Pathophysiology of diabetes mellitus

PATHOPHYSIOLOGY
OF
DIABETES MELLITUS
CREATED BY:
NIVARANY ANANTHAN

Definition of Diabetes Mellitus
(DM)
• Diabetes is a group of metabolic disorders characterized by
abnormal fuel metabolism, which results most notably in
hyperglycemia and dyslipidemia, due to defects in insulin
secretion, insulin action, or both. Diabetes is a serious chronic
disease without a cure, and it is associated with significant
morbidity and mortality, both acute and chronic. Acute
complications are due to severe hyperglycemia. Chronic
complications are characterized by damage, dysfunction, and
eventual failure of various organs, especially the eyes, kidneys,
nerves, heart, and brain. The common denominator is vascular
damage.

 Diabetes is a group of metabolic disorders characterized by abnormal fuel metabolism
resulting chiefly in hyperglycemia and dyslipidemia.
 Diabetes is a common chronic disease affecting more than 1 in 10 adults in the US. It is
more common in people who are older and socioeconomically disadvantaged.
 Diabetes is a serious disease associated with acute (due to hyperglycemia) and chronic
(due to vascular damage) complications.
 Diabetes is clinically diagnosed if a fasting plasma glucose is ≥ 126 mg/dl more than once or
when an individual has symptoms of diabetes and her casual plasma glucose is ≥ 200
mg/dl.
 Impaired fasting glucose and impaired glucose tolerance define intermediate dysmetabolic
states (pre diabetes) with increased risk for cardiovascular disease and death.
 Type 1 diabetes is caused by an autoimmune destruction of the beta cells of the pancreas
due to an interplay between genetic susceptibility and environmental modifiers.
 Type 2 diabetes, the most prevalent form of diabetes, is characterized by a combination of
insulin resistance and insulin deficiency.
 The metabolic syndrome is characterized by insulin resistance, central obesity,
hypertension, dyslipidemia, and increased risk for cardiovascular and disease death.
 Gestational diabetes develops secondary to the insulin resistant state of pregnancy and
may be associated with fetal macrosomia, a higher rate of cesarean section and a high risk
for developing type 2 diabetes in the future.

SYMPTOMS OF DIABETES
MELLITUS
• Acute Symptoms
• Acute symptoms of diabetes are due to severe hyperglycemia and
include polyuria, polydipsia, polyphagia, weight loss and blurred vision.
Patients may exhibit impaired growth and increased susceptibility to
infections (e.g. recurrent vaginal candidiasis or urinary tract infections).
Acute marked hyperglycemia may lead to diabetic ketoacidosis (DKA) in
type 1 diabetes or to the hyperglycemic hyperosmolar nonketotic
syndrome (HHNS) in type 2 diabetes. These conditions are covered
further in the lecture on diabetic complications and discussed during
the small group sessions.

• Chronic Symptoms
• Chronic symptoms of diabetes are due to vascular damage from
persistent hyperglycemia. Vascular damage leads to end-organ damage.
Other conditions associated with diabetes, such as hypertension,
dyslipidemia (as well as smoking) accelerate the development of
vascular damage and the chronic complications of diabetes, which are
the following:

Microvascular
Microvascular complications are a significant cause of morbidity.
Persistent hyperglycemia is the major cause for the microvascular
complications which are highly specific for diabetes.
 retinopathy with potential loss of vision
 nephropathy leading to kidney failure
 peripheral neuropathy leading to pain, foot ulcers, and limb amputation
 autonomic neuropathy causing gastrointestinal , genitourinary, cardiovascular
sexual dysfunction

Macrovascular
Macrovascular complications are the main cause of mortality. Although persistent
hyperglycemia may contribute to macrovascular complications, it is the associated
conditions (hypertension, dyslipidemia, smoking) that account for most of the burden
of the macrovascular complications.

 coronary heart disease which is the major cause of death for patients
with diabetes
 peripheral vascular disease
 cerebrovascular disease

Physiology of Insulin Release and
Action
The endocrine pancreas consists of the islets of Langerhans, which are small
endocrine glands scattered throughout the pancreas. The four different types of
islets and its secretory products are shown in Table 2. We will review only insulin
here.
Islet Cell Type

Secretory Products

A cell (alpha)

Glucagon

B cell (beta)

Insulin

D cell (delta)

Somatostatin

F cell

Pancreatic Polypeptide

Diagnosis of Diabetes and Glucose
Intolerance
Diabetes is a dysmetabolic disorder affecting multiple bodily functions. Its diagnosis is based on
the presence of hyperglycemia. The diagnostic criteria for diabetes were modified in 1997 and
again in 2003 by the American Diabetes Association, as shown in Table 1. The criterion for FPG
was derived from the strong association of FPG with retinopathy in various populations with a
high prevalence of diabetes (such as the Pima Indians in Arizona). The cut off value of FPG ≥126
mg/dl was chosen to separate the bimodal distribution of the rate of chronic complications
(figure will be shown in lecture).

