ENDOCRINE PANCREAS

The endocrine pancreas secretes two

major peptide Hormones: Insulin and
Glucagon, whose coordinated functions
are to regulate glucose, fatty acid, and
amino acid metabolism.
The endocrine pancreas also secretes:
Somatostatin
Pancreatic Polypeptide
Ghrelin

The endocrine cells of the pancreas are

arranged in clusters called:
the Islets of Langerhans, which
compose 1% to 2% of the pancreatic
mass. They are scattered throughout the
glandular substance of the exocrine
pancreas.
There are approximately 1 million islets of
Langerhans, each containing about 2500
cells.

The islets of Langerhans contain

following cell types

Schematic drawing showing the arrangement

of cell types and the hormones they secrete in
an islet of Langerhans

Structure and Synthesis of Insulin

Insulin is a peptide hormone consisting of two
straight chains, an A chain (21 amino acids)
and a B chain (30 amino acids).
Two disulfide bridges link the A chain to the B
chain, and a third disulfide bridge is located
within the A chain.
The synthesis of insulin is directed by a gene
on chromosome 11 .

The mRNA directs ribosomal synthesis of

preproinsulin which contains of four
peptides:
A Signal peptide, the A and B chains of
insulin,
and a connecting peptide (C peptide).
The signal peptide is cleaved early in the
biosynthetic process , yielding proinsulin.
Proinsulin is packaged in secretory granules on
the Golgi apparatus.
During this packaging process, proteases
cleave the connecting peptide, yielding insulin.

Insulin and the cleaved connecting peptide

are packaged together in secretory granules,
and when the cell is stimulated, they are
released in equimolar quantities into the
blood.
The secretion of connecting peptide
(C peptide) is the basis of a test for cell
function in persons with type I diabetes
mellitus who are receiving injections of
exogenous insulin.

INSULIN SECRETION BY

CELLS

Regulation of Insulin Release

Summarized the factors that influence the

secretion of insulin by cells, the most important
is Glucose.
Increases in blood glucose concentration
rapidly stimulate the secretion of insulin. The steps
of insulin secretion are:

1. Transport of glucose into the cell. The cell

membrane contains GLUT 2, a specific
transporter for glucose that moves glucose from
the blood into the cell by facilitated diffusion (Step
1).

2. Metabolism of glucose inside the cell.

Once inside the cell, glucose is
phosphorylated to glucose- 6-phosphate by
glucokinase (Step 2), and glucose-6phosphate is subsequently oxidized (Step
3).
ATP, one of the products of this oxidation
step, appears to be the key factor that
regulates insulin secretion.

3.

ATP closes ATP-sensitive K+ channels. K+

channels in the -cell membrane are regulated (i.e.,
opened or closed) by changes in ATP levels. When
ATP levels inside the cell increase, the K+
channels close (Step 4), which depolarizes the -cell
membrane (Step 5).

4. Depolarization opens voltage-sensitive Ca2+

channels.
Ca2+ channels, also in the -cell membrane, are
regulated by changes in voltage; they are opened by
depolarization and closed by hyperpolarization. The
depolarization caused by ATP opens these Ca2+
channels (Step 6). Ca2+ flows into the cell down
its electrochemical gradient and the intracellular
Ca2+ concentration increases (Step 7).

5. Increased intracellular Ca2+ causes

insulin secretion. Increases in intracellular
Ca2+ concentration cause exocytosis of the
insulin-containing secretory granules (Step 8).
Insulin is secreted into pancreatic venous
blood and then delivered to the systemic
circulation.

Oral glucose is a more powerful stimulant

for insulin secretion than intravenous
glucose. The reason for this difference is that
oral glucose stimulates the secretion of
glucose-dependent insulinotropic
peptide (GIP), a gastrointestinal
hormone that has an independent
stimulatory effect on insulin secretion.
Intravenous glucose does not cause the
release of GIP and thus only acts directly.

Action of Insulin
The action of insulin on target cells begins when
the
hormone binds to its receptor in the cell
membrane.
The insulin receptor is a tetramer composed of
two subunits and two subunits.
The subunits lie in the extracellular domain, and
the subunits span the cell membrane.
A disulfide bond connects the two subunits, and
each subunit is connected to a subunit by a
disulfide bond.
The subunits have intrinsic tyrosine kinase
activity.

Structure of the insulin receptor

Major Actions of Insulin and

the Effect on Blood Levels

Diabetes Mellitus
Clinical diabetes mellitus is a
syndrome of disordered
metabolism with inappropriate
hyperglycemia due to an
absolute or relative deficiency of
insulin. There may also be a
defect in insulin action (insulin
resistance).

Classification
Diabetes is classified into 4 main groups
based on known pathological and etiologic
mechanisms:
1) Type 1
2) type 2
3) other specific types
4) gestational diabetes

Type 1 Diabetes Mellitus

Type 1 diabetes is immune-mediated in more

than 95% of cases (type 1a) and idiopathic in
less than 5% (type 1b).
Type 1b diabetes: Approximately 5% of
patients with the clinical features of type 1
diabetes lack serum evidence of autoimmunity.
The rate of pancreatic cell destruction
may vary, but in most cases the process is
prolonged, extending over months or years.

Type 1 a- 95%
Most patients with type 1 diabetes at diagnosis have
circulating antibodies against cell proteins:
Islet cell antibodies (ICA)
Insulin autoantibodies (IAA)
Antibodies to glutamic acid decarboxylase 65 (GAD),
Tyrosine phosphatase IA2 (ICA512)
Zinc transporter 8 (ZnT8)
These antibodies can often be detected well before the
onset of frank hyperglycemia, even decades earlier,
providing evidence that the autoimmune process may be
prolonged.
After diagnosis, autoantibody levels often decline with
increasing duration of the disease.

Genetics of Type 1
Diabetes
Family members of patients with type1
diabetes have an increased lifetime risk of
developing type 1 diabetes.
The offspring of a mother with type 1
diabetes have a risk of 3%, whereas the risk is
6% for children of affected fathers.
The risk in siblings of affected individuals is
related to the number of human leukocyte
antigen (HLA) haplotypes , that the sibling
shares.

The DR haplotypes DR3 and DR4 are

major susceptibility risk factors for
type 1 diabetes.
As many as 95% of type 1 diabetic
patients have a DR3 or a DR4 haplotype
or bothcompared with 45% to 50% of
Caucasian nondiabetic controls.
Individuals who express both a DR3 and a
DR4 allele carry the highest risk for type 1
diabetes in the United States.

Environmental Factors in Type 1

Diabetes
Numerous environmental events have been
proposed to trigger the autoimmune process
in genetically susceptible individuals; however,
none have been conclusively Iinked to diabetes.
Environmental factors associated with increased
risk of type 1 diabetes include viruses (mumps,
congenital rubella, Coxsackie virus B4), toxic
chemical agents such as vacor and other
destructive cytotoxins such as hydrogen cyanide.
Accumulating evidence shows that in the
process of modernizing and improving public
health, the risk of type 1 diabetes has increased.

