DIABETES MELLITUS

Diabetes mellitus is a disease of metabolic dysregulation, most notably dysregulation of glucose

metabolism, accompanied by long-term vascular and neurologic complications. Diabetes has several
clinical forms, each of which has a distinct etiology, clinical presentation, and course. Insight into
diabetes and its complications has been advanced by extensive metabolic studies, the use of
radioimmunoassays for insulin and glucagon, and the application of molecular biology strategies.

The identification of what was once termed isletin (i.e., insulin) as the active glucose-lowering agent
in the islets and its isolation and use in diabetic animals by Banting and Best in Toronto and by
Paulesco in Romania culminated in the successful treatment of Leonard Thompson on January 11,
1922. The availability of insulin cured an otherwise uniformly fatal disease. Further clinical
experience, however, revealed that insulin-treated patients developed seemingly inexorable long-term
complications leading to blindness, kidney failure, and peripheral and cardiovascular disease. A
uniformly fatal disease had thus been transformed into a chronic disease with significant morbidity
and premature mortality.

In the 75 years since its first use, insulin has been purified and its amino acid sequence established.
Insulin has been synthesized by solid-phase techniques and, more recently, by modification of
porcine insulin and by recombinant methods in bacteria or yeast, providing a limitless supply.
Modifications of insulin have provided an array of insulin formulations that can be used creatively to
achieve specific glucose targets. Insulin analogues-created by the substitution of specific amino
acids-which do not self-aggregate and are more rapidly acting, have been approved, and others are
being investigated. Whole organ pancreas transplantation has become increasingly successful in
recent years, and the transplantation of isolated islets and the use of hybrid devices (i.e., islets
encapsulated in artificial chambers) are under active investigation. The Diabetes Control and
Complications Trial (DCCT) demonstrated the effectiveness of intensive therapy in maintaining
normal glucose control and preventing or delaying the long-term complications of diabetes. DCCT
established a new standard of therapy for insulin-dependent diabetes mellitus (IDDM) and, by
extension, for non-insulin-dependent diabetes mellitus (NIDDM). New methods of intensive therapy
that are more user-friendly and less likely to cause hypoglycemia must also be established. The
development of noninvasive glucose sensors and implantable insulin pumps will advance this cause.
New therapies directed at preventing complications, independent of glycemic control, are being
investigated, and other studies are examining whether IDDM and NIDDM can be prevented.

Epidemiology

All of the early observations regarding diabetes focused on its most dramatic expression, IDDM,
because it affected children and ran a rapid downhill course. IDDM and the other major clinical form
of diabetes, NIDDM, were not clearly distinguished until relatively recently. In 1936, the existence of
IDDM (then termed insulin-sensitive diabetes) and NIDDM (then termed insulin-insensitive diabetes)
was first documented. Subsequent studies that used bioassays and radioimmunoassays for insulin
demonstrated the pathophysiological difference between the two forms of diabetes. Patients with
IDDM have an absolute insulin deficiency associated with immunologically mediated destruction of
the islets, whereas NIDDM patients, who have a nearly normal islet mass, do not secrete sufficient
insulin to meet the increased demand caused by insulin resistance.
The National Diabetes Data Group (NDDG) and the World Health Organization (WHO) adopted
similar definitions for the different clinical forms of diabetes in 1979. The definitions were based on
characteristic clinical presentations and pathophysiology and were supported by immunologic
markers and inheritance. Although the definitions avoided the age criteria formerly carried by the
terms juvenile-onset and adult-onset diabetes, IDDM is generally a disease of childhood: most cases
appear in patients younger than 20 years, and peak onset is around the time of puberty. Fewer than 10
percent of IDDM cases may first appear in patients older than 50 years. Such patients are thin and
prone to ketosis, and they share genetic and immunologic markers with IDDM patients whose disease
begins in youth. Patients who develop IDDM in the setting of polyendocrine deficiency syndrome
type II typically are 30 years of age or older at onset; most cases of NIDDM occur in patients older
than 40 years. NIDDM develops in a small percentage of patients in their 20s and 30s. Such patients
are often very obese, the offspring of two parents with NIDDM, women with a history of gestational
diabetes, or members of a racial or ethnic group with a particularly high prevalence of NIDDM. The
American Diabetes Association issued revised guidelines for use of fasting plasma glucose levels as
the criterion for diagnosis of diabetes in 1997.

IDDM

IDDM is rare, affecting one in 250 persons in the United States, where approximately 10,000 to
15,000 new cases are reported each year. The highest prevalence of IDDM is found in northern
Europe, where more than one in every 150 Finns develop IDDM by 15 years of age. Data suggest
that for unknown reasons, the incidence of IDDM is increasing in Europe. IDDM is less common
among black and Asian populations, in which the frequency of IDDM is less than half that among
whites.

NIDDM

Compared with IDDM, NIDDM is common, with an overall prevalence of 6.6 percent in the United
States. In the second half of the 20th century, NIDDM has become one of the most frequent chronic
diseases in the United States and most other industrialized nations. More than 600,000 new cases are
reported each year, and the projected prevalence for the next decade is 10 percent. One half of the
NIDDM populations are unaware of their disorder. The increase in the prevalence of NIDDM in the
United States is commonly attributed to an aging population that is also increasingly obese and
sedentary. NIDDM is particularly common in certain racial and ethnic groups, such as Native
Americans; the natives of Nauru, in the South Pacific, and Mauritius, in the Indian Ocean; Hispanic
Americans; Asians; and African Americans. The prevalence of NIDDM among persons older than 65
years exceeds 18 percent, and compared with normal-weight individuals, obese people (i.e., those
who have a body mass index greater than 30) are at 10 to 20 times greater risk for NIDDM. Almost
90 percent of NIDDM patients are obese. Abdominal (i.e., android, as opposed to gynecoid) obesity,
which reflects increased visceral fat and can be conveniently measured as an increased waist-to-hip
ratio, is an even more important risk factor for NIDDM than obesity. Finally, certain isolated ethnic
populations, such as the Pima Indians of Gila River, Arizona, and the Nauruan islanders, have
NIDDM prevalences as high as 50 percent in the adult population. The high prevalence of NIDDM in
these isolated populations has developed in the setting of dietary changes, a rising prevalence of
obesity, and an increasingly sedentary lifestyle (on the reservation in the case of the Pimas and with
growing wealth for the Nauruans).

Although genetic and immunologic markers for IDDM had been identified, the NDDG found them
neither specificenough nor sensitive enough to be used to define IDDM or to distinguish between
IDDM and NIDDM. Similarly, measurements of the secretion of insulin or C-peptide have not
reliably differentiated between IDDM and NIDDM and are not used to define either disorder.
Identification of an antibody directed against glutamic acid decarboxylase (anti-GAD) as a marker for
IDDM and standardization of the anti-islet cell antibody (ICA) assay offer improved specificity and
sensitivity in identifying persons at risk for IDDM. In addition, the search for the genetic cause of
IDDM has identified several loci on chromosome 6 that may account for the major genetic
component of IDDM, and the use of candidate gene and genomic strategies has allowed many
potential causes of NIDDM to be ruled out.

OTHER FORMS OF DIABETES

In addition to the two major clinical forms of diabetes, several other forms of diabetes that have a
relatively clear etiology have been recognized. Diabetes that results from pancreatic destruction (e.g.,
from recurrent pancreatitis, pancreatectomy, or toxins such as the rodenticide Vacor) is termed
secondary diabetes, as is diabetes associated with drugs that increase insulin resistance (e.g.,
glucocorticoids) or decrease insulin secretion (e.g., phenytoin or beta-adrenergic blockers).
Gestational diabetes usually develops during the last trimester of pregnancy. The vast majority of
these cases are similar in pathophysiology to NIDDM. Patients become glucose tolerant after
delivery; however, 30 to 50 percent of women with gestational diabetes redevelop NIDDM within 10
years of the initial diagnosis. A relatively rare form of diabetes, in which the affected individuals are
not prone to ketosis and which is inherited as an autosomal dominant trait, has been identified. It
most commonly develops in thin adolescents and is known as maturity-onset diabetes of the young
(MODY). A glucokinase with an abnormally high K m (Michaelis constant) has been identified in
some, but not all, families with MODY and is associated with decreased insulin secretion. Another
rare form of diabetes that may be associated with insulin deficiency or can phenotypically resemble
NIDDM and is associated with hearing loss, other central nervous system abnormalities, and a mutant
mitochondrial transfer RNA with maternal inheritance has been identified predominantly in Japanese
families.

Although NIDDM, IDDM, and gestational diabetes constitute most of the cases of diabetes in the
United States and other industrialized countries, famine diabetes may be the most common form in
countries with limited food supplies. Malnutrition and carbohydrate-restricted diets in particular are
known to be associated with decreased insulin secretion.

IMPAIRED GLUCOSE TOLERANCE

The definition of diabetes implies both abnormal glucose levels and long-term vascular
complications, features shared by all forms of diabetes. In the general population, glucose levels after
a glucose challenge (e.g., the 75 g oral glucose tolerance test) have a normal distribution. Those
values that are considered abnormal but are not associated with specific long-term microvascular
complications are stipulated to represent impaired glucose tolerance. The diagnostic blood glucose
values for impaired glucose tolerance were based on the findings of several large epidemiological
studies. The rationale for this separate diagnostic category is that patients with impaired glucose
tolerance, although at no risk for retinopathy or nephropathy, are at greater risk for macrovascular
disease than persons with normal glucose tolerance. In addition, 30 to 50 percent of patients with
impaired glucose tolerance develop NIDDM within 10 years after diagnosis. Possible intervention at
this prediabetic stage to prevent subsequent development of NIDDM is being studied.

