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20145860 Insulin Therapy for Diabetes

20145860 Insulin Therapy for Diabetes

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Published by: venkateshgunturu on Dec 26, 2010
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Pharmacology Report

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5-Pancreatic peptides (PP): Facilitation of digestive processes. Secretory Products Approximate Percent of Islet Mass 20 75 3 to 5 less than 2 Glucagon.& Glucagon and insulin secretion. located only in the posterior portion of the head of the human pancreas. gastric emptying. 3-Amylin: modulates appitite. proglucagon Insulin. 4-Somatostatin: inhibition of the secretion cells. proinsulin.Within these islets at least 4 hormones producing region are present. glucagon cells are scarce (< 0. amylin Somatostatin Pancreatic polypeptide (PP) Within pancreatic polypeptide-rich lobules of adult islets. See the table. & self inhibition. Cell Types A cell (alpha) B cell (beta) D cell (delta) F cell (PP cell)1 1 Pancreatic islet cells and their secretory products. 2-Glucagon : metabolizes glycogen store. Hormones : 1-Insulin : the storage & anabolic hormone of the body.Diabetes Mellitus Endocrine Function of The Pancreas : Approximately 1 million Islets of Langerhans in an adults human Pancreas.. 19 .5%) and F cells make up as much as 80% of the cells. C-peptide.

Less common -Usually Juvenile onset.Diabetes Mellitus occur in the absence of . The most common 2-Idiopathic usually related to genetics.(Atherosclerosis) -Treatment usually using oral hypoglycemic drugs. -Impaired fat metabolism is also there. or without concurrent impairment of insulin action. -There is an increase risk of atheroma formation. -In 10 – 20% of the individuals of type 2 diabetes which was initially diagnosed actually have both type 1. -Adminsteration of insulin is essential. & type 2 19 . With .or inadeguacy of pancreatic insulin secretion. -Can be treated with pancreas transplants. Type 2 Diabetes Mellitus (Insulinindependent): -Characterized by tissue resistence to the action of insulin combined with relative insulin deficiency. -Persons in northern Europe & from Sardinia at higher incidence. TYPES OF DIABETES MELLITUS : Type 1 Diabetes Mellitus (Insulin-dependent) : Causes: 1-Occurs from selective β-cell & severe or absolute insulin deficiency (An autoimmune disease to β-cells of panceas).

(Specially in the first pregnancy time) -4% of all the pregnancies in USA is diagnosed to have GDM. normal range (70-110 mg/dsl of blood volume). Type 3 Diabetes mellitus : Causes: -Other specific causes of an elevated blood glucose level which is non-pancreatic disease. ketoacidosis may occur as a result of infection or use of medication that enhances resistence e. Type 4 Diabetes Mellitus (Gestational Diabetes Mellitus .g : corticosteroids. -Placental hormones have an insulin resistance like action specially in the third trimester of pregnancy..or slowly growing type 1 and ultimately will require full insulin replacement. Cells of the endocrine function in the pancreas as microscopic 19 . -GDM women should be continuously diagnosed in the period between 24th-28th week of pregnancy.or “GDM”): -Related to pregnancy. -In uncontrolled individual dehydration can leads to serious condition known as”nonketotic hyperosmolar coma” were blood glucose level rise to 6-20 times the normal blood glucose range . usually related to drug therapy (Drug-induced diabetes). -There is no ketosis.

It is hydrolyzed in to insulin & residual segment called C-peptide by removal of 4 amino acids.INSULIN THERAPY FOR DIABETES INSULIN Chemistry: Insulin is a small protein with a molecular weight of 5808 in humans. Proinsulin . -Insulin as we said is stored in a specific granule crystals with Zink(Zn++) as 6 molecules of insulin & 2 (Zn++) atoms. Species differences are there in the amino acids of both chains. Insulin & C-peptide are secreted in equal amounts. C-peptide have no known biologic functions. a long single-chain protein molecule. is processed within Golgi apparatus and packaged into granules. It contains 51 amino acids arranged in two chains (A & B) linked by disulfide bridges. 19 .

