Diabetes mellitus

 Definition .
 Insulin (synthesis , release , action).
 Types of diabetes mellitus .
 CLINICAL PRESENTATION OF DIABETES
 DIAGNOSIS AND INVESTIGATION OF DIABETES
 RISK FACTOR
 FOCUS HISTORY

 Diabetes mellitus is derived from the Greek
word diabetes meaning siphon - to pass through and the
Latin word mellitus meaning honeyed or sweet. This is
because in diabetes excess sugar is found in blood as
well as the urine

 Diabetes mellitus (DM) is a syndrome of chronic
hyperglycaemia is due to one of two mechanisms:
 Inadequate production of insulin ,
or
 Inadequate sensitivity of cells to the action of insulin.
 It affects more than 220 million people worldwide, and it is
estimated that it will affect 440 million by the year 2030.

 is a peptide hormone produced by beta cells in
the pancreas.
 it regulates the metabolism of carbohydrates and fats by
promoting the absorption of glucose from the blood
to skeletal muscles and fat tissue and by causing fat to
be stored rather than used for energy.
 Insulin also inhibits the production of glucose by the
liver.

 The responsible gene of insulin is the gene in short arm of
chromosome 11 .
 The ribosomes manufacture pre-proinsulin from insulin mRNA.
The hydrophobic ‘pre’ portion of pre-proinsulin allows it to transfer
to RER .
 Then the endopeptidase enzyme will digest the initial sequence
and give proinsulin . (The proinsulin molecule folds back on itself
and is stabilized by disulphide bonds ) .
 Proinsulin is transported in the vesicules from the RER to Golgi
apparatus. Then the endopeptidase will separate c chain from
proinsulin that gives mature insulin and c-peptide .

 Then the insulin and c-peptide it will go out from golgi
apparatus by secretory vesicules .
 Equimolar quantities of insulin and C-peptide are released into
the circulation via the ‘regulated pathway’.
 A small amount of insulin is secreted by the beta cell directly
via the ‘constitutive pathway’, which bypasses the secretory
granules

 regulated
secretion
 proteins are packaged as
described in the constitutive
pathway .
 but they are only secreted in
response to a specific signal,
such as neural or hormonal
stimulation .
 Examples of cells that use
regulated pathway are:
goblet cells
(secrete mucus), beta
cells of the pancreas
(secrete insulin) .
 constitutive secretion.
 Proteins are continuously secreted
from the cell regardless of
environmental factors.
 No external signals are needed to
initiate this process.
 Proteins are packaged in vesicles in
the Golgi apparatus and are secreted
via exocytosis, all around the cell.
 Cells that secrete constitutively have
Golgi apparatus scattered throughout
the cytoplasm.
 Fibroblasts, osteoblasts and chondroc
ytes are some of the many cells that
perform constitutive secretion.

 GLUT-1 – enables basal non-insulin-stimulated glucose
uptake into many cells .
 GLUT-2 – transports glucose into the beta cell, a
prerequisite for glucose sensing, and is also present in the
renal tubules and hepatocytes.
 GLUT-3 – enables non-insulin-mediated glucose uptake
into brain neurones and placenta.
 GLUT-4 – enables much of the peripheral action of
insulin. It is the channel through which glucose is taken
up into muscle and adipose tissue cells following stimulation of
the insulin receptor .

 Glucose enters the beta cell via the GLUT-2 transporter protein,
which is closely associated with the glycolytic enzyme glucokinase.
Metabolism of glucose within the beta cell generates ATP.
 ATP closes potassium channels in the cell membrane. If a
sulfonylurea binds to its receptor, this also closes potassium
channels.

 Closure of potassium channels predisposes to cell membrane
depolarization, allowing calcium ions to enter the cell via
calcium channels in the cell membrane.
 The rise in intracellular calcium triggers activation of
calcium-dependent phospholipid protein kinase which, via
intermediary phosphorylation steps, leads to fusion of the
insulin-containing granules with the cell membrane and
exocytosis of the insulin-rich granule contents.

 the receptor for insulin is embedded in the plasma
membrane. The insulin receptor is composed of two alpha
subunits and two beta subunits linked by disulfide bonds.
The alpha chains are entirely extracellular and house
insulin binding domains, while the linked beta chains
penetrate through the plasma membrane.

