808 PSEUDO HYPOPARATHYROIDISM
In pseudo-hypoparathyroidism, the tissues fail to respond to ing after removal of the cause of secondary hyperplasia).
parathyroid hormone though parathyroid glands are usually
normal. It is a rare inherited condition with an autosomal
SECTION III
dominant character. e patients are generally females and are
characterised by signs and symptoms of hypoparathyroidism
and other clinical features like short stature, short metacarpals
and metatarsals, at nose, round face and multiple exostoses.
Since renal tubules cannot adequately respond to para-
thyroid hormone, there is hypercalciuria, hypocalcaemia and
hyperphosphataemia.
PSEUDOPSEUDO HYPOPARATHYROIDISM
Systemic Pathology
Pseudopseudo-hypoparathyroidism is another rare familial
disorder in which all the clinical features of pseudo-
hypoparathyroidism are present except that these patients have
no hypocalcaemia or hyperphosphataemia and the tissues
respond normally to parathyroid hormone. Pseudopseudo-
hypoparathyroidism has been considered an incomplete form
of pseudo-hypoparathyroidism.
PARATHYROID TUMOURS
Parathyroid adenoma and carcinoma are the neoplasms found
in parathyroid glands, the former being much more common
than the latter.
PARATHYROID ADENOMA
e commonest tumour of the parathyroid glands is an
adenoma. It may occur at any age and in either sex but is found
more frequently in adult life. Most adenomas are rst brought to
attention because of excessive secretion of parathyroid hormone
causing features of hyperparathyroidism as described above.
MORPHOLOGIC FEATURES Grossly, a parathyroid
adenoma is small (less than 5 cm diameter) encapsulated,
yellowish-brown, ovoid nodule and weighing up to 5 gm or
more.
Microscopically, majority of adenomas are predominantly
composed of chief cells arranged in sheets or cords. Oxyphil
cells and water-clear cells may be found intermingled in
varying proportions. Usually, a rim of normal parathyroid
parenchyma and fat are present external to the capsule which
help to distinguish an adenoma from di use hyperplasia.
PARATHYROID CARCINOMA
Carcinoma of the parathyroid is rare and produces manifes-
tations of hyperparathyroidism which is often more
pronounced. Carcinoma tends to be irregular in shape and is
adherent to the adjacent tissues. Most parathyroid carcinomas
are well-di erentiated. It may be di cult to distinguish
carcinoma of parathyroid gland from an adenoma but local
invasion of adjacent tissues and distant metastases are helpful
criteria of malignancy in such cases.
GIST BOX 25.5 Diseases of Parathyroid Gland
ΠHyperparathyroidism occurs due to excessive production
of parathyroid hormone and may be primary (due to
disease of the parathyroid glands), secondary (caused by
diseases in other parts of the body) and tertiary (develop-
Œ Hypoparathyroidism is of 3 types—primary, pseudo- and
pseudopseudo-hypoparathyroidism.
ΠThe commonest tumour of the parathyroid glands is an
adenoma; carcinoma of the parathyroid is rare and most
often is well-di erentiated.
ENDOCRINE PANCREAS
e human pancreas, though anatomically a single organ,
histologically and functionally, has 2 distinct parts—the
exocrine and endocrine. e exocrine part of the gland and
its disorders have already been discussed in Chapter 19. e
discussion here is focused on the endocrine pancreas and its
two main disorders: diabetes mellitus and islet cell tumours.
NORMAL STRUCTURE
e endocrine pancreas consists of microscopic collections
of cells called islets of Langerhans found scattered within the
pancreatic lobules, as well as individual endocrine cells found
in duct epithelium and among the acini. e total weight of
endocrine pancreas in the adult, however, does not exceed
1-1.5 gm (total weight of pancreas 60-100 gm). e islet cell
tissue is greatly concentrated in the tail than in the head or
body of the pancreas. Islets possess no ductal system and they
drain their secretory products directly into the circulation.
Ultrastructurally and immunohistochemically, 4 major and 2
minor types of islet cells are distinguished, each type having its
distinct secretory product and function. ese are as follows:
A. Major cell types:
1. Beta (β) or B cells comprise about 70% of islet cells and
secrete insulin, the defective response or de cient synthesis of
which causes diabetes mellitus.
2. Alpha (α) or A cells comprise 20% of islet cells and secrete
glucagon which induces hyperglycaemia.
3. Delta (δ) or D cells comprise 5-10% of islet cells and secrete
somatostatin which suppresses both insulin and glucagon
release.
4. Pancreatic polypeptide (PP) cells or F cells comprise 1-2%
of islet cells and secrete pancreatic polypeptide having some
gastrointestinal e ects.
B. Minor cell types:
1. D1 cells elaborate vasoactive intestinal peptide (VIP)
which induces glycogenolysis and hyperglycaemia and causes
secretory diarrhoea by stimulation of gastrointestinal uid
secretion.
2. Enterochroma n cells synthesise serotonin which in
pancreatic tumours may induce carcinoid syndrome.
Major disease of endocrine pancreas is diabetes mellitus;
others are uncommon islet cell tumours.
DIABETES MELLITUS
DEFINITION AND EPIDEMIOLOGY
As per the WHO, diabetes mellitus (DM) is de ned as a hetro-
geneous metabolic disorder characterised by common feature
of chronic hyperglycaemia with disturbance of carbohydrate,
fat and protein metabolism. At this point, it is also important Etiologic classi cation of diabetes mellitus 809
Table 25.4
to understand another related term, metabolic syndrome (also (as per American Diabetes Association, 2007).
