1. Diabetes mellitus
Is a clinical syndrome characterized by hyperglycemia duo to absolute or relative insulin
deficiency? So carbohydrate, protein & fat metabolism are affected. Acute decompensated
complication lead to death while chronic metabolic derangement leads to permanent &
irreversible functional & structural change in the cells of the body lead to complication of
Blood glucose distribution is unimodal with no clear division between normal &
Current diagnostic criteria for diabetes have been selected on the bases of identifying those
who have a degree of hyperglycemia which has been shown to be associated with a
significantly increased risk of disability & death from vascular disease, irrespective of the
basic cause of the hyperglycemia.
Diabetes is by far the most common of the endocrine disorder. Difference in both genetic
& environmental factor for diabetes make prevalence of both type of diabetes varies in
different countries, e.g. In Britain is 2-3 % majority have primary diabetes & ratio of type
2: type 1 is 7:3. In other countries: 80-90% type2, 10-20% type1. In USA the prevalence
of diabetes is 2-4%.
Classification of diabetes mellitus:
1. Type 1 DM-previously called insulin dependent diabetes (IDDM).
2. Type 2 DM-previously called non insulin dependent diabetes (NIDDM).
* Other specific type of diabetes:
• Cystic fibrosis
2. Excessive endocrine hormone antagonist to insulin:
• GH ( acromegaly)
• Glucocorticoid ( Cushing syndrome)
• Thyroid hormone( thyrotoxicosis)
• Glucagons ( glucagonoma)
• Catecholamines (Phaeochromocytoma)
• human placental lactogen ( pregnancy)
3. Medication: steroid, thiazide, phenytoin, vacor (rodenticide)
4. Liver disease.
5. Associated with genetic syndromes: e.g.
• DIDMOAD syndrome
• Muscular dystrophy
• Friedreich`s ataxia
• Down's syndrome
2. • Klinefelter’s syndrome
• Turner's syndrome.
* Gestational diabetes.
Environmental factor & genetic both interact to identify those with the genetic
Type 1 Diabetes:
It is a polygenic inheritance, about 95% of type1 DM is HLA DR3 or 4, but since 50% of
population is also HLA DR3 or 4, search for type1 DM specific HLA gene continued, & it
is mainly related to amino acid at position 57 of HLA DQ β chain. E.g. aspartic acid
positive homozygosity has HLA linked resistance to the development of type 1 DM while
aspartic acid 57 negative homozygosity (alanine, valine, and serine) substituted for
aspartate has maximum susceptibility. Other factors may play role e.g. environmental
factor or auto immune factor for pancreatic cell destruction. The concordance rate between
monozygotic twins is < 40%.
1. Viruses: infecting the β cells, mumps, hepatitis, infectious mononucleosis, congenital
rubella, Coxsackie's virus B4, cytomegalovirus, mengo virus.
2. Diet: in certain circumstances diet may influence the development of human type1 DM,
e.g. anti-gliadin Abs reported in 54% of children (non of whom had celiac disease) at
diagnosis of type1DM under 2 years of age. Other diet as wheat & milk protein, bovine
serum albumin(BSA) a major constituent of cow's milk and coffee have been shown to
have the strongest diabetogenic effect & are evidently are capable of triggering the string
of events which results ultimately in destruction of pancreatic islet insulin secreting cells.
3. Stress: stress may progress the development of type 1 diabetes by stimulating the
secretion of counter-regulating hormones and possibly by modulating immune activity.
4. Immunological factors: hyperglycemia occurs with clinical symptoms of DM only when
90% of insulin secreting cells is already destroyed. There are many evidences that type1
DM is a slow autoimmune disease as:
-HLA- linked genetic predisposition.
-associate with other autoimmune disease.
-presence of circulating islet cells & insulin auto antibody in new cases.
-recurrence of insulitis & selective destruction of insulin secreting cells in pancreatic
A: Insulitis: infiltration of islets with mononuclear cells
B: patchiness of the lesion.
C: β cell specifity of the destructive process within infiltrative islets where the glucagons
& other hormones (somatostatin) remain intact & finally regression of infiltration.
Type 2 Diabetes:
A: Genetic factors: Type 2 diabetes is not HLA linked & no evidence that autoimmunity
or virus has any effect but study of monozygotic twins that concordance rate 100% for
type2 DM reveals that genetic factor is more important, type 2 DM is commonly
3. associated with several other disorders such as obesity, hypertension &hyperlipidemia,
this cluster is a specific entity (syndrome X-or the metabolic syndrome) with insulin
resistance being the primary defect. A mutation of the glucokinase gene is associated with
some cases of the uncommon syndrome of maturity onset diabetes in the young (MODY),
constitute less than 5% of all cases of type 2 diabetes.
B: Environmental factors: life style, obesity & underactivity are associated with the
development of type2 DM.