 Insulin and Carbohydrate Metabolism .
 Glucose is liberated from dietary carbohydrate such as
starch or sucrose by hydrolysis within the small intestine,
and is then absorbed into the blood. Elevated concentrations
of glucose in blood stimulate release of insulin, and insulin
acts on cells thoughout the body to stimulate uptake,
utilization and storage of glucose. The effects of insulin on
glucose metabolism vary depending on the target tissue.
Two important effects are:

 The only mechanism by which cells can take up glucose is by
facilitated diffusion through a family of hexose transporters. In
many tissues - muscle being a prime example - the major
transporter used for uptake of glucose (called GLUT4) is made
available in the plasma membrane through the action of insulin.

 When insulin concentrations are low, GLUT4 glucose transporters
are present in cytoplasmic< vesicles, where they are useless for
transporting glucose. Binding of insulin to receptors on such cells
leads rapidly to fusion of those vesicles with the plasma membrane
and insertion of the glucose transporters, thereby giving the cell an
ability to efficiently take up glucose. When blood levels of insulin
decrease and insulin receptors are no longer occupied, the glucose
transporters are recycled back into the cytoplasm.
 It should be noted here that there are some tissues that do not
require insulin for efficient uptake of glucose: important examples are
brain and the liver. This is because these cells don't use GLUT4 for
importing glucose, but rather, another transporter that is not insulin-
dependent.

 . A large fraction of glucose absorbed from the small intestine
is immediately taken up by hepatocytes, which convert it into
the storage polymer glycogen.
 Insulin has several effects in liver which stimulate glycogen
synthesis. First, it activates the enzyme hexokinase, which
phosphorylates glucose, trapping it within the cell.
Coincidently, insulin acts to inhibit the activity of glucose-6-
phosphatase. Insulin also activates several of the enzymes
that are directly involved in glycogen synthesis, including
phosphofructokinase and glycogen synthase. The net effect is
clear: when the supply of glucose is abundant, insulin "tells"
the liver to bank as much of it as possible for use later.

A well-known effect of insulin is to decrease the
concentration of glucose in blood .

diabetes is classified into:
 Type 1 diabetes, which has an immune
pathogenesis
and is characterized by severe insulin deficiency .
 Type 2 diabetes, which results from a
combination of
insulin resistance and less severe insulin deficiency
.

 Type 1 diabetes mellitus is characterized by loss of the
insulin-producing beta cells of the islets of Langerhans in the
pancreas, leading to insulin deficiency. This type can be
further classified as immune-mediated or idiopathic. The
majority of type 1 diabetes is of the immune-mediated nature,
in which a T-cell-mediated autoimmune attack leads to the
loss of beta cells and thus insulin. It causes approximately
10% of diabetes mellitus cases in North America and Europe.
 termed "juvenile diabetes" because a majority of these
diabetes cases were in children.

 Type 1 diabetes is partly inherited, with multiple genes,
including certain HLA genotypes, known to influence the risk
of diabetes. In genetically susceptible people, the onset of
diabetes can be triggered by one or more environmental
factors, such as a viral infection or diet. There is some
evidence that suggests an association between type 1
diabetes and Coxsackie B4 virus. Unlike type 2 diabetes, the
onset of type 1 diabetes is unrelated to lifestyle.

 Type 2 diabetes mellitus is characterized by insulin
resistance, which may be combined with relatively
reduced insulin secretion. The defective responsiveness
of body tissues to insulin is believed to involve
the insulin receptor. However, the specific defects are
not known. Type 2 diabetes is the most common type.

 Type 2 diabetes is due primarily to lifestyle factors and
genetics.A number of lifestyle factors are known to be
important to the development of type 2 diabetes,
including obesity , lack of physical activity, poor diet and
stress .

Type 1
diabetes
Type 2 diabetesFeature
SuddenGradualOnset
Mostly in
children
Mostly in adultsAge at onset
Thin or
normal
Often obeseBody size
CommonRareKetoacidosis
Usually presentAbsentAutoantibodies
Low or absent
Normal, decreased
or increased
Endogenous insulin
50%90%
Concordance
in identical twins
~10%~90%Prevalence

 Gestational diabetes mellitus (GDM) resembles type 2
diabetes in several respects, involving a combination of
relatively inadequate insulin secretion and responsiveness. It
occurs in about 2–10% of all pregnancies and may improve
or disappear after delivery .

 Prediabetes indicates a condition that occurs
when a person's blood glucose levels are
higher than normal but not high enough for a
diagnosis of type 2 DM .
 Latent autoimmune diabetes of adults (LADA) is a
condition in which type 1 DM develops in
adults .

