TYPE I DIABETES MELLITES

8/7/2019 TYPE I DIABETES MELLITES

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BYG.MUTHULAKSHMI

M.Tech Biopharmaceutical technology


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INTRODUCTIONType 1 diabetes mellites is a chronic disease results from

severe or absolute insulin deficiency that is pancreatic cellsfails to produce insulin.

Two main causes:1. Immune mediated- most prevalent

Destruction ofF-cells of pancreas by T-cells.2. Idiopathic

No known cause and autoimmunity but patientscannot produce insulin


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FACTORS CONTRIBUTE TO TYPE I DIABETES

MELLITUS

y Genetic factors: specific HLA allele type (HLA-DR3/4, DQ2/8)

yViral infection: congenital rubella infection increasethe risk of type I diabetes mellitus

y Environmental factors: Increased free radicals andtoxic doses of nitrosamines

y From mother to young:Onset of type I diabetes mellitus is seen in youngbefore 5yrs of age due to transfer of auto insulinantibodies.


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PANCREASy Three types of cells

E cell - Glucagon,

ProglucagonF cell Insulin, C-peptide, Proinsulin,amylin

cell SomatostatinF cell Pancreaticpolypeptide


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INSULIN

y Insulin is a polypeptide hormoneformed, after elimination of C peptideby hydrolysis. Its molecular weight is58KDa consist of two chains of21 and

30 amino acids, connected by twodisulfide bridges. Belongs to the groupof peptides called IGF (insulin likegrowth factors) or somatomedins.

y Insulin concentration in blood is 10-8

to 10-11 My Exist as a monomer during biological

action

y Exist as dimer in aqueous and neutral

solution and in the presence of zinc


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INSULIN SECRETIONSecretion is biphasic

immediate effect of shortduration and sustainedeffect

Pancreatic cells releasesinsulin into portal venoussystem

Basal insulin alues of 5-

15U/ml (30-90 pmol/L)are found in normalhumans, with a peak riseto 60-90 U/ml (360-540pmol/L) during meals


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REGULA

TION OF

INSULIN RELEA

SEy Nutrient secretagogues: Increase level of glucose in blood

y Non-nutrient secretagogues:Neural stimuli - cephalic phase of secretion. Stimulatedby vagus nerve, cholinergic and muscarinic receptors inFcells activate phospholipase C with subsequentintracellular events activating protein kinase A ,triggeringcalcium release and insulin secretion.

Adrenergic pathway- Catecholamines inhibit insulinrelease through E2-adreno receptors and stimulate insulinsynthesis byF- adrenoreceptors.


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Contd..y Peptide hormones

Somatostatin inhibit insulin secretion

GLP-1 combined with glucose it enhances proinsulinbiosynthesis. The mechanism of action is mediated by C-AMP pathway.

y

Amino acidsArginine cationic amino acid activates insulinsecretion by depolarizing the cell.

Leucine + glutamine- enhances insulin secretion.


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Regulation of insulin release


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EFFECT NUTRIENTS HORMONE NEURAL

Stimulatory GlucoseAminoacids

GLP-1GlucagonGrowth hormoneGIPCholecystokininGastrinVIPGastrin releasing peptide

adregenicpathwayVagal(parasympathetic)

Inhibitory AdrenocorticosteroidsSomatostatin

AdrenalinNoradrenalinGalaninNeuropeptide YCalcitonin gene-relatedpeptide (CGRP)Prostaglandin E

adrenergic


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Long term influences on insulin

secretiony Insulin secretion decreases during

Neonatal maturation

ExerciseStarvation

Aging

` Growth hormone deficiency

Excess thyroid hormone

y Insulin secretion increases during pregnancy


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INSULIN RECEPTOR

y Insulin exerts its action on varioustissues by binding with the receptorpresent on the membrane surface

y

Insulin receptor consists of twocovalently linked heterodimers.

y subunit extracellular andconsitutes recognition site

y subunit spans the membrane,contains tyrosine kinase


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ACTION OF INSULIN

y Insulin action at cellularlevel encompassescarbohydrate, lipids,

aminoacid metabolismand mRNA transcriptionand translation.


