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DIABETES MELLITUS

Diabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism. A defective or
deficient insulin secretory response, which translates into impaired carbohydrate (glucose) use, is a
characteristic feature of diabetes mellitus, as is the resulting hyperglycemia
Diabetes mellitus is a chronic disorder characterized by abnormalities in fuel metabolism,
including glucose, lipids, and amino acids.
Abnormalities in glucose tolerance are central in both the diagnosis of diabetes and classic
complications of the disease. Because of associated abnormalities in lipid metabolism, people
with diabetes are also prone to develop atherosclerosis, especially those with type 2 diabetes.
Classification of Diabetes Mellitus
•1. Type 1 diabetes (β -cell destruction, leads to absolute insulin deficiency)
••••••Immune-mediated
••••••Idiopathic
•2. Type 2 diabetes (insulin resistance with relative insulin deficiency)
•3. Genetic defects of β -cell function
••••••Maturity-onset diabetes of the young (MODY), caused by mutations in:
•••••••Hepatocyte nuclear factor 4α [HNF-4α ] (MODY1)
•••••••Glucokinase (MODY2)
•••••••Hepatocyte nuclear factor 1α [HNF-1α ] (MODY3)
•••••••Insulin promoter factor [IPF-1] (MODY4)
•••••••Hepatocyte nuclear factor 1β [HNF-1β ] (MODY5)
•••••••Neurogenic differentiation factor 1 [Neuro D1] (MODY6)
••••••Mitochondrial DNA mutations
•4. Genetic defects in insulin processing or insulin action
••••••Defects in proinsulin conversion
••••••Insulin gene mutations
••••••Insulin receptor mutations
•5. Exocrine pancreatic defects
••••••Chronic pancreatitis
••••••Pancreatectomy
••••••Neoplasia
••••••Cystic fibrosis
••••••Hemachromatosis
••••••Fibrocalculous pancreatopathy
•6. Endocrinopathies
••••••Acromegaly
••••••Cushing syndrome
••••••Hyperthyroidism
••••••Pheochromocytoma
••••••Glucagonoma
•7. Infections
••••••Cytomegalovirus
••••••Coxsackie virus B
•8. Drugs
••••••Glucocorticoids
••••••Thyroid hormone
••••••α -interferon
••••••Protease inhibitors
••••••β -adrenergic agonists
••••••Thiazides
••••••Nicotinic acid
••••••Phenytoin
•9. Genetic syndromes associated with diabetes
••••••Down syndrome
••••••Kleinfelter syndrome
••••••Turner syndrome
10. Gestational diabetes mellitus
In order to understand the pathogenesis of the two major diabetes types, first we will briefly review normal
insulin secretion and the mechanism of insulin signaling, since these aspects are critical to understanding the
pathogenesis of diabetes.

NORMAL INSULIN PHYSIOLOGY


Normal glucose homeostasis is tightly regulated by three interrelated processes: glucose production in the
liver; glucose uptake and utilization by peripheral tissues, chiefly skeletal, muscle; and actions of insulin and
counter-regulatory hormones, including glucagon, on glucose.
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. Insulin promotes glucose uptake and utilization in tissues (discussed
later). The skeletal muscle is the major insulin-responsive site for postprandial glucose utilization, and is
critical for preventing hyperglycemia and maintaining glucose homeostasis.

Figure 24-27 Hormone production in pancreatic islet cells. Immunoperoxidase staining shows a dark reaction
product for insulin in β cells (A), glucagon in α cells (B), and somatostatin in δ cells (C). D, Electron
micrograph of a β cell shows the characteristic membrane-bound granules, each containing a dense, often
rectangular core and distinct halo. E, Portions of an α cell (left) and a δ cell (right) also exhibit granules,
but with closely apportioned membranes. The α -cell granule exhibits a dense, round center. (Electron
micrographs courtesy of Dr. A. Like, University of Massachusetts Medical School, Worcester, MA.)
Figure 24-28 Insulin synthesis and secretion. Intracellular transport of glucose is mediated by GLUT-2, an
insulin-independent glucose transporter in β cells. Glucose undergoes
oxidative metabolism in the β cell to yield ATP. ATP inhibits an inward rectifying potassium channel
receptor on the β -cell surface; the receptor itself is a dimeric complex of the
sulfonylurea receptor and a K+ -channel protein. Inhibition of this receptor leads to membrane depolarization,
influx of Ca2+ ions, and release of stored insulin from β cells.

Figure 24-29 Metabolic actions of insulin in striated muscle, adipose tissue, and liver.

Figure 24-30 Insulin action on a target cell. Insulin binds to the α subunit of insulin receptor, leading to
activation of the kinase activity in the β -subunit, and sets in motion a phosphorylation (i.e., activation)
cascade of multiple downstream target proteins. The mitogenic functions of insulin (and the related insulin-like
growth factors) are mediated via the mitogen-activated protein kinase (MAP kinase) pathway. The metabolic
actions of insulin are mediated primarily by activation of the phosphatidylinositol-3-kinase (PI-3K) pathway.
The PI-3K-signaling pathway is responsible for a variety of effects on target cells, including translocation of
GLUT-4 containing vesicles to the surface; increasing GLUT-4 density on the membrane and rate of glucose
influx; promoting glycogen synthesis via activation of glycogen synthase; and promoting protein synthesis and
lipogenesis, while inhibiting lipolysis. The PI-3K pathway also promotes cell survival and proliferation.

The types of diabetes


Type 1 diabetes mellitus - Due to beta-cell destruction leading to an absolute insulin deficiency.
Beta-cell loss may be immune-mediated (90%) or idiopathic (10%). Depending on the rate of
beta-cell destruction (rapidly in children and young adults, and more slowly in older adults), all
patients eventually require insulin for glucose control and survival. Patients are prone to
ketoacidosis. Type 1 diabetes is caused by the autoimmune destruction of beta cells in
approximately 90% of people and results in an absolute deficiency of insulin.
Type 2 diabetes mellitus - Due to a combination of insulin resistance and relative insulin
deficiency. Often associated with obesity or an increase in truncal (visceral) fat. Ketoacidosis is
uncommon; may occur during periods of illness or stress. Hypertension and dyslipidemia are
frequently associated. Generally does not require exogenous insulin early in course of the illness.
Type 2 diabetes is the consequence of a combination of insulin resistance and progressive beta-
cell failure.
DIAGNOSIS OF DIABETES
Tests
Casual Plasma
Stage FPG* Glucose OGTT§
Normal <100 mg/dL (5.5 2-hour PG < 140 mg/dL
mmol/L)†
Prediabetes Impaired fasting glucose Impaired glucose tolerance 2-hour
≥ 100 and <126 mg/dL PG ≥ 140 mg/dL (7.7 mmol/L) but
(7.0 mmol/L) <200 mg/dL (11.1 mmol/L)
Diabetes FPG ≥ 126 mg/dL (7.0 ≥200 mg/dL (11.1 2-hour PG ≥ 200 mg/dL (11.1
mmol/L) mmol/L) plus mmol/L)

symptoms
FPG = fasting plasma glucose; PG = plasma glucose; OGTT = oral glucose tolerance test.
The classic symptoms of diabetes are polyuria, polydipsia, and unexplained weight loss.

Predisposition factors:
• Age > 45 years
• Overweight (body mass index [BMI] ≥ 25 kg/m2)
• Family history of diabetes (i.e., parents or siblings with diabetes)
• Member of a high-risk ethnic population (African American, Hispanic, Native American,
Asian American, and Pacific Islanders)
• History of gestational diabetes or delivery of infant weighing more than 9 lb
• Habitual physical inactivity
• History of hypertension or dyslipidemia (HDL ≤ 35 mg/dL or high triglycerides ≥ 250
mg/dL)
• Previously identified with either impaired fasting glucose or impaired glucose tolerance
(prediabetes)
• Polycystic ovary syndrome
• History of vascular disease

The susceptibility for type 1 diabetes is associated with the genetic expression of certain proteins
coded by the human leukocyte antigen (HLA) region of the major histocompatibility complex.
These proteins are present on the surface of lymphocytes and macrophages and are considered
essential for triggering the autoimmune destruction of the beta cells. Although all of the genetic
markers (HLA and others) for type 1 diabetes are not known, future progress in this field will
allow population screening for genetic susceptibility.

