Injection therapy, insulin

Insulin is a peptide hormone, secreted by the pancreas, that regulates glucose metabolism in the body. Insufficient production of insulin or failure of insulin to stimulate target sites in liver, muscle, and adipose tissue leads to the serious metabolic disorder known as diabetes mellitus. Diabetes afflicts millions of people worldwide. Diabetic individuals typically exhibit high levels of glucose in the blood, but insulin injection therapy allows diabetic individuals to maintain normal levels of blood glucose. 

Therapy for insulin-dependent diabetes mellitus is usually achieved by daily subcutaneous injections of insulin, and insulin-mimetics which can be orally administered may be useful for the treatment of type I diabetes (insulin dependent) if suitable complexes of low toxicity can be identified (510, 511). 

To facilitate multiple subcutaneous injections of insulin, particularly during intensive insulin therapy, portable pen-sized injectors have been developed. These contain cartridges of insulin and replaceable needles. 

Raskin P, Bode BW, Marks JB, Hirsch IB, Weinstein RL, McGill JB, Peterson GE, Mudaliar SR, Reinhardt RR. Continuous subcutaneous insulin infusion treatment and multiple daily injection therapy are equally effective in type 2 diabetes. Diabetes Care 2003 26 2598-603. 

DeVries JH, Snoek FJ, Kostense PJ, Masurel N, Heine RJDutch Insulin Pump Study Group. A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Diabetes Care 2002 25(11) 2074-80. 

Albright ES, Desmond R, Bell DSH. Efficacy of conversion from bedtime NPH insulin injection to once- or twice-daily injections of insulin glargine in type 1 diabetic patients using basal/bolus therapy. Diabetes Care 2004 27 632-3. 

Mohn A, Matyka KA, Harris DA, Ross KM, Edge JA, Dunger DB. Lispro or regular insulin for multiple injection therapy in adolescence. Differences in free insulin and glucose levels overnight. Diabetes Care 1999 22(l) 27-32. 

To facilitate multiple subcutaneous injections of insulin, particularly during intensive insulin therapy, portable pen-sized injectors have been developed. These contain cartridges of insulin and replaceable needles. Disposable insulin pens are also available for selected formulations. These include regular insulin, insulin lispro, insulin aspart, NPH insulin, and premixed 70%/30% and 50%/50% NPH/regular, 75% NPL/25% lispro, 50% NPL/50% lispro, and 70% NPA/30% aspart insulin. They have been well accepted by patients because they eliminate the need to carry syringes and bottles of insulin to the workplace and while traveling. 

Type 1 diabetes is treated with insulin replacement therapy, usually by insulin injection or insulin pump, along with attention to dietary management and careful monitoring of blood glucose levels. Today most insulin is produced using genetic recombination techniques insulin analogues are a form of modified insulin with different onset-of-action times or duration-of-action times. 

Tupola S, Rajantie J. Documented symptomatic hypoglycaemia in children and adolescents using multiple daily insulin injection therapy. Diabet Med 1998 15(6) 492-6. 

Buysschaert et al. (1983) reported a better glycaemic control of totally insulin-dependent diabetic patients under continuous insulin infusion compared with conventional insulin therapy (Lager et al., 1983). An improved metabolic control, an increased glucose-disposal rate and an inverse insulin resistance following a more physiological insulin regimen with continuous insulin infusion compared with conventional therapy was also reported (Jarret, 1986). Similar results were observed by Muhlhauser et al. (1987) where an intensified insulin injection therapy performed as routine treatment of Type-1 diabetics significantly lowered HBA) levels (Fig. 13). 

In Type-I diabetes, which is due to the loss of insulin-producing cells as a consequence of autoimmune disorders, substitution of insulin is the most important measure. However, merely to inject one daily dose is not an adequate therapy. Here, the objective is to mimic the daily variations in plasma insulin which are closely related to food intake. One such attempt which has improved microvascular complications is intensified insulino-therapy through multiple daily injections of insulin. Another approach is to develop techniques of islet transplantation and using a bioartificial pancreas. In the case of islet transplantation, tissues will not only respond to changes in blood glucose levels but also to hormones of the entero-insular axis. 

In some cases, cell surface expression of certain species can be induced for example, interleukin-1 has been shown to induce the biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells [197]. Such materials may also be exploitable as candidates for bioadhesion studies. Millions of lives of patients with diabetes have been saved since the introduction of insulin therapy. However, several daily injections of insulin are required to maximize glucose control in diabetic patients. Insulin is administered by subcutaneous injection, but this route of administration has a slow onset and subsequent prolonged duration of action. These limitations show up more when higher doses of insulin are injected, which results in a long duration of action and forces the patients to consume additional amounts of food to limit the risk of hypoglycemia [198]. 

Since each of these disorders is caused by the lack of an enzyme, scientists are trying to design a way to replace the lost activity. Oral medication will not work because enzymes are proteins. They would simply be digested, fike any other dietary protein. Enzyme replacement therapy is one approach that is being studied. This would involve periodic injections of the enzyme into the bloodstream, a treatment just fike the injection of insulin by diabetics. Enzyme replacement therapy would require a large supply of the enzyme. Eollowing the model of insulin, the gene for the enzyme could be cloned into bacteria. The bacteria would then produce the protein, which would be purified for use by humans. 

An estimated five million people in North America and 30 million in the world are diabetic. Almost half of these people require repeated, often daily, injections of insulin to maintain approximately normal glucose levels. While gross metabolic control is achieved, diabetics are still subject to unavoidable complications. Conventional insulin therapy is inadequate for the restoration of normoglycemia sufficient to prevent these degenerative sequelae of diabetes (1). Hence, artificial pancreata have been designed and developed to deliver insulin continuously in direct response to the physiological need to provide the finer control of glycemia necessary for homeostasis in insulin-dependent diabetes. 

Patients with insulin-dependent diabetes receive subcutaneous insulin injections daily. The goal of insulin therapy is to provide adequate glucose control through each 24 hour period while minimizing the number of injections required to achieve that control. Repeated injections at the same site may result in atrophy or hyperplasia at the injection site. Insulin preparations of short, intermediate and long duration are available (Table 10.10). 

Siebenhofer A, Plank J, Berghold A, Horvath K, Sawicki PT, Beck P, Pieber TR. Meta-analysis of short-acting insulin analogues in adult patients with type 1 diabetes continuous subcutaneous insulin infusion versus injection therapy. Diabetologia 2004 47(11) 1895-1905. 

As a result of derivatization of insulin during isolation and purification steps, and during storage of the pharmaceutical preparations, therapeutic insulin contains smaller amounts of desamido insulins, covalent insulin dimers, and other insulin derivatives. Physical and chemical stability of insulin in formulations for injection therapy has recently been reviewed in a previous volume of this series (Brange and Langkjser, 1993) and in a monograph (Brange, 1994). 

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