This action might not be possible to undo. Are you sure you want to continue?
INSULIN THERAPY FOR DIABETES
Names & Numbers 1AC:
AC: AC: AC: AC: AC:
Hormones : 1-Insulin : the storage & anabolic hormone of the body. proglucagon Insulin. proinsulin. Secretory Products Approximate Percent of Islet Mass 20 75 3 to 5 less than 2 Glucagon. 3-Amylin: modulates appitite. 5-Pancreatic peptides (PP): Facilitation of digestive processes. 19 . glucagon cells are scarce (< 0. 2-Glucagon : metabolizes glycogen store. Cell Types A cell (alpha) B cell (beta) D cell (delta) F cell (PP cell)1 1 Pancreatic islet cells and their secretory products. amylin Somatostatin Pancreatic polypeptide (PP) Within pancreatic polypeptide-rich lobules of adult islets. & self inhibition. See the table.& Glucagon and insulin secretion.Within these islets at least 4 hormones producing region are present.Diabetes Mellitus Endocrine Function of The Pancreas : Approximately 1 million Islets of Langerhans in an adults human Pancreas. C-peptide.. gastric emptying.5%) and F cells make up as much as 80% of the cells. located only in the posterior portion of the head of the human pancreas. 4-Somatostatin: inhibition of the secretion cells.
or without concurrent impairment of insulin action. -In 10 – 20% of the individuals of type 2 diabetes which was initially diagnosed actually have both type 1. -There is an increase risk of atheroma formation. With .or inadeguacy of pancreatic insulin secretion. & type 2 19 . Less common -Usually Juvenile onset.(Atherosclerosis) -Treatment usually using oral hypoglycemic drugs. -Adminsteration of insulin is essential. The most common 2-Idiopathic usually related to genetics.Diabetes Mellitus occur in the absence of . 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). -Persons in northern Europe & from Sardinia at higher incidence. Type 2 Diabetes Mellitus (Insulinindependent): -Characterized by tissue resistence to the action of insulin combined with relative insulin deficiency. -Can be treated with pancreas transplants. -Impaired fat metabolism is also there.
-Placental hormones have an insulin resistance like action specially in the third trimester of pregnancy. Type 3 Diabetes mellitus : Causes: -Other specific causes of an elevated blood glucose level which is non-pancreatic disease. Cells of the endocrine function in the pancreas as microscopic 19 . ketoacidosis may occur as a result of infection or use of medication that enhances resistence e.or slowly growing type 1 and ultimately will require full insulin replacement.or “GDM”): -Related to pregnancy. -There is no ketosis. Type 4 Diabetes Mellitus (Gestational Diabetes Mellitus .(Specially in the first pregnancy time) -4% of all the pregnancies in USA is diagnosed to have GDM.g : corticosteroids. usually related to drug therapy (Drug-induced diabetes). normal range (70-110 mg/dsl of blood volume). -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 . -GDM women should be continuously diagnosed in the period between 24th-28th week of pregnancy..
C-peptide have no known biologic functions. is processed within Golgi apparatus and packaged into granules.INSULIN THERAPY FOR DIABETES INSULIN Chemistry: Insulin is a small protein with a molecular weight of 5808 in humans. 19 . Species differences are there in the amino acids of both chains. Insulin & C-peptide are secreted in equal amounts. It contains 51 amino acids arranged in two chains (A & B) linked by disulfide bridges. a long single-chain protein molecule. It is hydrolyzed in to insulin & residual segment called C-peptide by removal of 4 amino acids. Proinsulin . -Insulin as we said is stored in a specific granule crystals with Zink(Zn++) as 6 molecules of insulin & 2 (Zn++) atoms.
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. Within the endoplasmic reticulum. al. 1997). 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 . proinsulin is generated. Human Insulin. The amino acid diagram of human insulin. composed of 110 amino acids (Smith. it immediately is detected and the insulin mRNA is translated as a single chain precursor called preproinsulin in the pancreas. It is relatively inactive and has to be processed into proinsulin in order to eventually make the insulin hormone. et. showing the A and B chains and 3 disulfide bonds The Process of insulin formation: Once food enters the body. 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. External standard insulin used contains 28 units per milligram. Preproinsulin is the primary translation product of the insulin gene.
