Diabetes

Diabetes

Diabetes

Diabetes

Diabetes
Diabetes Type 1
GENERAL PRINCIPLES
Type 1 diabetes (T1D) is an illness in which autoimmune
destruction of pancreatic beta cells causes insulin
deficiency and hyperglycemia.
Insulin
deficiency
can
lead
to
acute
metabolic
decompensation known as diabetic ketoacidosis (DKA);
however, exogenous insulin taken in excess can produce
life-threatening hypoglycemia.
Chronic hyperglycemia is the root cause of disabling
microvascular
complications
and
contributes
to
macrovascular disease.
The treatment goal of T1D is normalization of blood glucose
(BG) by physiologically based insulin replacement therapy.

Diabetes
Diabetes Type 1
Epidemiology
The overall prevalence of the disease is 0.25% to 0.5% of
the population, or 1 in 400 children and 1 in 200 adults in
the United States.
The incidence of T1D is increasing in developed countries,
and it is appearing at younger ages.
The peak onset occurs at age 10 to 12 years, but it can be
diagnosed from a few months of age into the ninth decade
of life.
Males and females are equally affected.
T1D accounts for 5% to 10% of all cases of diabetes and
needs to be accurately diagnosed so that insulin therapy is
not delayed or withheld inappropriately.

Diabetes
Diabetes Type 1
Etiology and Pathogenesis
The autoimmune process that selectively destroys
pancreatic beta cells is Tcell mediated with an unknown
antigenic stimulus, in genetically susceptible individuals.
Environmental factors, including coxsackie and rubella
viruses, and dietary factors, such as early exposure to
cows milk, have been implicated.
Insulitis (lymphocytic infiltration of pancreatic islets) is an
early finding, followed by apoptosis of beta cells, which
leads to their virtual absence later in the disease course.
Antibodies to beta-cell antigens can be found in the
majority of patients before diagnosis, and for some time
after the onset of clinical diabetes.

Diabetes
Diabetes Type 1
Etiology and Pathogenesis
The autoimmune process that selectively destroys
pancreatic beta cells is Tcell mediated with an unknown
antigenic stimulus, in genetically susceptible individuals.
These disease markers are antibodies to glutamic acid
decarboxylase (GAD65), to tyrosine phosphatases IA-2
and IA-2 beta, and to insulin (IAA).
Of these markers, GAD65 is positive in 80% of children and
adults near the time of diagnosis, whereas IA-2 and IAA are
positive in ~50% of children and are less likely to be
present in adults.
The presence of two antibodies has high sensitivity and
specificity for rapid progression to insulin dependency and
may help clarify the diagnosis in some patients.

Diabetes
Diabetes Type 1
Etiology and Pathogenesis
In cases of T1D in which no evidence of autoimmunity can
be detected, the classification used is idiopathic T1D.

Diabetes
Diabetes Type 1
Etiology and Pathogenesis
Several organ-specific autoimmune diseases occur with
increased frequency in patients with T1D, including
autoimmune
thyroiditis
(Hashimotos
and
Graves
diseases), Addisons disease, pernicious anemia, celiac
sprue, vitiligo, alopecia, and chronic active hepatitis.
In a study of 265 adults with T1D, the risk of thyroid
disease was 32% for the proband, 25% for siblings, and
42% for parents, with females more commonly affected
than males.
The risk of developing autoimmune thyroid disease
increases with age, so periodic screening should
continue throughout adulthood in patients with T1D and
their family members.

Diabetes
Diabetes Type 1
Etiology and Pathogenesis
The genetic susceptibility to T1D is manifested by linkage with
several gene loci and association with HLA-DR and DQ.7
Genome-wide association studies identified additional risk loci
BACH2, C1QTNF6, CTSH, and PRKCQ.
The IDDM1 gene located in the HLA region of chromosome
6p21.3, and the IDDM2 gene in the region 5 upstream of the
insulin gene on chromosome 11p15.5 contribute 42% and
10%, respectively, to the observed familial clustering.
In the family of a patient with T1D, the risk of an identical twin
developing T1D is 50%, an offspring is 6%, and a sibling is 5%.
The striking familial discordance supports the importance of
environmental factors.

Diabetes
Diabetes Type 1
Pathogenesis of Complications
Patients with both T1D and type 2 diabetes mellitus (T2D)
are susceptible to organ dysfunction that is caused by longterm exposure to hyperglycemia and which leads to
devastating morbidity and mortality.
The microvascular complications of diabetes are
retinopathy, nephropathy, and neuropathy.

Diabetes
Diabetes Type 1
Pathogenesis of Complications
Although they share some pathogenic features, they may not
appear at the same time or with the same severity in all
individuals with diabetes. The pathogenesis of each of these
complications includes increased oxidative stress or the
generation of reactive oxygen species with inadequate scavenger
activity.
Advanced glycation end-products are formed by
processes of glycation and/or oxidation of proteins,
nucleotides, and lipids, and have intrinsic cellular toxicity.
High levels of glucose and reactive oxygen species have
been shown to increase diacylglycerol and stimulate protein
kinase C activity, causing alterations in intracellular signal
transduction and production of cytokines and growth factors.

