Administration of Insulin

Insulin, a large polypeptide, is not suitable for oral administration. Even if the insulin molecule survived digestion by proteases in the stomach and small intestine, this compound is much too large to be absorbed through the gastrointestinal wall. Consequently, insulin is usually administered through subcutaneous injection. Insulin may also be administered by the intravenous route in emergency situations (e.g., diabetic coma). 

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The first hormonal signal found to comply with the characteristics of both a satiety and an adiposity signal was insulin [1]. Insulin levels reflect substrate (carbohydrate) intake and stores, as they rise with blood glucose levels and fall with starvation. In addition, they may reflect the size of adipose stores, because a fatter person secretes more insulin than a lean individual in response to a given increase of blood glucose. This increased insulin secretion in obesity can be explained by the reduced insulin sensitivity of liver, muscle, and adipose tissue. Insulin is known to enter the brain, and direct administration of insulin to the brain reduces food intake. The adipostatic role of insulin is supported by the observation that mutant mice lacking the neuronal insulin receptor (NDRKO mice) develop obesity. 

Administration of insulin—sites to be used rotation of injection sites (see Home Care Checklist Rotating Insulin Injection Sites) angle of injection administration at die time of day prescribed by the health care provider disposal of die needle and syringe... 

While the major application of albumin microspheres is in the area of chemotherapy, there have been studies reporting the release of such varied compounds as 1-norgestrel (97), insulin (98), and hematoporphyrins (99) from bovine serum albumin, and the antibacterial sulfadiazine from ovalbumin (100). In general, burst phenomena are found for all systems studied. However, the results from the insulin study are worthy of note in that blood glucose levels were depressed for more than 14 days following the administration of insulin-containing BSA microspheres to diabetic rats. The smaller microspheres were absorbed by day 28 and the larger particles by day 56. 

Prolonged hypoglycemic effect in diabetic dogs due to subcutaneous administration of insulin liposomes, Diabetes, 31. 506-511. 

Intensive insulin therapy, the administration of insulin three or more times daily to maintain preprandial blood glucose levels between 70 and 120 g/dL and postprandial blood glucose levels less than 180 g/dL, has been shown to decrease the incidence of proteinuria and albuminuria in patients with diabetes, both with and without documented nephropathy. The development and progression of nephropathy is also delayed in patients with type 1 DM receiving intensive insulin therapy. Continued benefits of intensive insulin therapy have been demonstrated up to 8 years after the study.16... 

G Gwinup, AN Elias, ES Domurat. Insulin and C-peptide levels following oral administration of insulin in intestinal-enzyme protected capsules. Gen Pharmacol 22 143-246, 1991. 

Hypoglycaemia remains the most frequent complication of insulin administration to diabetics. It usually occurs due to (a) administration of an excessive amount of insulin (b) administration of insulin prior to a mealtime, but with subsequent omission of the meal or (c) due to increased physical activity. In severe cases this can lead to loss of consciousness, and even death. Although it may be treated by oral or i.v. administration of glucose, insulin-induced hypoglycaemia is sometimes treated by administration of glucagon. 

Ilium et al. [49] evaluated chitosan solutions as delivery platforms for nasal administration of insulin to rats and sheep. They reported a concentration-dependent absorption-enhancing effect with minimal histological changes of the nasal mucosa in all concentrations applied. 

Lipodystrophy Rarely, administration of insulin subcutaneously can result in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue). 

Combination insulin therapy Concurrent administration of insulin and an oral... 

Geriatric Considerations - Summary Ensure that the older adult can demonstrate the appropriate use of insulin by assessing his or her ability to draw up the correct dose from a multidose bottle, read syringe markings, and administer the dose subcutaneously. Comorbidities such as poor vision, arthritis, tremor, or cognitive impairment may impair this process. Insulin pens maybe advantageous for some patients. Administration of insulin in the arm results in slower absorption than seen with abdominal administration. 

Medicinal chemistry has many examples of the development of successful therapeutics based on an exploration of endogenous compounds. The treatment of diabetes mellitus, for example, is based upon the administration of insulin, the hormone that is functionally deficient in this disease. The current treatment of Parkinson s disease is based upon the observation that the symptoms of Parkinson s disease arise from a deficiency of dopamine, an endogenous molecule within the human brain. Since dopamine cannot be given as a drug since it fails to cross the blood-brain barrier and enter the brain, its biosynthetic precursor, L-DOPA, has been successfully developed as an anti-Parkinson s drug. Analogously, the symptoms of Alzheimer s disease arise from a relative deficiency of acetylcholine within the brain. Current therapies for Alzheimer s-type dementia are based upon the administration of cholinesterase... 

Insulin Preparations. Since diabetes mellitus is a defect of one or more of insulin production, secretion, or action, the administration of insulin replacement as a treatment for diabetes in the 1920s was a landmark discovery. Historically, most commercial insulin came from either bovine or porcine sources. Beef insulin differs from human insulin by three amino acid substitutions pork insulin differs by only one residue. For many years, standard insulin preparations were 70% beef and 30% porcine. However, the biosynthesis of human insulin has now displaced the animal insulins, especially bovine insulin which was more antigenic. Mass production of human insulin by recombinant DNA methods is achieved by inserting the human proinsulin gene into either E. coli or yeast and treating the resulting proinsulin to yield the human insulin molecule. Insulin preparations may be divided into four major types ... 