called syndrome X or insulin resistance syndrome), consisting I. TYPE 1 DIABETES MELLITUS 10%
of a combination of metabolic abnormalities which increase the (earlier called Insulin-dependent, or juvenile-onset diabetes)

CHAPTER 25
risk to develop diabetes mellitus and cardiovascular disease. Type IA DM: Immune-mediated
Major features of metabolic syndrome are central obesity,
Type IB DM: Idiopathic
hypertriglyceridaemia, low LDL cholesterol, hyperglycaemia
and hypertension. II. TYPE 2 DIABETES MELLITUS 80%
(earlier called non-insulin-dependent, or maturity-onset
DM is a leading cause of morbidity and mortality world
diabetes)
over. It is expected to continue as a major health problem
owing to its serious complications, especially end-stage renal III. OTHER SPECIFIC TYPES OF DIABETES 10%
disease, IHD, gangrene of the lower extremities, and blindness A. Genetic defect of β-cell function due to mutations in
in the adults. Top 5 countries with highest prevalence of DM are various enzymes (earlier called maturity-onset diabetes of
the young or MODY) (e.g. hepatocyte nuclear transcription
India, China, US, Indonesia and Japan. In India, its incidence is

The Endocrine System

factor—HNF, glucokinase)
estimated at 7% of adult population (approximately 65 million
a ected people), largely due to genetic susceptibility combined B. Genetic defect in insulin action (e.g. type A insulin resistance)
with changing life style of low-activity high-calorie diet in the C. Diseases of exocrine pancreas (e.g. chronic pancreatitis,
growing Indian middle class. e incidence is somewhat low in pancreatic tumours, post-pancreatectomy)
Africa. But prevalence of DM is expected to rise in developing D. Endocrinopathies (e.g. acromegaly, Cushing’s syndrome,
countries of Asia and Africa due to urbanisation and associated pheochromocytoma)
obesity and increased body weight. e rise in prevalence is E. Drug- or chemical-induced (e.g. steroids, thyroid hormone,
more for type 2 diabetes than for type 1. It is anticipated that by thiazides, β-blockers etc)
the year 2030 the number of diabetics globally will double from F. Infections (e.g. congenital rubella, cytomegalovirus)
the present gure of 250 million. G. Uncommon forms of immune-mediated DM (sti man
syndrome, anti-insulin receptor antibodies)
CLASSIFICATION AND ETIOLOGY H. Other genetic syndromes (e.g. Down’s syndrome,
Klinefelter’s syndrome, Turner’s syndrome)
e older classi cation systems dividing DM into primary
(idiopathic) and secondary types, juvenile-onset and maturity IV. GESTATIONAL DIABETES MELLITUS 4%
onset types, and insulin-dependent (IDDM) and non-insulin
dependent (NIDDM) types, have become obsolete and TYPE 2 DM is type comprises about 80% cases of DM. It
undergone major revision due to extensive understanding of was previously called maturity-onset diabetes, or non-insulin
etiology and pathogenesis of DM in recent times. dependent diabetes mellitus (NIDDM) of obese and non-
As outlined in Table 25.4, current classi cation of DM obese type.
based on etiology divides it into two broad categories—type 1 Although type 2 DM predominantly a ects older individuals,
and type 2; besides there are a few uncommon speci c etiologic it is now known that it also occurs in obese adolescent children;
types, and gestational DM. American Diabetes Association hence the term MOD for it is inappropriate. Moreover, many
(2007) has identi ed risk factors for type 2 DM listed in type 2 DM patients also require insulin therapy to control
Table 25.5. hyperglycaemia or to prevent ketosis and thus are not truly
Brief comments on etiologic terminologies as contrasted non-insulin dependent contrary to its older nomenclature.
with former nomenclatures of DM are as under:
OTHER SPECIFIC ETIOLOGIC TYPES OF DM Besides the
TYPE 1 DM It constitutes about 10% cases of DM. It was two main types, about 10% cases of DM have a known speci c
previously termed as juvenile-onset diabetes (JOD) due to its etiologic defect listed in Table 25.4. One important subtype
occurrence in younger age, and was called insulin-dependent
DM (IDDM) because it was known that these patients have
absolute requirement for insulin replacement as treatment. Major risk factors for type 2 diabetes mellitus
Table 25.5
(ADA Recommendations, 2007).
However, in the new classi cation, neither age nor insulin-
dependence are considered as absolute criteria. Instead, based 1. Family history of type 2 DM
on underlying etiology, type 1 DM is further divided into 2 2. Obesity
subtypes:
3. Habitual physical inactivity
Subtype 1A (immune-mediated) DM characterised by auto-
4. Race and ethnicity (Blacks, Asians, Paci c Islanders)
immune destruction of β-cells which usually leads to insulin
de ciency. 5. Previous identi cation of impaired fasting glucose or impaired
glucose tolerance
Subtype 1B (idiopathic) DM characterised by insulin
6. History of gestational DM or delivery of baby heavier than 4 kg
de ciency with tendency to develop ketosis but these patients
are negative for autoimmune markers. 7. Hypertension
ough type 1 DM occurs commonly in patients under 30 8. Dyslipidaemia (HDL level < 35 mg/dl or triglycerides
years of age, autoimmune destruction of β-cells can occur at > 250 mg/dl)
any age. In fact, 5-10% patients who develop DM above 30 years 9. Polycystic ovary disease and acanthosis nigricans
of age are of type 1A DM and hence the term JOD has become
10. History of vascular disease
obsolete.
810 in this group is maturity-onset diabetes of the young (MODY)
which has autosomal dominant inheritance, early onset of
hyperglycaemia and impaired insulin secretion.
GESTATIONAL DM About 4% pregnant women develop DM
SECTION III
due to metabolic changes during pregnancy. Although they
revert back to normal glycaemia after delivery, these women
are prone to develop DM later in their life.
PATHOGENESIS
Depending upon etiology of DM, hyperglycaemia may result
from the following:
” Reduced insulin secretion
” Decreased glucose use by the body
Systemic Pathology
” Increased glucose production.
Pathogenesis of two main types of DM and its complications
is distinct. In order to understand it properly, it is essential to
rst recall physiology of normal insulin synthesis and secretion.
NORMAL INSULIN METABOLISM e major stimulus
for both synthesis and release of insulin is glucose. e steps
involved in biosynthesis, release and actions of insulin are as
follows (Fig. 25.22):
Synthesis Insulin is synthesised in the β-cells of pancreatic
islets of Langerhans:
i) It is initially formed as pre-proinsulin which is single-chain
86-amino acid precursor polypeptide.
ii) Subsequent proteolysis removes the amino terminal signal
peptide, forming proinsulin.
iii) Further cleavage of proinsulin gives rise to A (21 amino
acids) and B (30 amino acids) chains of insulin, linked together
by connecting segment called C-peptide, all of which are stored
in the secretory granules in the β-cells. As compared to A and
B chains of insulin, C-peptide is less susceptible to degradation
in the liver and is therefore used as a marker to distinguish
endogenously synthesised and exogenously administered
insulin.