Obesity probably acts as diabetogenic factor (through increasing resistance to the action of
insulin) in those genetically predisposed to develop type2 DM.
85% of type2 DM are obese, 15% of type2 DM are non obese, but not all obese person
develop diabetes, only few obese people develop diabetes.
C: age: Type2 DM is principally disease of middle age & elderly.
In young ages diabetes is more in male than female, in middle age female are more.
During pregnancy HPL increase leading to anti insulin effect, so pancreas secretes more
insulin, in women genetically predisposed to diabetes may not be able to meet these
demands & both types of diabetes may occur.
Gestational diabetes is hyperglycemia occurring for the 1st
time during pregnancy. This
may or may not disappear after delivery. Repeated pregnancy increase the risk of
permanent diabetes particularly in obese women. 80% of patients with gestational diabetes
develop permanent diabetes & require treatment.
E: pancreatic pathology:
There is only moderate reduction of total mass of islet tissue. There are some typical
pathological changes in pancreas in type2 patients, the most consistent of these changes is
probably deposition of amyloid which accompany atrophy of normal tissue, particularly
islet epithelial cell. Heavy deposition of islets with amyloid is rare without diabetes, but
small quantities are very common in elderly non diabetic patients.
Etiology of type2 DM is not only by simple deficiency of insulin, but other factors are:
1. Increase hepatic production of glucose.
2. Insulin resistance which usually accompanies obesity this includes:
• Abnormal insulin molecule
• An excessive amount of circulating antagonists.
• Target tissue defect(common cause)
Whatever the etiology, in all cases the hyperglycemia of diabetes develops because of an
absolute (type1) or a relative (type2) deficiency of insulin leads to
Insulin has profound effect on carbohydrate, protein, fat and electrolyte metabolism, it has
anabolic effect and anticatabolic effect, so balance of these effects in the fasting, post
absorptive state, after food, and during exercise is controlled by:
1. Variation in relative concentration of insulin, the only anabolic hormone and several
catabolic hormones, namely: glucagons, growth hormone, cortisol, catecholamine and
4. 2. Insulin exerts its anticatabolic effect in lower range for that of anabolic effect.
1.5 hour of meal increase insulin, decrease growth hormone and glucagons.
At rest 90% of energy requirement of muscle come from fatty acids & ketone bodies,
initially in exercise glycogen from liver oxidized, increased peripheral uptake of glucose
and nonesterified fatty acid by increased insulin receptor affinity, then glycogen store is
depleted rapidly, so glucose fall, insulin fall, and anaerobic glycolysis start,
Catecholamine and cortisol levels increase stimulating lipolysis and gluconeogenesis
(formation of glucose from amino acids).the increase in hepatic production matches the
increased extra hepatic utilization so that glucose level not changes markedly.
As anaerobic glycolysis continue blood lactate concentration increase and this is recycled
by the liver as new glucose.
In the absence of insulin there will be:
1. Decrease peripheral utilization of glucose.
2. Increase hepatic glucogenesis from liver to circulation.
So there is:
1. An extracellular glucose excess.
2. Intracellular glucose deficiency.
There is also a decrease in amino acid entry to muscle, & an increase in lipolysis.
If hyperglycemia develops over many months or many years as in type2, the renal
threshold for glucose rise & features of diabetes are slight that is why many cases of type2
DM are not diagnosed.
Distinction between type1 and type2 DM
Type1 DM Type2 DM
Age of onset <40 years >50 years
Duration of symptoms Weeks Months-years
Body weight Normal or low Obese
Ketonuria Yes No
No Yes 10-20%
Family history of
Acute complication Ketoacidosis Hyperosmolar
Overlap occurs particularly in age e.g.
MODY: maturity onset diabetes in young people.
LADA: latent autoimmune diabetes in adult: some people with apparent type 2 DM have
evidence of autoimmune activity against pancreatic β cells. And may have slowly evolving
variant of type1 DM.
5. The classical symptoms of polyuria, thirst, polydipsia, recurrent blurred vision, error of
refraction, parasthesia( usually when the onset is sub acute) fatigue are manifestations of
hyperglycemia & osmotic diuresis & are therefore more common to both types of Diabetes
however many patients with type2 diabetes have an insidious onset of hyperglycemia and
may be relatively asymptomatic initially particularly in obese patient.
In type1, weight loss despite normal or increased appetite is a common feature. Nocturnal
enuresis duo to polyuria may signal the onset of diabetes in very young children, when the
condition is severe and of acute onset, DKA with features of dehydration, hypotension,
acidosis, drowsiness, stuperous, coma may be the presenting feature. Loss of subcutaneous
fat and muscle wasting are features of more slowly developing insulin deficiency.
Occasionally an initial episode of DKA is followed by a symptom interval in type1
diabetic during which no treatment is required usually it lasts weeks to months, but
sometimes may reach 1-2 years, and this is called honey moon period in diabetes.
