Preface (Vorwort) Diabetes and the Brain

Preface (Vorwort) Diabetes and the Brain
Type 2 Diabetes
Hermes J. Florez, Alex A. Sanchez,
and Jennifer B. Marks
Type 2 diabetes (T2D) is the most common form of diabetes, a metabolic disorder characterized by hyperglycemia resulting from defects in insulin action,
insulin secretion, or both. Early diagnosis of T2D and the high-risk category of
pre-diabetes may help reduce the associated public health and clinical burden.
Available diagnostic strategies include fasting plasma glucose, oral glucose tolerance test, and casual plasma glucose in the presence of symptoms of hyperglycemia. Potential use of hemoglobin A1c as part of the strategy for screening and diagnosis has been recently proposed. Those with risk factors for T2D
should be targeted including patients with overweight/obesity, those with family
history of T2D, those aged 45 years and older, race/ethnic minorities (such as
Native Americans, African Americans, Latinos, and Asian Americans), women
with history of gestational diabetes, and those with metabolic syndrome abnormalities (high blood pressure, low HDL cholesterol, and high triglycerides).
Lifestyle modification (i.e., weight loss through diet and increased physical
activity) has proven effective in reducing incident T2D in high-risk groups.
Prevention trials using pharmacological therapy (metformin, α-glucosidase
From: Contemporary Diabetes: Diabetes and the Brain
Edited by: G. J. Biessels, J. A. Luchsinger (eds.), DOI 10.1007/978-1-60327-850-8_2
C Humana Press, a part of Springer Science+Business Media, LLC 2009
Florez et al.
inhibitors, or thiazolidinediones) have also reported a significant lowering of
the incidence of T2D. As a chronic condition, T2D requires continuous care to
prevent damage to various organs, including the eyes, kidney, nervous system,
and cardiovascular system. Appropriate glycemic control, blood pressure and
lipid management, nutrition and physical activity, taking into account functional
status and comorbidities, are needed to prevent microvascular and macrovascular complications. A variety of oral antihyperglycemic agents, which target
different mechanisms in the pathogenesis of T2D, are as follows: insulin sensitizers, insulin secretagogues, α-glucosidase inhibitors, and the new dipeptidyl
peptidase (DPP)-IV inhibitors. Injectable agents for the treatment of insulindeficient T2D include traditional insulin preparations, newer insulin analogs,
amylin, and incretin mimetics. Additional aspects of T2D management in the
older adult include the assessment of geriatric syndromes and psychosocial
screening. Efforts to improve T2D care following recommended guidelines are
still very much needed.
Key words: Type 2 Diabetes; Diagnosis; Epidemiology;
Management; Insulin resistance; Insulin secretion.
Diabetes mellitus is a group of metabolic disorders characterized by
hyperglycemia, which can result from defects in insulin secretion, insulin
action, or both. Diabetes is a chronic illness that requires continuing medical
care and patient self-management education to prevent acute complications
and to reduce long-term complications.
The American Diabetes Association (ADA) diagnostic criteria for diabetes and the two high-risk categories of pre-diabetes, impaired fasting
glucose (IFG) and impaired glucose tolerance (IGT), updated in 2003 are
defined in Table 1 (1). There are three ways to diagnose diabetes. Because of
simplicity of use, acceptability to patients, and low cost, the fasting plasma
glucose (PG) is the preferred diagnostic test. In the presence of symptoms
of diabetes (polyuria, polydipsia, weight loss, etc.), a casual plasma glucose of greater or equal than 200 mg/dl is diagnostic. The 75-g oral glucose
tolerance test (OGTT) is more sensitive and modestly more specific than
fasting PG, but it is less reproducible and less frequently performed in clinical settings. In the absence of unequivocal hyperglycemia, any test used to
diagnose diabetes must be confirmed on a subsequent day by a PG measured
either in the fasting state or 2 h after an oral glucose load.