Pathogenesis of type 1 diabetes:


For type 1 diabetes, the primary pathogenic step is the activation of host T lymphocytes against
specific antigens present in the patient's own beta cells. These activated T cells orchestrate a
slow destruction of the beta cells via the recruitment of T and B lymphocytes, macrophages, and
cytokines. Morphologic study of the pancreases of children who died at the onset of diabetes has
shown an inflammatory infiltrate of mononuclear cells confined to the islets-called insulitis. The
final result is the total destruction of the beta cells over a span of years. The finding of high-titer
islet-cell antibodies (ICAs) in the serum of a child is highly predictive for progression to type 1
diabetes. Various antigens that are expressed by the beta cell have been implicated as the target
for the autoimmune attack. Candidate antigens include insulin itself and a 64-kDa protein (now
recognized as glutamic acid decarboxylase [GAD]). The triggering event for T-cell activation
against these autoantigens is unknown but may involve the exposure to some environmental
substance that is antigenically similar to the autoantigen. The T cells that are activated against
this environmental antigen can then cross-react with the antigen on the beta cells-a process called
molecular mimicry. Suspected environmental triggers for type 1 diabetes are viruses, toxins, and
foods.
Pathogenesis of type 2 diabetes:
Type 1 diabetes is characterized by an absolute insulin deficiency; however, type 2 diabetes is
characterized by both a defect in insulin action (insulin resistance) and a relative insulin
deficiency. Insulin resistance generally precedes insulin deficiency by several years or decades in
most models of type 2 diabetes although recent reports have suggested that a beta-cell defect
may be the initiating trigger for both. Elevated levels of fasting or postglucose load insulin levels
are the hallmark of insulin resistance. Several quantitative techniques may be used to assess
insulin sensitivity or insulin resistance.

PATHOGENESIS. The pathogenesis of the two types isdiscussed separately, but first we briefly review
normal insulin metabolism, since some aspects of insulin release and action are important in the
consideration of pathogenesis.
Normal Insulin Metabolism. The chemical structure,molecular biology, biosynthesis, and secretory path-
ways of insulin are now understood in elegant detail.The insulin gene is expressed in the beta cells of the
pancreatic islets, where insulin is synthesized andstored in granules prior to secretion. Release from
beta cells occurs as a biphasic process involving two poolsof insulin. A rise in the blood glucose
levels, for example, calls forth an immediate release of insulin, presumably that stored in the beta-cell
granules. If the secretory stimulus persists, a delayed and protractedresponse follows, which involves
active synthesis of insulin. The most important stimulus that triggers insulin release is glucose, which
also initiates insulin synthesis. Other agents, including intestinal hormones and certain amino acids
(leucine and arginine), as wellas the sulfonylureas, stimulate insulin release but notsynthesis.
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) glucose conversion to
triglycerides, (4) nucleic acid synthesis, and (5) protein synthesis.Its principal metabolic function is to
increase the rate oj glucose transport into certain cells in the body.These are the striated muscle cells,
including myocardial cells, fibroblasts, and fat cells, representing collectivelyabout two thirds of the entire
body weight.
Insulin interacts with its target cells by first bindingto the insulin receptor. Since the amount of
insulin bound to the cells is affected by the availability ofreceptors, their number and function are
important in regulating the action of insulin. Receptor-bound insu lin triggers a number of intracellular
responses, including activation or inhibition of insulin-sensitive enzymes in mitochondria, protein
synthesis, and DNA synthesis. One of the important early effects of insulininvolves translocation of
glucose transport units (GLUTs) from the Golgi apparatus to the plasmamembrane, thus facilitating
cellular uptake of glucose. There are several different forms of GLUTs, whichdiffer in their tissue
distribution and affinity for glucose. There is increasing evidence that some forms ofdiabetes may be
related to reduced expression andactivity of these carrier proteins (p. 573).
Pathogenesis of Type I Diabetes.This form of diabetes results from a severe, absolute lack of insulin
caused by a reduction in the beta-cell mass.Type I diabetes (IDDM) usually develops in childhood, be-
coming manifest and severe at puberty. Patientsdepend on insulin for survival; hence the term insulin-
dependent diabetes mellitus. Without insulin, theydevelop serious metabolic complications such as acute
ketoacidosis and coma.
Three interlocking mechanisms are responsible forthe islet cell destruction: genetic susceptibility, autoim-
munity, and an environmental insult.A postulated sequence of events involving these three mechanisms is
shown in Figure 17-1. It is thought thatgenetic susceptibility linked to specific alleles of the class II
major histocompatibility complex predisposes certainpersons to the development ofautoimmunity against
beta cells of the islets. The autoimmune reaction eitherdevelops spontaneously or, more likely, is triggered
by an environmental agent (e.g., a virus or chemical) thatcauses an initial mild injury to the beta cells.
The immune reaction directed against the altered beta cellsthen causes further beta-cell injury, and
eventually, when most of the cells are destroyed, overt diabetes mellitus appears (Fig. 17-2). With this
overview we can discuss each of the pathogenetic influences separately.
METABOLIC DERANGEMENTS. Insulin is a major ana-
bolic hormone in the body and therefore derangement
of insulin function affects not only glucose metabolism
but also fat and protein metabolism. Indeed, all path-
ways of intermediary metabolism are disrupted to a
lesser or greater degree in patients with diabetes mel-
litus.
The most profound deficiency of insulin and there-
fore the most severe metabolic derangements are usu-
ally encountered in type I diabetes. The utilization of
glucose in muscle and adipose tissue is sharply dimin-
ished or abolished. Concurrently there is stimulation of
glycogenolysis, which is normally inhibited by insulin
and favored by glucagon. Fasting blood glucose may
reach levels many times greater than normal, and
when the level of circulating glucose exceeds the renal
threshold, glycosuria ensues. The excessive glycosuria
induces an osmotic diuresis and thus polyuria, causing
a profound loss of water and electrolytes (Na, K, Mg,
P; Fig. 17-4). This obligatory water loss combined
with the hyperosmolarity resulting from the increased
levels of glucose in the blood tends to deplete intracel-
lular water, as, for example, in the osmoreceptors of
the thirst centers of the brain. In this manner, intense
thirst (polydipsia) appears. Through poorly defined
pathways, increased appetite (polyphagia) develops,
thus completing the classic triad of diabetic findings—
polyuria, polydipsia, and polyphagia. With a deficiency
of insulin, the scales swing from insulin-promoted
anabolism to catabolism of proteins and fats. Proteoly-
sis follows, and the glucogenic amino acids are re-
moved by the liver and used as building blocks in
gluconeogenesis, worsening the deranged carbohydrate
metabolism.
Two important acute metabolic complications of
diabetes mellitus follow, diabetic ketoacidosis and non-
ketotic hyperosmolar coma.

Diabetic ketoacidosis occurs almost exclusively in


type I diabetes and is the result of severe insulin deficiency coupled with absolute or relative
increases of
glucagon (see Fig. 17-4). The insulin deficiency causes
excessive breakdown of adipose stores, resulting in
increased levels of free fatty acids. Oxidation of such
free fatty acids within the liver through acetyl CoA
produces ketone bodies. Glucagon is the hormone that
accelerates such fatty acid oxidation. The rate at which
ketone bodies are formed may exceed the rate at which
acetoacetic acid and b-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.
In type II diabetes, polyuria, polydipsia, and poly-
phagia may accompany the fasting hyperglycemia, but
ketoacidosis is rare. Adults, particularly elderly diabet-
ics, develop nonketotic hyperosmolar coma, a syn-
drome engendered by the severe dehydration resulting
from sustained hyperglycemic diuresis, which is cou-
pled with the inability of these patients to drink water.
The absence of ketoacidosis and its symptoms (nausea,
vomiting, respiratory difficulties) delays the seeking of
medical attention in these patients until severe dehy-
dration and coma occur.
MORPHOLOGY. At death a diabetic may have many
morphologic changes suggestive of the diagnosis and
a few virtually diagnostic findings, or there may be no
lesions that might not also be found in age-matched
nondiabetics. This variability is poorly understood, but
three factors are probably significant: (1) the duration of
the disease, (2) the adquacy of metabolic control, and
(3) genetic factors. The duration of diabetes stronglyuences the development of anatomic changes. Gen-
erally, regardless of the type of diabetes, with disease
of 10 to 15 years' duration patients develop dermal,
renal, and retinal microangiopathy, as well as athero-
sclerosis more severe than that found in age-matched
controls. Those with poor control of hyperglycemia are
at greater risk, for reasons already discussed. Genes
other than those responsible for the diabetic state also
condition the likelihood of complications. The occurrence
of both diabetic nephropathy and retinopathy seems to
be related to the genetic background, because some
persons seem to be protected despite the long duration
of their disease.
Basement Membrane Thickening (BMT) and Microan-
giopathy. Thickening of basement membrane is charac-
teristic of diabetes mellitus. When it affects capillaries it
is referred to as microangiopathy. This microvascular
alteration is most evident in the capillaries of the skin,
skeletal muscle, retina, renal glomeruli, and renal me-
dulla. However, BMT is also seen in such nonvascular
structures as renal tubules, Bowman's capsule, periph-
eral nerves, placenta, and possibly other sites. The
normal basal lamina consists of a relatively uniform layer
of extracellular material separating parenchymal or en-
dothelial cells from the surrounding connective tissue
stroma. In diabetes this single layer is widened and
sometimes replaced by concentric layers of hyaline ma-
terial composed predominantly of type IV collagen. It
should be noted that despite the increase in the thick-
ness of basement membranes, diabetic capillaries are
more leaky than normal to plasma proteins. This
change may be responsible for the glomerular lesions,
and possibly neuropathy. It should be noted that indis-
tinguishable microangiopathy can be found in aged non-
diabetic patients, but rarely to the extent seen in pa-
tients with long-standing diabetes.
Pancreas. Changes in the pancreas are inconstant and
only rarely of diagnostic value. Distinctive changes are
more commonly associated with type I diabetes than
with type II diabetes. Indeed, the pancreas may appear
virtually normal in persons with type II diabetes unless
precise quantitation of the islet cell mass is attempted.
One or more of the following changes may be present:
(1) Reduction in the size and number of islets is seen
most commonly in type I diabetes, particularly with
rapidly progressive disease. Most of the islets are so
small as to escape detection in routinely stained sec-
tions. Subtle reduction in the islet cell mass can be
demonstrated in type II disease as well, but doing so
requires special morphometric studies. (2) Increase in
the number and size of islets is especially characteris-
tic of nondiabetic newborns of diabetic mothers. Pre-
sumably, fetal islets undergo hyperplasia in response to
the maternal hyperglycemia. (3) Beta-cell degranulation
implies depletion of stored insulin and is most commonly
seen in type I disease. (4) Amyloid replacement of islets appears as deposits of pink, amorphous material
beginning in and around capillaries and between cells. At
advanced stages the islets may be virtually obliterated(Fig. 17-5). 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 nondiabetics. (5) Two types of leukocytic
infiltration are found in the islets, principally in type I
diabetes. The most common pattern is a heavy T-lym-
phocyte infiltration within and about the islets (insulitis).
This is seen early in the course of the disease and
results from an immune reaction. Eosinophilic infiltrates
may also be found, particularly in diabetic infants who
fail to survive the immediate postnatal period.
Vascular System. Diabetes exacts a heavy toll on the
vascular system. Whatever the age at onset, in the
course of 10 to 15 years of the disease most diabet-
ics develop significant vascular abnormalities. Ves-
sels 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, atheroscle-
rosis in diabetics is indistinguishable from that in
nondiabetics (p. 279).

