INSULIN -It is a peptide hormone consisting of 51 amino acids. -It is secreted by (β-cells of...

INSULIN

-It is a peptide hormone consisting of 51 amino acids.

-It is secreted by (β-cells of islets of Langerhans.

-It is secreted in the form of proinsulin which splits into insulin & C-peptide.

Actions:

- Carbohydrate metabolism; Hypoglycaemic effect"- Increases uptake & utilization of glucose by tissues.- Stimulates glycogenesis (in liver & muscles).- Stimulates lipogenesis (in liver & adipose tissue).- Inhibits gluconeogenesis & glycogenolysis.

- Fat metabolism;- Stimulates lipogenesis.- Inhibits lipolysis.-Inhibits ketogenesis.

-Protein metabolism: Anabolic effect.

- Electrolytes:- K: Intracellular shift.- Na: Aldosterone-like action (salt and water retention)

Regulation of secretion;- Stimulation: e.g. glucose, amino acids, sulphonylureas.- Inhibition: e.g. hypoglycaemia, hypokalaemia, somatostatin.Insulin deficiency or resistance: Results in disturbance of- Carbohydrate metabolism: "Hyperglycaemia"- Decreased uptake & utilization of glucose.- Decreased glycogenesis & lipogenesis.- Increased glycogenolysis & gluconeogenesis.

- Fat metabolism: "Hyperlipidaemia & Ketosis"- Decreased lipogenesis.- Increased lipolysis.- Increased ketogenesis.- Protein metabolism; "Catabolism"- Water & Electrolytes;- Osmotic diuresis due to gylcosuria.- Loss of K.

DIABETES MELLITUS

Definition:

A clinical syndrome characterized by disturbance of carbohydrate metabolism resulting from insulin deficiency or resistance or both & is characterized by "Hyperglycaemia".

Diabetes mellitus is the most common endocrine disease & its frequency is about 1-2% in most populations.

DIABETES MELLITUSAetiology;

I- Primary diabetes: ( > 95 % ) - Type I: Insulin-dependent diabetes mellitus (IDDM )- Previously termed juvenile-onset diabetes.- There is insulin deficiency due to damage of (β-cells).

- Factors that may play a role in the pathogenesis include:1- Genetic predisposition:- There is association with certain HLA types e.g. HLA-

DR3, DR4, B8, B15.- Incidence in identical twins is 50%.

DIABETES MELLITUS

2- Infectious agents: Viruses e.g. coxsackie B, rubella, mumps.

3- Immunological mechanisms;- Presence of pancreatic islet cell antibody

( PICA ).- May be associated with autoimmune

diseases.

DIABETES MELLITUS Primary diabetes - Type II: Non-insulin-

dependent diabetes mellitus (NIDDM).- Previously termed maturity-onset diabetes.- Insulin level is variable, usually increased in early

stages & decreased in late stages.- It results most probably from insulin resistance

which may be due to:• Insulin resistance at the receptor level.• Insulin resistance at the post-receptor level.• Increased anti-insulin hormones especially

glucagon.• Abnormal structure of insulin ( dysinsulinogenesis ).

DIABETES MELLITUS

• - Factors that may play a role in pathogenesis include:

1- Genetic predisposition:• No association with certain HLA types.• Incidence in identical twins is near 100%.• Maturity-onset diabetes of the young ( MODY )

is inherited as an autosomal dominant disorder.

DIABETES MELLITUS

2- Obesity; 80% of patients are obese.

DIABETES MELLITUS

• II- Secondary diabetes: ( < 5% )• 1- Pancreatic diseases;• Chronic pancreatitis, cystic fibrosis, cancer

pancreas, pancreatectomy, haemochromatosis.• 2- Endocrinal diseases:• - Cushing's syndrome, thyrotoxicosis.• - Pregnancy ( Gestational diabetes ).

DIABETES MELLITUS

• 3- Chronic liver failure.• 4- Drugs:• Corticosteroids, contraceptive pills,

thiazides, frusemide, diazoxide.• 5- Insulin receptor abnormalities.• 6- Genetic diseases: e.g.• Down's syndrome• 7- Malnutrition-related diabetes.

DIABETES MELLITUS

Type I diabetes

Type II diabetes

1- Incidence

< 1 0 %

> 90%

2- Age of onset

<30yr Usually 12-14

>40yr

3- Body weight

Usually underweight

Usually overweight

4- Severity

Severe

Mild or moderate

5- Stability

Unstable

Stable

6- Ketosis

Common

Very rare

7- Complications

More common

Less common

8- Insulin

Essential for therapy

Usually not required

9 - O ra l a n tid ia b e tic s

Of no effect

Effective

74

Comparison between type I & type II primary diabetes

Presentations of Diabetes

1 - Asymptomatic & accidentally discovered.