Pathogenesis

IDDM
IDDM is characterized by absolute insulin deficiency, making patients dependent on exogenous
insulin for survival. Although IDDM characteristically has an acute clinical onset with symptoms of
hyperglycemia (including polyuria, polydipsia, weight loss, blurred vision, or all four) preceding
ketoacidosis or diagnosis by only days or weeks, the natural history of IDDM is now known to
include a long asymptomatic preclinical period. During this preclinical period, insulin-producing beta
cells are progressively destroyed. The normal pancreas contains 1.0 to 1.5 million islets, and roughly
80 percent of islet cells are insulin-secreting beta cells. Clinical diabetes appears when more than 90
percent of the islet beta cells have been destroyed.

Figure 1

Stages of
IDDM/Beta Cell
Mass

The autoimmune destruction of beta cells is associated with, and probably caused by, lymphocytic
infiltration, termed insulitis. Characteristic changes in T cell subsets (e. g., increased suppressor-
inducer T cells and decreased helper-inducer T cells) have been observed to precede islet destruction.
Patients destined to develop IDDM can be identified by the appearance of ICAs as long as 10 years
before the clinical appearance of diabetes. These antibodies are not cytotoxic and are probably
markers of immune destruction. Although several studies have suggested that islet destruction is
inexorably progressive, other data suggest that the presence of ICAs might be intermittent and that
the presence of these antibodies, especially in low titers, might not reliably predict the development
of IDDM. Other antibodies, directed against insulin and glutamic acid decarboxylase, have also been
identified early in the evolution of IDDM. When more than one of the antibodies is present in
association with decreased insulin secretion or with an HLA type that is characteristic of IDDM, the
predictive value of the tests increases. Several autoantigens that may be involved in the pathogenesis
of IDDM, including insulin, GAD65, GAD67, heat shock protein, and other islet cell antigens, have
been identified. Whether viral infections precipitate or cause IDDM in susceptible persons is not
clear.

Genetics

Although IDDM is clearly a heritable disease, the pattern of heredity has escaped definition. In a
study of monozygotic (i.e., identical) twins and triplets among whom IDDM had developed in one
sibling, the disease developed in only 50 percent of the remaining siblings. This observation strongly
suggests that an environmental influence is superimposed on the heritable component of IDDM.
Follow-up of such pairs and triplets has demonstrated that individuals with IDDM develop ICAs first,
followed by decreased insulin secretion in response to intravenous glucose. Fasting and postprandial
plasma glucose levels of such people remain in the normal range until shortly before the appearance
of clinical diabetes.

Some HLA loci (DR3 and DR4) are associated with an increased risk of developing IDDM, whereas
other loci appear to be protective. Substitution of alanine, valine, or serine for the more usual aspartic
acid at position 57 of the  chain encoded by the HLA-DQ locus also has been found to be closely
associated with the increased risk of developing IDDM. All of the genetic linkages are located in the
MHC class II region on chromosome 6.

NIDDM

Insulin Resistance in NIDDM

Although the immediate cause of IDDM, the destruction of insulin-producing beta cells, has been
recognized for decades, the cause of NIDDM continues to be debated vigorously. In their first studies
of circulating insulin levels measured by radioimmunoassay, Berson and Yalow noted normal or even
high insulin levels in older, obese, non-insulin-treated diabetic patients. Consistent with this finding,
autopsy studies of pancreata from patients who had NIDDM revealed only modestly reduced islet
mass compared with pancreata from nondiabetic individuals of a similar age and weight. To explain
the observation of increased glucose levels with normal or high absolute insulin levels, the concept of
insulin resistance (i.e., decreased sensitivity to insulin action) was proposed. After the first step in
insulin action was identified as the binding of insulin to specific high-affinity cell surface insulin
receptors, in vivo studies using insulin clamp techniques demonstrated a modest decrease in insulin
receptors in insulin-resistant patients. The major locus of resistance, predominantly in muscle,
appears to be distal to the receptor (postrecep tor). Further identification, isolation, and cloning of the
insulin receptor has allowed the study of its function in nondiabetic individuals and in patients with
NIDDM. In the vast majority of cases of NIDDM, no abnormalities are apparent either in the
structure of the insulin receptor or in the tyrosine kinase that is integral to its function. However,
insulin-mediated stimulation of tyrosine kinase and autophos phorylation are impaired in NIDDM.
These effects are reversible with improved glycemia and probably do not entirely account for insulin
resistance. Identification of a series of substrates for the receptor tyrosine kinase, including insulin
receptor substrates 1 and 2, which, when activated, serve as docking proteins for other insulin-
responsive proteins, has advanced understanding of insulin action. No primary abnormalities in these
proteins have been documented in NIDDM.

Figure 2

Mechanisms of
Normal Glucose
Homeostasis and
Insulin Resistance

The major sequela of insulin resistance is decreased muscle uptake of glucose. This abnormality
would explain the generally higher postprandial glucose values seen in persons with impaired glucose
tolerance or early NIDDM, because the major fraction of p ostprandial glucose disposal is by muscle
uptake. paired glucose uptake by muscle may be secondary to abnormal glucose transporters;
decreased glucose phosphorylation, which is the rate-limiting step in glucose metabolism in the
muscle; impaired glycogen synthesis; relatively unsuppressed glycogenolysis or gluconeogenesis; or
a combination of these conditions. Unfortunately, insulin deficiency and hyperglycemia can cause
many of these conditions, making the identification of the primary underlying abnormality
problematic.

The Wounded Beta Cell in NIDDM

The demonstration of insulin resistance in many, if not all, patients with NIDDM is not sufficient,
however, to explain the evolution of impaired glucose tolerance to frank diabetes. First, even in the
presence of decreased glucose transport and insulin resistance, the increased hepatic glucose output
that causes the fasting hyperglycemia most characteristic of NIDDM remains unexplained. Second,
although many persons are insulin resistant-including most obese persons and patients with
polycystic ovary syndrome, acromegaly, and Cushing's syndrome-only a minority of these persons
develop NIDDM. All of the defects associated with insulin resistance can be overcome with
increased insulin delivery. Thus, most patients with insulin resistance do not develop diabetes,
because they can increase insulin secretion sufficiently to overcome the resistance. Patients who
decompensate and develop NIDDM either are incapable of increasing insulin secretion beyond a
certain level or seem to tire of producing increased insulin and develop NIDDM as insulin secretion
wanes. In fact, although many studies have demonstrated hyperinsulinemia in patients with impaired
glucose tolerance, a decrease in insulin secretion uniformly accompanies the transition to NIDDM. In
addition, although the absolute level of insulin secretion may be elevated before clinical diabetes
develops in the patient, 20 to 40 percent of the insulin is proinsulin and proinsulin split products,
which represent incomplete cleavage of the connecting peptide (or C-peptide) from proinsulin during
posttranslational processing. In contrast, proinsulin accounts for less than 15 percent of total insulin
in nondiabetics. Because proinsulin and its split products are less than 10 percent as biologically
active as insulin, the true insulin activity in prediabetes may not be elevated.

As insulin secretion wanes, the loss of first-phase insulin secretion is a common finding. Normal
insulin secretion in response to a rapidly administered intravenous glucose dose includes a rapid
release of insulin in the first one to three minutes and a more prolonged release of insulin beginning
10 minutes after infusion. A third phase, consisting of a very slow leak of insulin, has also been
described. The first phase, or spike, of the spike-and-dome secretion profile is lost not only in
NIDDM but also by the waning beta cells of the pancreas in IDDM. A similar phenomenon has been
induced in animal models by partial pancreatectomy. Thus, the loss of first-phase secretion is
common in limited or stressed beta cell masses.

A major feature of NIDDM is that both insulin resistance and insulin secretion are improved if basal
(or fasting) glucose levels are normalized, regardless of the means of normalization. Dietary, insulin,
and oral agent therapies have all been documented to improve endogenous insulin secretion. The
reversible effect of elevated glucose concentrations on insulin resistance and secretion has been
termed glucotoxicity. Although its mechanism is unknown, glucotoxicity may explain why
hyperglycemia begets worse hyperglycemia. Finally, a specific pattern of central obesity, reflecting
increased visceral fat deposition, is particularly related to the risk of developing NIDDM. The
increased release of free fatty acids from these visceral fat stores, with direct delivery to the liver and
pancreas, has been postulated to underlie abnormal lipid metabolism and insulin resistance.

Genetics
In view of these observations, abnormal insulin secretion must be considered integral to the
development of NIDDM; it may even be the rate-limiting step. Studies of monozygotic twins have
demonstrated a strong genetic influence in NIDDM; virtually all identical siblings of NIDDM
patients also develop NIDDM. Patients at high risk for NIDDM (e.g., Pima Indians and children of
two parents with NIDDM) are insulin resistant before impaired glucose tolerance develops. Although
several studies have demonstrated normal or high insulin secretion at this stage, others have shown
abnormal secretory pulsations or decreased secretion. No HLA markers specific for NIDDM have
been identified.

Thus, NIDDM is an inherited disorder in which insulin resistance and abnormal insulin secretion play
important pathogenetic roles. Impaired glucose tolerance precedes the development of NIDDM and is
characterized by insulin resistance, which causes postp randial hyperglycemia because of decreased
muscle uptake of glucose. Insulin resistance appears to be a heritable characteristic. Although 30 to
50 percent of patients having impaired glucose tolerance progress to NIDDM, the remainder do not.
The critical factor associated with the progression from impaired glucose tolerance to NIDDM is a
decline in insulin secretion. Whether abnormal insulin secretion is acquired or also inherited is
unknown. However, the possibility that two independently inherited t raits are involved in a disease
as common as NIDDM seems remote. No mutations specific to insulin secretion or insulin resistance,
using candidate gene and genomic strategies, have been identified to explain the majority of NIDDM
cases. MODY is the only form of NIDDM with a well-characterized single-gene mutation, which
provides a pathophysiologic explanation for its glucose intolerance (although in only about one half
of the families with MODY); mutations in glucokinase lead to defective insulin secretion.

SECONDARY DIABETES

Diabetes secondary to other causes is relatively rare and generally easy to diagnose. Its
pathophysiology is also readily understood. Several causes of secondary diabetes, such as chronic
pancreatitis or pancreatectomy, result in a loss of beta cells and insulin secretory capacity. A large
fraction of beta cell mass must be lost and pancreatic damage must be profound before diabetes
develops. Drugs such as glucocorticoids increase insulin resistance. Gestational diabetes develops in
the setting of elevated placental somatomammotropin (human placental lactogen), which increases
resistance.