Latent autoimmune diabetes of

adulthood (LADA)
Type 1 diabetes can present at any age,
although peaks in incidence occur before
school age and again at around puberty.
Older adults often present with a more
indolent onset that sometimes leads to
misdiagnosis and has led to the use of
the term :
latent autoimmune diabetes of
adulthood (LADA) to distinguish these
patients.

These initially unrecognized patients may

retain enough cell function at the outset to
avoid ketosis,
but develop increasing dependence on
insulin therapy over time as their cell mass
diminishes.
Islet cell antibody surveys among
northern Europeans indicate that up to
15% of patients previously diagnosed
with type 2 diabetes may actually
have LADA.

Type 2 diabetes mellitus

Type 2 diabetes mellituspreviously called
non-insulindependent diabetes or adult-onset
diabetes mellitusresults from relative insulin
deficiency, in contrast to the absolute insulin
deficiency of patients with type 1 diabetes.
Insulin resistance and abnormal insulin
secretion are central to the development of type 2
DM.
Insulin resistance can be broadly defined as
a decrease in tissue responsiveness to
insulin.

Type 2 DM is characterized
by:
1) Impaired insulin secretion
2) Insulin resistance
3) Excessive hepatic glucose
production
4) Abnormal fat metabolismDyslipidemia

Genetic and Environmental Factors

in Type 2 Diabetes
Type 2 diabetes accounts for 80% to 90% of
cases of diabetes in the United States.

Type 2 diabetes has a strong

genetic link!
!!!!!!!!
Depending on the population studied,
monozygotic twins have lifetime concordance
rates for type 2 diabetes exceeding 90%.

Despite the critical role of genetics in type 2

diabetes, environment contributes as well.
There is generally a low incidence of type 2
diabetes in underdeveloped countries,
especially in rural areas.
Western countries and westernizing countries
suffer from a much higher incidence.

This is related to :

Access of food
with high caloric
content and
decreased physical
activity !!!

Obesity in Type 2 Diabetes

The majority of people with type 2 diabetes have
excess adiposity !!!
Obesity, particularly visceral or central
(as evidenced by the hip-waist ratio) is in
more than 80% of patients with Type 2
Diabetes Mellitus.
More fat in the upper part of the body (particularly
the abdomen, chest, neck, and face) and relatively
less fat on the appendages, which may be quite
muscular (the metabolically obese).
This centripetal fat distribution has been termed
Android and is characterized by a high waist
circumference.

It differs from the more centrifugal Gynecoid form

of obesity, in which fat is localized more in the hips
and thighs and less in the upper parts of the
trunk.
A larger waist circumference increases the
risk for diabetes for any given body mass
index (BMI).
Thus in patients with the metabolic syndrome, a
waist circumference >40 in (102 cm) in men and
>35 in (88 cm) in women is associated with an
increased risk of diabetes.

Obesity classes
BMI = kilograms

eg: 80 kg= 24,7 kg/m2

meters 2
BMI

1.8 m2

Classification

< 18.5
18.524.9
25.029.9
30.034.9
35.039.9
40.0

underweight
normal weight
overweight
class I obesity
class II obesity
class III obesity (total obesity)

Maturity-onset diabetes of
the young (MODY)
Autosomal Dominant Genetic Defects of
Pancreatic Cells.
This subgroup of monogenic disorders is
characterized by the onset of diabetes in late
childhood or before the age of 25 years as a
result of a partial defect in glucose-induced insulin
release and accounts for up to 5% of diabetes in
North American and European populations.
A strong family history of early-onset diabetes
occurring in one parent and in one-half of the
parent's offspring suggests autosomal dominant
transmission

In contrast to most patients with type 2

diabetes, these patients are generally nonobese
and lack associated insulin resistance.
Instead they exhibit predominantly a defect in
glucose-stimulated insulin secretion.
However, because they are not ketosis-prone
and may initially achieve good glycemic control
without insulin therapy, their disease has been
called maturity-onset diabetes of the young
(MODY).
Several distinct types have been described with
single-gene defects, and all have been shown to
produce a defect in glucose-induced insulin
release.

enzyme. Most of the other forms of MODY are due to

mutations of nuclear transcription factors that
regulate the expression of genes in cells or cell
precursors

Other causes of DM
DM can result from pancreatic exocrin diseas,
When the majority of pancreatic islets are
destroyed.
Cystic fibrosis-related DM is an important
consideration in that patient population.
Hormones that antagonize insulin action can also
lead to DM. Thus, DM is often a
feature of endocrinopathies such as acromegaly
and Cushing's disease.
Viral infections have been implicated in pancreatic
islet destruction but are an extremely rare cause of
DM. A form of acute onset of type 1 diabetes
termed fulminant diabetes has been noted in
Japan and may be related to viral infection of islets.

Gestational Diabetes
Mellitus
Glucose intolerance developing
during pregnancy is classified as
gestational diabetes mellitus
(GDM) .
Insulin resistance is related to metabolic changes of
late pregnancy and the increased insulin
requirements may lead to IGT or diabetes.
GDM occurs in -7% (range 1 - 14%) of pregnancies
in the United States.
Most women revert to normal glucose tolerance
postpartum but have a substantial risk (35-60%)
of developing DM in the next 10-20 years.

The International Association of the Diabetes

and Pregnancy Study Groups and the
American Diabetes Association (ADA)

diabetes
diagnosed at the initial
prenatal visit should be
classified as ,,overt" diabetes
rather than GDM.
recommend that

With the rising rates of obesity, the number

of women being diagnosed with GDM or overt

Clinical Features of Diabetes Mellitus

When insulin deficiency is severe during DM

Type 1 and of acute onset, the above
symptoms progress in an accelerated manner.
Ketoacidosis exacerbates the
dehydration and hyperosmolality by
producing anorexia, nausea, and vomiting,
thus interfering with oral fluid replacement.
As plasma osmolality exceeds 330 mOsm/kg
(normal, 285-295 mOsm/kg), impaired
consciousness ensues.

With progression of acidosis to a pH of 7.1 or

less, deep breathing with a rapid ventilatory
rate (Kussmaul respiration) occurs as the
body attempts to eliminate carbonic acid.
With worsening acidosis (to pH 7.0 or less),
the cardiovascular system may be unable to
maintain compensatory vasoconstriction
Severe circulatory collapse may result.

Many patients with Type 2 diabetes have an

insidious onset of hyperglycemia and may be
relatively asymptomatic initially.
The diagnosis may be made only after
glycosuria or hyperglycemia is noted during
routine laboratory studies.
Chronic skin infections are common.
Generalized pruritus and symptoms of
candidal vaginitis are frequently the initial
complaints of women with type 2 diabetes.
Men may complain of an itchy rash of the
prepuce.