In type2 chronic skin infection are common, generalized pruritis, pruritis vulvae, or
balanitis is a common presenting symptom, due to fungal(candidia) infection of external
genitalia, which flourish on skin and mucous membrane contaminated by glucose.
Diabetic retinopathy, depression or loss of tendon reflex on ankle and impaired perception
in the legs indicates neuropathy. Proteinuria in addition to glycosuria in nephropathy,
signs in atherosclerosis are common. These were features of established DM.
Two other conditions present:
One is potential diabetes, the other is latent diabetes.
In potential diabetes there is normal glucose tolerance test (GTT) but increase risk of
diabetes for genetic reason e.g. children of 2 diabetic parent chance: 15-20%.
There is normal GTT but in conditions cause burden on
Pancreases as pregnancy, infection, mental and physical stress or during treatment with
corticosteroid, thiazide, or when overweight leads to abnormal result.
Potential & latent diabetes usually complain of no symptoms & usually shows no
abnormality on exam.
Best to do it 1-2hours after main meal which select much milder cases than fasting urine.
Disadvantage is individual variation in renal threshold for glucose. It can be done by using
clinitest tablet or by using dipstick method.
Differential diagnosis of glycosureia:
Although glycosuria reflects diabetes over 90% of patients 2 major classis of nondiabetic
glycosuria must be considered.
A-Non diabetic glycosuria due to glucose.
Glucose appeared in urine despite normal blood glucose e.g. Fanconi’s syndrome,
dysfunction of the proximal renal tubules, chronic renal failure, pregnancy(common to
have glyosuria by ↑GFR during pregnancy&↑glucose load 50% of pregnant has sugar in
urine specially after the 1st
trimester&in the last weeks lactose may be present).
B-Non diabetic glycosuria due to sugars other than glucose, lactosuria during late
pregnancy&lactation is most common e.g.
C-Alimentary glycosuria (lag storage).
6. Normal or after gastric surgery or hyperthyroidism or hepatic disease, this is benign ¬
related to diabetes.
By using Acetest tablet or Ketostix&Ketodiastix, utilize a Nitroprusside reaction,
measuring only acetone&acetoacetic acid. Conditions leads to ketonuria apart from DKA
are starvation, high fat diet, alcoholic ketoacidosis &fever.
Blood glucose estimation
HbA1 reaction between glucose &N-terminal amino acid of both β chains of the Hb
Normally 5-8% and give good diabetic control within preceeding2-3 months .a rise of 1%
in HbA1C correspond to an approximate average↑ of 2mmol/L in blood glucose .HbA1C
may be diminished in anemia&pregnancy and may be difficult to interpretate it in patients
with uremia or haemoglobinopathy.
It’s not used as a diagnostic method in diabetes mellitus.
Diagnosis of DM:
When laboratory facilities are very limited, typical diabetic symptoms with glycosuria
may have to suffice to make the diagnosis, ideally however, confirmation with blood
glucose or plasma glucose level is best, the diagnosis should be definite as life long
treatment &follow up are implied
I-Symptoms of diabetes + one abnormal blood glucose level.
2-If symptoms are absent, two abnormal blood glucose level
Abnormal blood glucose is:
--Fasting plasma glucose≥126mg/dl, after an overnight (at least 8hour) fast.
--Random plasma glucose concentration ≥200mg/dl
3-In doubtful cases, a diagnostic GTT (Glucose tolerance test)
Indications for oral GTT;
•Fasting plasma glucose is 110-126mg/dl
•Random plasma glucose is 140-199mg/dl
The patient should be on unrestricted CHO diet for 3 days ,fast overnight ,outpatient
should rest for half hour, stop smoking ,fasting plasma glucose is measured ,75gm glucose
in 300ml of water is given then after 2 hour plasma glucose is measured.
The test is interpretated as follow
<110 110-125 ≥126
<140 ≥140but <200 ≥200
IGT (Impaired glucose tolerance) &IFG (Impaired fasting glucose) both terms refer to a
stage intermediate between normal and diabetes.
IGF refers to a level of plasma glucose between 110-126mg/dl.
Many patients with IGT (20-30%) later develop permanent diabetes, which is virtually
always type2 DM, many of these are obese & simple dietary advice should be offered.
Note: Plasma or serum glucose levels are 10-15% higher than whole blood glucose
because structural components of blood cells are absent so that more glucose present per
Management of DM
Three methods of treatment are available for diabetic patients:
1/ diet alone, 2/ diet & an oral hypoglycemia drug, 3/ diet & insulin.
Approximately 50% of new case of diabetes can be controlled adequately by diet alone,
20-30% will need an oral hypoglycemic drug& 20-30% will require insulin.
Regardless of etiology the type of treatment required is determined by the circulating
plasma immunoreactive insulin concentration.
