University of Colorado Denver
Child Health Associate / Physician Assistant (CHA/PA) Program
Department of Pathology
April 17, 2009
PANCREAS PATHOLOGY AND DIABETES MELLITUS*
Francisco G. La Rosa, M.D.
ASSISTANT PROFESSOR
Department of Pathology
Francisco.LaRosa@UCDenver.edu
LEARNING OBJECTIVES:
This chapter intends to provide the basic knowledge on exocrine and endocrine pancreas pathology
at the organ, cellular and molecular levels. A basic review of the embryology, anatomy and histology
of the pancreas will be provided to better understand the basic principles of pancreas pathology.
Special emphasis will be given to the study of congenital and genetic anomalies, inflammatory
processes, metabolic diseases, benign and malignant tumors, and diabetes mellitus.
The present outline is given to the students as an aid for their study in reviewing the most important
topics of pancreas pathology and diabetes mellitus. However, this handout does not intend to replace
the basic reading in textbooks and other academic literature. We recommend the reading of the
corresponding sections in the book chapters 12 and 14, ‘Pathology’ by Stevens and Lowe, suggested
in this course. If possible, it is recommended that the students review other bibliographic references
for a more complete understanding of pancreas pathology.
This Chapter is divided in 5 sections, with the following learning objectives:
1. Describe the basic Embryology, Surgical Anatomy, Histology and Function of the exocrine
and endocrine pancreas.
2. Describe the most important congenital anomalies of the pancreas.
3. Describe the most important pathologic features of Acute and Chronic Pancreatitis (clinical
and laboratory features and histo-pathological findings).
4. Describe the most important Pancreatic and Islet Cell Tumors (morphologic and clinical
features).
5. Describe the basic differences in the patho-physiology of Type I and Type II Diabetes Mellitus.
(pathogenesis, laboratory tests, complications and treatment).
PANCREAS
I.
EMBRYOLOGY, SURGICAL ANATOMY, HISTOLOGY AND FUNCTION
A.
1.
2.
3.
4.
EMBRYOLOGICAL DEVELOPMENT
Ventral pancreas and dorsal pancreas
Formation of acini and islets
Pancreatic ducts:
a. Santorini's duct
b. Wirsung's duct
Ampulla of Vater
+++++++++++++++++
*NOTE: This handout does not follow the outline of the lecture, and we suggest not using it to follow
up the oral presentation. The corresponding Power Point presentations are posted at:
http://www.uchsc.edu/pathology/department/didactic/presentations/faculty/Pancreas-Diabetes-CHAPA.doc
http://www.uchsc.edu/pathology/department/didactic/presentations/faculty/Pancreas-CHAPA.ppt
http://www.uchsc.edu/pathology/department/didactic/presentations/faculty/Diabetes-CHAPA.ppt
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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B.
SURGICAL ANATOMY OF PANCREAS
The pancreas is retroperitoneal in location, pale yellow, coarsely lobulated and J-shaped,
weighing between 60-125 grams in the adult. It stretches transversely across the upper
abdomen, from the curve of the second part of the duodenum to the hilum of the spleen, with a
rich blood supply (6 groups of arteries and 5 major groups of draining lymphatics). The head,
which has the greatest thickness, surrounds the common bile duct and is adherent to the
duodenum. A constriction at the neck (formed by the superior mesenteric artery) separates the
head from the body. There is no sharp distinction between the body and the tail, the narrowest
portion of the pancreas.
The ductal system of the pancreas consists of a main channel, the duct of Wirsung, which
begins in the tail and drains 15-30 side branches that are formed by the convergence of smaller
ductules. It courses through the body of the pancreas, and joins the common bile duct (CBD) at
its terminal end. In most people, the pancreatic duct and the CBD enter the duodenum together
at the ampulla of Vater. There is also an accessory pancreatic duct, which may be the major
duct in some people.
C.
HISTOLOGY AND FUNCTION OF PANCREAS
The pancreas has two components:
1. Exocrine (80-85%)
2. Endocrine (15-20%)
The functional unit of the exocrine pancreas is the acinus, which is composed of pyramidalshaped acinar cells, arranged around a central lumen. These cells synthesize inactive
proenzymes, which are stored in the cell as zymogen granules and under appropriate stimuli,
released into ductules, which connect the acini. The pancreas secretes l.5 to 3 liters of alkaline
fluid containing enzymes and zymogens per day. Regulation of secretion is complex involving
both humoral (CCK, secretin) and neural factors.
Activation of zymogens (trypsinogen, chymotrypsinogen, procarboxypeptidases, proelastase,
phospholipase) occurs in the duodenum, where enterokinase facilitates conversion of
trypsinogen to trypsin, and trypsin activates the other enzymes. Some enzymes are released in
their active form (amylase, lipase).
Self-digestion of the pancreas does not normally occur because:
1. Enzymes are elaborated as inactive precursors, activated only in the duodenum
2. Zymogens are sequestered in membrane bound granules.
3. Protease inhibitors are present within pancreatic secretions
II.
CONGENITAL ANOMALIES
1. Annular pancreas
2. Aberrant pancreatic tissue
3. Cystic fibrosis
a. Autosomal recessive
b. CF gene: chromosome 7
c. 1/2000 White people
d. 50% mortality before age 21
e. High sodium and chloride in sweat
f. Thick mucus precipitates
g. Obstruction of:
- pancreatic ducts: cystic dilatations surrounded by fibrosis
- bronchi and bronchioles: bronchitis, bronchiectasis, pneumonia
- bile ducts: cystic dilatations
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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h. Congenital cysts
4. Diffuse pancreatic islet hyperplasia
5. Absence of alpha cells
6. Zollinger Ellison Syndrome
III.
ACUTE AND CHRONIC PANCREATITIS
Pancreatitis is inflammation of the pancreas, accompanied by acinar cell injury. There is a spectrum
both clinically and histologically, depending on the duration and severity.
Acute pancreatitis: This most often refers to acute hemorrhagic (necrotizing) pancreatitis, which is
always a medical emergency. There is a milder self-limited form termed interstitial or edematous
pancreatitis.
Chronic pancreatitis: This refers to persistent or recurrent episodes of active inflammation,
eventually leading to fibrosis and pancreatic insufficiency.
B1.
ACUTE (HEMORRHAGIC) PANCREATITIS
This is an acute condition resulting from extensive destruction of pancreatic substance,
occurring due to release of activated pancreatic enzymes into the parenchyma.
Patients present with severe abdominal pain, associated with increased levels of pancreatic
enzymes (amylase, lipase) in the blood and/or urine, with necrosis and hemorrhage of
pancreatic tissue and fat necrosis.
B1a.
Major causes of acute pancreatitis
- Biliary tract disease
- Alcoholism (binge drinking?)
