Metabolic disorders

Contents
 Diabetes mellitus
 Definition of DM
 Classification of DM
 Criteria for diagnosis of DM
 Pathogenesis of DM
 Clinical manifestation of DM
 Disorders of uric acid metabolism
 Gout disease
 Disorders of ca metabolism
 Hypercalcemia and hypocalcaemia
A group of metabolic
disorders sharing the common
feature of hyperglycemia
Hyperglycemia results from
defects in
◦ Insulin secretion
◦ Insulin action
◦ or, most commonly, both
Classification of diabetes
mellitus
There are 4 types of DM
1. Type 1 DM
2. Type 2 DM
3. Other specific types of DM
4. Gestational DM
Classification
Type 1 diabetes :
◦ β-cell destruction
◦ absolute deficiency of insulin
Insulin-dependent diabetes mellitus IDDM
- most common type in patients
younger than 20 years of age
Juvenile DM
Type 2 diabetes:
◦ 90-95% of diabetic patients
◦ vast majority: overweight
Non-insulin dependent diabetes NIDDM
Adult-onset diabetes
 Diabetes mellitus

secondary

primary

Type 1 Type 2

Absolute insulin deficiency Insulin resistance

 insulin-dependent DM non-insulin-dependent DM
 IDDM NIDDM
Secondary Causes
 Diseases of the exocrine pancreases.
 Pancreatitis
 Pancreatectomy.
 Neoplasia
 Cystic fibrosis.
 All lead to impaired insulin secretion
exocrine pancreatic disease

chronic pancreatitis
Gestational DM

 After 20 weeks of gestational age during

pregnancy glucose intolerance develops.

 It is caused by the antagonizing action of

pregnancy maintaining hormones.
 Human placental lactogens.
 Prolactin
 estrogen
 Progesterone.
Normal Glucose Homeostasis
Normal glucose homeostasis is
tightly regulated by three
interrelated processes:
1. glucose production in the liver;
2. glucose uptake and utilization by
peripheral tissues, chiefly
skeletal muscle;
3. actions of insulin and counter-
regulatory hormones, including
glucagon, on glucose
 Glucose Homeostasis
Insulin Glucagon levels
levels
Fasting Low High
states
Glucagon promotes Hepatic
gluconeogenesis, glycogeno
Reduced glycogen synthesis
Prevent hypoglycemia
Postprand High Low
ial state
Insulin promotes glucose uptake
and utilization in tissues
Prevents hyperglycemia
Glucose is the
most important
stimulus that
triggers insulin
synthesis and
release
 Description for previous slide

 A rise in blood glucose levels results in glucose uptake into

pancreatic β cells, facilitated by an insulin-independent,
glucose-transporting protein, GLUT-2. Metabolism of glucose
via glycolysis generates ATP, resulting in increase in
cytoplasmic ATP/ADP ratios. This inhibits the activity of the
ATP-sensitive K+-channel on the β-cell membrane, leading to
membrane depolarization and the influx of extracellular Ca 2+
through voltage-dependent Ca2+-channels.[64] The resultant
increase in intracellular Ca2+ stimulates secretion of insulin,
presumably from stored hormone within the β-cell granules.
This is the phase of immediate release of insulin. If the
secretory stimulus persists, a delayed and protracted
response follows that involves active synthesis of insulin.
Other agents, including intestinal hormones and certain
amino acids (leucine and arginine), stimulate insulin release
but not synthesis.
metabolic function of insulin
1. increase rate of glucose transport
into striated muscle cells and adipocytes
◦ In muscle cells,
 glucose either stored as glycogen or used for
protein synthesis or oxidized to generate ATP
◦ In adipose tissue,
 glucose primarily stored as lipid (lipogenesis)
increase rate of glucose transport into striated
muscle cells (including myocardial cells), to a
lesser extent, adipocytes, representing collectively
about two-thirds of the entire body weight.

