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MELLITUS
DIABETES MELLITUS
Diabetes mellitus is not a single disease entity but rather a group of metabolic
disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in
diabetes results from defects in insulin secretion, insulin action, or, most commonly,
both. The chronic hyperglycemia and attendant metabolic dysregulation of diabetes
mellitus may be associated with secondary damage in multiple organ systems,
especially the kidneys, eyes, nerves, and blood vessels. Diabetes affects an estimated
21 million people in the United States (or nearly 7% of the population), as many as a
third of whom are undiagnosed. Diabetes is a leading cause of end-stage renal disease,
adult-onset blindness, and nontraumatic lower extremity amputations in the United
States, underscoring the impact of this disease on the burden of health care costs. It
also greatly increases the risk of developing coronary artery disease and
cerebrovascular disease. In concert with great technologic advances, there have been
pronounced changes in human behavior, with increasingly sedentary life styles and
poor eating habits. This has contributed to the simultaneous escalation of diabetes and
obesity worldwide, which some have termed the "diabesity" epidemic.
Diagnosis
Blood glucose levels are normally maintained in a very narrow range, usually 70 to
120 mg/dL. The diagnosis of diabetes is established by elevation of blood glucose by
any one of three criteria:

1.c A random blood glucose concentration of 200 mg/dL or higher, with classical
signs and symptoms (discussed below)
2.c A fasting glucose concentration of 126 mg/dL or higher on more than one
occasion, or
3.c An abnormal oral glucose tolerance test (OGTT), in which the glucose
concentration is 200 mg/dL or higher 2 hours after a standard carbohydrate
load (75 gm of glucose ).

Derangements in carbohydrate metabolism proceed along a continuum. Individuals

with serum fasting glucose values less than 110 mg/dL, or less than 140 mg/dL
following an OGTT, are considered to be euglycemic. However, those with serum
fasting glucose greater than 110 but less than 126 mg/dL, or OGTT values of greater
than 140 but less than 200 mg/dL, are considered to have impaired glucose
tolerance. Individuals with impaired glucose tolerance have a significant risk of
progressing to overt diabetes over time, with as many as 5% to 10% advancing to full-
fledged diabetes mellitus per year. In addition, those with impaired glucose tolerance
are at risk for cardiovascular disease, due to abnormal carbohydrate metabolism and
the coexistence of other risk factors (see Chapter 10).
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Classification
Although all forms of diabetes mellitus share hyperglycemia as a common feature, the
underlying causes of hyperglycemia vary widely. The vast majority of cases of
diabetes fall into one of two broad classes:
Type 1 diabetes is characterized by an absolute deficiency of insulin secretion
 caused by pancreatic ȕ-cell destruction, usually resulting from an autoimmune
attack. Type 1 diabetes accounts for approximately 10% of all cases.Type 2
diabetes is caused by a combination of peripheral resistance to insulin action
and an inadequate compensatory response of insulin secretion by the
pancreatic ȕ cells ("relative insulin deficiency"). Approximately 80% to 90%
of patients have type 2 diabetes.
A variety of monogenic and secondary causes make up the remaining cases of diabetes
(Table 20-5). It should be stressed that while the major types of diabetes have different
pathogenic mechanisms, the long-term complications in kidneys, eyes, nerves, and
blood vessels are the same and are the principal causes of morbidity and death.
Normal Insulin Physiology and Glucose Homeostasis
Before discussing the pathogenesis of the two major types of diabetes, we briefly
review normal insulin physiology and glucose metabolism. Normal glucose
homeostasis is tightly regulated by three interrelated processes: (1) glucose
production in the liver, (2) glucose uptake and utilization by peripheral tissues,
chiefly skeletal muscle, and, (3) actions of insulin and counter-regulatory hormones
(e.g., glucagon). The principal metabolic function of insulin is to increase the rate of
glucose transport into certain cells in the body (Fig. 20-21). These are the striated
muscle cells (including myocardial cells) and, to a lesser extent, adipocytes,
representing collectively about two-thirds of the entire body weight. Glucose uptake
in other peripheral tissues, most notably the brain, is insulin independent. In muscle
cells, glucose is then either stored as glycogen or oxidized to generate adenosine
triphosphate (ATP). In adipose tissue, glucose is primarily stored as lipid. Besides
promoting lipid synthesis (lipogenesis), insulin also inhibits lipid degradation
(lipolysis) in adipocytes. Similarly, insulin promotes amino acid uptake and protein
synthesis while inhibiting protein degradation. Thus, the metabolic effects of insulin
can be summarized as anabolic, with increased synthesis and reduced degradation of
glycogen, lipid, and protein. In addition to these metabolic effects, insulin has several
mitogenic functions, including initiation of DNA synthesis in certain cells and
stimulation of their growth and differentiation.
Table 20-5. Etiologic Classification of Diabetes Mellitus
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ȕ-cell destruction, leads to absolute insulin deficiency



 

Insulin resistance with relative insulin deficiency





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MODY, caused by mutations in:
HNF-4Į(MODY1)
Glucokinase (MODY2)
HNF-1Į(MODY3)
IPF-1 (MODY4)
HNF-1ȕ(MODY5)
Neuro D1 (MODY6)
Mitochondrial DNA mutations












