Insulin formulations and delivery methods ? ? ? First, the development of insulin ª¥ Since 1921, insulin extracted from bovine pancreas for diabetes treatment success so far, nearly 80 years of history. The initial extraction of insulin the pancreas is broken up, with acid ethanol extraction, the extract and after vacuum evaporation, and then NaCl salting out, precipitation by insulin "salt cake", the salt cake dissolved in water, adjust pH to the isoelectric point of insulin pH5.0 ~ 5.5, so settle down insulin, namely as "amorphous insulin." The content of 50% to 60% efficiency value of about 10U/mg. Although the initial amorphous insulin treatment that many patients, but its side effects, many systemic and local allergic reactions. Available in 1926 that further strengthen the recrystallization of amorphous insulin, reported in 1934 to promote insulin re-crystallization of zinc, was developed to repeatedly re-crystallization, thus making a significant increase in the purity of insulin. 97% of its content, to titers 25U/mg. 40 years is the widespread use of "re-crystallization of insulin." Application of this systemic allergic reaction to insulin disappeared, local allergy and lipoatrophy than rare. However, since 1956, RIA technology development, testing using the serum of patients with recrystallized insulin, found that 90% of the insulin antibody, and found that also contain a small amount of impurities. Insulin is made up of 51 amino acids, molecular weight of 5734, found by radioimmunoassay, and recrystallization of insulin in the molecular weight of 9,000 ~ 15,000 with pig insulin and intermediate metabolites and pancreatic protein complex, to further reduce their immunogenicity, 60 Since people were further purified insulin crystals refined by adding zeolite anion-exchange chromatography in the regular insulin molecules of impurities removed, get a more pure "single peak of insulin", a single peak of insulin available after repeated chromatography "High purity of insulin" - one component of insulin (purity 99.9%, proinsulin <1 / 10 million). Single peak insulin or through the clinical application of single-component insulin, the antibody detection rate decreases with increasing purity, dosage will be reduced accordingly. Although with the increase in insulin purity, improved clinical efficacy, but the animal insulin to human insulin composition is different. Human insulin containing 21 amino acids from the A chain and contains 30 amino acids of the B chains, two peptide chains linked by disulfide bonds. Commonly used porcine insulin B chain on the first 30 amino acids are alanine, and human insulin are threonine, and therefore proposed the application of the superiority of human insulin. But the body of insulin extraction and chemical synthesis of human insulin, insulin-expensive limited clinical application. Gene technology to promote the early 80s the development of the pharmaceutical industry in 1978, the first fermentation with E. coli E, the first synthetic human insulin, respectively, A chain and B chain, and then the two chains by disulfide bond together to become insulin molecules. 1986 developed another way, the first biosynthetic insulin, and then digested with trypsin and carboxypeptidase to be human insulin C peptide. This approach is similar to the secretion of human islet B cells than the A, B-chain synthesis is more convenient. The late 20th century, 70, Denmark Novo Nordisk (Novo Nordisk) company was the first production of semi-synthetic insulin. In China in 1992, the company officially listed NoVo human insulin of insulin that is, all its applications is the yeast fermentation substrate. 1982 United States Lilly (Eli Lilly) Company first synthesized by recombinant DNA human insulin, marking the beginning of era of biotechnology drugs in 1996, they developed the first insulin analogue lispro 1 insulin (lispro). There are currently more than 300 insulin analogues have been prepared in the laboratory out, and some have entered the market. If available for insulin lispro (lispro) and insulin aspart (aspart), long-acting insulin glargine (glargine) and to special insulin (determir). The good news is, China's Tonghua Li Dongbao companies and companies willing to develop and produce a short-acting human insulin and long-acting insulin analogues. Second, classification and characteristics of commonly used insulin ª¥ There are several ways the classification of insulin from the production process can be divided into non-genetic engineering, genetic engineering of insulin and insulin; from the effect of the length of time and the speed of onset can be divided into quick (or short effect), short-acting, in effect and long-acting insulin; different from the amino acid sequence can be divided into animal insulin, human insulin and insulin analogues. In the clinical classification of the latter two often combined. (A) in accordance with the amino acid sequence classification 1. Animal Insulin: The animal pancreatic extract and the appropriate purified porcine or bovine insulin. Structure of porcine insulin and human