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 fe-
males of reproductive age (p. 308). 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 the subject of a later discussion.
The bases of accelerated atherosclerosis are not well
understood, and in all likelihood multiple factors are
involved. About a third to a half of the patients have
elevated blood lipid levels, known to predispose to
atherosclerosis, but the remainder also have an in-
creased 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 lipo-
proteins (HDL) have been demonstrated in type II dia-
betes. Since HDL is a "protective molecule" against
atherosclerosis (p. 279), this could contribute to in-
creased susceptibility to atherosclerosis. Diabetics have
increased platelet adhesiveness to the vessel wall, pos-
sibly owing to increased thromboxane A2 synthesis and
reduced prostacyclin. In addition to all these factors,
diabetics tend to have an increased incidence of hyper-
tension, which is a well-known risk factor for atheroscle-
rosis (p. 280).
Hyaline arteriolosclerosis, the vascular lesion asso-
ciated with hypertension (p. 462), 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.
17-6). Not surprisingly, in the diabetic it is related not
only to the duration of the disease but also to the level
of the 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. It is
presumed that the plasma proteins penetrate into the
abnormally permeable walls of the arterioles.
Kidneys. The kidneys are prime targets of diabetes. In
fact, renal failure is second only to myocardial infarction
as a cause of death from this disease. Four types of
lesions, collectively termed "diabetic nephropathy,"
are encountered: (1) glomerular lesions; (2) renal vas-
cular lesions, principally arteriolosclerosis; (3)pyelo-
nephritis, including necrotizing papillitis; and (4) gly-
cogen and fatty changes in the tubular epithelium.

A variety of forms of glomerular involvement may


be present: capillary basement membrane thickening,
diffuse glomerulosclerosis, nodular glomerulosclerosis
(Kimmelstiel-Wilson lesion), "fibrin caps," and "capsular
drops." The last two are sometimes called exudative
lesions. The sclerotic lesions of the glomeruli destroy
renal function and constitute potentially fatal forms of
diabetic nephropathy, but the exudative lesions are
largely of diagnostic interest. Changes in the capillary basement membrane take
the form of thickening of the basement membranes of
the glomerular capillaries throughout their entire length
and are part and parcel of diabetic microangiopathy.
Under the electron microscope, thickening of the glo-
merular basement membrane can be detected within a
few years of the onset of diabetes, sometimes without
any associated change in renal function.
Diffuse glomerulosclerosis is found in most patients
with disease of more than 10 years' duration. It consists
of a diffuse increase in mesangial matrix along with
mesangial cell proliferation and is always associated
with basement membrane thickening. These lesions al-
most always begin in the vascular stalk and sometimes
appear to be continuous with the hyaline arteriolosclero-
sis in the afferent and efferent arterioles (Fig. 17-7).
When the diffuse glomerulosclerosis becomes
marked, these patients manifest the nephrotic syn-
drome (p. 444), characterized by proteinuria, hypoal-
buminemia, and edema.

Nodular glomerulosclerosis describes a glomerular


lesion made distinctive by ball-like deposits of a
laminated matrix within the mesangial core of the
lobule (Fig. 17-8). These nodules tend to develop in
the periphery of the glomerulus, and since they arise
within the mesangium they push the peripheral capillary
loops ahead of them. Often these patent loops create
haios about the nodule. This lesion has also been called
intercapillary glomerulosclerosis and Kimmelstiel-Wilson
lesion, after the pioneers who described it. Nodularglomerulosclerosis occurs irregularly throughout the kid-
ney 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. Uninvolved glomeruli
and lobules all show striking diffuse glomerulosclerosis.
The deposits are PAS-positive and contain mucopoly-
saccharides, lipids, and fibrils, as well as collagen fibers,
as do the matrix deposits of diffuse glomerulosclerosis.
Often they contain trapped mesangial cells.
Nodular glomerulosclerosis is encountered in perhaps
10 to 35% of diabetics and is a major cause of morbid-
ity and mortality. Like diffuse glomerulosclerosis, the
appearance is related to the duration of the disease but
conditioned by the genetic background. Unlike the dif-
fuse form, which may also be seen in association with
old age and hypertension, the nodular form of glomer-
ulosclerosis is, for all practical purposes, highly sug-
gestive of diabetes.

