Type 2 Diabetes Mellitus: Update on Diagnosis, Pathophysiology, and Treatment
Richard J. Mahler and
Michael L. Adler
Division of Diabetes, Endocrinology, and Metabolism, Cornell
University Medical College, New York, New York 10021
Address all correspondence and requests for reprints to: Dr. Richard J. Mahler, Division of Diabetes, Endocrinology, and Metabolism, Cornell University Medical College, 220 East 69th Street, New York, New York 10021.
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Introduction
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SIXTEEN million individuals in the United
States with type 2 diabetes mellitus and an additional 3040 million
with impaired glucose tolerance result in health care costs exceeding
100 billion dollars annually (1). Treatment is predominantly directed
at microvascular and macrovascular complications (2). In type 1
diabetes mellitus the relationship between glycemic control and
microvascular complications has been well established (3). The
relationship between tight glycemic control and microvascular disease
in type 2 diabetes mellitus appears to be established in the recently
completed United Kingdom prospective diabetes study (4, 5).
Despite the morbidity and mortality associated with retinopathy,
nephropathy, and neuropathy, cardiovascular disease remains the leading
cause of death in type 2 diabetes mellitus (6, 7). Consequently, the
treatment of confounding risk factors of obesity, hypertension, and
hyperlipidemia assumes major importance and must be coordinated with
good glycemic control for reduction in total mortality in type 2
diabetes mellitus (6, 7, 8, 9, 10, 11).
Based on the emerging relationship between the degree of glycemic
control and microvascular complications as well as the contribution of
hyperglycemia in the development of macrovascular disease, it is the
purpose of this review to summarize the current state of knowledge to
provide a rational basis for the treatment of type 2 diabetes
mellitus.
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Classification of type 2 diabetes mellitus
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The definition of type 2 diabetes mellitus, previously termed
noninsulin-dependent diabetes mellitus, was recently modified by the
American Diabetes Association. Several criteria may be used
independently to establish the diagnosis: 1) a 75-g oral glucose
tolerance test with a 2-h value of 200 mg/dL or more, 2) a random
plasma glucose of 200 mg/dL or more with typical symptoms of diabetes,
or 3) a fasting plasma glucose of 126 mg/dL or more on more than one
occasion (7). Fasting glucose values are preferred for their
convenience, reproducibility, and correlation with increased risk of
microvascular complications.
The term impaired fasting glucose has been defined as fasting plasma
glucose of 110 or more and 125 mg/dL or less (7). Impaired glucose
tolerance (IGT) is defined as a 2-h plasma glucose value of 140 or more
and of less than 200 mg/dL during an oral glucose tolerance (12).
Individuals with impaired fasting glucose and IGT are considered
to be at high risk for the development of diabetes and macrovascular
disease (13, 14). Although one third of these patients will eventually
develop diabetes, dietary modification and exercise can lower the risk
of progression from impaired glucose tolerance to type 2 diabetes; and
may also prevent the development of IGT in nondiabetic individuals at
high risk (14). Pharmacological agents may also be of benefit in
limiting the progression from IGT to diabetes (13, 15).
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Pathophysiology of type 2 diabetes mellitus
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Type 2 diabetes mellitus is a heterogeneous disorder with
varying prevalence among different ethnic groups. In the United States
the populations most affected are native Americans, particularly in the
desert Southwest, Hispanic-Americans, and Asian-Americans (1). The
pathophysiology of type 2 diabetes mellitus is characterized by
peripheral insulin resistance, impaired regulation of hepatic glucose
production, and declining ß-cell function, eventually leading to
ß-cell failure.
The primary events are believed to be an initial deficit in insulin
secretion and, in many patients, relative insulin deficiency in
association with peripheral insulin resistance (16, 17).
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The ß-cell
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ß-Cell dysfunction is initially characterized by an impairment
in the first phase of insulin secretion during glucose stimulation and
may antedate the onset of glucose intolerance in type 2 diabetes
(18).