2- Classic symptoms:- Polyuria, polydipsia, polyphagia, pruritus

and parasthesias.- Loss of weight especially in IDDM.3- Diabetic complications.4- Diabetic coma.

COMPLICATIONS OF DIABETESI- Cardiovascular complications:1- Microangiopathy; ( Small vessel disease )- Affecting small blood vessels especially:• Vasa nervosa leading to neuropathy.• Glomeruli leading to nephropathy.• Retinal vessels leading to retinopathy.- There is thickening of basement membrane &

deposition of glycated proteins & lipids leading to:

• Increased vascular permeability.• Narrowing & occlusion of lumen with

neovascularization.

COMPLICATIONS OF DIABETES• 2- Atherosclerosis: ( Large vessel disease )

e.g. - Coronary heart disease:• Angina, infarction ( may be painless ), heart

failure, arrhythmias, sudden death.• - Cerebrovascular disease:.• - Peripheral vascular disease:• May cause manifestations of ischaemia e.g.

intermittent claudications & gangrene.• - Renovascular hypertension.• 3- Cardiomyopathy: May be due to small

vessel affection.• 4- Increased incidence of hypertension.

COMPLICATIONS OF DIABETES• II- Cutaneous complications:• 1- Pruritus:• Especially pruritus vulvae which may be

due to monilial infection, glycosuria, parasthesia or allergy to antidiabetic drugs.

• 2- Infections:• Multiple furuncles, carbuncles,

abscesses, cellulitis & fungal infections especially in anogenital & interdigital regions.

COMPLICATIONS OF DIABETES• 3- Necrobiosis lipoidica diabeticorum; • • Painless papules formed of central

yellowish area surrounded by brownish border.

• • Usually occur over the anterior surfaces of the legs.

• • Ulceration may occur.• 4- Diabetic dermopathy:• • Painless reddish papules.• • Usually occur over the shins ( shin spots ).• • May heal leaving a scar.

COMPLICATIONS OF DIABETES5- Xanthomata: due to hyperlipidaemia.

6- Skin abnormalities of diabetic foot:7- Delayed healing of wounds.8- In IDDM: tight waxy skin over the dorsum of fingers & hands.9- Complications of treatment: e.g.• Insulin lipodystrophy or insulin hypertrophy.• Skin rash with sulphonylureas.10-Interdiqital Fungal Infection

COMPLICATIONS OF DIABETES

COMPLICATIONS OF DIABETES• III- Neurological Complications: • A- Cerebral:• 1- Coma of different types:• 2- Cerebral atherosclerosis & thrombosis• 3- Fungal infections• B- Spinal cord: ( rare )

COMPLICATIONS OF DIABETESC- Radiculopathy:• Presenting with pain, parasthesias, sensory

loss, weakness & wasting.• Roots of sciatic nerve are especially affected. D- Neuropathy; peripheral , autonomic. E- Diabetic amyotrophy• There are weakness & wasting of proximal

muscles of pelvis & front of the thigh ( quadriceps ).

• May be associated with pain & sensory loss.

COMPLICATIONS OF DIABETES• IV- Ocular Complications:• 1- Diabetic retinopathy:• • Proliferative retinopathy, which may lead to

retinal detachment & vitreous haemorrhage.


• 2- Diabetic cataract.• 3- glaucoma.• 4- Errors of refraction.• 5- Ocular infections e.g. blepharitis & panophthalmitis.• 6- Neurological complications of the eye: e.g.• - Paralysis of ocular nerves especially oculomotor nerve.• - Rarely Argyl-Robertson pupil. bilateral small pupils that

constrict when the patient focuses on a near object (they “accommodate”), but do not constrict when exposed to bright light (they do not “react” to light).


• V- Urinary Complications:• 1- Urinary tract infections:• - Pyelonephritis• - Cystitis, urethritis & pyelitis.• 2- Diabetic Nephropathy:

COMPLICATIONS OF DIABETES• - Clinical Picture:• 1 - Long-standing diabetes.• 2- Proteinuria:• - Microalbuminuria followed by• - Macroproteinuria followed by• - Heavy proteinuria & nephrotic syndrome.• 3- Hypertension.• 4- Lately, chronic renal failure.• 5- Diabetic retinopathy & neuropathy are usually present.

COMPLICATIONS OF DIABETES• VI- Respiratory Complications:• 1- Pulmonary infections especially tuberculosis.• 2- During ketosis: Kussmaul's breathing & acetone odour.