At a clinical level the age & weight of the patient at diagnose are closely correlated with
the plasma insulin concentration& indicate with a high degree of probability the type of
treatment likely to be required.
However the regimen eventually adopted in each individual case is chosen by therapeutic
The daily energy requirement should be decided according to age, sex, actual weight,
e.g. an obese middle aged or elderly person 1000- 1600 Kcal daily.
An elderly person not over weight 1400- 1800 Kcal/ day
A young active person 1800- 3000 Kcal/ day
The body wt. should be maintained at or slightly below the ideal for the patient height.
The proportion of energy derived from CHO, protein & fat should be as follow.
CHO 50- 60%
8. Fat 25- 35%
All the CHO prescribed should be taken in the form of starches and other complex sugars.
Simple sugars such as glucose & sucrose should generally be avoided because they may
cause a sudden rise in the blood glucose concentration. Fiber- rich foods (e.g barley, oats,
legumes, beans & lentils) has been associated with improved blood glucose control &
lower blood lipids in both normal, diabetic & hyperlipidemic persons.
Excessive salt intake is to be avoided; it should be particularly restricted in people with
hypertension & those with nephropathy.
In addition to reducing calorie intake, overweight patients should be strongly encouraged
to take regular exercise, in the form of walking, swimming or cycling, for approximately
30 minutes daily, as this improves insulin sensitivity and the lipid profile and lowers blood
Drug treatment for type2 DM:
Oral hypoglycaemia drugs (OHD)
Are considered only after a regimen of dietary treatment combined with exercise has failed
to achieve the therapy targets set.
There are (2) major groups of OHD.
Sulphonylureas (SUs) and biguanides (BGs)
SU act by stimulating insulin release from the β cells (insulin secretagogue).They act
through a sulphonylurea receptor which is linked to a k+ channel on the β-cell surface
.k+transport triggers insulin secretion.
BG exerts their action by ↓ gluconeogenesis & by ↑ the peripheral utilization of glucose.
Selection of a specific SU preparation will depend on factors such as availability, cost, and
the physician's experience.
SUs can cause hypoglycaemia and their use should therefore be closely monitored in the
elderly & in those with nephropathy.
Tolbutamide is a short- acting SU and may be selected in Patients with renal impairment.
The initial daily dose is 0.5 gm, which can be ↑ if necessary to 1.5 gm in divided doses.
Chlorpropamide has a half- life of about 36h the usual maintenance dose is
100- 350 mg/ day. toxic effects include cholestatic Jaundice, skin rash & blood dyscrasia.
Feature of disulfiram- like reaction occur in some patients after taking alcohol.
Occasionally chlorpropamide can induce (SIADH).
▪ Of the second generation sulphonylureas. gliclazide and glipizide cause few side- effects
but glibenclamide is proving to induce sever hypoglycemia and should be avoided in
elderly. newer long acting preparation such as glimepiride and a modified- release form of
gliclazide can be administered once daily with no apparent ↑ risk of hypoglycaemia.
Glibenclamide may be given in an initial dose of 1.25- 2.5 mg which can be ↑ up to a
maximum daily dose of 15 mg.
Metformin is the only BG preparation now marketed in most Easters Mediterranean region
countries. Metformin is primarily used in the obese not responding to dietary therapy.
The starting dose is 500- 850 mg with or after food, once daily, which can be ↑ to 500 mg
tds or 850 mg b.d because of the risk of lactic acidosis its contraindicated in:
- Patients with impaired renal function.
- Elderly people above the age of 70 years.
9. - Patients with heart failure, hepatic impairment, or predisposition to lactic
For the same reason, treatment with metformin should be discontinued during surgery,
sever infection & intercurrent illnesses.
SU may be combined with metformin, when therapy targets are not achieved with either
drug alone.in pregnancy in certain cases metformin or glibenclamide(the only
sulphonylurea that dose not cross the placenta)is used.
Other oral hypoglycaemia drugs:
Alpha- glucosidase inhibitors:
They delay CHO absorption in the gut by selectively inhibiting disaccharidases. Acarbose
(Glucobay) is currently available and is taken in a dose of 50- 100 mg with each meal. It
principally lowers post- prandial blood glucose, modestly improves overall glycaemic
control & reduces HbA1C. Acarbose can be combined with a sulphonylurea. The main side
effects are flatulence, abdominal bloating and diarrhea.
They are a new class of compound for treatment of type 2 D.M. they work by enhancing
the action of endogenous insulin. Insulin sensitivity is improved only in patients with
insulin resistance. Plasma insulin concentrations are not increased & hypoglycemia is not
a problem. The beneficial non- hypoglycemic effects of this compound include ↓ in
plasma insulin & triglyceride levels, ↑ in HDL cholesterol level. ↓ Lipid oxidation,
favorable redistribute of body fat. ↓ In vascular resistance. & improvement in endothelial
function but deleterious effect includes elevation of LDL cholesterol level, oedema&
The e.g. of there drugs are Rosiglitazone & Pioglitazone, they may cause liver failure. The
drug to be commercially available is troglitazone.
