Diabetes mellitus - 2

Diabetes Mellitus- Clinical
manifestations and complications

(Part-2)
Biochemistry for medics
www.namrata.co

11/2/2013


1

Contents
Clinical Manifestations of Type 1
DM
Clinical manifestations of Type 2
DM
Acute complications
Chronic complications

Clinical Manifestations Type 1 DM
• Polyuria-Increased urination is a consequence of osmotic
diuresis secondary to sustained hyperglycemia. This results
in a loss of glucose as well as free water and electrolytes in
the urine.
• Thirst (Polydipsia) is a consequence of the hyperosmolar
state, as is blurred vision, which often develops as the
lenses are exposed to hyperosmolar fluids.
• Weight loss despite normal or increased appetite is a
common feature of type 1 when it develops sub acutely.
The weight loss is initially due to depletion of water,
glycogen, and triglycerides; thereafter, reduced muscle
mass occurs as amino acids are diverted to form glucose
and ketone bodies.
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(contd.)
• Lowered plasma volume produces symptoms of
postural hypotension. Total body potassium loss and
the general catabolism of muscle protein contribute to
the weakness.
• Paresthesias may be present at the time of diagnosis,
particularly when the onset is sub acute. They reflect a
temporary dysfunction of peripheral sensory nerves,
which clears as insulin replacement restores glycemic
levels closer to normal, suggesting neurotoxicity from
sustained hyperglycemia. When absolute insulin
deficiency is of acute onset, the above symptoms
develop abruptly.
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(contd.)
Ketoacidosis
o Ketoacidosis exacerbates the dehydration and
hyperosmolality by producing anorexia , nausea
and vomiting, interfering with oral fluid
replacement.
o The patient's level of consciousness can vary
depending on the degree of hyperosmolality.

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Diabetic ketoacidosis – contd.
oWhen insulin deficiency develops relatively slowly and
sufficient water intake is maintained, patients remain
relatively alert and physical findings may be minimal.
oWhen vomiting occurs in response to worsening
ketoacidosis, dehydration progresses and compensatory
mechanisms become inadequate to keep serum
osmolality below 320–330 mOsm/L.
oUnder these circumstances, stupor or even coma may
occur.
oThe fruity breath odor of acetone further suggests the
diagnosis of diabetic ketoacidosis.
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(contd.)
• Hypotension in the recumbent position is a
serious prognostic sign.
• Loss of subcutaneous fat and muscle wasting
are features of more slowly developing insulin
deficiency. In occasional patients with slow,
insidious onset of insulin deficiency,
subcutaneous fat may be considerably
depleted.
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• While many patients with type 2 diabetes
present with increased urination and thirst,
many others have an insidious onset of
hyperglycemia and are asymptomatic initially.
This is particularly true in obese patients,
whose diabetes may be detected only after
Glycosuria or hyperglycemia is noted during
routine laboratory studies.
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(contd.)
o Occasionally, type 2 patients may present with
evidence of neuropathic or cardiovascular
complications because of occult disease present for
some time prior to diagnosis.
o Chronic skin infections are common. Generalized
pruritus and symptoms of vaginitis are frequently the
initial complaints of women.
o Diabetes should be suspected in women with chronic
Candida vulvovaginitis as well as in those who have
delivered large babies (> 9 lb, or 4.1 kg) or have had
polyhydramnios, preeclampsia, or unexplained fetal
losses.
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(contd.)
•Obese diabetics may have any variety of fat
distribution; however, diabetes seems to be more
often associated in both men and women with
localization of fat deposits on the upper segment of
the body (particularly the abdomen, chest, neck,
and face) and relatively less fat on the appendages,
which may be quite muscular.
•Standardized tables of waist-to-hip ratio indicate
that ratios of "greater than 0.9" in men and
"greater than 0.8" in women are associated with an
increased risk of diabetes in obese subjects
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(contd.)
• Mild hypertension is often present in obese
diabetics.
• Eruptive xanthomas 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.
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Complications of Diabetes Mellitus
• Acute Complications of DM
o Diabetic ketoacidosis
o Hyperosmolar non ketotic coma
o Lactic acidosis
o Hypoglycemia