Initiation of the insulin response depends upon the transmembranous
transport of glucose and coupling of glucose to the glucose sensor. The
glucose/glucose sensor complex then induces an increase in glucokinase
by stabilizing the protein and impairing its degradation. The induction
of glucokinase serves as the first step in linking intermediary
metabolism with the insulin secretory apparatus. Glucose transport in
ß-cells of type 2 diabetes patients appears to be greatly reduced,
thus shifting the control point for insulin secretion from glucokinase
to the glucose transport system (19, 20). This defect is improved by
the sulfonylureas (21, 22).
Later in the course of the disease, the second phase release of newly
synthesized insulin is impaired, an effect that can be reversed, in
part at least in some patients, by restoring strict control of
glycemia. This secondary phenomenon, termed desensitization or ß-cell
glucotoxicity, is the result of a paradoxical inhibitory effect of
glucose upon insulin release and may be attributable to the
accumulation of glycogen within the ß-cell as a result of sustained
hyperglycemia (23). Other candidates that have been proposed are
sorbital accumulation in the ß-cell or the nonenzymatic glycation of
ß-cell proteins.
Other defects in ß-cell function in type 2 diabetes mellitus include
defective glucose potentiation in response to nonglucose insulin
secretagogues, asynchronous insulin release, and a decreased conversion
of proinsulin to insulin (24, 25).
An impairment in first phase insulin secretion may serve as a marker of
risk for type 2 diabetes mellitus in family members of individuals with
type 2 diabetes mellitus (26, 27, 28, 29, 30) and may be seen in patients with
prior gestational diabetes (31). However, impaired first phase insulin
secretion alone will not cause impaired glucose tolerance.
Autoimmune destruction of pancreatic ß-cells may be a factor in a
small subset of type 2 diabetic patients and has been termed the
syndrome of latent autoimmune diabetes in adults. This group may
represent as many as 10% of Scandinavian patients with type 2 diabetes
and has been identified in the recent United Kingdom study, but has not
been well characterized in other populations (4, 5, 6, 30).
Glucokinase is absent within the ß-cell in some families with
maturity-onset diabetes of young (31). However, deficiencies of
glucokinase have not been found in other forms of type 2 diabetes (32, 33).
In summary, the delay in the first phase of insulin secretion, although
of some diagnostic import, does not appear to act independently in the
pathogenesis of type 2 diabetes. In some early-onset patients with type
2 diabetes (perhaps as many as 20%) (4, 5), there may be a deficiency
in insulin secretion that may or may not be due to autoimmune
destruction of the ß-cell and is not due to a deficiency in the
glucokinase gene. In the great majority of patients with type 2
diabetes (±80%), the delay in immediate insulin response is
accompanied by a secondary hypersecretory phase of insulin release as a
result of either an inherited or acquired defect within the ß-cell or
a compensatory response to peripheral insulin resistance. Over a
prolonged period of time, perhaps years, insulin secretion gradually
declines, possibly as a result of intraislet accumulation of glucose
intermediary metabolites (34). In view of the decline in ß-cell mass,
sulfonylureas appear to serve a diminishing role in the
long term management of type 2 diabetes (35). Unanswered is whether
amelioration of insulin resistance with earlier detection or newer
insulin-sensitizing drugs will retard the progression of ß-cell
failure, obviating or delaying the need for insulin therapy.
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Insulin resistance
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Emanating from the prismatic demonstration by Yalow and Berson of
the presence of hyperinsulinism in type 2 diabetes, insulin resistance
has been considered to play an integral role in the pathogenesis of the
disease (36). Recent critical reviews, however, have questioned the
primacy, specificity, and contribution of insulin resistance to the
disease state (37, 38). As chronic hyperinsulinemia inhibits both
insulin secretion (39) and action (40), and hyperglycemia can impair
both the insulin secretory response to glucose (41) as well as cellular
insulin sensitivity (42, 43), the precise relation between glucose and
insulin level as a surrogate measure of insulin resistance has been
questioned. Lean type 2 diabetic patients over 65 yr of age have been
found to be as insulin sensitive as their age-matched nondiabetic
controls (44). Moreover, in the majority of type 2 diabetic patients
who are insulin resistant, obesity is almost invariably present (45, 46). As obesity or an increase in intraabdominal adipose tissue is
associated with insulin resistance in the absence of diabetes, it is
believed by some that insulin resistance in type 2 diabetes is entirely
due to the coexistence of increased adiposity (47). Additionally,
insulin resistance is found in hypertension, hyperlipidemia, and
ischemic heart disease, entities commonly found in association with
diabetes (16, 48, 49), again raising the question as to whether insulin
resistance results from different pathogenetic disease processes or is
unique to the presence of type 2 diabetes (16, 50, 51).
