20145860 Insulin Therapy for Diabetes

8/8/2019 20145860 Insulin Therapy for Diabetes

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Names & Numbers

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Personal Use

INSULINTHERAPY FOR

DIABETESPharmacology Report


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Endocrine Function of The Pancreas :

Approximately 1 million Islets of Langerhans

in an adults human Pancreas.Within these islets at

least 4 hormones producing region are present.

See the table..

Pancreatic islet cells and their secretory products.

Cell Types Approximate Percent of Islet Mass Secretory Products

A cell (alpha) 20 Glucagon, proglucagon

B cell (beta)75 Insulin, C-peptide, proinsulin, amylin

D cell (delta)3 to 5

Somatostatin

F cell (PP cell)1less than 2

Pancreatic polypeptide (PP)

1Within pancreatic polypeptide-rich lobules of adult islets, located only in the posterior

portion of the head of the human pancreas, glucagon cells are scarce (< 0.5%) and F

cells make up as much as 80% of the cells.

Hormones :1-Insulin : the storage & anabolic hormone of the

body.

2-Glucagon : metabolizes glycogen store.

3-Amylin: modulates appitite, gastric emptying,&

Glucagon and insulin secretion.

4-Somatostatin: inhibition of the secretion cells. &

self inhibition.

5-Pancreatic peptides (PP): Facilitation of digestive

processes.

Diabetes Mellitus


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Diabetes Mellitus occur in the absence of ,or inadeguacy

of pancreatic insulin secretion. With , or without

concurrent impairment of insulin action.

TYPES OF DIABETES MELLITUS :

Type 1 Diabetes Mellitus (Insulin-dependent)

:

Causes:

1-Occurs from selective-cell & severe or absolute insulin

deficiency(An autoimmune disease to-cells ofpanceas). The most common

2-Idiopathic usually related to genetics. Less common

-Usually Juvenile onset.

-Adminsteration of insulin is essential.

-Can be treated with pancreas transplants.

-Persons in northern Europe & from Sardinia at higher

incidence.

Type 2 Diabetes Mellitus (Insulin-

independent):

-Characterized bytissue resistence to the action of

insulin combined with relative insulin deficiency.

-Impaired fat metabolism is also there.

-There is an increase risk ofatheroma

formation.(Atherosclerosis)

-Treatment usually using oral hypoglycemic drugs.

-In10 20% of the individuals of type 2 diabetes which

was initially diagnosed actually have both type 1, & type 2


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,or slowly growing type 1 and ultimately will require full

insulin replacement.

-There is no ketosis, ketoacidosis may occur as a result

of infection or use of medication that enhances resistencee.g : corticosteroids.

-In uncontrolled individual dehydration can leads to

serious condition known asnonketotic hyperosmolar

coma were blood glucose level rise to 6-20 times the

normal blood glucose range . 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, usually related to drug

therapy (Drug-induced diabetes).

Type 4 Diabetes Mellitus(Gestational Diabetes

Mellitus ,or GDM):

-Related to pregnancy.

-Placental hormones have an insulin resistance like action

specially in the third trimester of pregnancy.(Specially in

the first pregnancy time)

-4% of all the pregnancies in USA is diagnosed to have

GDM.-GDM women should be continuously diagnosed in the

period between 24th-28th week of pregnancy.

Cells of the

endocrine

function in the

pancreas as

microscopic


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INSULIN

Chemistry:

Insulin is a small protein with a molecular weight

of 5808 in humans. It contains 51 amino acids

arranged in two chains (A & B) linked by disulfide

bridges.

Species differences are there in the amino acids of

both chains.

Proinsulin , a long single-chain protein molecule, is

processed within Golgi apparatus and packaged into

granules. It is hydrolyzed in to insulin & residual segment

called C-peptide by removal of 4 amino acids.

Insulin & C-peptide are secreted in equal amounts.

C-peptide have no known biologic functions.

-Insulin as we said is stored in a specific granule crystals

with Zink(Zn++) as 6 molecules of insulin & 2 (Zn++)

atoms.