Metabolism

IDDM

Insulin is the major anabolic hormone in humans. When insulin requirements and insulin delivery are
mismatched, the consequences are abnormal glucose, lipid, and protein metabolism. Insulin causes its
myriad cellular effects by binding to specific high-affinity receptors. The insulin receptor has been
isolated and purified and its DNA sequence determined and cloned. The insulin receptor is a
heterodimer with an extracellular binding domain, a transmembrane domain, and an intracellular
domain, which has tyrosine kinase activity. The tyrosine kinase moiety promotes
autophosphorylation at several sites after insulin binding. Phosphorylation and dephosphorylation
play an important role in mediating the activity of the insulin receptor. Several proximal substrates of
the activated receptor have been identified, including insulin receptor substrates 1 and 2, which bind
and activate proteins that mediate insulin's biologic effects.
In IDDM, there is clearly no major abnormality in the insulin receptor or in insulin action. The
predominant abnormality is insulin deficiency, which leads to the following consequences.

1. Hyperglycemia secondary to unrestrained hepatic glucose output, resulting from glycogenolysis

and gluconeogenesis, and decreased muscle uptake.
2. Elevated levels of free fatty acids secondary to lipolysis.

3. Elevated serum ketone levels secondary to unrestrained hepatic ketogenesis from free fatty
acids.

4. Increased levels of triglycerides secondary to decreased lipoprotein lipase, resulting in increased

synthesis of very low density lipoproteins (VLDLs) and decreased VLDL clearance.

5. An increase in branched-chain amino acids and a decrease in protein synthesis.

6. Because glucose acts as an osmotic diuretic, hyperglycemia results in dehydration when glucose
levels exceed the renal tubular reabsorption maximum.

Although insulin deficiency is sufficient to cause all of the abnormalities noted above, elevated levels
of counterregulatory hormones such as glucagon, epinephrine, norepinephrine, growth hormone, and
cortisol exacerbate many of the metabolic abnormalities. In patients who are insulin deficient,
elevated levels of glucagon and catecholamines promote ketogenesis and hepatic glucose output.
Diabetic ketoacidosis can develop in patients without increased levels of glucagon, growth hormone,
or catecholamines, but it develops at a slower rate than in patients with elevated levels of
counterregulatory hormones. Because ketogenesis is more sensitive than hepatic glucose output to
insulin suppression, low levels of insulin are usually associated with hyperglycemia but not with
ketosis.

The complete destruction of insulin-producing beta cells in the islets of Langerhans predisposes
IDDM patients to labile glucose control. In the absence of significant quantities of endogenous
insulin, glucose metabolism depends completely on exogenous i nsulin. The progressive destruction
of beta cells that is now recognized to constitute the natural history of IDDM predictably leads to
metabolic instability as the diabetic lesions advance. Early in the clinical course of IDDM, however,
metabolic instability is not invariably present. The first recognized manifestation of this phenomenon
is the so-called honeymoon period in recent-onset IDDM patients. During this period, insulin can be
tapered or even discontinued for weeks or months. Presumably, patients in whom the honeymoon
period develops still retain sufficient beta cell function to survive without exogenous insulin. Over
time, however, the beta cell mass declines further, eventually resulting in complete insulin deficiency.
In addition to the honeymoon period, patients in whom IDDM develops at a later age (i.e., in their
late teens or 20s) characteristically have a milder early course. During this period of stability, insulin
secretion can be stimulated, albeit at low levels. Relatively normal glucose control often can be
effected with single-injection insulin regimens. Stable metabolic control can also be maintained in
IDDM patients who are treated very early in the course of their diabetes with intensive insulin
regimens aimed at maintaining normoglycemia. Such treatment has been demonstrated to preserve
endogenous secretion. Although beta cell function wanes over time, it does so more slowly than in
conventionally treated patients.

After an initial period of metabolic stability that is generally short but variable, most IDDM patients
develop the full-blown insulin deficiency and metabolic instability that characterize IDDM. Overall,
glucose control is highly variable in IDDM because of the mismatch between insulin requirements
and insulin delivery in most conventional insulin regimens. Even with intensive insulin regimens that
rely on frequent self-monitoring of blood glucose to guide the dose and timing of insulin injections,
glucose control is not normal. The labile glucose levels can be explained by several variables that
influence glucose control in diabetes, including prandial state, exercise, stress, and nonphysiologic
insulin delivery. In turn, numerous variables influence insulin availability.

The most dramatic expression of metabolic instability in IDDM is ketoacidosis. Ketoacidosis can be
precipitated by interruption of insulin therapy or by a stress state, with elevated counterregulatory
hormone levels, and inadequate insulin therapy. Insul in deficiency and glucagon enhance ketone
production from free fatty acids supplied by lipolysis. Ketogenesis and unrestrained hepatic glucose
output lead to hyperglycemia with consequent dehydration and ketoacidosis.

NIDDM

The metabolic consequences of partial insulin deficiency (or insulin resistance with inadequate
insulin) are predictable. Hyperglycemia leads to dehydration and a hyperosmolar state. In contrast to
patients who have IDDM, patients who have NIDDM are ketosis resistant because their ambient
insulin concentration is generally sufficient to suppress ketogenesis. However, under extreme stress
(e.g., septic shock or myocardial infarction), NIDDM patients can develop ketoacidosis. More
commonly, elderly patients with NIDDM are at risk for hyperglycemic, hyperosmolar, nonketotic
coma. This metabolic emergency develops in NIDDM patients who become increasingly
hyperglycemic because of stress, steroid administration, or tube feedings. As glucose levels rise in
these patients, failure to replace free-water loss, often because of impaired thirst or mental status or
denial of access to fluids, leads to increasing hyperglycemia and osmolarity, and, ultimately, to
depressed mentation.

In general, glucose levels in NIDDM are far less labile than in IDDM, tending to be lower before
meals and to increase after meals. Elevated postprandial glucose levels in patients who have impaired
glucose tolerance result from decreased muscle uptake associated with insulin resistance. With the
development of NIDDM, however, increased hepatic glucose output causes fasting hyperglycemia
and significantly contributes to postprandial hyperglycemia. Fasting glucose levels and measures of
chronic glycemia tend to be stable and reproducible in a given unstressed NIDDM patient. Other
metabolic abnormalities commonly associated with NIDDM include elevated VLDL and triglyceride
levels; small, dense low-density lipoprotein (LDL) particles that are particularly atherogenic; and
decreased levels of high-density lipoprotein (HDL) cholesterol.

Diagnosis and Screening

The clinical presentation of IDDM should be unmistakable. No special diagnostic tests other than
measurement of blood glucose and, depending on the clinical presentation, urine and serum ketones
and electrolytes are required. Although screening tests that measure ICAs are commercially available,
the sensitivity of such tests is less than 75 percent, even in ideal circumstances. Moreover, a high
degree of specificity is critical for a test of any disease of low prevalence. Combining measurement
of ICAs with insulin response to an intrave nous glucose tolerance test or the combination of several
autoantibodies increases the specificity. To be justifiable, however, a screening program must result
in improved health status by identifying the disease in its pre clinical state. Although the use of
prophylactic immunotherapy is being investigated [see Innovative and Experimental Treatments of
IDDM, below], no such benefit would now accrue, and widespread screening programs for IDDM are
not recommended.

Compared with IDDM patients, patients with NIDDM are much more likely to have no symptoms or
fewer symptoms, and diagnosis may require measurement of fasting glucose lev els or an oral
glucose tolerance test. In 1997, the Expert Committee of the American Diabetes Association issued
new guidelines for the diagnosis of diabetes. These guidelines were based on epidemiological studies
correlating fasting plasma glucose levels with the prevalence of diabetic retinopathy. The committee
recommends that the fasting plasma glucose level used as the diagnostic criterion for NIDDM be
lowered from 140 mg/dl or greater to 126 mg/dl or greater. In addition, the committee recommends
that oral glucose tolerance testing be avoided, except in cases of suspected gestational diabetes, and
that all adults older than 45 years undergo a fasting glucose test at least once every three years to
screen for diabetes. Although as many as 50 percent of patients with NIDDM are unaware of their
disorder, the benefits of early diagnosis remain unproved, and widespread screening with glucose
tolerance testing cannot be endorsed.

management of iddm

The primary component of diabetes care is self-care. Of all chronic diseases, diabetes is unique
because its management involves a host of lifestyle adaptations. In addition to the medications
required, the management of IDDM requires self-monitoring and attention to all aspects of daily
living, from diet to exercise.

GLYCEMIC GOALS OF THERAPY: THE DCCT

The specific goals of therapy formerly included maintaining normal growth, development, and body
weight; preventing symptomatic hyperglycemia, clinical hypoglycemia, and ketoacidosis; and
promptly detecting and treating complications. The glycemic goals of therapy were highly
controversial until the results of the DCCT demonstrated that intensive therapy directed at
maintaining normal glucose levels had a large and beneficial effect on the development and
progression of long-term diabetic complications.

The debate regarding the relation between metabolic control and the genesis of long-term
complications in diabetes mellitus began within 10 years of the introduction of insulin therapy.
During the first decades of insulin use, clinicians began to observe the occurrence of microvascular
and neurologic complications. These long-term complications, including retinopa thy, neuropathy,
and nephropathy, had not been observed in the preinsulin era, because patients with IDDM had not
survived long enough for them to occur. Although many theories were advanced to explain the
occurrence of these complications, the most popular hypothesis suggested imperfect glucose control
as the cause. The so-called glucose hypothesis gained support from studies in animal models of
diabetes and from epidemiological studies. Although vociferous proponents of the glucose hypothesis
espoused the importance of what they termed tight metabolic control, there were no definitive clinical
data to support the efficacy of any particular mode of therapy in preventing the development or
slowing the progression of complications. Moreover, there were no available therapies that could
maintain normal or near-normal levels of glycemia over time.