For therapeutic purposes, human insulin is now produced
by recombinant DNA technology.
Figure 25.22 A, Pathway of normal insulin synthesis and release in β-cells of pancreatic islets. B, Chain of events in action of insulin on target cell.
Release Glucose is the key regulator of insulin secretion from
β-cells by a series of steps:
i) Hyperglycaemia (glucose level more than 70 mg/dl or
above 3.9 mmol/L) stimulates transport into β-cells of a glucose
transporter, GLUT2. Other stimuli in uencing insulin release
include nutrients in the meal, ketones, amino acids etc.
ii) An islet transcription factor, glucokinase, causes glucose
phosphorylation, and thus acts as a step for controlled release
of glucose-regulated insulin secretion.
iii) Metabolism of glucose to glucose-6-phosphate by glycolysis
generates ATP.
iv) Generation of ATP alters the ion channel activity on the
membrane. It causes inhibition of ATP-sensitive K+ channel
on the cell membrane and opening up of calcium channel with
resultant in ux of calcium, which stimulates insulin release.
Action Half of insulin secreted from β-cells into portal vein
is degraded in the liver while the remaining half enters the
systemic circulation for action on the target cells:
i) Insulin from circulation binds to its receptor on the target
cells. Insulin receptor has intrinsic tyrosine kinase activity.
ii) is, in turn, activates post-receptor intracellular signalling
pathway molecules, insulin receptor substrates (IRS) 1 and
2 proteins, which initiate sequence of phosphorylation and
dephosphorylation reactions.
iii) ese reactions on the target cells are responsible for the
main mitogenic and anabolic actions of insulin—glycogen
synthesis, glucose transport, protein synthesis, lipogenesis.
iv) Besides the role of glucose in maintaining equilibrium of
insulin release, low insulin level in the fasting state promotes
hepatic gluconeogenesis and glycogenolysis, reduced glucose
uptake by insulin-sensitive tissues and promotes mobilisation
of stored precursors, so as to prevent hypoglycaemia.
PATHOGENESIS OF TYPE 1 DM e basic phenomenon
in type 1 DM is destruction of β-cell mass, usually leading
to absolute insulin de ciency. While type 1B DM remains
idiopathic, pathogenesis of type 1A DM is immune-mediated
and has been extensively studied. Currently, pathogenesis of
type 1A DM is explained on the basis of 3 mutually-interlinked
mechanisms: genetic susceptibility, autoimmunity, and certain
environmental factors (Fig. 25.23,A).
1. Genetic susceptibility Type 1A DM involves inheritance
of multiple genes to confer susceptibility to the disorder:
i) It has been observed in identical twins that if one twin has
type 1A DM, there is about 50% chance of the second twin
developing it, but not all. is means that some additional
modifying factors are involved in development of DM in these
cases.
ii) About half the cases with genetic predisposition to type 1A
DM have the susceptibility gene located in the HLA region of
chromosome 6 (MHC class II region), particularly HLA DR3,
HLA DR4 and HLA DQ locus.
2. Autoimmunity Studies on humans and animal models
on type 1A DM have shown several immunologic abnormalities:
i) Presence of islet cell antibodies against GAD (glutamic acid
decarboxylase), insulin etc, though their assay largely remains
a research tool due to tedious method.
ii) Occurrence of lymphocytic in ltrate in and around the
pancreatic islets termed insulitis. It chie y consists of CD8+ T
lymphocytes with variable number of CD4+ T lymphocytes and
macrophages.
iii) Selective destruction of β-cells while other islet cell types
(glucagon-producing alpha cells, somatostatin-producing delta
cells, or polypeptide-forming PP cells) remain una ected. is
is mediated by T-cell mediated cytotoxicity or by apoptosis.
iv) Role of T cell-mediated autoimmunity is further supported
by transfer of type 1A DM from diseased animal by infusing T
lymphocytes to a healthy animal.
Figure 25.23 Schematic mechanisms involved in pathogenesis of two main types of diabetes mellitus.
v) Association of type 1A DM with other autoimmune diseases 811
in about 10-20% cases such as Graves’ disease, Addison’s
disease, Hashimoto’s thyroiditis, pernicious anaemia.
vi) Remission of type 1A DM in response to immunosuppres-
CHAPTER 25
sive therapy such as administration of cyclosporin A.
3. Environmental factors Epidemiologic studies in type
1A DM suggest the involvement of certain environmental
factors in its pathogenesis, though role of none of them has
been conclusively proved. In fact, the trigger may precede
the occurrence of the disease by several years. It appears that
certain viral and dietary proteins share antigenic properties
with human cell surface proteins and trigger the immune
attack on β-cells by a process of molecular mimicry. ese
The Endocrine System
factors include the following:
i) Certain viral infections preceding the onset of disease
e.g. mumps, measles, coxsackie B virus, cytomegalovirus and
infectious mononucleosis.
ii) Experimental induction of type 1A DM with certain
chemicals has been possible e.g. alloxan, streptozotocin and
pentamidine.
iii) Geographic and seasonal variations in its incidence suggest
some common environmental factors.
iv) Possible relationship of early exposure to bovine milk
proteins and occurrence of autoimmune process in type 1A DM
is being studied.
KEY POINTS Pathogenesis of type 1A DM can be summed
up by interlinking the above three factors as under:
1. At birth, individuals with genetic susceptibility to this
disorder have normal β-cell mass.
2. β-cells act as autoantigens and activate CD4+ T lympho-
cytes, bringing about immune destruction of pancreatic
812 β-cells by autoimmune phenomena and takes months to years.
Clinical features of diabetes manifest after more than 80% of
β-cell mass has been destroyed.
3. e trigger for autoimmune process appears to be some
infectious or environmental factor which speci cally targets
SECTION III
β-cells.
PATHOGENESIS OF TYPE 2 DM e basic metabolic defect
in type 2 DM is either a delayed insulin secretion relative to
glucose load (impaired insulin secretion), or the peripheral
tissues are unable to respond to insulin (insulin resistance).