insulin is similar to only one amino acid different from that of the B chain of 30 amino acids different from human insulin B30-bit is on the alanine replaced threonine. Bovine insulin and human insulin has three amino acids different, first and foremost on the human insulin-B30-bit alanine replaced threonine, in addition also on the A8 and A10 bit threonine and isoleucine for into alanine and valine. Because the molecular structure of animal insulin and human insulin differ in part, and contains impurities, so there are some immunogenicity, probably in the human body to produce antibodies in some patients after injection of skin allergies. In addition, the effectiveness of the lowest animal insulin, insulin from animal insulin for employment, increased risk of hypoglycemia, so the dose should be reduced by 15% to 20%. Currently animal insulin has been gradually phased out, very little clinical application. 2. Human insulin: a molecular weight of 5734, is a small molecule protein, human insulin from proinsulin cleavage, the A, B two chains, one chain contains 21 amino acids A, B chain containing 30 amino acids, two chain disulfide bonds between the two connections within the A chain and a disulfide bond, the 6 and 11 amino acids connected. Currently, many major hospitals at home and abroad by recombinant DNA technology with the production of neutral human insulin products, including Novo Nordisk's Novolin, Eli Lilly's Humulin and produced by domestic Tonghua Dongbao Gan Shulin series, there are short-acting, in effect, in effect short-premixed preparations (30% short-acting premixed insulin preparations are Novolin 30R and Humulin 70/30, in effect short-acting and 50% each preparations have Novolin 50R, etc.). 3. Insulin analogue: human insulin as a hexamer, subcutaneous injection can not be directly absorbed into the bloodstream, to be depolymerized into monomers or dimers to enter the blood circulation through the capillaries to play a role, and different decomposition and absorption between individuals very different, And the final concentration of insulin into the circulation decline. The late 20th century, 90 in the structure and composition of insulin-depth study found that modification of the peptide chain may change its chemical and biological characteristics, developed more suitable for human physiological needs of the insulin analogues. Or absorb faster, absorb more slowly or gently, but do not alter the main biological function of human insulin and recombinant human insulin compared to better simulate endogenous insulin secretion. Among them, rapid-acting insulin analogue insulin molecules through the modification of the role of between and within the important region to the onset, peak and duration shorter than human insulin, more physiological postprandial insulin spectrum, clinical use of blood glucose after the meal can be more stable, generally do not cause low blood sugar at night; and long-acting insulin analogue insulin by changing the isoelectric point or molecular weight increase of the methods of insulin to break down, extend the absorption, the absorption variability is small and no peak, to better simulate physiological basis of insulin secretion, after the application of clinical practice to prove the risk of hypoglycemia compared with human insulin in a small effect. The characteristics of several insulin analogues: (1), insulin lispro (lispro) brand name, excellent bleeding music (Humalog), the product is the United States in 1996, Lilly Company developed the world's first 1 and insulin analogues, have been in the United States and European countries approved for clinical , May 2005 to enter the Chinese market. U.S. Food and Drug Administration (FDA) has approved its use of type 1 and type 2 diabetes. Insulin lispro is Escherichia coli (E coli) strains using recombinant DNA technology for the synthesis of the host's acting insulin analogues, human insulin with different structures is that the B chain C terminal proline and 29 of 28 sequential exchange of lysine, thus weakening the interaction between the monomers so difficult to form a hexamer, after subcutaneous injection in monomeric form. Its main features are: soluble, low self-binding, subcutaneous absorption of local fast onset and short duration peak (see Table 1). The pharmacokinetic characteristics more in line with changes in human physiological insulin and glucose spectrum. Insulin lispro compared with human insulin, insulin receptor affinity rather, while the insulin-like growth -1 (IGF-1) receptor affinity is higher than 50% of human insulin. Clinically, the rapid-acting insulin analogue insulin lispro with both long-term and long-acting insulin analogues in the joint for multiple daily injections (MDII), can also be used in insulin pump (CSII), you can immediately prior to meals injection, and even meal, postprandial injection. Studies have shown that when the maternal serum concentration of insulin lispro (100 ~ 200) mU / mL, it will not cross the placenta. Existing applications, excellent clinical data show that secretion of music: not found to cause fetal abnormalities; without increasing complications of diabetes and fetal adverse events; to better control blood sugar gestational diabetes. Produced by domestic Gan Li insulin lispro (brand name, Sau Lin-speed), ¢ò clinical trial showed superior efficacy and similar bleeding music. (2) insulin aspart (aspart) trade name aspart (Novolog), developed by the Danish company Novo Nordisk in 1999 in Germany, Sweden and the UK the first market, in December 2002 to enter China. Currently, FDA has approved it for type 1 and type 2 diabetes. Insulin aspart is saccharomycescerevisiae (baker yeast) host using recombinant DNA technology for the synthesis of human insulin analogues available. And the difference between human insulin is negatively charged will replace the B chain of aspartate 28 of the proline, which hinders the charge repulsion between the self-aggregation of insulin monomers. In solution, the analogue to a mixture of monomer and dimer form, so when the subcutaneous insulin absorption faster than normal. Insulin aspart and human insulin receptor affinity was 88%, and IGF-1 binding capacity similar to natural insulin. Available human insulin analogue insulin aspart pharmacokinetics and insulin lispro are similar can be used for MDII and CSII, insulin pump therapy is used, the incidence of hypoglycemia than regular insulin (RI) MDII low, HbA1c standard time shortened. Studies have demonstrated that in children with type 1 diabetes, insulin aspart can be safely and effectively reduces postprandial blood glucose, has been approved in Europe for 2 to 6 years old children. Currently, insulin aspart for patients with diabetes in pregnancy Clinical study was relatively small. (3) insulin glargine (glargine) trade name Lantus (lantus), by the French Sanofi-Aventis (Sanofi - Aventis) developed long-acting basal insulin analogue, for the first time in the German market in 2000 , April 2004 FDA approved the use of adult type 1 and type 2 diabetes and children with type 1 diabetes, the same year in June, EMEA approved the use of type 1 and type 2 diabetes. June 2005 in China market. Li Gan company of development and production of insulin glargine, the trade name long show lin, has also been listed in China. Insulin glargine is a non-pathogenic strains as host Ecoli synthesis of recombinant human insulin analogues, human insulin with the difference lies in the A chain of 21 amino acids are glycine replaced by aspartate, and increased terminal B-chain C 2 arginine, so that the isoelectric point of from 5 to 6 to 7, the hexamer structure is more stable. Insulin glargine in acidic solution (pH = 4.0) was dissolved, after subcutaneous injection of 7.4 pH (neutral environment) can form micro-precipitates, these micro-deposits in the longer time to release a steady insulin monomer, which makes the decomposition of insulin absorption and action time to play a long-lasting effect sustained release, and its hypoglycemic effect sustainable 24h, and no obvious peak, can simulate the normal basis for human insulin secretion. Due to structural changes in the last two positions are not involved in insulin receptor binding, it will not affect the biological activity of insulin. Number of major clinical studies showed that the combination with RI, insulin glargine treatment (can not mix and can not diluted) group was significantly lower than the mean fasting blood glucose in patients with NPH group. However, one study showed that two groups of patients in the treatment of end point HbA1c levels were not significantly different. Compared with bedtime injection of NPH, bedtime injection of insulin glargine lower incidence of nocturnal hypoglycemia. Failure of oral hypoglycemic drug therapy can be added with insulin glargine treatment. (4) to special insulin (determir) brand name Novo Peace (levemir), developed by the Danish company Novo Nordisk. This product in June 2004 approved in the EU market. June 2005 FDA approval of its treatment for type 2 diabetes, type 1 diabetes research is still in phase ¢ó clinical trial. In particular insulin is a soluble long-acting insulin analogues in preparations of insulin, compared with the ordinary people, and its B chain, in addition to 30 amino acids, and 29 in the B chain of lysine added a 14-C fatty acids side chain, thus increasing its molecular weight, where the presence of zinc ions, insulin hexamer molecules still exist in the form. The absorption after subcutaneous injection of slow diffusion, in the plasma ~ 99% and 98% albumin binding, release of an extremely slow speed into the blood, plasma concentrations of stable curves of a small valley, the role of long duration. Similar with insulin glargine, especially in the long-acting insulin analogues in daily injections of insulin can be 1, to provide a basis for the insulin levels in diabetic patients, fasting blood glucose control, with RI or short-acting insulin analogues such as MS, is also with daily injections of 2 reported. T1DM patients abroad study found that 1000 cases, in particular the effect of insulin reduced HbA1c than