The tools to achieve long-term, near-normal glucose control, such as self-monitoring of blood
glucose and intensive insulin regimens, became available in the late 1970s. Objective methods of
measuring long-term glycemia and complications were developed at the same time. These
developments made it possible to design and conduct clinical experiments to settle the debate.

Design of the trial

The DCCT, initiated in 1983, was designed to determine whether intensive diabetes management
aimed at achieving glycemic levels as close as possible to the near-diabetic range would affect the
development (primary prevention) or the progression (secondary intervention) of long-term
complications in IDDM.

Two cohorts of patients were enrolled in the study. At baseline, patients in the primary prevention
cohort were 13 to 39 years of age, had had diabetes for one to five years, and had no evidence of
retinopathy or nephropathy. Patients in the secondary in tervention cohort had had IDDM for as long
as 15 years and had at least one microaneurysm and an albumin excretion rate of less than 200 mg/24
hr at baseline.

Intensive treatment and metabolic goals in the trial

The two study cohorts were randomly assigned either to conventional therapy, which consisted of one
or two daily in jections of insulin and daily glucose monitoring, or to intensive therapy. The clinical
goal of conventional therapy was to prevent symptoms of hyperglycemia or hypoglycemia; however,
numerical blood glucose targets were not specified. The goals of intensive therapy were to achieve
blood glucose control that was as close as possible to the nondiabetic range, including preprandial
blood glucose levels of 70 to 120 mg/dl and peak postprandial levels of less than 180 mg/dl, and to
achieve hemo globin A1c (HbA1c) levels in the nondiabetic range (< 6.05 percent). To reach these
goals, patients who were assigned to intensive therapy self-administered three or more insulin
injections daily or made use of an insulin pump; patients were guided by frequent self-monitoring of
blood glucose. Insulin therapy was frequently adjusted in response to changes in ambient blood
glucose levels, diet, and exercise.

Results of the Trial

During the mean follow-up of 6.5 years (range, three to nine years), intensive therapy produced mean
HbA1c levels that were approximately two percent lower than those produced by conventional
treatment (seven percent and nine percent, respectively); however, intensive therapy did not lower
mean HbA1c levels to the nondiabetic range. Compared with conventional therapy, intensive therapy
decreased the risk of development and progression of diabetic retinopathy, nephropathy, and
neuropathy by approximately 40 to 76 percent. The beneficial effects of intensive therapy appeared to
increase over time.

Accompanying the salutary effects of intensive therapy on long-term complications was an

approximately threefold increase in severe hypoglycemia, which was defined as any episode that
required assistance to treat. The incidence of hypoglyce mia that resulted in coma or seizures or that
required emergency room treatment also increased by approximately twofold to threefold. The more
severe hypoglycemic reactions, such as those resulting in seizures or coma, were relatively rare (16
episodes per 100 patient-years in the intensive treatment group and five episodes per 100 patient-
years in the conventional treatment group). Other adverse effects that accompanied intensive therapy
included an increased risk of weight gain and of catheter infections in the patients who used an
insulin pump. In concert, none of these adverse effects caused significant morbidity or mortality. No
macrovascular events or deaths ascribed to hypoglycemia occurred. Moreover, the increased
frequency of hypoglycemia with intensive therapy had no adverse effects on neurocognitive function
as measured by frequent testing. Finally, despite the demands of intensive therapy, quality of life did
not differ between the two treatment groups.

Treatment recommendations

The DCCT Research Group, the American Diabetes Association, and other groups have concluded
that the large and consistent effects of intensive therapy in reducing the risk of developing long-term
complications outweigh the considerable effort and costs involved in such treatment and the
increased risk of hypoglycemia that accompanies it. Intensive therapy has been en dorsed as the
treatment of choice for most patients with IDDM. Realistically, not all patients will be able to
implement intensive therapy; however, the goal for all patients should be to decrease glycemia to as
close to the normal range as safety and lifestyle considerations will allow. For patients who cannot
implement intensive treatment, therapies of variable intensity are available.

For more than a decade, intensive therapy has been mandatory for women with IDDM who are trying
to conceive or who are pregnant, because such treatment has been shown to im prove neonatal
outcome. Intensive management of the pregnant patient with IDDM is particularly difficult because
of changing insulin requirements during pregnancy and should be attempted only by physicians
expert in intensive therapy.

Many questions and challenges remain in the wake of the DCCT. First, whether and to what extent
nonresearch patients with IDDM can implement intensive therapy remain to be seen. Second,
remarkable resources were made available to facilitate the implement ation of intensive therapy.
Whether satisfactory resources are or can be made available in the nonresearch setting is unknown.
Expert treatment teams must be established to help implement and manage intensive therapy.
Financial barriers must be removed to make intensive therapy as widely available as possible. Third,
according to a strict interpretation of the study results, it was intensive therapy, not the achievement
of normoglycemia, that proved to be effective in preventing the development and slowing the
progression of diabetic complications. It is not clear that all methods of treatment designed to achieve
normoglycemia have similar effects. It is likely that the achievement of normoglycemia was the
major reason that intensive therapy was effect ive, and similar treatment methods, such as the use of
artificial pancreata (implantable pumps with built-in glucose sensors), are likely to provide similar
benefits when they become available.

On the other hand, pancreas transplantation, which is another means of achieving normoglycemia,
introduces variables, such as immunosuppression, that might have effects on outcome. Such therapy
may need to be evaluated to determine its cost-benefit ratio. Finally, no patients with NIDDM, the
most common form of diabetes, were included in the DCCT; therefore, whether the DCCT results can
be applied to patients with NIDDM is unknown. The similarity between the complications of IDDM
and those of NIDDM, as well as the similar relation between progression of retinopathy and levels of
chronic glycemia in both diseases, suggests that intensive therapy should also be effective in
NIDDM. However, there are scant direct data to support this hypothesis. Moreover, no long-term
studies have established the relative risks of different therapies designed to achieve normoglycemia in
NIDDM. The high insulin doses that are ultimately required to treat many patients with NIDDM may
be atherogenic, a concern that tempers enthusiasm for the widespread implementation of intensive
therapy in patients with this disease.

SELF-MONITORING

During the past decade, interest in more accurate self-monitoring of metabolic status has increased,
and more devices to help patients perform such monitoring have been developed. Patients should
perform self-monitoring of blood glucose levels for the following reasons:

1. Hypoglycemia is the major side effect of insulin therapy. Accurate, timely self-monitoring of
blood glucose is necessary to recognize, prevent, and treat hypoglycemia.
2. Development of insulin delivery regimens that more closely resemble normal physiology
depends on frequent feedback of ambient glucose levels, which only self-monitoring can
provide.

3. The results of self-monitoring provide information that helps educate diabetic patients about
their disease and the effect of exercise, dietary variation, illness, and other factors on
symptoms and glucose control.

Glucose profiles in IDDM are highly labile, and urine glucose tests cannot provide accurate
information regarding contemporaneous blood glucose levels. Furthermore, the consequences of
hypoglycemia are potentially severe. Therefore, the need for an accurate, user-friendly method for
frequently measuring blood glucose levels at home, in school, or on the job is clear. Reagent strips
and meters to make the measurements more precise and accurate have been developed.

The frequency of monitoring in IDDM depends on the risk of hypoglycemia and the goals of therapy
for a particular individual. At a minimum, IDDM patients should able to monitor their blood glucose
level when they change their insulin doses, diet, or activity or when hypoglycemia would be
particularly dangerous (e.g., before a car trip). In addition, self-monitoring during intercurrent
illnesses can help patients adjust insulin doses. As the complexity of treatment regimens increases,
patients must check their glucose level more frequently, depending on their specific insulin regimen
and daily activity and meal schedule. Fasting and predinner or prebed measurements are often
employed. Intensive regimens require, at a minimum, preprandial and prebed measurements. Insulin
doses are adjusted according to the results.

When unusually high blood glucose levels reveal the risk of ketoacidosis resulting from a
superimposed illness, inadequate insulin intake, or both, the patients should test their urine for
ketones and be instructed to call their health care provider if more than trace urine ketones are found.
Ketone testing should also be performed whenever a patient is nauseated or vomiting, because these
symptoms may indicate ketoacidosis.

MONITORING BY A HEALTH CARE PROVIDER

The utility of measuring the concentration of glycosylated proteins-the nonenzymatic product of

glucose and the amino groups of circulating and membrane proteins-as an index of chronic glucose
levels is well established. The concentration of a glycosylated protein reveals the mean blood glucose
concentration integrated over the lifespan of the protein, which reaches steady state at approximately
one half of the lifespan. Thus, the concentration of glycosylated hemoglobin-HbA1, HbA1c, or
glycohemoglobin, depending on the specific method used-indicates mean glucose levels over
approximately 60 days because the average erythrocyte life span is 120 days; the concentration of a
glycosylated albumin or serum protein (e.g., fructosamine) reveals mean blood glucose levels over a
20-day period. These measures provide an objective means of assessing long-term glycemia and
judging the efficacy of therapeutic interventions. In at least one study, patients whose HbA 1c was
measured had a better health status, with lower glycemia and fewer hospitalizations, than a randomly
selected group of patients whose HbA1c level was not made known to the patient or physician. In
IDDM, three to four HbA1c measurements a year are sufficient for clinical management. Assays that
reflect a shorter period of glycemia, such as assays of fructosamine, need to be repeated more
frequently and are less useful in diabetes management.

