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Diabetes MellitusDiabetes Mellitus Is a clinical syndrome Is a clinical syndrome

characterized by an elevated of characterized by an elevated of blood glucose due to relative or blood glucose due to relative or absolute deficiency of insulin.absolute deficiency of insulin.

((insulin is produced by insulin is produced by ββ -cells in -cells in the islets of Langerhans).the islets of Langerhans).

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Aetiology and ClassificationAetiology and Classification

1.1. PrimaryPrimary ( the majority) ( the majority)

A.A. IDDMIDDM ( (Insulin dependent Insulin dependent diabetes mellitus), diabetes mellitus), type I, juvenile type I, juvenile onset).onset).

B.B. NIDDMNIDDM( ( non-insulin dependent non-insulin dependent diabetes mellitus) diabetes mellitus) type II, maturity type II, maturity onset).onset).

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2.2. SecondarySecondary due to : due to :

A. Pancreatic diseasesA. Pancreatic diseases

viruses, autoimmune viruses, autoimmune diseases, chemical toxins).diseases, chemical toxins).

B. Insulin antagonistsB. Insulin antagonists

*Growth hormone*Growth hormone *Adrenocortical hormones (*Adrenocortical hormones (increase increase gluconogenesis and decrease gluconogenesis and decrease utilization of glucose by utilization of glucose by peripheral tissues)peripheral tissues), ,

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**AdrenalineAdrenaline ( ( increases increases

glycogenglycogen breakdown and breakdown and

suppresses of insulin suppresses of insulin

secretion)secretion). .

**Thiazides diureticsThiazides diuretics

**ThyroidThyroid *Gestational.*Gestational.

C. Liver cirrhosis and C. Liver cirrhosis and

hepatitishepatitis..

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IDDMIDDM Usually affecting a young age group or Usually affecting a young age group or

at any age.at any age. Characterized by absolute def. of Characterized by absolute def. of

insulin and massive insulin and massive ββ -cell necrosis.-cell necrosis. Associated with viruses, auto-immune Associated with viruses, auto-immune

diseases.diseases. Require exogenous insulin.Require exogenous insulin. May associated with Islet cell May associated with Islet cell

antibodies.antibodies. No genetic predisposition.No genetic predisposition.

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NIDDMNIDDMThe majority of patients.The majority of patients.Genetic factors is strong.Genetic factors is strong.Obesity.Obesity.Age over 40.Age over 40. Inactivity, diet and pregnancy.Inactivity, diet and pregnancy.No autoimmune diseases or No autoimmune diseases or

viruses.viruses.

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Clinically usually milder than Clinically usually milder than IDDM.IDDM.

Some beta Some beta ββ-- cell function, but cell function, but insulin secretion is variable- insulin secretion is variable- normal, high or low.normal, high or low.

Resistance to insulin by target Resistance to insulin by target tissues, decrease in insulin tissues, decrease in insulin receptors, or an abnormal receptors, or an abnormal insulin moleculeinsulin molecule..

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Clinical presentation of DMClinical presentation of DM

1.1. HyperglycemiaHyperglycemia Due to reduced rate of Due to reduced rate of

removal of glucose from the removal of glucose from the blood by periph. Tissues, or blood by periph. Tissues, or an increase rate of release of an increase rate of release of glucose from the liver into glucose from the liver into

circulation.circulation.

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2.2. GlycosuriaGlycosuria When BS more than 180mg/dlWhen BS more than 180mg/dl ( 10 mmol).( 10 mmol).

3.3. Polyuria, Polyuria, polydepsia, polydepsia, polyphagia, thirst polyphagia, thirst and nocturia.and nocturia.

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4.4. Loss of weight and Loss of weight and tiredness, pruritus.tiredness, pruritus.

5.5. Impotence.Impotence.6.6. Kitoacidosis.Kitoacidosis.7.7. Neuropathy, Neuropathy,

nephropathy and nephropathy and retinopathyretinopathy

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DiagnosisDiagnosisGlycosuria.Glycosuria.

Random blood sugar (more Random blood sugar (more than 14 mmol/L, or 250 than 14 mmol/L, or 250 mg/dL).mg/dL).

Glucose tolerance test.Glucose tolerance test.

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TreatmentTreatment1.1.Diet.Diet.