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Diabetic ketoacidosis
• Diabetic Ketoacidosis (DKA) is a state of
inadequate insulin levels resulting in high
blood sugar and accumulation of organic acids
and ketones in the blood.
• It is a potentially life-threatening complication
in patients with diabetes mellitus.
• It happens predominantly in type 1 diabetes
mellitus, but it can also occur in type 2
diabetes mellitus under certain circumstances.
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Diabetic ketoacidosis- Causes
• DKA most frequently occurs in known diabetics.
• It may also be the first presentation in patients who
had not previously been diagnosed as diabetics.
• There is often a particular underlying problem that has
led to the DKA episode.
• This may be intercurrent illness
(pneumonia, influenza, gastroenteritis, a urinary tract
infection), pregnancy, inadequate insulin
administration (e.g. defective insulin pen
device), myocardial infarction (heart attack), stroke or
the use of cocaine.
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Diabetic ketoacidosis- Causes (contd.)
• Young patients with recurrent episodes of DKA may have an
underlying eating disorder, or may be using insufficient
insulin for fear that it will cause weight gain.
• In 5% of cases, no cause for the DKA episode is found.
• Diabetic ketoacidosis may occur in those previously known
to have diabetes mellitus type 2 or in those who on further
investigations turn out to have features of type 2 diabetes
(e.g. obesity, strong family history);
• This is more common in African, African-American and
Hispanic people.
• Their condition is then labeled "ketosis-prone type 2
diabetes".

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Diabetic ketoacidosis- Pathophysiology
• DKA results from relative or absolute insulin
deficiency combined with counter regulatory
hormone excess (Glucagon, Catecholamines,
cortisol, and growth hormone).
• The decreased ratio of insulin to Glucagon
promotes Gluconeogenesis, glycogenolysis, and
Ketone body formation in the liver, as well as
increases in substrate delivery from fat and
muscle (free fatty acids, amino acids) to the liver.
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• Normally, the free fatty acids released by
adipolysis are converted to triglycerides or VLDL
in the liver.
• However, in DKA, hyperglucagonemia alters
hepatic metabolism to favor Ketone body
formation, through activation of the enzyme
carnitine palmitoyl Transferase I.
• This enzyme is crucial for regulating fatty acid
transport into the mitochondria, where beta
oxidation and conversion to ketone bodies occur.
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• The ketone bodies, however, have a low pH and
therefore turn the blood acidic (metabolic acidosis).
• The body initially buffers this with the bicarbonate
buffering system, but this is quickly overwhelmed and
other mechanisms to compensate for the acidosis,
such as hyperventilation to lower the blood carbon
dioxide levels.
• This hyperventilation, in its extreme form, may be
observed as Kussmaul respiration.
• Ketones, too, participate in osmotic diuresis and lead
to further electrolyte losses.
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DKA- Clinical manifestations
• Nausea and vomiting
• Pronounced thirst
• Excessive urine production and abdominal
pain that may be severe.
• Hyperglycemia is always present .
•In severe DKA, breathing becomes labored
and of a deep, gasping character (a state
referred to as "Kussmaul respiration").
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DKA- Clinical manifestations (contd.)
•The abdomen may be tender to the point that an
acute abdomen may be suspected, such as acute
pancreatitis, appendicitis or gastrointestinal
perforation.
•Coffee ground vomiting (vomiting of altered
blood) occurs in a minority of patients; this tends
to originate from erosions of the esophagus.
• In severe DKA, there may be confusion, lethargy,
stupor or even coma (a marked decrease in the
level of consciousness).
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DKA- Clinical manifestations (contd.)
• On physical examination there is usually clinical
evidence of dehydration, such as a dry mouth
and decreased skin turgor.
• If the dehydration is profound enough to cause a
decrease in the circulating blood volume,
tachycardia (a fast heart rate) and low blood
pressure may be observed.
• Often, a "ketotic" odor is present, which is often
described as "fruity".
• If Kussmaul respiration is present, this is
reflected in an increased respiratory rate.
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Diagnosis of DKA
• Diabetic Ketoacidosis may be diagnosed when
the combination of hyperglycemia (high blood
sugars), ketones on urinalysis and acidosis are
demonstrated.
• Arterial blood gas measurement is usually
performed to demonstrate the acidosis
• Urea and creatinine estimations (measures of
kidney function, which may be impaired in DKA
as a result of dehydration) and electrolytes.
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Diagnosis of DKA
• Markers of infection (complete blood count, Creactive protein) and acute pancreatitis (amylase
and lipase) may be measured.
• Given the need to exclude infection, chest
radiography and urinalysis are usually
performed.
• If cerebral edema is suspected because of
confusion, recurrent vomiting or other
symptoms, computed tomography may be
performed to assess its severity and to exclude
other causes such as stroke.
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Management of DKA
• The main aims in the treatment of diabetic
ketoacidosis are replacing the lost fluids and
electrolytes while suppressing the high blood
sugars and ketone production with insulin.
• Fluid replacement- The amount of fluid
depends on the estimated degree of
dehydration
• Insulin is usually given continuously.
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Management of DKA (contd.)
• Potassium levels can fluctuate severely during the treatment of