NPH, less chance of hypoglycemia at night NPH. Present to insulin in children and pregnant women, particularly the application of the safety, efficacy, lack of adequate clinical outcomes. (5) Apidra (glulisine) trade name Apidra (no Chinese name), developed by the French Sanofi-Aventis. FDA has approved the April 2004 for adults with type 1 and type 2 diabetes, the European Committee for Medicinal Products for human use (CHMP) has approved the listing. This product is not yet in the domestic market. Apidra to insulin rDNA origin Glulisine, is a recombinant DNA human insulin available analogues. This product usually before meals or after meals 20min 15min injection, 10 ~ 20min onset, 1h after the peak, the role can be maintained 4h, lower postprandial glucose peak. It can be coupled with long-acting insulin preparations. Current clinical research on the products is relatively small, particularly in children, pregnant women in the application of the safety, effectiveness, and its teratogenic, mutagenic and other side effects in clinical studies were still ongoing. But there are some trials have demonstrated the application in the safety of children and good compliance. (B) the effect of the duration of classification 1. Acting insulin are insulin analogues. Including insulin aspart and lispro insulin. Available short-acting insulin analogue of human insulin to avoid the shortcomings. Its rapid onset, peak fast, half-life is short, clear fast, and postprandial hyperglycemia state synchronization, restoration of basic state quickly, more in line with the physiological requirements, which can make patients with diabetes can control the level of glycated hemoglobin in the ideal range, more better control of postprandial blood glucose, to obtain a lower incidence of hypoglycemia, and more flexible way of life and treatment. Usually within 15min in the fasting or postprandial injection immediately, starting the reaction time was 10 ~ 20min, the maximum reaction time was 40min, the duration of action for the 3 ~ 5h. When using rapid-acting insulin analogues should be noted, for patients with type 1 diabetes or poor islet function in patients with type 2 diabetes, insulin secretion as the basis of very little, but lost the role of insulin analogues available soon, so similar in use of insulin lispro material should be appropriately increased basal insulin dose. 2. Short-acting insulin of animal origin, including normal insulin injection, neutral insulin injection, including human insulin injection or Novolin R refills or special charge, Humulin R injection or refills or special charge, Ganshu Lin R injection fluid or cartridge. Short-acting insulin in solution was not retained by the modified insulin, whose appearance is brighter. Their relatively rapid onset, after subcutaneous administration, the initial reaction time was 30min, the maximum reaction time was 3h, maintaining the reaction time was 8h. Short-acting insulin is used to cover the meal insulin requirements, the main control postprandial blood glucose, in order to have time to absorb, it should be 20 ~ 30min before the injection of a meal, if lower fasting blood glucose, can be injected immediately before meals. Current clinical use of short-acting human insulin has some shortcomings) the slow onset, due to the onset 30min after the injection, which requires patients injected 30min before a meal, postprandial blood glucose can not be effectively controlled. Injected 30min before a meal, and the lives of patients with great inconvenience. (2) the role of peak slow to reach peak 90min after injection, the body can not synchronize physiological blood glucose peak, and thus on the postprandial glycemic control. And if you want better control of postprandial glucose, insulin dose required is relatively large, it is very easy to hypoglycemia the next meal phenomenon. Diabetic patients increased concerns on insulin injections. 3. The effect of insulin: The most common preparation is a low-protamine zinc insulin, insulin with protamine and zinc ions to form complexes, and insulin protamine molecule ratio of 1:1, a white suspension, only the subcutaneous injection, the initial reaction time is 1 ~ 2h, the maximum reaction time was 12h, to maintain the role of time was 24h, usually used in conjunction with short-acting insulin to provide the basis of the amount of insulin the day, with long-acting insulin release profile compared to Variation small. Most commonly used to control the next morning fasting blood glucose injection before going to bed. The main varieties of animal origin, including low-protamine zinc insulin injection million Surin, recombinant human insulin Novolin N or refills or special charge, Humulin NPH or refills or special charge, Ganshu Lin N, or cartridge. 4. Animal origin for the long-acting insulin protamine zinc insulin (PZI), and insulin glargine and insulin in particular. PZI protamine zinc insulin protamine zinc in the low increase on the basis of the ratio of protamine, is more close to human body fluids PH, lower solubility, effect lasts longer. Usually injected once a day, and with the use of short-acting insulin to provide basal insulin requirements. 