Type 2 Diabetes
Table 1
The diagnostic criteria for diabetes and the classification of impaired fasting
glucose (IFG) and impaired glucose tolerance (IGT)
FPG (mg/dl)
2-HPG (mg/dl)
Sx of diabetes + CPG
≥100 and <126
≥140 and < 200
+ and CPG≥200 mg/dl
FPG, fasting plasma glucose (FPG); 2-HPG, plasma glucose 2 h after a challenge with
75 g glucose; CPG, casual plasma glucose; Sx (symptoms) of diabetes: polydipsia, polyuria,
and unexplained weight loss.
Adapted from American Diabetes Association (1).
The 2006 joint report from the World Health Organization (WHO) and
International Diabetes Federation (IDF) also provides an update on guidelines for diagnosis of diabetes (2). Their diagnostic criteria (i.e., fasting PG
≥ 7.0 mmol/l [126 mg/dl] or 2-h PG ≥ 11.1 mmol/l [200 mg/dl])remained
unchanged since these criteria distinguish a group with significantly
increased premature mortality and higher risk of microvascular and cardiovascular complications.
Recently, a committee of experts in the area of diagnosis, monitoring,
and management of diabetes provided a review of the available evidence
and made recommendations regarding the screening and diagnosis of diabetes using hemoglobin A1c (HbA1c) (3). The main factors in support of
using HbA1c as a screening and diagnostic test included (a) HbA1c does
not require patients to be fasting; (b) HbA1c reflects longer-term glycemia
than does PG; (c) HbA1c laboratory methods are now well standardized and
reliable (more information in the National Glycohemoglobin Standardization Program web site at; (d) errors caused by non-glycemic
factors affecting HbA1c, such as hemoglobinopathies, are infrequent and
can be minimized by confirming the diagnosis of diabetes with a PG-specific
test. Several recommendations were made: (1) screening standards should be
established that prompt further testing and closer follow-up, including fasting PG ≥100 mg/dl, random PG ≥130 mg/dl, or HbA1c > 6.0% (2) HbA1c
≥ 6.5–6.9%, confirmed by a PG-specific test (fasting PG or OGTT), should
establish the diagnosis of diabetes; (3) HbA1c ≥ 7%, confirmed by another
HbA1c or a PG-specific test (FPG or OGTT) should establish the diagnosis
of diabetes.
Hyperglycemia insufficient to meet the diagnostic criteria for diabetes is
categorized as either IFG or IGT, depending on whether it is identified by a
fasting PG or by an OGTT. According to the ADA, IFG is diagnosed when
Florez et al.
the fasting PG level is ≥100 mg/dl (≥110 mg/dl based on WHO/IDF criteria)
but <126 mg/dl. IGT exists when the PG level 2 h after a 75-g oral glucose
load is ≥140 mg/dl but <200 mg/dl. These are considered to be pre-diabetic
states. Furthermore, an international committee (IDF/ADA/EASD) reported
that a HbA1c ≥ 6% but < 6.5% helps identifying people at very highrisk of developing diabetes (
Diabetes and its complications constitute a significant public health problem worldwide and are an important cause of morbidity and mortality.
In fact, diabetes has reached epidemic proportions throughout the world,
and the prevalence is expected to continue to rise. The International Diabetes Federation estimates that more than 245 million people around the
world have diabetes (4). This total is expected to rise to 380 million within
20 years. Each year a further 7 million people develop diabetes. Diabetes,
mostly type 2 diabetes (T2D), now affects 5.9% of the world’s adult population with almost 80% of the total in developing countries. The regions with
the highest rates are the Eastern Mediterranean and Middle East, where 9.2%
of the adult population is affected, and North America (8.4%). The highest
numbers, however, are found in the Western Pacific, where some 67 million
people have diabetes, followed by Europe with 53 million.
According to new 2007 prevalence data estimates recently released
by the Centers for Disease Control and Prevention (CDC), diabetes now
affects nearly 24 million people in the United States (USA), an increase of
more than 3 million in approximately 2 years (5). Among adults, diabetes
increased in both men and women and in all age groups, but still disproportionately affects the elderly. Almost 25% of the population aged 60 years
and older had diabetes in 2007. Another 57 million people are estimated to
have pre-diabetes. It has been projected that one in three Americans born in
2000 will develop diabetes, with the highest estimated lifetime risk among
Latinos (males, 45.4% and females, 52.5%) (6).