Some patients can remain undiagnosed for

many years and the initial presentation may
be due to complications such as visual
disturbance due to retinopathy or foot pain or
infection due to a peripheral neuropathy.
Patients with a more severe insulin deficiency
have the classical symptoms of polyuria,
thirst, blurred vision, paresthesias, and
fatigue..

Some patients, especially the obese, may

have Acanthosis nigricans
hyperpigmented, hyperkeratotic skin in the
axilla, groin, and back of neck. This sign is
associated with significant insulin
resistance. Hypertension may be present
especially in the obese patient.
Eruptive xanthomata on the flexor
surface of the limbs and on the buttocks
and lipemia retinalis due to
hyperchylomicronemia can occur in
patients with uncontrolled type 2 diabetes
who also have a familial form of
hypertriglyceridemia.

Eruptive xanthomata

Eruptive xanthomata

Acanthosis nigricans

Acantosis nigricans (back of neck)

Acantosis nigricans (the axilla)

Criteria for the Diagnosis of Diabetes

Oral Glucose Tolerance Test

Give 75 g of glucose dissolved in 300 mL of water
after an overnight fast in subjects who have been
receiving at least 150 to 200 g of carbohydrate daily
for 3 days before the test.

Other Laboratory Testing in

Diabetes Mellitus
1) Urine Glucose
2) Microalbuminuria and Proteinuria
3) Urine and Serum Ketone (especially

in type 1 DM)
4) HBA1C (Glycated Hemoglobin)
5) Lipoproteins

Lipoproteins in Diabetes
Levels of circulating lipoproteins are dependent
on normal levels and action of insulin, just as is
the plasma glucose.
In type 1 diabetes, moderately deficient
control of hyperglycemia is associated with only
a slight elevation of low-density lipoprotein
(LDL) cholesterol and serum triglycerides and
little if any changes in HDL cholesterol.
Once the hyperglycemia is corrected,
lipoprotein levels are generally normal.

However, patients with type 2 diabetes

frequently have a dyslipidemia that is
characteristic of the insulin resistance syndrome.
Its features are :
High serum triglyceride level (300-400
mg/dL
Low HDL cholesterol (<30 mg/dL)
Qualitative change in LDL particles.

Because low HDL and high LDL cholesterol is

a major feature predisposing to macrovascular
disease, the term dyslipidemia has
preempted the previous label of
hyperlipidemia, which mainly described the
elevated triglycerides.
Measures designed to correct obesity
and hyperglycemia, such as exercise ,
diet, and hypoglycemic therapy
substantially correct the dyslipidemia but
most patients require
pharmacotherapy.

Management of Diebetes Mellitus

Diet

and

Exersise

A well-balanced, nutritious diet remains

a fundamental element of therapy for
diabetes. However, in more than half of cases,
patients with diabetes fail to follow their diets.
It is important to relate dietary objectives to the
type of diabetes. In patients with type 2
diabetes,limiting the carbohydrate intake . In
those patients with obesity and type 2 diabetes,
weight reduction by caloric restriction is an
important goal of the diet ( vegetables fiber-

containing foods, some fruits and low fat)

In those patients with obesity and type 2

diabetes, weight reduction by caloric restriction is
an important goal of the diet. Patients with type 1
diabetes or type 2 diabetes who take insulin
should be taught carbohydrate counting, so they
can administer their insulin bolus for each meal
based on its carbohydrate content. The current
recommendations for both types of diabetes
continue to limit cholesterol to 300 mg daily,
and individuals with LDL cholesterol more
than 100 mg/dL should limit dietary
cholesterol to 200 mg daily. Omega-3 fatty
acids in high doses have been shown to lower
plasma triglycerides and VLDL cholesterol. They
may also reduce platelet aggregation.

ADA and EASD recomedations 2015

Agents for the treatment of hyperglycemia in
Type 2 DM

Biguanides-Metformin
Representative of this class of agents reduces
hepatic glucose production and improves
peripheral glucose utilization slightly. Metformin
activates AMP-dependent protein kinase and
enters cells through organic cation transporters.
Metformin reduces fasting plasma glucose (FPG) ,
improves the lipid profile and promotes modest
weight loss.
1) It May have fewer gastrointestinal side
effects: diarrhea,anorexia,nausea,metallic taste
2) Vitamin B l2 1evels are -30% lower during
metformin
treatment.

3) The major toxicity of metformin

Lactic Acidosis is very rare and can be
prevented by careful patient selection.
Metformin should not be used:
*In patients with renal insufficiency (glomerular
filration rate [GFR] <60 mL/min by ADA and <30,
with a reduced dose when the GFR is <45 mL/min
by National Institute for Health and Clinical
Excellence in the United Kingdom)
*Any form of acidosis
*Unstable congestive heart failure (CHF), low EF
*Liver disease
*Severe hypoxemia

Insulin Secretagogues-Agents thet

Affect The ATF-sensitive K+ Channel on
the beta cell.
Sulfonylureas
First -generation sulfonylureas: (chlorpropamide
tolazamide, tolbutamide) have a longer half-life a
greater incidence of hypoglycemia,and more
frequent drug interactions and are no longer
useded
Second-generation sulfonylureas have a more rapid
onset of action and better coverage of the
postprandial glucose rise and the shorter half-life:
Gliclazide(Diabeton MR) Glimepiride( Amaril) ,
glipizide ,glyburide. Gliclazide is preferred
sulfonylurea.

Sulfonylureas reduce both fasting and postprandial

glucose. sulfonylureas increase insulin acutly and thus
should be taken shortly before a meal; with chronic
therapy though the insulin release is more sustained.
Repaglinide Nateglinide and Mitiglinide are not
sulfonylureas but also interact with the ATP-sensitive
potassium channel. Because of their short half-life
these agents are given with each meal or immediately
before to reduce meal-related glucose excursions.
Insulin secretagogues especially the longer acting
ones have the potential to cause hypoglycemia,
especially in elderly individuals. Hypoglycemia is
usually related to delayed meals increased physical
activity alcohol intake or renal insufficiency.

Weight gain a common side effect of sulfonylurea

therapy.
Most sulfonylureas are metabolized in the liver to
compounds, that are cleared by the kidney.
Thus their use in individuals with significant
hepatic or renal dysfunction is not advisable.
Sulfonylureas act on beta cell via SUR 1 (sulfonylurea
reseptor 1). SUR2A is found in cardiac and skeletal
muscle, and SUR2B in vascular smooth muscle.
Certain channel closers have much higher affinity for
SUR1-containing channels than SUR2-containing
channels (the sulfonylureas tolbutamide and gliclazide
and the meglitinides nateglinide and mitiglinide), while
others have similar affinities for both of them
(glyburide, glimepiride, and repeglinide).