showing the A and B chains and 3 disulfide bonds The Process of insulin formation: Once food enters the body. Within the endoplasmic reticulum. it immediately is detected and the insulin mRNA is translated as a single chain precursor called preproinsulin in the pancreas. Human Insulin. External standard insulin used contains 28 units per milligram. By the removal of its signal peptide (see figure below) during insertion into the endoplasmic reticulum. Now the mature form of insulin has been made into 19 . et.. The amino acid diagram of human insulin. Preproinsulin is the primary translation product of the insulin gene.Human pancreas contains up to 8 mg of insulin representing up to 200 biologic units Note: Unit: is defined on the basis of the hypoglycemic activity of insulin in rabbits. composed of 110 amino acids (Smith. 1997). It is relatively inactive and has to be processed into proinsulin in order to eventually make the insulin hormone. proinsulin is generated. proinsulin is exposed to several specific endopeptidases to excise the C peptide chain (see figure below) of 31 amino acids from the single-stranded polypeptide to derive insulin. al.

Preproinsulin is transcribed as a 110 amino acid chain and by the removal of the signal peptide. Once insulin is properly made and the beta cell is appropriately stimulated. The extra C peptide and signal peptide.clusters of endocrine cells in inslets of Langorhans (Purves. Mechanism of insulin secretion: In hyperglycemia there is an increase level of ATP. al. This 19 . Which closes the ATP-dependent potassium channels . then mannose) -Certain amino acids (e. Arginine). -Hormones such as glucagon-like polypeptide-1 . insulin is secreated from the cell into the blood. 2001). Converting preproinsulin to insulin. et. Potassium (K+) plays an essential role in the secretion of insulin through ATP-dependent potassium channels. Formation of disulfide bonds between the A. proinsulin is produced . vagal activity. and removal of the intervening C peptide chain produces biologically active Insulin of 51 amino acids Insulin secretion: Insulin is released from the pancreatic β-cells at a low basal rate which is stimulated to increase by a variety of stimuli including: -Sugers (Mainly Glucose .decreased (K+) efflux results in depolarization of the Bcell and opening of the voltage –gated calcium channels. are packaged in the Golgi into secretory ganules to accumulate and be recycled in the cytoplasm.g Leucine .& B-chain components are made. which was clipped off..

causing the calcium channel to open up allowing calcium ions to flow inward. This rise inactivates the potassium channel that depolarizes the membrane. The ensuing rise in levels of calcium leads to the exocytotic release of insulin from their storage granule.results in an increase (Ca+2) which is excitatory leading to increase insulin secretion. Insulin secretion in beta cells is triggered by rising blood glucose levels. Starting with the uptake of glucose by the GLUT2 transporter. 19 . the glycolytic phosphorylation of glucose causes a rise in the ATP:ADP ratio.

meglitinides. The extracellular and cytoplasmic domains are connected by two hydrophobic bonds that cross the cell membrane.g : Sulfonylureas drugs block the potassium channels. 19 .Some drugs can be used to increase insulin secretion by affecting this pathway like (Sulfonylureas. Insulin degradation: -The liver & the kidney participates in the removal of insulin. While in subcutanouous insulin injection insulin degradation is mainly by the kidney. Normally 60% of the insulin is removed by the liver & the kidney removes the remaining. The receptor consists of two extracellular ((Alpha)hormone binding)domains & two intracellular ((Beta)cytoplasmic )domains that contains tyrosine kinase enzyme. Have life of circulating insulin is 3-5 min.(t1/2 ) The insulin receptors: As we have study before that insulin receptor is a transmembrane type of receptors. & D-phenylalanine) e.

tyrosine kinase is activated starting phosphorylation of the cytoplasmic domain protein followed by intracellular proteins and enzymes that produce cellular response to insulin. the receptor is interanalized inside the cell (endocytosis) and the number of receptors on cell surface is decreased (receptor down-regulation) to limit the insulin activity. After activation. Thus. the receptor is converted from the inactive monomeric to the active dimeric state allowing the 2 cytoplasmic domains to be attached to each other. 19 . The receptor may be degraded inside the cell or merge again on cell surface to be reused.Upon insulin binding.