Figure 7

Hemoglobin/Glucose
Levels

INSULIN

Insulin is available in various species, formulations, and degrees of purification. In general, all
insulins available in the United States are highly purified, containing less than 50 ppm of proinsulin.
Porcine and bovine insulins differ from human insulin by one and three amino acids, respectively.
Despite the differences in amino acid sequence and the anti-insulin antibodies generated when
bovine, porcine, or a combination of bovine and porcine insulin is administered, these insulins exhibit
potency similar to that of human insulin and seldom cause immune-mediated problems. During the
rare cases of antibody-mediated insulin resistance or of local or systemic insulin allergy, either
desensitization or a change to highly purified porcine or human insulin is effective. Highly purified
porcine insulin, containing less than 10 ppm of proinsulin, or human insulin is necessary only in
those relatively rare patients who have immune-mediated complications after receiving less pure,
more antigenic animal-source insulins. In addition, those patients using insulin intermittently (e.g.,
patients with gestational diabetes) and who may be at greater risk for immune-mediated
complications should be treated with pure porcine or human insulin. Human insulin is synthesized by
modifying porcine insulin or by using recombinant methods in Escherichia coli or yeast. Although
relatively few diabetic patients have an absolute indication for human insulin (or an absolute
contraindication for animal-species insulins), insulin manufacturers would like to shift production
from animal to human insulin for economic reasons.

Insulin formulations may be classified as rapid acting (i.e., regular or crystalline zinc insulin [CZI]),
intermediate acting (i.e., Lente or neutral protamine Hagedorn [NPH] insulin), or long acting (i.e.,
Ultralente insulin). A new rapid-acting, recombinant human insulin (lispro or Humalog), created by
the reversal of the 28th and 29th amino acids of the b chain, does not polymerize as readily as CZI.
Instead of hexamers, most of the insulin is in the monomeric form and is absorbed more rapidly and
cleared more rapidly. Although each formulation has a different profile of action, variability in
insulin absorption from person to person, and even in a single individual, renders these profiles crude
estimates. In addition, the human insulins generally have a slightly faster onset and shorter duration
than corresponding animal-species insulins. Several fixed-combination formulations (e.g., 70 percent
NPH and 30 percent regular) are available. These are only rarely useful in IDDM because fixed-ratio
formulations rarely meet the ever-changing insulin requirements of patients with IDDM; however,
the fixed-combination insulins may be appropriate in NIDDM. Formulations can be combined in a
daily regimen to provide insulin delivery that approximates normal physiology. The more complex
regimens require more frequent injections and glucose tests to guide the choice of dose. Patients
treated with intensive regimens should be given individual algorithms to help them select the correct
dose of regular insulin for a given blood glucose level, meal, and exercise routine. Because the onset
of action of subcutaneous regular insulin is delayed, however, patients must administer preprandial
regular insulin 30 to 60 minutes before the meal. In this respect, lispro insulin is more convenient
because it can be given 10 to 15 minutes before the meal.

Figure 8

Insulin Profiles for

Six Different
Treatment
Regimens

Insulin delivery devices have been developed to facilitate the frequent administration of regular
insulin that is part of intensive treatment regimens. Mechanical syringes, air jet injectors, battery-
powered external pumps, and implantable pumps have all been effective in intensive regimens and
can result in near-normal glycemia. Similar metabolic results can be obtained with three or more
daily injections. The major risk of most intensive regimens is a twofold to threefold increase in severe
hypoglycemia. (A study using implantable pumps that deliver insulin intravenously or
intraperitoneally suggested that in such regimens, severe hypoglycemia may not be as frequent a
problem as it is in subcutaneous regimens.) In addition, weight gain often accompanies intensive
therapy, and the devices that use subcutaneous catheters can result in inflammation or infections at
the catheter insertion sites.

DIET

Dietary therapy is a crucial component of diabetes care. As with monitoring and insulin therapy, the
level of therapeutic intensity should be based on the patient's lifestyle and motivation and on the
overall goals of diabetes care. The modern approach to dietary therapy for IDDM emphasizes
matching insulin to diet, not vice versa. To facilitate matching insulin doses to meals and to prevent
hypoglycemia, the IDDM patient should eat consistent, regular meals. Observation of a prudent diet
that is high in carbohydrates (45 to 50 percent of calories), low in fat (< 30 percent of calories), and
low in cholesterol (< 300 mg) is recommended. More sophisticated dietary approaches include
exchange lists to help patients maintain a similar carbohydrate content from meal to meal and
optimize the insulin choice. Because different carbohydrates are digested at different rates and have
different effects on glucose levels, glycemic indices have been developed for use in more intensive
regimens. These indices account for the effects that different carbohydrate-containing foods have on
glucose levels. Given the importance of diet in the management of IDDM, a dietitian should be part
of the health care team.

EXERCISE
Another component of diabetes care, exercise, is important in maintaining cardiovascular
conditioning, insulin sensitivity, and general well-being. However, patients must be instructed to
adjust their meals, their insulin intake, or both to prevent hypoglycemia during, immediately after, or
even six to 12 hours after exercise [see Hypoglycemia, below]. High-impact sports can be particularly
hazardous to patients with advanced retinopathy or to patients with peripheral neuropathy or vascular
disease, who are at risk for foot trauma.

DIABETIC KETOACIDOSIS

Diabetic ketoacidosis (DKA) occurs infrequently, with 10 to 15 cases occurring for every 1,000
patient-years. Most cases occur after diabetes has been diagnosed; ketoacidosis is not usually the first
manifestation of diabetes. With the availability of self-monitoring of blood glucose and urine ketone
monitoring, most patients should be able to recognize and control evolving DKA; early and
aggressive treatment with extra insulin and fluids can forestall its development. In a sense, DKA
often represents either a failure of patient education or an inability of the patient to comply with a
prescribed regimen.

Although mortality associated with DKA should approach zero, a survey in Rhode Island revealed a
fatality rate of almost 10 percent. Despite this sobering statistic, DKA should be considered a
treatable, nonfatal metabolic emergency, and a careful clinical review should accompany any case
that results in death. Fatal cases most commonly occur when DKA is not recognized as the clinical
presentation of IDDM in children or when it is precipitated by severe illness, such as sepsis or
myocardial infarction, in adults with IDDM. In children, fatal cerebral edema can occur, albeit rarely;
it usually develops six to 12 hours after treatment for DKA is initiated. The clinical presentation of
DKA includes signs and symptoms of dehydration (secondary to osmotic diuresis and vomiting),
Kussmaul's respirations (to increase expiration of volatile acids), nausea and vomiting, and depressed
mentation. Plasma glucose is elevated, usually from 350 to 700 mg/dl, and an anion gap acidosis is
typically present, accompanied by elevated levels of ketone bodies (acetoacetate, -hydroxybutyrate,
and acetone) detectable in urine and serum. Although potassium and phosphate levels may initially be
normal or even high, hydration and correction of the acidosis invariably lowers serum levels,
unmasking a profound total body depletion. Other factors can alter the usual laboratory values of the
disorder. Preliminary insulin treatment by the patient, profound inanition, or pregnancy can result in
so-called euglycemic DKA, in which glucose levels are less than 250 mg/dl.

The fundamental treatment of DKA includes replacement of lost volume and electrolytes (especially
potassium), insulin administration, and diagnosis and treatment of underlying medical conditions.
Since its introduction in 1974, so-called low-dose intravenous insulin therapy has remained the most
commonly used treatment for DKA. Although treatment in an intensive care unit is not mandatory,
the clinical setting should permit insulin administration and frequent monitoring of vital signs,
glucose, and electrolytes. When the patient is obtunded or in a coma, his or her airway should be
protected to prevent aspiration. A large-caliber intravenous line is required for the administration of
intravenous fluid. A 70 kg patient with DKA has a mean volume deficit of 5 to 8 L, a mean sodium
chloride deficit of 350 to 600 mEq, and a mean potassium deficit of 200 to 400 mEq. Intravenous
replacement of these deficits is critical. As the anion gap is corrected, a hyperchloremic metabolic
acidosis often supervenes.

Although DKA can be managed satisfactorily with insulin given intramuscularly or even
subcutaneously, intravenous administration is far more predictable and results in fewer instances of
hypoglycemia and hypokalemia. The role of bicarbonate and phosphate replacement continues to be
controversial. No studies have provided support for bicarbonate use, although most textbooks
continue to advise bicarbonate administration when the arterial pH is less than 7.05. Severe
phosphate depletion (a level of < 2.0 mEq/L) can result in rhabdomyolysis and diaphragmatic
abnormalities. It can also lead to 2,3-diphosphoglycerate depletion and thus to abnormal dissociation
of hemoglobin and oxygen. Although phosphate administration can reverse all of these abnormalities,
the importance of phosphate replacement therapy is questionable; controlled clinical trials have not
demonstrated that phosphate replacement improves outcome in patients with DKA.

HYPOGLYCEMIA

Hypoglycemia is more common than diabetic ketoacidosis and potentially as dangerous a metabolic
emergency. Clinical hypoglycemia can range from annoying symptoms accompanying a
biochemically low glucose level (< 55 mg/dl) to confusion, seizures, or loss of consciousness (during
severe hypoglycemia). The symptoms that most commonly characterize nonsevere hypoglycemia are
adrenergic and include tremulousness, diaphoresis, and tachycardia. Obviously, severe hypoglycemia
can have disastrous consequences, depending on the setting.

Glucagon and epinephrine are the major counterregulatory hormones that are secreted in response to
hypoglycemia and restore glucose levels by stimulating hepatic glucose output as insulin levels
decline. Furthermore, catecholamine secretion, which usually accompanies hypoglycemia, can alert
the patient to treat the episode because it produces sympathoadrenal symptoms. Although they are
less important, cortisol, growth hormone, and thyroxine also play a role in maintaining glucose
levels. Patients rapidly recognize most episodes and can effectively treat themselves with a quickly
absorbed oral carbohydrate. Approximately 15 g of carbohydrate is sufficient to restore blood glucose
levels to normal. The use of complex carbohydrates and foods with a high fat content, such as
chocolate, may delay digestion and absorption of saccharides and is not appropriate for treatment of
hypoglycemia. If a patient cannot swallow or cooperate, either intravenous dextrose or intramuscular
or subcutaneous glucagon should be given. The administration of 25 ml (i.e., one-half ampule) of 50
percent dextrose (12.5 g) as an intravenous push is generally sufficient to reverse clinical
hypoglycemia. Even less is required in infants and children. Glucagon injection kits contain 1 mg of
glucagon, which increases glucose levels in 15 to 30 minutes. Glucagon may cause nausea, vomiting,
and headache, especially in children.