Insulin Secretagogues- Agents That Enhance

GLP1-Reseptor Signaling
"Incretins" amplify glucose-stimulated insulin
secretion. They are devided into two groups:
GLP-1 reseptor agonists , agents that directly act
on GLP-1 reseptor: Exenatide and Liraglutide
( Viktoza)
GLP -1 receptor agonists increase glucose-stimulated
insulin secretion,suppress glucagon,and slow
gastric emptying. Dont cause hypoglycemia
They are available in injectable formulations.
1)

The major side effects are: nausea, vomiting and

diarrhea.

Liraglutide has been shown to cause thyroid

cancer in rats and mice. The risk increased with
high doses and prolonged use. It is not known if
liraglutide may cause thyroid cancer in humans.
So GLP-1 reseptor agonists are contraindicated in
individuals with medullary carcinoma of the thyroid
or multiple endocrine neoplasia.
There is limited experience in patients with
congestive heart failure New York Heart Association
(NYHA) class I-II and liraglutide should therefore be
used with caution. There is no experience in
patients with congestive heart failure NYHA class
III-IV and liraglutide is therefore not recommended
in these patients.

2) Second group of incretins:

DPP-IV inhibitors: Sitagliptin (Yanuvia),
Saxagliptine, Vildagliptine-inhibit degradation of native
GLP- l and thus enhance the incretin effect.
DPP-IV inhibitors cause insulin secretion. Dont have
hypoglycemia and weight gain .
Appear to have a preferential effect on postprandial
blood glucose.
Reduced doses should be given to patients with renal
insufficiency.
Agents of both incretin groupes are widely used in
whole world , but we have, not much data about side
effects, especially long term side effects.
There are going trials about these 2 groups of
incretins and we hope to get satisfactory information.

Thiazolidinediones
Thiazolidinediones are insulin sensitizers exerting
their antidiabetic effects through the activation of
PPAR-y (peroxisome proliferator-activated receptor
y). They reduce insulin resistance.
Troglitazone, the first drug in this class to go into
widespread clinical use, was withdrawn from clinical
use because of drug-associated fatal liver failure.
Two other drugs in the same class are available for
clinical use: Rosiglitazone and Pioglitazone.
Circulatinginsulin levels decrease with use of the
thiazolidinediones indicating a reduction in
insulin resistance.

In addition to glucose-lowering, the

thiazolidinediones have effects on lipids and
other cardiovascular risk factors. Rosiglitazone
therapy is associated with increases in total
cholesterol, LDL cholesterol (15%), and
HDL cholesterol (10%). Thiazolidinediones are
associated with weight gain. Peripheral
edema and CHF are more common in
individuals treated with these agents. The
drugs are contraindicated in diabetic
individuals with CHF(NYHA) class III and IV
and liver disease. Thiazolidinediones have
also rarely been reported as being associated
with new onset or worsening macular edema
which resolved or improved once the drug was

Alpha-Glucosidase Inhibitors
Acarbose and Miglitol
Drugs of this family are competitive inhibitors of
intestinal brush border -glucosidases. -Glucosidase
inhibitors reduce postprandial hyperglycemia by
reducing glucose absorption. These drugs must be
taken just before each meal. The major side
effect(diarrhea,flatulence,abdominal distention) are
related to increased delivery of oligosaccharides to the
large bowel. When acarbose is given alone, there is no
risk of hypoglycemia. However, if combined with insulin
or sulfonylureas, it may increase risk of hypoglycemia
from these agents. This class of agents is not as potent
as other oral agents in lowering the HbA1c.

Sodium-Glucose Co-Transporter 2
Inhibitors (SGLT2)
These agents lower the blood glucose by selectively inhibiting this
co-transporter which is expressed almost exclusively in the
proximal convoluted tubule in the kidney.

This inhibits glucose reabsorption, lowers the

renal threshold for glucose,and leads to increased
urinary glucose excretion. Thus the glucose-lowering
effect is insulin independent and not related to changes in insulin
sensitivity or secretion.
Because these agents are the newest class to treat type 2
DM , clinical experience is limited. Due to the increased urinary
glucose urinary or vaginal infections are more common and
the diuretic effect can lead to reduced intravascular volume. As part
of the FDA approval of canagliflozin in 2013 ,postmarketing studies
for cardiovascular outcomes and for monitoring bladder and urinary
cancer risk are under way.

Insulin Therapy
Insulin is indicated for individuals with type 1
diabetes as well as for those with type 2 diabetes
whose hyperglycemia does not respond to diet
therapy and other diabetes drugs.
Human insulin is now produced by recombinant
DNA techniques (biosynthetic human insulin).
Insulins in Europe and United States are available
only in a concentration of 100 U/mL (U100). For use
in rare cases of severe insulin resistance in which
large quantities of insulin are required, a U 500 (500
U/mL) regular human insulin is available from Eli Lilly.

Insulin preparations differ with regard to their time of onset and

duration of biologic action .

1) The short-acting preparations are:

a) Regular insulin
and
b) The rapidly acting insulin analogs.(Lispro, Aspart, Glulisine)
They are dispensed as clear solutions at neutral pH and contain
small amounts of zinc to improve their stability and shelf life.

2) The long-acting preparations are :

a)Neutral protamine hagedorn (NPH) insulin
and
b) The longacting insulin analogs.(Glargine, Detemir)
NPH insulin is dispensed as a turbid suspension at neutral pH. The
long-acting insulin analogs are dispensed as clear solutions;
insulin glargine is at acidic pH and insulin detemir is at neutral
pH

Summary of Bioavailability
Characteristics of the Injectable Insulins

Representative Insulin regimens for

the treatment of Diabetes Mellitus

Premixed Insulins
(Insulin combinations )

Acute Complications of Diabetes

Mellitus
Hypoglycemia
Hypoglycemic reactions are the most common complications
that occur in patients with diabetes who are treated with
insulin.
Hypoglycemia may result from :
1) delay in taking a meal
2) unusual physical exertion without supplemental calories
3) increase in insulin dose
In addition, it can occur in any patient taking oral agents that
stimulate pancreatic cells (eg, sulfonylureas, meglitinide,
d-phenylalanine analogs), particularly if the patient is
elderly, has renal or liver disease, or is taking certain other
medications that alter metabolism of the sulfonylureas (eg,
phenylbutazone, sulfonamides, or warfarin). It occurs more
frequently with the use of long-acting sulfonylureas.

The signs and symptoms of Hypoglycemia

The signs and symptoms of hypoglycemia may be
divided into those resulting from :
1) Stimulation of the autonomic nervous system :
When the blood glucose falls to around 54 -70 mg/dL,
the patient starts to experience both sympathetic
* tachycardia
* palpitations,
* sweating
* tremulousness
and parasympathetic nervous system symptoms.
*nausea
* hunger

And
2)Those arising from Neuroglycopenia
(insufficient glucose for normal central
nervous system function)
If these autonomic symptoms are ignored and
the glucose levels fall further (to around 50
mg/dL), then neuroglycopenic symptoms
appear, including irritability, confusion,

blurred vision, tiredness, headache,

and difficulty speaking. A further decline
in glucose (below 30 mg/dL) can then lead to

loss of consciousness or even a

seizure.

