Type 2 Diabetes Mellitus: Update on Diagnosis, Pathophysiology, and Treatment

Richard J. Mahler and Michael L. Adler

J. Clin. Endocrinol. Metab. 1999 84: 1165-1171, doi: 10.1210/jc.84.4.1165

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The Journal of Clinical Endocrinology & Metabolism
Copyright © 1999 by The Endocrine Society
CLINICAL REVIEW 102
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
S IXTEEN million individuals in the United States with
type 2 diabetes mellitus and an additional 30 – 40 mil-
lion 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 diabe-
tes mellitus appears to be established in the recently com-
pleted United Kingdom prospective diabetes study (4, 5).
Despite the morbidity and mortality associated with ret-
inopathy, nephropathy, and neuropathy, cardiovascular dis-
ease 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 –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 ra-
tional basis for the treatment of type 2 diabetes mellitus.
Classification of type 2 diabetes mellitus
The definition of type 2 diabetes mellitus, previously
termed noninsulin-dependent diabetes mellitus, was re-
cently modified by the American Diabetes Association. Sev-
eral criteria may be used independently to establish the di-
agnosis: 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 in-
creased risk of microvascular complications.
Received May 22, 1998. Revision received October 22, 1998. Accepted
November 11, 1998.
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.
1165
Vol. 84, No. 4
Printed in U.S.A.
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 con-
sidered 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).
Pathophysiology of type 2 diabetes mellitus
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 b-cell function, eventually leading to b-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).
The b-cell
b-Cell dysfunction is initially characterized by an impair-
ment in the first phase of insulin secretion during glucose
stimulation and may antedate the onset of glucose intoler-
ance in type 2 diabetes (18).
Initiation of the insulin response depends upon the trans-
membranous 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 glu-
cokinase serves as the first step in linking intermediary me-
tabolism with the insulin secretory apparatus. Glucose trans-
port in b-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
1166 MAHLER AND ADLER
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 b-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 b-cell as a result of sustained hyperglycemia (23).
Other candidates that have been proposed are sorbital ac-
cumulation in the b-cell or the nonenzymatic glycation of
b-cell proteins.
Other defects in b-cell function in type 2 diabetes mellitus
include defective glucose potentiation in response to non-
glucose 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 –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 b-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 Scan-
dinavian patients with type 2 diabetes and has been identi-
fied in the recent United Kingdom study, but has not been
well characterized in other populations (4 – 6, 30).
Glucokinase is absent within the b-cell in some families
with maturity-onset diabetes of young (31). However, defi-
ciencies 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 secre-
tion, 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 de-
struction of the b-cell and is not due to a deficiency in the
glucokinase gene. In the great majority of patients with type
2 diabetes (680%), the delay in immediate insulin response
is accompanied by a secondary hypersecretory phase of in-
sulin release as a result of either an inherited or acquired
defect within the b-cell or a compensatory response to pe-
ripheral 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 b-cell mass, sul-
fonylureas 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 de-
tection or newer insulin-sensitizing drugs will retard the
progression of b-cell failure, obviating or delaying the need
for insulin therapy.
Insulin resistance
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
JCE & M • 1999
Vol 84 • No 4
critical reviews, however, have questioned the primacy,
specificity, and contribution of insulin resistance to the dis-
ease 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 com-
monly 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 pres-
ence 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, im-
paired early phase insulin release and loss of normal oscil-
latory 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 un-
equivocally contribute to the fully established disease.
The liver
The ability of insulin to suppress hepatic glucose produc-
tion 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 di-
abetes 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).
 CLINICAL REVIEW
Therapy for type 2 diabetes mellitus
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 reduc-
tion is the major goal of dietary therapy (61– 64). Traditional
recommendations emphasize reduction of both the total and
saturated fat content and replacement with complex carbo-
hydrates to 50 –55% of the dietary calories. In type 2 diabetic
patients, such diets may cause marked postprandial hyper-
glycemia. 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 gly-
cemic 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 du-
ration of type 2 diabetes have to be considered on an indi-
vidual 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 (67–70). 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 mecha-
nisms 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 li-
poprotein cholesterol levels.
Pharmacotherapy therapy for type 2 diabetes mellitus
Current therapeutic agents available for type 2 diabetes