A rise in obesity rates is to blame for much of the increase in T2D
(7). Nearly two-thirds of American adults are overweight or obese (8). The
prevalence of abdominal obesity (i.e., large waist circumference) among US
adults has increased continuously during the past 15 years. Over one-half
of US adults have abdominal obesity (9). This is a major concern given the
strong association between measures reflecting abdominal obesity and the
development of T2D (10).
The risk of developing diabetes rises not only with overweight/obesity
(body mass index, BMI>25 kg/m2 ) and lack of physical activity, but with
Type 2 Diabetes
increasing age (>45 years) and family history (1). Specific population subgroups have a higher prevalence of diabetes than the population as a whole.
Recent data showed that compared to white non-Hispanics (6.6%) diabetes
remains higher in race/ethnic minority groups: Native Americans and Alaska
Natives (16.5%), African Americans (11.8%), Latinos (10.4%), which
includes rates for Puerto Ricans (12.6%), Mexican Americans (11.9%), and
Cubans (8.2%), and Asian Americans (7.5%) (11). Women with a history
of prior gestational diabetes or polycystic ovarian syndrome are at increased
risk. Also, the predictive value of traditional and non-traditional risk factors
has been evaluated in cohort studies (12, 13). In addition to age, family history of diabetes, obesity and pre-diabetes, and those with other metabolic
syndrome components (high blood pressure, low HDL cholesterol, and high
triglycerides) are at higher risk. The greater the number of these metabolic
risk factors in a given person, the higher the chance of that individual developing diabetes.
There are two underlying mechanism that lead to the onset of clinical
T2D: inadequate insulin action in target tissues (insulin resistance) and
inadequate secretion from pancreatic β-cells (Fig. 1) (14). Insulin resistance arises prior to the onset of clinical disease, but predicts the development of diabetes (15–17). Environmental factors, particularly obesity and
a sedentary lifestyle, are important contributors to the development of diabetes, largely because of their effects on insulin sensitivity (18–20). When
target tissues become insulin resistant, glucose uptake is decreased, hepatic glucose production increases, and lipolysis is enhanced. In muscle,
the increased free fatty acid (FFA) availability accelerates fat oxidation,
resulting in decreased insulin-mediated glucose uptake and disposal. In the
liver, elevated FFAs promote gluconeogenesis and increase hepatic glucose
When inadequate insulin secretion from pancreatic β-cell dysfunction is
also present, hyperglycemia develops, heralding the onset of T2D (14–17).
In the natural history of progression to diabetes, β-cells initially increase
insulin secretion in response to insulin resistance and, for a period of time,
are able to effectively maintain glucose levels below the diabetic range.
However, when β-cell function begins to decline, insulin production is inadequate to overcome the insulin resistance, and blood glucose levels rise.
Insulin resistance, once established, remains relatively stable over time.
Therefore, progression of T2D is a result of worsening β-cell function with
pre-existing insulin resistance.
Florez et al.
Fig. 1. Defects in the pancreas and in target tissues for insulin action in type 2 diabetes.
In the non-diabetic individual, insulin suppresses hepatic glucose output, stimulates glucose uptake and utilization in muscle and adipose tissue, and suppresses lipolysis in adipose tissue. When these tissues become resistant to the actions of insulin, hepatic glucose
production increases, glucose uptake is decreased, and lipolysis is enhanced. Increased
free fatty acids (FFAs) from lipolysis stimulate cellular uptake of FFAs and lipid oxidation. In muscle, the increased FFA availability accelerates fat oxidation, resulting in
decreased insulin-mediated glucose uptake and utilization. In the liver, elevated FFAs
stimulate gluconeogenesis and increase hepatic glucose output. When β-cell dysfunction is present, insulin resistance in the target tissues leads to hyperglycemia and to the
development of type 2 diabetes. (From DeFronzo, R. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Copyright ©
2009 American Diabetes Association from Diabetes, 2009; 58:773–795. Reprinted with
permission from the American Diabetes Association.)