3-4 hours after subcutaneous injection 20 hours of onset, 12-peak, the role of maintenance of 24-36 hours. Because long-acting preparations are mostly suspension dosage form, may cause instability in the absorption and efficacy. Long-acting insulin analogue was dissolved in the acidic environment of the state, to clarify the solution. The onset time of subcutaneous injection of 1.5 hours, and its role for sustainable 24h, day 1, to overcome the current peak in the efficiency of insulin uptake and disadvantages of short half-life is the ideal supplement basal insulin preparations. 5. Premixed insulin, also known as dual-phase insulin, is a mixture containing the two insulin, which can have a short-acting and intermediate-acting insulin effect. There is currently commercially available with Novolin 30R is 30% of the short-acting and 70% of R N in the effect of insulin; Novolin 50R is 50% with short-acting and 50% of R N in the effect of insulin; Humulin 70/30 is 30% with short-acting and 70% of R N in the effect of insulin; excellent music secretion 75/25 (equivalent to 25% of the optimal secretion of music, in effect the equivalent of more than role) and aspart 30, Connaught and the sharp 30 Special charge is a soluble insulin aspart protamine binding and crystallization of insulin aspart biphasic mixture. Short-acting preparations in the rapid onset component, you can better control postprandial blood glucose, in effect slow release of the main ingredients from sustainable alternative basal insulin secretion. Easy to use premixed insulin, a relatively small number of injections, patient compliance is good, but because of limited mixing program for some special cases, it is difficult to ideal blood sugar control. Third, the insulin drug delivery (A) subcutaneous injection (pen insulin syringes): The oral insulin in the gastrointestinal tract vulnerable to low pH value and the enzymatic destruction, and it's small intestine through the rate, it is still currently used insulin injections, usually by subcutaneous administration. After half a century of development, mode of administration of insulin has also been updated, in addition to ordinary syringes for injection of insulin, the widely used clinically for the pen insulin syringes, refills will be made into the form of insulin, with a dedicated injection pen, you can simplify the operation, the injected dose is more accurate, easy to carry, reducing pain, by patients are welcome. Disadvantage is that flexibility can not be mixed insulin as needed. Special filling device is a 3ml pre-filled disposable insulin injection device, designed as a pen shape, out of direct discarded. Avoid the potential replacement cartridge error dose or species, but the cost is higher, the affordability of patients is limited. (B) Intravenous infusion: only short-acting insulin. (C) of the insulin pump: continuous subcutaneous insulin infusion (CSII) of the mode of administration of insulin-dependent patients, especially for patients with brittle diabetes, has brought great convenience. The wider is the current open-loop insulin pump, which is short-acting insulin by the placing storage needle through the catheter and infusion pump were connected with the use of adjustable micro-computer control of insulin infusion to simulate the physiological secretion of insulin on an ongoing basis and meals pulsatile-release, and with self-blood glucose monitoring, blood glucose control can close to normal physiological levels, adjust the dose of a more flexible, reducing the pain of repeated injections. Continuous improvement by insulin pump, and its shape is like an ordinary pager and portable, the current major clinical use of intensive insulin therapy and insulin-dependent brittle diabetic patients. But because of its more expensive, limiting its application. Adverse reactions are infusion site infection due to pump failure or human error led to disruption or excessive infusion of insulin infusion. (D) jet injection system is a needle-free subcutaneous injection of insulin which enables patients to receive the system, the device expensive and cumbersome application is currently limited. (E) non-injection drug delivery: long-term administration of insulin to patients has brought unimaginable pain and trouble, non-injection drug delivery become a research hotspot. Current research mainly in the following ways: 1. Inhalation preparation (1) absorption by the lung bioavailability of inhaled insulin is approximately 10% -15%, equivalent dose equivalent to insulin injections 3 times. Pharmacokinetics showed rapid onset of its role and subcutaneous injection of ultra-short acting insulin analogues similar. Currently there are two kinds of inhaled insulin formulations, dry powder insulin and insulin-soluble liquid, aerosol is required when using the diameter of alveolar easily absorbed 1 ~ 3¦Ìm particles. A number of studies show that inhaled insulin aerosol can significantly lower fasting and postprandial blood glucose, oral