Glucose Intolerance

Diabetes

Classic symptoms of diabetes PLUS
casual plasma glucose ≥ 200 mg/dL
or
100 < Morning < FPG 126
mg/dL (IFG)

Morning FPG ≥ 126 mg/dl or

140 < 2-hour PG < ßß200
mg/dL (IGT)

2-hour PG ≥ 200 mg/dl

Unless unequivocal hyperglycemia with metabolic decompensation is present, a
diagnosis of diabetes must be confirmed by repeating any of the tests on a
different day.
FG = impaired fasting glucose, IGT = impaired glucose tolerance. Classic
symptoms of diabetes include: polyuria, polydipsia, and unexplained weight
loss.
Casual is defined as any time of the day without regard to time since last meal.
FPG = fasting plasma glucose, defined as no consumption of food or beverage
(other than water) for at least 8 hours.
2-hour PG = 2 hour post load glucose during a 75-gram oral glucose tolerance
test.

Glucose intolerance, denoted by Impaired Fasting Glucose (IFG) or Impaired Glucose
Tolerance (IGT), is not a clinical entity on its own but rather an independent risk factor
for progression to clinical diabetes and development of macrovascular complications.
Individuals with glucose intolerance are at increased risk for cardiovascular disease and
death indicating a continuing risk along glucose levels. However, persons with glucose
intolerance do not exhibit an increased prevalence of microvascular, or diabetesspecific complications.

Insulin Synthesis and Secretion
The beta cell synthesizes pro-insulin which is converted to insulin and C-peptide
after proteolytic cleavage (figure 2). Both C-peptide and insulin are released in the
circulation in equomolar amounts. This is the major site of regulation of circulating
insulin. C-peptide has no known biological activity. A very small amount of proinsulin is also secreted n the circulation. Insulin is a 51-amino acid peptide with 2
chains connected by a disulfide bond. Insulin's half-life is 3-5 minutes and about
50% of it is cleared in a single pass through the liver.

INSULIN SYNTHESIS AND
SECRETION

Insulin Action

Anabolic Effects - require high insulin (e.g.
post-prandial)

Anti-catabolic Effects - require
low insulin (e.g. fasting)

Liver

• stimulates glycolysis and glycogen
storage
• stimulates chylomicrons and VLDL
uptake

• inhibits gluconeogenesis
and glycogen breakdown
• promotes triglycerids
synthesis

Muscle

• stimulates glucose uptake (via GLUT-4
receptors) and glycogen synthesis
• stimulates amino-acid uptake and
protein synthesis

• inhibits gluconeogenesis
and glycogen breakdown

Adipose

• Increases glucose transport (via GLUT-4
receptors)
• Induces activity of Lipoprotein Lipase
which hydrolyzes circulating
triglycerides leading to uptake of FFA
and glycerol

• Inhibits intracellular
breakdown of triglycerides

Classification of Diabetes Based on
Etiology
• Knowledge of the physiology of insulin release and action
helps us think about the pathophysiology of diabetes.
Similar to other endocrine conditions, any defect along
the pathway will results in abnormal fuel metabolism,
which will be manifested primarily as hyperglycemia. In
1997, the American Diabetes Association revised the
nomenclature for the major types of diabetes. The terms
insulin dependent diabetes mellitus and non-insulindependent diabetes mellitus and their acronyms, IDDM
and NIDDM, were eliminated. These terms had been
confusing and had frequently resulted in classifying the
patient based on treatment rather than etiology. The
new classification of diabetes based on etiology is shown
below:

•



Type 1 diabetes: pancreatic beta islet cell destruction leading to absolute insulin
deficiency
autoimmune (most common)
idiopathic (rare)

• Type 1b presents like type 1 (with DKA), then behaves like type 2
• Type 2 diabetes: varying degrees of insulin resistance and insulin deficiency
• Gestational diabetes

Other specific types Maturity onset diabetes of the young (MODY)


Currently 6 monogenetic defects of beta cell function defined with defects in
islet cell glucokinase or in various transcriptions factors such as HNF-1alpha,
HNF-4alpha, IPF-1. The end result is impaired insulin release and hyperglycemia.
 Autosomal dominant pattern. Onset of hyperglycemia generally before age 25




Genetic defects in insulin action
Mutant insulin gene, insulin exhibits impaired receptor binding (rare)
Mutation of insulin receptor. Often associated with acanthosis nigricans
(thickening and discoloration of skin) and some forms of polycystic ovarian
syndrome (uncommon)