Mechanism of insulin secretion: In hyperglycemia there is an increase level of ATP. then mannose) -Certain amino acids (e. Arginine). Formation of disulfide bonds between the A. Which closes the ATP-dependent potassium channels .clusters of endocrine cells in inslets of Langorhans (Purves. which was clipped off. This 19 .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. Potassium (K+) plays an essential role in the secretion of insulin through ATP-dependent potassium channels. insulin is secreated from the cell into the blood. vagal activity. -Hormones such as glucagon-like polypeptide-1 .g Leucine . 2001). Converting preproinsulin to insulin. Once insulin is properly made and the beta cell is appropriately stimulated. The extra C peptide and signal peptide.. 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 .& B-chain components are made. proinsulin is produced . Preproinsulin is transcribed as a 110 amino acid chain and by the removal of the signal peptide. al. et.
Insulin secretion in beta cells is triggered by rising blood glucose levels. causing the calcium channel to open up allowing calcium ions to flow inward. the glycolytic phosphorylation of glucose causes a rise in the ATP:ADP ratio. This rise inactivates the potassium channel that depolarizes the membrane.results in an increase (Ca+2) which is excitatory leading to increase insulin secretion. Starting with the uptake of glucose by the GLUT2 transporter. 19 . The ensuing rise in levels of calcium leads to the exocytotic release of insulin from their storage granule.
Some drugs can be used to increase insulin secretion by affecting this pathway like (Sulfonylureas. & D-phenylalanine) e.g : Sulfonylureas drugs block the potassium channels. Have life of circulating insulin is 3-5 min. Normally 60% of the insulin is removed by the liver & the kidney removes the remaining. The extracellular and cytoplasmic domains are connected by two hydrophobic bonds that cross the cell membrane. Insulin degradation: -The liver & the kidney participates in the removal of insulin. meglitinides. While in subcutanouous insulin injection insulin degradation is mainly by the kidney. 19 .(t1/2 ) The insulin receptors: As we have study before that insulin receptor is a transmembrane type of receptors. The receptor consists of two extracellular ((Alpha)hormone binding)domains & two intracellular ((Beta)cytoplasmic )domains that contains tyrosine kinase enzyme.
The receptor may be degraded inside the cell or merge again on cell surface to be reused. Thus. 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. 19 .Upon insulin binding. the receptor is converted from the inactive monomeric to the active dimeric state allowing the 2 cytoplasmic domains to be attached to each other. tyrosine kinase is activated starting phosphorylation of the cytoplasmic domain protein followed by intracellular proteins and enzymes that produce cellular response to insulin. After activation.
brain B cells of pancreas. placenta. other tissues Muscle. adipose Gut. kidney. 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. liver. kidney Glucose Km )(mmol/L to 2 1 Function Basal uptake of glucose. such as the techniques of the recombinant DNA 19 . kidney. transport across the blood-brain barrier Regulation of insulin release. other aspects of glucose homeostasis Uptake into neurons. gut Brain. especially red cells.Effects of Insulin in its target: Insulin mediates its effects through Glucose transporters(GLUTs) see the table Transporter Tissues All tissues.
time of onset. Rapid & short acting insulin are dispensed as clear solutions at neutral PH which also contains Zn+ to improve stability. concentration. amino acid sequence. Insulin glargine & insulin detemir are the soluble longacting insulins. 19 .methods of preparation .production. Inhaled form of rapid-acting insulin also is marketed as a powder for alveolar absorption. duration of their biologic action. Intermediate-acting NPH(Neutral Protamine Hagedorn) are dispensed as a turbid suspension at neutral pH with protamine in phosphate buffer. Human insulin is prepared by the use of recombinant DNA techniques to produce the human insulin in bacteria (Eschrishia coli is widely used). solubility. 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. 2-Short-acting with rapid onset of action. 3-Intermediate-acting. Bovine insulin was removed from the USA due to concern about “mad-cow” disease. about 17 to 20 preparation are their in USA. 4-Long-acting with slow onset of action. Historically insulin preparations were derived from bovine & porcine glands. preparation of porcine insulin was stopped in 2005.
