Human insulin genome sequence map,biochemical structure of insulin for recombinant DNA insulin

Insulin is a essential molecule for type I diabetes that is marketed by very few companies. It is the first molecule, which was made by recombinant technology; but the commercialization process is very difficult. Knowledge about biochemical structure of insulin and human insulin genome sequence map is pivotal to large scale manufacturing of recombinant DNA Insulin. This paper reviews human insulin genome sequence map, the amino acid sequence of porcine insulin, crystal structure of porcine insulin, insulin monomer, aggregation surfaces of insulin, conformational variation in the insulin monomer, insulin X-ray structures for recombinant DNA technology in the synthesis of human insulin in Escherichia coli.     

老年肥胖患者血浆抵抗素水平与胰岛素抵抗相关

目的研究抵抗素在老年肥胖患者及健康对照血浆中的平均水平,探讨抵抗素与肥胖及胰岛素抵抗的关系。方法竞争性酶联免疫吸附法检测43例老年肥胖患者及41例对照的空腹血浆抵抗素水平,测量身高、体重、腰围、臀围,计算体重指数（BMI）及腰臀比（WHR）,口服葡萄糖耐量试验（OGTT）测定空腹血浆葡萄糖浓度及胰岛素浓度,计算胰岛素敏感指数（ISI）。结果空腹血浆抵抗素与BMI呈正相关（r=0．23,P〈0．05）,与胰岛素呈负相关（r=-0．34,P〈0．05）,与ISI呈负相关（r=-0．31,P〈0．05）,未发现与血脂、年龄、性别及WHR之间的相关性。结论人类血浆抵抗素与肥胖及胰岛素抵抗相关。     

Human proinsulin gene-transfected Chinese hamster ovary cells secrete immunoreactive insulin

BACKGROUND: Considering the difficulties in pancreas transplantation, the development of an artificial pancreas can be one of the new approaches. The present study was designed to assess whether or not Chinese hamster ovary (CHO) cells, which were transfected with the human proinsulin (hPI) gene, secrete immunoreactive insulin (IRI) and respond to glucose loading. MATERIALS AND METHODS: A complementary DNA encoding hPI was obtained by polymerase chain reaction amplification from human pancreatic tissue and was inserted into the plasmid pcDNA I/NEO to construct an expression vector for the hPI gene. CHO cells were transfected with hPI gene using lipofectin, and the hPI gene-expressing clones (CHO/I) were selected. RESULTS: Five clones of CHO/I cells, releasing IRI into the culture supernatant, were separated. Immunohistochemistry with a monoclonal antibody demonstrated the IRI in the cytoplasm of CHO/I cells, and transmission electron microscopic examination demonstrated the prominently developed mitochondria, but no secretion granules. ELISA assay demonstrated the secretion of IRI into the culture supernatant of CHO/I, but CHO/I cells did not respond to the glucose loading. When CHO/I cells were transplanted subcutaneously into the back of nude mice, the growing tumors secreted IRI. CONCLUSIONS: These results demonstrate that the hPI gene can be transfected into mammalian cells and function in vivo, and suggest that this kind of gene technology may be applicable in the development of an artificial pancreas.     

Human insulin. A review of its biological activity, pharmacokinetics and therapeutic use

Human insulin, whether produced by recombinant DNA techniques (biosynthetic, insulin crb) or enzymatic modification of porcine insulin (semisynthetic, insulin emp) is equivalent in biological activity to porcine insulin following intravenous administration. Slight differences between human and porcine insulin in hypoglycaemic activity after subcutaneous injection appear to be related to differences in absorption, and are unlikely to be of major clinical importance. Similarly, reported minor differences in counterregulator hormone response to human insulin compared with porcine insulin need further study, but they are unlikely to have important clinical implications. In clinical use the therapeutic efficacy of human insulin is similar to that of porcine insulin. The lower antigenicity with human insulin relative to purified porcine insulin is of potential therapeutic value, and it is logical to use human insulin in newly diagnosed diabetics, in patients treated intermittently with insulin, in cases of immunological insulin resistance, and in patients with allergy and local reaction against animal insulin. Thus, human insulin seems to have no disadvantages compared with purified porcine insulin and may have some advantages. While there appears to be no compelling reason to change patients whose diabetes is presently well controlled with purified porcine insulin to human insulin, the availability of human insulin at a price equal to or less than that of animal origin makes such a change logical. In the meantime, human insulin should be considered the insulin of 'first choice' for newly diagnosed diabetics requiring insulin therapy and in carbohydrate intolerance and diabetes occurring during pregnancy.     