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GLUCOSE TRANSPORTERSTRANSPORTER

TISSUES GLUCOSEKm(mmol/L)

FUNCTION

GLUT -1 All tissues, especially red blood cells and brain

1-2 Basal uptake of glucose,transport across the blood

brain barrier.GLUT -2 B cells of pancreas, Liver,

kidney, gut15-20 Regulation of insulin

release, other aspects ofglucose homeostasis

GLUT -3 Brain, Kidney, placenta,

other tissues


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PHYSIOLOGICAL ACTION OF INSULINy MUSCLE: Insulin uptake is through GLUT-4 and muscle

accounts for 60%- 70% whole body insulin mediateduptake.

y Effects:Increases glucose transportIncreased glycogen synthesisIncreased protein synthesis

Increased aminoacid synthesisSupression of proteolysis


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y In case of insulin deficiency ,

there is an increase in protein break down leads

to increase level of nitrogen in the urine (honey-urine-disease).

imbalance in protein turnover and proteinbalance leads to muscle wastage.

decreased synthesis of intestinal mucosalproteins results in gastrointestinal complications.


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ACTION ON LIVERy While glucose uptake in liver is not insulin- dependent, it

accounts for about 30% of total body insuin mediatedglucose disposal.

y EFFECTS:

Promotes glucose storage as glycogen

Increases triglyceride synthesis and VLDL formation

Inhibits conversion of fatty acids and amino acids to ketoacids

inhibits glycogenolysis and gluconeogenesis

inhibits conversion of amino acids to glucose


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ACTION ON ADIPOSE TISSUEy Insulin uptake is through GLUT-4 and constitutes 10% of

total body insulin mediated glucose uptake

y Effects: Increased triglyceride synthesis

Lipoprotein lipase is induced and activated byinsulin to hydrolyze triglycerides from lipoproteins

Glucose transport into cell provides glycerolphosphate to esterification of fattyacids


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ACTION ON BRAINy While the brain is not insulin-dependent, insulin receptors

are concentrated in the olfactory bulb, hypothalamus,hippocampus,40 retina and vessels of the choroid plexus,as well as in regions of the striatum and cerebral cortex.Insulin is believed to act as a neuropeptide, involved insatiety, appetite regulation, olfaction, memory andcognition.

y There is suggestion of a potential link to Alzheimersdisease.


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CONTD..y PITUITARY: Insulin receptors present in anterior pituitary

gland stimulates production of growth hormone and inturn stimulates IGF-1 production by liver

y KIDNEY: The kidney does not require insulin for glucosetransport.Insulin receptors are found in the proximaltubules; insulin regulates mineral transport and

gluconeogenesis in the kidney.Insulin is degraded in thekidney.


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TYPE I DIABETES MELLITUSIn Normal individuals:y Glucose concentration is in the range of3.5-7mM throughout the day.y Fasting or pre-prandial insulin concentration is 6.1mMy

2-hr Postprandial glucose level peaks within 30-60 min after meal anddoes not exceed 7.8mM.y HbA1c level in the range of4%-6%

In treatment regimens for type I diabetes patients,y Blood glucose concentration of5.0-7.2 mM, and6.1-8.3 mM at bedtime

is maintained.y HbA1c level in the range less than 6.5% is maintained

In treatment regimens for type I diabetes patients,


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COMPLICATIONS IN HYPERGLYCEMIAy Acute complications:

Thirst, polyuria, glucosuria, hunger, hyperosmolar

hyperglycemic nonketotic coma, an often fatal result ofosmotic diuresis and dehydration. Ketoacidosis due toexcessive lipolysis

y Late complications:

microvascular-retinopathy, nephropathy and neuropathy,

and macrovascular-ischemic heart disease ,peripheralvascular disease, and stroke.