hypoglycemic agents in patients with poor efficacy of insulin aerosol can be combined with significantly improved blood sugar. Some potential problems with inhaled insulin, the bioavailability of his state by the impact of lung function. At present the main products are Pfizer's inhaled insulin powder formulations of insulin Exubera, Novo Nordisk's inhaled formulations of liquid formulations NN1998 (AERxiDMS) and Eli Lilly's inhaled powder preparations and so on. (2) has been reported by the nasal mucosa of nasal absorption of inhaled insulin can significantly lower blood glucose, but smaller nasal absorption, nasal ciliary clearance is stronger, so the absorption efficiency is low. For increasing the absorption efficiency will be increased by adding surfactant irritation caused by nasal mucosa, so few studies. (3) the oral mucosa absorption of insulin by the oral mucosa of the method is called "ORALIN". Found, T2DM patients with ORALIN 15min before a meal to give insulin, and subcutaneous injection of insulin similar effect. 2. Oral Insulin The small intestine in humans and animals there are certain specific areas, accounting for about 25% of intestinal mucosa, allowing some particles into the lymph factor and circulatory system. Using this feature can be included into the insulin microspheres made of different materials (vesicles, nano-ball), to carry insulin into the circulatory system. Steric vector of insulin and to prevent contact with the gastrointestinal tract enzymes, and the trypsin inhibitor and insulin were encapsulated in microspheres system, could increase drug bioavailability. Development of oral insulin in recent years, can simulate the physiological insulin secretion, has proved to have lower blood glucose, plasma insulin increased the role of the more promising drugs. Formulations of the present study are capsules, capsules, microcapsules and the compound encapsulated emulsion. The main disadvantage is affected by many factors dose is difficult to accurately calculate, on the gastrointestinal mucosa may have side effects. Existing products are developed by Generex oral tablet Oralin, Lilly's U.S. AI-401 and other oral dosage forms. 3. There are also eye drops and Insulin penetrant through the skin, are in the study. Fourth, insulin and other drugs and the interaction of factors (A) against the drug insulin 1. Glucocorticoids, adrenocorticotropic hormone, glucagon, estrogen, oral contraceptives, thyroxine, epinephrine, thiazide diuretics, phenytoin, phenyl alanyl blood glucose levels can be increased 2. Calcium channel blocker, clonidine, danazol, diazoxide, growth hormone, heparin, H2 receptor antagonists, marijuana, morphine, nicotine and other changes in glucose metabolism can make blood sugar. 3. Smoking can be antagonized by the release of catecholamines and the hypoglycemic effect of insulin. (B) synergistic effect of the drug insulin 1. Salicylates, anti-clotting drugs, sulfa drugs, and anticancer drugs methotrexate competition with insulin and plasma protein binding of free insulin in the blood increased. 2. Oral hypoglycemic agents and insulin have synergistic hypoglycemic effect. Anabolic steroid, androgen, or monoamine oxidase inhibitors, non-steroidal anti-inflammatory analgesic drugs may enhance the hypoglycemic effect of insulin. 3. ¦Â-receptor blockers such as propranolol combination with insulin can increase the risk of low blood sugar, hypoglycemia can cover up to extend the time low blood sugar. 4, and a lot of moderate ethanol can enhance the role of insulin-induced hypoglycemia. 5. Chloroquine, quinidine, quinine can delay the degradation of insulin to enhance its hypoglycemic effect. 6. Angiotensin-converting enzyme inhibitors, bromocriptine, fibrate, ketoconazole, lithium, mebendazole, or theophylline may increase the hypoglycemic effect of insulin that may cause lower blood sugar. (C) Other factors 1. ª¥ long-term use of insulin antibody production animal insulin, insulin-producing antibodies, can significantly reduce the insulin effect. 2. Post-receptor defect of insulin receptor or Can cause insulin dosage increased, but the hypoglycemic effect is not obvious. ª¥ 3. ª¥ liver disease cirrhosis, the liver of insulin, glucagon, growth hormone inactivation reduced degradation, may have hyperinsulinemia, hyperlipidemia high glucagon, etc. occur, the number of insulin receptors on target cells to reduce , expressed as insulin resistance, blood glucose fluctuations at this time, the application of insulin than the large number of very difficult to get good control of blood glucose. ª¥ 4. ª¥ hyperglycemia and glucose toxicity Blood glucose not only its own role by promoting their absorption, can also affect the secretory function of islet B cells. Under normal conditions in the body, acute hyperglycemia can promote their own insulin secretion and glucose utilization in chronic hyperglycemia, the suppression of insulin secretion and glucose metabolism, a phenomenon known as glucose toxicity, which led to decreased blood glucose increase in insulin effect, as well as reduce the dose of insulin.