Meglitinide and amino acid derivatives;
These drugs are oral prandial glucose regulators. Repaglinide directly stimulates
endogenous insulin secretion and is taken immediately before food. It's less likely to cause
hypoglycemia than sulphonylurea.
Nateglinide has a similar mode of action, restores first- phase insulin secretion, and is
prescribed with metformin.
The incretin mimetics are medications that mimic the action of incretins, peptide hormones that originate
in the gastrointestinal tract.Glucagon –like peptide(GLP-1)is an incretin hormone are released during
nutrient absorption, augmenting insulin secretion. They also reduce postprandial glucagon secretion and
delay gastric emptying time. As a result, patients using these medications can have improved postprandial
glucose excursions and early satiety.Incretin hormones have a very short life-span in circulation as they
are rapidly destroyed by DPP-IV (Dipeptyl Peptidase-IV).By opposing the action of DPP-IV the drug
Sitagliptin helps to prolong the incretin effect. this helps reduce blood glucose level.Sitagliptin is taken
orally once daily the tablets are 100mg.side effects are uncommon ,nausea flatulence when combined
with glitazone swelling of the feet may be seen, hypoglycemia may occurs, its contraindicated in type1
DM,previously had diabetes ketoacidosis and renal problem.
Synthetic GLP-1 receptor antagonists with longer therapeutic action include exenatide(synthetic exendine
4)and liraglutide.incretin-based therapies are most useful in obese patients and can be used in
combination with other oral anti-diabetic agents.
It's indicated in type2 DM in the following situations
1/ when diet & OHD fail to control hyperglycemia and achieve therapy targets. (Fasting
plasma glucose level 80- 120 mg/ dl, post prandial 90- 145 mg/dl is optimal, fasting
plasma glucose level less than 160 mg/ dl, post prandial less than 180 mg/dl is acceptable
while fasting plasma glucose level more than 160 mg/dl and post prandial more than 180
mg/dl is poor).
2/Diabets during pregnancy when diet alone is inadequate.
3/ when OHD are contraindicated.
4/ during stressful conditions such as infection & surgery.
Management of type1 DM:
The principles, guidelines and recommendation made for type2 DM generally apply to
Insulin therapy aims at:
1/ achieving good metabolic control by mimicking physiological insulin secretion as much
2/minimizing the risk of hypoglycemia.
Matching insulin requirement with CHO intake & physical activity & combining it with
frequent self monitering are prerequisites for a successful therapeutic strategy in type1
Insulin are either bovine or porcine, human insulin produced by recombinant DNA
technology recently rDNA & protein engineery technique, that alters the Amino Acid
sequence of insulin have been used to produce (nonomeric) analogues of insulin which are
more rapidly absorbed from the site of injection. (e.g. lispro or aspart)
Insulin preparation of any species may be used.
Two major types of insulin preparations are usually used: short- and intermediate acting.
Except in occasional circumstances, long acting insulin are generally not needed.
The strength of insulin and the calibration of syringes should be uniform throughout the
country, for example 40- 100, in order to avoid confusion.
Insulin is usually given by the s.c route, i.v or i.m routes may be used in emergencies such
as in cases of diabetic ketoacidosis. The use of other routes such as intraperitoneal or nasal
is still in the experimented stage.
- Implantable insulin pumps are still in the experimental stage.
- Injection should be given in to the deep s.c tissue at a 45° angle or at a 90°
angle when the s.c layer is greater than the needle length.
- Rotation of injection sites is recommended to reduce insulin injection site
- Absorption from the abdomen is faster than from thighs or upper arms and
may be preferred for short- acting preparation.
11. - The majority of pts will require more than one daily injection if good
glycaemic control is to be achieved. However a once- daily injection of an
intermediate acting preparation may be effectively used in some patients.
- Twice- daily mixtures of short- and intermediate acting insulin is a commonly
- In some cases, a mixture of short- and intermediate acting insulin may be
given in the morning. Further dose of short- acting insulin are given before
lunch and the evening meal and an evening dose of intermediate- acting
insulin is given at bed time. Other regimens basal on the same principles may
- A regimen of multiple injection of short- acting insulin before the main
meals, with an appropriate dose of intermediate- acting insulin given at bed
time, may be used, particularly when strict glycaemic control is mandatory.
The dose of the insulin preparations is adjusted according to frequent monitoring of blood
glucose levels. Blood glucose monitory should be intensified during intercurrent illness &
other stressful conditions & the insulin dose may have to be ↑.
Emphasis should be placed on the importance of regular follow- up. During follow up
visits, education should be reinforced, growth monitored, blood glucose monitoring results
reviewed, & measurement of HbAlc, urine glucose & ketones.