Patients with severe hypoglycemia usually respond rapidly to treatment, although patients who are
postictal or in a prolonged coma may require days, or even longer, to regain normal mental status and
cognitive function. In rare instances, neurologic deficits can be permanent after hypoglycemia. In
view of the potential consequences of prolonged hypoglycemia, hypoglycemia should always be
treated immediately. Patients should be instructed to treat themselves as though they have
hypoglycemia when they suspect it on clinical grounds, even if they are unable to confirm it with a
glucose test.

One purpose for self-monitoring of blood glucose is to aid patients in detecting and treating
hypoglycemia, although the benefit of self-monitoring in reducing hypoglycemia has not been
demonstrated. The consensus, however, is that patients at risk for hypoglycemia should self-monitor
their blood glucose to help adjust their regimen and prevent hypoglycemia.

Several factors contribute to the development of severe hypoglycemia. Hypoglycemic episodes that
occur during stress, exercise, or sleep or in the setting of alcohol or illicit drug use may not result in
recognizable hypoglycemic symptoms. Thus, hypoglycemia may go untreated, leading to more
severe hypoglycemia. Furthermore, some risk factors for hypoglycemia, such as alcohol use, have
multiple effects that can precipitate, prolong, or worsen the severity of hypoglycemia. Alcohol, for
instance, impairs judgment and inhibits hepatic glucose output (thereby delaying recovery). Patients
who do recognize incipient hypoglycemia but who do not respond expeditiously (e.g., by waiting for
a meal in a restaurant or continuing to drive after symptoms first appear) are also at increased risk for
severe hypoglycemia. Finally, because glucagon and epinephrine are the major defenses against
prolonged hypoglycemia, their absence promotes longer, more severe hypoglycemic episodes via two
mechanisms: (1) without glucagon and epinephrine, hepatic glucose output in response to
hypoglycemia is decreased, and (2) in the absence of epinephrine, the character of hypoglycemic
symptoms may change, resulting in failure to recognize the symptoms and to treat the episode. The
glucagon response to hypoglycemia often wanes after five years of IDDM. the absence of the
glucagon response, epinephrine secretion provides adequate counterregulation; however, epinephrine
response can also be lost, sometimes in association with other autonomic neuropathies. Overall, many
patients lose the ability to counterregulate within 10 years of IDDM onset. Moreover, a lowered
glucose threshold for glucagon and epinephrine release in response to hypoglycemia has been
observed in patients undergoing intensive insulin therapy. The lower glucose level necessary to
stimulate counterregulation narrows the safety margin of therapy. For instance, the first symptom of
hypoglycemia may occur only at glucose levels as low as 35 mg/dl and may consist of confusion,
which interferes with self-treatment. The predilection for hypoglycemia with intensive therapy may
be secondary to previous hypoglycemia; a period of hypoglycemia-free therapy may restore
hypoglycemia awareness, if not normal hormonal counterregulation.

INNOVATIVE AND EXPERIMENTAL TREATMENTS OF IDDM

As our understanding of the pathophysiology of IDDM has evolved, experimental treatments for the
disorder have also evolved. Although a true artificial pancreas has not been developed for lack of a
reliable glucose sensor to provide automatic feedback and adjustment of insulin delivery, several
implantable pumps are being investigated. These devices currently rely on self-monitored blood
glucose levels to direct the choice of insulin doses.

Whole organ pancreas transplantation is now far more successful in restoring normoglycemia than in
the past but requires major surgery and immunosuppression. For that reason, most transplant
programs reserve the procedure for IDDM patients who are undergoing concurrent kidney
transplantation and thus who already require surgery and immunosuppression. Although
complications of diabetes are more likely to be preventable in younger patients, whole organ
transplantation is not appropriate for them because of the risks associated with major surgery and
long-term immunosuppression.

Given the limitations of whole organ transplantation, investigators have turned to the transplantation
of isolated islets, which does not require major surgery. Furthermore, the ability to immunomodulate
the isolated islets (by masking or removing cell surface antigens) may allow transplantation with little
or no immunosuppression. Alternatively, islets can be placed in semipermeable hollow tubes that
allow glucose and insulin to enter and leave but shield the islets from lymphocytes and macrophages.
Islet transplants have been successful in animal models and in a very limited number of human
subjects.

Finally, because the immunopathogenesis of IDDM is now better understood and because IDDM can
be detected in its preclinical state, it is theoretically possible to interrupt IDDM development with
immunotherapy. Several studies have successfully used immunosuppressive drugs, including
azathioprine, prednisone, and cyclosporine, to prevent further islet destruction in IDDM patients
identified during their early clinical presentation. Unfortunately, most of the identified patients had
already lost most islet function, and withdrawing immunotherapy even briefly led to rapid
deterioration. Moreover, the toxicity of the drugs makes long-term treatment difficult. Nevertheless,
earlier identification of preclinical IDDM and development of more specific, less toxic
immunotherapy strategies hold the promise of preventing IDDM. A large, multicenter trial is
examining whether insulin therapy, administered by subcutaneous injection and intravenously or
orally, will delay the development of IDDM in persons identified in the preclinical stage.

Management of NIDDM

The clinical goals of therapy for NIDDM are similar to those for IDDM. Just as the established costs
and risks of therapy and the long-term benefits, as documented in the DCCT, must be balanced for
IDDM, they must also be weighed for NIDDM. Unfortunately, the long-term benefits and risks of
tight control in NIDDM are not as well studied as in IDDM. A relatively small DCCT-like study in
patients with NIDDM has demonstrated a benefit of intensive therapy on long-term complications.
The study was in Japanese patients who were very thin and required very small doses of insulin,
making extrapolation to the non-Japanese NIDDM population problematic. Although the benefits of
intensive therapy in NIDDM probably mirror those in IDDM, the specific costs and risks of intensive
therapy for NIDDM almost certainly differ from those of IDDM. For example, many NIDDM
patients can be treated with diet, a relatively nonintrusive, cost-effective treatment, which, when
successful, decreases multiple cardiovascular risk factors in addition to improving glucose tolerance.
When normoglycemia can be achieved at low cost and risk, it should be pursued. As more complex
therapies are required to achieve normoglycemia in NIDDM, the cost-benefit ratio must be
considered more carefully, and as in IDDM, attempts to achieve normoglycemia must be tempered by
individual patient factors. Although in general, normoglycemia in NIDDM can be achieved with less
complex drug regimens and with a lower risk of hypoglycemia than in IDDM, most NIDDM patients
are not treated intensively, exposing them to the risk of long-term complications.

DIET

Diet is preeminent in NIDDM therapy. No drug therapy can match the extraordinary risk-to-benefit
ratio provided by diet therapy. For the more than 85 percent of NIDDM patients who are obese,
weight loss is the major goal of diet therapy. Given the increased risk of coronary vascular disease in
NIDDM, a prudent low-fat, low-cholesterol diet is also important. The hypocaloric diet should be
structured around three meals a day and should have realistic goals. Attaining ideal body weight is
often not possible, but fortunately, a modest weight loss (e.g., 5 to 10 kg) may ameliorate or cure the
diabetes. Although the many diets that stress liquid supplements, grapefruit extracts, special vitamin
formulations, and celebrity sponsors may be attractive to patients, there is no evidence that these
usually costly approaches are more successful than diets that stress smaller portions of balanced
meals. In fact, although any hypocaloric diet will result in weight loss, the transition from
supplements and formulations to normal meals often results in significant weight regain. Protein-
sparing, modified fasts, especially those using low-quality liquid protein supplements (usually
extracted from horse by-products), can result in arrhythmias and sudden death. Very low calorie diets
(< 800 kcal/day) effectively promote weight loss in the very obese but can also be accompanied by
significant complications and must be monitored closely by a knowledgeable physician. Surgical
procedures, such as gastric plication (stapling) with small bowel bypass, can be very effective, but
they can be accompanied by morbidity and mortality and are therefore reserved for patients with
severe obesity.

The expected benefits from weight loss include decreased hyperglycemia (or normoglycemia),
decreased blood pressure and lipid levels, and decreased risk of cardiovascular and joint diseases.
These benefits usually accrue at no cost or risk to the patient. The problem, of course, is that the
benefits are rarely seen, because the vast majority of obese patients who diet succeed initially but
regain the lost weight within one to two years. Each successive attempt to lose weight is increasingly
difficult. Although diabetic patients have even more to gain by losing weight than do nondiabetic
persons, they appear to have more difficulty doing so than do nondiabetic individuals.

MONITORING

Monitoring patients with NIDDM is less demanding than monitoring patients with IDDM. Glucose
profiles of NIDDM patients are relatively stable, and the risk of hypoglycemia among NIDDM
patients is low because at least one third of such patients are treated with diet alone. In addition,
compared with IDDM patients, NIDDM patients treated with oral agents or with insulin tend to be at
lower risk for hypoglycemic episodes. Finally, the risk of ketoacidosis is extremely low, and urine
testing for ketones is not routinely required. Insulin and sulfonylurea-treated NIDDM patients who
are at risk for hypoglycemia should monitor their blood glucose level, especially when drug treatment
is initiated or doses are being adjusted. After a satisfactory dose has been determined, the stability of
the blood glucose profile makes frequent testing often unnecessary. Some NIDDM patients are
treated with more complex insulin regimens (e.g., two mixed or split injections) and require more
frequent self-monitoring. In contrast, NIDDM patients treated with diet alone do not need to monitor
their blood glucose routinely.

In NIDDM, the correlations between day-to-day fasting glucose levels, between fasting glucose
levels and HbA1c levels, and between HbA1c levels over time are relatively high (r > 0.80). This
glycemic stability makes monitoring in patients with NIDDM easier than in patients with IDDM.
Laboratory measurements of fasting glucose or HbA 1c every three to six months usually provide an
accurate index of chronic glycemia in stable NIDDM patients. If there is any change in diet, exercise,
drug regimens, or health status, more frequent monitoring is necessary.

