Block5.Lecture1(Insulin)

8/13/2019 Block5.Lecture1(Insulin)

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Diabetes Mellitus DM is a heterogeneous group of

disorders characterized by elevated

blood sugar levels caused by absolute orrelative lack of Insulin

One of the leading cause of deaths in

the US

75% of those afflicted with diabetes die

from heart disease


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Diabetes mellitus Type 1 diabetes- -cell failure at outset

Insulin dependent

Type 2 diabetes- Gradual -celldeterioration

Diet, exerciseand oral hypoglycemicagents for early stages of disease

Late-stage disease, insulin therapynecessary


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TypeI Diabetes (IDDM)

IDDM results from absolute lack of insulincaused by loss of cells

destruction of islet cells is related toautoimmunity and environmental factors

environmental factors include certaindrugs/chemicals, and viruses

common in


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Type - II Diabetes (NIDDM)

more common (~ 90%) and stronggenetic predisposition

may have adequate insulin but unable tobe taken up by cells or have inadequatelevels

affects people primarily after age 40,most of them are obese.

Insulin resistanceis an important factor


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Pancreatic hormonesIslets of Langerhans of pancreas A (alpha) cells produce Glucagon

B (, Beta) cells produce Insulin

D (Delta) cells Somatostatin

F (PP) cellsPancreatic polypeptide


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INSULIN


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Insulin: History Frederick Banting(a young Canadian

surgeon)

JJR Macleod(Professor of Physiolology) Charles Best( a 4th- year Medical

student)

JB Collip(a chemist)

Nobel Prize in Medicine and Physiologywas awarded to Banting and Macleod in1923


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Insulin

Synthesis of Insulin : Synthesized in -cells of pancreatic islets

as a single chain peptidepreproinsulin(110 AA)from which 24 AAsare firstremoved to produceproinsulin

Proinsulinis converted to insulin (35 AA

removed in Golgi apparatus by proteolysis)and C peptide.


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Insulin synthesis and release

-cells

Preproinsulin

Proinsulin

insulin and C peptide.


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Insulin

Mechanism of action : Insulin binds to Insulin receptors on the

plasma membrane and activates tyrosinekinase(phosphorylation)primarily inliver, adipose tissue and skeletal muscle

Insulin promotes uptake of glucoseby the

skeletal muscle and adipose tissue by therecruitment of GLUT-1 and GLUT-4molecules into the plasma membrane


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Insulin

Mechanism of action : Insulin alters the phosphorylation state

of key metabolic enzymes, leading toenzymatic activation or inactivation

Insulin induces the transcription ofseveral genesinvolved in glucose

catabolism and specifically inhibitstranscription of other genes involved ingluconeogenesis


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Insulin: Mechanism of action

Insulin binds to Alpha subunit

Phosphrylation of tyrosine in beta sub unit - TyrosineKinase activation

Activate Insulin receptor substrate (IRS)

Translocation of glucose transportersto cell membrane increase Glucose uptake in to the cells,

Increase glycogen synthesis,

Alter protein and fat metabolism


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Insulin release

from cells is regulated by chemical,

hormonaland neuronalmechanisms

Chemical Most important stimulus:glucose

Glucose induces a brief pulse of insulin

output within 2 min (first phase)followedby a delayed but more sustained secondphaseof insulin release


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Insulin release

Chemical

Glucose entry into the cells indirectlyinhibits the ATP sensitive K+channelresulting in depolarization of the

membrane triggering Ca2+

mediatedexocytosis of insulin storing granules

Glucose and other nutrients are moreeffective in invoking insulin releasewhen given orally than IV


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Insulin Release


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Insulin release

Hormonal GH, Corticosteroids, thyroxine modify

insulin release in response to glucose

PGE inhibits insulin release

Somatostatin inhibits release of bothinsulin and glucagon

Glucagon increases release of insulin aswell as somatostatin

Insulin inhibits glucagon release


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Insulin release

Neural Adrenergic

2receptor activation decreases

insulin release (predominant)by inhibiting

cell adenylyl cyclase**

Adrenergic 2

stimulation increases insulinrelease (less dominant)by stimulating cell

adenylyl cyclase Vagal stimulation causes insulin secretion

through IP3/DAG- increased intracellularCa2+in the cells


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Insulin release

Neural

The primary central site of regulation ofinsulin secretion is in the hypothalamus

- stimulation of ventrolateral nuclei

evokes insulin release

- stimulation of ventromedial nucleidecreases insulin release


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Actions of Insulin

Overall effects of insulin:to favor storageof fuel

Insulin promotes systemic cellular K+

uptakeLiver

Inhibits gluconeogenesis(glucoseproduction from protein, pyruvate, FFA

and glycerol) and increases glycolysis

Inhibits glycogenolysisand stimulatesglycogen synthesis(glycogenesis)