- Idiopathic
- Other:
Trauma
Extension from adjacent tissues
Blood-borne bacterial infection
Viral infections
Ischemia
Vasculitis
Drugs
Hyperlipidemia
Hypercalcemia
Familial
B1b.
Acute Pancreatitis in AIDS patients
Increased incidence
High incidence of infections involving pancreas
Cytomegalovirus, Cryptosporidium, Mycobacterium avium intracellulare (MAI)
Medications: Didanosine, pentamidine
B1c.
Pathogenesis of Acute Pancreatitis
Trypsin is felt to play a key role as it is able to activate the various proenzymes that
take part in autodigestion.
Proteases cause parenchymal destruction, lipases and phospholipases cause fat
necrosis (both within the organ and elsewhere within the abdominal cavity) and
elastase dissolves elastic fibers within blood vessels leading to hemorrhage.
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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Trypsin is also able to activate the kinin system as well as (indirectly) the clotting and
complement systems.
The process of autodigestion and zymogen activation may occur by one of the
following mechanisms.
1.
Direct acinar cell injury – autodigestion
Alcohol, ischemia, trauma may cause direct toxic injury to acinar cells.
2.
Alteration of intracellular transport of enzymes
Improper activation by lysosomal hydrolases.
3.
Duct obstruction
Gallstones impacted in the Ampulla of Vater can cause Pancreatic duct
obstruction. The may lead to increase intraductal pressures, with intercellular
enzyme leakage. However, clinical and experimental studies suggest that
obstruction alone is insufficient to cause hemorrhagic pancreatitis and may need
additional factors (i.e. duodenal reflux of bile acids).
B1d.
Laboratory findings
Acidosis
Leukocytosis
Hyperglycemia
Hypocalcemia
Precipitation of calcium soaps (saponification) in areas of fat necrosis.
Hypertriglyceridemia
B1e.
Gross appearance
Marked edema, grey-white proteolytic destruction of parenchyma, hemorrhage and
chalky white fat necrosis, giving the pancreas a variegated appearance. Foci of fat
necrosis can also be found in the omentum and mesentery.
B1f.
The four morphologic hallmarks of acute pancreatitis
1. Destruction of pancreatic substance
2. Hemorrhage and necrosis of blood vessels
3. Fat necrosis/saponification in pancreas and peripancreatic tissue
4. Acute inflammatory infiltrate
B1g.
Complications and sequelae
Systemic organ failure
Shock
Acute renal failure
Acute respiratory distress syndrome (ARDS)
Abscess formation
Pseudocyst formation
Duodenal obstruction
(Development of chronic pancreatitis uncommon)
B1h.
Prognosis
Mortality rate of acute hemorrhagic pancreatitis may be as high as 30%.
B2.
CHRONIC (RELAPSING) PANCREATITIS
This refers to progressive destruction of pancreatic tissue by continuing inflammatory
disease. Causes irreversible morphologic change and pain. Despite their similar
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
4
etiologies, chronic pancreatitis is not usually preceded by an attack of classic acute
pancreatitis.
B2a.
Causes of Chronic Pancreatitis
Alcoholism (? chronic)
Biliary tract disease
Hypercalcemia
Hyperlipidemia
Pancreas divisum
Tropical pancreatitis
Familial pancreatitis
IDIOPATHIC (40%)
Familial (1%)
B2b.
Pathogenesis of Chronic Pancreatitis
The pathophysiology is unclear. Particularly in chronic alcoholics, there may be
hypersecretion of pancreatic juice with an increased protein content, in the absence of
increased fluid or HCO3 secretion. Plugs formed by the precipitation of protein within
ducts is an early finding. The copreciptiation of calcium carbonate results
in
the
formation of intraductal stones, leading eventually to pressure atrophy of the pancreas.
Note: Many people believe that "Alcoholic pancreatitis" probably represents acute
exacerbation of chronic asymptomatic pancreatitis rather than true acute pancreatitis.
B2c.
Gross appearance
Lobular architecture is replaced by fibrous tissue, giving rise to a white appearance and
a hard consistency of the parenchyma. May actually look like carcinoma.
B2d.
Histology
Features include atrophy of acini, marked increase in interlobular fibrous tissue, and
chronic inflammation. Ducts are dilated and contain protein plugs, which may calcify.
Ductal epithelium may show squamous metaplasia, due to injury and repair.
B2e.
Complications of Chronic Pancreatitis
Pancreatic pseudocyst
Malnutrition
Diabetes mellitus
Severe pain requiring narcotics
Increased incidence of pancreatic carcinoma
B2f.
Prognosis
Chronic Pancreatitis is characterized by relentless and progressive loss of pancreatic
parenchyma. It is associated with a mortality rate approaching 50% within 20-25 years.
Causes of death include attacks of exacerbation, malnutrition, infection and the
development of pancreatic carcinoma.
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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IV.
PANCREATIC AND ISLET CELL TUMORS
Pancreatic adenocarcinoma, derived from ductal epithelium is the most common pancreatic tumor.
Malignant tumors derived from acinar cells (acinic cell carcinoma) and islet cell tumors (benign or
malignant) are much less common. Benign tumors are rare.
A.
PANCREATIC ADENOCARCINOMA
Pancreatic carcinoma accounts for 5% of all cancer deaths and its incidence has been slowly
increasing. The peak incidence occurs within the 7th decade (rare before age 50), with tumors
being more common in blacks than whites and in men than women. Most tumors arise within
the head of the pancreas (60%), the remainder arising in the body (l5%) and tail (5%) with 20%
diffusely involving the pancreas.
Presenting signs and symptoms are non-specific and may include weight loss, abdominal or
back pain and depression. Tumors arising in the head of the pancreas or in the periampullary
structures may present early with symptoms of obstructive jaundice. More commonly, however,
due to its ability to grow silently with the retroperitoneum, pancreatic carcinoma is often
incurable at the time of diagnosis.
A1a.
Risk factors for Pancreatic Carcinoma
Smoking
Fatty diet
Exposure to chemicals: B-naphthylamine, Benzidine
Chronic pancreatitis
Mutation in K-ras and p16INK4 genes
NOT a risk factor for developing Pancreatic carcinoma: CAFFEINE
A1b.
Gross appearance
Grey, yellow-white, poorly demarcated with infiltrative margins. Hard consistency due
to the abundant fibrous tissue reaction (desmoplasia) elicited by the tumor.
A1c.
Histology
Consists of infiltrating tumor composed of duct-like structures embedded in a
desmoplastic or fibrous stroma, which replaces the acinar cell parenchyma of the
pancreas.
Neoplastic glands are lined by cuboidal to columnar cells which frequently produce
mucin. Neoplastic glands often invade the perineural space (perineural invasion).
A1d.