Hypoglycemic Unawareness

With repeated episodes of hypoglycemia,

there is adaptation and autonomic symptoms
do not occur until the blood glucose levels are
much lower and so the first symptoms are
often due to neuroglycopenia. This
condition, which is referred to as
hypoglycemic unawareness, results from
failure of the sympathetic nervous system to
respond to hypoglycemia

Complications of diabetes that

increase the risk for hypoglycemia
include:

1) Autonomic neuropathy
2)Gastroparesis
3)Renal failure

Treatment of Hypoglacemia
To treat insulin-induced hypoglycemia, the
diabetic patient should carry glucose tablets
or juice at all times. For most episodes,
ingestion of 15 g of carbohydrate is sufficient
to reverse the hypoglycemia. The patient
should be instructed to check the blood
glucose in 15 minutes and treat again if the
glucose level is still low. A parenteral glucagon
emergency kit (1 mg) should be provided to
every patient with diabetes who is on insulin
therapy. Family or friends should be instructed
how to inject it subcutaneously or
intramuscularly into the buttock, arm or thigh

Glucagon is contraindicated in
sulfonylureainduced hypoglycemia
where it paradoxically causes insulin
release.
People with diabetes on hypoglycemic
drug therapy should also wear a
MedicAlert bracelet or necklace or carry
a card in his or her wallet.

Medical personnel treating severe

hypoglycemia can give 50 mL of 50%

glucose solution by rapid intravenous
infusion. If intravenous therapy is not
available, 1 mg of glucagon can be
injected intramuscularly. If the patient is
stuporous and glucagon is not available, small
amounts of honey or maple syrup or glucose
gel (15 g) can be inserted within the buccal
pouch, although, in general, oral feeding is
contraindicated in unconscious patients.
Rectal administration of maple syrup or honey
(30 mL per 500 mL of warm water) has been
effective.

Most patients who arrive at emergency departments

in hypoglycemic coma appear to recover fully;

however, profound hypoglycemia or delays

in therapy can result in permanent
neurologic deficit or even death.
Furthermore, repeated episodes of
hypoglycemia may have a cumulative adverse
effect on intellectual functioning. The physician
should carefully review with the patient the events
leading up to the hypoglycemic episode. Associated
use of other medications, as well as alcohol or
narcotics, should be noted. Careful attention should
be paid to diet, exercise pattern, insulin or
sulfonylurea dosage, and general compliance with
the prescribed diabetes treatment regimen.

Diabetic Ketoacidosis
This acute complication of diabetes mellitus may be the
first manifestation of previously undiagnosed type 1
diabetes or may result from increased insulin
requirements in type 1 diabetes patients during the
course of infection, trauma, myocardial infarction, or
surgery.
Patients with type 2 diabetes may also develop
ketoacidosis under severe stress such as sepsis, trauma,
or major surgery.

1 or type 2 DM and severe

(> 16.7 mmol/L [300 mg/dL] )

Individuals with type

hyperglycemia
should be assessed for clinical stability, including
mentation and hydration.

Acute insulin deficiency(relative or absolute)

results in rapid mobilization of energy from
stores in muscle and fat depots, leading to an
increased flux of amino acids to the liver for
conversion to glucose and of fatty acids for
conversion to ketones :
acetoacetate, - hydroxybutyrate, and
acetone
In response to both the acute insulin
deficiency and the metabolic stress of ketosis,
the levels of insulin-antagonistic hormones
(corticosteroids, catecholamines, glucagon,
and GH) are consistently elevated.
Furthermore, in the absence of insulin,
peripheral utilization of glucose and ketones is

The combination of increased

production and decreased utilization
leads to an accumulation of these
substances in blood, with lasma
glucose levels reaching 500 mg/dL
(27.8 mmol/L) or more and plasma
ketones reaching levels of 8 to 15
mmol/L or more. -Hydroxybutyrate
is the predominant ketone and its
ratio to acetoacetate increases from
1:1 to as much as 5:1.

Symptoms and Signs

The appearance of diabetic ketoacidosis is usually
preceded by a day or more of polyuria and
polydipsia associated with marked fatigue, nausea,
and vomiting. Eventually, mental stupor ensues and
can progress to frank coma. On physical
examination, evidence of dehydration in a
stuporous patient with rapid and deep respirations
and the fruity breath odor of acetone strongly
suggest the diagnosis. Postural hypotension with
tachycardia indicates profound dehydration and salt
depletion. Abdominal pain and even tenderness
may be present in the absence of abdominal
disease, and mild hypothermia is usually present.

Laboratory Findings
Typically, the patient with moderately severe diabetic ketoacidosis
has :
Plasma glucose of 350 to 900 mg/dL (19.4-50 mmol/L),
Serum ketones are
positive at a dilution of 1:8 or greater
(serum or plasma assays for -hydroxybutyrate are
preffered because they more accurately reflect the true ketone
body level)
Hyperkalemia of 5 to 8 mEq/L
Slight hyponatremia of approximately 130 mEq/L
Hyperphosphatemia of 6 to 7 mg/dL
And
an elevated blood urea nitrogen and creatinine. Acidosis may
be severe (pH ranging from 6.9 to 7.2 with a Bicarbonate
concentration ranging from 5 to 15 mEq/L); pCO2 is low (15-20
mm Hg) secondary to hyperventilation

The fluid depletion is typically about 100

mL/kg. The hyperkalemia occurs despite total
body potassium depletion, because of the shift of
potassium from the intracellular to extracellular
spaces in systemic acidosis. The average total
body potassium deficit resulting from osmotic
diuresis, acidosis, and gastrointestinal losses is
about 3 to 5 mEq/kg body weight.
Serum sodium is generally reduced, due to loss of
sodium ions by polyuria and vomiting (7-10
mEq/kg), and because severe hyperglycemia shifts
intracellular water into the interstitial compartment
(for every 100 mg/dL of plasma glucose above
normal, serum sodium decreases by 1.6
mEq/L)

Serum osmolality can be calculated by :

A convenient formula for estimating
effective serum osmolality :
mOsm/kg= 2(measured Na+)
+Glucose (mg/dl)

18
The effective serum osmolality in humans
is generally between 280 and 300

mOsm/kg.
Central nervous depression or coma
occurs when the effective serum osmolality

Treatment

Patients with mild DKA are alert and have pH between

7.25 - 7.30;
Patients with moderate DKA have pH between
7.0 - 7.24 and are alert or slightly drowsy;
Patients with severe DKA are stuporous and have pH<7.0
Those with mild DKA can be treated in the emergency room,
but those with moderate or severe DKA require admission to
the intensive care unit or step-down unit.
The therapeutic goals are :
1) To restore plasma volume and tissue perfusion
2) Reduce blood glucose and osmolality toward normal
3) Correct acidosis
4) Replenish electrolyte losses
5) And identify and treat precipitating factors