liver. brain B cells of pancreas. other aspects of glucose homeostasis Uptake into neurons. kidney. other tissues Muscle. other tissues Insulin-mediated uptake of glucose Absorption of fructose GLUT 1 GLUT 2 to 20 15 GLUT 3 GLUT 4 GLUT 5 less than 1 ≈5 to 2 1 GLUCOSE TRANSPORTERS INSULIN PREPARATIONS CHARACTERS: Commercial insulin preprations differ in a number of ways. transport across the blood-brain barrier Regulation of insulin release. kidney Glucose Km )(mmol/L to 2 1 Function Basal uptake of glucose. adipose Gut. placenta. kidney. especially red cells. such as the techniques of the recombinant DNA 19 . gut Brain.Effects of Insulin in its target: Insulin mediates its effects through Glucose transporters(GLUTs) see the table Transporter Tissues All tissues.

methods of preparation . Rapid & short acting insulin are dispensed as clear solutions at neutral PH which also contains Zn+ to improve stability.production. Bovine insulin was removed from the USA due to concern about “mad-cow” disease. time of onset. 2-Short-acting with rapid onset of action. solubility. 4-Long-acting with slow onset of action. about 17 to 20 preparation are their in USA. preparation of porcine insulin was stopped in 2005. Intermediate-acting NPH(Neutral Protamine Hagedorn) are dispensed as a turbid suspension at neutral pH with protamine in phosphate buffer. duration of their biologic action. amino acid sequence. Historically insulin preparations were derived from bovine & porcine glands. 19 . PRINCIPLE TYPES & DURATION OF ACTION OF INSULIN PREPARATIONS: There are four primary types of insulin preparations: 1-Rapid –acting with very fast onset & short duration. concentration. Human insulin is prepared by the use of recombinant DNA techniques to produce the human insulin in bacteria (Eschrishia coli is widely used). Insulin glargine & insulin detemir are the soluble longacting insulins. Inhaled form of rapid-acting insulin also is marketed as a powder for alveolar absorption. 3-Intermediate-acting.

19 . & to meet the mealtime requirements. Daily the most sophisticated insulin regimen delivers rapid-acting through a continuous subcutaneous insulin infusion device called (Insulin Pump).Current regimens generally use long-acting & short-acting insulins to provide basal or background coverage.

Insulin glulisine is formulated by substituting an asparagine for lysine in B3 & glutamic acid for lysine at B29. Insulin aspart is created by the substitution of B28 proline with an aspartic acid. Insulin lispro is the first monomeric insulin analog to be marketed . Its 19 . Advantages of Insulin lispro: -Non immunogenic like bovine insulin. -Very low propensity.1-Rapid-acting insulins: Three injected form of insulin analogs: 1-Insulin lispro (Humalog). which is produced by rDNA technology. & one inhaled form as: -Human insulin recombinant inhaled. Advantages also is similar to insulin lispro. Their duration of action is rarely more than 3-5 hours except the inhaled form which lasts 6-7 hours. All of them are permitted for prandial insulin replacement. 3-Insulin glulisine (Apidra). Advantages is similar to insulin lispro. -Rapidly acting compared to human insulin. They are preffered for use in insulin pump. 2-Insulin aspart (Novolog). Inhaled human insulin is a powder form of rDNA which is marketed for pre-prandial & blood suger correction which is used in adults with type 1 & 2 diabetes.

-Individual insulin molecules slowly dissolve away from the crystalline depot & provides a low continuous level of circulating insulin. or isophane).contraindicated in children. 19 . -It’s the only type of insulin that is administered intravenously as a solution. or adults with lung disease. teenagers. -Usually used in clinics for management of diabetic ketoacidosis. By attachment of two arginine molecules to the B-chain carboxyl terminal & substitution of glycine for asparagines at A-21 position which is soluble in acidic media but precipitates in neutral pH after subcutaneous injection. 3-Intermediate-acting& long-acting insulins: a-NPH (neutral protamine Hagedorn.convenient insulin replacement. -Absorption & onset of action are delayed. 2-Short-acting insulin -Is suitable for emergency. b-Insulin glargine (ultra-long-acting soluble insulin analog) (Lantus is the common trade name). -After subcutaneous injection proteolytic tissue enzymes degrade the protamine to permit absorption of insulin. -Usually mixed with rapid-acting insulin & given 2-4 times daily for Diabetes type 1. -NPH has an onset of 2-5 hours & duration of action of 412 hours. -It was designed to provide reproducible .