Managing the Complications of Diabetes. Diabetes is more than just a disorder of elevated glucose it is a systemic disease that affects many organ systems. In addition to the metabolic problems there are numerous neurological, circulatory, and renal complications, even when the blood glucose level is properly controlled. The main reason is the unnatural administration of insulin by injection, instead of the constant secretion by the pancreas in response to changing blood glucose levels. Diabetics have a predisposition of atherosclerosis, with an increased risk for heart attacks and stroke. 

Ritschel, W.A., and G.B. Ritschel, Rectal administration of insulin. Methods Find Exp Clin Pharmacol, 1984. 6(9) 513-29. 

By the use of a breath-powered unit dose dry powder inhaler, which was adapted to the physical properties of TI, relative bioavailability was 50% for the first 3 hours and 30% over the entire 6-hour period in 12 healthy volunteers (Pfutzner et al. 2002). However, although the studies demonstrated pulmonary administration of TI has the advantages of fast onset of action, short duration of action, and lower variability over the SC injections of insulin no attempt has been made to compare pulmonary administration of insulin alone with the same inhaler device. This method of encapsulating biomacromolecules has some advantages and must be considered when electing to deliver a molecule. 

Effects on lipid metabolism Adipose tissue responds within minutes to administration of insulin, which causes a significant reduc tion in the release of fatty acids ... 

Developments in the administration of insulin through the skin, the mouth, the nose, and the lung have been reviewed (183). Methods of absorption other than subcutaneous, such as nasal insulin, buccal insulin, rectal insulin, and insulin in enteric-coated capsules, are still experimental. A problem in nasal administration is still how to get a daily reproducible dose (184). The frequency of hypoglycemia is comparable to the frequency with subcutaneous insulin (185). Nasal irritation, sometimes with congestion, and dyspnea (186) can occur. Pulmonary insulin, delivered by aerosol inhalation, is another experimental method. No lung obstruction was reported, but the uptake varied considerably (187). 

Gizurarson S, Bechgaard E. Intranasal administration of insulin to humans. Diabetes Res Clin Pract 1991 12(2) 71-84. 

In healthy volunteers, there was a dose-related increase in blood insulin concentrations after the administration of insulin detemir (2). However, there was no clear dose-response metabolic effect and individual variability was high. 

After the administration of insulin lispro it is not necessary to delay a meal until sufficient insulin is absorbed. Insulin lispro can be given immediately before or during a meal and can be used when rapid action is important, as in outpatient treatment of ketonuria (1) or in continuous subcutaneous insulin infusion (2). Insulin lispro can be successful in patients with subcutaneous insulin resistance (3). 

Danne T, Amna J, Schober E, Deiss D, Jacobsen JL, Friberg HH, Jensen LH. A comparison of postprandial administration of insulin aspart in children and adolescents with type 1 diabetes. Diabetes Care 2003 26 2359-64. 

Insulin probably exists in the pancreas as a zinc compound, but administration of insulin, per se, is effective in controlling diabetes. The main reason for using a zinc-containing preparation such as neutral protamine zinc insulin is that it is stable, dissolves more slowly and lasts longer than insulin, itself, when given by hypodermic injection. 

FIGURE 2.1 Changes in blood glucose level versus time profiles in type 1 diabetic rats following multiple oral administration of SS-ILP and subcutaneous insulin (only at the first dosing) (open square), insulin solution (open circles), and subcutaneous administration of insulin solution (closed circles). Insulin solution was used as control (open circles). The dose of insulin was 25 IU/kg (oral) and 0.1 IU/kg (subcutaneous) body weight. Each value represents mean SE (n — 5-10). Statistically significant difference from control p < 0.05 p < 0.01. (From Morishita, M. et al., J. Control. Release, 110, 587, 2006. With permission from Elsevier.)... 

Fasano, A., and S. Uzzau. 1997. Modulation of intestinal tight junctions by zonula occludens toxin permits enteral administration of insulin and other macromolecules in an animal model. J Clin Invest 99 1158. 

Damge, C., et al. 1997. Poly(alkyl cyanoacrylate) nanospheres for oral administration of insulin. J Pharm Sci 86 1403. 

Ziv, E., et al. 1994. Oral administration of insulin in solid form to nondiabetic and diabetic dogs. J Pharm Sci 83 792. 

The insulin solution and Ch-coated liposomes and plain liposomes containing insulin were tested for their influence on the blood glucose level after intragastric administration to normal rats. When compared with the change in the blood glucose level caused by the subcutaneous administration of insulin solution, Ch-coated liposomes had a pharmacological effect of approximately 5% (Figure 3.2). The effect of the plain liposomes and insulin solution was... 

FIGURE 3.2 Blood glucose concentration-time profiles in normal rats after oral administration of insulin-containing chitosan-coated liposomes, insulin-containing plain liposomes and insulin solution, and subcutaneous administration of insulin solution. Sol, solution Lip, liposomes Ch, chitosan s.c., subcutaneous. The results are expressed as the mean values. 

Kimura, T., et al. 1996. Oral administration of insulin as poly(vinyl alcohol)-gel spheres in diabetic rats. Biol Pharm Bull 19 897. 

Pharmacokinetic and Pharmacodynamic Parameters for Insulin and Glucose Following Rectal Administration of Insulin, SNAP, and Carboxy-PTIO... 

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