Prospective studies have demonstrated the presence of either insulin
deficiency or insulin resistance before the onset of type 2 diabetes
(48). Two studies have reported the presence of insulin resistance in
nondiabetic relatives of diabetic patients at a time when their glucose
tolerance was still normal (52, 53). In addition, first degree
relatives of patients with type 2 diabetes have been found to have
impaired insulin action upon skeletal muscle glycogen synthesis due to
both decreased stimulation of tyrosine kinase activity of the insulin
receptor and reduced glycogen synthase activity (54, 55). Other studies
in this high risk group have failed to demonstrate insulin resistance,
and in the same group, impaired early phase insulin release and loss of
normal oscillatory pattern of insulin release have been described (56, 57). Based upon these divergent studies, it is still impossible to
dissociate insulin resistance from insulin deficiency in the
pathogenesis of type 2 diabetes. However, both entities unequivocally
contribute to the fully established disease.
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The liver
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The ability of insulin to suppress hepatic glucose production both
in the fasting state and postprandially is normal in first degree
relatives of type 2 diabetic patients (26). It is the increase in the
rate of postprandial glucose production that heralds the evolution of
IGT (52). Eventually, both fasting and postprandial glucose production
increase as type 2 diabetes progresses. Hepatic insulin resistance is
characterized by a marked decrease in glucokinase activity and a
catalytic increased conversion of substrates to glucose despite the
presence of insulin (53). Thus, the liver in type 2 diabetes is
programmed to both overproduce and underuse glucose. The elevated free
fatty acid levels found in type 2 diabetes may also play a role in
increased hepatic glucose production (50). In addition, recent evidence
suggests an important role for the kidney in glucose production via
gluconeogenesis, which is unrestrained in the presence of type 2
diabetes (58).
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Therapy for type 2 diabetes mellitus
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Diet. Diet therapy, although important for the prevention as
well as the treatment of all stages of type 2 diabetes, continues to
remain poorly understood and high controversial (59, 60). When obesity
coexists with hyperglycemia, as seen in the majority of individuals
with type 2 diabetes, weight reduction is the major goal of dietary
therapy (61, 62, 63, 64). Traditional recommendations emphasize reduction of
both the total and saturated fat content and replacement with complex
carbohydrates to 5055% of the dietary calories. In type 2 diabetic
patients, such diets may cause marked postprandial hyperglycemia. As
there is considerable patient variability in the rate of glucose
absorption, arduous attention to postprandial glucose monitoring and
the addition of high fiber contents to the diet become critically
important. Moreover, as the glycemic response of the diet is also
dependent upon the texture and content of other food stuffs in the diet
as well as the rate of intestinal motility, the diet as well as the
stage and duration of type 2 diabetes have to be considered on an
individual basis (59, 65, 66).
Exercise. Exercise has been shown to be beneficial in the
prevention of the onset of type 2 diabetes mellitus as well as in the
improvement of glucose control as a result of enhanced insulin
sensitivity (67, 68, 69, 70). Decreased intraabdominal fat, an increase in
insulin-sensitive glucose transporters (GLUT-4) in muscle, enhanced
blood flow to insulin-sensitive tissues, and reduced free fatty acid
levels appear to be the mechanisms by which exercise restores insulin
sensitivity (71). In addition, exercise provides the added benefits of
lowering blood pressure, improving myocardial performance, and lowering
serum triglycerides while raising high density lipoprotein cholesterol
levels.