Tumor Behavior
1. Local extension
Retroperitoneal spread behind pancreas
Fixation to vessels
Invasion of adjacent structures (duodenum, spleen)
Involvement of lymphatics, blood vessels, lymph nodes
2. Distant metastases
Hematogenous metastases to liver, lungs, adrenals, kidneys, bone, brain, skin.
3. Migratory thrombophlebitis (Trousseau's syndrome)
Thromboembolic phenomena occur in up to l0% of patients and include pulmonary
embolism, venous thrombosis, portal vein thrombosis.
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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A1e.
Prognosis for Pancreatic Carcinoma
Only 20% of tumors are resectable
1 year survival l0%
5 year survival l%
B.
ISLET CELL TUMORS
Islet cell tumors are rare in comparison to pancreatic adenocarcinoma. They most commonly
occur in adults and may be hormonally functional or non-functional. They may be single or be
multiple and can be either benign or malignant.
B1a.
Clinical syndromes of islet cell hyperfunction
1. Hyperinsulinism and hypoglycemia
2. Zollinger-Ellison syndrome - Gastrinoma
3. Multiple Endocrine Neoplasia
B1b.
Beta cell tumor (Insulinoma)
This is the most common islet cell tumor and is capable of producing profound and
symptomatic hypoglycemia. Patients usually present with blood glucose of less than
50 mg/dl, with hypoglycemic attacks consisting of central nervous system
manifestations such as confusion, stupor or coma. These symptoms are promptly
relieved by the administration of glucose.
The hypoglycemia/hyperinsulinemia may be due to:
Solitary adenomas (70%)
Multiple adenomas (10%)
Malignant islet cell tumor (10%)
(Diffuse hyperplasia - 10%)
B1c.
Gross Appearance
Usually small, firm yellow-brown, encapsulated nodules.
B1d.
Histology
Composed of bland appearing cells with abundant eosinophilic cytoplasm and centrally
placed nuclei, arranged in nests or cords (trabeculae), resembling other
neuroendocrine tumors (i.e. carcinoid)
The distinction of benign from malignant (as with most endocrine tumors) depends on
clinical proof of malignancy, i.e. invasion beyond the pancreas and presence of known
metastatic disease.
B1d.
Zollinger-Ellison Syndrome: Gastrinoma
This syndrome is a triad of:
1. Peptic ulcer disease (severe, multiple)
2. Gastric hypersecretion, serum hypergastrinemia
3. Pancreatic islet cell tumors **
** Although gastrinomas occur most commonly in the pancreas, l0-l5% may occur in
the duodenum.
Unlike insulinomas, in which most tumors are benign, 60% of
gastrinomas are malignant. Otherwise, their histologic and gross appearances are
similar.
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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V.
TYPE I AND TYPE II DIABETES MELLITUS (DM)
Diabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism. A characteristic
feature of diabetes mellitus is the presence of hyperglycemia due to an impaired carbohydrate
(glucose) use. This may be a consequence of a defective insulin secretory response or an inability of
the peripheral tissues to respond to insulin.
A.
CLASSIFICATION AND INCIDENCE
Diabetes mellitus represents a heterogeneous group of disorders that have hyperglycemia as a
common feature. It may arise secondarily from any disease causing extensive destruction of
pancreatic islets, such as pancreatitis, tumors, certain drugs, iron overload (hemochromatosis),
certain acquired or genetic endocrinopathies, and surgical excision. However, the most
common and important forms of diabetes mellitus arise from primary disorders of the islet cell
insulin system. These can be divided into two major variants that differ in their patterns of
inheritance, insulin responses, and origins.
A1.
Type I diabetes, also called insulin-dependent diabetes mellitus and previously
referred to as juvenile onset diabetes. This variant accounts for 10% to 20% of all cases of
primary diabetes.
A2.
Type II diabetes, includes the remaining 80% to 90% of patients, also called noninsulin-dependent diabetes mellitus and previously referred to as adult-onset diabetes.
It should be stressed that, although the two major types of diabetes have different pathogenetic
mechanisms and metabolic characteristics, the long-term complications in blood vessels,
kidneys, eyes, and nerves occur in both types and are the major causes of morbidity and death
from diabetes.
A3.
Incidence.
Diabetes affects an estimated 13 million people in the United States. With an annual mortality
rate of about 35,000, diabetes is the seventh leading cause of death in the United States. The
lifetime risk of developing type II for the American adult population is estimated at 5% to 7%; for
type I, the lifetime risk is about 0.5%. The prevalence of diabetes mellitus varies widely around
the world and among racial and ethnic groups, probably as a reflection of genetic and
environmental factors that have yet to be totally elucidate.
B.
PATHOGENESIS
The two types are discussed separately, but first normal insulin metabolism is briefly reviewed,
because many aspects of insulin release and action are important in the consideration of
pathogenesis.
B1.
Normal Insulin Physiology.
The insulin gene is expressed in the beta cells of the pancreatic islets, where insulin is
synthesized and stored in granules before secretion. Release from beta cells occurs as a
biphasic process involving two pools of insulin. A rise in the blood glucose level calls forth an
immediate release of insulin, presumably that stored in the beta-cell granules. If the secretory
stimulus persists, a delayed and protracted response follows, which involves active synthesis of
insulin. The most important stimulus that triggers insulin release is glucose, which also initiates
insulin synthesis.
Insulin is a major anabolic hormone. It is necessary for (1) transmembrane transport of glucose
and amino acids, (2) glycogen formation in the liver and skeletal muscles, (3) conversion of
glucose to triglycerides, (4) nucleic acid synthesis, and (5) protein synthesis. Its principal
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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metabolic function is to increase the rate of glucose transport into certain cells in the body.
These are the striated muscle cells, including myocardial cells, fibroblasts, and fat cells,
representing collectively about two thirds of the entire body weight.
Insulin interacts with its target cells by first binding to the insulin receptor; the number and
function of these receptors are important in regulating the action of insulin. The insulin receptor
is a tyrosine kinase that triggers a number of intracellular responses that affect metabolic
pathways.
B2.
Laboratory Diagnosis.
A singular feature of diabetes mellitus is impaired glucose tolerance. This is unmasked by the
oral glucose tolerance test, in which blood glucose levels are sampled after overnight fasting
and then at different times after oral ingestion of glucose. In normal persons, blood glucose
levels rise discreetly, and a brisk pancreatic insulin response ensures a return to normoglycemic
levels within an hour. In diabetic individuals and in those in a preclinical stage, blood glucose
rises to abnormally high levels for several hours. This may result from an absolute lack of
pancreatic insulin release, from impaired target tissue response to insulin, or both.
Currently, the following criteria are utilized for the laboratory diagnosis of diabetes mellitus:
1. Fasting (overnight) venous plasma glucose concentrations ~ 140 mg/dl on more than
one occasion.
