern the outcome of diabetic late complications, including DNU. By conducting a candidate gene case-control association study, present study explores the possibility if the inter-individual variations of VEGF gene structure by any means encode the genetic susceptibility/resistance in the course of DNU. The distribution of VEGF gene polymorphisms frequencies were analyzed at positions –7*C/T, -1001*G/C, -1154*G/A and –2578*C/A and were evaluated by ARMS-PCR in 248 type 1 diabetic subjects (81 DNU+, 167 DNU−) and 113 healthy controls, all from "British-Caucasian" origin. When the frequency of the polymorphic alleles/genotypes between patients and controls, and also between two subgroups within patient's group with each other (DNU+ vs. DNU−) or with healthy controls were compared, only in one situation a significant difference was evident. The distribution of a VEGF gene polymorphism at promoter region (–7*C/T) at allelic (but not at genotypic) level was notably different between diabetics, with and without neuropathy, while the minor allele (T) conferred a protective effect (P=0.03; OR = 1.75). The present study may imply a prognostic value for VEGF gene polymorphism at promoter region (–7*C/T) in DNU. However, it requires further studies to appreciate better the phenotypic impact of this polymorphism in this chronic complication of diabetes. A catalog of candidate genes polymorphisms that functionally reflect a protection/predisposition to DNU can provide the genotypic profile that can be useful to reasonably predict the overall behavior of diabetic subjects to the metabolic derangements relative to development of DNU, which in turn may require adoption of relevant preventive and therapeutic measures.

Leptin, a peptide hormone, is the product of "ob" Gene. Leptin regulate body weight and composition through reducing appetite and energy expenditure in rodents and humans. The aim of this study was to evaluate differences in expression of Leptin Gene in different tissues of streptozotocin induced diabetic rats. 40 Sprague Dawely rat were selected. Intra peritoneal injection was carried out in 20 rats and another 20 rats were used as control. After injection of 60mg/kg Streptozotocin, animals were transformed into diabetic. Glucose was measured by glucose oxidase method. Leptin and insulin were measure by commercially available immunoassay kits. After one week treatment, different tissues including adipose tissues, Spleen, epidydimis, and Liver of both control and experimental animals were dissected. For investigation of any changes of the Leptin gene expression in different tissues, RNA was extracted using Trizo1 method. By using RT-PCR technique, Leptin cDNA and β-actin cDNA as internal control were constructed and PCR was carried out. The RT-PCR products were detected on 2% agarose gel using electrophoresis. Mean serum levels of Leptin was 5.23± 0.45 ng/ml before injection of streptozotocin and markedly decreased in STZ induced diabetic rats to 0.79±0.25 ng/ml. This decrease was statistically significant P<0.05). There was a direct and significant correlation between leptin and insulin in streptozotocin-induced diabetic rats (r=0.37, P<0.05) while, this was reverse in control rats (r= -0.28, P<0.05). Using RT-PCR method, Leptin gene expression in different tissues including fat epidydimis, liver, and spleen showed that the intensity of leptin band with 452 bp was decreased in diabetic rats in comparison to normal rats. Actin Gene expression was identified in PCR products having 403 bp and the intensity was constant in both groups. The reduction rates of "ob" mRNA in fat epidydimis tissue in STZ diabetic rats was remarkable in comparison to Spleen and Liver. It is speculated that Leptin gene could be under regulation of insulin dependent mechanism in diabetic rats and by modulating Leptin gene expression in diabetic patients, it may be useful in clinical practices.

To determine the importance of type 2 Diabetes mellitus as a risk factor for osteoporosis in postmenopausal women, this study was designed in endocrine clinic of zanjan in 2003. As a case-control study, 40 diabetic and 40 healthy menopause women have been recruited. These two groups were matched in terms of their age, length of their menopausal period and body mass index. Serum Calcium, Phosphorus, Alkaline phosphatase and Estradiol were measured in all the cases and bone densities in three sites (Femoral neck, lumbar spine and forearm) were evaluated with DXA. All data were analyzed using T-test, analysis of variance, chi-square and multiple regression tests. The frequency of osteoporosis and osteopenia in diabetic women were not significantly different from non diabetics. The mean bone density in femoral neck was higher in diabetic group (P= 0.013). In both groups there was a significant relationship between bone density and length of menopause (P<0.01). The relationship between BMI and Bone density was significant only in femoral neck (P<0.01) in both groups. In diabetic women, the higher HbA1c accompanied with the lower bone density in lumbar spine. Although the level of HbA1c as a marker of blood glucose control, has a relationship with lumbar spine density in diabetics, Diabetes type 2 is not a risk factor for osteoporosis, So screening, diagnosis and management of osteoporosis in diabetes type 2, Should be done independently and according to other risk factors.