Following puberty, & more than 5 years after diagnosis, annual eye examination with
assessment of the retina& testing for micro albuminuria are recommended.
Factors associated with ↑ mortality & morbidity in diabetic patients.
• Duration of diabetes.
• Early age at onset of disease.
• High glycated Hb.
• Raised B.P.
Acute complications of diabetes:
Includes hypoglycaemia, diabetic ketoacidosis.
Non- ketotic hyperosmolar diabetic coma, Lactic acidosis and acute circulating failure.
Defined as a blood glucose concentration of less than 45 mg/dl, common in those taking
insulin in comparism to suphonylurea drugs.
Sever hypoglycaemia defined as hypoglycaemia requiring the assistance of another person
for recovery. Can result in serious morbidity, and has a recognized mortality of 2-4% in
insulin- treated patient.
When hypoglycemia develops in non-diabetic people, it is called `spontaneous
Symptoms of hypoglycaemia:
12. Including those related to acute activation of the autonomic N.S and those secondary to
glucose deprivation of the brain (neuroglycopenia).
Symptoms of autonomic activation includes sweating, trembling, pounding heart, hunger
Neuroglycopenic symptoms including confusion, drowsiness, speech difficulty, inability
to concentrate and incoordination.
Non- specific features are nausea, tiredness and headache.
Cause and prevention
The most common cause is unpunctual or in adequate meals, unexpected or unusual
exercise, and ingestion of alcohol other causes includes defective glucose counter –
regulator /unawareness of hypoglycemia, gastroparesies due to autonomic neuropathy
Presence of other endocrine disorders e.g. Addison's disease.
Nocturnal hypoglycemia occur because the basic cause is the physiological diurnal
variation in the amount of insulin required to achieve homeostasis which is probably
related to the diurnal rhythm in the secretion of counter-regulatory hormones such as
glucocorticoid and Growth hormone which are insulin antagonists .
Diagnosis is by measuring blood glucose between 2:00 and 3:00 hours and the treatment
-Split evening dose of insulin -take unmodified insulin not before 23:00 hours.
Management of hypoglycemia
If pt. able to swallow, glucose should be given orally. In diabetics with depot insulin or
sulphonylurea particularly chlorpropamide there is possibility of relapse.
In emergency Tx I.V glucose given as 50 ml. of 50% dextrose ,localized
thrombophilibitis is the hazard .On regaining conscious the pt. should be given oral CHO
and continuous I.V infusion of dextrose (5%or 10%)may be necessary to prevent
recurrence of hypoglycemia .I.M glucagon (1mg)may be of value may be ineffective if
hepatic glycogen store are depleted as in prolonged starvation , if pt. fail to regain
conscious cerebral edema should be considered other causes include alcoholic
intoxication, a postictal state or cerebral hemorrhage and C.T scan of brain may be
Cerebral edema has high mortality and morbidity and needs treatment with mannitol and/
Nowadays this complication account for 2% of deaths among diabetes and prior to
discovery of insulin was more than 50%.
Mechanism underlying the development of ketoaidosis:
In the presence of marked insulin deficiency suppression of lipolysis is lost and plasma
concentration non-esterified fatty acids may remain constantly elevated.
Fatty acids are taken up by the liver and degraded through 8 steps within the mitochondria
of the liver cells. Each stage yields one molecule of acetyl coA. normally most of these
molecules enter the citric acid cycle by condensing with oxaloacetic acid but in the
absence of insulin more is formed than can enter the citric acid cycle, and acetyl coA is
converted to acetoacetic acid, most of this is then reduced to β hydroxyl butyric acid,
while some is decarboxylated to acetone. These ketone bodies when formed in small
amounts are oxidized and utilized as metabolic fuel. When the rate of ketone production
by the liver exceeds that of removal by the peripheral tissue, then hyperketonemia results.
13. Ketone bodies increase osmolality of plasma so leads to withdrawal of water from the
They release Hydrogen ion from body fluids and lead to fall in pH and HCO3- usage, so
HCO3-/H2CO3 fall and increase hydrogen ion leads to stimulation of pulmonary
ventilation and air hunger. Clinically the severity of ketoacidosis can be assessed rapidly
by measuring the plasma HCO3- , if less than 12mmole/L indicates severe acidosis, the
average loss of fluid and electrolyte in moderately severe DKA in adults is as follows:
--Water 6 liters; about half from intracellular compartment, the reminder is loss of extra
--Na loss 500 mmole
--K 350 mmole
Every patient in DKA is potassium depleted but the plasma content of K gives very little
indication of the total body deficit.
The state of consciousness is very variable in DKA; a patient with dangerous ketoacidosis,
requiring urgent treatment may walk into the consulting room. For this reason the term
DKA is to be preferred to (diabetic coma).