Progression of diabetic glomerulosclerosis and its


constant companion, advanced arteriolosclerosis,
usually leads to obliteration of the vascular channels
in the glomerulus and to serious, sometimes fatal,
impairment of renal function. As a consequence of
glomerular sclerosis, the tubules suffer ischemia and are
replaced by interstitial fibrous tissue. 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.
Exudative lesions take two forms. Glassy, homoge-
neous, strongly eosinophilic deposits in the parietal layer
of Bowman's capsule, called capsular drops, may hang
into the uriniferous space. Similar-looking deposits, fibrin
caps, may develop over the outer surface of glomerular
capillary loops. Both the capsular drop and the fibrin cap
are attributed to excessive leakage of plasma proteins
from glomeruli that were severely injured by either dif-
fuse or nodular glomerulosclerosis. Neither of these two
lesions causes any impairment in renal function.
Renal atherosclerosis and arteriolosclerosis consti-
tute on/y one part of the systematic involvement of
vessels in diabetics. 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. Hyaline arterioloscle-
rosis 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, possibly,
ultimately the glomeruli. Both the acute and chronicforms of this disease occur in nondiabetics as well as in
diabetics; they are described more fully on page 453.
These inflammatory disorders are more common in dia-
betics than in the general population, and once affected,
diabetics tend to have more severe involvement.
One special pattern of acute pyelonephritis, necrotiz-
ing papillitis, is much more prevalent in diabetics than
in nondiabetics. It is however, not limited to diabetics
but is also seen with obstructions of the urinary tract as
well as with analgestic abuse. As the term implies,
necrotizing papillitis is an acute necrosis of the renal
papillae (Fig. 17-9). Diabetics are particularly prone to
develop this lesion, owing to the combination of ische-
mia resulting from microangiopathy and increased sus-
ceptibility to bacterial infection. One or more papillae
may be involved, bilaterally or unilaterally. The infarcted
papilla may slough off and be excreted in the urine,
permitting a clinical diagnosis by examination of the
urinary sediment. In diabetics, bilateral necrosis of all
papillae is not uncommon. When many papillae are
involved, papillary necrosis causes acute irreversible
renal failure. This lesion is described more fully on page
454.
Tubular lesions are also encountered in diabetes
mellitus. Perhaps the most striking is the deposition of
glycogen within the epithelial cells of the distal portions
of the proximal convoluted tubules (and sometimes in
the descending loop of Henle). This lesion is variously
termed glycogen infiltration, glycogen nephrosis, or Ar-
manni-Ebstein cells. The glycogen creates clearing of
the cytoplasm of the affected cells. This condition is
believed to be a reflection of severe hyperglycemia and
glycosuria for a period of days of weeks prior to death.
No tubular malfunction has been connected with this
tubular change.
Eyes. Visual impairment, sometimes even total blind-
ness, is one of the more feared consequences of long-
standing diabetes. This disease is presently the fourthleading cause of acquired blindness in the United
States. The ocular involvement may take the form of
retinopathy, cataract formation, or glaucoma. Retinop-
athy, the most common pattern, consists of a constella-
tion of changes that together are considered by many
ophthalmologists to the virtually diagnostic of the dis-
ease. The lesion in the retina takes two forms—
nonproliferative or background retinopathy and prolif-
erative retinopathy. The former includes intraretinal or
preretinal hemorrhages, retinal exudates, edema, venous
dilatations, and, most important, thickening of the retinal
capillaries (microangiopathy) and the development of
microaneurysms. The retinal exudates can be either
"soft" (microinfarcts) or "hard" (deposits of plasma
proteins and lipids). The microaneurysms are discrete
saccular dilatations of retinal choroidal capillaries that
appear through the ophthalmoscope as small red dots.
The pathogenesis of retinal microaneurysms is multifac-
torial. Selective loss of retinal capillary pericytes occurs
early and is believed to be a consequence of changes in
the basement membrane. Dilatations tend to occur at
focal points of weakening, resulting from loss of peri-
cytes. In addition, retinal edema resulting from excessive
capillary permeability might cause focal collapse, making
the vessels vulnerable to aneurysmal dilatation.
The so-called proliferative retinopathy is associated
with neovascularization and fibrosis. This lesion can lead
to serious consequences, including blindness, especially
when it involves the macula. Vitreous hemorrhages can
result from rupture of the newly formed capillaries. It is
of interest that about half the patients with retinal mi-
croaneurysms also have nodular glomerulosclerosis.
Conversely, patients who have nodular glomerulo-
sclerosis are almost certain to have retinal micro-
aneurysms.

Nervous System. The central and peripheral nervous


systems are not spared by diabetes. The most frequent
pattern of involvement is a peripheral, symmetric neu ropathy of the lower extremities that affects both motor
and sensory function but particularly the latter. Other
forms include: (i) autonomic neuropathy, producing dis-
turbances in bowel and bladder function, and sometimes
sexual impotence, and (ii) diabetic mononeuropathy that
may manifest as sudden foot drop, wrist drop, or iso-
lated cranial nerve palsies. The neurologic changes may
be due to microangiopathy and increased permeability of
the capillaries that supply the nerves as well as direct
axonal damage caused by alterations in metabolism
discussed earlier.
The brain, along with the rest of the body, develops
widespread microangiopathy. Such microcirculatory le-
sions may lead to generalized neuronal degeneration.
There is in addition some predisposition to cerebral
vascular infarcts and brain hemorrhages, perhaps re-
lated to the hypertension and atherosclerosis often seen
in diabetics. Degenerative changes have also been ob-
served in the spinal cord. None of the neurologic disor-
ders, including the peripheral neuropathy, is specific
for this disease.
Figure 24-31 Stages in the development of type 1 diabetes mellitus. The stages are listed from left to right, and
hypothetical β -cell mass is plotted against age. (From Eisenbarth GE:
Type 1 diabetes: a chronic autoimmune disease. N Engl J Med 314:1360, 1986. Copyright © 1986,
Massachusetts Medical Society. All rights reserved.)

Figure 24-33 Obesity and insulin resistance: the missing links? Adipocytes release a variety of factors (free
fatty acids and adipokines) that may play a role in modulating insulin resistance in peripheral tissues
(illustrated here is striated muscle). Excess free fatty acids (FFAs) and resistin are associated with insulin
resistance; in contrast, adiponectin, whose levels are decreased in obesity, is an insulin-sensitizing adipokine.
Leptin is also an insulin-sensitizing agent, but it acts via central receptors (in the hypothalamus). The
peroxisome proliferator-activated receptor gamma (PPARγ ) is an 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 adipokine and FFA levels that favor a state of insulin
sensitivity.

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 might be delayed. In most patients, however,
morphologic changes are likely to be found in arteries (macrovascular disease), basement membranes of small
vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), nerves (neuropathy), and
other tissues. These pertinent clinical, genetic, and histopathologic features that distinguish type 1 and type 2
diabetes.
In both forms, 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. In most instances, these
complications appear approximately 15 to 20 years after the onset of hyperglycemia. Cardiovascular events
such as myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents are the most
common causes of mortality in long-standing diabetics. The impact of cardiovascular disease can be gauged
from the fact that it accounts for up to 80% of deaths in type 2 diabetes; in fact, diabetics have a 3 to 7.5 times
greater incidence of death from cardiovascular causes compared to the nondiabetic population[100] ( Fig. 24-
41 ). The hallmark of cardiovascular disease is accelerated atherosclerosis of the large and medium-sized
arteries (i.e., macrovascular disease). The pathogenesis of accelerated atherosclerosis involves multiple
factors.
Figure 24-34 Long-term complications of diabetes.

Figure 24-35 A, Insulitis, shown here from a rat (BB) model of autoimmune diabetes, also seen in type 1
human diabetes. (Courtesy of Dr. Arthur Like, University of Massachusetts,
Worchester, MA.) B, Amyloidosis of a pancreatic islet in type 2 diabetes.
Figure 24-36 Severe renal hyaline arteriolosclerosis. Note a markedly thickened, tortuous afferent arteriole.
The amorphous nature of the thickened vascular wall is evident. (Periodic acid-Schiff [PAS] stain; courtesy of
M.A. Venkatachalam, MD, Department of Pathology, University of Texas Health Science Center at San
Antonio, TX.)

Figure 24-37 Renal cortex showing thickening of tubular basement membranes in a diabetic patient (PAS
stain).

Figure 24-38 Electron micrograph of a 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, CT.)
Figure 24-39 Nephrosclerosis in a patient 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 24-40 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 cause sufficient central nervous system compromise to lead to coma and eventual death if left untreated.
TABLE Type 1 Versus Type 2 Diabetes Mellitus (DM)
Type 1 DM Type 2 DM
Clinical Onset: <20 years Onset: >30 years
Normal weight Obese
Markedly decreased blood insulin Increased blood insulin (early);normal to
moderate decreased insulin (late)
Anti-islet cell antibodies No anti-islet cell antibodies
Ketoacidosis common Ketoacidosis rare; nonketotic hyperosmolar
coma
Genetics 30–70% concordance in twins 50–90% concordance in twins
Linkage to MHC Class II HLA genes No HLA linkage
Linkage to candidate diabetogenic genes
(PPARγ , calpain 10)
Pathogenesi Autoimmune destruction of β -cells mediated Insulin resistance in skeletal muscle, adipose
s by T cells and humoral mediators (TNF, IL-1, tissue and liver
NO)
β -cell dysfunction and relative insulin
deficiency
Absolute insulin deficiency
Islet cells Insulitis early No insulitis
Marked atrophy and fibrosis Focal atrophy and amyloid deposition
β -cell depletion Mild β -cell depletion

CLASSIFYING DIABETES MELLITUS AND RELATED CONDITIONS

"Diabetes" literally means "siphon", because of the osmotic diuresis


produced by the glycosuria. This was known all-too-well to Hippocrates, who
may have named it.

Diabetes mellitus (MELL-uh-tuss, please) is "a chronic disorder of carbohydrate,


fat, and protein metabolism characterized in its fully expressed clinical form by an
absolute or relative insulin deficiency, fasting hyperglycemia, glycosuria, and a
striking tendency toward the development of atherosclerosis, microangiopathy,
nephropathy, and neuropathy" (old Big Robbins).
Diabetes is our commonest serious metabolic disease, affecting maybe 5% of
the population. On the average, it takes 15 years off the patient's life (JAMA 285:
628, 2001) and accounts for a tremendous amount health care expenses.

You will need to know the terminology (which is often not used correctly):

Diabetes mellitus ("overt diabetes", "manifest diabetes", etc.): the patient


has...

 signs and/or symptoms of diabetes plus any serum glucose of 200


mg/dL of more, or...
 a serum glucose of 200 mg/dL or more at the 2-hour point of a
glucose tolerance test, or...
 elevated fasting blood sugar over 126 mg/dL on two occasions with
the patient in his or her usual state of health.