16
2. Insulin is anabolic
◦ increased synthesis and reduced degradation
of glycogen, lipid, and protein.
3. has several mitogenic functions
◦ initiation of DNA synthesis in certain cells and
◦ stimulation of their growth and differentiation.
glucose is the most important stimulus
that triggers insulin synthesis and release
by pancreatic β cells.
insulin also inhibits lipid degradation (lipolysis) in
adipocytes.

17
proteins Glycoge
triglycerides n
nucleic acids

Plasma
glucose 70 –
120 mg/dl

Diet

Normal Glucose Metabolism Action of

Insulin action on peripheral tissues
 Description for previous slide.

 Insulin action on a target cell. Insulin binds to the α subunit of

insulin receptor, leading to activation of the kinase activity in
the β-subunit, and sets in motion a phosphorylation (i.e.,
activation) cascade of multiple downstream target proteins. The
mitogenic functions of insulin (and the related insulin-like growth
factors) are mediated via the mitogen-activated protein kinase
(MAP kinase) pathway. The metabolic actions of insulin are
mediated primarily by activation of the phosphatidylinositol-3-
kinase (PI-3K) pathway. The PI-3K-signaling pathway is
responsible for a variety of effects on target cells, including
translocation of GLUT-4 containing vesicles to the surface;
increasing GLUT-4 density on the membrane and rate of glucose
influx; promoting glycogen synthesis via activation of glycogen
synthase; and promoting protein synthesis and lipogenesis,
while inhibiting lipolysis. The PI-3K pathway also promotes cell
survival and proliferation
Pathogenesis of Type I
Diabetes
Type 1 diabetes is
characterized by an absolute
deficiency of insulin caused by
pancreatic β-cell destruction.
It accounts for approximately
10% of all cases.
Type 1 DM
1. genetic suceptibility
2. viral infection ( trigger )
3. autoimmune destruction of
beta-cells by CD8+ T
lymphocytes
Type 1 DM
1. genetic suceptibility
2. viral infection ( trigger ):

epidemiologic association with:

◦ Mumps
◦ Rubella
◦ Cosackie B virus
◦ Cytomegalovirus
Type 1 DM
1. genetic suceptibility
2. viral infection ( trigger )
3. autoimmune destruction of
beta-cells by CD8+ T
lymphocytes
Mechanism of β cell
destruction
 caused primarily by T lymphocytes reacting
against as yet poorly defined β-cell antigens

 CD4+ T cells Th1 subset activate macrophages

 CD8+ cytotoxic T lymphocytes directly kill β
cells
 Cytokines like IFN-γ, TNF, IL-1 damage islet
cells
 Autoantibodies against β cell enzyme glutamic
acid decarboxylase (GAD) detected in 70-80%
of patients
 β cell apoptosis
 Type 1 diabetes

◦ genetic susceptibility
◦ viral disease (trigger)
◦ autoimmune destruction of β - cells

◦ lack of insulin
 insulin dependant
◦ early onset: childhood, puberty
Pathogenesis of Type 2 Diabetes
Mellitus
two metabolic defects characterize type 2
diabetes are
insulin resistance
◦ a decreased ability of peripheral tissues to
respond to insulin) and
β-cell dysfunction
◦ inadequate insulin secretion in the face of
insulin resistance and hyperglycemia.
Inmost cases, insulin resistance precede
β-cell dysfunction.
28
Definition
A group of metabolic
disorders sharing the common
feature of hyperglycemia
Hyperglycemia results from
defects in
◦ Insulin secretion
◦ Insulin action
◦ or, most commonly, both
 Glycogen
AS

Diabetes
> 200mg/dL

Diet

> 180mg/dl
 PATHOGENESIS OF TYPE 2
DIABETES MELLITUS
Environmental factors, such as a sedentary
life style and dietary habits

genetic factors are even more important than

in type 1 diabetes.
◦ Concordance rate among identical twins is 50-90%
◦ among first-degree relatives with type 2 diabetes
(and in fraternal twins), the risk of developing the
disease is 20% to 40%, compared to 5% to 7% in
the population at large
◦ Genes are not linked to immune tolerance and
regulation
Insulin Resistance
Defined as resistance of peripheral
tissues to the actions of insulin.
Results in impaired glucose uptake,
storage and metabolism. Insulin cannot
also suppress hepatic gluconeogenesis.