胰岛素类似物与胰岛素抗体(IAA)相关性研究

目的通过比较2型糖尿病患者中使用与未使用外源性胰岛素类似物治疗的两类人群胰岛素抗体阳性率的差异,探讨胰岛素类似物的免疫原性及胰岛素抗体(IAA)形成的危险因素。方法选取183例正在使用胰岛素类似物治疗的T2DM患者为治疗组,472例未使用胰岛素治疗的T2DM患者为非治疗组,比较2组胰岛素抗体阳性率的差异。将治疗组分为胰岛素抗体阳性组和阴性组。分析2组中性别、年龄、糖尿病病史、体重指数(BMI)、使用胰岛素类似物治疗的时间、胰岛素类似物使用剂量、总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、血尿素氮(BUN)、血清肌酐(Cr)、尿酸(UA)、收缩压(SBP)、舒张压(DBP)、促甲状腺激素(TSH)、游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)、糖化血红蛋白(HbA1c)因素的差异。明确形成胰岛素抗体的危险因素。结果治疗组胰岛素抗体阳性率高于非治疗组(P=0.000)。治疗组中胰岛素抗体阳性组年龄、糖尿病病程、胰岛素使用时间、胰岛素使用剂量、SBP、DBP、HbA1c达标率与阴性组比...     

Intentional overdose with insulin glargine and insulin aspart

Reports of intentional massive overdoses of insulin are infrequent. A review of the literature revealed no reports of overdose attempts with either insulin glargine or insulin aspart. We report the case of a 33-year-old woman without diabetes mellitus who intentionally injected herself with an overdose of both products, which belonged to her husband. She arrived at the emergency department 15 hours after her suicide attempt, which took place the night before. Her husband had checked her blood glucose level throughout the night and had given her high-carbohydrate drinks and foods. The patient had a history of obsessive-compulsive disorder, major depression, and numerous suicide attempts. She recovered from the resulting hypoglycemia after 40 hours of dextrose infusion and was transferred to a mental health facility. The main danger associated with insulin overdose is the resultant hypoglycemia and its effects on the central nervous system; hypokalemia, hypophosphatemia, and hypomagnesemia also can develop with excess insulin administration. Dextrose infusion, with liberal oral intake when possible, and monitoring for electrolyte changes, making adjustments as needed, are recommended for the treatment of intentional insulin overdose.     

Inhaled insulin

Inhalation of regular insulin for meal time glucose control has been found to be safe, efficacious and reliable in Type I and Type II diabetics. The administration of regular insulin through the human lungs by inhalation has been conducted in at least 14 short studies in both normal and diabetic subjects beginning as early as 1925. In all studies, significant insulin absorption and lowering of blood glucose was observed in the absence of penetration enhancers. Although a concern of variable dosing was raised in early studies, the development of new reproducible delivery systems has ensured that the variability of aerosol insulin can be as good, if not better, than subcutaneous (SC) injection. In the longest controlled studies in humans to date, both Type I and Type II insulin-dependent diabetics used a novel inhaled dry powder insulin delivery system for 3 months for meal time glucose control. The study results indicate that inhaled insulin provides equivalent glucose control, measured by hemoglobin A1c, when directly compared to SC injection. Interim results from an additional study with Type II diabetics who were failing oral hypoglycemic agents suggest that adjunctive therapy with inhaled insulin markedly improved glycemic control with a low risk of hypoglycemia. In all the 3 month studies the system was efficacious, well tolerated, well liked, and resulted in reproducible results. A potential advantage of aerosol insulin is that it is more rapidly absorbed (serum peak at 5-60 min) and cleared than SC injection (peak at 60-150 min), which provides a more relevant and convenient therapy for meal time glucose control. The relative efficiency of insulin delivery by aerosol, compared to SC injection, has been estimated from the dose measured at the exit point of the aerosol device, and found to range between 8 and 25% of SC, depending on the study.     

胰岛素泵诺和锐治疗2型糖尿病胰岛素抵抗的临床观察

目的:比较基因重组人胰岛素与人胰岛素类似物以胰岛素泵为输入载体时对于2型糖尿病胰岛素抵抗的疗效.方法:34例2型糖尿病胰岛素抵抗的患者随机分为两组:诺和锐治疗组及诺和灵对照组各17例,均为使用胰岛素强化治疗血糖控制不佳的胰岛素抵抗患者.根据毛细血糖监测结果调整胰岛素用量,比较两组血糖达标后每日药量及达标所需时间.结果:治疗组达标后每日药量及达标所需时间均显著少于对照组.结论:胰岛素泵诺和锐治疗2型糖尿病胰岛素抵抗的疗效明显优于胰岛素泵诺和灵.     

赖脯胰岛素联合甘精胰岛素在模拟胰岛素泵强化治疗糖尿病中的效果

目的比较赖脯胰岛素联合甘精胰岛素与胰岛素泵在2型糖尿病强化治疗中的疗效和安全性。方法将2型糖尿病病人随机分成两组,A组的病人采用三餐前赖脯胰岛素联合甘精胰岛素治疗,B组的病人采用胰岛素泵（使用赖脯胰岛素）降糖治疗。监测两组病人治疗前后全天血糖谱的变化,观察并比较血糖达标所需要的时间、胰岛素用量、低血糖发生率等情况。结果A组与B组相比,在血糖达标所需的时间、胰岛素用量及低血糖发生率等方面没有显著性差异（P〉0.05）。结论赖脯胰岛素联合甘精胰岛素治疗2型糖尿病患者,在疗效、安全性方面接近胰岛素泵,在治疗费用方面则具有一定的优势。     

Stability of insulin mixtures in disposable plastic insulin syringes

The miscibility of short and long acting porcine, human and bovine insulins has been investigated using HPLC. Soluble insulin is rapidly lost from solution when mixed with both isophane and zinc insulin, although the mechanism may be different in these two cases. The time for up to 50% or more to be lost is often less than 2 min. The percentage lost is dependent upon the ratio of the mixture and the type and origin of the insulin. In the case of soluble: zinc mixtures it is greatest for porcine and least for bovine, in the case of soluble: isophane mixtures it was least for human and greatest for bovine. The greater the original amount of soluble insulin present the less the loss. The results help explain recent clinical reports that mixtures of soluble and zinc insulins fail to achieve satisfactory control of post-prandial blood sugar levels.     