Type 2 DM is a heterogeneous disorder with a more complex
etiology and is far more common than type 1, but much less is
known about its pathogenesis. A number of factors have been
Systemic Pathology
implicated though, but HLA association and autoimmune
phenomena are not implicated. ese factors are as under
(Fig. 25.23,B):
1. Genetic factors Genetic component has a stronger
basis for type 2 DM than type 1A DM. Although no de nite
and consistent genes have been identi ed, multifactorial
inheritance is the most important factor in development of
type 2 DM:
i) ere is approximately 80% chance of developing diabetes
in the other identical twin if one twin has the disease.
ii) A person with one parent having type 2 DM is at an
increased risk of getting diabetes, but if both parents have type
2 DM the risk in the o spring rises to 40%.
2. Constitutional factors Certain environmental factors
such as obesity, hypertension, and level of physical activity
play contributory role and modulate the phenotyping of the
disease.
3. Insulin resistance One of the most prominent metabolic
features of type 2 DM is the lack of responsiveness of peripheral
tissues to insulin, especially of the skeletal muscle and liver.
Obesity, in particular, is strongly associated with insulin
resistance and hence type 2 DM. Mechanism of hyperglycaemia
in these cases is explained as under:
i) Resistance to action of insulin impairs glucose utilisation
and hence hyperglycaemia.
ii) ere is increased hepatic synthesis of glucose.
iii) Hyperglycaemia in obesity is related to high levels of free
fatty acids and cytokines (e.g. TNF-α and adiponectin) a ect
peripheral tissue sensitivity to respond to insulin.
e precise underlying molecular defect responsible for
insulin resistance in type 2 DM has yet not been fully identi ed.
Currently, it is proposed that insulin resistance may be possibly
due to one of the following defects:
a) Polymorphism in various post-receptor intracellular
signal pathway molecules.
b) Elevated free fatty acids seen in obesity may contribute
e.g. by impaired glucose utilisation in the skeletal muscle,
by increased hepatic synthesis of glucose, and by impaired
β-cell function.
c) Insulin resistance syndrome is a complex of clinical
features occurring from insulin resistance and its resultant
metabolic derangements that includes hyperglycaemia and
compensatory hyperinsulinaemia. e clinical features are in
the form of accelerated cardiovascular disease and may occur
in both obese as well as non-obese type 2 DM patients. e
features include: mild hypertension (related to endothelial
dysfunction) and dyslipidaemia (characterised by reduced
HDL level, increased triglycerides and LDL level).
4. Impaired insulin secretion In type 2 DM, insulin
resistance and insulin secretion are interlinked:
i) Early in the course of disease, in response to insulin
resistance there is compensatory increased secretion of insulin
(hyperinsulinaemia) in an attempt to maintain normal blood
glucose level.
ii) Eventually, however, there is failure of β-cell function to
secrete adequate insulin, although there is some secretion of
insulin i.e. cases of type 2 DM have mild to moderate de ciency
of insulin (which is much less severe than that in type 1 DM)
but not its total absence.
e exact genetic mechanism why there is a fall in insulin
secretion in these cases is unclear. However, following
possibilities are proposed:
a) Islet amyloid polypeptide (amylin) which forms brillar
protein deposits in pancreatic islets in longstanding cases of
type 2 DM may be responsible for impaired function of β-cells
of islet cells.
b) Metabolic environment of chronic hyperglycaemia
surrounding the islets (glucose toxicity) may paradoxically
impair islet cell function.
c) Elevated free fatty acid levels (lipotoxicity) in these cases
may worsen islet cell function.
5. Increased hepatic glucose synthesis One of the normal
roles played by insulin is to promote hepatic storage of glucose
as glycogen and suppress gluconeogenesis. In type 2 DM, as a
part of insulin resistance by peripheral tissues, the liver also
shows insulin resistance i.e. in spite of hyperinsulinaemia
in the early stage of disease, gluconeogenesis in the liver is
not suppressed. is results in increased hepatic synthesis of
glucose which contributes to hyperglycaemia in these cases.
KEY POINTS In essence, hyperglycaemia in type 2 DM is not
due to destruction of β-cells but is instead a failure of β-cells to
meet the requirement of insulin in the body. Its pathogenesis
can be summed up by interlinking the above factors as under:
1. Type 2 DM is a more complex multifactorial disease.
2. ere is greater role of genetic defect and heredity.
3. Two main mechanisms for hyperglycaemia in type 2
DM—insulin resistance and impaired insulin secretion, are
interlinked.
4. While obesity plays a role in pathogenesis of insulin
resistance, impaired insulin secretion may be from many
constitutional factors.
5. Increased hepatic synthesis of glucose in initial period of
disease contributes to hyperglycaemia.
MORPHOLOGIC FEATURES IN PANCREATIC ISLETS
Morphologic changes in islets have been demonstrated in
both types of diabetes, though the changes are more distinc-
tive in type 1 DM:
1. Insulitis:
In type 1 DM, characteristically, in early stage there is
lymphocytic in ltrate, mainly by T cells, in the islets
which may be accompanied by a few macrophages and
polymorphs. Diabetic infants born to diabetic mothers,
however, have eosinophilic in ltrate in the islets.
In type 2 DM, there is no signi cant leucocytic in ltrate in the
islets but there is variable degree of brous tissue in the islets.
 CLINICAL FEATURES 813
It can be appreciated that hyperglycaemia in DM does not
cause a single disease but is associated with numerous diseases
and symptoms, especially due to complications. Two main

CHAPTER 25
types of DM can be distinguished clinically to the extent shown
in Table 25.6. However, overlapping of clinical features occurs
as regards the age of onset, duration of symptoms and family
history. Pathophysiology in evolution of clinical features is
schematically shown in Fig. 25.25.
Type 1 DM:
i) Patients of type 1 DM usually manifest at early age, generally
below the age of 35.
ii) e onset of symptoms is often abrupt.

The Endocrine System

Figure 25.24 Amyloidosis of the pancreatic islet tissue. The islets are
mostly replaced by structureless eosinophilic material which stains
positively with Congo red.
2. Islet cell mass:
In type 1 DM, as the disease becomes chronic there is
progressive depletion of β-cell mass, eventually resulting in
total loss of pancreatic β-cells and its hyalinisation.
In type 2 DM, β-cell mass is either normal or mildly reduced.
Infants of diabetic mothers, however, have hyperplasia
and hypertrophy of islets as a compensatory response to
maternal hyperglycaemia.
3. Amyloidosis:
In type 1 DM, deposits of amyloid around islets are absent.