INSULIN THERAPY FOR DIABETES


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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.

External standard insulin used contains 28 units per

milligram.

Human Insulin. The amino acid diagram of human insulin, showing the A and B

chains and 3 disulfide bonds

The Process of insulin formation:

Once food enters the body, it immediately is detected and the

insulin mRNA is translated as asingle chain precursor called

preproinsulin in the pancreas. By the removal of its signal peptide(see figure below) during insertion into the endoplasmic reticulum,

proinsulin is generated. Preproinsulin is the primary translation

product of the insulin gene, composed of 110 amino acids (Smith,

et. al., 1997). It is relatively inactive and has to be processed into

proinsulin in order to eventually make the insulin hormone. Within

the endoplasmic reticulum, 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. Now the mature form of insulin has been made into


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clusters of endocrine cells in inslets of Langorhans (Purves, et. al.,

2001). The extra C peptide and signal peptide, which was clipped

off, are packaged in the Golgi into secretory ganules to

accumulate and be recycled in the cytoplasm. Once insulin is

properly made and the beta cell is appropriately stimulated, insulin

is secreated from the cell into the blood.

Converting preproinsulin to insulin. Preproinsulin is transcribed as a 110

amino acid chain and by the removal of the signal peptide, proinsulin is

produced . Formation of disulfide bonds between the A- & B-chain

components are made, and removal of the intervening C peptide chain

produces biologically active Insulin of 51 amino acids

Insulin secretion:

Insulin is released from the pancreatic -cells at a low basal

rate which is stimulated to increase by a variety of stimuli

including:

-Sugers (Mainly Glucose , then mannose)

-Certain amino acids (e.g Leucine , Arginine).

-Hormones such as glucagon-like polypeptide-1 , vagal activity.

Potassium (K+) plays an essential role in the secretion of insulin

through ATP-dependent potassium channels.

Mechanism of insulin secretion: In hyperglycemia there is an

increase level of ATP. Which closes the ATP-dependent potassium

channels .decreased (K+) efflux results in depolarization of the B-

cell and opening of the voltage gated calcium channels. This


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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, the

glycolytic phosphorylation of glucose causes a rise in the ATP:ADP ratio.

This rise inactivates the potassium channel that depolarizes the

membrane, causing the calcium channel to open up allowing calcium ions

to flow inward. The ensuing rise in levels of calcium leads to the

exocytotic release of insulin from their storage granule.


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Some drugs can be used to increase insulin secretion by

affecting this pathway like (Sulfonylureas, meglitinides, &

D-phenylalanine) e.g :

Sulfonylureas drugs block the potassium channels.

Insulin degradation:

-The liver & the kidney participates in the removal of insulin.

Normally 60% of the insulin is removed by the liver & the kidney

removes the remaining. While in subcutanouous insulin injection insulin

degradation is mainly by the kidney.

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.

The receptor consists of two extracellular ((Alpha)hormone

binding)domains & two intracellular ((Beta)cytoplasmic )domains

that contains tyrosine kinase enzyme.

The extracellular and cytoplasmic domains are connected by two

hydrophobic bonds that cross the cell membrane.


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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.

Thus, tyrosine kinase is activated starting phosphorylation of thecytoplasmic domain protein followed by intracellular proteins and

enzymes that produce cellular response to insulin.

After activation, the receptor is interanalized inside the cell

(endocytosis) and the number of receptors on cell surface isdecreased (receptor down-regulation) to limit the insulin activity.

The receptor may be degraded inside the cell or merge again on

cell surface to be reused.