 Genetic defects of β-cell
function:
 Maturity onset diabetes of the
young.
 Mitochondrial DNA mutations.
 Genetic defects in insulin
processing or insulin action :
 Defects in proinsulin conversion.
 Insulin gene mutations.
 Insulin receptor mutations.
 Exocrine pancreatic defects :
 Chronic pancreatitis.
 Pancreatectomy.
 Pancreatic neoplasia.
 Cystic fibrosis.
 Hemochromatosis.
 Fibrocalculous pancreatopathy.
 Endocrinopathies :
 Growth hormone excess
(acromegaly) .
 Cushing syndrome .
 Hyperthyroidism .
 Pheochromocytoma .
 Glucagonoma .
 Infections :
 Cytomegalovirus infection .
 Coxsackievirus B .
 Drugs :
 Glucocorticoids.
 Thyroid hormone.
 β-adrenergic agonists.
 Statins.

 Presentation may be acute, subacute or asymptomatic.
 Acute presentation
 Young people often present with a 2–6-week
history and report the classic triad of symptoms:
 Polyuria – due to the osmotic diuresis that results
when blood glucose levels exceed the renal
threshold
 Thirst – due to the resulting loss of fluid and
electrolytes
 Weight loss – due to fluid depletion and the
accelerated breakdown of fat and muscle
secondary to insulin deficiency.
 Ketonuria is often present in young people and
may progress to ketoacidosis if these early
symptoms are not recognized and treated.

 Subacute presentation
 The clinical onset may be over several months
or years, particularly in older patients.
Thirst, polyuria and weight loss are typically
present but patients may complain of such
symptoms as lack of energy, visual blurring
(owing to glucose-induced changes in
refraction) or pruritus vulvae or balanitis
that is due to Candida infection.

 Complications as the presenting feature
 These include:
 Staphylococcal skin infections
 Retinopathy noted during a visit to the
optician
 A polyneuropathy causing tingling and
numbness in the feet
 Erectile dysfunction
 Arterial disease, resulting in myocardial
infarction or peripheral gangrene.

 Asymptomatic diabetes
 Glycosuria or a raised blood glucose may
be detected on routine examination (e.g.
for insurance purposes) in individuals who
have no symptoms of ill-health. Glycosuria
is not diagnostic of diabetes but indicates
the need for further investigations. About
1% of the population have renal
glycosuria. This is an inherited low renal
threshold for glucose, transmitted either
as a Mendelian dominant or recessive
trait.

Evidence of weight loss and dehydration
may be present, and the breath may smell
of ketones. Older patients may present
with established complications, and the
presence of the characteristic retinopathy
is diagnostic of diabetes. In occasional
patients, there will be physical signs of an
illness causing secondary diabetes
.Patients with severe insulin resistance
may have acanthosis nigricans, which is
characterized by blackish pigmentation at
the nape of the neck and in the axillae.

 Acanthosis nigricans presents as thickened,
hyperpigmented skin predominantly of the
flexures . It can appear warty or velvety when
advanced. In early life it is seen in obese
individuals who have very high levels of
insulin owing to insulin resistance (and this is
sometimes termed ‘pseudo-acanthosis
nigricans’). In older people it normally
reflects an underlying malignancy (especially
gastrointestinal tumours). Rarely it is
associated with hyperandrogenism in females.

WHO criteria for the diagnosis of diabetes are:
 Fasting plasma glucose >7.0 mmol/L (126
mg/dL)
 Random plasma glucose >11.1 mmol/L (200
mg/dL)
 One abnormal laboratory value is diagnostic
in symptomatic individuals; two values are
needed in asymptomatic people. The glucose
tolerance test is only required for borderline
cases and for diagnosis of gestational
diabetes.
 HbA1c >6.5 (48 mmol/mol).

Glucose tolerance test – WHO criteria
Diabetes
mellitus
Impaired
glucose
Tolerance
normal
>7.0mmol/L<7.0mmol/L<7.0 mmol/Lfasting
>11.1mmol/L7.8-
11.0mmol/L
<7.8mmol/L2h after glucose

 Adult: 75 g glucose in 300 mL water
 Child: 1.75 g glucose/kg bodyweight
 Only a fasting and a 120-min sample are
needed
 Results are for venous plasma – whole blood
values are lower.
 Note: There is no such thing as mild diabetes.
All patients who meet the criteria for
diabetes are liable to disabling long-term
complications.