Gastric intubation is recommended in the

comatose patient to prevent vomiting and
aspiration that may occur as a result of gastric
atony, a common complication of diabetic
ketoacidosis. In patients with preexisting
cardiac or renal failure or those in severe
cardiovascular collapse, a central venous
pressure catheter or a Swan-Ganz catheter
should be inserted to evaluate the degree of
hypovolemia and to monitor subsequent fluid
administration.
Plasma glucose should be recorded hourly
and electrolytes and pH at least every 2 to 3
hours during the initial treatment period. A
bedside glucose meter should be used to

1.Fluid replacement. In most adult patients, the fluid

deficit is 4 to 5 L. Once the diagnosis of diabetic
ketoacidosis is established in the emergency
department, administration of at least 2 L of isotonic
saline (0.9% saline solution) in an adult patient in the
first 2 to 3 hours is necessary to help restore plasma
volume and stabilize blood pressure while acutely
reducing the hyperosmolar state. In addition, by
improving renal plasma flow, fluid replacement also
restores the renal capacity to excrete hydrogen ions,
thereby ameliorating the acidosis as well.
After the first 2 L of fluid have been given, the fluid
should be changed to 0.45% saline solution given at a
rate of 300 to 400 mL/h, because water loss exceeds
sodium loss in uncontrolled diabetes with osmotic
diuresis.

Failure to give sufficient volume replacement

(at least 3-4 L in 8 hours) to restore normal
perfusion is one of the most serious
therapeutic shortcomings affecting
satisfactory recovery. In the same way,
excessive fluid replacement (>5 L in 8 hours)
may contribute to acute respiratory distress
syndrome or cerebral edema. When blood
glucose falls to approximately 250
mg/dL, the fluids should be changed to a
5% glucose solution to maintain plasma
glucose in the range of 250 to 300 mg/dL.
This prevents the development of
hypoglycemia and also reduces the likelihood
of cerebral edema, which may result from a

2. Insulin. Immediately after the initiation of

fluid replacement, a rapid bolus of 0.3 U of
regular insulin per kilogram of body weight
should be given intravenously to prime the
tissue insulin receptors. This inhibits both
gluconeogenesis and ketogenesis while
promoting utilization of glucose and keto
acids. Following the initial bolus, an insulin
infusion is initiated at a rate of 0.1 U/kg/h.
When a continuous infusion of insulin is used,
25 U of regular human insulin should be
placed in 250 mL of isotonic saline

3. Potassium. Total body potassium loss from polyuria and

vomiting may be as high as 200 mEq. However, because of
shifts of potassium from cells into the extracellular space as
a consequence of acidosis, serum potassium is usually
normal to slightly elevated prior to institution of treatment.
As the acidosis is corrected, potassium flows back into the
cells, and hypokalemia can develop if potassium
replacement is not instituted. If the patient is not uremic and
has an adequate urine output, potassium chloride in doses
of 10 to 30 mEq/h should be infused during the second
and third hours after beginning therapy. Replacement
should be started sooner, if the initial serum potassium is
inappropriately normal or low, and should be delayed, if
serum potassium fails to respond to initial therapy and
remains above 5 mEq/L, as in cases of renal insufficiency.
Cooperative patients with only mild ketoacidosis may
receive part or all of their potassium replacement orally.

5. Phosphate. Phosphate replacement is

seldom required in treating diabetic
ketoacidosis. However, if severe
hypophosphatemia of less than 1 mg/dL
(<0.35 mmol/L) develops during insulin
therapy, a small amount of phosphate can be
replaced per hour as the potassium salt.
6. Hyperchloremic acidosis during therapy.
In most patients, as the ketoacidosis clears
during insulin replacement, a hyperchloremic,
low-bicarbonate pattern emerges with a
normal anion gap. This is a relatively benign
condition that reverses itself over the
subsequent 12 to 24 hours once intravenous

4. Sodium bicarbonate. The use of sodium bicarbonate in

management of diabetic ketoacidosis has been questioned
because clinical benefit was not demonstrated. It is therefore
recommended that bicarbonate be administered to diabetic
patients in ketoacidosis if the arterial blood pH is 7.0 or less
with careful monitoring to prevent overcorrection.
One to two ampules of sodium bicarbonate (one ampule
contains 44 mEq/50 mL) should be added to 1 L of 0.45%
saline. (Note: Addition of sodium bicarbonate to 0.9% saline
would produce a markedly hypertonic solution that could
aggravate the hyperosmolar state already present.) This should
be administered rapidly (over the first hour). It can be repeated
until the arterial pH reaches 7.1, but it should not be given
if the pH is 7.1 or greater, because additional bicarbonate
increases the risk of rebound metabolic alkalosis as ketones are
metabolized. Alkalosis shifts potassium from serum into cells,
which can precipitate a fatal cardiac arrhythmia.

Transition to Subcutaneous
Insulin Regimen
Once the diabetic ketoacidosis is controlled and the
patient is awake and able to eat, subcutaneous
insulin therapy can be initiated. Initially, the patient
may still have significant tissue insulin resistance
and may require a total daily insulin dose of 0.6 to
0.7 U/kg. Half of the total daily dose can be given
as a long-acting basal insulin and the other half as
short-acting insulin premeals. The patient should
get injection of the basal insulin and a dose of the
rapid-acting insulin analog with the first meal and
the insulin infusion discontinued an hour later.

Hyperglycemic, Hyperosmolar State

This form of hyperglycemic coma is characterized by
severe hyperglycemia, hyperosmolality, and
dehydration in the absence of significant ketosis.
It occurs in patients with mild or occult diabetes and
patients are typically middle-aged or elderly. Lethargy
and confusion develop as serum osmolality exceeds
300 mOsm/kg, and coma can occur if osmolality
exceeds 330 mOsm/kg. Underlying renal insufficiency
or congestive heart failure is common, and the
presence of either worsens the prognosis. A
precipitating event such as pneumonia, cerebrovascular
accident, myocardial infarction, burns, or recent
operation can often be identified.

Pathogenesis
A partial or relative insulin deficiency may
initiate the syndrome by reducing glucose
utilization by muscle, fat, and liver, while
promoting hyperglucagonemia and
increasing hepatic glucose output. The
result is hyperglycemia that leads to
glycosuria and osmotic diuresis with
obligatory water loss. The presence of
even small amounts of insulin is believed
to prevent the development of ketosis by
inhibiting lipolysis in the adipose stores.

If a patient is unable to maintain adequate

fluid intake because of an associated acute
or chronic illness or has suffered excessive
fluid loss (eg, from burns or therapy with
diuretics), marked dehydration results. As
plasma volume contracts, renal
insufficiency develops; this, then, limits
renal glucose excretion and contributes
markedly to the rise in serum glucose and
osmolality. As serum osmolality exceeds
320 to 330 mOsm/kg, water is drawn out
of cerebral neurons, resulting in mental
obtundation and coma.