Endocrinopathies



Includes acromegaly, Cushing's syndrome, glucagonoma and
pheochromocytoma
 Caused by excess secretion of hormones which antagonize insulin
including growth hormone, cortisol, glucagon and epinephrine
 Drug/chemical induced diabetes


Many drugs may impair insulin resistance or insulin secretion leading to
diabetes in predisposed individuals
 Major drugs include synthetic glucocorticoids, cyclosporin A, nicotinic
acid, interferon, pentamidine, occasionally thiazide diuretics

 Infections


Congenital rubella is the most common virus implicated in the
development of diabetes
 Coxsackievirus B, adenovirus, mumps and cytomegalovirus have all
been implicated in inducing certain cases of the disease

Type 1 Diabetes Mellitus
• Type 1 diabetes (DM-1) was previously known as IDDM
(insulin dependent diabetes mellitus) or juvenile-onset
diabetes. About 5-10% of patients with diabetes have DM-1.
Type 1 diabetes affects 3 in 1000 children and its incidence is
increasing worldwide both in low and high prevalence
populations,

Epidemiology/Pathogenesis of Type 1 Diabetes
Type 1 diabetes is primarily a disease of the young given its peak incidence
at the age of 10 to 12 years for girls and 12 to 14 years for boys; however,
the disease can occur at any age, but most patients are diagnosed before
age 20. Type 1 diabetes refers to cell-mediated autoimmune destruction of
pancreatic beta islet cells, which leads to absolute insulin deficiency and
predisposes individuals to diabetic ketoacidosis (DKA). The etiology is most
often autoimmune in origin, but idiopathic destruction of beta islet cells
without evidence of autoimmunity is also classified under this group.
Although the presentation and progression is variable, all patients with
DM-1 require insulin for survival.
The autoimmune nature of DM-1 has been intensively investigated, and it
has long been assumed that the pathogenesis of the disease can be
explained by an interplay between genetics and environment. The
pathogenesis can be summarized as follows: in a genetically predisposed
individual, (currently not well-defined) environmental factors trigger an
autoimmune process (activation of T lymphocytes reactive to islet cell
antigens) that leads to destruction of islet cells and insulin deficiency
(Figure 3).

Figure 3. Pathogenesis of Type 1
Diabetes

Clinical Findings
Diabetic ketoacidosis (see lecture on complications) may be the presenting clinical
picture for DM-1 but more often, DM-1 presents with the classic symptoms of diabetes
such as polyuria, polydipsia, polyphagia, blurry vision and unexplained weight loss.Upon
presentation, DM-1 patients may also exhibit diabetic dyslipidemia, characterized by low
HDL and high TG rich particles (such as VLDL, chylomicrons). Insulin deficiency, in type 1
diabetes, will lead to release of FFA from adipose tissue and transport to the liver where
they re-esterified to VLDL and secreted back in the circulation. Additionally, in the
absence of insulin, LPL will not function appropriately, and clearance of TG-rich particles
will be deficient. Increased (hepatic) production and decreased clearance of TG-rich
particles, therefore leads to the characteristic dyslipidemia of diabetes. In type 1
diabetes, the dyslipidemia is fully corrected with adequate insulin therapy.

Type 2 Diabetes Mellitus
Type 2 diabetes (DM-2), previously known as NIDDM or adult-onset diabetes, is the most prevalent
form of diabetes, accounting for over 90% of all cases of diabetes.

• Epidemiology/Pathogenesis
• Type 2 diabetes (DM-2), previously known as NIDDM or adult-onset diabetes, is the most
prevalent form of diabetes, accounting for over 90% of all cases of diabetes. Type 2
diabetes is characterized by varying degrees of insulin resistance and insulin deficiency. It
is thought that the earliest defect in the pathogenesis of DM-2 is impaired insulin action
or insulin resistance. Resistance to the action of insulin will result in impaired insulin
mediated glucose uptake in the periphery (by muscle and fat), incomplete suppression of
hepatic glucose output and impaired triglyceride uptake by fat. To overcome the insulin
resistance (and therefore prevent abnormal fuel metabolism and maintain normal
glucose and lipid levels), beta islet cells will increase the amount of insulin secreted.
Higher circulating insulin levels will overcome the impedance to the action of insulin.
This state of high insulin levels with euglycemia persists for many years. Abnormal fuel
metabolism (hyperglycemia and dyslipidemia) occurs when there is a mismatch between
insulin requirements, as dictated by insulin resistance, and insulin supply, as dictated by
beta cell function. Therefore, for DM-2 to develop, two defects are necessary: insulin
resistance and insulin deficiency relative to the resistance (figure 4).

Figure 4. Pathogenesis of type 2
Diabetes and the Metabolic
Syndrome

Pathophysiology of diabetes mellitus

Pathophysiology of diabetes mellitus

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