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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.
Insulin preparations
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Insulin preparations
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
Insulin preparations
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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
Insulin preparations
Kn
kebQ
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Insulin preparations
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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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Therapeutic uses of Insulin
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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Therapeutic uses of Insulin
Diabetic Ketoacidosis (Diabetic coma)
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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Therapeutic uses of Insulin
Diabetic Ketoacidosis (Diabetic coma)
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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Therapeutic uses of Insulin
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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Therapeutic uses of Insulin
Diabetic Ketoacidosis (Diabetic coma)
Management (contd):
If arterial blood pH is
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Therapeutic uses of Insulin
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***
Adverse effects of Insulin :
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Adverse effects of Insulin :
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
Recommended