Features of DKA can be compared with that of hypoglycemia as follows:
Hypoglycemia Coma with ketosis
History No food, too much insulin,
Too little or no insulin, an
infection or digestive
Onset In good previous health
relative to last insulin
Ill-health for several days
Symptoms That of hypoglycemia,
Of glycosuria &
dehydration, abdominal pain
Signs Moist skin & tongue, full
pulse, normal or raised
systolic blood pressure,
shallow or normal breathing,
Dry skin & tongue, weak
pulse, low blood Pressure,
air hunger diminished
Urine No ketonuria
Normal plasma bicarbonate
Reduced plasma bicarbonate
DKA should be treated in hospital, IV fluid replacement is required since even the patient
is able to swallow fluid given by mouth may be poorly absorbed, the components of
14. Use only Unmodified clear insulin, start IV insulin infusion 5 unit/hour, if this is not
practical so a loading dose of 10-20 units can be given i.m, & immediately followed by 4-
6 units hourly, the blood glucose concentration should fall by 55-110 mg/dl/hour. If after 2
hour from treatment no fall, then the dose of insulin should be doubled, until a satisfactory
response is obtained.
When the blood glucose concentration has fallen to 180-250mg/dl the dose of insulin
should be reduced to 1-4 units hourly.
Average fluid deficit is 6 liter: 3liters extra cellular replace by saline
3 intracellular replaced by glucose
Early rapid rehydration by isotonic saline (0.9% Nacl) is essential; otherwise the
administered insulin will not reach the poorly perfused tissue. If the plasma Na greater
than 155 mmole/liter so 0.45% saline may be given initially instead of 0.9%,
NaHCO3 indicated in pH <7.1 in the presence of:
300-500 cc of 1.26% NaHCO3 may be given over 30 minutes into a large vein, otherwise
correction of the total bicarbonate deficit should not be attempted because rapid correction
1. Aggravate tissue hypoxia
2. Reduce consciousness by paradoxical acidosis of CSF
3. HCO3 & insulin increase risk of hypokalemia
The intracellular water deficit must be replaced by using 5 or 10% dextrose & not by more
saline; it is best given when the blood glucose concentration approaches normal.
KCL should be started cautiously initially but according to frequent estimation of K-level;
it can be given as the following
1. If plasma K more than 5.5 mmol/L give no K
2. If 3.5-5.5 mmole/l give 20mmole KCL/L of infused fluid.
3. If<3.5mmol/L give 40 mmole KCL/Litter of infused fluid.
Infection must be carefully sought & vigorously treated, leukocytosis is invariably seen in
DKA this represents a stress response & doesn’t necessarily indicate infection, and also
pyrexia may not be present initially because of vasodilatation secondary to acidosis.
Additional procedures which may be required:
-catheterization if after 3h no urine passed
-nasogastric tube to keep stomach empty (in unconscious or semiconscious patient)
-Central venous line if C.V.S. compromised.
-plasma expander if BP doesn't rise with IV saline.
Precipitating cause of DKA:
1. Infection: overwhelming infection precipitate DKA in type2DM.
2. Erratic insulin supply.
3. In type2 DM who have failure of treatment by oral hypoglycemic agents & need insulin,
so when they refuse to take it, leads to DKA
15. 4. Acute MI
7. Massive trauma or other serious illness.
2-5% mostly in:
2. Serious complicating illness
3. Those who present in coma
Complication of DKA:
1. Fluid overload, cerebral oedema
3. Hypo& hyperkalemia
6. Acute gastric dilatation (rare)
Poor prognostic sign in DKA at Admission include:
Hypotension, azotemia, deep coma
Cause of death:
In children :cerebral oedema .
2. Storage of insulin
3. Admission of patient with early signs of ketoacidosis.
Non-ketotic hyperosmolar diabetic coma:
This condition is characterized by severe hyperglycemia>900mg/dl without severe
hyperketonemia or acidosis. Severe dehydration and prerenal uremia are common. This
usually affects elderly patients, many with previously undiagnosed diabetes. Mortality is
over 40% its treatment is differing from that of ketoacidosis in two main aspects:
1. These patients are sensitive to insulin & approximately half the dose of insulin
recommended for the treatment of ketoacidosis is needed.
2. The plasma osmolality should be measured as:
Plasma osmolality= 2[Na+] +2([K+] + [glucose] + [urea]), the normal value is 280-
300mmole/kg, and the conscious level is depressed when it is high (>340mmole/kg)
The patient should be given 0.45% saline until the osmolality approaches normal, when
0.9% should be substituted through C.V.P. line.
Thromboembolic complication is common and prophylactic S.C. heparin is recommended.
The patient is likely to be a diabetic taking biguanide who is very ill & over breathing, but
not so profoundly dehydrated as in coma of ketoacidosis, plasma HCO3- is markedly
reduced (pH, 7.2)
Diagnosis by high (usually 5.0mmole/L) concentration of lactic acid in the blood.