Despite major advances in understanding the pathophysiology of T2D,
unraveling the complex link between genetic risk and environmental factors
in this burgeoning epidemic has proven difficult (21). Linkage approaches
have clarified the etiology of monogenic diabetic syndromes and congenital lipodystrophies, and candidate gene association studies have identified a number of common variants implicated in T2D. Several genetic loci
have now been reproducibly associated with T2D in genome-wide scans.
For example, common variants in the gene that encodes the transcription factor 7-like 2 (TCF7L2), involved in the control of insulin secretion, have been strongly associated with T2D (22). At the individual level,
Type 2 Diabetes
carrying the TCF7L2-risk allele increases T2D risk 50%. However, at the
population level, the attributable risk is lower than 25% and varies with
the allele frequency. The presence of the TCF7L2 rs7903146-risk allele
increases TCF7L2 gene expression in β-cells, possibly impairing glucagonlike peptide-1-induced insulin secretion and/or the production of new mature
β-cells. It is expected that the detection of other such genes in genome-wide
association scans will help elucidate the genetic architecture and pathophysiology of T2D.
Prevention efforts may start with promotion of healthy lifestyle and
appropriate screening in those at higher risk: individuals ≥ 45 years of
age and those with a BMI ≥ 25 kg/m2 (22). Screening should also be considered for people who are <45 years of age and are overweight if they
have another risk factor for diabetes: physical inactivity, first-degree relative with diabetes, members of high-risk ethnic populations (e.g., African
American, Latino, Native American, Asian American, Asian American, and
Pacific Islander), women who delivered a baby weighing > 9 lb or were
diagnosed with gestational diabetes, hypertension, low HDL cholesterol,
high triglycerides, women with polycystic ovarian syndrome, IGT, or IFG
on previous testing, other clinical conditions associated with insulin resistance (e.g., severe obesity and acanthosis nigricans), and history of cardiovascular disease (CVD). Repeat testing may be carried out at 3-year
Lifestyle modification (i.e., weight loss through diet and increased physical activity) has proven effective in reducing incident T2D in high-risk
groups. The Da Qing Study (China) randomly allocated 33 clinics (557 persons with IGT) to 1 of 4 study conditions: control, diet, exercise, or diet plus
exercise (23). Compared with the control group, the incidence of diabetes
was reduced in the three intervention groups by 31, 46, and 42%, respectively, and with a modest weight loss in study participants. The Finnish
Diabetes Prevention Study evaluated 522 obese persons with IGT randomly
allocated on an individual basis to a control group or a lifestyle intervention
group that emphasized physical activity, weight loss, limited total dietary
intake and intake of saturated fat, and increased intake of dietary fiber
(24). During the trial, the incidence of diabetes was reduced by 58% in the
lifestyle group compared with the control group. The US Diabetes Prevention Program is the largest trial of primary prevention of diabetes to date and
was conducted at 27 clinical centers with 3,234 overweight and obese participants with IGT randomly allocated to 1 of 3 study conditions: control, use
of metformin, or intensive lifestyle intervention (25). The goal of lifestyle
Florez et al.
intervention was to achieve and maintain 7% or greater weight loss through
a low-calorie, low-fat diet and 150 or more minutes of moderate physical
activity weekly. Nearly half the participants were African American, Hispanic American, Asian American, or Native American. Over 3 years, the
incidence of diabetes was reduced by 31% in the metformin group and by
58% in the lifestyle group; the latter value is identical to that observed in the
Finnish Study. To prevent 1 case of diabetes, only 7 patients needed to be
treated with lifestyle change, compared with 14 patients treated with metformin. The magnitude of risk reduction in the lifestyle intervention group
was similar across all ethnic groups, and participants in all age and BMI
subgroups achieved a clinically significant reduction in risk. In contrast, metformin was relatively ineffective in older and less obese participants.