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Pharmacotherapy therapy for type 2 diabetes mellitus
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Current therapeutic agents available for type 2 diabetes mellitus
include sulfonylureas and related compounds, biguanides,
thiazolidenediones,
-glucosidase inhibitors and insulin (Table 1
). In addition, several other classes of
therapeutic agents will soon become available. A rational approach
would be to begin with the agents particularly suited to the stage and
nature of the disease, progressing, if necessary, to combination
therapy. Pharmacological agents acting through different mechanisms of
action should be chosen to improve glucose values while minimizing
adverse effects.
Sulfonylureas and related agents. Sulfonylureas
have been used to treat type 2 diabetes since 1942 and require
functional pancreatic ß-cells for their hypoglycemic effect (22, 73).
All currently available sulfonylureas bind to specific
receptors on ß-cells, resulting in closure of potassium ATP channels.
As a result, calcium channels open, leading to an increase in
cytoplastic calcium that stimulates insulin release (74). A newer
sulfonylurea, glimiperide, given in doses of 1, 4, or 8 mg
preprandially, appears to have a more rapid onset than previous
sulfonylureas (both glyburide and
glipizide) and consequently less risk of hypoglycemia
(75). To a lesser degree than insulin administration,
sulfonylureas, through endogenous hyperinsulinemia, cause
a propensity for hypoglycemia and weight gain (76). Still controversial
is the influence of sulfonylureas on cardiovascular
mortality, an observation first described by the University Group
Diabetes Program (77). Because of the variability of baseline data and
subsequent studies that failed to substantiate the observation,
sulfonylureas have not been considered to potentiate
cardiovascular risk in diabetic patients (78). However, newer data has
shown that sulfonylureas, with the exception of
glimiperide, block the vasodilator response to ischemia in animals,
thereby potentially increasing cardiovascular risk. At present, the
question regarding sulfonylurea use in cardiac mortality in humans
remains unanswered (79, 80). Placed in the context of our increasing
understanding of the pathogenesis of type 2 diabetes,
sulfonylureas would be most appropriate in those patients
in whom hypoinsulinemia is the predominant cause of hyperglycemia.
These patients would typically be lean, with lower basal and
postprandial insulin levels. In addition, based upon the recent United
Kingdom study, these patients tend to be younger (<46 yr of age) and
are more likely to require insulin therapy (81).
Repaglinide is a new agent that binds to pancreatic
ß-cells and stimulates insulin release. It is structurally different
from sulfonylureas and binds to a nonsulfonylurea receptor
(82). The drug is taken preprandially and has a rapid onset and limited
duration of action, which may decrease the incidence of weight gain and
hypoglycemic episodes. Limited published clinical data demonstrate an
efficacy similar to that of sulfonylureas; as with
sulfonylureas, repaglinide shows an added
benefit when given with metformin (82, 83).
Biguanides. After withdrawal of the biguanide, phenformin,
from the U.S. market in 1975, a second generation biguanide, metformin,
was introduced and widely distributed throughout Western Europe,
Canada, and Mexico. With a frequency of lactic acidosis 1/10th that of
the parent compound and a strong record of safety and efficacy, the
drug was carefully introduced into the American market in 1995.
Glucose lowering by the drug occurs primarily by decreasing hepatic
glucose production and, to lesser extent, by decreasing peripheral
insulin resistance. The drug acts by causing the translocation of
glucose transporters from the microsomal fraction to the plasma
membrane of hepatic and muscle cells. It does not stimulate insulin
release and does not, when given alone, cause hypoglycemia (84).
Moreover, it does not cause weight gain, and it improves the lipid
profile by causing a decline in total and very low density lipoprotein
triglyceride, total cholesterol, and very low density cholesterol
levels and an increase in high density lipoprotein cholesterol levels
(85, 86, 87, 88, 89, 90). It is ideally suited for obese patients with type 2 diabetes
who are unresponsive to diet alone and are presumed to be insulin
resistant. When introduced gradually in 500- or 850-mg increments to a
maximum dose of 2000 mg daily, a reduction in hemoglobin
A1c (HbA1c) up to 2.0% (60 mg/dL decrement in
average glucose level) can be anticipated. It is effective as
monotherapy or in combination with other agents, such as insulin
secretagogues, other insulin-sensitizing drugs, or inhibitors of
glucose absorption.