Causes
Genetic defects in insulin receptor and
signal transduction- The genes are not
yet known in humans
Obesity
Obesity and Insulin
Resistance
Central (abdominal) obesity is associated
with type 2 DM
Adipose tissue is an endocrine tissue
capable of secreting hormones called
adipokines (adipose cytokines)
Adiponectin, leptin, resistin
High levels of intracellular free fatty acids
in obese individuals can block insulin
signaling
Adiponectin and leptin (which are insulin
sensitizing molecules) are decreased in
obesity
Morbid obesity with BMI of 46 34
 Description for previous slide

 Obesity and insulin resistance: the missing links? Adipocytes

release a variety of factors (free fatty acids and adipokines)
that may play a role in modulating insulin resistance in
peripheral tissues (illustrated here is striated muscle).
Excess free fatty acids (FFAs) and resistin are associated
with insulin resistance; in contrast, adiponectin, whose levels
are decreased in obesity, is an insulin-sensitizing adipokine.
Leptin is also an insulin-sensitizing agent, but it acts via
central receptors (in the hypothalamus). The peroxisome
proliferator-activated receptor gamma (PPARγ) is an
adipocyte nuclear receptor that is activated by a class of
insulin-sensitizing drugs called thiazolidinediones (TZDs).
The mechanism of action of TZDs may eventually be
mediated through modulation of adipokine and FFA levels
that favor a state of insulin sensitivity.
 glucose

β
 glucose

β
 glucose

β
 glucose

β
 Pathogenesis of type 2 diabetes
mellitus.
 Genetic predisposition and
environmental influences converge to
cause insulin resistance.
 Compensatory β-cell hyperplasia can
maintain normoglycemia, but
eventually β-cell secretory
dysfunction sets in, leading to
impaired glucose tolerance and
eventually frank diabetes.
 Rare instances of primary β-cell
failure can directly lead to type 2
diabetes without a state of insulin
resistance.
41
DIAGNOSIS
 Normal blood glucose =70 to 120 mg/dL.
 Diagnosis of diabetes is established by noting
elevation of blood glucose by any one of three
criteria:

1. A random glucose > 200 mg/dL, with

classical signs and symptoms

2. A fasting glucose > 126 mg/dL on more

than one occasion

3. An abnormal oral glucose tolerance test

(OGTT), in which the glucose is > 200 mg/dL 2
hours after a standard carbohydrate load
Clinical Features of DM
Classic Triad of
Polyuria,
Polydypsia and
Polyphagia
 Type 1 DM Type 2 DM
Clinical Onset: <20 yrs Onset:>30 yrs
Normal weight Obese
Insulin deficiency Relative insulin
deficiency
Antiislet cell No anti-islet cell
antivodiies antibody
DKA common DKA rare
Genetics 30-70% concordance 50-90% concordance
in twins in twins
Link to MHC class II No HLA link
genes
Pathogenesi Autoimmune
s destruction
Insulitis No insulitis
Hyperglycemia exceeds renal threshold
for reabsorption and glycosuria starts.

Glycosuria
induces osmotic diuresis
and Polyuria with profound loss of
water and electrolytes.

Serum hyperosmolarity causes water to

move out of cells (intracellular
dehydration), brain osmoreceptors
are triggred causing polydyspsia.
Meanwhile, proteolysis provides amino
acids for gluconeogenesis by the liver.

Proteolysisand lipolysis induce a

negative energy balance and
Polyphagia.

Polyuria,polydypsia and
polyphagia.