DKA, because insulin decreases potassium levels in the blood by
redistributing it into cells.
• Serum potassium levels are initially often mildly raised even
though total body potassium is depleted. Hypokalemia often
follows treatment.
• This increases the risk of irregularities in the heart rate.
Therefore, continuous observation of the heart rate is
recommended, as well as repeated measurement of the
potassium levels and addition of potassium to the intravenous
fluids once levels fall below 5.3 mmol/l.
•If potassium levels fall below 3.3 mmol/l, insulin administration
may need to be interrupted to allow correction of the
hypokalemia.
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Management of DKA (contd.)
Bicarbonate
• Sodium bicarbonate solution is administered
to rapidly improve the acid levels in the blood.
• Cerebral edema- administration of fluids is
slowed; intravenous Mannitol and hypertonic
saline (3%) are used

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2) Hyperglycemic Hyperosmolar State
(HHS)
Pathophysiology
• Relative insulin deficiency and inadequate fluid
intake are the underlying causes of HHS.
• Insulin deficiency increases hepatic glucose
production (through glycogenolysis and
gluconeogenesis) and impairs glucose utilization in
skeletal muscle .
• Hyperglycemia induces an osmotic diuresis that
leads to intravascular volume depletion, which is
exacerbated by inadequate fluid replacement.
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(HHS)- contd.
Clinical Features• HHS occurs in elderly individuals with type 2 DM, with a several
week history of polyuria, weight loss, and diminished oral intake
that culminates in mental confusion, lethargy, or coma.
The physical examination reveals• Profound dehydration and hyperosmolality
• Hypotension, tachycardia, and altered mental status.
• Nausea, vomiting, abdominal pain and the Kussmaul respirations
characteristic of DKA are absent.
• HHS is often precipitated by a serious, concurrent illness such as
myocardial infarction or stroke.
• Sepsis, pneumonia, and other serious infections are frequent
precipitants and should be sought.

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(HHS)- contd.
• Most notable are the marked hyperglycemia
[plasma glucose may be >55.5 mmol/L (1000
mg/dL)], hyperosmolality (>350 mosmol/L), and
prerenal azotemia.
• In contrast to DKA, acidosis and ketonemia are
absent or mild.
Treatment- The rehydration in HHS should be
slower to avoid neurological damage.
The insulin dose requirements are usually lower
than in DKA.
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3) Lactic acidosis
• Lactic acidosis occurs in hypoxic individuals and is
due to an excessive production of lactate by
peripheral tissues.
•It is characterized by extreme metabolic acidosis.
•There is high anion gap with low or absent ketones
and high lactate levels.
TreatmentSodium bicarbonate is needed to correct the
acidosis.
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4) Hypoglycemia
•Hypoglycemia caused by excess insulin is the most
common complication of insulin therapy, occurring
in more than 90 % of the patients.
• In normal individuals, hypoglycemia triggers a
compensatory secretion of counter regulatory
hormones, most notably glucagon and epinephrine,
which promote hepatic production of glucose.
However patients with type 1 diabetes also develop
a deficiency of glucagon secretion.
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4) Hypoglycemia- contd.
•These patients thus rely on epinephrine secretion
to prevent severe hypoglycemia.
•However as the disease progresses, type 1
diabetes patients show diabetic autonomic
neuropathy and impaired ability to secrete
epinephrine in response to hypoglycemia.
•The combined deficiency of glucagon and
epinephrine secretion creates a condition
sometimes called “Hypoglycemia unawareness”.
•Thus patients with long standing diabetes are
particularly vulnerable to hypoglycemia
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Chronic Complications of DM
• Chronic complications can be divided into
vascular and nonvascular complications.
• The vascular complications of DM are further
subdivided into microvascular and
macrovascular
• Microvascular complications includeo Retinopathy
o Neuropathy, and
o Nephropathy

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Chronic Complications of DM- contd.
Macro vascular complications includeo Coronary artery disease (CAD),
o Peripheral arterial disease (PAD),
o Cerebrovascular disease.
Nonvascular complications include Gastroparesis, infections, and skin changes.
Long-standing diabetes may be associated with
hearing loss.
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Mechanisms of Complications
• Advanced Glycosylation End Products
Increased intracellular glucose leads to the
formation of advanced glycosylation end products
(AGEs) via the nonenzymatic glycosylation of intraand extra cellular proteins.
AGEs have been shown to cross-link proteins (e.g.,
collagen, extracellular matrix proteins), accelerate
atherosclerosis, promote glomerular dysfunction,
reduce nitric oxide synthesis, induce endothelial
dysfunction, and alter extracellular matrix
composition and structure.
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Mechanisms of Complications- contd.
2) Sorbitol pathway
o Hyperglycemia increases glucose metabolism
via the Sorbitol pathway.
oIncreased sorbitol concentration alters redox
potential, increases cellular osmolality,
generates reactive oxygen species, and likely
leads to other types of cellular dysfunction.