The fasting criteria are down from 140 mg/dL (Am. Fam. Phys. 58:
1355, 1998). It identifies people at risk for health problems from
hyperglycemia.

There's talk today about distinguishing "impaired fasting glucose"


(IFG, i.e., 110-125 mg/dL) and "impaired glucose tolerance" (IGT,
i.e., 121-179 mg/dL at the two-hour mark). See Arch. Int. Med. 161:
397, 2001.

Type I diabetes and Type II diabetes (below) are sometimes called


"primary diabetes", since they seem to be genetic diseases in their own
right.

Secondary diabetes is said to exist when the metabolic disturbances are


the result of some other identifiable illness, injury, molecular abnormality,
etc., etc.

Impaired glucose tolerance ("glucose intolerance", "subclinical diabetes",


"asymptomatic diabetes", "chemical diabetes", "latent diabetes"): fasting
blood sugar is normal, but a glucose tolerance test is abnormal. Current
recommendations are NOT go looking for this: Am. J. Med. 105(1A): 15S,
1998.

Gestational diabetes mellitus: diabetes mellitus first appearing during


pregnancy, and perhaps disappearing when the pregnancy ends.

"Previous Abnormality of Glucose Tolerance" ("prediabetes", "latent


diabetes"): the patient once had measurable glucose intolerance (as,
when she was pregnant), but is chemically normal now (but may be at risk
for future diabetes mellitus, depending on the circumstances).

"Potential Abnormality of Glucose Tolerance" ("prediabetes"): the


monozygotic twin of a type II diabetic, or (less justifiably) someone else
with a strong family history.
Not diabetes: Glucose intolerance only under some obvious physiologic
stress (myocardial infarction, pneumonia, severe burns, terror of
venipuncture, etc.) Mostly an epinephrine effect; probably cortisol
contributes as well.

The new system recommended by the WHO and the American Diabetes
Association (Br. Med. J. 317: 359, 1998):
Type I: autoimmune and idiopathic situations in which beta cell function is
extreme, and there is an absolute insulin lack;

Type II: defects in insulin secretion, and/or a relative lack of insulin, and/or
insulin resistance;

Type III: damage to the whole pancreas (old pancreatitis, cystic fibrosis --
diabetes from CF is uncommon but happens J. Ped. 142: 97, 2003) and
autosomal dominant genetic syndrome (I'm clueless as to why these are
lumped together);

Type IV: Gestational diabetes

Insulitis
Type I diabetes
WebPath photo

PRIMARY DIABETES TYPE I ("juvenile onset", "labile", "ketoacidosis-prone", "insulin-


dependent"): 10% of diabetics.

One person in 300 in the U.S. gets this kind of diabetes (rates vary considerably
from nation to nation; * rates are higher at higher latitudes).

Typical case: A child (average age twelve years, but we now know you
can get the disease at any age) presents with polyuria, polydipsia, and
polyphagia of relatively sudden onset. The child is found to have very high
blood glucose levels causing osmotic diuresis.

Before the era of injectable insulin, diabetic ketoacidosis (DKA) and death
followed in short order.

You remember the pathophysiology of ketoacidosis from your


physiology course. Future clinicians: Ketoacids impart the familiar
"rotten apples" sweetness to these patients' breath.

Today, the child looks forward to a period of fairly good health while taking
injectable insulin, checking blood glucose several times a day with
chemical strips and a reflectance meter.

After 10-15 years, unless control is good, the diabetic starts to suffer with
infections, eye problems, peripheral neuropathy, gangrene of the lower
extremities, kidney disease, stroke, and coronary atherosclerosis.

Historically, death usually came about forty years after onset as the result
of a myocardial infarction. By this time, 50% of patients had lost their
kidneys, and nearly as many were blind, stroked out, legless, and/or in
chronic pain from neuropathy. A well-treated, compliant diabetic typically
does better today.

The essential lesion in type I diabetes is a severe absolute lack of insulin.

* Only half of patients have any evidence of insulin production (measure


C-peptide in serum).

Insulin deficiency and hyperglycemia explain the presentation but do not


explain the later complications of the disease.

"Type I diabetes is a genetically programmed, chronic autoimmune disease"


(NEJM 314: 1360, 1986, an early review; update Nature 351: 519, 1991), with
the acute-symptomatic phase sometimes triggered by an acute viral illness.

In other words, the etiology is kind-of-complex.

Genetic factors:

Siblings of those with Type I diabetes are at increased risk (25x).

Identical twins of those with Type I diabetes have a 50% chance of


eventually getting it also.

Type I diabetes is strongly associated with HLA-related antigens


DR3 and DR4. (* If one has the misfortune to have both, it's even
worse.... The former association with some HLA-B antigens was
due to their linkage to DR3 and DR4; and currently, it appears that
the also-linked DQ is the closest important site.)

* As is so common when the immune system attacks gland


parenchyma, the beta cells of these patients express HLA
class II histocompatibility antigens. No one knows whether
this is cause or effect.

* The molecular defect that permits type I diabetes to occur


seems to be homozygous absence of aspartic acid in
position 57 of the HLA class II DQ chain (Nature 329: 599,
1987; Nature 333: 710, 1988), at least in the U.S. Update on
HLA links: J. Clin. Endo. Metab. 89: 4037, 2004. The famous
locus IDDM1, where certain polymorphisms give a risk for
type I diabetes, is a component of the HLA system (Diabetes
50: 1200, 2001).

The gene IDDM2 ("implicated in diabetes melitus") is a


complicated, highly variable tandem repeat adjacent to the
real insulin gene. Two variants are strongly linked to type I
diabetes (update Diabetes 53: 1884, 2004).

The animal model of autoimmune diabetes is the non-obese


diabetic mouse, which gets that way because of genes at
three (or more) loci (Nature 353: 260, 1991; J. Imm. 152:
204, 1994). Update J. Immuno. 169: 6617, 2002; to date; the
exact reasons for the famous mouse's diabetes remain
elusive.

* The BB (formerly BB/W) rat is a strain discovered in 1977.


These rats have autoimmune insulitis, and the majority
develop acute-onset type I diabetes. They helped us find the
IDDM1 and IDDM2 loci (Acta. Diabet. 35: 109, 1998).

Autoimmune factors:

Several types of IgG anti-beta-cell antibodies occur. One or more is


present in the vast majority of type I diabetics the acute phase
(contrast 0.5% in healthy people). It is now quite clear that they are
etiologic, and that they are usually present before age 2 in children
destined to get type I diabetes (Ann. Int. Med. 140: 882, 2004).

Their specificities include anti- glutamic acid decarboxylase (Nature


347: 151, 1990; NEJM 322: 1555, 1990; Lancet 341: 1378 & 1383,
1993; diabetogenic epitope Lancet 343: 1607, 1994; true both of
NOD mice and people: Nature 366: 69 & 72, 1993).

There is also cell-mediated immunity directed against beta cells in


most patients who have been studied. Again, the autoantigen is
glutamic acid decarboxylase. Update Nature 391: 177, 1998.

There was generally a dense lymphocytic infiltrate in the islets of


patients dying in the acute phase (rare nowadays).

* Maybe 1 in 5 of these people ends up with another autoimmune


glandular disease (autoimmune Addison's disease, Hasmimoto's
autoimmune thyroiditis, Grave's disease of the thyroid). Likewise,
plenty of people, with or without other autoantibodies, have anti-
islet cell antibodies but never go on to develop autoimmune
diabetes.

The claim from the early 1990's that cow's milk is the trigger for
autoimmune diabetes flopped (JAMA 276: 609 & 647, 1996, NEJM
329: 1853, 1993, and J. Clin. Endo. 87: 3192, 2002).

* All the recent stuff is from obvious "independent thinkers"


(ignoring what we know of immunology: Food & Chem. Tox.
42: 707, 2004) and studies that invited recall bias (Ann. Nutr.
Metab. 47: 267, 2003).

* The non-obese diabetic mouse does get some protection


from drinking mother's milk instead of cow's milk. The
experimentalists speculat at length about how perhaps this is
because mother's milk contains insulin and/or other peptides
to which the gut lymphocytes need to become tolerant
(Diabetes 48: 1501, 1999). But think -- the experiment
requires taking the experimental mice away from their
mothers. This must have many far-reaching effects beyond
just the exposure to cow's milk.

A few groups are "curing" mice of type I diabetes using immune


manipulation (Freund's adjuvants, etc., etc.) Update J. Clin. Inv.
108: 63, 2001.

Viral factors: Clinically, Type I diabetes often follows a viral illness.

Worth knowing: Kilham rat parvovirus infection produces type I


autoimmune diabetes in diabetes-resistant rats (Diabetes 45: 557,
1996; J. Immuno. 165: 2866, 2000). This is now a robust finding (J.
Imm. 173: 137, 2004).