Defects in proinsulin conversion
Insulin gene mutations
Insulin receptor mutations
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Chronic pancreatitis
Pancreatectomy
Neoplasia
Cystic fibrosis
Hemochromatosis
Fibrocalculous pancreatopathy

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Growth hormone excess (acromegaly)
Cushing syndrome
Hyperthyroidism
Pheochromocytoma
Glucagonoma
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Cytomegalovirus
Coxsackievirus B
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Glucocorticoids
Thyroid hormone
ȕ-adrenergic agonists
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Down syndrome
Kleinfelter syndrome
Turner syndrome
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HNF, hepatocyte nuclear factor; IPF-1, insulin promoter factor 1; MODY,

maturity-onset diabetes of the young; Neuro D1, neurogenic differentiation
factor 1.
Adapted from the Report of the American Diabetes Association (ADA)
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.
2iabetic Care 25 (Suppl.1):S5-S20, 2002.
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Figure 20-21 Metabolic actions of insulin in striated muscle, adipose tissue, and liver.
Insulin reduces the production of glucose from the liver. Insulin and glucagon have
opposing regulatory effects on glucose homeostasis. During fasting states, low
insulin and high glucagon levels facilitate hepatic gluconeogenesis and glycogenolysis
(glycogen breakdown) while decreasing glycogen synthesis, thereby preventing
hypoglycemia. Thus, fasting plasma glucose levels are determined primarily by
hepatic glucose output. Following a meal, insulin levels rise and glucagon levels fall
in response to the large glucose load. The most important stimulus that triggers
insulin release is glucose itself, which initiates insulin synthesis in the pancreatic ȕ
cells. Other agents, including intestinal hormones and certain amino acids (leucine
and arginine), stimulate insulin release but not its synthesis. In peripheral tissues
(skeletal muscle and adipose tissue), secreted insulin binds to the insulin receptor,
triggering a number of intracellular responses that promote glucose uptake and post-
prandial glucose utilization, thereby maintaining glucose homeostasis.
Abnormalities at various points along this complex signaling cascade, from synthesis
and release of insulin by ȕ cells to insulin receptor interactions in peripheral tissues,
can result in the diabetic phenotype.
Pathogenesis of Type 1 Diabetes Mellitus
Type 1 diabetes is an autoimmune disease in which islet destruction is caused
primarily by T lymphocytes reacting against as yet poorly defined ȕ-cell antigens,
resulting in a reduction in ȕ-cell mass. Recent studies have implicated immunologic
epitopes on insulin hormone itself as a target antigen for autoimmune injury, but it
remains to be convincingly established whether this is a universal phenomenon in all
cases of type 1 diabetes or in only a subset. What is also unclear is how immunologic
tolerance breaks down in the setting of type 1 diabetes. As in all autoimmune diseases,
genetic susceptibility and environmental influences play important roles in the
pathogenesis. Type 1 diabetes most commonly develops in childhood, becomes
manifest at puberty, and is progressive with age. Most individuals with type 1 diabetes
depend on exogenous insulin supplementation for survival, and without insulin, they
develop serious metabolic complications such as acute ketoacidosis and coma.
Although the clinical onset of type 1 diabetes is abrupt, this disease in fact results from
a chronic autoimmune attack on ȕ cells that usually starts many years before the
disease becomes evident (Fig. 20-22). The classic manifestations of the disease
(hyperglycemia and ketosis) occur late in its course, after more than 90% of the ȕ cells
have been destroyed. Several mechanisms contribute to ȕ-cell destruction, and it is
likely that many of these immune mechanisms work together to produce progr essive
loss of ȕ cells, resulting in clinical diabetes:
T lymphocytes react against ȕ-cell antigens and cause cell damage. These T
cells include CD4+ T cells of the TH1 subset, which cause tissue injury by
activating macrophages, and CD8+ cytotoxic T lymphocytes, which directly
kill ȕ cells and also secrete cytokines that activate macrophages. In the rare
cases in which the pancreatic lesions have been examined at the early active
stages of the disease, the islets show cellular necrosis and lymphocytic
infiltration. This lesion is called insulitis.Locally produced cytokines damage ȕ
cells. Among the cytokines implicated in the cell injury are IFN-Ȗ, produced by
T cells, and tumor necrosis factor and interleukin-1, produced by macrophages
that are activated during the immune reaction.Autoantibodies against a variety
of ȕ-cell antigens, including insulin and glutamic acid decarboxylase, are also
detected in the blood of 70% to 80% of patients and may contribute to islet
damage.