19 . Daily the most sophisticated insulin regimen delivers rapid-acting through a continuous subcutaneous insulin infusion device called (Insulin Pump). & to meet the mealtime requirements.Current regimens generally use long-acting & short-acting insulins to provide basal or background coverage.
Advantages of Insulin lispro: -Non immunogenic like bovine insulin. Advantages also is similar to insulin lispro. 3-Insulin glulisine (Apidra). -Rapidly acting compared to human insulin. Insulin lispro is the first monomeric insulin analog to be marketed . All of them are permitted for prandial insulin replacement. & one inhaled form as: -Human insulin recombinant inhaled. They are preffered for use in insulin pump. Advantages is similar to insulin lispro. 2-Insulin aspart (Novolog).1-Rapid-acting insulins: Three injected form of insulin analogs: 1-Insulin lispro (Humalog). which is produced by rDNA technology. Their duration of action is rarely more than 3-5 hours except the inhaled form which lasts 6-7 hours. Insulin glulisine is formulated by substituting an asparagine for lysine in B3 & glutamic acid for lysine at B29. Its 19 . -Very low propensity. Insulin aspart is created by the substitution of B28 proline with an aspartic acid. 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.
contraindicated in children. 19 . or isophane). -After subcutaneous injection proteolytic tissue enzymes degrade the protamine to permit absorption of insulin. or adults with lung disease.convenient insulin replacement. -It was designed to provide reproducible . -Individual insulin molecules slowly dissolve away from the crystalline depot & provides a low continuous level of circulating insulin. -NPH has an onset of 2-5 hours & duration of action of 412 hours. -Absorption & onset of action are delayed. teenagers. -It’s the only type of insulin that is administered intravenously as a solution. 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. 2-Short-acting insulin -Is suitable for emergency. -Usually mixed with rapid-acting insulin & given 2-4 times daily for Diabetes type 1. -Usually used in clinics for management of diabetic ketoacidosis. b-Insulin glargine (ultra-long-acting soluble insulin analog) (Lantus is the common trade name). 3-Intermediate-acting& long-acting insulins: a-NPH (neutral protamine Hagedorn.
Insulin pumps).0. 4-Lipodystrophy or hypertrophy of subcutaneous fat at the injection site. maximum effect after 46 hours. -Its usually acidic at a pH of 4. -Injected once daily & in insulin sensitive patient its splitted twice a day. 2-Hypokalemia because Insulin blocks potassium pump. insufficient caloric intake. Insulin Delivery Systems: Now there are three methods for insulin delivery: 1-Portable Pen Injections. -It should not be mixed with other insulins. 5-Weight gain. 2-Continuous Subcutaneous Insulin Infusion Devices (CSII.-Slow onset of action 1-1. 3-Anaphylactoid reaction (or Immunopathology). Complications & adverse effects: 1-Hypoglycemia may occur from insulin overdose. -It has a greater binding ability of 6-7 times that of native human insulin to insulin-like growth factor-1 (IGF-1).5 hours. or when combined with ethanol. -It has the same maxium efficacy like the native human insulin. 3-Inhaled Insulin. 19 . strenuous exercise. -Absorption pattern is independent to the site of injection.
Currently Available Insulin Preparations 19 ..Glucose monitoring: Today there are different types of glucose monitoring devices for home usage . also there is what is called CONTINUOUS GLUCOSE MONITORING SYSTEMS see the picture.
heart disease and limb amputation. Adequate control of diabetes leads to lower risk of complications associated with unmonitored diabetes including kidney failure (requiring dialysis or transplant). blindness. as well as to avoid acute problems of hyperglycemia or hypoglycemia.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. The most prevalent form of medication is hypoglycemic treatment through either oral hypoglycemics and/or insulin therapy. one goal for diabetics is to avoid or minimize chronic diabetic complications.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. 19 . There is emerging evidence that full-blown diabetes mellitus type 2 can be evaded in those with only mildly impaired glucose tolerance.