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Actions of InsulinLiver (contd)

Increases the synthesis of triglycerides

Increases protein synthesis

Muscle

Increases glucose transport and glycolysis

Increases glycogen deposition

Increases protein synthesis


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Actions of Insulin

Adipose tissue Increases glucose transport

Increases triglyceride synthesis(lipogenesis)

Decreases intracellular lipolysis


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Insulin

Overall effect of Insulin :

Synthesis of proteins and fats

(anabolic)

In the absence of insulin, most

body cells cannot take up glucose. Fats and proteins are broken down to

provide energy


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Actions of Insulin

Most of the metabolic actions of insulinexerted within seconds or minutes(rapidactions)

Others involving DNA mediated synthesis ofglucose transporter and some enzymes ofamino acid metabolism have a latency offew hours (intermediate actions)

In addition insulin exerts major long termeffectson multiplication and differentiationof cells


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Insulin is orally not activeas degraded inthe GIT

Insulin is inactivated by insulinase found

mainly in kidneySources of Insulin :

Beef pancreas (bovine insulin) / Pork

pancreas (porcine insulin)

Human insulin:recombinant DNAtechnology, exactly 51 AA, bacteria

Insulin preparations


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Human insulinis prepared by recombinantDNA techniquesto produce the humanpeptide in bacteria (E coli) and in yeast, orby enzymatic modification of porcine

insulin.



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Advantages of Human Insulin : Diminished antibody (less chance of

insulin resistance)

Less allergic reactions Less lipodystrophy (insulin is lipogenic

could get swelling of subcutaneous fat atsite of injection)

preferred in gestational diabetes

In surgery or infection

no

irst



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Rapidacting: Insulin Lispro, Insulin

Aspart and Insulin Glulisineonset within 15 minutes and duration is < 5

hrs); only given SC

Short acting;:Regular insulin(CrystallineZinc Insulin/Soluble Insulin), Semilenteinsulin

Duration of effect 5-15 hrs; onset is 30mins

Regular insulin can be given SC, IV or

IM


Kn

kebQ


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Therapeutic uses of Insulin

Diabetes mellitus (Type I - and sometimesType II, if not well-controlled, if othermeasures , ie exercsie, diet drug all FAIL)

If in surgery

Diabetic Ketoacidosis (Diabetic coma)

Hyperosmolar (nonketotic buthyperglycemic) coma


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Diabetes mellitus- Effective in all forms of DM (both type I and

type II)- Must for type I

- Most type II diabetics are treated withdietary changes, reduction in body weight,appropriate exercises and oralhypoglycemic agents

However, in many type II diabetesinwhich these treatments are inadequate tocontrol blood glucose levels, insulin maybe required

The ape tic ses of Ins lin


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Therapeutic uses of Insulin Diabetic Ketoacidosis (Diabetic coma)

- Generally seen in IDDM(type I )- Most common cause is infection; others are

trauma, stroke, pancreatitis, stressfulconditions and inadequate doses of insulin

Cardinal features:- Nausea and vomiting,

- Abdominal pain

- Dehydration

- Tachycardia

- Hyperventilationfrom acidosis

- Hypotension


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Th ti f I li


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Management:

1. Insulin:Regular insulin IV(bolus +infusion)

After patient becomes fully conscious,maintenance with SC inj

2. IV fluids: to correct dehydration

Normal saline (0.9 NaCl)

Th ti f I li


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Management (contd):

After blood sugar has reached 300mg/dl,5% glucose in N saline is the most

appropriate solution

because blood glucose falls beforeketones are fully cleared from the

circulation; also glucose is needed torestore the depleted hepatic glycogen


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Diabetic Ketoacidosis (Diabetic coma)Management (contd):

3. KCl

Acidosis causes loss of K+ in urine

Additionally, when insulin therapy isinstituted, ketosis subsides and K+ isdriven intracellularly-leading to severe

hypokalemia>>>cardiac arrhytimas.4. NaHCO3 Not routinely needed, because acidosis

subsides as ketosis is controlled


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Management (contd):

If arterial blood pH is


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Hyperosmolar (nonketotic hyperglycemic)

coma:- usually occurs in elderly type II diabetes

- General principle of treatment are same asfor ketoacidosis coma, except that fasterfluid replacement is to be instituted andNaHCO3is usually not required.