2. Following ingestion of 75 gm of glucose: (a) 2-hour venous plasma glucose
concentration ~ 200 mg/dl and (b) at least one plasma glucose value ~ 200 mg/dl
during the 2-hour test.
B3.
Pathogenesis of Type I Diabetes Mellitus.
This form of diabetes results from a severe, absolute lack of insulin caused by a reduction in the
beta-cell mass. Type I diabetes usually develops in childhood, becoming manifest and severe at
puberty. Patients depend on insulin for survival; hence the term insulin-dependent diabetes
mellitus. Without insulin, they develop serious metabolic complications such as acute
ketoacidosis and coma.
Three interlocking mechanisms are responsible for the islet cell destruction: genetic
susceptibility, autoimmunity, and an environmental insult.
(1) it is thought that genetic susceptibility linked to specific alleles of the class II major
histocompatibility complex predisposes certain persons to the development of autoimmunity
against beta cells of the islets
(2) the autoimmune reaction either develops spontaneously or, more likely, is triggered by
(3) an environmental event that alters beta cells, rendering them immunogenic. Overt diabetes
appears after most of the beta cells have been destroyed. With this overview, we can discuss
each of the pathogenetic influences separately.
B3a.
Genetic Susceptibility:
Type I diabetes mellitus occurs most frequently in persons of Northern European descent. The
disease is much less common among other racial groups, including blacks, Native Americans,
and Asians. Diabetes can aggregate in families; however, the precise mode of inheritance of
susceptibility genes remains unknown. About 6% of children of first-order relatives with type I
diabetes develop the disease. Among identical twins, the concordance rate (i.e., both twins
affected) is only 40%, indicating that both genetic and environmental factors must play an
important role.
At least one of the susceptibility genes for type I diabetes resides in the region that encodes the
class II antigens of the major histocompatibility complex on chromosome 6 (HLAD). About 95%
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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of Caucasian patients with type I diabetes have either HLA-DR3 or HLA-DR4 alleles, or both,
whereas in the general population the prevalence of these antigens is only 45%. There is an
even stronger association with certain HLA-DQ alleles that are probably in linkage
disequilibrium (i.e., co-inherited) with HLA-DR genes. In the DQ locus, HLADQ/3 peptide chains
with amino acid differences in the region close to the antigen-binding cleft of the molecule seem
to affect the risk for type I diabetes in Caucasians.
The mechanisms by which HLA-DR or -DQ genes influence susceptibility to type I diabetes are
not clear. It is well known that T lymphocytes can recognize an antigen only after the peptide
fragment of the antigen binds to the HLA class II molecule on the surface of the antigenpresenting cell, enabling presentation to the T -cell receptor. It is possible that genetic variations
in the HLA class II molecule may alter their recognition by the T -cell receptor or may modify the
presentation of the antigen because of variations in the antigen-binding cleft. Thus, class II HIA
genes may affect the degree of immune responsiveness to a pancreatic beta-cell autoantigen,
or a beta-cell autoantigen may be presented in a manner that promotes an abnormal
immunologic reaction.
In addition to the established influence of HLA-linked genes, human genome analysis has
revealed about 20 independent chromosomal regions associated with predisposition to the
disease. Identification of these genes will be a major emphasis in coming years.
B3b.
Autoimmunity:
Although the clinical onset of type I diabetes mellitus is abrupt, this disease in fact results from a
chronic autoimmune attack against beta cells that usually exists for years before disease onset.
The classic manifestations of the disease (hyperglycemia and ketosis) occur late, after more
than 90% of the beta cells have been destroyed. Several observations merit comment.
- Lymphocyte-rich inflammatory infiltrate, often intense (insulitis), is frequently observed in the
islets of patients early in the course of clinically manifest disease. The infiltrate consists mostly
of CD8 T lymphocytes, with variable numbers of CD4 T lymphocytes and macrophages.
Furthermore, CD4 T lymphocytes from diseased animals can transfer diabetes to normal
animals, thus establishing the primacy of T cell-mediated autoimmunity in type I diabetes.
- Islet beta cells are selectively destroyed, with preservation of other cell types.
- The insulitis is associated with expression of class II HLA molecules on the beta cells. Normal
beta cells do not possess cell surface class II molecules. This aberrant expression of HLA
molecules is most likely induced by locally produced cytokines (e.g., interferon-'Y) derived from
activated T cells.
- About 70% to 80% of patients with type I diabetes have islet cell antibodies when tested within
a year after diagnosis. Among the intracellular antigens against which autoantibodies react are
glutamic acid decarboxylase (GAD) and several other cytoplasmic proteins. Whether these and
other autoantibodies participate in causing damage to the beta cells or are formed against
sequestered antigens released by T cell-mediated injury is not entirely settled. It is intriguing,
however, to note that autoantibodies against GAD can be detected long before the onset of
clinical symptoms, and similar antibodies are found in mouse models of spontaneous diabetes.
These mice also have T cells reactive for GAD- Asymptomatic relatives of patients with type I diabetes (who are at increased risk) develop islet
cell autoantibodies months to years before they manifest overt diabetes.
- Approximately 10% of persons who have type I diabetes also have other organ-specific
autoimmune disorders such as Graves' disease, Addison's disease, thyroiditis, or pernicious
anemia.
To summarize, overwhelming evidence implicates autoimmunity and immune-mediated injury as
causes of beta-cell loss in type I diabetes. Indeed, immunosuppressive therapies have been
shown to ameliorate type I diabetes in experimental animals and in children with the disease.
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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B3c.
Environmental Factors:
Assuming that a genetic susceptibility predisposes to autoimmune destruction of islet cells, what
triggers the autoimmune reaction? One proposal is an immune response against a viral protein
that shares an amino acid sequence with a beta-cell protein (molecular mimicry). As mentioned,
autoantibodies and T cells reactive to GAD are often present in patients with type I diabetes;
surprisingly, this protein shares amino acid sequences with a coxsackievirus protein.
Alternatively, an environmental insult could trigger autoimmunity by damaging the beta cell.
Epidemiologic observations suggest the action of viruses. Seasonal trends that often
correspond to the prevalence of common viral infections have been noted in the diagnosis of
new cases. In addition to coxsackievirus B, implicated viral infections include mumps, measles,
rubella, and infectious mononucleosis. Although many viruses are beta cell tropic, direct virusinduced injury is rarely severe enough to cause diabetes mellitus. The most likely scenario is
that viruses cause mild beta-cell injury , which is followed by an autoimmune reaction against
altered beta cells in persons with HLA-linked susceptibility.
Summarizing, it is proposed that type I diabetes is a rare outcome of some relatively common
viral infection, delayed by the long latency period necessary for progressive autoimmune loss of
beta cells to occur and dependent on the modifying effects of the genetic background,
particularly that of HLA class II molecules.
B4.