 Impaired glucose tolerance (IGT)
 . This is not a clinical entity but a risk factor
for future diabetes and cardiovascular
disease. The diagnosis can only be made with
a glucose tolerance test, and is complicated
by poor reproducibility of the key 2-hour
value in this test. The group is heterogeneous;
some patients are obese, some have liver
disease and others are on medication that
impairs glucose tolerance. Individuals with
IGT have the same risk of cardiovascular
disease as those with frank diabetes, but do
not develop the specific microvascular
complications

 Impaired fasting glucose (IFG)
 This diagnostic category (fasting plasma
glucose between 6.1 and 6.9 mmol/L) has the
practical advantage that it avoids the need
for a glucose tolerance test. It is not a clinical
entity, but indicates future risk of frank
diabetes and cardiovascular disease. IFG only
overlaps with IGT to a limited extent, and the
associated risks of cardiovascular disease and
future diabetes are not directly comparable.
A lower cut-off of 5.6 mmol/L (rather than 6.1
mmol/L) has been recommended by the
American Diabetes Association (ADA) and
would, if implemented, greatly increase the
number of those in this category.

 Haemoglobin A1c (HbA1c)
 HbA1c is an integrated measure of an
individual’s prevailing blood glucose
concentration over several weeks.
Standardization of this measure has enabled
it to be proposed as an alternative diagnostic
test for diabetes by the American Diabetes
Association. As currently proposed, an
HbA1c >6.5% (48 mmol/mol) would be
considered diagnostic of diabetes, whereas a
level of 5.7–6.4% (39–46 mmol/mol) would
denote increased risk of diabetes. A WHO
Consultation recently also concluded that
HbA1c ‘can be used as a diagnostic test for
diabetes’.

 Unfortunately, there is relatively little
concordance between IGT, IFG and HbA1c as
markers of ‘prediabetes’. Furthermore, there
will be many people in a mixed population
who are ‘diabetic’ using the HbA1c criteria but
‘normal’ on glucose tolerance testing. Many
are uncomfortable with this concept.

 Other investigations
 No further tests are needed to diagnose diabetes.
Other routine investigations include urine testing
for protein, a full blood count, urea and
electrolytes, liver biochemistry and random lipids.
The latter test is useful to exclude an associated
hyperlipidaemia and, if elevated, should be
repeated fasting after diabetes has been brought
under control. Diabetes may be secondary to other
conditions ,may be precipitated by underlying
illness and be associated with autoimmune disease
or hyperlipidaemia. Hypertension is present in
50% of patients with type 2 diabetes and a higher
proportion of African and Caribbean patients.

 Genetic susceptibility
 No family history – 0.4 percent
 ●Offspring of an affected mother – 1 to 4 percent
 ●Offspring of an affected father – 3 to 8 percent
 ●Offspring with both parents affected – reported
as high as 30 percent.
 ●Non-twin sibling of affected patient – 3 to 6
percent
 ●Dizygotic twin – 8 percent
 ●Monozygotic twin – 30 percent within 10 years of
diagnosis of the first twin, and 65 percent
concordance by age 60 years

 Geography. The incidence of type 1 diabetes
tends to increase as you travel away from the
equator. People living in Finland and Sardinia
have the highest incidence of type 1 diabetes
— about two to three times higher than rates
in the United States and 400 times the
incidence among people living in Venezuela.
 Age. Although type 1 diabetes can appear at
any age, it appears at two noticeable peaks.
The first peak occurs in children between 4
and 7 years old, and the second is in children
between 10 and 14 years old.

 Many other possible risk factors for type 1 diabetes
have been investigated, though none have been proved.
Some other possible risk factors include:
 Exposure to certain viruses, such as the Epstein-Barr
virus, Coxsackie virus, mumps virus and
cytomegalovirus
 Early exposure to cow's milk
 Low vitamin D levels
 Drinking water that contains nitrates
 Early (before 4 months) or late (after 7 months)
introduction of cereal and gluten into a baby's diet
 Having a mother who had preeclampsia during
pregnancy
 Being born with jaundice

 Identifying risk factors for diabetes type 2 may
help to target specific patient groups for screening.
Risk factors for diabetes include the following :
 ●Age ≥45 years.
 ●Overweight (body mass index (BMI)
≥25 kg/m2). The risk with increased weight is also a
continuum, with significantly increased risk for
obese individuals (eg, BMI ≥30 kg/m2).
 ●Diabetes mellitus in a first-degree relative.
 ●Sedentary lifestyle.
 ●High-risk ethnic or racial group (eg, African-
American, Hispanic, Native American, Asian-
American, and Pacific Islanders).