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3) Activation of protein kinase C (PKC)
o Hyperglycemia increases the formation of
diacylglycerol leading to activation of protein
kinase C (PKC).
o Among other actions, PKC alters the
transcription of genes for fibronectin, type IV
collagen, contractile proteins, and extracellular
matrix proteins in endothelial cells and neurons.
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• A fourth theory proposes that hyperglycemia
increases the flux through the hexosamine
pathway, which generates fructose-6phosphate, a substrate for O-linked
glycosylation and proteoglycan production.
• The hexosamine pathway may alter function
by glycosylation of proteins

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Oxidative stress
• Hyperglycemia leads to increased production of
reactive oxygen species or Superoxide in the
mitochondria;
•These compounds may activate all four of the
pathways described above.
• Although hyperglycemia serves as the initial trigger
for complications of diabetes, it is still unknown
whether the same pathophysiological processes are
operative in all complications or whether some
pathways predominate in certain organs.
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Vascular complications
Microvascular complications
Ocular Complications
• DM is the leading cause of blindness between
the ages of 20 and 74 in the United States.
• Blindness is primarily the result of progressive
diabetic retinopathy and clinically significant
macular edema.

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Ocular Complications
Diabetic retinopathy
• Diabetic retinopathy is classified into two
stages: nonproliferative and proliferative.
• Nonproliferative diabetic retinopathy is marked
by retinal vascular micro aneurysms, blot
hemorrhages, and cotton wool spots .
• The appearance of neovascularization in
response to retinal hypoxia is the hallmark of
proliferative diabetic retinopathy
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Diabetic retinopathy

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Ocular Complications- contd.
Diabetic cataract
• Premature cataracts occur in diabetic patients
and seem to correlate with both the duration
of diabetes and the severity of chronic
hyperglycemia.
• Nonenzymatic glycosylation of lens protein
contributes to the premature occurrence of
cataract.
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Diabetic Cataract

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Ocular Complications- contd.
Glaucoma
• Glaucoma occurs in approximately 6% of persons
with diabetes.
• It is responsive to the usual therapy for openangle disease.
• Neovascularization of the iris in diabetics can
predispose to closed-angle glaucoma, but this is
relatively uncommon except after cataract
extraction, when growth of new vessels has been
known to progress rapidly, involving the angle of
the iris and obstructing outflow.
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Renal Complications
Diabetic nephropathy (nephropatia diabetica),
also known as Kimmelstiel-Wilson syndrome,
and intercapillary glomerulonephritis, is a
progressive kidney disease
• It is the principal cause of ESRD (End Stage
Renal Disease) in the western world.
• Like other microvascular complications, the
pathogenesis of diabetic nephropathy is related
to chronic hyperglycemia
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Diabetic nephropathy
The mechanisms involves the effects of• Soluble factors
oGrowth factors,
oAngiotensin II,
oEndothelin
oAGEs
• Hemodynamic alterations in the renal microcirculation
(glomerular hyper filtration or hyper perfusion,
increased glomerular capillary pressure), and
•Structural changes in the glomerulus (increased
extracellular matrix, basement membrane thickening
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and fibrosis).

Diabetic nephropathy-contd.
• The earliest detectable change in the course of diabetic
nephropathy is a thickening in the glomerulus.
• At this stage, the kidney may start allowing more albumin
than normal in the urine (albuminuria), and this can be
detected by sensitive medical tests for albumin.
• This stage is called "microalbuminuria".
• After 5–10 years of type 1 DM, ~40% of individuals begin
to show microalbuminuria.
• Microalbuminuria is defined as 30–300 mg/d of albumin
in a 24-h collection of urine.
• As diabetic nephropathy progresses, increasing numbers of
glomeruli are destroyed by nodular glomerulosclerosis.