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Effects of Insulin in its target:

Insulin mediates its effects through Glucose transporters(GLUTs)

see the table

TransporterTissues

Glucose Km(mmol/L)

Function

GLUT 1All tissues,

especially red

cells, brain

1to 2

Basal uptake ofglucose;

transport across

the blood-brainbarrier

GLUT 2B cells of

pancreas; liver,kidney; gut

15to 20

Regulation ofinsulin release,other aspects of

glucosehomeostasis

GLUT 3Brain, kidney,

placenta, othertissues

less than 1Uptake into

neurons, othertissues

GLUT 4 Muscle, adipose

5

Insulin-mediated

uptake ofglucose

GLUT 5 Gut, kidney 1to 2Absorption of

fructose

GLUCOSE TRANSPORTERS

INSULIN PREPARATIONS CHARACTERS:

Commercial insulin preprations differ in a number of ways,

such as the techniques of the recombinant DNA


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production, amino acid sequence, concentration,

solubility,methods of preparation , time of onset, duration

of their biologic action, about 17 to 20 preparation are

their in USA.

Historically insulin preparations were derived from

bovine & porcine glands. Bovine insulin was removed from

the USA due to concern about mad-cow disease;

preparation of porcine insulin was stopped in 2005.

Human insulin is prepared by the use of recombinant DNA

techniques to produce the human insulin in bacteria

(Eschrishia coli is widely used).

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.

4-Long-acting with slow onset of action.

Inhaled form of rapid-acting insulin also is marketed as

a powder for alveolar absorption.

Rapid & short acting insulin are dispensed as clear

solutions at neutral PH which also contains Zn+ to

improve stability.Intermediate-acting NPH(Neutral Protamine Hagedorn) are

dispensed as a turbid suspension at neutral pH with

protamine in phosphate buffer.

Insulin glargine & insulin detemir are the soluble long-

acting insulins.


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Current regimens generally use long-acting & short-acting

insulins to provide basal or background coverage, & to

meet the mealtime requirements.

Daily the most sophisticated insulin regimen deliversrapid-acting through a continuous subcutaneous insulin

infusion device called (Insulin Pump).


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1-Rapid-acting insulins:

Three injected form of insulin analogs:

1-Insulin lispro (Humalog).

2-Insulin aspart (Novolog).

3-Insulin glulisine (Apidra).

& one inhaled form as:

-Human insulin recombinant inhaled.

All of them are permitted for prandial insulin replacement.

Their duration of action is rarely more than 3-5 hoursexcept the inhaled form which lasts 6-7 hours. They are

preffered for use in insulin pump.

Insulin lispro is the first monomeric insulin analog to be

marketed , which is produced by rDNA technology.

Advantages of Insulin lispro:

-Non immunogenic like bovine insulin.

-Very low propensity.

-Rapidly acting compared to human insulin.

Insulin aspart is created by the substitution of B28 proline

with an aspartic acid.

Advantages is similar to insulin lispro.

Insulin glulisine is formulated by substituting an

asparagine for lysine in B3 & glutamic acid for lysine at

B29.

Advantages also is similar to insulin lispro.

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. Its


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contraindicated in children, teenagers, or adults with lung

disease.

2-Short-acting insulin

-Is suitable for emergency.

-Its the only type of insulin that is administered

intravenously as a solution.

-Usually used in clinics for management of diabetic

ketoacidosis.

3-Intermediate-acting& long-acting insulins:

a-NPH(neutral protamine Hagedorn, or isophane).

-Absorption & onset of action are delayed.

-After subcutaneous injection proteolytic tissue enzymes

degrade the protamine to permit absorption of insulin.

-NPH has an onset of 2-5 hours & duration of action of 4-

12 hours.

-Usually mixed with rapid-acting insulin & given 2-4 times

daily for Diabetes type 1.

b-Insulin glargine (ultra-long-acting soluble insulin

analog) (Lantus is the common trade name).

-It was designed to provide reproducible ,convenient

insulin replacement. By attachment of two arginine

molecules to the B-chain carboxyl terminal & substitutionof glycine for asparagines at A-21 position which is soluble

in acidic media but precipitates in neutral pH after

subcutaneous injection.

-Individual insulin molecules slowly dissolve away from

the crystalline depot & provides a low continuous level of

circulating insulin.


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-Slow onset of action 1-1.5 hours, maximum effect after 4-

6 hours.

-Injected once daily & in insulin sensitive patient its

splitted twice a day.

-It should not be mixed with other insulins.