 ●History of delivering a baby weighing >4.1
kg (9 lb) or of gestational diabetes mellitus.
 ●Hypertension (blood
pressure ≥140/90 mmHg).
 ●Dyslipidemia (serum high-density lipoprotein
cholesterol concentration
≤35 mg/dL [0.9 mmol/L] and/or serum
triglyceride concentration
≥250 mg/dL [2.8 mmol/L]).
 ●A1C ≥5.7 percent, impaired glucose
tolerance or impaired fasting glucose.
 ●Polycystic ovary syndrome.
 ●History of vascular disease

 Is the patient's diabetes generally well
controlled (with near-normal blood glucose
levels) - Patients with poorly controlled
blood glucose levels heal more slowly and
are at increased risk for infection and
other complications
 Does the patient have
severe hypoglycemic reactions - If the
patient has episodes of severe
hypoglycemia and therefore is at risk of
losing consciousness, this possibility must
be addressed, especially if the patient
drives or has significant underlying
neuropathy or cardiovascular disease

 Does the patient have diabetic nephropathy that
might alter the use ofmedications or intravenous (IV)
radiographic contrast material
 Does the patient have macrovascular disease, such
as coronary artery disease (CAD) that should be
considered as a source of acute symptoms
 Does the patient self-monitor his or her blood
glucose levels - If so, note the frequency and range
of values at each time of day
 When was the patient's hemoglobin A1c (HbA1c; an
indicator of long-term glucose control) last
measured, and what was it
 What is the patient’s immunization history - Eg,
influenza, pneumococcal, hepatitis B, tetanus,
herpes zoster

 The major components of the treatment of diabetes
are:
• Diet and ExerciseA
• Oral hypoglycaemic
therapyB
• Insulin TherapyC

 Diet is a basic part of management in every
case. Treatment cannot be effective unless
adequate attention is given to ensuring
appropriate nutrition.
 Dietary treatment should aim at:
◦ ensuring weight control
◦ providing nutritional requirements
◦ allowing good glycaemic control with blood
glucose levels as close to normal as possible
◦ correcting any associated blood lipid
abnormalities

The following principles are recommended as dietary guidelines
for people with diabetes:
 Dietary fat should provide 25-35% of total intake of calories but
saturated fat intake should not exceed 10% of total energy.
Cholesterol consumption should be restricted and limited to 300
mg or less daily.
 Protein intake can range between 10-15% total energy (0.8-1 g/kg
of desirable body weight). Requirements increase for children and
during pregnancy. Protein should be derived from both animal and
vegetable sources.
 Carbohydrates provide 50-60% of total caloric content of the diet.
Carbohydrates should be complex and high in fibre.
 Excessive salt intake is to be avoided. It should be particularly
restricted in people with hypertension and those with
nephropathy.

 Physical activity promotes weight reduction and
improves insulin sensitivity, thus lowering blood
glucose levels.
 Together with dietary treatment, a programme
of regular physical activity and exercise should
be considered for each person. Such a
programme must be tailored to the individual’s
health status and fitness.
 People should, however, be educated about the
potential risk of hypoglycaemia and how to
avoid it.

 There are currently four classes of oral anti-
diabetic agents:
i. Biguanides
ii. Insulin Secretagogues – Sulphonylureas
iii. Insulin Secretagogues – Non-sulphonylureas
iv. α-glucosidase inhibitors
v. Thiazolidinediones (TZDs)

 If glycaemic control is not achieved (HbA1c > 6.5%
and/or; FPG > 7.0 mmol/L or; RPG >11.0mmol/L)
with lifestyle modification within 1 –3 months,
ORAL ANTI-DIABETIC AGENT should be initiated.
 In the presence of marked hyperglycaemia in newly
diagnosed symptomatic type 2 diabetes (HbA1c >
8%, FPG > 11.1 mmol/L, or RPG > 14 mmol/L), oral
anti-diabetic agents can be considered at the
outset together with lifestyle modification.