The major risk continues to be that of lactic acidosis, which occurs
with a frequency of 1/20,000 patient yr. As the major route of
excretion of the drug is through the kidneys, it should not be given to
those with renal disease (creatinine
1.5 in males;
1.4 in females),
in the presence of hepatic disease, or in patients with tissue
ischemia. In addition, the drug should be withheld for 48 h after
iv contrast administration (91).
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Thiazolidenediones
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This new class of antidiabetic agents has been under investigation
since 1983 (92). To date, the only drug brought to market is
troglitazone, although companion drugs, including
Pioglitazone, englitazone, and BRL 49653 are
under active investigation (93). Troglitazone differs from
other thiazolidenediones in that it contains an
-tocopherol moiety
as part of its structure, which may also provide some antioxidant
properties (94).
Thiazolidenediones appears to act by binding to the peroxisome
proliferator activator receptor-
(95, 96). This nuclear receptor
influences the differentiation of fibroblasts into adipocytes and
lowers free fatty acid levels (95). Clinically, its major effect is to
decrease peripheral insulin resistance, although at higher doses it may
also decrease hepatic glucose production (15, 97). Although acting at a
different site than metformin, both troglitazone and
metformin appear to function as insulin sensitizers and require the
presence of insulin for their effects (98, 99). In contrast to
metformin, the effects of troglitazone may be progressive
over time, and its full hypoglycemic potency may not be achieved until
12 weeks of therapy (100). When given in doses of 200600 mg daily, a
maximum decrement in HbA1c of 1.5% (45 mg/dL) may be
anticipated when the drug is given alone. Whereas metformin generally
improves glycemic control in greater than 90% of patients, a response
to troglitazone is generally seen in approximately 60% of
patients (98). An elevated C peptide level may help to predict a
beneficial response of either drug, and as metformin and
troglitazone act at different sites to restore insulin
sensitivity, further improvement is seen when the two drugs are used in
combination (101). Moreover, as insulin resistance is invariably
accompanied by a relative insulin deficiency, either metformin or
troglitazone will be further benefited when either or both
drugs are given along with an insulin secretagogue.
Troglitazone may cause peripheral edema or dilutional
anemia, limiting its use in renal disease. However, the major concern
of the drug is that of hepatotoxicity. Occurring in 2% of patients, it
has been reported as early as 35 days and as late as 8 months after the
onset of therapy. Therefore, measurement of transaminases and bilirubin
monthly for the first 8 months of therapy and every 2 months thereafter
for the first year of therapy is mandatory. Early detection has
invariably led to reversal of hepatotoxicity (102, 103).
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-Glucosidase inhibitors
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Members of this class act by slowing the absorption of
carbohydrates from the intestines and thereby minimize the postprandial
rise in blood glucose (104). Gastrointestinal side-effects require
gradual dosage increments over weeks to months after therapy is
initiated. Serious adverse reactions are rare, and weight gain may be
minimized with this therapy. Acarbose, the agent of this
class in clinical use, may be added to most other available therapies
(105).
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Insulin
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Insulin therapy is indicated in the treatment of type 2 diabetes
for initial therapy of severe hyperglycemia, after failure of oral
agents, or during perioperative or other acute hyperglycemic states.
Insulin has been used in multiple combinations in type 2 diabetes, and
new insulin analogs are in clinical trials (106). The first available
insulin analog is lispro insulin, representing a two-amino acid
modification of regular human insulin. Lispro insulin does not form
aggregates when injected sc, allowing it to have a more rapid onset and
a shorter duration of action than regular insulin (107). Although these
properties may help minimize the postprandial rise in glucose and
decrease the risk of late hypoglycemia (108), the use of insulin in
type 2 diabetes is not without theoretical as well as practical
concerns. Insulin therapy can cause further weight gain in obese type 2
diabetics and increase the risk of hypoglycemia (although less commonly
than in type 1 diabetes) (109). In addition, the peripheral
hyperinsulinemia achieved by exogenous insulin therapy may be a risk
factor for cardiovascular disease (110, 111, 112).