-It has the same maxium efficacy like the native human

insulin.

-Absorption pattern is independent to the site of injection.

-It has a greater binding ability of 6-7 times that of native

human insulin to insulin-like growth factor-1 (IGF-1).

-Its usually acidic at a pH of 4.0.

Insulin Delivery Systems:

Now there are three methods for insulin delivery:

1-Portable Pen Injections.

2-Continuous Subcutaneous Insulin Infusion

Devices (CSII, Insulin pumps).

3-Inhaled Insulin.

Complications & adverse effects:

1-Hypoglycemia may occur from insulin overdose,

insufficient caloric intake, strenuous exercise, or when

combined with ethanol.

2-Hypokalemia because Insulin blocks potassium pump.

3-Anaphylactoid reaction (or Immunopathology).

4-Lipodystrophyor hypertrophy of subcutaneous fat at

the injection site.

5-Weight gain.


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Glucose monitoring:

Today there are different types of glucose monitoring

devices for home usage , also there is what is calledCONTINUOUS GLUCOSE MONITORING SYSTEMS see the

picture..

Currently Available Insulin Preparations


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Insulin

Preparation

Onset of

Action

(h)

Peak

action

(h)

Effective

duration of

action (h)

Maximum

duration (h)

Rapid-acting analogues

Insulin lispro

(Humalog) - - 1 3-4 4-6

Insulin aspart

(NovoLog) - -1 3-4 4-6

Insulin glulisine

(Apidra) - -1 3-4 4-6

Short-acting

Regular

(soluble) - 1 2-3 3-6 6-8

Intermediate-acting

NPH (isophane) 2-4 6-10 10-16 14-18

Long-acting analogue

Insulin glargine

(Lantus)3-4 8-16 18-20 20-24

Insulin detemir

(Levemir)

3-4 6-8 14 ~20

Approaches to management

Insulin and other drug based approaches

Currently, one goal for diabetics is to avoid or minimizechronic diabetic complications, as well as to avoid acute

problems of hyperglycemia or hypoglycemia. Adequatecontrol of diabetes leads to lower risk of complicationsassociated with unmonitored diabetes including kidneyfailure (requiring dialysis or transplant), blindness, heartdisease and limb amputation. The most prevalent form ofmedication is hypoglycemic treatment through either oralhypoglycemics and/or insulin therapy. There is emergingevidence that full-blown diabetes mellitus type 2 can beevaded in those with only mildly impaired glucose

tolerance.


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Patients with type 1 diabetes mellitus require directinjection of insulin as their bodies cannot produce enough(or even any) insulin. As of 2005, there is no otherclinically available form of insulin administration other

than injection for patients with type 1: injection can bedone by insulinpump, by jetinjector, or any of severalforms of hypodermic needle. Non-injective methods ofinsulin administration have been unattainable as theinsulin protein breaks down in the digestive track. Thereare several insulin application mechanisms underexperimental development as of 2004, including a capsulethat passes to the liver and delivers insulin into thebloodstream. There have also been proposed vaccines for

type I using glutamic acid decarboxylase (GAD), but theseare currently not being tested by the pharmaceuticalcompanies that have sublicensed the patents to them.

For type 2 diabetics, diabetic management consists of acombination of diet, exercise, and weight loss, in anyachievable combination depending on the patient. Obesityis very common in type 2 diabetes and contributes greatlyto insulin resistance. Weight reduction and exerciseimprove tissue sensitivity to insulin and allow its properuse by target tissues. Patients who have poor diabeticcontrol after lifestyle modifications are typically placed onoral hypoglycemics. Some Type 2 diabetics eventually failto respond to these and must proceed to insulin therapy.

Patient education and compliance with treatment is veryimportant in managing the disease. Improper use ofmedications and insulin can be very dangerous causinghypo- or hyper-glycemic episodes.