As first line therapy:
 Obese type 2 patients, consider use of metformin,
acarbose or TZD.
 Non-obese type 2 patients, consider the use of metformin
or insulin secretagogues
 Metformin is the drug of choice in overweight/obese
patients. TZDs and acarbose are acceptable alternatives
in those who are intolerant to metformin.a
 If monotherapy fails, a combination of TZDs, acarbose and
metformin is recommended. If targets are still not
achieved, insulin secretagogues may be added

Combination oral agents is indicated in:
 Newly diagnosed symptomatic patients with
HbA1c >10
 Patients who are not reaching targets after 3
months on monotherapy

 If targets have not been reached after optimal dose of
combination therapy for 3 months, consider adding intermediate-
acting/long-acting insulin (BIDS).
 Combination of insulin+ oral anti-diabetic agents (BIDS) has been
shown to improve glycaemic control in those not achieving target
despite maximal combination oral anti-diabetic agents.
 Combining insulin and the following oral anti-diabetic agents has
been shown to be effective in people with type 2 diabetes:
◦ Biguanide (metformin)
◦ Insulin secretagogues (sulphonylureas)
◦ Insulin sensitizers (TZDs)(the combination of a TZD plus insulin is not
an approved indication)
◦ α-glucosidase inhibitor (acarbose)
 Insulin dose can be increased until target FPG is achieved.

Examples: Phenformin, Metformin
Adverse effects:
Phenformin causes lactic acidosis (no longer used)
Mechanism of action:
 Facilitate glucose uptake by cells
 Increase peripheral utilization of glucose by
stimulating anaerobic utilization of glucose. In
this case glucose molecule produce 2 instead of
38 ATP. Therefore consume more glucose
 Inhibit hepatic gluconeogenesis
 Cause anorexia and weight loss (which is
beneficial)

 In elderly non-obese patients, short acting insulin secretagogues can be
started but long acting Sulphonylureas are to be avoided. Renal function
should be monitored.
 Oral anti-diabetic agent s are not recommended for diabetes in pregnancy
 Oral anti-diabetic agents are usually not the first line therapy in diabetes
diagnosed during stress, such as infections. Insulin therapy is
recommended for both the above
 Targets for control are applicable for all age groups. However, in patients
with co-morbidities, targets are individualized
 When indicated, start with a minimal dose of oral anti-diabetic agent,
while reemphasizing diet and physical activity. An appropriate duration of
time (2-16 weeks depending on agents used) between increments should
be given to allow achievement of steady state blood glucose control

Short-term use:
 Acute illness, surgery, stress and emergencies
 Pregnancy
 Breast-feeding
 Insulin may be used as initial therapy in type 2 diabetes
 in marked hyperglycaemia
 Severe metabolic decompensation (diabetic ketoacidosis,
hyperosmolar nonketotic coma, lactic acidosis, severe
hypertriglyceridaemia)
Long-term use:
 If targets have not been reached after optimal dose of
combination therapy or BIDS, consider change to multi-
dose insulin therapy. When initiating this,insulin
secretagogues should be stopped and insulin sensitisers
e.g. Metformin or TZDs, can be continued.

 The majority of patients 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 used regimen.
 In some cases, a mixture of short- and intermediate-acting
insulin may be given in the morning. Further doses of short-
acting insulin are given before lunch and the evening meal and an
evening dose of intermediate-acting insulin is given at bedtime.
 Other regimens based on the same principles may be used.
 A regimen of multiple injections of short-acting insulin before the
main meals, with an appropriate dose of an intermediate-acting
insulin given at bedtime, may be used, particularly when strict
glycaemic control is mandatory.

duratio
n
peakonsetexamplepreparation
6-8 hr
12-16
hr
3 hr
6-10
hr
1 hr
1hr
Soluble insulne (normal or regular
insuline )
Cristllince zinc insuline (insulin
semilent 20,40,80,100 iu/ml
Rapid action
28-
32hr
18-
30hr
12-
30hr
8-12
hr
8-12
hr
6-12
hr
2-4 hr
2-4 hr
2-4 hr
Insulin zinc suspention
NPH(neutral protamine
hagedorn)when subcutanous injeted
,it is neutralized in tissue where the
insulin –protien complex breaks down
and realeses insulin )
Globin zinc insulin injection
Intermediate
d action
24-
48hr
36hr
14-
20hr
6-8 hr
3-6 hr
6-8 hr
Protamine zinc insulin injection
Insulin zinc suspntion
Long action