* Retrovirus IDDMK(1,2)22 remains controversial as a cause of


type I diabetes. Some folks don't find it at all (Diabetes 48: 209 &
219, 1999); others find soft data suggesting a link (J. Hum. Genet.
46: 712, 2001).

* A Coxsackie B4 virus from the pancreas of a patient dying shortly


after the onset of the illness destroys the beta cells of NOD (non-
obese diabetic) mice; it's now clear that the virus causes a chronic
infection of these islands (J. Inf. Dis. 171: 1131, 1995). Since this
article, Coxsackie CB4 has been found commonly as a recent
infection in kids coming down with diabetes.

In the non-obese diabetic (NOD) mouse, there is a specific


defect in a group of T-suppressor cells. * A possible ligand to
enhance these cells in mice and humans: Nat. Med. 7: 1052,
2001.

The mechanism of Coxsackie B4 induction of diabetes now


seems clear -- the NOD mouse has lots of autoreactive-but-
unactivated T-cells, Coxsackie B4 produces a mild infection
of the beta cells, and bystander T-cells are activated
("bystander activation"). Happens in mice and maybe in kids.

Overwhelming infections with mumps or cytomegalovirus also have


been implicated in rare cases of "type I diabetes". The pancreas
can be destroyed by congenital rubella.

* A huge search for the "insulitis virus" in humans using molecular probes
found nothing: JAMA 257: 1145, 1987.

What does all this mean? In most cases of type I diabetes, it is hypothesized that
a viral infection triggers autoimmune destruction of the beta cells in genetically-
predisposed individuals.

However, in most of these children, there have been progressive


abnormalities of glucose metabolism in these patients long before the
onset of illness (Br. Med. J. 294: 5, 1987).
Some stress ("maybe the virus") apparently causes decompensation at
the "time of onset". Following recovery from the first episode of
ketoacidosis, the "honeymoon period" begins, when control is easy for
several years. (* Patients continue to produce some of their own insulin --
i.e., there is C-peptide in their blood -- during the "honeymoon".)

PRIMARY DIABETES TYPE II ("adult onset", "stable", "ketosis-resistant", "non-insulin-


dependent"): 90% of diabetics.

Typical case:

An overweight adult (most over age forty) is discovered on routine


screening to have elevated fasting glucose or glycosuria.

In other cases, the diabetes is discovered during evaluation of impotence,


pain, eye trouble, stroke, foot trouble, bad infection, or coronary disease.

Some patients have their diabetic predisposition unmasked by pregnancy.


Such women get better after the pregnancy, but are at greater risk for
eventually developing type II diabetes.

Before the era of injectable insulin, nothing much was done for type II
diabetics, even if the disease was detected. The patients got
complications and had shorter life spans.

Today, the adult looks forward to dieting, doing aerobic exercise, and
possibly getting treated with insulin or "diabetes pills", probably getting an
ACE inhibitor, and maybe a statin for lipid control. Complications will occur
as in Type I diabetes, depending on how well the patient is able to
manage the hyperglycemia. Death will probably be due to a myocardial
infarct.

Type II diabetes is a polygenic disorder, with its expression modified by a


person's exercise habits and amount of bodyfat.

Identical twins have nearly 100% concordance for Type II diabetes.

There are no good HLA associations or phenomena pointing to


autoimmunity.

A subtype of Type II diabetes which can present in young people


("maturity-onset diabetes of the young," MODY) is an autosomal dominant
with 90% penetrance, and several loci. See below.

MODY accounts for about 10% of diabetics in some communities,


and less-severe alleles of the genes are of course implicated in
common type II diabetes.

The defect is usually in the glucokinase gene (Nature 356: 721,


1992; mechanisms Lancet 340: 444, 1990; diagnosis Lancet 345:
1313, 1995; pathophysiology Diabetes 46: 204, 1997; this enzyme,
as you remember, is the key link in the signalling system by which
beta cells monitor blood glucose).

There are a few other MODY genes too, all in the insulin-release
system (Proc. Nat. Acad. Sci. 94: 13209, 1997; Diabetes 47: 1459,
1998; Diabete 52: 872, 2003). Update on genes Diabetes 53: 1894,
2004.

A single major genetic defect at a type II diabetes locus, and/or several


minor defects at several of the loci, seems to be the underlying cause of
type II diabetes.

Why these usually do not declare themselves at birth remains a


mystery. Perhaps all that would do so have been strongly selected-
against.

The insulin resistance genes to date, and the percentage of type II


diabetics with each (Nature 373: 384, 1995, also Am. J. Clin. Path. 105:
149, 1996):

1%... mitochondrial DNA syndromes (often goes with deafness;


Ann. Int. Med. 134: 721, 2001; many others)

?%... the mitochondrial uncoupling proteins (Diabetes 47: 1528,


1998; Diabetes 53: 1905, 2004).

1%... glucokinase

1%... insulin itself

1%... insulin receptor (* the severe form is "leprechaunism", a


progeria: Biochim. Biophys. Acta.1402: 86, 1998)

15%... insulin receptor substrate (it's very complicated: Diabetes


52: 1544, 2003)

1%... GLUT4, the glucose-through-the-membrane transporter

?%... adiponectin, released from adipocytes, causes liver and


muscle to burn triglyceride and be more insulin-sensitive (Nat. Med.
7 887, 2001; Nat. Med. 10: 452 & 524, 2004).

?%... hepatocyte nuclear factor alpha (causes MODY3; risk for


classic type II; Diabetes 53: 2122, 2004)

?%... ICAM-1 (Lancet 362: 1723, 2003)

?%... calpain 10 (J. Clin. Endo. Metab. 87: 2606, 2002)

?%... beta adrenergic receptors (gives the munchies / obesity and


diabetes: NEJM 333: 382, 1995; Clin. Endo. 59: 476, 2003).
?%... leptin (must be rare in humans, though of course in mice it's
famous)

?%... phosphoenolpyruvate carboxykinase (J. Clin. Endo. Metab.


89: 898, 2004.

?%... Sulfonylurea receptor (Lancet 361: 22, 2003).

?%... mitochondrial fat-burning systems (no gene yet; NEJM 350:


664, 2004);

Expect LOTS more to be discovered.

* The lipoatrophic diabetic mouse has zero bodyfat and extreme insulin
resistance with diabetes. A gene product awaits discovery and
characterization (Diabetes 51: 2113, 2002). This is supposed to be a
model for both a few human genetic syndromes and the lipoatrophy of HIV
patients on protease inhibitors (Ann. Int. Med. 133: 304, 2000).

Type II diabetes is now rampant in the third world and many of our own
First American peoples.

There is probably even more type II diabetes in the poor nations


today than in the U.S.

Until recently, the tendency was to blame the western diet ("the
poor nations have been coca-colonized": (Nature 357: 362, 1992). I
have always taught that the real reason is that the world's poor are
much better-fed than in the past, and most no longer lead lives of
constant hard physical labor. Stay tuned.

Of course, there has been stronger natural selection against


diabetes in countries like the U.S. and Western Europe that have
been well-fed for centuries. And in societies with episodes of
famine, there is a strong selection bias for type II diabetic body
chemistry (i.e., a tendency to hang onto carbohydrate calories), and
little chance to express the phenotype.

Whether or not it's related, unborn children exposed to famine have


a much stronger tendency to develop type II diabetes when they
grow up: Lancet 351: 173, 1998.

* The Pima Indians present a special problem; their rate of diabetes


is extremely high with a host of different genetic mutations for
insulin resistance (update Diabetes 53: 1181, 2004).

By age 65, the following percentages of U.S. ethnic groups have diabetes:

Hispanics 33%
Blacks 25%
Whites 17%
The pathophysiology of type II diabetes is fairly well understood.

In type II diabetes, basal insulin secretion is generally normal. In response


to glucose administration, insulin secretion may be abnormally low, normal
(rare), abnormally high, or delayed ("too much, too late").

Most Type II diabetics have insulin resistance in both liver and skeletal
muscle, and this appears to be the key lesion. In addition, however, there
is almost always some evidence of beta cell dysfunction.

The liver continues to make and put out glucose (gluconeogenesis)


when blood sugar is high, and fails to take up orally-administered
glucose. The skeletal muscles fail to take up glucose in response to
insulin.

The amount of insulin resistance is modified by obesity and


physical conditioning. There's also the baffling combination of gut
polypeptides, prostaglandins, beta-endorphins, etc., etc....

You already know "the metabolic syndrome / metabolic syndrome


X" (truncal obesity, insulin resistance, dyslipidemia). The cause
remains obscure.

The most recent suspect is resistin, produced (at least in


mice) by adipocytes, and able to render muscle and liver
resistant to the effects of insulin (NEJM 345: 1345, 2001).
It's produced especially well by the abdominal and omental
adipocytes; this may explain the special risk of "central
obesity".