HYPOGLYCEMIC MEDICATIONS

Hypoglycemic medications may be necessary in NIDDM patients in whom the dietary approach fails.
Diet failure usually means that the patient has not been able to achieve or maintain adequate weight
loss to alleviate the diabetes. Before drug therapy begins, the risks and costs of the drugs must be
balanced against the benefits. Although the benefits of intensive therapy in NIDDM may be
debatable, certain clinical criteria, such as hyperglycemic symptoms uncontrolled by diet or
hyperglycemia severe enough to lead to dehydration, warrant the use of drug therapy. All of the drug
therapies are more effective in the setting of continued attention to diet.

Once the health care provider has discussed the need for medication with the patient, there are several
choices of medication, each with distinct advantages and disadvantages.

Sulfonylureas are oral medications that act primarily by stimulating endogenous insulin secretion.
Their glucose-lowering effects were first noted as a side effect during the investigation of a
sulfonamide antibiotic. Although sulfonyl ureas decrease insulin resistance, this effect probably plays
a minimal role, if any, in lowering glucose levels. On average, sulfonylureas will lower HbA 1c levels
by one to two percent. The sulfonylureas have no effect on and no role in the treatment of IDDM, and
they are usually not effective in nonobese NIDDM patients. Several sulfonyl ureas are available in
the United States. Although more potent on a milligram-per-milligram basis, the second-generation
agents are not more efficacious than the first-generation drugs at maximal doses. As many as 20
percent of NIDDM patients who begin sulfonylurea therapy do not have an adequate hypoglycemic
response to maximal doses (these patients are termed primary failures), and each year, an additional
five to 10 percent of patients who initially responded stop responding to sulfonylurea therapy
(secondary failures). Many of the drug interactions and side effects of the first-generation
sulfonylureas do not occur or are reduced with the second-generation agents. Hypoglycemia
secondary to sulfonylureas is infrequent; however, it is often more prolonged and more dangerous
than hypoglycemia secondary to insulin. An increased frequency of hypoglycemia has been noted in
patients receiving initial doses of the second-generation sulfonylureas, and care should be taken to
start patients on low doses, which can be increased as needed. Weight gain often accompanies
treatment with sulfonylureas. Finally, the multicenter University Group Diabetes Program
documented an increased risk of cardiovascular mortality associated with tolbutamide, an effect that
is widely assumed to be a class action of these drugs.

The biguanide metformin is a relatively new addition to the medications available in the United
States for the treatment of NIDDM, although it has been widely used in Canada and Europe for more
than 20 years. It has a different mechanism of action from that of sulfonylureas-it predominantly
decreases hepatic glucose output. Unlike the sulfonylureas, metformin is effective in both obese and
nonobese patients and is not associated with hypoglycemia or weight gain. Its potency is similar to
that of the sulfonylureas, lowering HbA1c by one to two percent. The most common adverse effect of
metformin is gastrointestinal; it causes abdominal distention, discomfort, or even diarrhea in
approximately 10 percent of patients. This side effect can be decreased by advancing the dose slowly.
Lactic acidosis, a potentially fatal side effect that occurred more commonly with the biguanide
phenformin, rarely occurs with metformin (three episodes per 100,000 patient-years). The risk of
lactic acidosis is increased in patients with decreased glomerular filtration rate (serum creatinine >
1.4 mg/dl in women and > 1.5 mg/dl in men) and with circulatory failure (e.g., congestive heart
failure or shock). Because of the potentially fatal consequences of lactic acidosis, patients must be
carefully selected and followed. Metformin can be used as monotherapy or in combination with
sulfonylurea in patients in whom sulfonylurea therapy failed.

Another relatively new oral agent, which can be used to treat IDDM and NIDDM, is the -
glycosidase inhibitor acarbose. This nonabsorbed drug acts like dietary fiber, decreasing the rate of
absorption of carbohydrate by competitively inhibiting the intestinal wall enzymes that digest
polysaccharides into absorbable monosaccharides. The result is a blunted glycemic excursion in the
postprandial period. Acarbose is somewhat less potent than the sulfonylureas and metformin,
lowering HbA1c levels by 0.5 to 1.5 percent. However, it is effective in all diabetic patients, including
patients with IDDM, and may be used as monotherapy or in combination with any of the other
available hypoglycemic medications. When used as monotherapy, acarbose is not associated with
hypoglycemia or weight gain. The delivery of undigested polysaccharides to the large intestine
causes an increase in intestinal gas formation, which decreases the drug's acceptability for some
patients.

The newest therapy for NIDDM is the thiazolidinedione troglitazone, an insulinomimetic agent. In
dosages of 200 to 800 mg daily, troglitazone lowers HbA 1c by 0.5 to 1.0 percent and improves
triglyceride levels with less insulin and without significant weight gain or other serious side effects.

Insulin is the most effective hypoglycemic agent, and because there is no upper limit for insulin
doses, an effective dose can almost always be found. In NIDDM, the total dose of insulin is probably
more important than the profile of its delivery, in contrast to IDDM, where a physiologic profile is
critical. Relatively high doses (50 to more than 100 U/day) are generally required to achieve near-
normal glycemia in obese NIDDM patients. Insulin can be administered as intermediate or long-
acting formulations in the morning or at bedtime, as so-called mixed-split regimens (intermediate and
rapid-acting) before breakfast or before breakfast and dinner, or as fixed-combination formulations.
Although some patients with NIDDM, such as those who are not overweight, those who have
profound hyperglycemia with weight loss or ketosis, or those with very high triglyceride levels,
should be started on insulin as first-line therapy, most physicians reserve insulin for when the
relatively weaker oral agents have failed. Because the majority of NIDDM patients who start on oral
agents will eventually require insulin to maintain near-normal glycemia, the oral agents may be
viewed as temporizing measures.

The resistance to using insulin more frequently or more aggressively, by physicians and patients
alike, presumably resides in the need to inject it and fear of its side effects, including hypoglycemia
and weight gain. In fact, even when used in high doses, insulin therapy rarely causes severe
hypoglycemia in NIDDM patients. Moreover, most studies comparing insulin injection and oral agent
sulfonylurea therapy in NIDDM demonstrate similar levels of compliance. Obviously, patient
preferences must be taken into account and the choice of therapeutic agents must be individualized.

Combination therapy has been proposed for treating NIDDM, usually when monotherapy has failed.
One proposed strategy combines sulfonylureas and insulin. Using the in sulin-sparing effect of
sulfonylureas, this treatment attains similar levels of glycemia with insulin doses that are five to 20
percent lower than the dose of insulin required if used alone. Although the same metabolic results can
be achieved with higher insulin doses, some investigators have hypothesized that higher insulin levels
(or doses) may be atherogenic and should be avoided. The association between insulin level and
coronary artery disease was established in several large population studies that excluded patients with
diabetes, and there are few data that suggest lowering insulin levels affects NIDDM outcomes
positively. Furthermore, although insulin doses can be lowered with combination therapy, insulin
levels after combination therapy are not significantly different from insulin levels after monotherapy
with insulin. Thus, given the added expense and the potential for increased drug interactions, side
effects, and complications and for decreased compliance when two drugs are used, combination
therapy with insulin and sulfonylureas cannot be recommended routinely.

Other combinations, including metformin and sulfonylureas or acarbose and any of the other
hypoglycemic agents, can be used effectively, albeit at greater expense and increased risk of
hypoglycemia than with insulin alone.

EXERCISE

Exercise prescriptions for NIDDM are intended to aid weight loss, increase insulin sensitivity, and
promote cardiovascular conditioning. Because patients with NIDDM are at increased risk for
cardiovascular disease, patients who are beginning a new exercise regimen should be given
electrocardiograms and, if necessary, exercise stress tests. Like IDDM patients with peripheral
neuropathy, NIDDM patients with neuropathic, insensate feet and limited circulation are at risk for
foot trauma during high-impact sports.

INNOVATIVE AND EXPERIMENTAL THERAPY FOR NIDDM

Several new therapeutic principles to treat NIDDM have been developed. Glucagon-like peptide-I-(7-
37) (GLP-I-[7-37]), a naturally occurring polypeptide that is processed by the intestinal L cells from
the preproglucagon molecule, has been demonstrated to have potent effects on insulin secretion and
synthesis. In addition, GLP-I-(7-37) inhibits glucagon secretion and probably slows gastric emptying,
further contributing to its glucose-lowering effect. Intravenous or subcutaneous administration has
been shown to improve hyperglycemia in NIDDM without the risk of hypoglycemia. Finally, a large
multicenter study, the Diabetes Prevention Program, has been initiated to determine whether NIDDM
can be prevented or delayed in volunteers who are at high risk by virtue of having impaired glucose
tolerance.

HYPEROSMOLAR, HYPERGLYCEMIC NONKETOTIC COMA

Hyperosmolar, hyperglycemic nonketotic coma is associated with severe hyperglycemia (> 600
mg/dl) but, by definition, is not associated with ketosis or ketoacidosis. Volume depletion is severe
(the average fluid deficit is 25 percent of total body water), and the serum osmolality is greater than
350 mOsm/kg. Usually, either an illness or a drug or nutritional therapy (e.g., steroid treatment or
tube feeding with concentrated carbohydrate solutions) acutely exacerbates hyperglycemia; the
failure or inability to replace fluid loss precipitates profound dehydration, obtundation, and, finally,
coma. Precipitants, including infections, must be identified and treated. The hyperosmolar
dehydration is treated aggressively with hypotonic (one-half normal) saline to replete both solute and
free water. A low-dose insulin infusion is effective in lowering glucose levels. In contrast to diabetic
ketoacidosis, mortality from hyperosmolar, hyperglycemic nonketotic coma may be as high as 50
percent, perhaps reflecting the age of those affected and the severity of the precipitating illness. After
the initial episode is treated, patients often require no insulin.

Complications
All forms of diabetes mellitus are accompanied by a similar spectrum of microvascular and
neurologic complications. Complications such as retinopathy and nephropathy are specific for
diabetes; in contrast, macrovascular complications, including cardiac, peripheral, and cerebrovascular
disease, also occur in the nondiabetic population. The risk for developing macrovascular diseases in
the diabetic population, however, is much greater than the underlying risk in the general population.