 Insulin is metabolized in the liver by specific
protease (insulinase) and is also cleared by
peripheral tissues and the kidney. Being a
polypeptide, insulin is destroyed by the digestive
enzymes therefore it is inactive orally.
 Adverse effects: Hypoglycemia.
 Allergic reactions: Skin sensitivity, itching,
erythema and swelling This allergic reactions can
be treated by antihistaminics
 Fat necrosis at the site of injection: Can be
avoided by using smaller doses of insulin or
diluting insulin

 Patients should be educated to practice self-
care. This allows the patient to assume
responsibility and control of his / her own
diabetes management. Self-care should
include:
◦ Blood glucose monitoring
◦ Body weight monitoring
◦ Foot-care
◦ Personal hygiene
◦ Healthy lifestyle/diet or physical activity
◦ Identify targets for control
◦ Stopping smoking

Chronic complicationAcute complication
Microvascular complicationhypoglycemia
Macrovascular complicationDiabetes ketoacidosis (DKA)
Non ketotic hyperosmolar coma

PresentationsComplication
Microvascular
Impaired vision1_ retinopathy , cataract
Renal failure2_ nephropathy
Sensory loss , motor weakness3_peripheral neuropathy
Postural hypotension , impotence ,
gastropathy
4_autonomic neuropathy
Ulceration , infection5_ foot disease
Macrovasascular
Angina , MI1_coronary artery disease
TIA , stroke2_cerebral ischemia
Claudication3_ periphral vascular disease

Causes :
 Implance between injected insulin and
patient normal diet , activity and basal
insulin requirement .
 Irregular eating habit , unusual exertion and
alcohol excess .
 Impaired ability to counter regulate glucose
level after after hypoglycemia in diabetic
patient
 Glucagon response is lost .

Cause of hypoglycemia related to diabetes :
1. Missed or delayed meal .
2. Unusual exercise.
3. Alcohol.
4. Poorly designed insulin regimen , particularly that
predisposing to nocturnal hypoglycemia.
5. Other endocrine disorder as Addison disease
6. Malabsorption
7. Error in oral hypoglycemic agent or insulin does or
administration

 Symptoms of hypoglycemia begin at plasma
glucose 60 mg /dl ; brain impairment
develops at approximately 50 mg/ dl ( brain
damage after prolonged sever hypoglycemia
is not reversible )

Symptoms of hypoglycemia
Autonomic
•Sweating
•Tremor
•Tachycardia
•Anxiety
•Pallor
•Hunger
Neurological
•Confusion
•Drowsiness
•Speech difficulty
•Inability to concentrated
•Incoordination
Non specific
•Nausea
•Tridness
•Headache
Due to stimulation of sympathetic system as a
compensatory mechanism which glucose by
glycogenolysis.
Due to parasympathetic stimulation .

 But some patient with long duration of
diabetes do not have such symptoms and go
in to sever hypoglycemia and rapidly
occurring of hypoglycemia coma .

 It is a group of feature related to hypoglycemia due
to any cause and consists of :
1. History of hypoglycemia symptoms .
2. Fasting blood glucose of 40mg / dl or less
3. Immediate recovery after administration of glucose
.

1. Patient conscious : oral glucose drink .
2. Patient unconscious : 50 ml of 50% dextrose
water IV or injection of glucagon 1 mg IM .
3. Precaution : patient should carry some
tables of glucose for use in emergency .
(patient with hypoglycemia caused by oral
hypoglycemia agent or long acting insulin
should be admitted and observed because
the hypoglycemia may be recurrent due to
the prolonged duration of these drugs )

 DKA is a medical emergency with mortality
rate about 5% .
 It may be the initial manifestation of type 1
diabetes or may be result from increased
insulin requirement in type 1 diabetes
patient during the course of stress such as
infection , trauma , surgery or MI.
 Type 2 may developed DKA under sever stress
such as infection .

Precipitating factors :
1. Acute infection : bacterial or viral .
2. Omission or drastically reduction the dose
of insulin .
3. New onset of type1 diabetes ( about 25%
patient of type1 are first time diagnosis
when they present with ketoacidosis )

1. Hyperglycemia ( usually > 250 mg /dl ) the
magnitude of hyperglycemia doe not
correlate with the severity of metabolic
acidosis : moderate elevation of blood
glucose may be associated with life
threatening ketoacidosis . There is +++
glycosuria .
2. Metabolic acidosis
 Blood ph < 7.3
 Serum bicarbonate < 15 meg / l

3. Hyperketonemia and ketonuria
Urinary ketones strongly ++++ .

1. Hyperglycemia
insulin level glucose level
Osmotic
dieresis
Loss of fluid and
electrolytes
Dehydration , hypovolemia and SODIUM ,
potassium and other electrolyte depletion .