Figure 20-22 Stages in the development of type 1 diabetes mellitus. The stages are
listed from left to right, and hypothetical ȕ-cell mass is plotted against age. (From
Eisenbarth GE: Type 1 diabetes-a chronic autoimmune disease. N Engl J Med
314:1360, 1986.)
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Type 1 diabetes has a complex pattern of genetic association, and putative
susceptibility genes have been mapped to at least 20 chromosomal regions. Of these,
the principal susceptibility locus for type 1 diabetes resides in the region that encodes
the class II MHC molecules on chromosome 6p21 (HLA-2 . Between 90% and 95% of
Caucasians with type 1 diabetes have HLA-2
, or 2
, or both, in contrast to about
40% of normal subjects, and 40% to 50% of patients are 2
2
 heterozygotes, in
contrast to 5% of normal subjects. Despite the high relative risk of type 1 diabetes in
individuals with particular class II alleles, most persons who inherit these alleles do
not develop the disease. Another gene shown to be weakly associated with the disease
encodes the T-cell inhibitory receptor CTLA-4. Individuals with type 1 diabetes show
increased frequency of a splice variant that may abrogate the normal ability of this
receptor to keep self-reactive T lymphocytes under control. As mentioned above, we
do not know the actual genes in the many other susceptibility loci. There is also
evidence to suggest that environmental factors, especially infections, may be involved
in type 1 diabetes as in other autoimmune diseases. It has been proposed that viruses
may be an initiating trigger, perhaps because some viral antigens are antigenically
similar to ȕ cell antigens (molecular minicry), but this idea is unproved. The
controversy is compounded by recent evidence indicating that infections are actually
protective.
Pathogenesis of Type 2 Diabetes Mellitus
While much has been learned in recent years, the pathogenesis of type 2 diabetes
remains enigmatic. Environmental influences, such as a sedentary life style and dietary
habits, clearly have a role, as will become evident when obesity is considered.
Nevertheless, genetic factors are even more important than in type 1 diabetes, with
linkage demonstrable to multiple "diabetogenic" genes. Among identical twins, the
concordance rate is 50% to 90%, while among first-degree relatives with type 2
diabetes (including fraternal twins) the risk of developing the disease is 20% to 40%,
as compared with 5% to 7% in the population at large. Unlike type 1 diabetes,
however, the disease is not linked to genes involved in immune tolerance and
regulation, and there is no evidence to suggest an autoimmune basis to type 2 diabetes.
The two metabolic defects that characterize type 2 diabetes are (1 a decreased ability
of peripheral tissues to respond to insulin (insulin resistance and (2 ȕ-cell
dysfunction that is manifested as inadequate insulin secretion in the face of insulin
resistance and hyperglycemia (Fig. 20-23). In most cases, insulin resistance is the
primary event and is followed by increasing degrees of ȕ-cell dysfunction.
Insulin Resistance

Figure 20-23 Pathogenesis of type 2 diabetes mellitus. Genetic predisposition and

environmental influences converge to cause insulin resistance. Compensatory ȕ-cell
hyperplasia can maintain normoglycemia, but eventually ȕ-cell secretory dysfunction
sets in, leading to impaired glucose tolerance and eventually frank diabetes. Rare
instances of primary ȕ-cell failure can directly lead to type 2 diabetes without a state
of insulin resistance.
Insulin resistance is defined as resistance to the effects of insulin on glucose uptake,
metabolism, or storage. Insulin resistance is a characteristic feature of most individuals
with type 2 diabetes and is an almost universal finding in diabetic individuals who are
obese. The evidence that insulin resistance has a major role in the pathogenesis of type
2 diabetes can be gauged from the findings that (1) insulin resistance is often detected
10 to 20 years before the onset of diabetes in predisposed individuals (e.g., offspring
of type 2 diabetics), and (2) in prospective studies, insulin resistance is the best
predictor for subsequent progression to diabetes. It is recognized that insulin
resistance is a complex phenomenon, influenced by a variety of genetic and
environmental factors.
Genetic Defects of the Insulin Receptor and Insulin Signaling Pathway
Loss-of-function abnormalities of either the insulin receptor or its down-stream
signaling molecules are obvious candidates for mediating insulin resistance in type 2
diabetes. Much of the role of genetic defects in the insulin signaling pathway has been
elucidated from targeted disruption of these genes in knockout mouse models of
diabetes. Unfortunately, the extrapolation of these single-gene knockout models to
human disease has been less than gratifying, underscoring the multifactorial etiology
of insulin resistance in humans. Point mutations of the insulin receptor are relatively
rare, accounting for no more than 1% to 5% of patients with insulin resistance (see
"Monogenic Forms of Diabetes"). The vast majority of individuals with conventional
type 2 diabetes, however, do not harbor inactivating mutations in either the insulin
receptor or other components of the insulin-signaling pathway.
Obesity and Insulin Resistance
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Figure 20-24 Obesity and insulin resistance: the missing links? Adipocytes release a
variety of factors (free fatty acids [FFAs] and adipocytokines) that may have a role in
modulating insulin resistance in peripheral tissues (illustrated here is striated muscle).
Excess FFAs and resistin are associated with insulin resistance; in contrast,
adiponectin, whose levels are decreased in obesity, is an insulin-sensitizing
adipocytokine. Leptin is also an insulin-sensitizing agent but acts via central receptors
(in the hypothalamus). The peroxisome proliferator-activated receptor Ȗ (PPARȖ) is a
adipocyte nuclear receptor that is activated by a class of insulin-sensitizing drugs
called thiazolidinediones (TZDs). The mechanism of action of TZDs may eventually
be mediated through modulation of adipocytokine and FFA levels that favor a state of
insulin sensitivity.
The association of obesity with type 2 diabetes has been recognized for decades, with
visceral obesity being common in the majority of type 2 diabetics. Insulin resistance is
the link between obesity and diabetes (Fig. 20-24). The risk for diabetes increases as
the body mass index (a measure of body fat content) increases, suggesting a dose-
response relationship between body fat and insulin resistance. Although many details
of the "adipo-insulin axis" remain to be elucidated, there has been a substantial
increase in our recognition of some of the putative pathways leading to insulin
resistance:

ole of free fatty acids (FFAs : Cross-sectional studies have demonstrated an
inverse correlation between fasting plasma FFAs and insulin sensitivity. The
level of intracellular triglycerides is often markedly increased in muscle and
liver tissues in obese individuals, presumably because excess circulating FFAs
are deposited in these organs. Intracellular triglycerides and products of fatty
acid metabolism are potent inhibitors of insulin signaling and result in an
acquired insulin resistance state. These "lipotoxic" effects of FFAs are most
likely mediated through a decrease in activity of key insulin-signaling
proteins.
ole of adipocytokines in insulin resistance: Adipose tissue is not
 merely a passive storage depot for fat; it can operate as a functional endocrine
organ, releasing hormones in response to extracellular stimuli or changes in the
metabolic status. A variety of proteins released into the systemic circulation by
adipose tissue have been identified, and these are collectively termed
adipocytokines. Among these are leptin, adiponectin, and resistin; changes in
their levels are associated with insulin resistance. For example, adiponectin
levels are reduced in states of obesity and insulin resistance, suggesting that,
under physiologic conditions, this cytokine contributes to insulin sensitivity in
peripheral tissues. Conversely, levels of resistin are increased in obesity, and
this cytokine contributes to insulin resistance.
ole of the PPA
Ȗ and
thiazolidinediones (TZ2 : TZDs are a class of antidiabetic compounds that
were first developed in the early 1980s as antioxidants. The target receptor for
TZDs has been identified as PPARȖ, a nuclear receptor and transcription
factor. PPA
Ȗ is most highly expressed in adipose tissue, and its activation by
TZ2s results in modulation of gene expression in adipocytes, eventually
leading to reduction of insulin resistance. The targets of PPARȖ activation
include several of the adipocytokines discussed above. PPARȖ activation also
decreases concentrations of FFAs, which you will recall as another element
contributing to insulin resistance in obesity.A family of proteins called sirtuins,
which were identified as being involved in aging, have also been implicated in
diabetes. The best-studied mammalian sirtuin, called Sirt-1, has been shown to
improve glucose tolerance, enhance ȕ cell insulin secretion, and increase
production of adiponectin. It remains to be seen if sirtuin abnormalities are
involved in the pathogenesis of type 2 diabetes.
To summarize, insulin resistance in type 2 diabetes is a complex and multifactorial
phenomenon. Genetic defects in the insulin signaling pathway are not common, and
when present, they are more likely to be subtle variations in function of multiple
components in this pathway rather than a single profound inactivating mutation.
Insulin resistance is present in the overwhelming majority of individuals, and obesity
is central to this phenomenon (see Fig. 20-24). Several possible links between obesity
and insulin resistance have been suggested, including excessive amounts of FFAs and
a variety of adipocyte-specific products (adipocytokines). TZDs are insulin-sensitizing
drugs that act via the PPARȖ receptor, and represent one of the many major advances
achieved in ameliorating insulin resistance in diabetes.
ȕ-Cell Dysfunction
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ȕ-cell dysfunction in type 2 diabetes reflects the inability of these cells to adapt
themselves to the long-term demands of peripheral insulin resistance and increased
insulin secretion. In states of insulin resistance, insulin secretion is initially higher for
each level of glucose than in controls. This hyperinsulinemic state is a compensation
for peripheral resistance and can often maintain normal plasma glucose for years.
Although the data in humans are scant, studies from animal models of diabetes support
the aforementioned sequence of events wherein ȕ-cell hyperplasia in the pre-diabetic
state is followed by decrease in ȕ-cell mass that coincides with clinical progression to
diabetes. Eventually, however, ȕ-cell compensation becomes inadequate, and there is
progression to overt diabetes. The underlying bases for failure of ȕ-cell adaptation is
not known, although it is postulated that several mechanisms, including adverse
effects of high circulating FFAs ("lipotoxicity") or chronic hyperglycemia
("glucotoxicity"), may have a role. ȕ-cell dysfunction in type 2 diabetes encompasses
both qualitative and quantitative aspects.
Qualitative ȕ-cell dysfunction is initially manifest as subtle abnormalities, such
as loss in the normal pulsatile, oscillating pattern of insulin secretion, and
attenuation of the rapid first phase of insulin secretion triggered by elevation in
plasma glucose . Over time, the secretory defect progresses to encompass all
phases of insulin secretion, and even though some basal insulin secretion
persists in type 2 diabetes, it is inadequate for overcoming insulin
resistance.Quantitative ȕ-cell dysfunction is manifest as a decrease in ȕ-cell
mass, islet degeneration, and deposition of islet amyloid. Islet amyloid protein
(amylin) is a characteristic finding in individuals with type 2 diabetes, and it is
present in more than 90% of diabetic islets examined. Islet amyloidosis is
associated with a decrease in ȕ-cell mass, although it is uncertain whether the
amyloid is a cause or consequence of cell damage in type 2 diabetes. In this
context, it is important to note that even a "normal" ȕ-cell mass in diabetic
individuals may, in fact, indicate a relative reduction as compared with the
expected hyperplasia needed to compensate for insulin resistance.
Monogenic Forms of Diabetes
Types 1 and 2 diabetes are genetically complex, and despite the associations with
multiple susceptibility loci, no single gene defect (mutation) can account for
predisposition to these entities. In contrast, monogenic forms of diabetes (Table 20-5)
are uncommon examples of the diabetic phenotype occurring secondary to loss-of-
function mutations within a single gene. Monogenic causes of diabetes result from
either a primary defect in ȕ-cell function or a defect in insulin-insulin receptor
signaling.
Pathogenesis of the Complications of Diabetes
Most of the available experimental and clinical evidence suggests that the
complications of diabetes are a consequence of the metabolic derangements, mainly
hyperglycemia. At least three distinct metabolic pathways seem to be involved in the
pathogenesis of long-term diabetic complications, although the primacy of any one has
not been established. These pathways include:
1. Non-enzymatic glycosylation. This 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 blood glucose level; indeed, the
measurement of glycosylated hemoglobin levels in blood is useful 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 of
collagen and other long-lived 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 pathogenic to
extracellular matrix components and to the target cells of diabetic complications:
AGE formation on proteins such as collagen causes cross-links between
polypetides; this in turn may trap nonglycosylated plasma and interstitial
proteins. In large vessels, trapping low-density lipoprotein, for example,
retards its efflux from the vessel wall and enhances the deposition of
cholesterol in the intima, thus accelerating atherogenesis. In capillaries,
including those of renal glomeruli, plasma proteins such as albumin bind to the
glycated basement membrane, accounting in part for the basement membrane
thickening characteristic of diabetic glomerulopathy.Circulating plasma
proteins are modified by the addition of AGE residues; these proteins, in turn,
 bind to AGE receptors on several cell types (endothelial cells, mesangial cells,
macrophages). The biologic effects of AGE-receptor signaling include (1)
release of cytokines and growth factors from macrophages and mesangial cells;
(2) increased endothelial permeability; (3) increased procoagulant activity on
endothelial cells and macrophages; and (4) enhanced proliferation and
synthesis of extracellular matrix by fibroblasts and smooth muscle cells. All
these effects can potentially contribute to diabetic complications.
2. Activation of protein kinase C. Activation of intracellular protein kinase C (PKC) by
calcium ions and the second messenger diacylglycerol (DAG) is an important signal
transduction pathway in many cellular systems. Intracellular hyperglycemia can
stimulate the de novo synthesis of DAG from glycolytic intermediates and hence
cause activation of PKC. The down-stream effects of PKC activation are numerous
and include production of pro-angiogenic molecules such as vascular endothelial
growth factor, implicated in the neovascularization seen in diabetic retinopathy, and
pro-fibrogenic molecules like transforming growth factor ȕ, leading to increased
deposition of extracellular matrix and basement membrane material.
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3. Intracellular hyperglycemia with disturbances in polyol pathways. In some tissues
that do not require insulin for glucose transport (e.g., nerves, lens, kidneys, blood
vessels), hyperglycemia leads to an increase in intracellular glucose that is then
metabolized by the enzyme aldose reductase to sorbitol , a polyol, and eventually to
fructose. While accumulated sorbitol and fructose have traditionally been implicated
in causing cell injury via increased intracellular osmolarity and water influx,
accumulating evidence suggests that the deleterious consequences of the aldose
reductase pathway arise primarily by an increase in cellular susceptibility to oxidative
stress. This is because intracellular antioxidant reserves are diminished in the course of
sorbitol metabolism. The importance of this pathway in human diabetes is not clear
because clinical trials using an aldose reductase inhibitor fail to significantly
ameliorate the development of diabetic neuropathy.
SUMMARY