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INSULIN THERAPYy Insulin therapy is the only efficacious treatment for type I

diabetes mellites.y Ideally, insulin therapy should imitate the normal level of insulin

secretion.y In people who do not have diabetes, the release of insulin follows

2 patterns:

A baseline secretion of insulin and intermittent pulses of insulin

release following each meal .Administration of exogenous

insulin in a basal-bolus regimen attempts to mimic the natural

release of insulin through multiple daily injections.


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Contd..y Earlier, bovine and porcine insulin was used for

treatment of type I diabetes mellites

Production ofhuman insulin Semisynthetic method: Porcine insulin is changed

enzymatically Ex: Velosulin, Hoechst insulin

Biosynthetical DNA-technology methodProduction from bakers yeast Novo-Nordisk insulin

Production from Ecoli-bacteria Eli-Lilly insulin


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STRUCTURE ACTIVITY RELATIONSHIPHigh binding affinity to insulin receptor is accomplished

by amino acids at positionsA chain: A1, A2, A3, A16, A19, A21, A13

B chain: B6, B12, B15, B23, B24, B25, B17B8, B9, B12, B13, B16, and B23- B28 are amino acid

positions required for dimer formationHexamer formation is stabilised through association ofsix

His B10with two zinc atoms

Subsitutions at B26- B30 maintains high binding affinity.This region is not critical for binding of insulin receptorbut binding affinity in IGF-1 receptor is altered.


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Contd..yAspartic acid subsituted at His B10 which is essential

for hexamer formation, is absorbed twice as rapidly as

regular insuliny 3.5 fold increasing affinity for insulin receptor compare

to regular insulin

yAbout twice as potent than regular insulin in

metabolic assays.


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TYPES OF INSULINy Insulin, classified based on the action profile as

y Rapid/Short-acting insulin

Used for bolus (meal time) needsUsed for elevated BG

y Intermediate/Long-acting insulin

Used for basal (between meal) needs

Not intended to cover meals


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Dosage unity One international unit of insulin (1 IU) is defined as the biological

equivalent of about 45.5 g pure crystalline insulin (1/22 mg exactly).This corresponds to the old USP insulin unit, where one unit (U) of

insulin was (arbitrarily) set equal to the amount required to reduce theconcentration of blood glucose in a fasting rabbit to 45 mg/dl (2.5mmol/L).


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REGULAR INSULIN

y It is a man made human insulinstructurally identical to that of human

insulin secreted by pancreas.

y Normal insulin concentration peaks at30-45 min and returns to basal level after2-3 hr.

y Does not mimic endogenous insulin

level due to delayed absorption fromsubcutaneous injection site

y Disparity in plasma glucose levels createbrief hyperglycemic period immediatelyafter meal and post hypoglycemic period3-4 hr after a meal. Ex:Novolin

Onset of action Peak duration

30-60min 2-4hr 6-10hr


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RAPID ACTING INSULIN

y

These are insulin analogsof human insuliny Types: Insulin lispro

(Humalog ), Insulinaspart (Novolog ), Insulin

glulisine (Apidra

)y Best mimics normal

insulin secretion duringmeals.

Onset of action Peak Duration

10-15 min 1hr 3-5 hr


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INSULIN LISPRO(HUMALOG)y First rapid acting analogue produced by Eli lilly

company. Its M.Wis 5808.

y

Lysine in B29 and proline in B28 position is reversed ininsuline lispro . It does not alter insulin receptorbinding affinity.

y Does not self associate because of changes in terminal

portion of B chain. Thus it dissociates rapidly from SCinjection site

y It has high affinity towards IGF-1 receptor comparedwith human insulin


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INSULIN LISPRO


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Pharmacokinetic propertiesyAbsorption: Rapid absorption from injection site.

Absorption is more quickly from intenstinal site than

from deltoid or femoral sites. Heat increasesabsorption.

y Distribution:volume of distribution is 0.26-0.36L/Kg

y Bioavailablity: 55%-77%

y Elimination: dose dependent half life is 26-52 min.