* Liposuction completely fails to alter the metabolic


abnormalities caused by obesity (NEJM 350: 2549, 2004).

Two other players in the complex business of insulin resistance is a


pair of little-known hormones, amylin ("islet-amyloid polypeptide",
"IAPP", pumped out of beta cells along with insulin) and
* calcitonin-gene related polypeptide (CGRP, h-CGRP, from nerve
and gut), both acting on skeletal muscle to increase its resistance
to insulin (PNAS 88: 7713, 1988). * They act on the same receptor,
which is not present in fat or parenchymal cells (Diabetes 40: 395,
1991; Diabetes 40(S1): #267, #255, several others, 1991).

Amylin has been reported to be greatly increased in the


serum of some type II diabetics. Excreted through the
kidneys, it also might account for some of the insulin
resistance in renal failure. See Diabetes Care 39(S1): A111-
A113, 1990.

More recently, many workers have concluded that neither


hormone is present in sufficient quantities to exert an
important physiological effect in asymptomatic or diabetic
humans (Diabetes 40: 305 & 310, 1991). Nevertheless, the
hormones have been conserved over mammalian evolution
for some reason, and assays and preparations are poorly-
standardized (late 1990). Amylin update Lancet 341: 1249,
1993.

Most recently, genetically scrambled mice who overexpress


amylin do get hyperglycemic, with a syndrome much like
human type II diabetes (Proc. Nat. Acad. Sci. 93: 3492,
1996). Definitely stay tuned.

I predict that when the underlying cause of type II diabetes (i.e.,


simultaneous insulin resistance and aberrant insulin production) is
worked out, it will prove to be primarily a mitochondriopathy. Stay
tuned.

The "Somogyi phenomenon" is a rebound hyperglycemia from all the


stress hormones that pour out when the blood glucose drops too low from
too much insulin. If a diabetic is hungry, gaining weight, and feeling
crummy, consider reducing the insulin levels.

The "dawn phenomenon, i.e., hyperglycemia and insulin resistance in the


morning without previous "Somogyi" hypoglycemia, is due to the high
output of hGH during while you're finishing up your sleep in the morning.

* WARNING: Many clinicians use the term "insulin resistance" to refer instead to
hard-to-manage diabetics of any type who require more than 200 units of insulin
daily (a whopping dose). Many of these patients ave antibodies against insulin,
while others have severe type II diabetes or any of several other problems. See
NEJM 315: 212, 1987.

Hyperosmolar nonketotic diabetic coma (HNKK, HONK) is the usual cause of "diabetic
coma" in Type II diabetics (see Arch. Int. Med. 147: 499, 1987), though most of them
never get it.

Classically, some acute stress (often the 'flu) increases the demand on the Type
II diabetic's struggling beta cells, and the supply of insulin is exhausted. Plasma
glucose levels suddenly go extremely high, causing osmotic diuresis, electrolyte
disturbances, and death.

Or the illness may simply cause dehydration, producing a vicious cycle with
insulin resistance, stress hormones, soaring glucose levels, and ongoing
dehydration.

Ketoacidosis is uncommon in type II diabetes, but can occur.

SECONDARY DIABETES has many etiologies

Pancreatic diabetes: destruction of the islets by disease of the exocrine


pancreas.

Causes: pancreatitis, carcinoma, hemochromatosis ("bronze diabetes" --


don't overlook this one!), trauma, surgery, etc. etc.
Endocrine diabetes: glucose intolerance due to other endocrine disturbances

Causes: Cushing's syndrome (from any cause), acromegaly, amylin from


pancreatic cancer, obesity (??), stress, amylin production by cancer of the
pancreas (see above), etc. etc. It would be logical to place pregnancy here
too, though it is officially classed elsewhere.

Some people put the one-gene insulin resistance syndromes here.

Rarely, people make autoantibodies that block insulin receptors (South. Med. J.
92: 717, 1999). Update J. Clin. Endo. Metab. 89: 2222, 2004; contrary to popular
belief, acanthosis nigricans in a young diabetic (while commonly seen) does not
imply antibodies to insulin receptors.

Of course acanthosis nigricans is a darkening and thickening of the


epidermis in the armpits and groin. When not part of a paraneoplastic
syndrome, it is usually a marker for insulin resistance of some cause;
however the underlying basic biology remains elusive.

REMEMBER: Regardless of the cause of the prolonged hyperglycemia, we now


know that the complications in remote organs (arteries, eyes, kidneys, nerves)
will be the same.

ANATOMIC PATHOLOGY OF DIABETES MELLITUS: These are usually the effects,


rather than the causes, of hyperglycemia.

DIABETIC BLOOD VESSEL DISEASE

LARGE VESSEL DISEASE ("macroangiopathy"): accelerated


atherosclerosis

Diabetics have a variety of poorly-understood disturbances of lipid


metabolism. Nonenzymatic glycosylation of lipoproteins seems to
be a problem, LDL's stick best to glycosylated collagen, etc., and
glycation products (when they bind to their special receptors in the
intima) cause the production of fibrous tissue.

The result is the rapid development of severe atherosclerosis, with


strokes, gangrene of the lower extremities, and myocardial infarcts
taking their toll, often early in life. Of course, this is all much worse
if the diabetic also smokes cigarets.

Good glycemic control does help the accelerated


atherosclerosis, confirming the idea that it's due largely to
the accumulation of advanced glycation products which
cause collagen production.

Big news: Administering the soluble form of the glycation


product receptor seems to stop the accelerated
atherosclerosis. Definitely stay tuned. Nature 4: 1025, 1998.
{09378} diabetic gangrene
{48076} diabetic gangrene
{48022} diabetic ulcer
{48023} diabetic ulcer
{48150} diabetic ulcer

Diabetic gangrene
Cornell

SMALL VESSEL DISEASE ("microangiopathy"): hyaline arteriolar


sclerosis

This is a complex problem.

The basement membrane of the capillaries and the arterioles


becomes much thicker ("hyaline arteriolar sclerosis"). Its
expansion eventually compromises the lumen of the vessels.

Not surprisingly, these vessels are relatively inelastic, and


this is an early, important problem: Br. Med. J. 312: 744,
1996.

Even if the lumen is not badly compromised and the wall


isn't excessively stiff, the small vessels of diabetics open and
close chaotically, and proper tissue perfusion cannot be
assured.

Additionally, the pericytes can proliferate (especially in the


glomeruli, where pericytes are called "mesangial cells") or
die off (especially in the retina, where pericytes are called
"mural cells"). This causes trouble at both sites.

* Endothelial cells can also proliferate, narrowing the lumen


further.

* Other factors that are cited are the over-sticky platelets of


diabetics, increased blood viscosity, increased RBC rigidity,
and increased numbers of free radicals.

Microangiopathy augments the ischemia caused by


atherosclerosis, which is why so many diabetics lose legs. It may
account for other problems also.

Yes! Tight diabetic control reduces and even reverses


microangiopathy. See NEJM 309: 1546 & 1551, 1983, and many
others since.

Most diabetics eventually become hypertensive. Nobody knows


why, but inability to handle sodium seems essential: Am. J. Med.
Sci. 307(S1): S-53, 1994.
Many diabetics are greatly troubled by congestive heart failure as the
disease progresses, and perhaps nonenzymatic glycosylation of the heart
muscle proteins itself is part of the problem, since even if you control for
other factors, poor glycemic control correlates strongly with the
development of CHF (Circulation 103 2668, 2001).

DIABETIC KIDNEY DISEASE ("diabetic nephropathy"; Disease-A-Month 44:


214, 1998; NEJM 341: 1127, 1999):

Renal failure causes much disability and death among type I diabetics;
this is now the #1 single cause of end-stage renal disease in the U.S.
Type II diabetics generally die of something else before their kidneys fail.

Renal vascular lesions

Arteriolar sclerosis of both afferent and efferent arterioles at the


glomerular pole is highly characteristic of diabetes. (The other
diseases of renal arterioles, notably common-type high blood
pressure, only cause sclerosis of the afferent arteriole.)

* Atherosclerosis of intrarenal arteries is common in diabetics and


rare in non-diabetics; it is not the major problem.

Glomerular lesions

Always present:

1. Thickening of the glomerular basement membrane


because of increased production of GBM (sometimes called
"diffuse glomerulosclerosis").

2. Increased amounts of mesangial matrix (also sometimes


called "diffuse glomerulosclerosis"). Increased number of
mesangial cells in the early lesion, later decreased as the
entire glomerulus is replaced by matrix ("hyalinization" of the
glomerulus.)

* 3. The GBM, mesangial matrix, and tubular basement


membranes (also thick) are bind albumin and other proteins
non-specifically ("all that sticky sugar....")

* These three features, together, are pathognomonic of


diabetes mellitus (but you probably knew already....) They
occur separately in other diseases.