2.2. Diet and oral Diet and oral hypoglycemic agents.hypoglycemic agents.

3.3. Diet and insulinDiet and insulin..

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INSULININSULIN* Is a polypeptide hormone ( * Is a polypeptide hormone ( two two

peptide chain connected by peptide chain connected by disulfide bonds)disulfide bonds)..

* Synthesized as a pro-insulin * Synthesized as a pro-insulin which undergoes proteolytic which undergoes proteolytic cleavage to form insulin and cleavage to form insulin and peptide C (give better index peptide C (give better index of insulin level).of insulin level).

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Secretion is stimulated by high Secretion is stimulated by high glucose level, some amino glucose level, some amino acids and GIT hormones.acids and GIT hormones.

Blood Glucose is taken up by Blood Glucose is taken up by glucose transporter into glucose transporter into ββ -cell -cell of the pancreas, where its of the pancreas, where its phosphorylated by phosphorylated by GLUCOKINASEGLUCOKINASE (glucose sensor).(glucose sensor).

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Glucose products enter the Glucose products enter the mitochondrial respiratory chain mitochondrial respiratory chain and generate and generate ATPATP, which causes a , which causes a block of block of KK channels, leading to channels, leading to influx of influx of CaCa resulting in pulsatile resulting in pulsatile insulin exocytosis ( insulin exocytosis ( sulfonylureas sulfonylureas and meglitinides acts by inhibition and meglitinides acts by inhibition of K channelsof K channels).).

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PHARMACOKINETICSPHARMACOKINETICS* Insulin secreted from * Insulin secreted from ββ -cells enters -cells enters

the portal vein and passes to the liver.the portal vein and passes to the liver.

* 50% of it stay in the liver and the rest * 50% of it stay in the liver and the rest

passes into systemic circulationpasses into systemic circulation

(concentration is 15% of that entering (concentration is 15% of that entering

the liver).the liver).

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* * When insulin is injected the When insulin is injected the

concentration in systemic concentration in systemic circulation and peripheral circulation and peripheral organs is the same.organs is the same.

* It is given by injection, * It is given by injection, digested if swallowed.digested if swallowed.

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* About 10% appears in * About 10% appears in

the urine. the urine.

* Inactivated by the liver * Inactivated by the liver

and kidneys (extensive and kidneys (extensive

first pass metabolism).first pass metabolism).

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* * The half-life is 5 min.The half-life is 5 min.

* It is available in needles * It is available in needles and syringes, insulin and syringes, insulin pens, external infusions pens, external infusions and implantable pumpsand implantable pumps..

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ACTIONS OF INSULINACTIONS OF INSULIN

1.1. Reduction of blood Reduction of blood glucose level by:glucose level by:

A. Stimulations of glucose A. Stimulations of glucose uptake by peripheral uptake by peripheral tissues( which convert it tissues( which convert it into glycogen and fat).into glycogen and fat).

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B. Stimulation of glycogen B. Stimulation of glycogen synthesis.synthesis.

C. Reduction of hepatic output of C. Reduction of hepatic output of glucose [ diminished glucose [ diminished

breakdown of glycogen, and breakdown of glycogen, and diminished gluconeogenesis diminished gluconeogenesis (glucose from proteins)].(glucose from proteins)].

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2- Fat: Inhibits the breakdown 2- Fat: Inhibits the breakdown of fat (lipolysis).of fat (lipolysis).

3- Enhances protein 3- Enhances protein synthesis.synthesis.

4- Enhances K+ entry into 4- Enhances K+ entry into cells.cells.

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5- Enhances amino acids entry 5- Enhances amino acids entry

across cell membrane.across cell membrane.

6- It stimulate appetite (if falls 6- It stimulate appetite (if falls

below normal level).below normal level).

7- Causes osmotic diuresis if 7- Causes osmotic diuresis if

glucose level above renal glucose level above renal

threshold.threshold.

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SOURCES OF INSULINSOURCES OF INSULIN

1- Animal: beef or pork1- Animal: beef or pork..

2-2- HumanHuman:: Less immunogenic than animal Less immunogenic than animal

insulins.insulins.

* Absorbed more rapidly if given S/C.* Absorbed more rapidly if given S/C.

* Requirement is less than animal * Requirement is less than animal ones.ones.

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* * Produced by recombinant DNA Produced by recombinant DNA technology using special technology using special strain of E.COLI or yeast.strain of E.COLI or yeast.