- Patients are prone to thrombosis (due tohyperviscosity and sluggish circulation),prophylactic heparin therapy isrecommended (along with insulin to reducehyperglycemia)


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Split-mixed regimen

- Calculated daily dose of insulin is split in 2or 3 doses; and insulin preparations usedare of mixed types (rapid-acting+intermediate acting (30:70, 50:50 etc) or

rapid-acting+longer-acting, etc)

- Frequently used


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Ad e se effects of Ins lin


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Adverse effects of Insulin

Hypoglycemia (most important!)- most frequent and potentially the mostserious reaction

- can occur in any diabetic followinginadvertent large doses of insulin injection,by missing a meal or by performing avigorous exercise

Ad ff t f I li


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Adverse effects of Insulin

Hypoglycemia-symptoms can be related to1. Peripheral symptoms: counter regulatorysympathetic stimulation-sweating, anxiety,

palpitation, tremor (WARNING SIGNAL!)>>get sugar!

2. Then, Neuroglucopenic symptoms(due to

deprivation of brain of its essential nutrient-glucose)-dizziness, headache, behavioralchanges, visual disturbances, fatigue,weakness, muscular incoordination, etc ->ultimatel coma

Adverse effects of Insulin :


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Hypoglycemia- generally, the reflex sympathetic

symptoms occur before the

neuroglucopenic

- diabetic neuropathy can abolish theautonomic symptoms***

- when blood glucose falls further (< 40mg/dl) >>>mental confusion, seizuresand coma occur

Treatment:Glucose (candy, syrup etc) mustbe given orally or IV (10% dextrose forsevere cases); reverse the symptomsrapidly

Somogyi phenomenon***



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Local reactions at site:Swelling, erythema andstinging sensation: Lipodystrophy(lipoatrophy orlipohypertrophy) of subcutaneous fat at theinjection site (not seen with new preparations)>>make sure u change

positions!

Allergic reactions(Anaphylactoid reactions):

due to contaminating proteins added to insulin inits formulation (protamine, zinc, etc)or because ofthe sensitivity of one of the components (very rare

with human/highly purified insulins)

Weight gain(insulin is anabolic),

edema(Na and water retention)

hypokalemia(uptake of K+ into cells)

D i i


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Drug interactions :

- -blockers prolong hypoglycemiaby

inhibiting compensatory mechanismsoperating through 2receptors (1selective are less liable).Additionally,warning signs of hypoglycemia like

palpitation, sweating, tremor and anxietyare masked.Rise in BP can occur due tounopposed action of releasedEpinephrine

- Thiazides, Furosemide, Corticosteroids,OCPs, Albuterol, Nifedipine tend to raiseblood sugar and reduce effectiveness ofinsulin

Drug interactions :


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Drug interactions :- Acute ingestion of alcohol can precipitate

hypoglycemia by depleting hepatic

glycogen

- Salicylates, lithium and theophylline mayalso accentuate hypoglycemia by

enhancing insulin secretion and peripheralglucose utilization


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Insulin resistance

- When insulin requirement is increased(> 200 IU/dayfor therapeutic purpose),insulin resistance is said to have developed

- 2 types:

1. Acute:develops rapidly and is usually ashort term problem.

Causes:

- infection, trauma, surgery, emotional

stress; corticosteroids and otherhyperglycemic hormones (e.g. Epi) may beproduced in excess as a reaction to thestress-----oppose insulin action


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Insulin resistance

1. Acute:Causes:

- Ketoacidosis

2. Chronic:

- Generally seen in patients treated for yearswith conventional preparations of bovine

or porcine insulins- Antibodies are formed against insulins

- Treatment is to switch over to humaninsulin , less seen in dna tech


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Insulin resistance

- Pregnancy, Metabolic syndrome,Acromegaly, Cushings syndrome,Pheocromocytoma, Hypertension, Use oforal contraceptives, Corticosteroids are

associated with insulin resistance


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Delivery of insulin

Disposable Syringe (subcutaneousadministration)

Portable pen device Insulin pump/ Continuous

subcutaneous insulin infusion devices(CSII)

Inhalation Exubera approved byFDAhas led to nasal polyps, concernfor lung cancers

>>>withdrawn from the market


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Insulin injections


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Insulin pumps

Made up of a pump reservoir (like a regular syringe)filled with insulin, a small battery operated pumpand a computer chip that allows the user to control

exactly how much insulin the pump delivers


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New forms of Insulin Therapy

New routes of delivery:Implantable pellets- to release insulin over

days or weeks

Intraperitoneal, Oral (by encapsulatinginsulin into liposomes) and rectal routesare being tried

Transplantation and gene therapy- underinvestigation

Documents

Block5.Lecture1(Insulin)