Often present:

Nodular glomerulosclerosis or (nodular) Kimmelstiel-Wilson


disease. Big balls of GBM-mesangial matrix material in the
glomerular tufts. Highly characteristic of diabetes.
{08892} KW disease; note balls of hyaline, and thick GBM (i.e., you can actually tell
where it is)
{17159} diabetes with hyalinized arteriole
{16789} diabetic glomerulosclerosis, electron micrograph (thick GBM)
{16790} diabetic glomerulosclerosis, electron micrograph (thick GBM)
{16791} diabetic glomerulosclerosis, H&E
{16792} diabetic glomerulosclerosis, PAS; nice capsular drop too
{16793} diabetic glomerulosclerosis, H&E
{08893} Kimmelstiel-Wilson diabetic nodular glomerulosclerosis; H&E
{08895} Kimmelstiel-Wilson diabetic nodular glomerulosclerosis, PAS
{09877} Kimmelstiel-Wilson diabetic nodular glomerulosclerosis
{17158} Kimmelstiel-Wilson diabetic nodular glomerulosclerosis
{17171} end-stage diabetic glomerulosclerosis

Nodular glomerulosclerosis Nodular glomerulosclerosis


PAS stain
KU Collection KU Collection

Sometimes present:

* "Fibrin caps" ("exudative lesion", "hyperfiltration lesion") --


hyaline crescents on a glomerular tuft

* "Capsular drops" -- hyaline material on the inside surface


of Bowman's capsule (highly characteristic of diabetes.)

Clinically, patients have albuminuria (rarely heavy proteinuria), then


renal failure (probably due to the mesangium crunching the
glomerular capillaries).

The etiology of diabetic glomerulopathy is complex and poorly-


understood. Intrarenal fluid dynamics are involved. We don't even
know why the kidneys enlarge in diabetics (NEJM 324: 1662, 1991,
still good).

Tight control of blood glucose does seem to benefit these


patients, and reduces the hyperfiltration response to amino
acids (NEJM 324: 1629, 1991). Patients are now put on
ACE-inhibitors and protein-restricted to prevent progression
of the renal disease. (Yes, it can regress de to therapy:
NEJM 348: 2285, 2003).

* Ace-inhibitor plus a calcium channel blocker works


marvellously to prevent diabetic kidney disease: NEJM 351:
1941, 2004.

Other renal lesions in diabetes:

* Thick tubular basement membranes (not a health problem).

* Fatty change of tubular cells (systemic lipid disturbance, not a


health problem).
* Glycogen in proximal tubular cells (Armanni-Ebstein lesion, a sign
of heavy glycosuria, not itself a health problem).

{46306} Armanni-Ebstein; lots of glycogen in the tubular cells

Kidney infections (gram-negative bacilli causing infection of renal pelvis in


pyelonephritis, staphylococci causing cortical infections, candida
infections, etc.)

Renal papillary necrosis -- just like it sounds. (* "Baby Robbins"


misnames it "necrotizing papillitis". The lesion is seen in diabetes,
obstruction, sickle cell disease, Wegener's, or abuse of the
analgesic phenacetin.)

{49306} pyelonephritis and papillary necrosis in a diabetic

EYES: Diabetes is the commonest cause of blindness before old age in the US.
Review: Lancet 350: 197, 1998.

Cataracts: a variety of types, including some clearly caused by sorbitol


deposition (proof Proc. Nat. Acad. Sci. 9: 2780, 1995).

Glaucoma: reason for its being more common with diabetes is uncertain.

Diabetic retinopathy: the most serious diabetic eye problem

Nonproliferative phase (NEJM 322: 978, 1990)

Edema, protein exudates, hemorrhages, microinfarcts


("cotton-wool patches") all indicate vascular problems

Microaneurysms (the first change, and highly characteristic


of diabetes): ballooning of capillaries where perhaps a
pericyte has come off.

{09365} diabetic retinopathy; hemorrhages and exudates


{22036} diabetic retinopathy; microaneurysms
{22039} diabetic retinopathy
{22042} diabetic retinopathy, notice the hemorrhages
{22045} diabetic retinopathy -- bleed
{22904} microaneurysm
{23156} cotton wool patches
{23180} diabetic retinopathy
{23183} diabetic retinopathy

Proliferative phase: new vessels grow, eventually invading vitreous


humor, with hemorrhage, granulation tissue, fibrosis, retinal
detachment. These patients get photocoagulation.

{09366} proliferative retinopathy


{22895} proliferative retinopathy
{22901} proliferative retinopathy -- "scar contracts" and tears off the retina
The molecular biology remains puzzling. Sudden
normalization of a poorly-controlled diabetic's glucose can
accelerate proliferative retinopathy (Arch. Ophth. 116: 874,
1998).

OTHER PROBLEMS FOR DIABETICS

Infections (bacterial and fungal)

Why diabetics get more infections is still poorly-understood.


Candida may thrive on the glucose, hyperglycemia slows down
polys, poor circulation keeps the body from fighting infection, etc.,
etc.).

{48090} diabetic abscess


{48091} diabetic abscess

Gallstones (made of cholesterol; nobody knows why these are more


common in diabetics, but the average gallbladder volume is much higher
in non-insulin-dependent diabetics, perhaps promoting stasis and nidation:
Dig. Dis. Sci. 43: 344, 1998.)

Altered platelet function (significance?)

Complications of pregnancy -- all the common problems are commoner in


diabetic mothers, and babies are bigger (partly the hyperglycemia,
probably partly some growth factor or other: Br. J. Ob. Gyn. 103: 427,
1996) and at extra risk for a variety of birth defects (all of which seem to
be preventable by euglycemia through pregnancy).

Diabetic xanthomas (yellow skin bumps -- pseudotumors made of lipid-


laden macrophages), necrobiosis (focal necrosis of the dermis), and many
other skin abnormalities

Diabetic skin
Lecture notes and
some great photos

* One team found that nonenzymatic glycosylation actually altered


keratinocyte surface receptors so they could not take up glucose.
This may have something to do with the poor epidermal healing
and some of the other changes (Diabetes 50: 1627, 2001).

{12214} necrobiosis lipoidica diabeticorum

* Hepatic fatty change, even in sober diabetics. Probably this has to do


with Syndrome X. Stay tuned.

* Scleredema -- pseudosclerodermatous changes over the back and


shoulders caused by accumulation of glycosaminoglycans. This may be a
marker for longstanding poor control.
* "Diabetic dermopathy" is purple-brown patches on the shins (less often,
the upper legs and/or forearms) which may grow to coalesce. This
supposedly has something to do with the microangiopathy and may be
seen in other situations with vascular insufficiency.

Chronic hyperglycemia results in non-enzymatic glycosylation of many


body proteins.

Hemoglobin A1c is glycosylated hemoglobin which can be measured


in the blood to assess the quality of diabetic control (though, of
course, home blood glucose testing several times a day by a highly
motivated patient is even better....)

We pathologists like to see you order a hemoglobin A1c on


stable patients twice a year, with the target of a final HgbA1c
value <7%. Arch. Path. Lab. Med. 215: 191, 2001.

The literature is suddenly exploding with talk about "advanced


glycosylation (glycation) products", i.e., proteins which have
undergone a series of reactions with glucose. For one thing, at
least some human cells have a surface receptor for these products,
which then activate genes in blood vessels (Proc. Nat. Acad. Sci.
91: 8807, 1994) and glomeruli (Proc. Nat. Acad. Sci. 91: 9519,
1994; Diabetes 44: 824, 1995).

Hemoglobin A1c is an obvious choice for a diabetes screening


device, and has been studied as such (JAMA 276: 1264, 1996); it's
still not in common use.

* ADDITIONAL INFORMATION ABOUT DIABETES

Much more about the laboratory diagnosis of diabetes and hypoglycemia is


available from your lecturer. Phone me when you're on rotations if I can help you
with a diabetes-related problem. Some current articles:

J. Clin. Endo. Metab. 85: 1584, 2000. Glycogen synthetase is deficient in


diabetic muscle, but contrary to older reports, this is probably the result
rather than the cause of type II diabetes.

NEJM 346: 393, 2002. Exercise can actually forestall the development of
type II diabetes; apparently, the more, the better; supports many other
studies, and better than metformin.

Br. Med. J. 318: 1169, 1999. the current pop claim that hemophilus
influenzae B vaccine causes diabetes in children doesn't hold up.

NEJM 350: 1398, 2004. The current claims that immunization causes
diabetes are examined in a massive Danish study. Intense scrutiny of kids
who did and did not get each of the common vaccines shows no
apparently difference in the risk for diabetes.
It takes only a few seconds to make up a lie. It takes years [and in
this case, millions of dollars] to refute it. And even then, people still
adopt their "most cherished beliefs" on emotion. -- Ed.