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Type 1 diabetes is an autoimmune disease
characterized by progressive destruction of islet ȕ cells,
leading to absolute insulin deficiency. Several immune
mechanisms probably contribute to ȕ-cell damage, including
T cells, cytokines, and autoantibodies.Type 2 diabetes has no
autoimmune basis; instead, features central to its
pathogenesis are insulin resistance and ȕ-cell dysfunction,
resulting in relative insulin deficiency.Obesity has an
important relationship with insulin resistance (and hence,
type 2 diabetes), probably mediated by cytokines released
from adipose tissues (adipocytokines). Other players in the
"adipo-insulin axis" include free fatty acids (which may cause
"lipotoxicity") and the PPARȖ receptor, which modulates
adipocytokine levels.Monogenic forms of diabetes are
uncommon and are caused by single-gene defects that result
in primary ȕ-cell dysfunction (e.g., glucokinase mutation) or
lead to abnormalities of insulin-insulin receptor signaling
(e.g., insulin receptor gene mutations).The long-term
 complications of diabetes are similar in both types and
involve three underlying mechanisms: formation of AGEs
through nonenzymatic glycosylation, activation of PKC, and
accumulation of intracellular sorbitol .
Morphology of Diabetes and Its Late Complications
Pathologic findings in the pancreas are variable and not necessarily
dramatic. The important morphologic changes are related to the
many late systemic complications of diabetes. There is extreme
variability among patients in the time of onset of these
complications, their severity, and the particular organ or organs
involved. In individuals with tight control of diabetes the onset may
be delayed. In most patients, however, morphologic changes are
likely to be found in arteries 4',
!-. basement
membranes of small vessels 4'
"-. kidneys 4! 