as improper administration is quite dangerous. Non-injective methods of insulin administration have been unattainable as the insulin protein breaks down in the digestive track. less insulin is required. Obesity is very common in type 2 diabetes and contributes greatly to insulin resistance. when food intake is reduced. For type 2 diabetics. exercise. In addition. There have also been proposed vaccines for type I using glutamic acid decarboxylase (GAD).Patients with type 1 diabetes mellitus require direct injection of insulin as their bodies cannot produce enough (or even any) insulin. Weight reduction and exercise improve tissue sensitivity to insulin and allow its proper use by target tissues. 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. exercise decreases insulin requirements as exercise increases glucose uptake by body cells whose glucose uptake is controlled by insulin. Improper use of medications and insulin can be very dangerous causing hypo. In addition. Some Type 2 diabetics eventually fail to respond to these and must proceed to insulin therapy. diabetic management consists of a combination of diet. and vice versa. There are several insulin application mechanisms under experimental development as of 2004. but these are currently not being tested by the pharmaceutical companies that have sublicensed the patents to them. For example. A previously satisfactory dosing may be too much if less food is consumed causing a hypoglycemic reaction if not intelligently adjusted. in any achievable combination depending on the patient. 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. there are 19 . or any of several forms of hypodermic needle.or hyper-glycemic episodes. As of 2005. including a capsule that passes to the liver and delivers insulin into the bloodstream. and weight loss. Patients who have poor diabetic control after lifestyle modifications are typically placed on oral hypoglycemics. by jet injector.
The American Diabetes Association in 1994 recommended that 60-70% of caloric intake should be in the form of carbohydrates. New advances in technology have overcome much of this problem. the user is still at risk of giving too much or too little insulin unless blood glucose measurements are made. 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. This is somewhat controversial. portable insulin infusion pumps are available from several manufacturers. Small. The FDA has approved a treatment called Exenatide. but these pumps lack a continuous "feed-back" mechanism. One of the conclusions is that caloric intake must be limited to that which is necessary for 19 . An article summarizing the view of the American Diabetes Association gives many recommendations and references to the research. with some researchers claiming that 40% is better.available several types of insulin with varying times of onset and duration of action. Diet and supplements For most Type 1 diabetics there will always be a need for insulin injections throughout their life. and some Type 2 diabetics can fully control the disease by dietary modification. However. 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. based on the saliva of a Gila monster. to control blood sugar in patients with type 2 diabetes. This is very similar to how the pancreas works. 75% carbohydrate diet. Thus. both Type 1 and Type 2 diabetics can see dramatic normalization of their blood sugars through controlling their diet. Insulin therapy creates risk because of the inability to continuously know a person's blood glucose level and adjust insulin infusion appropriately. while others claim benefits for a high-fiber.
Fats would become the primary calorie source for the body. at least two studies have shown that cinnamon can act significantly reducing some effects of diabetes. meats. Low Carb Diet .It has been shown that a high fiber diet works better than the diet recommended by the American Diabetes Association in controlling diabetes. NWFP Agricultural University. seeds. or 6 g of cinnamon per day reduces serum glucose. The study on people published in 2003 conducted in the Department of Human Nutrition. and complications due to insulin resistance would be minimized. and favoring legumes and whole grains.lowering the glycemic index of one's diet can improve the control of diabetes.It has been suggested that the gradual removal of carbohydrates from the diet and replacement with fatty foods such as nuts.maintaining a healthy weight. fish. olives. eggs. LDL cholesterol. triglyceride. Pakistan concluded: The results of this study demonstrate that intake of 1. and total cholesterol in people with type 2 diabetes and suggest that the inclusion 19 . avocados.and white bread. High fiber diet . One study on people used fine ground cinnamon (Cinnamomum cassia) for oral consumption. This includes avoidance of such foods as potatoes. and may control blood sugar levels with the same efficacy as oral diabetes drugs. and vegetables may help reverse diabetes. oils. Cinnamon Though not yet evaluated by the Food and Drug Administration. 3. Peshawar. 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. Specific diets Glycemic index . Another study used an extract (MHCP) on laboratory rats.
Biophysics and Molecular Biology.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". 19 . The study on laboratory rats at Department of Biochemistry. Iowa State University published in 2001 used purified hydroxychalcone from cinnamon. Part of the study's conclusion stated that "the MHCP is fully capable of mimicking insulin" and recommended further studies.
This action might not be possible to undo. Are you sure you want to continue?
We've moved you to where you read on your other device.
Get the full title to continue reading from where you left off, or restart the preview.