-It has a greater binding ability of 6-7 times that of native human insulin to insulin-like growth factor-1 (IGF-1). 5-Weight gain. 3-Anaphylactoid reaction (or Immunopathology). Insulin pumps). maximum effect after 46 hours. 2-Continuous Subcutaneous Insulin Infusion Devices (CSII.5 hours. 4-Lipodystrophy or hypertrophy of subcutaneous fat at the injection site. Complications & adverse effects: 1-Hypoglycemia may occur from insulin overdose. -Absorption pattern is independent to the site of injection. 2-Hypokalemia because Insulin blocks potassium pump. 3-Inhaled Insulin. -Injected once daily & in insulin sensitive patient its splitted twice a day.0. -Its usually acidic at a pH of 4. -It should not be mixed with other insulins. 19 . -It has the same maxium efficacy like the native human insulin. or when combined with ethanol. insufficient caloric intake. strenuous exercise. Insulin Delivery Systems: Now there are three methods for insulin delivery: 1-Portable Pen Injections.-Slow onset of action 1-1.

Currently Available Insulin Preparations 19 . also there is what is called CONTINUOUS GLUCOSE MONITORING SYSTEMS see the picture.Glucose monitoring: Today there are different types of glucose monitoring devices for home usage ..

Adequate control of diabetes leads to lower risk of complications associated with unmonitored diabetes including kidney failure (requiring dialysis or transplant). as well as to avoid acute problems of hyperglycemia or hypoglycemia.Insulin Preparation Insulin lispro (Humalog) Insulin aspart (NovoLog) Insulin glulisine (Apidra) Regular (soluble) NPH (isophane) Insulin glargine (Lantus) Insulin detemir (Levemir) Onset of Action (h) ¼-½ ¼-½ ¼-½ Peak action (h) ½. blindness. one goal for diabetics is to avoid or minimize chronic diabetic complications. heart disease and limb amputation.1 ¼ ½ -1 ¼ ½ -1 ¼ Effective duration of action (h) 3-4 3-4 3-4 Maximum duration (h) Rapid-acting analogues 4-6 4-6 4-6 Short-acting ½-1 2-4 3-4 3-4 2-3 6-10 8-16 6-8 3-6 10-16 18-20 14 6-8 14-18 20-24 ~20 Intermediate-acting Long-acting analogue Approaches to management Insulin and other drug based approaches Currently. 19 . There is emerging evidence that full-blown diabetes mellitus type 2 can be evaded in those with only mildly impaired glucose tolerance. The most prevalent form of medication is hypoglycemic treatment through either oral hypoglycemics and/or insulin therapy.

Improper use of medications and insulin can be very dangerous causing hypo. including a capsule that passes to the liver and delivers insulin into the bloodstream. Weight reduction and exercise improve tissue sensitivity to insulin and allow its proper use by target tissues. or any of several forms of hypodermic needle. diabetic management consists of a combination of diet. For type 2 diabetics. by jet injector. Some Type 2 diabetics eventually fail to respond to these and must proceed to insulin therapy. in any achievable combination depending on the patient.Patients with type 1 diabetes mellitus require direct injection of insulin as their bodies cannot produce enough (or even any) insulin. Obesity is very common in type 2 diabetes and contributes greatly to insulin resistance. and vice versa. but these are currently not being tested by the pharmaceutical companies that have sublicensed the patents to them. when food intake is reduced.or hyper-glycemic episodes. as improper administration is quite dangerous. In addition. In addition. there is no other clinically available form of insulin administration other than injection for patients with type 1: injection can be done by insulin pump. Non-injective methods of insulin administration have been unattainable as the insulin protein breaks down in the digestive track. There have also been proposed vaccines for type I using glutamic acid decarboxylase (GAD). A previously satisfactory dosing may be too much if less food is consumed causing a hypoglycemic reaction if not intelligently adjusted. For example. There are several insulin application mechanisms under experimental development as of 2004. Patients who have poor diabetic control after lifestyle modifications are typically placed on oral hypoglycemics. there are 19 . less insulin is required. exercise. Insulin therapy requires close monitoring and a great deal of patient education. Patient education and compliance with treatment is very important in managing the disease. As of 2005. and weight loss. exercise decreases insulin requirements as exercise increases glucose uptake by body cells whose glucose uptake is controlled by insulin.