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"-. retina 4

"-. nerves 4
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tissues. These changes are seen in both type 1 and type 2 diabetes
(Fig. 20-25).
 Lesions in the pancreas are inconstant and rarely of
diagnostic value. Distinctive changes are more commonly associated
with type 1 than with type 2 diabetes. One or more of the following
alterations may be present.
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 This is most
often seen in type 1 diabetes, particularly with rapidly
advancing disease. Most of the islets are small,
inconspicuous, and not easily detected.+1







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 (insulitis) principally composed of T
lymphocytes similar to that in animal models of autoimmune
diabetes (Fig. 20-26A). This may be seen in type 1 diabetics
at the time of clinical presentation. 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.



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demonstrated only by special morphometric studies.'!

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appears as deposition of pink, amorphous material beginning
in and around capillaries and between cells. At advanced
stages the islets may be virtually obliterated (Fig. 20-26B);
fibrosis may also be observed. This change is often seen in
long-standing cases of type 2 diabetes. Similar lesions may be
found in elderly nondiabetics, apparently as part of normal
aging.



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hyperplasia in response to the maternal hyperglycemia.
 

*, Disease. Diabetes exacts a heavy toll on
the vascular system. The hallmark of diabetic macrovascular disease
is accelerated atherosclerosis affecting the aorta and large and
medium-sized arteries. Except for its greater severity and earlier age
of onset, atherosclerosis in diabetics is indistinguishable from that in
nondiabetics (Chapter 10). 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
women as in diabetic men. In contrast, myocardial infarction is
uncommon in nondiabetic women 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. This is discussed later.
‘

. the vascular lesion associated with
hypertension (Chapters 10 and 14), is both more prevalent and more
severe in diabetics than in nondiabetics, but it is not specific for
diabetes and may be seen in elderly nondiabetics without
hypertension. It takes the form of an amorphous, hyaline thickening
of the wall of the arterioles, which causes narrowing of the lumen
(Fig. 20-27). Not surprisingly, in diabetics it is related not only to the
duration of the disease but also to the level of blood pressure.
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features of diabetes is !

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The thickening is most evident in the capillaries of the skin, skeletal
muscle, retina, renal glomeruli, and renal medulla. However, it may
also be seen in such nonvascular structures as renal tubules, the
Bowman capsule, peripheral nerves, and placenta. By both light and
electron microscopy, the basal lamina separating parenchymal or
endothelial cells from the surrounding tissue is markedly thickened
by concentric layers of hyaline material composed predominantly of
type IV collagen (Fig. 20-28). It should be noted that !


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indistinguishable microangiopathy can be found in aged nondiabetic
patients, but rarely to the extent seen in individuals with long-
standing diabetes.
 

2"
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(see also Chapter 14). Renal failure is second only to myocardial
infarction as a cause of death from this disease. Three lesions are
encountered: (1) glomerular lesions; (2) renal vascular lesions,
principally arteriolosclerosis; and (3) pyelonephritis, including
necrotizing papillitis.
The most important glomerular lesions are capillary basement
membrane thickening, diffuse mesangial sclerosis, and nodular
glomerulosclerosis. 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
(Fig. 20-29).

'
 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 individuals with disease of more than 10 years' duration. When
glomerulosclerosis becomes marked, patients manifest the nephrotic
syndrome, characterized by proteinuria, hypoalbuminemia, and
edema (Chapter 14).
2!
' describes a glomerular lesion made
distinctive by ball-like deposits of a laminated matrix situated in the
periphery of the glomerulus (Fig. 20-30). These nodules are PAS
positive and usually contain trapped mesangial cells. This distinctive
change has been called the Kimmelstiel-Wilson lesion, after the
pathologists who described it. Nodular glomerulosclerosis is
encountered in approximately 15% to 30% of long-term diabetics
and is a major cause of morbidity and mortality. Diffuse mesangial
sclerosis may also be seen in association with old age and
hypertension; on the contrary, the nodular form of
glomerulosclerosis, once certain unusual forms of nephropathies
have been excluded (see Chapter 14), is essentially pathogonomic of
diabetes. Both the diffuse and the nodular forms of
glomerulosclerosis induce sufficient ischemia to cause scarring of the
kidneys, manifested by a finely granular cortical surface (Fig. 20-31).
page 783
page 784
/

"
!










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',
!

! 
 The kidney is one of the most
frequently and severely affected organs; however, the changes in the
arteries and arterioles are similar to those found throughout the body.
‘








" 





"



 Such efferent arteriolosclerosis is rarely if
ever encountered in persons who do not have diabetes.
"






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1!

"





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"

  Both the acute and chronic forms of this disease
occur in nondiabetics as well as in diabetics but 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, 
0

 (or papillary necrosis), is much
more prevalent in diabetics than in nondiabetics.
3
'


 
 Visual impairment, sometimes
even total blindness, is one of the more feared consequences of long-
standing diabetes. "

,,'

'

1

"
'




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'
.

' 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. "



"



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'4


,
4 1!-



!