In type 2 DM, characteristically chronic long-standing cases
show deposition of amyloid material, amylin, around the
capillaries of the islets causing compression and atrophy of
islet tissue (Fig. 25.24).
β-cell degranulation:
In type 1 DM, EM shows degranulation of remaining β-cells
of islets.
In type 2 DM, no such change is observed.
iii) At presentation, these patients have polyuria, polydipsia
and polyphagia.
iv) e patients are not obese but have generally progressive
loss of weight.
v) ese patients are prone to develop metabolic complications
such as ketoacidosis and hypoglycaemic episodes.
Type 2 DM:
i) is form of diabetes generally manifests in middle life or
beyond, usually above the age of 40.
ii) e onset of symptoms in type 2 DM is slow and insidious.
iii) Generally, the patient is asymptomatic when the diagnosis
is made on the basis of glucosuria or hyperglycaemia during
physical examination, or may present with polyuria and
polydipsia.
iv) e patients are frequently obese and have unexplained
weakness and loss of weight.
v) Metabolic complications such as ketoacidosis are
infrequent.
PATHOGENESIS OF COMPLICATIONS
It is now known that in both type 1 and 2 DM, severity and
chronicity of hyperglycaemia forms the main pathogenetic
mechanism for ‘microvascular complications’ (e.g. retinopathy,
nephropathy, neuropathy); therefore control of blood glucose
level constitutes the mainstay of treatment for minimising

Table 25.6 Contrasting features of type 1 and type 2 diabetes mellitus.

FEATURE TYPE 1 DM TYPE 2 DM

1. Frequency 10-20% 80-90%
2. Age at onset Early (below 35 years) Late (after 40 years)
3. Type of onset Abrupt and severe Gradual and insidious
4. Weight Normal Obese/non-obese
5. HLA Linked to HLA DR3, HLA DR4, HLA DQ No HLA association
6. Family history < 20% About 60%
7. Genetic locus Unknown Chromosome 6
8. Diabetes in identical twins 50% concordance 80% concordance
9. Pathogenesis Autoimmune destruction of β-cells Insulin resistance, impaired insulin secretion
10. Islet cell antibodies Yes No
11. Blood insulin level Decreased insulin Normal or increased insulin
12. Islet cell changes Insulitis, β-cell depletion No insulitis, later brosis of islets
13. Amyloidosis Infrequent Common in chronic cases
14. Clinical management Insulin and diet Diet, exercise, oral drugs, insulin
15. Acute complications Ketoacidosis Hyperosmolar coma
814
SECTION III
Systemic Pathology
Figure 25.25 Pathophysiological basis of common signs and symptoms due to uncontrolled hyperglycaemia in diabetes mellitus.
development of these complications. Longstanding cases
of type 2 DM, however, in addition, frequently develop
‘macrovascular complications’ (e.g. atherosclerosis, coronary
artery disease, peripheral vascular disease, cerebrovascular
disease) which are more di cult to explain on the basis of
hyperglycaemia alone.
e following biochemical mechanisms have been
proposed to explain the development of complications of
diabetes mellitus (Fig. 25.26,A):
1. Non-enzymatic protein glycosylation e free amino
group of various body proteins binds by non-enzymatic
mechanism to glucose; this process is called glycosylation and is
directly proportionate to the severity of hyperglycaemia. Various
body proteins undergoing chemical alterations in this way
include haemoglobin, lens crystalline protein, and basement
membrane of body cells. An example is the measurement of
a fraction of haemoglobin called glycosylated haemoglobin
(HbA1C) as a test for monitoring glycaemic control in a diabetic
patient during the preceding 90 to 120 days which is lifespan
of red cells (page 265). Similarly, there is accumulation of
labile and reversible glycosylation products on collagen and
other tissues of the blood vessel wall which subsequently
become stable and irreversible by chemical changes and form
advanced glycosylation end-products (AGE). e AGEs bind to
receptors on di erent cells and produce a variety of biologic
and chemical changes e.g. thickening of vascular basement
membrane in diabetes.
2. Polyol pathway mechanism is mechanism is
responsible for producing lesions in the aorta, lens of the eye,
kidney and peripheral nerves. ese tissues have an enzyme,
aldose reductase, that reacts with glucose to form sorbitol and
fructose in the cells of the hyperglycaemic patient as under:
aldose reductase
Glucose + NADH + H+ Sorbitol + NAD+
sorbitol
dehydrogenase
Sorbitol + NAD Fructose + NADH + H+
Intracellular accumulation of sorbitol and fructose
so produced results in entry of water inside the cell and
consequent cellular swelling and cell damage. Also, intra-
cellular accumulation of sorbitol causes intracellular de ciency
of myoinositol which promotes injury to Schwann cells and
retinal pericytes. ese polyols result in disturbed processing
of normal intermediary metabolites leading to complications
of diabetes.
3. Excessive oxygen free radicals In hyperglycaemia, there
is increased production of reactive oxygen free radicals from
mitochondrial oxidative phosphorylation which may damage
various target cells in diabetes.
COMPLICATIONS OF DIABETES
As a consequence of hyperglycaemia of diabetes, every tissue
and organ of the body undergoes biochemical and structural
alterations which account for the major complications in
diabetics which may be acute metabolic or chronic systemic.
Both types of diabetes mellitus may develop complications
which are broadly divided into 2 major groups:
I. Acute metabolic complications: ese include diabetic keto-
acidosis, hyperosmolar nonketotic coma, and hypoglycaemia.

Figure 25.26 Long-term complications of diabetes mellitus. A, Pathogenesis. B, Secondary systemic complications.
II. Late systemic complications: ese are atherosclerosis,
diabetic microangiopathy, diabetic nephropathy, diabetic
neuropathy, diabetic retinopathy and infections.
I. ACUTE METABOLIC COMPLICATIONS Metabolic
complications develop acutely. While ketoacidosis and
hypoglycaemic episodes are primarily complications of type 1
DM, hyperosmolar nonketotic coma is chie y a complication
of type 2 DM (also see Fig. 25.25).