Pathogenesis of Type II Diabetes Mellitus.
Much less is known about the pathogenesis of type II diabetes, despite its being by far the more
common type. There is no evidence that autoimmune mechanisms are involved. Life style
clearly plays a role, as will become evident when obesity is considered. Nevertheless, genetic
factors are even more important than in type I diabetes. Among identical twins, the concordance
rate is 60% to 80%. In first-degree relatives with type II diabetes (and in nonidentical twins), the
risk of developing disease is 20% to 40%, compared with 5% to 7% in the population at large.
Unlike type I diabetes, the disease is not linked to any HLA genes. Rather, epidemiologic
studies indicate that type II diabetes appears to result from a collection of multiple genetic
defects, each contributing its own predisposing risk and each modified by environmental factors.
Most of the hypothesized defects remain unidentified.
The two metabolic defects that characterize type II diabetes are an inability of peripheral tissues
to respond to insulin (insulin resistance) and a derangement in beta-cell secretion of insulin. The
primacy of the secretory defect, in comparison with insulin resistance, is a matter of continuing
debate.
B4a.
Insulin Resistance:
Although insulin deficiency is present late in the course of type II diabetes, it is not of sufficient
magnitude to explain the metabolic disturbances. Rather, the evidence suggests that insulin
resistance is a major factor in the development of type II diabetes.
At the outset, it should be noted that insulin resistance is a complex phenomenon that is not
restricted to the diabetes syndrome. In both obesity and pregnancy, insulin sensitivity of target
tissues decreases (even in the absence of diabetes), and serum levels of insulin may be
elevated to compensate for insulin resistance. Thus, either obesity or pregnancy may unmask
subclinical type II diabetes by increasing the insulin resistance to a degree that cannot be
compensated by increased production of insulin.
The cellular and molecular basis of insulin resistance is not entirely clear. There is a decrease in
the number of insulin receptors, and, more important, the postreceptor signaling by insulin is
impaired. As discussed previously, binding of insulin to its receptors leads to translocation of
glucose transport units (GLUTs) to the cell membrane, which in turn facilitates uptake of
glucose. It is widely suspected that reduced synthesis and translocation of GLUTs in muscle
and fat cells underlies insulin resistance in obesity as well as in type II dia-betes. Other
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
11
postreceptor signaling defects also have been described. From a physiologic standpoint, insulin
resistance, regardless of its mechanism, results in ( I) the inability of circulating insulin to
properly direct the disposition of glucose (and other metabolic fuels); (2) a more persistent
hyperglycemia; and therefore (3) more prolonged stimulation of the pancreatic beta cells.
B4b.
Deranged Beta-Cell Secretion of Insulin:
In populations at risk for development of type II diabetes (i.e., relatives of patients), a modest
hyperinsulinemia may be observed, attributed to beta-cell hyperresponsiveness to physiologic
elevations in blood glucose. With the development of overt disease, the pattern of insulin
secretion exhibits a subtle change. Early in the course of type II diabetes, insulin secretion
appears to be normal and plasma insulin levels are not reduced. However, the normal pulsatile,
oscillating pattern of insulin secretion is lost, and the rapid first phase of insulin secretion
triggered by glucose is obtunded. Collectively, these and other observations suggest
derangements in beta-cell responses to hyperglycemia early in type II diabetes, rather than
deficiencies in insulin synthesis per se.
However, later in the course of the disease, a mild to moderate deficiency of insulin is present,
which is less severe than that of type I diabetes. The cause of the insulin deficiency in type II
diabetes is not entirely clear, but irreversible beta-cell damage appears to be present. Unlike
type I diabetes, there is no evidence for viral or immune-mediated injury to the islet cells.
According to one view, all the somatic cells of diabetics, including pancreatic beta cells, are
genetically vulnerable to injury , leading to accelerated cell turnover and premature aging, and
ultimately to a modest reduction in beta-cell mass. Chronic hyperglycemia, by causing
persistent beta-cell stimulation, may contribute by exhaustion of beta-cell function.
B4c.
Obesity:
Regardless of which initiating event is proposed for type II diabetes, obesity is an extremely
important environmental influence. Approximately 80% of type II diabetics are obese. As noted
previously, nondiabetic obese individuals exhibit insulin resistance and hyperinsulinemia.
However, when obese patients with type II diabetes are compared with weight-matched nondiabetics, it appears that the insulin levels of obese diabetics are below those observed in
obese non-diabetics, suggesting a relative insulin deficiency. Fortunately, in many obese
diabetics, especially early in the course of the disease, weight loss (and physical exercise) can
reverse impaired glucose tolerance. Although obesity is emphasized as a factor in insulin
resistance, such resistance is also encountered in non-obese patients with type II diabetes.
To summarize, type II diabetes is a complex, multifactorial disorder involving both impaired
insulin release and end-organ insensitivity. Insulin resistance frequently associated with obesity,
produces excessive stress on beta cells, which may fail in the face of sustained need for a state
of hyperinsulinism. A genetic factor is definitely involved, but how it fits into this puzzle remains
unclear.
C.
PATHOGENESIS OF THE COMPLICATIONS OF DIABETES
The morbidity associated with long-standing diabetes of either type results from complications
such as microangiopathy, retinopathy, nephropathy, and neuropathy. The basis of these chronic
long-term complications is the subject of a great deal of research. Most of the available
experimental and clinical evidence suggests that the complications of diabetes result from
metabolic derangements, mainly hyperglycemia. The most telling evidence comes from the
finding that kidneys, when transplanted into diabetics from nondiabetic donors, develop the
lesions of diabetic nephropathy within 3 to 5 years after transplantation. Conversely, kidneys
with lesions of diabetic nephropathy demonstrate a reversal of the lesion when transplanted into
normal recipients. Finally, multicenter studies clearly show delayed progression of diabetic
complications by strict control of the hyperglycemia.
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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Many mechanisms linking hyperglycemia to the complications of long-standing diabetes have
been explored. Currently, two such mechanisms are considered important.
Nonenzymatic glycosylation is the process by which glucose chemically attaches to free amino
groups of proteins without the aid of enzymes. The degree of nonenzymatic glycosylation is
directly related to the level of blood glucose. Indeed, the measurement of glycosylated
hemoglobin (HbA1c) levels in blood is a useful adjunct in the management of diabetes mellitus,
because it provides an index of the average blood glucose levels over the 120-day life span of
erythrocytes. The early glycosylation products on collagen and other long-Iived proteins in
interstitial tissues and blood vessel walls undergo a slow series of chemical rearrangements to
form irreversible advanced glycosylation end products (AGEs), which accumulate over the
lifetime of the vessel wall. AGEs have a number of chemical and biologic properties that are
potentially pathogenic.