• VII- Gastrointestinal Compilations:• 1- Dry beefy tongue.• 2- Loosening of teeth.• 3- Delayed gastric emptying• 4- During ketosis: nausea, vomiting, abdominal pain & may be

haematemesis.• 5- Diarrhea: usually nocturnal & may be malabsorption due to bacterial

overgrowth.• 6- Constipation.• 7- Fatty liver.• 8- Gallstones & chronic cholecystitis.• 9- Pancreatitis.


VIII- Genital Complications:• A- In males: Impotence & loss of testicular

sensation. • B- In females:• 1- Gynaecological:• - Pruritus vulvae.• - Infections e.g. vaginal moniliasis.

COMPLICATIONS OF DIABETES2- Obstetric:• A- Effects of diabetes on pregnancy:• - The mother:• Increased incidence of toxaemia, hypertension, hydramnios &

placental dysfunction.• - The fetus:• • Large birth weight.• • Congenital anomalies• • Neonatal hypoglycaemia.• • Respiratory distress syndrome.• • Increased incidence of abortion, premature labor, stillbirth &

neonatal death.

COMPLICATIONS OF DIABETESIX - Diabetic Foot;• • It results from the combined effect of:• - Vascular insufficiency (atherosclerosis & microangiopathy).• - Neuropathy (sensory, autonomic & motor).• - Infections.• • It includes the following manifestations:• - Features of ischaemia e.g. intermittent claudications & may

end into gangrene. Trophic changes especially trophic ulcers & Charcot's arthropathy.

• - Features of neuropathy.• - Infections.


X- Joint Complication:• • Osteoarthrosis.• • Increased incidence of gouty arthropathy.• • Charcot's arthropathy.

COMA IN DIABETES

1) Diabetic Ketoacidosis;• - Pathogenesis:• • It occurs in IDDM.• • There is severe insulin deficiency leading to:• - Severe hyperglycaemia.• - Lipolysis & Ketogenesis i.e. production of

ketone bodies including acetoacetic acid & (β-hydroxybutyric acid.

COMA IN DIABETES • • These abnormalities lead to:• - Increased excretion of glucose & ketoacids in

urine leading to marked polyuria & dehydration.• - Metabolic acidosis.• - Electrolyte disturbances.• - Coma due to the combined effect of ketone

bodies, acidosis, dehydration & electrolyte disturbances.

COMA IN DIABETES

• - Precipitating factors:• 1 - Infections.• 2- Trauma & surgery.• 3- Severe physical & emotional stress.• 4- Myocardial infarction & cerebrovascular stroke.• 5- Pregnancy & labour.• 6- Starvation.• 7- Severe vomiting.• 8- Inadequate treatment.

COMA IN DIABETES Clinical Picture:• 1- Gradual onset with marked polyuria & polydipsia.• 2- Anorexia, nausea, vomiting, abdominal pain & may

be haematemesis.• 3- Kussmaul's ( acidotic ) breathing & acetone odour

of breath.• 4- Signs of dehydration: dry tongue & skin, sunken

eyes & decreased skin turgor.• 5- Signs of volume depletion: rapid week pulse & low

BP. • 6- Deterioration of consciousness & coma.

COMA IN DIABETES

Investigations:• • Urine analysis: positive for glucose & ketones.• • High blood glucose level.• • Serum K: normal or high despite depletion of

body K due to extracellular shift.• • Decreased pH & HCO3.

COMA IN DIABETES 2) Hypoglycaemic coma: - Precipitating factors:• It may occur due to overdosage of insulin or sulphonylureas, missed meal or

performing unusual exercise.Clinical Picture;

• 1- Sudden onset with irritability, tremors, pallor, sweating, tachycardia & palpitation.

• 2- Arrhythmias & precipitation of angina.• 3- Rapid full pulse & dilated pupils.• 4- Hyperreflexia & may be extensor plantar reflex.• 5- Convulsions & coma.• 6- Brain damage & death in severe prolonged cases.• 7- Rapid improvement with IV glucose.

Investigations:• • Urine analysis: no glucose.• • Blood glucose level: low ( usually < 45 mg/dl).

COMA IN DIABETES

• 3) Hyperosmolar non-ketotic coma:• - Pathogenesis:• • It occurs in NIDDM.• • There is insulin deficiency leading to marked

hyperglycaemia but without ketosis.• • Osmotic diuresis leads to dehydration with

high serum glucose & Na (increased plasma osmolality ).

COMA IN DIABETES

- Clinical Picture:• 1 - Gradual onset with marked polyuria &

polydipsia.• 2- Signs of dehydration: dry tongue & skin,

sunken eyes & decreased skin turgor.• 3- Signs of volume depletion: rapid week pulse

& low BP.• 4- Deterioration of consciousness & coma.