mellitus include sulfonylureas and related compounds, bi-
guanides, thiazolidenediones, a-glucosidase inhibitors and
insulin (Table 1). In addition, several other classes of ther-
apeutic agents will soon become available. A rational ap-
proach would be to begin with the agents particularly suited
to the stage and nature of the disease, progressing, if nec-
essary, to combination therapy. Pharmacological agents act-
ing 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 b-cells for their hypoglycemic effect (22, 73). All
currently available sulfonylureas bind to specific receptors
TABLE 1. Oral agents used in the management of type 2 diabetes mellitus
Class Mechanism of action
Sulfonylureas and repaglinide Increase insulin secretion
Biguanides Decrease hepatic gluoneogenesis
Decrease peripheral insulin resistance
Thiazolidenediones Decrease peripheral insulin resistance
Reduce fatty acids
a-glucosidase inhibitors Slow absorption of carbohydrates
1167
on b-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 de-
gree than insulin administration, sulfonylureas, through en-
dogenous hyperinsulinemia, cause a propensity for hypo-
glycemia 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 observa-
tion, 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 car-
diac 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 b-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 pub-
lished 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 through-
out 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 de-
creasing hepatic glucose production and, to lesser extent, by
decreasing peripheral insulin resistance. The drug acts by
causing the translocation of glucose transporters from the
Indication(s)
Insulinopenia
Obesity 1 insulin resistance
Insulin resistance
Postprandial hyperglycemia
1168 MAHLER AND ADLER
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 den-
sity cholesterol levels and an increase in high density li-
poprotein cholesterol levels (85–90). 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 max-
imum 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 secreta-
gogues, other insulin-sensitizing drugs, or inhibitors of glu-
cose 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 adminis-
tration (91).
Thiazolidenediones
This new class of antidiabetic agents has been under in-
vestigation 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 thiazoli-
denediones in that it contains an a-tocopherol moiety as part
of its structure, which may also provide some antioxidant
properties (94).
Thiazolidenediones appears to act by binding to the per-
oxisome proliferator activator receptor-g (95, 96). This nu-
clear 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 func-
tion 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 200 – 600 mg daily,
a maximum decrement in HbA1c of 1.5% (45 mg/dL) may be
anticipated when the drug is given alone. Whereas met-
formin 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
JCE & M • 1999
Vol 84 • No 4
further benefited when either or both drugs are given along
with an insulin secretagogue. Troglitazone may cause pe-
ripheral 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 re-
ported 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).
a-Glucosidase inhibitors
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 ther-
apy. Acarbose, the agent of this class in clinical use, may be
added to most other available therapies (105).
Insulin
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 com-
binations 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 reg-
ular 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). Al-
though 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 in-
crease 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 –112).
Combination therapies
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 ther-
apy 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.
Investigational therapies
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 ob-
servation is glucagon-like peptide (GLP-1) (114). Given par-
 CLINICAL REVIEW
enterally or through the buccal mucosa, GLP-1 lowers glu-
cose levels, decreases glucagon levels, and delays gastric
emptying (115–117). 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 b-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
b-cell function. When given parenterally, it appears to de-
crease the glucagon level and delay gastric emptying,
thereby facilitating insulin action (119, 120). It, too, will re-
quire caution in its use in patients with gastroparesis.
Insulin-like growth factor I (IGF-I) levels decline with ag-
ing in parallel with the decline in insulin sensitivity (121).
Although a cause and effect relationship has not been es-
tablished, 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 ad-
ministration, expense, and theoretical potential to worsen
vascular complications, particularly retinopathy (122). Be-
cause of these concerns, IGF-I trials have been temporarily
discontinued.
Therapeutic paradigm and conclusions
Any approach to treatment of type 2 diabetes must com-
bine 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 fac-
tors. 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 thera-
peutic 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 b-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-sensi-
tizing agent, either metformin or troglitazone. If HbA1c val-
ues 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 a-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 b-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 b-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 pa-
1169
tients 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 endocrinolo-
gists will play an essential part in this goal.
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