AGE formation on proteins such as collagen causes crosslinks between polypeptides; this in
turn may trap non-glycosylated plasma and interstitial proteins. Trapping of circulating lowdensity lipoprotein (LDL), for example, retards its efflux from the vessel wall and promotes the
deposition of cholesterol in the intima, thus accelerating atherogenesis. AGEs may also affect
the structure and function of capillaries, including those of the renal glomeruli, which develop
thickened basement membranes and become leaky.
AGEs bind to receptors on many cell types-endothelium, monocytes, macrophages,
lymphocytes, and mesangial cells. Binding induces a variety of biologic activities, including
monocyte emigration, release of cytokines and growth factors from macrophages, increased
endothelial permeability, and enhanced proliferation of fibroblasts and smooth muscle cells and
synthesis of extracellular matrix. All these effects can potentially contribute to diabetic
complications.
Intracellular hyperglycemia with disturbances in polyol pathways is the second major
mechanism proposed for complications related to hyperglycemia. In some tissues that do not
require insulin for glucose transport (e.g., nerves, lens, kidney, blood vessels), hyperglycemia
leads to an increase in intracellular glucose, which is then metabolized by aldose reductase to
sorbitol, a polyol, and eventually to fructose. These changes have several untoward effects. The
accumulated sorbitol and fructose lead to increased intracellular osmolarity and influx of water,
and, eventually, to osmotic cell injury. In the lens, osmotically imbibed water causes swelling
and opacity. Sorbitol accumulation also impairs ion pumps and is believed to promote injury of
Schwann cells and pericytes of retinal capillaries, with resultant peripheral neuropathy and
retinal microaneurysms. In keeping with this hypothesis, experimental inhibition of aldose
reductase is capable of ameliorating the development of cataracts and neuropathy.
D.
MORPHOLOGY OF DIABETES MELLITUS AND ITS LATE COMPLICATIONS
Pathologic findings in the pancreas are variable and not necessarily dramatic. Rather, the
important morphologic changes in diabetes are related to its many late systemic complications,
because they are the major causes ofmorbidity and mortality. There is extreme variability
among patients in the time of onset of these complications, their severity , and the particular
organ or organs involved. In those with tight control of diabetes, the onset may be delayed. In
most patients, however, after 10 to 15 years, morphologic changes are likely to be found in
arteries (atherosclerosis) , the basement membranes of small vessels (microangiopathy),
kidneys (diabetic nephropathy) , retina (retinopathy) , nerves (neuropathy) , and other tissues.
These changes are seen in both types of diabetes.
D1.
Pancreas.
Lesions in the pancreas are inconstant and rarely of diagnostic value. Distinctive changes are
more commonly associated with type I than with type II diabetes. One or more of the following
alterations may be present.
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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- Reduction in the number and size of islets. This is most often seen in type I diabetes,
particularly with rapidly advancing disease, Most of the islets are small, inconspicuous, and not
easily detected.
- Leukocytic infiltration of the islets (insulitis) , principally composed of T lymphocytes, is
observed in type I diabetes. This may be seen at the time of clinical presentation, and
presumably has been present for some time before the onset of overt disease. The distribution
of insulitis may be strikingly uneven. Eosinophilic infiltrates may also be found, particularly in
diabetic infants who fail to survive the immediate postnatal period.
- By electron microscopy, beta-cell degranulation may be observed, reflecting depletion of
stored insulin in already damaged beta cells. This is more commonly seen in patients with newly
diagnosed type I diabetes, when some beta cells are still present.
- In type II diabetes, there may be a subtle reduction in islet cell mass, which is demonstrated
only by special morphometric studies.
- Amyloid replacement of islets in type II diabetes appears as deposits of pink, amorphous
material beginning in and around capillaries and between cells. At advanced stages, the islets
may be virtually obliterated, and fibrosis also may be observed. This change is often seen in
long-standing cases of type II diabetes. As mentioned earlier, the amyloid in this instance is
composed of amylin fibrils derived from the beta cells. Similar lesions may be found in elderly
non-diabetics, apparently as part of normal aging.
- An increase in the number and size of islets is especially characteristic of nondiabetic
newborns of diabetic mothers. Presumably, fetal islets undergo hyperplasia in response to the
maternal hyperglycemia.
D2.
Vascular System.
Diabetes exacts a heavy toll on the vascular system. Vessels of all sizes are affected, from the
aorta down to the smallest arterioles and capillaries. The aorta and large and medium-sized
arteries suffer from accelerated severe atherosclerosis. Except for its greater severity and
earlier age of onset, atherosclerosis in diabetics is indistinguishable from that in non-diabetics.
Myocardial infarction, caused by atherosclerosis of the coronary arteries, is the most common
cause of death in diabetics. Significantly, it is almost as common in diabetic females as in
diabetic males. In contrast, myocardial infarction is uncommon in nondiabetic females of
reproductive age. Gangrene of the lower extremities, as a result of advanced vascular disease,
is about 100 times more common in diabetics than in the general population. The larger renal
arteries are also subject to severe atherosclerosis, but the most damaging effect of diabetes on
the kidneys is exerted at the level of the glomeruli and the microcirculation.
Hyaline arteriolosclerosis, the vascular lesion associated with hypertension, is both more
prevalent and more severe in diabetics than in non-diabetics, but it is not specific for diabetes
and may be seen in elderly non-diabetics without hypertension. It takes the form of an
amorphous, hyaline thickening of the wall of the arterioles, which causes narrowing of the
lumen. In the diabetic it is related not only to the duration of disease but also to the level of
blood pressure. The cause and nature of this vascular change are still uncertain. Although at
one time it was attributed to hypertension, so common among diabetics, it can also be seen in
diabetics who do not have hypertension. The hyaline material consists of plasma proteins and
basement membrane material. As noted earlier, it is presumed that the plasma proteins
penetrate into the abnormally permeable walls of the arterioles and are trapped.
The pathogenesis of accelerated atherosclerosis is not well understood, and in all likelihood
multiple factors are involved. About one third to one half of patients have elevated blood lipid
levels, known to predispose to atherosclerosis, but the remainder also have an increased
predisposition to atherosclerosis. Qualitative changes in the lipoproteins, brought about by
excessive nonenzymatic glycosylation, may affect their turnover and tissue deposition. Low
levels of high-density lipoproteins (HDLs) have been demonstrated in patients with type II
diabetes. Because HDL is a "protective molecule" against atherosclerosis, this could contribute
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
14
to increased susceptibility to atherosclerosis. Diabetics have increased platelet adhesiveness to
the vessel wall, possibly owing to increased thromboxane A2 synthesis and reduced
prostacyclin. In addition to all these factors. Diabetics tend to have an increased incidence of
hypertension, which is a well known risk factor for atherosclerosis.
D3.
Diabetic Microangiopathy.