,



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2
,


" includes intraretinal or preretinal
hemorrhages, retinal exudates, microaneurysms, venous dilations,
edema, and, most importantly, thickening of the retinal capillaries
(micro-angiopathy). The retinal exudates can be either "soft"
(microinfarcts) or "hard" (deposits of plasma proteins and lipids)
(Fig. 20-32). 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 of these changes is the microangiopathy, which is
thought to lead to loss of capillary pericytes and hence to focal
weakening of capillary structure.
"
!

,


"





,0

!
  This lesion leads to serious
consequences, including blindness, especially if it involves the
macula. Vitreous hemorrhages can result from rupture of newly
formed capillaries; the resultant organization of the hemorrhage can
pull the retina off its substratum (retinal detachment).
page 784
page 785
 

2
" 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 peripheral 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 direct axonal damage due to alterations in sorbitol
metabolism (as discussed).

Figure 20-25 Long-term complications of diabetes.

Figure 20-26 . Insulitis, shown here from a rat (BB) model of autoimmune diabetes,
and seen in type 1 human diabetes. 5. Amyloidosis of a pancreatic islet in type 2
diabetes. (. Courtesy of Dr. Arthur Like, University of Massachusetts, Worchester,
Massachusetts.)
Figure 20-27 Severe renal hyaline arteriolosclerosis. Note a markedly thickened,
tortuous afferent arteriole. The amorphous nature of the thickened vascular wall is
evident. (PAS stain; courtesy of Dr. M.A. Venkatachalam, Department of Pathology,
University of Texas Health Science Center at San Antonio.)

Figure 20-28 Renal cortex showing thickening of tubular basement membranes in a

diabetic patient (PAS stain).

Figure 20-29 Renal glomerulus showing markedly thickened glomerular basement

membrane (B) in a diabetic. L, glomerular capillary lumen; U, urinary space.
(Courtesy of Dr. Michael Kashgarian, Department of Pathology, Yale University
School of Medicine, New Haven, Connecticut.)

Figure 20-30 Nodular glomerulosclerosis in a person with long-standing diabetes.

(Courtesy of Dr. Lisa Yerian, Department of Pathology, University of Chicago,
Chicago, Illinois.)

Figure 20-31 Nephrosclerosis in a person with long-standing diabetes. The kidney has
been bisected to demonstrate both diffuse granular transformation of the surface (left
and marked thinning of the cortical tissue (right . Additional features include some
irregular depressions, the result of pyelonephritis, and an incidental cortical cyst (far
right .

Figure 20-32 Diabetic retinopathy, demonstrating advanced proliferative retinopathy

with retinal hemorrhages, exudates, neovascularization, and tractional retinal
detachment in the lower right corner. (Courtesy of Dr. Rajendra Apte, Washington
University School of Medicine, St. Louis, Missouri.)
Clinical Features
It is difficult to sketch with brevity the diverse clinical presentations of diabetes
mellitus. Only a few characteristic patterns will be presented (Table 20-6). In the
initial 1 or 2 years following manifestation of overt type 1 diabetes, the exogenous
insulin requirements may be minimal to none secondary to ongoing endogenous
insulin secretion (referred to as the "honeymoon period"), but shortly thereafter any
residual ȕ-cell reserve is exhausted and insulin requirements increase dramatically.
Although ȕ-cell destruction is a gradual process, the transition from impaired glucose
tolerance to overt diabetes may be abrupt, heralded by an event with increased insulin
requirements such as infection. The onset is marked by polyuria, polydipsia,
polyphagia, and in severe cases, ketoacidosis, all resulting from metabolic
derangements (Fig. 20-33). Since insulin is a major anabolic hormone in the body,
deficiency of insulin results in a catabolic state that affects not only glucose
metabolism but also fat and protein metabolism. 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.
The resultant hyperglycemia exceeds the renal threshold for reabsorption, and
glycosuria ensues. The glycosuria induces an osmotic diuresis and thus polyuria,
causing a profound loss of water and electrolytes. 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.
Table 20-6. Type 1 versus Type 2 Diabetes Mellitus
'
 
Ä 




Onset <20 years Onset >30 years

Normal weight Obesity

Markedly decreased blood insulin Increased blood insulin (early);

normal to moderate decreased
insulin (late)

Antibodies to islet cells No antibodies to islet cells

Ketoacidosis common Ketoacidosis rare; nonketotic

hyperosmolar coma




30% to 70% concordance in twins 50% to 90% concordance in twins

Linkage to MHC class II HLA genes No HLA linkage

Linkage to candidate "diabetogenic"
genes


"

Autoimmune destruction of ȕ-cells Insulin resistance in skeletal muscle,

mediated by T cells and humoral adipose tissue, and liver
mediators
 Absolute insulin deficiency ȕ-cell dysfunction and relative
insulin deficiency





Insulitis early No insulitis

Marked atrophy and fibrosis Focal atrophy and amyloid

deposition

ȕ-cell depletion Mild ȕ-cell depletion

HLA, human leukocyte antigen; MHC, major histocompatibility complex.