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Pharmacodynamic propertiesy Insulin lispro reach the maximum concentration

within 38 min compared to 101 min for human insulin

y

Mean residence time that is average time a drugremains in the body for insulin lispro is halfthe timeof regular insulin.

y Lower post prandial rise in serum glucose level and

lower occurrence of hypoglycemia due to its shortduration of action.


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INSULIN ASPART ( NOVOLOG)y Proline at B28 position is

replaced by aspartic acid

y

Introduction of chargedgroup prevents theformation of dimers andhexamers.

y

Affinity towards insulinreceptors and IGF-1receptor is similar to thatof human insulin


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Pharmacokinetic propertiesyAbsorption: choice of injection affects action profile.

Abdominal administration decreases plasma glucoselevel in short duration compared to deltoid or thighmuscle . Faster rate of absorption and narrow peak

y Distribution: Low plasma protein binding


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Pharmacodynamic propertiesy Peak serum concentration reaches approximately twice

as that of human insulin

y

Mean residence time is 40-50 miny Occurrence of post prandial rise in glucose level after 4

hr of administration

y Increase occurrence of hypoglycemia in night time.


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INSULIN GLULISINE(APIDRA)y Substitution of

asparagine by lysine inB3 and Lysine at position

B29 by glutamine.y Isoelectric point shifted

from 5.1 to 5.5 increasessolublity .

y

Increased affinitytowards IGF-1 receptorthus there is a risk oftumorogenecity.


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Pharmacokinetic properties

yAbsorption: Faster absorption due to its high solublity

y Bioavailablity: 70%

y Elimination: 13-17minPharmacodynamic properties

y Peak concentration occur within 6omin

y Lower occurrence of hypoglycemia, nocturnal

hypoglycemia.


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INTERMEDIATE ACTING INSULIN

NPH insulin is anintermediate acting insulinwherein absorption

and onset of action isdelayed by appropriateamount insulin andprotomine so that neither ispresent is uncomplexed formProtamine is a mixture ofsix major and some minorcompounds isolated fromthe sperm of rainbow trout

Onset ofaction

Peak Duration

1-2 hr 4-14 hr 10-16 hr


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Pharmacokinetic propertiesyAbsoption: After subcutaneous injection, proteolytic

tissue enzymes degrade the protamine to permitabsorption of insulin.

y It has onset of action 2-5 hr and duration of 4-12 hr

y It cannot be injected intravenously and intravenously

y It can be mixed with regular insulin.


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LONG ACTING INSULIN

y Mimics the basal insulinsecretion level

y Given once in a day or

twice

Onset ofaction

Peak Duration

1 -2 hr flat 23-24 hr


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INSULIN DETEMIR (LEVEMIR)y It is an acylated

derivative of humaninsulin

y

It binds to albuminthrough fatty acid chainattached to lysine atresidue at B29

y Lower affinity for insulinreceptor necessiates

higher doses.y Given twice daily for

smooth basal insulinlevel


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INSULINE GLARGINE(LANTUS)

y Subsitution of glycine forasparagine at position A21and addition of 2 argininerings at B30.

y Isoelectric pH shifts from5.4 to 6.7 makes it moresoluble at acidic solutionand less soluble at

physiological pH.y Increase in affinity towards

IGF-1 receptor


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Pharmacokinetic propertiesy Absorption and Bioavailability:After subcutaneous

injection of insulin glargine , the insulin serumconcentrations indicated a slower, more prolonged

absorption and a relatively constant concentration/timeprofile over 24 hours with no pronounced peak incomparison to NPH insulin.

y Metabolism: Insulin glargine is partly metabolized at thecarboxyl terminus of the B chain in the subcutaneous

depot to form two active metabolites with in vitro activitysimilar to that of insulin, M1 (21A-Gly-insulin) and M2(21A-Gly-des-30B-Thr-insulin). Unchanged drug and thesedegradation products are also present in the circulation


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Mixed insulin(Humulin70/30)y Humulin 70/30 is a mixture of 70% Human Insulin