2. Metabolic acidosis
insulin level release of fatty acids from
adipose tissue
Ketone bodies production from fatty acid
more rapidly than can be metabolized
Accumulation of acid in form of keton
bodies
Fall in blood PH
Hyperventilation
-ve intropic on
heart
Vd and hypotension
Potassium depletion

 Feature of dehydration and acidosis
 Symptoms
1. Intense thirst.
2. Polyuria.
3. Nausea, vomiting .
4. Abdominal pain more common in children .

 Signs
1. Dry tongue , inelastic skin , sunken eyes.
2. Kusmauls respiration ( rapid and deep
breathing ) .
3. Hypotension .
4. Rapid weak pulse.
5. Hypothermia.
6. Fruity breath odor of acetone .

6. Level of consciousness is variable . Patient
with severe ketoacidosis may conscious and
alter . Drowsiness is usual but coma is
uncommon . Level of consciousness depend
on serum osmolarity not on level of acidosis .
When serum osmolarity exceeds 320-330
mosm/ l . CNS depression or coma develops .
( normal value is 280-300mosm/l ) .

 Formula for calculation of serum osmolarity
is :
Serum osmolality = 2[NA] + K+ glucose / 18

1. Fingerstick blod glucose and electrolytes
hourly for 3 hours then 2-4 hourly
thereafter.
2. Bp , pulse, temperature and respiration
hourly .
3. Urine output.
4. Urinary ketones
5. ECG, ABG, Plasma osmolarity.

 DKA is medical emergency and should be
treated in hospital . The principle of
treatment are :
1. Fluid replacement.
2. Regular insulin by IV OR IM.
3. Potassium replacement .
4. AB if infection is present .

 This condition, in which sever hyperglycemia
develops without significant ketosis , is the
metabolic emergency characteristic of
uncontrolled type2 diabetes . Patient
present in middle or later life , often with
mild or previously undiagnosed diabetes
.infection, myocardial infraction , stroke, or
recent surgery is precipitating factor .

 Clinical feature
1. Dehydration .
2. Stupor or coma.
3. Nausea and vomiting .
4. Abdominal pain less common (no acidosis)
5. Hyperventilation

There are three factors responsible for tissue
necrosis in the feet of diabetic patients:
 Neuropathy : patient does not feel pain due
to sensory neuropathy therefore if he gets
injury , there is no feeling of pain resulting
in negligence of wound care . This leads to
tissue necrosis .
 Ischemia .
 Infections : diabetic patient is more prone
to have skin infection and there is
decreased ability of wound healing .

 Treat infection .
 Ensure good diabetic control .
 Control edema .
 Remove callous skin .
 Take care of foot .

 Hyperglycemia diagnosis for the first time in
pregnancy . It occur in individuals who have
an inherited predisposition to develop
diabetes and may take the form of either
type 1 or type2 .
 Increase rate of perinatal morbidity and
neonatal mortality and also with high
incidence of subsequent diabetes in mother.

 Diet modification and insulin ( does not pass
placental ).
 Does not increase the risk of congenital
abnormalities.
 Not all diabetes in pregnancy are gestational
diabetes , true diabetes type 1 may first
time appear during pregnancy .

Pathogenesis:
•Histologically the earliest lesion is thickening of the
capillary basement membrane.
•On fluorescein angiography the first abnormality is the
capillary dilatations (microaneurysms).
• Microaneurysm may give rise to haemorrhage or
exudate.
•Vascular occlusion, initially of capillaries and later of
arteries and veins, leads to large ischaemic areas
(cotton-wool spots).

Background Retinopathy:
• Micro aneurysms
• Scattered exudates
• Hemorrhages(flame shaped, Dot
and Blot)
• Cotton wool spots (<5)
• Venous dilatations

 Proliferative Retinopathy
 New vessels (on disc)
 Fibrous proliferation (on disc)
 Hemorrhages (preretinal)

 Cataracts.
 Glaucoma
 Macular edema.
Ischaemic maculopathy.
Proliferative retinopathy.
Vitreous Bleeding.
Rubeosis Iridis

Diabetes mellitus

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Diabetes mellitus