page 785
page 786

Figure 20-33 Sequence of metabolic derangements leading to diabetic coma in type 1

diabetes mellitus. An absolute insulin deficiency leads to a catabolic state, eventuating
in ketoacidosis and severe volume depletion. These bring about sufficient central
nervous system compromise to cause coma, and eventual death if left untreated.
page 786
page 787
In individuals with type 1 diabetes, deviations from normal dietary intake, unusual
physical activity, infection, or any other forms of stress may rapidly influence the
treacherously fragile metabolic balance, predisposing one to diabetic ketoacidosis. The
plasma glucose is usually in the range of 500 to 700 mg/dL as a result of absolute
insulin deficiency and unopposed effects of counter-regulatory hormones
(epinephrine , glucagon). The marked hyperglycemia causes an osmotic diuresis and
dehydration characteristic of the ketoacidotic state. The second major effect is
activation of the ketogenic machinery. Insulin deficiency leads to activation of
lipoprotein lipase, with resultant excessive breakdown of adipose stores, giving rise to
increased levels of FFAs, oxidation of which by the liver produces ketone bodies.
Ketogenesis is an adaptive phenomenon in times of starvation, generating ketones as a
source of energy for consumption by vital organs (e.g., brain). The rate at which
ketone bodies are formed may exceed the rate at which they can be used by peripheral
tissues, leading to ketonemia and ketonuria. If the urinary excretion of ketones is
compromised by dehydration, the plasma hydrogen ion concentration increases,
resulting in metabolic ketoacidosis.
Type 2 diabetes mellitus may also present with polyuria and polydipsia, but unlike
type 1 diabetes, patients are often older (>40 years) and frequently obese. However,
with the increase in obesity and sedentary life style in our society, type 2 diabetes is
now seen in children and adolescents with increasing frequency. In some cases
medical attention is sought because of unexplained weakness or weight loss. Most
frequently, however, the diagnosis is made after routine blood or urine testing in
asymptomatic persons.
In the decompensated state, individuals with type 2 diabetes may develop
hyperosmolar nonketotic coma, a syndrome engendered by the severe dehydration
resulting from sustained osmotic diuresis in patients who do not drink enough water to
compensate for urinary losses from chronic hyperglycemia. Typically, the person is an
elderly diabetic who is disabled by a stroke or an infection and is unable to maintain
adequate water intake. Furthermore, the absence of ketoacidosis and its symptoms
(nausea, vomiting, respiratory difficulties) delays the seeking of medical attention in
these patients until severe dehydration and coma occur.
As previously discussed, it is the long-term effects of diabetes, more than the acute
metabolic complications, that are responsible for the overwhelming proportion of
morbidity and mortality attributable to this disease. In most instances, these
complications appear approximately 15 to 20 years after the onset of hyperglycemia.
In both forms of long-standing diabetes, cardiovascular events such as
myocardial infarction, renal vascular insufficiency, and cerebrovascular
accidents are the most common causes of mortality. The impact of
cardiovascular disease can be gauged by its involvement in as many as 80% of
deaths of type 2 diabetics; in fact, diabetics have a 3 to 7.5 times greater
incidence of death from cardiovascular causes than nondiabetic populations.
The hallmark of cardiovascular disease is accelerated atherosclerosis of the
large and medium-sized arteries (i.e., macrovascular disease). The importance
of obesity in the pathogenesis of insulin resistance has already been discussed,
but it is also an independent risk factor for development of
atherosclerosis.2iabetic nephropathy is a leading cause of end-stage renal
disease in the United States. The earliest manifestation of diabetic nephropathy
is the appearance of small amounts of albumin in the urine (>30 mg/day, but
<300 mg/day; i.e., microalbuminuria). Without specific interventions,
approximately 80% of type 1 diabetics and 20% to 40% of type 2 diabetics will
develop overt nephropathy with macroalbuminuria (>300 mg/day) over the
next 10 to 15 years, usually accompanied by the appearance of hypertension.
The progression from overt nephropathy to end-stage renal disease can be
highly variable and is evidenced by a progressive drop in glomerular filtration
rate. By 20 years after diagnosis, more than 75% of type 1 diabetics and about
20% of type 2 diabetics with overt nephropathy will develop end-stage renal
disease, requiring dialysis or renal transplantation.Visual impairment,
sometimes even total blindness, is one of the more feared consequences of
long-standing diabetes. This disease is currently the fourth leading cause of
acquired blindness in the United States. Approximately 60% to 80% of patients
develop some form of diabetic retinopathy approximately 15 to 20 years after
diagnosis. In addition to retinopathy, diabetics also have an increased
propensity for glaucoma and cataract formation, both of which contribute to
visual impairment in diabetes.2iabetic neuropathy typically presents with
decreased sensation in the distal extremities with less evident motor
abnormalities (sensorimotor neuropathy). The loss of pain sensation can result
in the development of ulcers that heal poorly and are a major cause of
morbidity. As many as 20% to 40% of diabetics also develop autonomic
dysfunction over time, as manifested by impediments in bowel and bladder
control.2iabetics are plagued by an enhanced susceptibility to infections of the
skin, as well as to tuberculosis, pneumonia, and pyelonephritis. Such
infections cause the deaths of about 5% of diabetics. In an individual with
diabetic neuropathy, a trivial infection in a toe may be the first event in a long
 succession of complications (gangrene, bacteremia, pneumonia) that may
ultimately lead to death.
pages 775 - 787
+1



"
4
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