Isophane Suspension and 30% Human Insulin Injection(rDNA origin). Itis an intermediate-acting insulin

combined with the more rapid onset of action of Regularhuman insulin. The duration of activity may last up to 24hours following injection.

y As with all insulin preparations, the duration of action of

Humulin 70/30 is dependent on dose, site of injection,blood supply, temperature, and physical activity


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Insulin preparations


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Modes ofAdministrationSubcutaneous administration:

y Insulin is usually taken as subcutaneousinjections by single-use syringes with

needles, an insulin pump, or byrepeated-use insulin pens with needles.y Administration schedules often attempt

to mimic the physiologic secretion ofinsulin by the pancreas. Hence, both along-acting insulin and a short-actinginsulin are typically used

y Standard mode of subcutaneousinjection is by using disposable needlesand syringes.


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Insulin pensy To facilitate multiple sub

cutaneous injections ofinsulin.

y Contain cartridges ofinsulin and replaceableneedles.

y Pen-like device withcartridges holding 150-300

units of insuliny Reusable or Disposabley Dial insulin dosage and

inject (like a syringe)


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INSULIN PUMPSy Insulin pumps are used to create an artificial insulin

secretion subcutaneously that can suppress excessiveblood glucose.

y In general, it continuously delivers a basal rate ofexogenous insulin automatically and also hascapability of manually adding extra insulin to the basalrate for the intensive insulin secretion by a continuoussubcutaneous insulin infusion (CSII) technique.


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Contd..y Most of the insulin pumps

consist of a small processingmodule with a display, adisposable insulin reservoir,

and an insulin syringe, andare powered by batteries.y Advantages :

Better control overbackground or 'basal' insulindosage.

y Limitations: Cost, catheterproblems, and no "closedloop" means of controllinginsulin delivery based oncurrent blood glucose levels.


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Inhaled insuliny FDA has approved an inhaled insulin preparation of

finely powdered form and aerosolized human insulin

y Insulin has been readily absorbed through alveolarwalls but the molecule should be small.

y It has a rapid onset of action and peak action similar to

rapid acting insulins and duration of action similar toregular insulin


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y Exubera , powder form of inhaled insulin wasintroduced in Jan-06 by Pfizer and Nektar therapeutics

y

Bio availablity is only 10% to 40%y It is discontinued due to patients uncompliance.

yAIR insulin system introduced by Eli lilly in a drypowder form was also discontinued due to its high

particle size of 5 to 50m.


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Buccal insulinDrug delivery through the buccal mucosa hasfollowing advantages,

y

Direct contact with mucosay relatively large surface for absorption (100200 cm);

y level of vascularization is very high in some areas;

yweak variations of pH (GI);

y buccal enzymatic activity is mainly intracellular andless developed than in other mucosae.


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Drawbacks

y The buccal mucosa is not an absorptive organ.

y

Sublingual area is thin and nonkeratinized, highlypermeable (high drug input);

y Cheek mucosa is thicker and nonkeratinized, fairlypermeable (low but sustained drug input); and

y In summary, the continuous, but variable, saliva flowand the robust multilayered structure of the oralepithelium constitute an effective barrier topenetration of drugs.


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oral-lyny Generex US-based company develop oral-lyn

y Oral-lyn is a liquid formulation of human regular

insulin with a spray propellant for prandial insulintherapy.

y The formulation results in an aerosol with relativelylarge micelles (85% of that having a mean size >10 m)

and therefore cannot go into the lungs.


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y On administration with Rapid Mist device insulinpasses through superficial layers of mucosa into theblood stream

y Each 28 mlcanister contains 400 U of regular humaninsulin.

y The drug is under clinical trials


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Oral insulinAdvantages:

y Increased patients compliance

y

Direct absorption from the gut.y Transfer of insulin directly to liver

y Control hepatic glucose production to the same extentof natural insulin.

y This more physiological insulin delivery would beassociated with reduced peripheral hyperinsulinemia


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obstacles:y Enzymatic degradation in the gut.

y Insulin has to pass through the high viscous mucouslayer of the gut

Disadvantages:

y 50% of insulin is degraded by liver thus peripheralinsulin concentration is low.