The aim of this study was to determine the best Anthropometric indices for prediction of the risk of type 2 Diabetes in lower and higher 60 years old population in Tehran. As a prospective study among 4479 non-diabetic men and women over 20 years from the participants of Tehran Lipid and Glucose Study (TLGS) who had complete data of blood pressure, plasma glucose in the fasting state and 2 hours after ingestion of 75 g glucose (2-hPG) as well as fasting serum lipids, anthropometric measurement including body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and demographic data at baseline and were followed for a mean duration of 3.6 years. Subjects reevaluated for measurement of fasting Glucose and 2-hPG at follow-up. Diabetes and its associated risk factors were defined according to the ADA criteria. Different measurements of general and central obesity were defined based on the WHO criteria. Logistic regression analysis with stepwise conditional method was used to estimate the Odds Ratio (OR) with 95% CI. A total of 166 new cases of type 2 diabetes (3.7%) were diagnosed during 3.6 years of follow-up, with an approximately one percent per year incidence rate (men=3.7% and women =3.7%, P= 0.95). Diabetic subjects of follow-up were significantly more obese than nondiabetics considering their BMI, WC and WHR. In subjects aged< 60 years high WC was a predictor of diabetes only in model 1 and 2, while general obesity and high WHR predicted diabetes risk in all the 3 models. In these 3 models the OR of general obesity were 5.3(2.9-9.5), 3.4(1.8-6.3), 2.4(1.1-5.1) and the OR of high WHR were 3.5(2.1-5.8), 3.4(1.4-5.8) and 2.6(1.3-4.9), respectively. In subjects aged≥ 60 years general obesity predicted diabetes only in models 1 and 2, while high WHR was a predictor of diabetes risk only in model 1. In this age group, high WC predicted diabetes in all models 1, 2, 3 with the OR of 4.6 (2.3-4.1), 4.5 (2.3-8.9) and 3.8 (1.8-7.7), respectively. General obesity and high WHR in young Iranian subjects (< 60years) and high WC in older ones (≥ 60 years) are the important anthropometric indices for prediction of type 2 diabetes. Age should be considered when using different anthropometric indices for predicting the risk of type 2 diabetes.

The liver plays a main role in the production and metabolism of lipoproteins, and then impaired lipid metabolism is often seen in patients with liver cirrhosis and chronic hepatitis (CH). As a result, plasma lipid levels could be as useful indicators of liver function and patient's prognosis especially in liver cirrhosis. We measured the lipoprotein levels in 77 consecutive patients with liver cirrhosis and CH. 47 men (61%) and 30 women (39%) with mean age 43years (SD=16.4) and mean BMI 26(SD=4.2) have been recruited as patients group. Child score and MELD scale was determined in patients group. The control group was age and sex matched with patients group. In case group, the levels of HDL LDL, TG, and total cholesterol were significantly lower than control group (p <0.0001). In patients with cirrhosis, the levels of LDL, HDL and total cholesterol were progressively lower when comparing patients in Child class A with patients in class C (p<0.0001).This difference was more significant in LDL and total cholesterol and between upper Child scores, similarly decreasing in LDL, HDL, and total cholesterol level was observed when MELD score increased (P<0.0001). There is a correlation between plasma lipid levels and liver function, so it may be mentioned as an accessible and reliable indicator of liver function in cirrhotic and CH patients.

Elevated total plasma Homocysteine, is an independent risk factor for cardiovascular disease. Folate and vitamin B12 have not only a protective effect on cardiovascular disease but also an essential effect on total Homocysteine concentrations (tHcy). This survey has been conducted to evaluate the determinants of tHcy in 1191 healthy Iranian adults. This study which was a part of the Cardiovascular Risk Factors Survey in the Population Lab Region, has been designed and conducted based on MONICA/WHO project. A total of 1191 people have been recruited and assessed on serum Homocysteine, Folic acid and vitamin B12, triglycerides, cholesterol, HDL-C, LDL-C, FBS, BMI, BP and smoking, with interview, questionnaires, examination and blood sampling. Blood samples were analyzed according to standard methods. The variables were assessed in 1191 participants include 416 men (34.9%) and 775 women (65.1%). Prevalence of hyperhomocysteinemia was correlated significantly with male sex and aging. Hcy levels were inversely related to serum Folate and vitamin B12 concentrations. After further adjustments, we detected a positive correlation between tHcy and age, male sex, smoking and BMI, and a negative one with LDL-C and diabetes. Although there was a correlation between tHcy and blood pressure, after age, sex, BMI and smoking adjustment, it just remained significant in women and with systolic blood pressure. We found that dietary and lifestyle parameters such as Folate intake and smoking habit are the main determinants of distribution of plasma Homocysteine in an apparently healthy population. We assumed that lifestyle changes could have considerable subsequences in public health. Our findings confirm the potential advantages of dietary improvements and increased intake of nutrients along with smoking cessation in order to prevent cardiovascular diseases in high-risk patients.

Cardiovascular diseases are described as the most important health problems in developing countries which are developed in parallel with industrialization of communities. Based on the high morbidity and mortality of cardiovascular disease, this study was performed for examining the population lab inhabitants’ knowledge and practice. In this cross – sectional study, 1576 inhabitants of the Population Lab Region were studied by cluster random sampling in 2002. 181 persons were selected from this population. The frequency of each cardio- vascular diseases risk factor such as; hyperlipidemia, smoking, obesity, hypertension, Diabetes, family history of heart attack, being man, stress and excitement, sedentary life style, salty food, vegetables fruits, fatty food and red meat consumption, were assessed. In addition, the population study's practice regarding controlling the risk factors of cardiovascular diseases was determined, as well. Moreover, specific questionnaire and direct interview were used for collecting data and then the gathering data was analyzed by SPSS and EPI – Info soft wares. In this study, 71.8% of people were women while 28.2% of them were men. Besides, there was a significant relationship between the people’s knowledge about cardiovascular disease and the level of their education (P < 0.001). According to the results, 65.2% of population believed that heart attack was the most prevalent cause of death in comparison with 44% of them considered car accident and 13.3% agreed with cancers. On the other hand, 74% of people used liquid oil in their food and 77.9% of them knew the side effects of unhealthy foods such as; salty food as one of the cardiovascular risk factors. The inhabitant's knowledge regarding to the risk factors of cardiovascular diseases was approximately acceptable. However, there was a significant different between their knowledge and practice. Therefore, providing suitable educational programs for improving people’s nutrition, physical activity and the other relevant factors for preventing cardiovascular risk factors would be mentioned.