1. Diabetic ketoacidosis (DKA) Ketoacidosis is almost
exclusively a complication of type 1 DM. It can develop
in patients with severe insulin de ciency combined with
glucagon excess. Failure to take insulin and exposure to stress
are the usual precipitating causes. Severe lack of insulin causes
lipolysis in the adipose tissues, resulting in release of free fatty
acids into the plasma. ese free fatty acids are taken up by
the liver where they are oxidised through acetyl coenzyme-A
to ketone bodies, principally acetoacetic acid and β-hydroxy-
butyric acid. Such free fatty acid oxidation to ketone bodies
is accelerated in the presence of elevated level of glucagon.
Once the rate of ketogenesis exceeds the rate at which the
ketone bodies can be utilised by the muscles and other tissues,
ketonaemia and ketonuria occur. If urinary excretion of ketone
bodies is prevented due to dehydration, systemic metabolic
ketoacidosis occurs. Clinically, the condition is characterised
by anorexia, nausea, vomitings, deep and fast breathing, mental
confusion and coma. Most patients of ketoacidosis recover.
2. Hyperosmolar hyperglycaemic nonketotic coma (HHS)
Hyperosmolar hyperglycaemic nonketotic coma is usually a
815
CHAPTER 25
The Endocrine System
complication of type 2 DM. It is caused by severe dehydration
resulting from sustained hyperglycaemic diuresis. e loss
of glucose in urine is so intense that the patient is unable to
drink su cient water to maintain urinary uid loss. e usual
clinical features of ketoacidosis are absent but prominent
central nervous signs are present. Blood sugar is extremely
high and plasma osmolality is high. rombotic and bleeding
complications are frequent due to high viscosity of blood. e
mortality rate in hyperosmolar nonketotic coma is high.
e contrasting features of diabetic ketoacidosis and
hyperosmolar non-ketotic coma are summarised in Table 25.7.
3. Hypoglycaemia Hypoglycaemic episode may develop in
patients of type 1 DM. It may result from excessive administration
of insulin, missing a meal, or due to stress. Hypoglycaemic
episodes are harmful as they produce permanent brain
damage, or may result in worsening of diabetic control and
rebound hyperglycaemia, so called Somogyi’s e ect.
II. LATE SYSTEMIC COMPLICATIONS A number of
systemic complications may develop after a period of 15-20
years in either type of diabetes. Late complications are largely
responsible for morbidity and premature mortality in diabetes
mellitus. ese complications are brie y outlined below and
have been discussed in detail in relevant chapters (Fig. 25.26,B).
1. Atherosclerosis Diabetes mellitus of both type 1
and type 2 accelerates the development of atherosclerosis.
Consequently, atherosclerotic lesions appear earlier than
in the general population, are more extensive, and are more
often associated with complicated plaques such as ulceration,
816 Contrasting features of diabetic ketoacidosis (DKA) and fructose as a result of hyperglycaemia, leading to de ciency
Table 25.7 and hyperosmolar hyperglycaemic non-ketotic of myoinositol.
coma (HHS).
5. Diabetic retinopathy Diabetic retinopathy is a leading
LAB FINDINGS DKA HHS cause of blindness. ere are 2 types of lesions involving retinal
SECTION III

i. Plasma glucose (mg/dL) 250-600 > 600 vessels: background and proliferative (page 489). Besides
ii. Plasma acetone + Less + retinopathy, diabetes also predisposes the patients to early
development of cataract and glaucoma.
iii. S. Na+ (mEq/L) Usually low N, ↑ or low
6. Infections Diabetics have enhanced susceptibility
iv. S. K+ (mEq/L) N, ↑ or low N or ↑
to various infections such as tuberculosis, pneumonias,
v. S. phosphorus (mEq/L) N or ↑ N or ↑ pyelonephritis, otitis, carbuncles and diabetic ulcers. is
vi. S. Mg++ N or ↑ N or ↑ could be due to various factors such as impaired leucocyte
vii. S. bicarbonate (mEq/L) Usually <15 Usually >20 functions, reduced cellular immunity, poor blood supply due
to vascular involvement and hyperglycaemia per se.
Systemic Pathology

viii. Blood pH <7.30 > 7.30

ix. S. osmolarity (mOsm/L) <320 > 330
x. S. lactate (mmol/L) 2-3 1-2
xi. S. BUN (mg/dL) Less ↑ Greater ↑
xii. Plasma insulin Low to 0 Some
calci cation and thrombosis (page 378). e cause for this
accelerated atherosclerotic process is not known but possible
contributory factors are hyperlipidaemia, reduced HDL
levels (see metabolic syndrome on page 809), nonenzymatic
glycosylation, increased platelet adhesiveness, obesity and
associated hypertension in diabetes.
e possible ill-e ects of accelerated atherosclerosis in
diabetes are early onset of coronary artery disease, silent
myocardial infarction, cerebral stroke and gangrene of the toes
and feet. Gangrene of the lower extremities is 100 times more
common in diabetics than in non-diabetics.
2. Diabetic microangiopathy Microangiopathy of diabetes
is characterised by basement membrane thickening of small
blood vessels and capillaries of di erent organs and tissues
such as the skin, skeletal muscle, eye and kidney. Similar type
of basement membrane-like material is also deposited in
nonvascular tissues such as peripheral nerves, renal tubules
and Bowman’s capsule. e pathogenesis of diabetic micro-
angiopathy as well as of peripheral neuropathy in diabetics
is believed to be due to recurrent hyperglycaemia that causes
increased glycosylation of haemoglobin and other proteins
(e.g. collagen and basement membrane material) resulting in
thickening of basement membrane.
3. Diabetic nephropathy Renal involvement is a common
complication and a leading cause of death in diabetes. Four
types of lesions are described in diabetic nephropathy (page
664):
i) Diabetic glomerulosclerosis which includes di use and
nodular lesions of glomerulosclerosis.
ii) Vascular lesions that include hyaline arteriolosclerosis of
a erent and e erent arterioles and atheromas of renal arteries.
iii) Diabetic pyelonephritis and necrotising renal papillitis.
iv) Tubular lesions or Armanni-Ebstein lesion.
4. Diabetic neuropathy Diabetic neuropathy may a ect
all parts of the nervous system but symmetric peripheral
neuropathy is most characteristic. e basic pathologic
changes are segmental demyelination, Schwann cell injury and
axonal damage (page 884). e pathogenesis of neuropathy is
not clear but it may be related to di use microangiopathy as
already explained, or may be due to accumulation of sorbitol
DIAGNOSIS OF DIABETES
Hyperglycaemia remains the fundamental basis for the
diagnosis of diabetes mellitus. In symptomatic cases, the
diagnosis is not a problem and can be con rmed by nding
glucosuria and a random plasma glucose concentration above
200 mg/dl.