16. Treatment with IV bicarbonate to raise pH above 7.2 also give insulin & glucagone.
Mortality rate is 50%.
Long term complication of diabetes:
The excess mortality is mainly due to large blood vessel disease. & accounts
for about 70% of all death.
The pathological change associated with atherosclerosis in diabetic patient are
similar to those seen in the non diabetic population but they occur earlier in life
and are more extensive & sever. Diabetic microangiopathy is disease of small
blood vessel it contributes to retinopathy &nephropathy.
In pathology of the diabetic microangiopathy there is thickening of the
capillary basement membrane with associated ↑ vascular permeability
throughout the body. The pathogenesis in diabetic complications is through
that to be due to↑ metabolism of glucose to sorbitol via the polyol pathway.
Macro vascular disease
Arterio sclerosis is a common problem in diabetic because of risk for vascular
disease so the risk should be ↓ by stop smoking & H.T should be treated ,
elevated plasma lipid should be treated it improve with control of
Silent myocardial infarction because of associated neuropathy & tendency of
vascular disease to be more diffuse making vascular reconstructive surgery
more difficult, nevertheless the indication & success is not significantly
different from others. Diabetic patent with existing cardiovascular disease
should receive lipid lowering statin if the plasma total cholesterol
concentration is >5.0mmol/L.
The frequency & severity of microvasculature complicate of type1DM can be
minimized by strike glycaemic control (mean HbA1c around 7%) using
intensive insulin therapy.
Causes of death in treated diabetic patients:
- C.V.D. 70%
- Renal failure 10%
- Cancer 10%
- Infections 6%
- DKA 1%
- Other 3%
17. Diabetic neuropathy:
* Polyneuropathy : Symmetrical, mainly sensory &distal
Asymmetrical, mainly motor &proximal
* Mononeuropathy (including mononeuritis multiplex)
- Visceral (autonomic).
Symmetrical sensory polyneuropathy.
This is frequent asymptomatic, the most commune sign are loss of tendon
reflex in the lower limbs ,↓ perception of vibration sense distally & glove and
stocking impairment of all other modalities of sensation. symptoms include
paraesthesia in the feet and sometime in the hand, pain in the lower limbs(dull
aching lancinating worse at night &mainly felt on the anterior aspect of the
leg),burning sensation on the sole of the feet &abnormal gait(commonly wide
-There may be perforating painless ulcer on the feet and painless distal
arthropathy characterized by disorganization of the joint (Charcot joint), on
investigation both motor and sensory conduction velocity is reduced and C.S.F
protein may be raised. For pain and parasthesia treatment is by intensive
insulin therapy, tricyclic antidepressant (amitryptiline or imipramine), other
drugs are anticonvulsants (gabapentin,pregabalin,carbamazepine and
Asymmetrical motor diabetic neuropathy
Sometime called diabetic amyotrophy. Present as sever & progressives
weakness & wasting of the proximal muscle of the lower limb. And is
commonly accompanied by sever pain on the anterior aspect of the leg
sometime there may also be marked weight loss (neuropathic cachexia) tendon
reflex may be absent on the affected side, again C.S.F. protein is commonly
Wrist drop .foot drop. 3rd
cranial nerve palsy & reversibility is high.
18. Autonomic neuropathy
This is not necessarily associated with peripheral somatic neuropathy.
Feature of autonomic neuropathy.
C.V.: postural hypotension, resting tachycardia, fixed heart rate
G.I.T.: Dysphagia, gastroparesis, abdominal fullness, nausea. Vomiting
nocturnal diarrhea, Constipation.
G.U.S: Atomic bladder, impotence & retrograde ejaculation, impotence affects
30% of diabetic male & is often multifactorial.
Other features: Gustatory sweating. Dependent edema on pupillay exam then is
↓ pupillay size resistant to mydriasis.
Loss of awareness of hypoglycemia.
Autonomic neuropathy is less related to poor metabolic control than somatic
neuropathy. And improved control rarely results in amelioration of symptoms.
Treatment is symptomatic, patients with gastro paresis may benefit from use of
metoclopramide .cisapride or erythromycin, diabetic diarrhea may benefit from
a trial of antibiotic orthostatic hypotension may be treated with salt tablets,
support stocking or 9 α fluorohydrocortisone.
Callus formula is the initial abnormally usually.
Foot ulcer is due to microangiopathy, macroangiopathy (ischemia), neuropathy
(plantar surface) or all 3.
Management: Removals of the callus skin best done by chiropodist, treat
infection, avoid weight bearing, and ensure good diabetic control. (Insulin may
be required in type2DM) control edema. Undertake angiogram to assess
feasibility of vascular re constriction where indicated.
Indication of amputation
1/ uncontrolled infection.
3/ extensive tissue destruction
4/ in tractable pain at rest in the limb.