COMA IN DIABETES

- Investigations:• • Urine analysis: glucose without ketone

bodies.• • Very high blood glucose level.• • High serum Na.• • Increased plasma osmolality.

COMA IN DIABETES 4) Lactic acidosis;• - Precipitating factors;• • It may be precipitated by:• - Tissue hypoxia e.g. shock, heart failure, respiratory

failure.• - Biguanides.• - Alcohol.• • There is anaerobic glycolysis with production of

lactic acid leading to severe acidosis.

COMA IN DIABETES

Clinical picture:• 1- Kussmaul's ( acidotic ) breathing.• 2- Deterioration of consciousness & coma.

Investigations:• • Decreased pH & HCO3.• • Increased plasma lactate.• • Increased anion gap.

COMA IN DIABETES

5) Other causes of coma in diabetics;• • Uraemic coma in patients with diabetic

nephropathy.• • Cerebral thrombosis on top of atherosclerosis.• • Cerebral mucormycosis.• • Associated causes of coma.

INVESTIGATIONS OF DIABETES1- Plasma glucose level: ( Fasting & 2 hours post-prandial)• - Normal levels:• -Fasting: 70-110 mg/dl.• - 2 hours post-prandial: less than 140 mg/dl.

• - Diagnosis of diabetes:• - Fasting: > 140 mg/dl ( on at least 2 occasions ).• - 2 hours post-prandial ( after ingestion of 75 gm glucose ):

> 200 mg/dl ( and at least one other occasion ).• - Recently, diabetes is diagnosed if fasting glucose > 126 mg/dl

( on at least 2 occasions).• - Levels between those of normal individuals & diabetics are termed

"impaired glucose tolerance“.

INVESTIGATIONS OF DIABETES

2- Urine analysis:• - For glucose:• Using strips• - For ketone bodies:• Using strips5- Monitoring of treatment of diabetes;• Plasma glucose monitoring. .


• Glycated haemoglobin ( glycosylated haemoglobin, HbA1C)

• - It is formed by linkage of glucose to (3-chains of HbA.

• - Its measurement estimates the diabetic control in the preceding several weeks (6-12 weeks ).

• - Its normal level: 6-8% of total haemoglobin.


6- Investigations for complications: e.g.• • Urine analysis including proteins & test for

microalbuminuria.• • Renal function tests & renal imaging.• • Plasma lipids.• •ECG.

7- Investigations for the cause: only if secondary diabetes is suspected.

TREATMENT OF DIABETES

• 1-Diet.• 2- Oral antidiabetic drugs.• 3- Insulin.• 4- General measures.• 5- Treatment of complications.• 6- Treatment of different types of coma.• 7- In secondary diabetes: treatment of the cause.• 8- New lines of treatment.


2) Oral anti-diabetic ( hypoglycaemic ) drugs: A- Sulphonylureas:

Preparations:Drug

Dose

Tolutamide (Rastinon)

500mg t.d.s.

Acetohexamide (Dimelor)

500mg/12hr

Chlorpropamide (Diabenase)

100-5 00 mg/d

Glibenclamide (Daonil)

5-15mg/d

Gliclazide (Diamicron)

80- 120 mg/d

Glipizide (Minidiab)

2.5-30 mg/d

Glimipride (Amaryl)

1-3 mg/d


B- Biguanides:- Indications:• NIDDM not controlled by diet alone especially

in obese patients.

- Preparations:• 1- Metformin ( Glucophage ): 500 mg t.d.s.• 2- Phenformin (Insoral ): 25 mg t.d.s. ( of no use

now ).


3) Insulin:- Indications:

• 1-IDDM.• 2- Severe NIDDM not controlled by diet & oral

hypoglycaemic drugs.• 3- During pregnancy.• 4- Diabetic ketosis & hyperosmolar coma.• 5- Severe stress e.g. infection, surgery.


Preparations:

Onset of

Peak of

Duration of

Action (hr)

Action (hr)

Action (hr) 1 - S h o rt ac tin g : e .g .

- Crystalline ( Regular )

0.5

3

6 - Semilente

1

6

12 2 - In te rm e d ia te a c tin g : e .g .

- Isophane ( NPH )

3

8

24 - Lente

3

8

24 3- Long acting: e.g.

- Protamine zink insulin (PZI)

4

16

36 - Ultralente

4

16

36


5) General measures:• 1- Regular physical exercise.• 2- Avoidance of smoking & alcohol.• 3- Multivitamins especially vitamin

B complex.

6) Treatment of diabetic complications

INSULIN -It is a peptide hormone consisting of 51 amino acids. -It is secreted by (β-cells of...

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