” e severity of clinical symptoms of polyuria and polydipsia
is directly related to the degree of hyperglycaemia.
” In asymptomatic cases, when there is persistently elevated
fasting plasma glucose level, diagnosis again poses no di culty.
” e problem arises in asymptomatic patients who have
normal fasting glucose level in the plasma but are suspected
to have diabetes on other grounds and are thus subjected to
oral glucose tolerance test (GTT). If abnormal GTT values
are found, these subjects are said to have ‘chemical diabetes’
(Fig. 25.27). e American Diabetes Association (2007) has
recommended de nite diagnostic criteria for early diagnosis of
diabetes mellitus (Table 25.8).
e following investigations are helpful in establishing the
diagnosis of diabetes mellitus:
I. URINE TESTING Urine tests are cheap and convenient
but the diagnosis of diabetes cannot be based on urine testing
alone since there may be false-positives and false-negatives.
Revised criteria for diagnosis of diabetes by oral GTT
Table 25.8
(as per American Diabetes Association, 2007).
PLASMA GLUCOSE VALUE* DIAGNOSIS
FASTING FOR > 8 HOURS VALUE
Below 100 mg/dl (< 5.6 mmol/L) Normal fasting value
100-125 mg/dl (5.6-6.9 mmol/L) Impaired fasting glucose (IFG)**
126 mg/dl (7.0 mmol/L) or more Diabetes mellitus
TWO HOUR AFTER 75 GM ORAL GLUCOSE LOAD
< 140 mg/dl (< 7.8 mmol/L) Normal post-prandial GTT
140-199 mg/dl (7.8-11.1 mmol/L) Impaired post-prandial glucose
tolerance (IGT)**
200 mg/dl (11.1 mmol/L) or more Diabetes mellitus
RANDOM VALUE
200 mg/dl (11.1 mmol/L) or more in Diabetes mellitus
a symptomatic patient
Note: * Plasma glucose values are 15% higher than whole blood glucose value.
** Individuals with IFG and IGT are at increased risk for development of type 2
DM later.
 ey can be used in population screening surveys. Urine is
tested for the presence of glucose and ketones.
1. Glucosuria Benedict’s qualitative test detects any
reducing substance in the urine and is not speci c for glucose.
More sensitive and glucose speci c test is dipstick method
based on enzyme-coated paper strip which turns purple when
dipped in urine containing glucose.
e main disadvantage of relying on urinary glucose test
alone is the individual variation in renal threshold. us, a
diabetic patient may have a negative urinary glucose test and
a nondiabetic individual with low renal threshold may have a
positive urine test.
Besides diabetes mellitus, glucosuria may also occur in
certain other conditions such as: renal glycosuria, alimentary
(lag storage) glucosuria, many metabolic disorders, starvation
and intracranial lesions (e.g. cerebral tumour, haemorrhage
and head injury). However, two of these conditions—renal
glucosuria and alimentary glucosuria, require further
elaboration here.
” Renal glucosuria (Fig. 25.27,B): After diabetes, the next
most common cause of glucosuria is the reduced renal
threshold for glucose. In such cases although the blood glucose
level is below 180 mg/dl (i.e. below normal renal threshold for
glucose) but glucose still appears regularly and consistently in
the urine due to lowered renal threshold.
Renal glucosuria is a benign condition unrelated to diabetes
and runs in families and may occur temporarily in pregnancy
without symptoms of diabetes.
” Alimentary (lag storage) glucosuria (Fig. 25.27,C): A rapid
and transitory rise in blood glucose level above the normal renal
threshold may occur in some individuals after a meal. During
this period, glucosuria is present. is type of response to meal
is called ‘lag storage curve’ or more appropriately ‘alimentary
glucosuria’. A characteristic feature is that unusually high blood
glucose level returns to normal 2 hours after meal.
2. Ketonuria Tests for ketone bodies in the urine are
required for assessing the severity of diabetes and not for
diagnosis of diabetes. However, if both glucosuria and ketonuria
are present, diagnosis of diabetes is almost certain. Rothera’s
test (nitroprusside reaction) and strip test are conveniently
performed for detection of ketonuria.
Figure 25.27 The glucose tolerance test, showing blood glucose curves (venous blood glucose) and glucosuria after 75 gm of oral glucose.
Besides uncontrolled diabetes, ketonuria may appear in 817
individuals with prolonged vomitings, fasting state or exercising
for long periods.
II. SINGLE BLOOD SUGAR ESTIMATION For diagnosis of
CHAPTER 25
diabetes, blood sugar determinations are absolutely necessary.
Folin-Wu method of measurement of all reducing substances
in the blood including glucose is now obsolete. Currently used
are O-toluidine, Somogyi-Nelson and glucose oxidase methods.
Whole blood or plasma may be used but whole blood values are
15% lower than plasma values.
A grossly elevated single determination of plasma glucose
may be su cient to make the diagnosis of diabetes. A fasting
plasma glucose value above 126 mg/dl (>7 mmol/L) is certainly
The Endocrine System
indicative of diabetes. In other cases, oral GTT is performed.
III. SCREENING BY FASTING GLUCOSE TEST Fasting
plasma glucose determination is a screening test for DM type
2. It is recommended that all individuals above 45 years of age
must undergo screening fasting glucose test every 3-years, and
relatively earlier if the person is overweight or at risk because of
the following reasons:
i) Many of the cases meeting the current criteria of DM are
asymptomatic and do not know that they have the disorder.
ii) Studies have shown that type 2 DM may be present for
about 10 years before symptomatic disease appears.
iii) About half the cases of type 2 DM have some diabetes-
related complication at the time of diagnosis.
iv) Course of the disease is favourably altered with treatment.