Modification of amino acids Modification of amino acids sequence of human insulin sequence of human insulin produced insulins with different produced insulins with different pharmacokinetic property.pharmacokinetic property.

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ADMINISTRATIONADMINISTRATION** Is not given orally (polypeptide is Is not given orally (polypeptide is degraded in the GIT).degraded in the GIT).

• Is given subcutaneously. Is given subcutaneously.

• In acute emergency its given IV.In acute emergency its given IV.

** Given by continuous subcutaneous Given by continuous subcutaneous Infusion to reduce multiple injections.Infusion to reduce multiple injections.

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Aerosol preparations inhaled and Aerosol preparations inhaled and absorbed through the lungs.absorbed through the lungs.

• Oral spray that is absorbed by Oral spray that is absorbed by buccal mucosa.buccal mucosa.

• OrallyOrally

Inactivated by INSULINASE Inactivated by INSULINASE enzyme, that is found in the liver enzyme, that is found in the liver and kidney.and kidney.

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INSULIN PREPARATIONSINSULIN PREPARATIONS

* They differ in their onset and duration * They differ in their onset and duration of action, which is due to the size and of action, which is due to the size and composition of insulin crystals and the composition of insulin crystals and the

amino acid sequence of the polypeptide amino acid sequence of the polypeptide ( the less soluble the longer duration).( the less soluble the longer duration).

* Dose, site of injection, blood supply, * Dose, site of injection, blood supply, temperature, and physical activity can temperature, and physical activity can alter the duration of action.alter the duration of action.

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PREPARATIONSPREPARATIONS1- Rapid-onset and 1- Rapid-onset and

ultrashort insulins.ultrashort insulins.

A.A. Regular insulin Regular insulin (soluble, crystalline (soluble, crystalline zinc insulin).zinc insulin).

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The only preparation which can The only preparation which can be be given IV in emergencygiven IV in emergency. . Usually it is given S/C. Usually it is given S/C. Clear Clear solution.solution.

Effect start in 15 min, peak 50-Effect start in 15 min, peak 50-120 min and last for 5-7 hours.120 min and last for 5-7 hours.

It is safe to be given It is safe to be given in pregnancy.in pregnancy.

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B. LISPRO,ASPART,B. LISPRO,ASPART, GLULISINE insulins.GLULISINE insulins.

Ultrashort preparations ( rapid Ultrashort preparations ( rapid onset and short duration).onset and short duration).

LISPRO insulin is rapidly LISPRO insulin is rapidly absorbed than regular insulin absorbed than regular insulin after S/C administration.after S/C administration.

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Peak action in 30-90 min.Peak action in 30-90 min.

Given 15 min before meal .Given 15 min before meal .

Can be given IV (insulin Can be given IV (insulin pump).pump).

ASPART and GLULISINE ASPART and GLULISINE insulins are similar to lispro.insulins are similar to lispro.

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2.2. Intermediate-actingIntermediate-acting

A.A. Lente insulinLente insulin Slow onset of action with Slow onset of action with

longer duration than longer duration than

Soluble insulin.Soluble insulin.

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B. Isophane insulinB. Isophane insulin

(12h) NPH insulin (12h) NPH insulin

suspension (neutral suspension (neutral

protamine hagedorn).protamine hagedorn). **Suspension of crystalline Suspension of crystalline

zinc insulin combined with zinc insulin combined with protamine.protamine.

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3.3. Long acting insulinsLong acting insulins

A.A. Ultralente insulin. Insulin Ultralente insulin. Insulin

zinc suspension.zinc suspension.

B. Insulin glargineB. Insulin glargine..

It is slow in action than NPH and It is slow in action than NPH and has prolonged hypoglycemic has prolonged hypoglycemic effect.effect.

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ADVERSE EFFECTS TO ADVERSE EFFECTS TO INSULININSULIN

1.1. HypoglycemiaHypoglycemia The most common, could be due to delay The most common, could be due to delay

food intake, large doses of insulin and food intake, large doses of insulin and physical exertion.physical exertion.

Confusion, coma, sweating, Confusion, coma, sweating, tachycardia, palpitation, tachycardia, palpitation, tremor, nausea and hungertremor, nausea and hunger..

Give glucose orally or IV, glucagons Give glucose orally or IV, glucagons IM,SC,IV.IM,SC,IV.