One of the most consistent morphologic features of diabetes is diffuse thickening of basement
membranes. The thickening is most evident in the capillaries of the skin, skeletal muscles,
retinas, renal glomeruli, and renal medullae. However, it may also be seen in such nonvascular
structures as renal tubules, Bowman's capsule, peripheral nerves, and placenta. By light
microscopy, the normal basal lamina consists of a relatively uniform layer of extracellular
material that separates parenchymal or endothelial cells from the surrounding connective tissue
stroma. In diabetics, this single layer is widened and sometimes replaced by concentric layers of
hyaline material composed predominantly of type IV collagen. Despite the increase in the
thickness of basement membranes, diabetic capillaries are more leaky than normal to plasma
proteins The microangiopathy underlies the development of diabetic nephropathy and some
forms of neuropathy. An indistinguishable microangiopathy can be found in aged nondiabetic
patients, but rarely to the extent seen in patients with long-standing diabetes.
D4.
Diabetic Nephropathy.
The kidneys are prime targets of diabetes, and renal failure is second only to myocardial
infarction as a cause of death from this disease. Three important lesions are encountered:
(1) glomerular lesions
(2) renal vascular lesions, principally arteriolosclerosis
(3) pyelonephritis, including necrotizing papillitis
The most important glomerular lesions are capillary basement membrane thickening, diffuse
glomerulosclerosis, and nodular glomerulosclerosis (Kimmelstiel-Wilson lesion). The glomerular
capillary basement membranes are thickened throughout their entire length. This change can be
detected by electron microscopy within a few years of the onset of diabetes, sometimes without
any associated change in renal function.
Diffuse glomerulosclerosis consists of a diffuse increase in mesangial matrix along with
mesangial cell proliferation and is always associated with basement membrane thickening. It is
found in most patients with disease of more than 10 years' duration. After glomerulosclerosis
becomes marked, patients manifest the nephrotic syndrome, characterized by proteinuria,
hypoalbuminemia, and edema.
Nodular glomerulosclerosis describes a glomerular lesion made distinctive by ball-Iike deposits
of a laminated matrix within the mesangial core of the lobule. These nodules tend to develop in
the periphery of the glomerulus, and because they arise within the mesangium, they push the
glomerular capillary loops even more to the periphery .Often these capillary loops create halos
about the nodule. This distinctive change has been called the Kimmelstiel-Wilson lesion, after
the pioneers who described it. Nodular glomerulosclerosis occurs irregularly throughout the
kidney and affects random glomeruli as well as random lobules within a glomerulus. In
advanced disease, many nodules are present within a single glomerulus, and most glomeruli
become involved. The deposits are positive on periodic acid-Schiff staining and contain
mucopolysaccharides, lipids, and fibrils as well as collagen fibers, as do the matrix deposits of
diffuse glomerulosclerosis.
Because tubules are perfused by vessels arising from glomerular efferent arterioles, advanced
glomerulosclerosis is associated with tubular ischemia and interstitial fibrosis. In addition,
patients with uncontrolled glycosuria may reabsorb glucose and store it as glycogen in the
tubular epithelium. This change does not affect tubular function.
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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Renal atherosclerosis and arteriolosclerosis constitute only one part of the systemic involvement
of blood vessels in diabetics. The kidney is one of the most frequently and most severely
affected organs; however, the changes in the arteries and arterioles are similar to those found
throughout the body. Hyaline arteriolosclerosis affects not only the afferent but also the efferent
arteriole. Such efferent arteriolosclerosis is rarely if ever encountered in persons who do not
have diabetes.
Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in the
interstitial tissue and then spreads to affect the tubules and, in extreme cases, the glomeruli.
Both the acute and chronic forms of this disease occur in non-diabetics as well as in diabetics.
However, these inflammatory disorders are more common in diabetics than in the general
population, and, once affected, diabetics tend to have more severe involvement. One special
pattern of acute pyelonephritis, necrotizing papillitis, is much more prevalent in diabetics than in
non-diabetics. As the term implies, necrotizing papillitis is an acute necrosis of the renal
papillae. Although this lesion is not limited to diabetics, they are particularly prone to develop it,
owing to the combination of ischemia resulting from microangiopathy and increased
susceptibility to bacterial infection.
The sclerotic lesions of the glomeruli destroy renal function and constitute potentially fatal forms
of diabetic nephropathy. Nodular glomerulosclerosis is encountered in perhaps 10% to 35% of
diabetics and is a major cause of morbidity and mortality. As with diffuse glomerulosclerosis, the
appearance is related to the duration of the disease but conditioned by the genetic background.
Unlike the diffuse form, which may also be seen in association with old age and hypertension,
the nodular form of glomerulosclerosis, for all practical purposes, implicates diabetes. Both the
diffuse and the nodular forms of glomerulosclerosis induce sufficient ischemia to cause overall
fine scarring of the kidneys, marked by a finely granular cortical surface.
D5.
Diabetic Ocular Complications.
Visual impairment, sometimes even total blindness, is one of the more feared consequences of
long-standing diabetes. This disease is the fourth leading cause of acquired blindness in the
United States. The ocular involvement may take the form of retinopathy, cataract formation, or
glaucoma. Retinopathy, the most common pattern, consists of a constellation of changes that
together are considered by many ophthalmologists to be virtually diagnostic of the disease. The
lesion in the retina takes two forms: non-proliferative (background) retinopathy and proliferative
retinopathy.
Non-proliferative retinopathy includes intraretinal or preretinal hemorrhages, retinal exudates,
microaneurysms, venous dilations, edema, and, most importantly, thickening of the retinal
capillaries (microangiopathy). The retinal exudates can be either "soft" (microinfarcts) or "hard"
(deposits of plasma proteins and lipids). The microaneurysms are discrete saccular dilations of
retinal choroidal capillaries that appear through the ophthalmoscope as small red dots. Dilations
tend to occur at focal points of weakening, resulting from loss of pericytes. Retinal edema
presumably results from excessive capillary permeability. Underlying all these changes is the
microangiopathy, which is thought to lead to loss of capillary pericytes and hence to focal
weakening of capillary structure.
The so-called proliferative retinopathy is a process of neovascularization and fibrosis. This
lesion can lead to serious consequences, including blindness, especially if it involves the
macula. Vitreous hemorrhages can result from rupture of the newly formed capillaries: the
resultant organization of the hemorrhage can pull the retina off its substratum (retinal
detachment).
D6.
Diabetic Neuropathy.
The central and peripheral nervous systems are not spared by diabetes. The most frequent
pattern of involvement is a peripheral, symmetric neuropathy of the lower extremities that affects
both motor and sensory function but particularly the latter. Other forms include autonomic
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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neuropathy, which produces disturbances in bowel and bladder function and sometimes sexual
impotence, and diabetic mononeuropathy, which may manifest as sudden footdrop, wristdrop,
or isolated cranial nerve palsies. The neurologic changes may be caused by microangiopathy
and increased permeability of the capillaries that supply the nerves as well as by direct axonal
damage due to alterations in sorbitol metabolism (discussed earlier).