The development of long-term complications in the diabetic patient changes a relatively benign,
albeit difficult-to-manage, metabolic condition into a devastating disease with profound morbidity
and mortality. The clinical course for the IDDM population is likely to include visual impairment or
blindness, renal failure, and vascular disorders. The risk of experiencing these complications is
reduced 35 to 76 percent with intensive diabetes management [see Glycemic Goals of Therapy: The
DCCT, above].

Although the incidence of specific complications may differ somewhat from one form of diabetes to
another, the clinical expression of these complications in the different clinical forms is identical. The
cause of the myriad complications is unknown. However, because they occur in forms of diabetes
that are genetically distinct but have disordered metabolism in common, some metabolic feature of
diabetes most likely causes the complications. Whether hyperglycemia per se causes all of the
complications, mediated perhaps through glycosylation of membrane proteins or through other
mechanisms, is unknown. The central role of hyperglycemia in causing diabetes-specific
complications (the glucose hypothesis) is supported by interventional studies in animal models of
diabetes and, most convincingly, by the results of the DCCT. A DCCT-like study in Japanese patients
supports a similar benefit of intensive therapy on long-term complications in NIDDM.

Risk factors other than hyperglycemia have been identified. The most potent risk factor is duration of
diabetes. Hypertension is a risk factor for nephropathy and probably retinopathy; pregnancy (in
IDDM) is a risk factor for progression of retinopathy. Finally, there may be a genetic component to
the risk of developing long-term complications.

RETINOPATHY

Given a long enough duration of diabetes, retinopathy occurred in almost all IDDM and most
NIDDM patients in the pre-DCCT era. After 15 years' duration, with conventional diabetes
management, more than 90 percent of IDDM patients had clinical retinopathy. The most common
form of retinopathy is nonproliferative (also termed background retinopathy). It begins with loss of
pericytes, the supporting cells of the retinal vasculature, and progresses to characteristic
microaneurysms that are visible by direct ophthalmoscopy. The microaneurysms, which measure 50
to 100 æm in diameter, can occur anywhere in the retina but tend to cluster near the macula, the part
of the retina responsible for central vision and visual acuity. Small punctate (or so-called dot-and-
blot) hemorrhages form when the microaneurysms leak blood. Leakage of serum leads to the
formation of hard exudates. These lesions are generally benign unless they occur near the macula and
in sufficient number to cause macular edema, which can decrease central vision and acuity.

Figure 9a

Nonproliferative
Retinopathy

As retinopathy progresses, terminal capillaries become obstructed, and the retina becomes ischemic.
Infarctions of the nerve layer appear as soft (so-called cotton-wool) exudates. In response to
ischemia, new vessels proliferate from the surface of the retina into the vitreous, giving the disorder
its name, proliferative retinopathy. The new vessels develop in response to a specific angiogenic
growth factor released by the ischemic retina. They are extremely fragile and can bleed into the
vitreous, causing temporary loss of vision until the blood is reabsorbed. Proliferative vessels that are
greater than one quarter of the disk diameter in size and that occur within one disk diameter of the
disk are especially likely to bleed. When the vitreous blood is reabsorbed, scars form, and traction on
the retina can lead to retinal detachment with profound and often permanent loss of vision.

Figure 9b

Proliferative
Retinopathy

Laser treatment of proliferative retinopathy and macular edema has been demonstrated to preserve
vision. The role of the internist and ophthalmologist is to detect and treat retinopathy requiring laser
therapy before irreversible damage occurs. Although fundus photography is the most sensitive means
of detecting retinopathy, ophthalmologists and even well-trained internists can detect retinopathy. An
examination with the pupil dilated is preferable. Because retinopathy virtually never occurs before
five years' duration in IDDM, regular ophthalmologic examinations need not be performed until five
years after diabetes onset. Because the duration of NIDDM is much more difficult to assess
accurately, annual examinations are recommended, commencing at the time of diabetes diagnosis.
Pregnancy is a recognized risk factor for progression of retinopathy in IDDM, and frequent eye
examinations are recommended during pregnancy. Finally, for patients with significant vitreous
scarring and debris and retinal detachments, vitrectomy can be performed. In this high-risk
procedure, fibroproliferative scars are excised, the retina is reattached if possible, and the debris-
filled vitreous is replaced with a salt solution. Vitrectomy can restore vision in selected cases.

NEPHROPATHY

Nephropathy is the diabetic complication associated with the highest mortality. Whereas the vast
majority of diabetic patients developed some degree of retinopathy in the pre-DCCT era, only 35 to
45 percent of IDDM patients and fewer than 20 percent of NIDDM patients developed clinical
nephropathy. The progression of nephropathy has been identified. It begins with low levels of
albumin excretion, or microalbuminuria (urine albumin levels of 30 to 300 mg/24 hr), as early as five
years after IDDM onset. This so-called incipient nephropathy progresses to macroalbuminuria (i.e,
urine albumin levels > 300 mg/24 hr as measured by a positive dipstick proteinuria test or with a 24-
hour collection) with accompanying hypertension after IDDM of 12 to 20 years' duration. Ultimately,
the nephrotic syndrome and the decrease in glomerular filtration rate (GFR) progress to end-stage
renal disease (ESRD). Unlike the risk of retinopathy, the risk of nephropathy does not continue to rise
with increasing duration. If dipstick proteinuria, the most reliable indicator of diabetic nephropathy,
has not occurred after 25 to 30 years of diabetes, the risk of developing nephropathy begins to
decrease. Duration of diabetes and, perhaps, family history of hypertension are risk factors for
nephropathy, whereas glucose control has not been clearly identified as a risk factor. Controlling
hypertension and using low-protein diets can decrease the rate of GFR decline late in the course of
nephropathy. Angiotensin-converting enzyme inhibitors have been demonstrated to play an especially
important role in reducing progression from microalbuminuria and from more advanced stages of
nephropathy in IDDM and NIDDM. Intensive diabetes treatment slows and perhaps prevents the
development of microalbuminuria and clinical-grade, dipstick-positive proteinuria (urine albumin
levels > 300 mg/24 hr). Whether intensive diabetes treatment affects the ultimate progression of
microalbuminuria to ESRD is unknown.

Figure 10

Progression of
Nephropathy in
IDDM

Diabetic patients with ESRD can be treated with transplantation, hemodialysis, or peritoneal dialysis.
Hemodialysis is associated with an increased risk of cardiovascular events and with a risk of retinal
bleeding caused by profound blood pressure fluctuations and anticoagulation. Thus, transplantation
and peritoneal dialysis are the preferred treatments.
NEUROPATHY

Neuropathy has protean manifestations in diabetes. The most common manifestation is the
peripheral, symmetric sensorimotor neuropathy that presents as numbness or tingling in the toes or
feet. The symptoms are usually only mildly disturbing and require no specific treatment. Patients
often report that these symptoms abate over time, as the neuropathy becomes more severe and
hypoesthesia or anesthesia takes the place of paresthesias and dysesthesias. The insensate feet
become vulnerable to trauma, and neuropathic foot ulcers are all too frequent causes of
hospitalization and amputation. In rare instances, peripheral neuropathies can be painful, with
dysesthesias interfering with sleep and activity. Tricyclic antidepressants, phenytoin, and
carbamazepine are all somewhat effective. Capsaicin, a topical treatment that depletes substance P, a
pain-modulating neurotransmitter, from type C nociceptive fibers, has been demonstrated to have
some efficacy. Narcotics should be avoided because the potential for addiction is high. The DCCT
demonstrated a major beneficial impact of intensive therapy on diabetic neuropathy. For patients
whose feet are at risk for ulceration, foot care education and inspection have been demonstrated to
reduce foot trauma and hospitalizations.

Other forms of diabetic neuropathy include mononeuropathies, entrapment syndromes, and

autonomic neuropathy. The mononeuropathies, which are generally asymmetric, affect cranial or
peripheral nerves and are thought to be secondary to vascular occlusion leading to nerve infarcts.
Entrapment syndromes, such as carpal tunnel syndrome, occur more frequently in diabetics than in
nondiabetics. Finally, autonomic neuropathy can affect the gastrointestinal, cardiovascular, or
genitourinary systems. The clinical syndromes include diabetic gastroparesis characterized by
delayed gastric emptying: early satiety and fullness and nausea and vomiting. Diabetic diarrhea
results in nocturnal diarrhea and incontinence alternating with constipation. Cardiovascular
neuropathy produces resting tachycardia with postural hypotension, and genitourinary neuropathy
causes impotence and hypotonia or atonia of the bladder resulting in overflow incontinence.
Gastroparesis is effectively treated with metoclopramide and diabetic diarrhea with clonidine;
impotence can be treated with penile injections or intraurethral administration of vasodilators or with
implantable prostheses or vacuum devices.

CARDIOVASCULAR DISEASE

Cardiovascular disease is not specific for diabetes. However, the risk of cardiac disease is increased
two to almost 10-fold in NIDDM. The relative risk of cardiovascular disease for diabetic women
(compared with nondiabetic women) is increased even more than for diabetic men, essentially erasing
the protective effect usually conferred by estrogen. Numerous risk factors for cardiovascular disease
accompany NIDDM, including obesity, hypertension, dyslipidemia (low HDLs and high VLDLs with
small, dense LDLs), and hyperglycemia. A study of survivors in the original Framingham Study
cohort has documented that the HbA1c level is associated with the occurrence of cardiac disease in
women, independent of other recognized risk factors. Development of nephropathy in IDDM or
NIDDM confers an especially high risk of coronary artery disease.

The incidence of peripheral vascular and cerebrovascular disease is also increased in patients with
diabetes, and these disorders are a source of significant morbidity and mortality among diabetic
patients. The combination of peripheral neuropathy and peripheral vascular disease results in a risk of
amputations in the diabetic population that is 40 times greater than that in the nondiabetic population.