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2.2. LipodystrophyLipodystrophy at the at the injection sites( rare with human injection sites( rare with human insulin).insulin).

3.3.Allergic reactionsAllergic reactions may may occur to any insulin including occur to any insulin including human (commonly due to zinc human (commonly due to zinc content).content).

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Insulin resistance and Insulin resistance and hormones that increase hormones that increase

blood glucoseblood glucose..

Due to decline in number Due to decline in number and affinity of receptors and affinity of receptors (required more than 200 (required more than 200 unit/day).unit/day).

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1.Glucagon1.Glucagon Polypeptide secreted from Polypeptide secreted from αα--

islet cells of the pancreas, islet cells of the pancreas, released in response to released in response to hypoglycemia, releases liver hypoglycemia, releases liver glycogen as glucose.glycogen as glucose.

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2. Adrenaline2. Adrenaline Raises blood sugar Raises blood sugar

by mobilizing liver by mobilizing liver

and muscle and muscle

glycogen.glycogen.

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3. Adrenal steroids3. Adrenal steroids

Antagonize the action of Antagonize the action of insulin, increases insulin, increases gluconeogenesis and reduce gluconeogenesis and reduce glucose uptake and glucose uptake and utilization by the tissues.utilization by the tissues.

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4. Oral contraceptives. 4. Oral contraceptives.

Impair carbohydrate Impair carbohydrate

tolerance.tolerance.5. Growth hormone 5. Growth hormone

antagonizes the effects of antagonizes the effects of

insulininsulin

6. Thyroid hormones.6. Thyroid hormones. Increases Increases

the requirement for insulin.the requirement for insulin.

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ORAL ORAL HYPOGLYCEMIC HYPOGLYCEMIC

AGENTSAGENTS

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ORAL HYPOGLYCEMIC ORAL HYPOGLYCEMIC AGENTSAGENTS

They have a place in 20-30% of They have a place in 20-30% of the patients.the patients.

* Their action is dependent on the * Their action is dependent on the presence of insulin- presence of insulin- sulphanylureassulphanylureas (at least 30% of (at least 30% of normal normal ββ- cell function is present).- cell function is present).

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1.1. SULPHANYLUREASSULPHANYLUREAS

Mode of actionMode of actionA. A. Stimulation of Insulin Stimulation of Insulin

release from the pancreasrelease from the pancreas by blocking the ATP- sensitive by blocking the ATP- sensitive K+ channels resulting in K+ channels resulting in depolarization and Ca+ influx.depolarization and Ca+ influx.

They do not increase insulin They do not increase insulin formation.formation.

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B.B. Increasing the binding of Increasing the binding of insulin to target tissues and insulin to target tissues and receptors and increasing the receptors and increasing the receptor number.receptor number.

C. Decreasing hepatic glucose C. Decreasing hepatic glucose output and increase glucose output and increase glucose uptake by the muscles.uptake by the muscles.

D.D. Reduction in serum glucagon Reduction in serum glucagon level.level.

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PreparationsPreparations

1.1. TolbutamideTolbutamide*Shortest duration of action*Shortest duration of action

*Half-life 8 h (6-12)*Half-life 8 h (6-12)

*Rapidly metabolized by oxidation *Rapidly metabolized by oxidation

in the liver.in the liver.

*Can be given in renal failure.*Can be given in renal failure.

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Causes:Causes: Hypoglycemia, GIT upset, rashes, Hypoglycemia, GIT upset, rashes,

alcohol intolerance, blood alcohol intolerance, blood disorders( rare)disorders( rare)

ContraindicatedContraindicated in pregnancy in pregnancy (should be treated with insulin).(should be treated with insulin).

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2.2. ChloropropamideChloropropamideHas long duration of action-36h. Has long duration of action-36h. with many adverse reactions, its with many adverse reactions, its use is declining.use is declining.

3.3. Glibenclamide Glibenclamide (daonil) (daonil)

(t1/2 10h(t1/2 10h))

5050

Second generationSecond generation

Commonly used in clinicalCommonly used in clinical practice.practice.