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Combination therapies
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Most available agents have been used in combination to treat type
2 diabetes. Although many combinations are not yet approved for use, a
rational choice for combination therapy would include an agent that
increases insulin levels and one that enhances sensitivity to insulin
and lowers glucose production. This combination of agents would appear
to correct most of the pathophysiological defects found in type 2
diabetic individuals.
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Investigational therapies
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It is well established that an oral glucose load evokes a greater
insulin response than glucose given by the iv route (113). One of the
gut polypeptides responsible for this observation is glucagon-like
peptide (GLP-1) (114). Given parenterally or through the
buccal mucosa, GLP-1 lowers glucose levels, decreases
glucagon levels, and delays gastric emptying (115, 116, 117). Its role as an
adjunctive treatment of type 2 diabetes is currently under
investigation. Caution in its application will be necessary in those
patients with gastroparesis.
Amylin is a ß-cell peptide cosecreted along with insulin. Found to be
absent or markedly reduced in type 1 diabetes (118), its presence in
type 2 diabetes varies with the state of ß-cell function. When given
parenterally, it appears to decrease the glucagon level and delay
gastric emptying, thereby facilitating insulin action (119, 120). It,
too, will require caution in its use in patients with
gastroparesis.
Insulin-like growth factor I (IGF-I) levels decline with aging in
parallel with the decline in insulin sensitivity (121). Although a
cause and effect relationship has not been established, the
administration of IGF-I can cause a modest improvement in insulin
sensitivity (121). Its potential benefit must be balanced with the
requirement for parenteral administration, expense, and theoretical
potential to worsen vascular complications, particularly retinopathy
(122). Because of these concerns, IGF-I trials have been temporarily
discontinued.
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Therapeutic paradigm and conclusions
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Any approach to treatment of type 2 diabetes must combine
education, diet, exercise, and management of multiple risk factors.
Control of hypertension and dyslipidemia is essential. Blood pressure
of less than 130/85 mm/Hg and a low density lipoprotein cholesterol
level below 130 mg/dL (low density lipoprotein cholesterol <100 mg/dL
if coronary artery disease is present) are a suggested standard of care
(123). The degree of glycemic control recommended will vary depending
upon age, education, and complicating risk factors. In otherwise
healthy individuals, near normalization of the glycosylated hemoglobin
level is recommended (124), and in all cases a HbA1c level
above 8.0% demands therapeutic intervention. In those patients in whom
insulinopenia is the likely cause of hyperglycemia manifested by lean
body weight, younger age, and enhanced insulin sensitivity, a
sulfonylurea or other ß-cell secretagogue would be favored, whereas
those patients who are likely to be insulin resistant with coexistent
features of hypertension, hyperlipidemia, and obesity would more likely
respond to an insulin-sensitizing agent, either metformin or
troglitazone. If HbA1c values continue to
exceed 8%, a second agent may be added, either a secretagogue or
another insulin-sensitizing agent depending upon patient
characteristics, and if postprandial hyperglycemia persists, an
-glucosidase inhibitor may be added. Ultimately, insulin therapy may
become necessary either early in the course of the disease to establish
control or later in the disease course as ß-cell failure ensues (2).
The addition of bedtime insulin to sulfonylureas may offer
some interim protection, and preliminary studies with insulin and the
insulin-sensitizing drugs have shown promising results in delaying
ß-cell failure (99). Whether such combinations will provide long term
benefit remains to be determined.
In just a few years in the United States, pharmacotherapy for
hyperglycemia has greatly expanded, allowing many patients whose
diabetes was formerly treated by insulin alone to be controlled with
oral agents. However, much remains to be learned. New therapies will
continue to evolve as insight into molecular mechanisms further expand
our therapeutic horizon. However, we must now actively try to diagnose
all type 2 diabetic individuals at an earlier stage and begin treatment
in an attempt to minimize the burden of diabetes-associated
complications. Diabetologists and endocrinologists will play an
essential part in this goal.
Received May 22, 1998.
Revised October 22, 1998.
Accepted November 11, 1998.
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