Weight loss and muscle

Reading assignment
Acute and chronic complications
of diabetes mellitus
Uric acid metabolism and
gout
 pathogenesis of hyperuricemia:
• Uric acid is the end product of the catabolism
of purines, derived either from the diet
or synthesized de novo.
• Uric acid is eliminated from the body mostly
through urine
• Normal values of uric acid in the blood is 7.0
mg/dl in men and 6.0 mg/dl in women
• Hyperuricemia can result from over
production of uric acid, decreased urinary
excretion of uric acid or a combination of both.
Classification:

1. Primary (idiopathic) Gout
• In this category the causes that result in
hyperuricemia are unknown,
Most cases (75-90%) of so- called idiopathic
Gout result from an as yet unexplained
impairment of uric acid excretion by the
kidney.
• In minority of the cases, though the
causes are unknown there is an over
production
of uric acid.
2. Secondary
• In this category the causes that result in
Hyperuricemia are known
a. Conditions that result in over production of uric acid
• Most common cause of overproduction of uric acid is
increased turn over of
nucleic acids, as seen in leukemia and Lymphomas and
after chemotherapy for
cancer.
• Accelerated ATP degradation for various reasons
results in over production of
uric acid
> Some genetic factors are also incriminated for over
production of uric acid
b. Conditions that result in Decreased
urinary excretion of uric acid
The most common cause of decreased
urinary excretion of uric acid is chronic
renal diseases that lead to renal failure.
Other factors are also incriminated as a
cause of decreased urinary excretion of
uric
acid.
Clinical features
 Stages of Gout
A. Asymptomatic hyperurecemia
B. Acute Gout attack
C. Intercritical period
D. Chronic tophaceous Gout
A. Asymptomatic hyperuricemia
Precedes clinically evident gout
by many years
In Acute gouty arthritis
Initially there is a
monoarticular
involvement and later in
the course of the
disease,
poly articular
involvement with fever
is common
Disorder of Ca metabolism
What is Calcium?
Calcium is a mineral that is
essential to bone health,
cardiovascular health, muscle
maintenance, circulatory health
and blood clotting
Regulating factors
Blood level of ca is regulated by
Parathyroid hormone
Vitamin D
calcitonin
calcitonin
There are two major mechanisms by
which hypercalcemia in malignancy
can occur:

(1) osteolytic metastases and local

release of cytokines and

(2) release of PTH-related protein

(PTHrP).
Primary hyperparathyroidism

nephrolithiasis 20%
Clinical findings of
hypocalcemia
Tetany
Neuromuscular irritability due to
low serum ionized calcium
Circumoral numbness,
parasthesias (tingling) or distal
extremities, carpopedal spasm
Life-threatening laryngospasm,
generalized seizures
Classic Physical Examination
Findings in Tetany
Chvostek sign elicited in subclinical
disease by tapping along the course of
the facial nerve, which induces
contractions of the muscles of the eye,
mouth or nose
Trousseau sign elicited by occluding
the circulation to the forearm and hand
by inflating a blood pressure cuff about
the arm for several minutes induces
carpal spasm, which disappears as
soon as the cuff is deflated.
Primary
Hyperparathyroidism
one of the most common
endocrine disorders
Most common nonmalignant
cause of hypercalcemia
Causes
Adenoma (85%), hyperplasia or
carcinoma(<1%)
Laboratory findings
Increased serum PTH, increased
calcium, decreased phosphorus
Secondary
Hyperparathyroidism
Hyperplasia of all four parathyroid
glands
Compensation for hypocalcemia due to
renal failure
◦ Hyperphosphatemia=> hypocalcemia
◦ Decreased Alpha 1 hydroxylase enzyme=>
Decreased Vitamin D=> Decreased
intestinal calcium Absorption
malabsorption
End Result= Hypocalcemia=>
Increased PTH
Hypocalcemia
Hypocalcemia
diet
steatorrhea
vitamin D insufficien

Renal
insufficiency
hyperplasia

+++ diet
steatorrhea
vitamin D insufficie

Renal
insufficiency
Laboratory findings in secondary
hyperparathyroidism
Increasedserum PTH
Decreased calcium
Quiz
Elaboratepathogenesis of type 2
Diabetes mellitus
The end

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