based on the saliva of a Gila monster. One of the conclusions is that caloric intake must be limited to that which is necessary for 19 . This is very similar to how the pancreas works. New advances in technology have overcome much of this problem. but these pumps lack a continuous "feed-back" mechanism. to control blood sugar in patients with type 2 diabetes. portable insulin infusion pumps are available from several manufacturers. They allow a continuous infusion of small amounts of insulin to be delivered through the skin around the clock. plus the ability to give bolus doses when a person eats or has elevated blood glucose levels. the user is still at risk of giving too much or too little insulin unless blood glucose measurements are made. Insulin therapy creates risk because of the inability to continuously know a person's blood glucose level and adjust insulin infusion appropriately.available several types of insulin with varying times of onset and duration of action. The FDA has approved a treatment called Exenatide. and some Type 2 diabetics can fully control the disease by dietary modification. An article summarizing the view of the American Diabetes Association gives many recommendations and references to the research. As diabetes can lead to many other complications it is critical to maintain blood sugars as close to normal as possible and diet is the leading factor in this level of control. Thus. with some researchers claiming that 40% is better. The American Diabetes Association in 1994 recommended that 60-70% of caloric intake should be in the form of carbohydrates. Diet and supplements For most Type 1 diabetics there will always be a need for insulin injections throughout their life. both Type 1 and Type 2 diabetics can see dramatic normalization of their blood sugars through controlling their diet. Small. This is somewhat controversial. However. 75% carbohydrate diet. while others claim benefits for a high-fiber.

and favoring legumes and whole grains. This includes avoidance of such foods as potatoes. and vegetables may help reverse diabetes. and may control blood sugar levels with the same efficacy as oral diabetes drugs.It has been suggested that the gradual removal of carbohydrates from the diet and replacement with fatty foods such as nuts. Pakistan concluded: The results of this study demonstrate that intake of 1. oils. NWFP Agricultural University. fish. avocados. meats. at least two studies have shown that cinnamon can act significantly reducing some effects of diabetes. Another study used an extract (MHCP) on laboratory rats. triglyceride. Specific diets Glycemic index . LDL cholesterol. The study on people published in 2003 conducted in the Department of Human Nutrition. Peshawar. Fats would become the primary calorie source for the body.maintaining a healthy weight. seeds. olives. High fiber diet . eggs. 3. Low Carb Diet .lowering the glycemic index of one's diet can improve the control of diabetes. and complications due to insulin resistance would be minimized. or 6 g of cinnamon per day reduces serum glucose.and white bread. and total cholesterol in people with type 2 diabetes and suggest that the inclusion 19 . The methodology of the dietary therapy has attracted lots of attentions from many scientific researchers and the protocols are ranging from nutritional balancing to ambulatory diet-care. One study on people used fine ground cinnamon (Cinnamomum cassia) for oral consumption.It has been shown that a high fiber diet works better than the diet recommended by the American Diabetes Association in controlling diabetes. Cinnamon Though not yet evaluated by the Food and Drug Administration.

19 . Biophysics and Molecular Biology. Iowa State University published in 2001 used purified hydroxychalcone from cinnamon.of cinnamon in the diet of people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases. The extract was named "MHCP". Part of the study's conclusion stated that "the MHCP is fully capable of mimicking insulin" and recommended further studies. The study on laboratory rats at Department of Biochemistry.

19 .

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