4. Glyburide (18h)4. Glyburide (18h)5.5. Glipizide (20h)Glipizide (20h)6.6. GlimperideGlimperide

They should not be used in liver They should not be used in liver and renal failureand renal failure

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2. THE BIGUANIDES2. THE BIGUANIDES Mechanism of action:Mechanism of action:

1.1. Slowing glucose absorption Slowing glucose absorption from GIT.from GIT.

2.2. Stimulation of glycolysis in Stimulation of glycolysis in periph. tissues. (stimulate periph. tissues. (stimulate glucose uptake by the glucose uptake by the

muscles)muscles)..

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3. Reduced hepatic 3. Reduced hepatic gluconeogenesis. (reduce gluconeogenesis. (reduce glucose release from the glucose release from the

liver).liver). 4. Reduced plasma glucagon 4. Reduced plasma glucagon level.level.5.5. Increase insulin binding to Increase insulin binding to

insulin receptors.insulin receptors.

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6.6. Inhibits LDL and Inhibits LDL and cholesterol with rise in cholesterol with rise in

HDL.HDL.

7.7. Rarely can cause Rarely can cause hypoglycemia.hypoglycemia.8. Proven to decrease CV 8. Proven to decrease CV

mortality.mortality.

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MetforminMetforminWell absorbed orallyWell absorbed orallyNot metabolized Not metabolized Excreted by the kidneysExcreted by the kidneysT1/2 2 hoursT1/2 2 hoursContraindicatedContraindicated in: renal in: renal

and liver failure , pregnancy, and liver failure , pregnancy,

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severe infections, cardio-severe infections, cardio-respiratory failure and alcohol respiratory failure and alcohol abuse. abuse.

Adverse effectsAdverse effects

1. GIT upset.1. GIT upset.

2. Interfere with vit B12 2. Interfere with vit B12

absorptionabsorption

3. Rarely lactic acidosis.3. Rarely lactic acidosis.

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C - α glucosidase inhibitorC - α glucosidase inhibitor

ACARBOSEACARBOSE, , MIGLITOLMIGLITOL

Delays the digestion of Delays the digestion of carbohydrates ,so carbohydrates ,so reduces carbohydrate reduces carbohydrate absorption in the absorption in the intestine.intestine.

5757

They reversibly inhibiting They reversibly inhibiting membrane bound membrane bound αα -glucosidase in the -glucosidase in the intestinal brush borders intestinal brush borders (enzyme responsible for (enzyme responsible for hydrolysis of hydrolysis of oligosaccharides to oligosaccharides to glucoseglucose).).

5858

They do not increase insulin They do not increase insulin release nor action on the target release nor action on the target tissues.tissues.Does not cause hypoglycemiaDoes not cause hypoglycemiaAcarbose is Poorly absorbed Acarbose is Poorly absorbed

and metabolized by intestinal and metabolized by intestinal bacteria.bacteria.

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MiglitolMiglitol is well is well absorbed, excreted absorbed, excreted unchanged in the urine. unchanged in the urine.

They can cause flatulence, They can cause flatulence, diarrhea and abdominal diarrhea and abdominal cramping. cramping.

Can be used with other Can be used with other drugsdrugs..

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D- D- Thiazolidinediones Thiazolidinediones or glitazonesor glitazonesPioglitazone Pioglitazone RosiglitazoneRosiglitazone

They reduce tissue resistance to They reduce tissue resistance to insulin.insulin.

Used in combination with metformin Used in combination with metformin or sulphanylureas.or sulphanylureas.

Onset of action is slow.Onset of action is slow.

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Both drugs are absorbed Both drugs are absorbed wellwell

Extensively bound to Extensively bound to albumin.albumin.

Metabolized by CYP450.Metabolized by CYP450.Excretion by the urine Excretion by the urine

(unchanged drug by bile).(unchanged drug by bile).Can be given in renal failureCan be given in renal failure

6262

*Not recommended in pregnancy*Not recommended in pregnancy..

*Pioglitazone can be used with *Pioglitazone can be used with insulin.insulin.

*Rosiglutazone is not used with *Rosiglutazone is not used with insulin( causing edema).insulin( causing edema).

It can be used with metformin It can be used with metformin and glyburide to improve sugar and glyburide to improve sugar control.control.

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CausesCauses::

Liver toxicityLiver toxicityWeight gainWeight gainRaises LDL level Raises LDL level (rosiglitazone).(rosiglitazone).

LDL is not affected with the use LDL is not affected with the use of pioglutazone.of pioglutazone.

Both may raise HDL.Both may raise HDL.Headache, anemia.Headache, anemia.