The brain, along with the rest of the body, develops widespread microangiopathy. Such
microcirculatory lesions may lead to generalized neuronal degeneration. There is in addition a
predisposition to cerebrovascular infarcts and brain hemorrhages, perhaps related to the
hypertension and atherosclerosis often seen in diabetics. Degenerative changes have also
been observed in the spinal cord. None of the neurologic disorders, including the peripheral
neuropathy, are specific for this disease.
E.
CLINICAL FEATURES
It is difficult to sketch with brevity the diverse clinical presentations of diabetes mellitus. Only a
few characteristic patterns are presented.
Type I diabetes, which begins by age 20 years in most patients, is dominated by polyuria,
polydipsia, polyphagia, and ketoacidosis-all resulting from metabolic derangements. Because
insulin is a major anabolic hormone in the body, a deficiency of insulin affects not only glucose
metabolism but also fat and protein metabolism. With insulin deficiency, the assimilation of
glucose into muscle and adipose tissue is sharply diminished or abolished. Not only does
storage of glycogen in liver and muscle cease, but also reserves are depleted by
glycogenolysis. Severe fasting hyperglycemia and glycosuria ensue. The glycosuria induces an
osmotic diuresis and thus polyuria, causing a profound loss of water and electrolytes (Na+, K+,
Mg++, PO4-). The obligatory renal water loss, combined with the hyperosmolarity resulting from
the increased levels of glucose in the blood, tends to deplete intracellular water, triggering the
osmoreceptors of the thirst centers of the brain. In this manner, intense thirst (polydipsia)
appears. With a deficiency of insulin, the scales swing from insulin-promoted anabolism to
catabolism of proteins and fats. Proteolysis follows, and the gluconeogenic amino acids are
removed by the liver and used as building blocks for glucose. The catabolism of proteins and
fats tends to induce a negative energy balance, which in turn leads to increasing appetite
(polyphagia), thus completing the classic triad of diabetes: polyuria, polydipsia, and polyphagia.
Despite the increased appetite, catabolic effects prevail, resulting in weight loss and muscle
weakness. The combination of polyphagia and weight loss is paradoxical and should always
raise the suspicion of diabetes.
In patients with type I diabetes, glucose intolerance is of the unstable or brittle type, in that the
blood glucose level is quite sensitive to administered insulin, deviations from normal dietary
intake, unusual physical activity, infection, or other forms of stress. Inadequate fluid intake or
vomiting can rapidly lead to significant disturbances in fluid and electrolyte balance. Therefore,
these patients are vulnerable, on the one hand, to hypoglycemic episodes and, on the other, to
ketoacidosis. This complication occurs almost exclusively in type I diabetes and is the result of
severe insulin deficiency coupled with absolute or relative increases of glucagon. The insulin
deficiency causes excessive breakdown of adipose stores, resulting in increased levels of free
fatty acids. Oxidation of free fatty acids within the liver through acetyl coenzyme A produces
ketone bodies (acetoacetic acid and /3hydroxybutyric acid). Glucagon accelerates such fatty
acid oxidation. The rate at which ketone bodies are formed may exceed the rate at which
acetoacetic acid and /3-hydroxybutyric acid can be utilized by muscles and other tissues, thus
leading to ketonemia and ketonuria. If the urinary excretion of ketones is compromised by
dehydration, the plasma hydrogen ion concentration increases and systemic metabolic
ketoacidosis results. Release of ketogenic amino acids by protein catabolism aggravates the
ketotic state. As discussed later, diabetics have increased susceptibility to infections. Because
the stress of infection increases insulin requirements, infections often precipitate diabetic
ketoacidosis.
Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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Type II diabetes may also present with polyuria and polydipsia, but the patients are often older
than those with type I diabetes (>40 years) and frequently are obese. In some cases, medical
attention is sought because of unexplained weakness or weight loss. Frequently, however,
routine blood or urine testing in asymptomatic persons makes the diagnosis. Although patients
with type II diabetes also have metabolic derangements, these are easier to control and less
severe. In the decompensated state, these patients develop hyperosmolar nonketotic coma, a
syndrome engendered by the severe dehydration resulting from sustained hyperglycemic
diuresis in patients who do not drink enough water to compensate for urinary losses. Typically,
the patient is an elderly diabetic, disabled by a stroke or an infection that increases
hyperglycemia, who has limited mobility and therefore inadequate water intake. The absence of
ketoacidosis and its symptoms (nausea, vomiting, respiratory difficulties) often delays the
seeking of medical attention in these patients until severe dehydration and coma occur.
In both forms of long-standing diabetes, atherosclerotic events such as myocardial infarction,
cerebrovascular accidents, gangrene of the leg, and renal insufficiency are the most threatening
and most frequent complications. Diabetics are also plagued by enhanced susceptibility to
infections of the skin and to tuberculosis, pneumonia, and pyelonephritis. Such infections cause
the deaths of about 5% of diabetics. The basis for this susceptibility is probably multifactorial;
impaired leukocyte function and poor blood supply secondary to vascular disease are involved.
A trivial infection in a toe may be the first event in a long succession of complications (gangrene,
bacteremia, and pneumonia) that ultimately lead to death.
Patients with type I diabetes are more likely to die from their disease than those with type II
diabetes. The causes of death are myocardial infarction, renal failure, cerebrovascular disease,
atherosclerotic heart disease, and infections, followed by a large number of other complications
more common in the diabetic than in the nondiabetic (e.g., gangrene of an extremity).
Hypoglycemia and ketoacidosis are uncommon causes of death today.
As mentioned at the outset, this disease continues to be one of the top 10 "killers" in the United
States. It is hoped that islet cell transplantation, which is still in the experimental stage, will lead
to a cure for diabetes mellitus. Until then, strict glycemic control offers the only hope for
preventing the deadly complications of diabetes.
Disclaimers:
1. The primary goal of this chapter is to study the learning objectives outlined at the beginning of this handout.
The material to study is provided in the lectures, the handouts and the recommended textbooks. All these
sources provide the content over which you will be tested. The lectures are intended to provide broad
information of the material found in the textbooks and handouts, and to give the students the opportunity to
ask questions on subjects not clear in the texts. The handouts do not seek to follow up the sequence of the
lectures, and most importantly, they are not a surrogate of the books.
2. The text presented in this handout has been edited by Dr. La Rosa from material found in your books, from
published articles and other educational works. This handout is solely for educational purpose and not
intended for commercial or pecuniary benefit. Reproduction of this handout can be done only for educational
use.
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Pathology of the Pancreas and Diabetes Mellitus - Francisco G. La Rosa, MD
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