IV. ORAL GLUCOSE TOLERANCE TEST Oral GTT is
performed principally for patients with borderline fasting
plasma glucose value (i.e. between 100 and 140 mg/dl). e
patient who is scheduled for oral GTT is instructed to eat a
high carbohydrate diet for at least 3 days prior to the test and
come after an overnight fast on the day of the test (for at least
8 hours). A fasting blood sugar sample is rst drawn. en 75
gm of glucose dissolved in 300 ml of water is given. Blood and
urine specimen are collected at half-hourly intervals for at least
2 hours. Blood or plasma glucose content is measured and
urine is tested for glucosuria to determine the approximate
renal threshold for glucose. Venous whole blood concen-
trations are 15% lower than plasma glucose values.
818 Currently accepted criteria for diagnosis of DM (as per
American Diabetes Association, 2007) are given in Table 25.8:
” Normal cut o value for fasting blood glucose level is
considered as 100 mg/dl.
” Cases with fasting blood glucose value in range of 100-125
SECTION III
mg/dl are considered as impaired fasting glucose tolerance
(IGT); these cases are at increased risk of developing diabetes
later and therefore kept under observation for repeating the
test. During pregnancy, however, a case of IGT is treated as a
diabetic.
” Individuals with fasting value of plasma glucose higher
than 126 mg/dl and 2-hour value after 75 gm oral glucose
higher than 200 mg/dl are labelled as diabetics (Fig. 25.27,D).
” In symptomatic case, the random blood glucose value
Systemic Pathology
above 200 mg/dl is diagnosed as diabetes mellitus.
V. OTHER TESTS A few other tests are sometimes
performed in speci c conditions in diabetics and for research
purposes:
1. Glycosylated haemoglobin (HbA1C) Measurement
of blood glucose level in diabetics su ers from variation due
to dietary intake of the previous day. Long-term objective
assessment of degree of glycaemic control is better monitored
by measurement of glycosylated haemoglobin (HbA1C), a minor
haemoglobin component present in normal persons. is is
because the non-enzymatic glycosylation of haemoglobin takes
place over 90-120 days, lifespan of red blood cells. HbA1C assay,
therefore, gives an estimate of diabetic control and compliance
for the preceding 3-4 months. is assay has the advantage
over traditional blood glucose test that no dietary preparation
or fasting is required. Increased HbA1C value almost certainly
means DM but normal value does not rule out IGT; thus the
test is not used for making the diagnosis of DM. Moreover,
since HbA1C assay has a direct relation between poor control
and development of complications, it is also a good measure
of prediction of microvascular complications. Care must be
taken in interpretation of the HbA1C value because it varies
with the assay method used and is a ected by presence of
haemoglobinopathies, anaemia, reticulocytosis, transfusions
and uraemia.
2. Glycated albumin is is used to monitor degree of
hyperglycaemia during previous 1-2 weeks when HbA1C can
not be used.
3. Extended GTT e oral GTT is extended to 3-4 hours for
appearance of symptoms of hyperglycaemia. It is a useful test
in cases of reactive hypoglycaemia of early diabetes.
4. Intravenous GTT is test is performed in persons who
have intestinal malabsorption or in postgastrectomy cases.
5. Cortisone-primed GTT is provocative test is a useful
investigative aid in cases of potential diabetics.
6. Insulin assay Plasma insulin can be measured by radio-
immunoassay and ELISA technique. Plasma insulin de ciency
is crucial for type 1 DM but is not essential for making the
diagnosis of DM.
7. Proinsulin assay Proinsulin is included in immunoassay
of insulin; normally it is <20% of total insulin.
8. C-peptide assay C-peptide is released in circulation
during conversion of proinsulin to insulin in equimolar
quantities to insulin; thus its levels correlate with insulin level
in blood except in islet cell tumours and in obesity. is test is
even more sensitive than insulin assay because its levels are not
a ected by insulin therapy.
9. Islet autoantibodies Glutamic acid decarboxylase and
islet cell cytoplasmic antibodies may be used as a marker for
type 1 DM.
10. Screening for diabetes-associated complications
Besides making the diagnosis of DM based on the de ned
criteria, screening tests are done for DM-associated complica-
tions e.g. microalbuniuria, dyslipidaemia, thyroid dysfunction
etc.
ISLET CELL TUMOURS
Islet cell tumours are rare as compared with tumours of the
exocrine pancreas. Islet cell tumours are generally small and
may be hormonally inactive or may produce hyperfunction.
ey may be benign or malignant, single or multiple. ey are
named according to their histogenesis such as: β-cell tumour
(insulinoma), G-cell tumour (gastrinoma), A-cell tumour
(glucagonoma) D-cell tumour (somatostatinoma), vipoma
(diarrhoeagenic tumour from D1 cells which elaborate VIP),
pancreatic polypeptide (PP)-secreting tumour, and carcinoid
tumour. However, except insulinoma and gastrinoma, all
others are extremely rare and require no further comments.
INSULINOMA β CELL TUMOUR
Insulinomas or beta (β)-cell tumours are the most common
islet cell tumours. e neoplastic β-cells secrete insulin
into the blood stream which remains una ected by
normal regulatory mechanisms. is results in characteristic
attacks of hypoglycaemia with blood glucose level falling to
50 mg/dl or below, high plasma insulin level (hyperinsulinism)
and high insulin-glucose ratio. e central nervous mani-
festations are conspicuous which are promptly relieved by
intake of glucose. Besides insulinoma, however, there are other
causes of hypoglycaemia such as: in starvation, partial gastrec-
tomy, di use liver disease, hypopituitarism and hypofunction
of adrenal cortex.
MORPHOLOGIC FEATURES Grossly, insulinoma is
usually solitary and well-encapsulated tumour which may
vary in size from 0.5 to 10 cm. Rarely, they are multiple.
Microscopically, the tumour is composed of cords and
sheets of well-di erentiated β-cells which do not di er from
normal cells. Electron microscopy reveals typical crystalline
rectangular granules in the neoplastic cells. It is extremely
di cult to assess the degree of anaplasia to distinguish
benign from malignant β-cell tumour.
GASTRINOMA G CELL TUMOUR, ZOLLINGER ELLISON
SYNDROME
Zollinger and Ellison described diagnostic triad consisting of
the following:
i) Fulminant peptic ulcer disease
ii) Gastric acid hypersecretion
iii) Presence of non-β pancreatic islet cell tumour.
Such non-β pancreatic islet cell tumour is the source of
gastrin, producing hypergastrinaemia and hence named
gastrinoma. De nite G cells similar to intestinal and gastric