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 12% in most populations.
DIABETES MELLITUS
Aetiology;
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. HLADR3, 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
74
Comparison between type I & type II primary diabetes
Type I diabetes
Type II diabetes
1- Incidence
< 10%
> 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- Oral antidiabetics
Of no effect
Effective
Presentations of Diabetes
- Asymptomatic & accidentally
discovered.
2- Classic symptoms:
- Polyuria, polydipsia, polyphagia, pruritus
and parasthesias.
- Loss of weight especially in IDDM.
3- Diabetic complications.
4- Diabetic coma.
1
COMPLICATIONS OF DIABETES
I- 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 DIABETES
5- 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
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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 DIABETES
C- 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.
COMPLICATIONS OF DIABETES
COMPLICATIONS OF DIABETES
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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).
COMPLICATIONS OF DIABETES
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•
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V- Urinary Complications:
1- Urinary tract infections:
- Pyelonephritis
- Cystitis, urethritis & pyelitis.
2- Diabetic Nephropathy:
COMPLICATIONS OF DIABETES
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- 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
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VI- Respiratory Complications:
1- Pulmonary infections especially tuberculosis.
2- During ketosis: Kussmaul's breathing & acetone odour.
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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.
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•
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•
COMPLICATIONS OF DIABETES
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 DIABETES
2- 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 DIABETES
IX - 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.
COMPLICATIONS OF DIABETES
COMPLICATIONS OF DIABETES
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 & (βhydroxybutyric 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
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•
- 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
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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 DIABETES
1- 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 strips
5- Monitoring of treatment of diabetes;
• Plasma glucose monitoring. .
INVESTIGATIONS OF DIABETES
INVESTIGATIONS OF DIABETES
• 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.
INVESTIGATIONS OF DIABETES
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
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•
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•
•
•
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.
TREATMENT OF DIABETES
2) Oral anti-diabetic ( hypoglycaemic ) drugs:
A- Sulphonylureas:
Preparations:
Drug
Dose
Tolutamide (Rastinon)
500mg t.d.s.
Acetohexamide (Dimelor)
Chlorpropamide (Diabenase)
500mg/12hr
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
TREATMENT OF DIABETES
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 ).
TREATMENT OF DIABETES
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.
TREATMENT OF DIABETES
Preparations:
1- Short acting: e.g.
- Crystalline ( Regular )
- Semilente
2- Intermediate acting: e.g.
- Isophane ( NPH )
- Lente
3- Long acting: e.g.
- Protamine zink insulin (PZI)
- Ultralente
Onset of
Peak of
Duration of
Action (hr)
Action (hr)
Action (hr)
0.5
1
3
6
6
3
3
8
8
24
24
4
4
16
16
36
36
12
TREATMENT OF DIABETES
5) General measures:
• 1- Regular physical exercise.
• 2- Avoidance of smoking & alcohol.
• 3- Multivitamins especially vitamin
B complex.
6) Treatment of diabetic complications