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• Although the appearance of microalbuminuria in type 1 DM,
is an important risk factor for progression to overt proteinuria
(in>300 mg/d), only ~50% of individuals will progress to
macroalbuminuria over the next 10 years.
• Once macroalbuminuria is present, there is a steady decline in
GFR (Glomerular Filtration Rate), and ~50% of individuals
reach ESRD (End Stage Renal Disease) in 7–10 years.
• Once macroalbuminuria develops, blood pressure rises
slightly and the pathologic changes are likely to be
irreversible.
• At this stage, a kidney biopsy clearly shows diabetic
nephropathy.
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Clinical Manifestations
• Kidney failure provoked by glomerulosclerosis leads to
fluid filtration deficits and other disorders of kidney
function.
• There is an increase in blood pressure and fluid
retention in the body causing edema.
• Other complications may be arteriosclerosis of the renal
artery and proteinuria.
•Foamy appearance or excessive frothing of the urine
(caused by the proteinuria)
• Unintentional weight gain (from fluid accumulation)
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Laboratory Diagnosis
• The first laboratory abnormality is a positive
microalbuminuria test.
• The urinalysis may also show glucose in the
urine, especially if blood glucose is poorly
controlled.
• Serum creatinine and BUN may increase as
kidney damage progresses.
• Dyslipidemia is a common associated finding.
• A Renal biopsy confirms the diagnosis.
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Diabetic nephropathy

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Neurological complications
Diabetic Neuropathy
•Diabetic neuropathy occurs in ~50% of
individuals with long-standing type 1 and type 2
DM.
• It may manifest as
polyneuropathy, mononeuropathy, and/or
autonomic neuropathy.
• Both myelinated and unmyelinated nerve
fibers are lost.
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Diabetic Neuropathy

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Diabetic Neuropathy
Polyneuropathy/Mononeuropathy
• The most common form of diabetic neuropathy is distal
symmetric polyneuropathy.
•It most frequently presents with distal sensory loss, but up to
50% of patients do not have symptoms of neuropathy.
•Loss of function appears in a stocking-glove pattern.
•Hyperesthesia, paresthesias, and dysesthesia also may occur.
•Symptoms may include a sensation of numbness, tingling,
sharpness, or burning that begins in the feet and spreads
proximally.
•Mononeuropathy (dysfunction of isolated cranial or
peripheral nerves) is less common than polyneuropathy in DM
and presents with pain and motor weakness in the
distribution of a single nerve.
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Diabetic Neuropathy- contd.
Autonomic Neuropathy
• Individuals with long-standing type 1 or 2 DM may
develop signs of autonomic dysfunction
• DM-related autonomic neuropathy can involve multiple
systems, including the cardiovascular, gastrointestinal,
genitourinary, and metabolic systems.
•Autonomic neuropathy may reduce counterregulatory
hormone release, leading to an inability to sense
hypoglycemia appropriately thereby subjecting the
patient to the risk of severe hypoglycemia and
complicating efforts to improve glycemic control.
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Diabetic gangrene
• The incidence of gangrene of the feet in diabetics is 30
times more than that in age-matched controls.
• The factors responsible for its development, in addition
to peripheral vascular disease, are small vessel disease,
peripheral neuropathy with loss of both pain sensation
and neurogenic inflammatory responses, and
secondary infection.
• The peripheral sensory neuropathy interferes with
normal protective mechanisms and allows the patient
to sustain major or repeated minor trauma to the foot,
often without knowledge of the injury.
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Diabetic gangrene- contd.
• Peripheral artery disease(PAD) and poor
wound healing impede resolution of minor
breaks in the skin, allowing them to enlarge
and to become infected.
• Approximately 15% of individuals with DM
develop a foot ulcer (great toe or MTP areas
are most common), and a significant subset
will ultimately undergo amputation (14–24%
risk with that ulcer or subsequent ulceration).
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Diabetic Foot

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Skin and Mucous Membrane
Complications
• Chronic pyogenic infections of the skin may
occur, especially in poorly controlled diabetic
patients
• Fungal infections are also very common in
diabetics
• It causes vulvovaginitis in most chronically
uncontrolled diabetic women with persistent
glucosuria and is a frequent cause of pruritus.
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Large vessel diseases (Macro vascular
complications)
Atherosclerosis and its effects produce the large
vessel diseases.
a) Involvement of the coronary vessels can produce
myocardial infarction,
b) Involvement of cerebral vessels can produce
‘stroke’.
c) Peripheral vascular disease-Atherosclerosis is
markedly accelerated in the larger arteries .
Clinical manifestations of peripheral vascular
disease include ischemia of the lower extremities,
impotence, and intestinal angina.
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For further details
FollowA case oriented approach towards Biochemistry
http://www.jaypeedigital.com/BookDetails.aspx?i
d=9789350901885&sr=1

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Diabetes mellitus - 2

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