Diabetes
Diabetes Type 1
Pathogenesis of Complications
Glucose enters peripheral nerves by mass action, is
converted first to sorbitol by aldose reductase, and is then
converted to fructose by sorbitol dehydrogenase. These
saccharides produce osmotic stress, increase glycation, and
cause alterations in the NADH/NAD ratio, which collectively
contributes to nerve fiber damage and loss leading to the
symptoms of peripheral neuropathy.

Diabetes
Diabetes Type 1
Pathogenesis of Complications
Diabetic retinopathy is associated with the adverse
effects of hyperglycemia on the vascular endothelium and
upregulation of cytokines such as vascular endothelial
growth factor.

Diabetes
Diabetes Type 1
Pathogenesis of Complications
In diabetic
nephropathy,
hyperglycemia induces
transforming growth factor , which stimulates matrix
synthesis and inhibits matrix degradation in renal
mesangial cells. Investigational agents that target these
processes are currently in clinical development.

Diabetes

Diabetes
Diabetes Type 2
GENERAL PRINCIPLES
Definition
Type 2 diabetes (T2D) results from a combination of
resistance
to
insulin
action
and
an
inadequate
compensatory insulin secretory response.
It is a metabolic disorder with carbohydrate intolerance as
the cardinal feature.

Diabetes
Diabetes Type 2
Epidemiology
Diabetes has an estimated total prevalence of 23.5 million
among people 20 years of age, or 10.7% of the adult
population. T2D accounts for about 95% of all cases of
diabetes in the United States and is a growing public health
concern.
Diabetes is the sixth leading cause of death in the United
States and a leading cause of morbidity and mortality in
other countries.
Diabetes is the leading cause of end-stage renal disease,
blindness in individuals age 20 to 74 years, and
nontraumatic limb amputation.
The major cause of mortality in diabetes is cardiovascular,
and the diagnosis of diabetes confers a two- to four-fold
increase in cardiovascular risk.

Diabetes
Diabetes Type 2
Etiology
The etiology of T2D is multifactorial. It is complex and
involves the interaction of genetic and environmental
factors.
Patients often have a family history of T2D, supporting the
role of genetic predisposition in the pathogenesis.
Genome-wide association studies have contributed to our
understanding of the genetic architecture of T2D. While
many genetic loci have been associated with T2D, these
new discoveries represent but a small proportion of the
genetic variation underlying the susceptibility to this
disorder.

Diabetes
Diabetes Type 2
Etiology
A number of environmental factors have been shown to
play a critical role in the development of T2D.
Sex, age, and ethnic background are important factors in
determining risk of developing T2D.
Excessive caloric intake leading to obesity, especially
visceral adiposity, and physical inactivity contribute
significantly to insulin resistance and, in epidemiologic
studies, are the factors associated with the increasing
incidence of T2D.
Lifestyle modification that includes weight loss and
exercise improves insulin resistance and prevents
diabetes in high-risk cohorts.

Diabetes
Diabetes Type 2
Pathophysiology
Insulin resistance, the inability of cells to respond to stimulation
by insulin, is present in most individuals with T2D.
Insulin resistance precedes the onset of T2D by years.
The cellular features of insulin resistance include reduction of
nonoxidative glucose storage as glycogen, impaired fatty acid
oxidation and reduced ability to switch between fatty acid and
glucose oxidation during hyperinsulinemia. Mitochondrial
content and oxidative capacity may be reduced in insulin
responsive tissues of persons with insulin resistance.
Inflammation also plays a role in insulin resistance, and elevated
levels of free fatty acids and inflammatory markers are present.
Insulin sensitivity declines with age, but this may be due to the
changes in body composition that occur with aging.

Diabetes
Diabetes Type 2
Pathophysiology
Insulin deficiency, on the other hand, typically follows a
period of hyperinsulinemia, which compensates for insulin
resistance.
The initial defects in insulin secretion are loss of first-phase
insulin release and loss of the oscillatory secretion pattern.
The clinical correlate of this early defect is postprandial
hyperglycemia. Further decline in insulin secretion leads to
inadequate suppression of hepatic glucose output and
presents clinically as fasting hyperglycemia.

Diabetes
Diabetes Type 2
Pathophysiology
Hyperglycemia and T2D develop when insulin secretion by
pancreatic beta cells is inadequate to meet the metabolic
demand.
Hyperglycemia contributes to impaired beta-cell function
and worsening insulin deficiency, a phenomenon known as
glucose toxicity.
Chronic elevation of free fatty acids, another characteristic
of T2D, may contribute to reduced insulin secretion and
islet cell apoptosis.