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y Biocon has taken over the oral insulin technologydeveloped by Nobex. IN-105 is a human insulin moleculeconjugated on position B29 with polyethylene glycol via anacyl chain

y IN-105 is declared to have the following characteristics:improved half-life in the digestive tract and improvedabsorption,lower immunogenicity as compared to insulin,

lower mitogenicity as compared to insulin,retains a similar pharmacological activity as insulin, andconserves safety profile and good clearance profile ascompared to insulin. It is under phase III clinical trials


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Adverse reactionsy Hypoglycemia: Most common complication of insulin

therapy. They may result from delay in taking a meal,inadequate carbohydrate intake, unusual physicalexertion or dose of insulin is too large.

y Symptoms are palpitations, sweating, nausea, hunger.

In persons with persistent hypoglycemia

manifestations of insulin excess may develop.Includes confusion, weakness, bizarre behavior, coma.

y Mainfestations of hypoglycemia are relieved by glucoseadministration.


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Contd..y Lipodystrophy: It occurs in the subcutaneous fatty

tissue if injected repeatedly at the same site

y W

eight gainy Immune allergy: immediate type hypersensitivity

results from histamine release from mast cellssensitized by anti-insulin IgE antibodies.

y

Immune insulin resistance: IgG anti-insulin antibodiesneutralizes the action of insulin


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Drug interactionsy Drug increases glucose lowering effects of insulin

pramlintide, ACE inhibitors, disopyramide, fibrates,

fluoxetime, propoxyphene, pentoxyfyline, salicylates,

y Drug decreases glucose lowering effects

corticosteroids, niacin, danazol, diuretics, isoniazid,

phenothiazin, somatropin, thyroid h0rmone, estrogen,protease inhibitors, atypical antipsycotics.


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DIABETES EXPOSUREy Although conventional hypoglycemic therapies prevent

acute metabolic complications in patients with diabetes,they do not restore metabolic homeostasis.

y The result of this imperfect treatment is a novel milieuthat includes various combinations of metabolic,hormonal, and physiologic alterations.

y These include hyperinsulinemia, hyperglycemia,hyperlipidemia, abnormalities in blood f low, and theformation of glycation products all of which constitute

diabetes exposure.y As a consequence of this exposure, diverse functional and

morphologic alterations develop that lead to severecomplications affecting the eyes, kidneys, and heart.


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DIABETIC RETINOPATHYy Structural changes:

thickening of the capillary basement membrane,loss of retinal pericytes,increased vessel permeability

and formation of capillary microaneurysms.These structural changes are accompanied bydecreased retinal blood flow, capillary occlusion,

angiogenesis, hemorrhage, fibrotic tissue formation,and tractional retinal detachment. Some of theseevents, or all of them in combination, can ultimatelyresult in impairment or complete loss of vision


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y Incidence, progression and development ofproliferative diabetic retinopathy is highest in type Idiabetes patients compared to type II diabetes patients

y High glycemic control reduces the onset of disease

y Hypertension, Higher ocular perfusion pressure andmyopia increases the risk of progression


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DIABETIC NEUROPATHYy Diabetic neuropathy is common in diabetic patients,

with a prevalence of more than 50%

y

The pathogenesis is multifactorial and considered tobe both hyperglycemia-induced pathologic changesintrinsic to neurons and ischemia-induced neuronaldamage by decreased neurovascular blood flow .

y Histologically, increases in endothelial cell area andluminar narrowing of capillaries are present in theendoneurium of patients with diabetes.


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DIABETIC NEPHROPATHYy Diabetic nephropathy is characterized by

thickening of the glomerular basement membrane,

increased fractional mesangial volume,y Expansion of the glomerular mesangium, which

occurs at the expense of the glomerular capillarylumen and filtration surface area, correlates mostclosely with the decline in renal function and thedevelopment of proteinuria


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TYPE I DIABETES MELLITES