基础胰岛素新剂型——地特胰岛素

从上个世纪20年代胰岛素在临床领域的问世，到目前各式各样的胰岛素及其类似物的广泛应用，胰岛素治疗糖尿病已经由单纯的延长生命衍变为一种颇具艺术技巧的治疗手段。内分泌医生不但要会用胰岛素，更要懂得如何针对不同患者选择合适的胰岛素；既要最大程度地使患者的糖代谢状态接近正常，又要尽可能的减少发生低血糖的风险。     

Inhaled insulin: a novel route for insulin delivery

Insulin has been in use for the treatment of patients with diabetes mellitus for over 75 years. However, despite the known benefits of tight glycaemic control, multiple insulin injections have still not gained widespread clinical acceptance. Although there have been attempts to find effective non-invasive routes for insulin delivery, none of the novel non-invasive approaches have become part of established practice. In fact, until recently it was believed that as a result of limitations, non-invasive insulin was not a clinically realistic option. However, preliminary studies have indicated that inhaled insulin may emerge as an effective, well-tolerated, non-invasive alternative to subcutaneous regular insulin. The pharmacokinetics of inhaled insulin show a more physiological profile compared to conventional insulin; however, further studies to confirm long-term pulmonary safety and efficacy are needed.     

Intermediate and long-acting insulins: a review of NPH insulin,insulin glargine and insulin detemir

ABSTRACT

Objective: To review intermediate- and long-acting insulins with specific emphasis on the newer insulin analogs.

Methods: A MEDLINE search, in English, was conducted with a cut-off of June 30, 2006, using the terms ‘NPH insulin’, ‘insulin analogs’, ‘insulin glargine’, ‘insulin detemir’ and ‘long-acting insulins’. All clinical trials from within the search period were included.

Results: The insulin analogs, insulin glargine and insulin detemir, were introduced in an attempt to improve glycemic control among patients with diabetes, without increasing the risk of hypoglycemia. This review indicates that both insulin analogs demonstrate better glycemic control than NPH insulin, based on measurements of HbA_1c, fasting glucose and intra-subject variability in blood glucose. This was accomplished with similar or reduced risk of hypoglycemia. Also, insulin detemir appears to be associated with less body weight increase than NPH insulin or insulin glargine.

Conclusion: The newer long-acting insulin analogs, insulin detemir and glargine, appear to provide better glycemic control than NPH insulin without increasing the risk of hypoglycemia.     

基础胰岛素在基础-餐时治疗方案中的应用

基础胰岛素是基础-餐时治疗的重要组成部分,可以有效降低糖尿病患者的空腹血糖和HbA1c,从而改善糖尿病患者的临床症状、疾病状态和生活质量.当前,临床使用的基础胰岛素主要包括中效NPH人胰岛素和两种长效胰岛素类似物--甘精胰岛素与地特胰岛素.     

Defining the role of insulin detemir in Basal insulin therapy

Insulin detemir is a novel long-acting insulin analogue with a unique mechanism underlying its prolonged duration of action. Unlike neutral protamine Hagedorn (NPH) insulin (insulin suspension isophane) and insulin glargine, which precipitate after administration, insulin detemir remains soluble after it is injected. The prolonged duration of action of insulin detemir is a result of the ability to self-associate into hexamers and dihexamers, and to bind reversibly to albumin. This mechanism of protraction provides a more prolonged, consistent and predictable glycaemic effect in patients with type 1 or type 2 diabetes mellitus compared with NPH insulin. Clinical studies have demonstrated that insulin detemir administered once or twice daily is at least as effective as NPH insulin and insulin glargine in achieving glycaemic control. Most trials have also shown that insulin detemir exhibits less intrapatient variability in glycaemic control compared with NPH insulin and insulin glargine. One of the benefits of insulin detemir is its favourable effect on bodyweight. Insulin detemir has shown weight neutrality in patients with type 1 diabetes and is associated with less weight gain than NPH insulin in clinical studies. Patients with type 2 diabetes using insulin detemir gain less weight than patients using NPH insulin and insulin glargine. In addition, a reduced risk of hypoglycaemia, particularly nocturnal hypoglycaemia, has been reported with insulin detemir compared with NPH insulin in patients with type 1 and type 2 diabetes. A reduced risk of major and nocturnal hypoglycaemia compared with insulin glargine in patients with type 1 diabetes has also been observed. Together, these data indicate that insulin detemir is a valuable new option for basal insulin therapy in patients with type 1 or type 2 diabetes.