Symptoms and Signs

The onset of the hyperglycemic,

hyperosmolar, nonketotic state may be
insidious, preceded for days or weeks by
symptoms of weakness, polyuria, and
polydipsia. A history of reduced fluid
intake is common, whether due to
inappropriate absence of thirst,
gastrointestinal upset, or, in the case of
elderly or bedridden patients, lack of access
to water. A history of ingestion of large
quantities of glucose-containing fluids, such
as soft drinks or orange juice, can occasionally

The absence of toxic features of ketoacidosis

may retard recognition of the syndrome and
thus delay institution of therapy until
dehydration is profound. Because of this delay
in diagnosis, the hyperglycemia,
hyperosmolality, and dehydration in
hyperglycemic, hyperosmolar, nonketotic
coma is often more severe than in diabetic
ketoacidosis.
Physical examination reveals the presence of
profound dehydration (orthostatic fall in
blood pressure and rise in pulse, supine
tachycardia, or even frank shock, dry mucous
membranes, decreased skin turgor). The
patient may be lethargic, confused, or

Laboratory Findings
Severe hyperglycemia is present, with blood
glucose values ranging from 800 to as high as 2400
mg/dL (44.4-133.2 mmol/L). In mild cases, where
dehydration is less severe, dilutional hyponatremia as
well as urinary sodium losses may reduce serum
sodium to about 120 to 125 mEq/Lthis protects,
to some extent, against extreme hyperosmolality.
Once dehydration progresses further, however, serum
sodium can exceed 140 mEq/L, producing serum
osmolalities of 330 to 440 mOsm/kg (normal, 280
to 295 mOsm/kg; Ketosis is usually absent or mild;
however, a small degree of ketonuria may be present
if the patient has not been eating because of illness.

Acidosis is not a part of the

hyperglycemic, hyperosmolar state,
but it may be present (often lactic
acidosis ) because of other acute
underlying conditions (eg, sepsis, acute
renal failure, myocardial infarction).
Prerenal azotemia is the rule with blood
urea nitrogen ( BUN) frequently over 100
mg/dL.

Treatment
There are some differences in fluid,
insulin, and electrolyte replacement
in this disorder, as compared with
diabetic ketoacidosis.
However, in common with the
treatment of ketoacidotic patients,
careful monitoring of the patient's
clinical and laboratory response to
therapy is essential.

1. Fluid replacement. The fluid deficit may be as much

as 100 to 200 mL/kg or about 9 L. If circulatory
collapse is present, fluid therapy should be initiated
with isotonic saline. In all other cases, initial
replacement with hypotonic (usually 0.45%)
saline is preferable, because these patients are
hyperosmolar with considerable loss of body water and
excess solute in the vascular compartment. As much as
4 to 6 L of fluid may be required in the first 8 to 10
hours. Because insulin therapy decreases plasma
glucose and therefore serum osmolality, a change to

isotonic saline may be necessary at some time

during treatment. Once blood glucose reaches 250
mg/dL, 5% dextrose in 0.45% or 0.9% saline solution
should be substituted. When consciousness returns,
oral fluids should be encouraged

2. Electrolyte replacement. Hyperkalemia is less

marked, and much less potassium is lost in the urine
during the osmotic diuresis of hyperglycemic,
hyperosmolar, nonketotic coma than in diabetic
ketoacidosis. There is, therefore, less severe total
potassium depletion, and less potassium replacement
is needed to restore potassium stores to normal.
However, because the initial serum potassium usually
is not elevated and because it declines rapidly as
insulin therapy allows glucose and potassium to enter
cells, it is recommended that potassium replacement
be initiated earlier than in ketotic patients: 10 mEq
of potassium chloride can be added to the initial
liter of fluid administered if the initial serum potassium
is not elevated and if the patient is making urine.

3. Insulin therapy. In general, less insulin

is required to reduce the hyperglycemia of
nonketotic patients than is the case for
patients in diabetic ketoacidosis. In fact,
fluid replacement alone can decrease
glucose levels considerably. An initial
insulin bolus of 0.15 U/kg is followed by an
insulin infusion rate of 0.1 U/kg/h titrated
to lower blood glucose by 50 to 70
mg/dL/h. Once the patient has stabilized
and the blood glucose falls to around 250
mg/dL, insulin can be given subcutaneously

Lactic Acidosis
When severely ill diabetic patients present with
profound acidosis and an anion gap over 15 mEq/L but
relatively low or undetectable levels of keto acids in
plasma, the presence of excessive plasma lactate (>5
mmol/L) should be considered, especially if other
causes of acidosis such as uremia are not present.
Lactic acid is the end product of the anaerobic
metabolism of glucose.
Type A lactic acidosis is associated with tissue hypoxia
from hypovolemia or endotoxic shock and need not be
associated with hyperglycemia. Type B lactic acidosis is
defined as that which occurs in the absence of clinical
evidence for tissue hypoxia and is associated with
diabetes per se or with biguanide therapy.

Most cases of metformin-associated lactic

acidosis occur in patients in whom there were
contraindications to the use of metformin, in
particular renal failure.
The main clinical features of lactic acidosis are
marked hyperventilation and mental confusion,
which may progress to stupor or coma.
Plasma glucose can be low, normal, or high in
diabetic patients with lactic acidosis, but usually
it is moderately elevated. Plasma bicarbonate
and arterial pH are quite low. Ketones are
usually absent from plasma, but small amounts
may be present in urine if the patient has not
been eating recently.

The diagnosis is confirmed by demonstrating, in a

sample of blood that is promptly chilled and
separated, a plasma lactate concentration of 6
mmol/L or higher (normal is 1 mmol/L).
Treatment
The cornerstone of therapy is aggressive treatment
of the precipitating cause. An adequate airway and
good oxygenation should be ensured. If hypotension
is present, fluids and, if appropriate, pressor agents
must be given to restore tissue perfusion.
Alkalinization with intravenous sodium bicarbonate
to keep the pH above 7.2 has been recommended in
the emergency treatment of severe lactic acidosis.

Chronic Complications of Diabetes Mellitus

Diabetes-related chronic complications can be
divided into vascular and nonvascular complications
and are similar for type 1 and type 2 DM.
The vascular complications of DM are subdivided
into
1) Microvascular:
Retinopathy Neuropathy Nephropathy
and
2) Macrovascular complications:
Ccoronary heart disease [CHD ]
Peripheral arterialdisease [PAD]
Cerebrovascular disease

Nonvascular complications include :

Gastrointestinal (gastroparesis diarrhea)
Genitourinary (uropathy/sexual
dysfunction)
Dermatologic
Infectious
Cataracts
Glaucoma
Cheiroarthropathy
Periodontal disease
Hearing loss

Prevalence of Chronic Complications by Type of Diabetes

Although all of the known complications of diabetes

can be found in both types of the disease, some are
more common in one type than in the other.
End-stage renal disease develops in up to 40%
of patients, with In type 1 diabetes, compared with
less than 20% of patients with type 2 diabetes.
Blindness occurs in both types.
Diabetic neuropathy- similarly, although is
common in both type 1 and type 2 diabetes
Severe autonomic neuropathy with
gastroparesis, diabetic diarrhea, resting tachycardia,
and postural hypotension is much more common in

type 1.