Diabetes
Diabetes Type 2
Pathophysiology
There are no definitive histopathologic findings of insulin
resistance; however, increased cellular triglyceride and reduced
numbers of mitochondria may be seen.
Histopathologic changes in the islets of Langerhans in longstanding T2D include amyloid accumulation and a reduction in
the number of insulin-producing beta cells.
Longitudinal data from the UK Prospective Diabetes Study
(UKPDS) suggest progressive beta-cell failure occurs during the
lifespan of individuals with T2D. Early in the course of diabetes,
improvement in insulin secretion can be achieved by reducing
insulin resistance and improving hyperglycemia, thereby
reducing the functional defects imposed by hyperglycemia and
elevated free fatty acids.

Diabetes
Diabetes Type 2
Pathophysiology
The definitive tests for insulin resistance measure insulinmediated glucose uptake
and/or hepatic glucose output and are available in research
settings.
In the clinical settings, insulin resistance is often inferred
when features of the
metabolic syndrome are present, with or without a
diagnosis of diabetes.

Diabetes
Diabetes Type 2
Classification
In addition to type 1 diabetes (T1D), T2D, and
gestational D, the American Diabetes Association (ADA)
classifies a heterogeneous group of hyperglycemic
disorders as other specific types of diabetes.
The most common of this group of disorders are the drugor chemical-induced forms of diabetes. Typical
offending agents include glucocorticoids, nicotinic acid,
thiazides, -adrenergic agonists, atypical antipsychotic
agents, and some antiretroviral agents. Hyperglycemia can
be relatively mild or quite severe with the institution of
these therapies.

Diabetes
Diabetes Type 2
Classification
Pancreatic disease can result in partial or complete
insulin deficiency. Patients with hemochromatosis or
advanced cystic fibrosis may present with nonketotic
hyperglycemia. Pancreatitis, pancreatectomy, pancreatic
neoplasia, or fibrocalculous pancreatopathy may cause
insulin deficiency, and insulin therapy may be needed early
in the course of the illness.
Diabetes can occur with critical illness and other
endocrine diseases such as Cushings syndrome and
acromegaly. Resolution of the diabetes often occurs when
the hormone excess is corrected.

Diabetes
Diabetes Type 2
Classification
Diabetes can be due to genetic defects of the beta-cell
and/or insulin action. It consists of monogenic and
polygenic forms.
The monogenic forms of diabetes generally occur in young
patients, often in the first two to three decades of life,
although if only mild asymptomatic elevations in blood
glucose (BG) occur the diagnosis may be missed until later
in life.

Diabetes
Diabetes Type 2
Classification
Maturity-onset diabetes in the young (MODY) is one of
the common monogenetic forms of diabetes. It is a
genetically and clinically heterogeneous group of disorders
resulting from mutations in any one of at least six different
genes, which cause a primary defect in pancreatic beta cell
function. MODY often presents with mild to moderate
nonketotic hyperglycemia in young adults with a family
history.
Obesity and insulin resistance are not characteristic
features of MODY.
Most of the T2D that is diagnosed in children and teenagers
is not MODY, but is rather early onset classic T2D.

Diabetes
Diabetes Type 2
Classification
There are other rare monogenetic forms of diabetes,
including mitochondrial gene defects and defects in the
insulin molecule or insulin receptor (type A insulin
resistance).
Patients with Downs syndrome, patients with PraderWilli
syndrome, and others may develop diabetes as a
consequence of obesity.

Diabetes
Diabetes Type 2
Classification
Latent autoimmune diabetes in adults (LADA) is an
insulin-deficient form of diabetes that develops more slowly
than classic T1D and is associated with other autoimmune
diseases.
The majority of patients with LADA require exogenous
insulin within 5 years of diagnosis. Later in the course of the
illness, patients with LADA may become C-peptide negative
and are at risk for ketoacidosis.
When LADA is suspected, testing for anti-GAD antibodies
and C peptide may help rule in or rule out the diagnosis.

Diabetes
Diabetes Type 2
Risk Factors
Individuals at high risk for the development of T2DM can
often be identified before the onset of clinical diabetes. Risk
factors for the development of T2D include:
Older age
Overweight or obesity (body mass index [BMI] 25 kg/m2)
Physical inactivity
First-degree relative with diabetes
Members of high-risk ethnic population (e.g., African
American, Latino, Native American, Asian American, Pacific
Islander)

Diabetes
Diabetes Type 2
Risk Factors
Individuals at high risk for the development of T2DM can
often be identified before the onset of clinical diabetes. Risk
factors for the development of T2D include:
Women who delivered a baby weighing >9 lb or were
diagnosed with gestational diabetes mellitus (GDM)
Women with polycystic ovary syndrome
A1C 5.7%, impaired glucose tolerance (IGT) or impaired
fasting glucose (IFG)
Other conditions associated with insulin resistance (e.g.,
metabolic syndrome, defined as three or more of the
characteristics listed in Table 29-2, acanthosis nigricans)

Diabetes

Diabetes

Diabetes