Insulin therapy requires close monitoring and a great dealof patient education, as improper administration is quitedangerous. For example, when food intake is reduced, lessinsulin is required. A previously satisfactory dosing may betoo much if less food is consumed causing a hypoglycemicreaction if not intelligently adjusted. In addition, exercisedecreases insulin requirements as exercise increasesglucose uptake by body cells whose glucose uptake is

controlled by insulin, and vice versa. In addition, there are


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available several types of insulin with varying times ofonset and duration of action.

Insulin therapy creates risk because of the inability to

continuously know a person's blood glucose level andadjust insulin infusion appropriately. New advances intechnology have overcome much of this problem. Small,portable insulin infusion pumps are available from severalmanufacturers. They allow a continuous infusion of smallamounts of insulin to be delivered through the skin aroundthe clock, plus the ability to give bolus doses when aperson eats or has elevated blood glucose levels. This isvery similar to how the pancreas works, but these pumps

lack a continuous "feed-back" mechanism. Thus, the useris still at risk of giving too much or too little insulin unlessblood glucose measurements are made.

The FDA has approved a treatment called Exenatide,based on the saliva of a Gilamonster, to control bloodsugar in patients with type 2 diabetes.

Diet and supplements

For most Type 1 diabetics there will always be a need forinsulin injections throughout their life. However, both Type1 and Type 2 diabetics can see dramatic normalization oftheir blood sugars through controlling their diet, and some

Type 2 diabetics can fully control the disease by dietarymodification. As diabetes can lead to many othercomplications it is critical to maintain blood sugars asclose to normal as possible and diet is the leading factor inthis level of control.

The American Diabetes Association in 1994 recommendedthat 60-70% of caloric intake should be in the form ofcarbohydrates. This is somewhat controversial, with someresearchers claiming that 40% is better, while others claimbenefits for a high-fiber, 75% carbohydrate diet.

An article summarizing the view of the American DiabetesAssociationgives many recommendations and referencesto the research. One of the conclusions is that caloricintake must be limited to that which is necessary for


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maintaining a healthy weight. The methodology of thedietary therapy has attracted lots of attentions from manyscientific researchers and the protocols are ranging fromnutritional balancing to ambulatory diet-care.

Specific diets

Glycemic index- lowering the glycemic index of one's dietcan improve the control of diabetes. This includesavoidance of such foods as potatoes,and white bread, andfavoring legumes and whole grains.

Low Carb Diet- It has been suggested that the gradualremoval of carbohydrates from the diet and replacement

with fatty foods such as nuts, seeds, meats, fish, oils,eggs, avocados, olives, and vegetables may help reversediabetes. Fats would become the primary calorie sourcefor the body, and complications due to insulin resistancewould be minimized.

High fiber diet- It has been shown that a high fiber dietworks better than the diet recommended by the AmericanDiabetes Association in controlling diabetes, and may

control blood sugar levels with the same efficacy as oraldiabetes drugs.

Cinnamon

Though not yet evaluated by the Food and DrugAdministration, at least two studies have shown thatcinnamon can act significantly reducing some effects ofdiabetes. One study on people used fine ground cinnamon

(Cinnamomum cassia) for oral consumption. Another studyused an extract (MHCP) on laboratory rats.

The study on people published in 2003 conducted in theDepartment of Human Nutrition, NWFP AgriculturalUniversity, Peshawar, Pakistan concluded:

The results of this study demonstrate that intake of 1, 3,or 6 g of cinnamon per day reduces serum glucose,triglyceride, LDL cholesterol, and total cholesterol in

people with type 2 diabetes and suggest that the inclusion
http://en.wikipedia.org/wiki/Low_Carb_Diethttp://en.wikipedia.org/wiki/Low_Carb_Diet


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of cinnamon in the diet of people with type 2 diabetes willreduce risk factors associated with diabetes andcardiovascular diseases.

The study on laboratory rats at Department ofBiochemistry, Biophysics and Molecular Biology, IowaState University published in 2001 used purifiedhydroxychalcone from cinnamon. The extract was named"MHCP". Part of the study's conclusion stated that "theMHCP is fully capable of mimicking insulin" andrecommended further studies.


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20145860 Insulin Therapy for Diabetes