In patients with type 1 diabetes,

complications from end-stage renal
disease are a major cause of death,
whereas patients with type 2
diabetes are more likely to have
macrovascular diseases leading to
myocardial infarction and stroke
as the main causes of death.
Cigarette use adds significantly to
the risk of both microvascular and
macrovascular complications in
diabetic patients.

Ophthalmologic Complications
Diabetic Retinopathy
Two main categories of diabetic retinopathy exist:
Nonproliferative (background) retinopathy represents
the earliest stage of retinal involvement by diabetes and is
characterized by such changes as microaneurysms, dot
hemorrhages, exudates, and retinal edema.
Proliferative retinopathy involves the growth of new
capillaries and fibrous tissue within the retina and into the
vitreous chamber.
Proliferative retinopathy is a leading cause of
blindness,particularly because it increases the risk of
retinal detachment.
Diabetic macular edema can occur at any stage !

For early detection of diabetic retinopathy,

adolescent or adult patients who have had
type 1 diabetes for more than 5 years and all
patients with type 2 diabetes should be
referred to an ophthalmologist for
examination and follow-up. In patients with
type 1 diabetes, after 10 to 15 years, 25% to
50% of patients show some signs of
retinopathy. This prevalence increases to 75%
to 95% after 15 years and approaches 100%
after 30 years of diabetes. In patients with
type 2 diabetes, 60% have nonproliferative
retinopathy after 16 years. When
hypertension is present in a patient with
diabetes, it should be treated vigorously

Treatment
The most effective therapy for diabetic
retinopathy is prevention.
Regular,comprehensive eye examinations
are essential for all individuals with DM
.Most diabetic eye disease can be
successfully treated if detected early.
Individuals with known retinopathy may
be treated with laser
photocoagulation.

Cataracts and Glaucoma

Two types of cataracts occur in diabetic patients :
Subcapsular cataract- occurs predominantly in
patients with type 1 diabetes, may come on fairly
rapidly, and has a significant correlation with the
hyperglycemia of uncotrolled diabetes!!!
And
Senile cataract- represents a sclerotic change of
the lens nucleus. It is by far the most common type of
cataract found in either diabetic or nondiabetic adults
and tends to occur at a younger age in diabetic
patients, particularly when glycemic control is poor.

Glaucoma occurs in approximately 6%

persons with diabetes.

of

Renal Complications
Diabetic Nephropathy
About 4000 cases of end-stage renal disease due to
diabetic nephropathy occur annually among diabetic
patients in the United States. This represents about
one-third of all patients being treated for renalfailure.
Diabetic nephropathy is initially manifested by
proteinuria; subsequently, as kidney function
declines, urea and creatinine accumulate in the
blood.
Subsequent renal failure can be predicted by
persistent urinary albumin excretion rates
exceeding 30 g/min

Microalbuminuria - defined as
in a 24-h collection urine

30-299 mg/d

Macroalbuminuria defined as >300

mg/24 h

urine
The American Diabetes Association (ADA)
recently suggested to change these terms to
persistent albuminuria.
Because some individuals with type 1 or type
2 DM have a decline in GFR in the absence
of albuminuria annual measurement of
the serum Creatinine to estimate GFR
should also be performed.

Treatment
The optimal therapy for diabetic nephropathy is
prevention by control of glycemia .
Interventions effective in slowing progression
of albuminuria include:
1 ) improved glycemic control
2) strict blood pressure control
3) administration of a n ACE inhibitor or ARB.

Dyslipideia should also be treated!!!

Hemodialysis- has been of limited

success in the treatment of renal failure
due to diabetic nephropathy, primarily
because of progression of large vessel
disease with resultant death and disability
from stroke and myocardial infarction.
Renal transplantation- especially from
related donors, is often successful. For
patients with compatible donors and no
contraindications (such as severe
cardiovascular disease), it is the
treatment of choice!!!

Cardiovascular Complications
Heart Disease
Microangiopathy occurs in the heart and may
explain the existence of congestive
cardiomyopathies found in diabetic patients
without demonstrable coronary artery disease. But
much more commonly, however, heart failure in
patients with diabetes is a consequence of
coronary atherosclerosis. Myocardial infarction
is three to five times more common in diabetic
patients than in age-matched controls and is the
leading cause of death in patients with type 2
diabetes.

 Women with diabetes lose the protection

against myocardial infarction that is usually

present during the childbearing years.
Risk factors for macrovascular disease in
diabetic individuals include dyslipidemia,
hypertension, obesity reduced physical
activity, abnormalities of platelet
adhesiveness, coagulation factors, cigarette
smoking. Reducing of these risk factors
would have beneficial effects!!!
According to guidelines of the ADA the
target lipid values in diabetic individuals (age
>40 years) without CVD should be as follows:

LDL <2.6 mmol/L ( 100 mg/dL);

HDL > 1 mmol/L (40 mg/dL) in men and > 1 3 mmol/L
(50 mg/dL) in women
Triglycerides < 1 . 7 mmol/L ( 1 50 mg/dL). In patients
>40 years
ADA recommends addition of a statin regardless of
the LDL level in patients with CHD and those
without CHD who have CHD risk factors.
If the patient is known to have CHD the ADA
recommends an LDL goal of < 1 .8 mmol/L (70
mg/dL)
In large recent clinical trials, statin usage is
associated with a mild increase in the risk of
developing type 2 DM. However the cardiovascular
benefits of statin use outweigh the mildly increased
risk of diabetes.

The ADA also recommends lowering

blood pressure to <140/80 mm Hg and
In some younger
individuals to <
130/80 mmHg .
Therapy should first emphasize
lifestyle modifications such as weight loss,
exercise stress management, and sodium
restriction.
If lifestyle modifications is not enough to
reach the goal, the ADA recommends

that all patients with diabetes and

hypertension be treated with an ACE

Aspirin (81-325 mg daily) has been shown

to effectively inhibit thromboxane synthesis by
platelets and reduce the risk of diabetic
atherothrombosis without increasing risks of
either vitreous or gastrointestinal hemorrhage.
Use of low-dose enteric-coated aspirin is
recommended in :
1)Adults with diabetes and evident
macrovascular disease
2)In those with increased cardiovascular
riskfactors
3)Or in those patients older than 30 years.

In general, the treatment of coronary

disease is not different in the diabetic
individual, but Revascula rization
procedures for CHD including percuta
neous coronary interventions (PCI) and
coronary artery bypass grafting
(CABG)may be less efficacious in the
diabetic individual, because of higher
rates of restenosis and lower long-term
patency and survival rates in older studies.