Type 2 diabetes prevention trials using other forms of pharmacological
therapy have also reported a significant lowering of the incidence of diabetes.
The α-glucosidase inhibitor acarbose reduced the risk by 32% in the STOPNIDDM trial (26), and the thiazolidinedione troglitazone reduced the risk
by 56% in the TRIPOD Study (27).
More recently, the investigators from the DREAM trial, a study in 5,269
adults with IGT, IFG, or both and no previous CVD were recruited from
191 sites in 21 countries and randomly assigned in a 2-by-2 factorial design
to receive rosiglitazone 8 mg/day and/or ramipril 15 mg/day. There was no
statistical evidence of an interaction between the ramipril and the rosiglitazone arms. After a mean follow-up of 3 years, the use of ramipril did not
reduce the incidence of diabetes (28), while the treatment with rosiglitazone
reduced by almost 60% the incidence of T2D and increased the likelihood
(+70%) of regression to normoglycemia (29).
Whether diabetes prevention strategies also ultimately prevent the development of diabetic vascular complications is unknown, but cardiovascular
risk factors are favorably affected (30). Preventive strategies that can be
implemented in routine clinical settings have been developed and evaluated.
Widespread application has, however, been limited by local financial considerations, even though cost-effectiveness might be achieved at the population
Prevention of Complications
Chronic poor glycemic control is associated with the development of
diabetic vascular complications, including microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular (coronary, cerebrovascular
and peripheral vascular disease). CVD is the cause of 65% of deaths in
patients with T2D (31).Epidemiologic studies have shown that the risk of
Type 2 Diabetes
a myocardial infarction (MI) or CVD death in a diabetic individual with no
prior history of CVD is comparable to that of an individual who has had a
previous MI (32, 33).
Microvascular complications can be delayed or prevented by maintaining
excellent chronic glycemic control, as has been demonstrated in a number of
interventional trials, including the Diabetes Control and Complications Trial
(DCCT), the United Kingdom Prospective Diabetes Study (UKPDS), the
Kumamoto Study, and the Stockholm Diabetes Intervention Study (34–39).
Further, even in acute illness, several studies have shown that intensive
insulin therapy and improved glycemic control are associated with better
outcomes (40, 41).
Intensive glycemic control also results in reduced macrovascular complications, i.e., CVD, as demonstrated in a number of epidemiological studies
(42–44). From the Diabetes Control and Complications Trial/Epidemiology
of Diabetes Interventions and Complications (DCCT/EDIC) Study of type
1 diabetes, it is clear that intensive glycemic control prior to the onset of
vascular disease has long-term beneficial effects on the risk of CVD in this
population (45). Patients with newly diagnosed T2D, aged 25–65 years at
baseline, whose HbA1c was reduced from 7.9 to 7% in the UKPDS, did not
exhibit a reduction in cardiovascular events, although a subgroup of patients
treated with metformin showed a trend to a lower incidence of events (46).
However, 10-year follow-up data from this study showed persistence of
microvascular benefits and long-term appearance of macrovascular benefits
in the insulin and sulfonylurea groups despite the fact that the differences in
HbA1c between the groups had disappeared (47).
Three recent trials in older adults with T2D have assessed the effect
of lowering blood glucose to near-normal levels on cardiovascular risk.
First, patients in the Action to Control Cardiovascular Risk in Diabetes
(ACCORD) trial (n = 10,251) had a mean age of 62.2 years at entry and 10
years of diabetes duration. Sixty-two percent were men, and 30% had prior
macrovascular disease and a baseline median HbA1c level of 8.1% (48).
Study patients were assigned to receive intensive therapy (median HbA1c
level achieved of 6.4%) or standard therapy (median HbA1c level achieved
of 7.5%). After a median follow-up of 3.4 years, compared to the standardtherapy group, those in the intensive-therapy group had higher overall mortality (4% vs. 5%) and cardiovascular mortality (1.8% vs. 2.6%) and greaternumber of hypoglycemic events (1% vs. 3.1%). Second, patients in the
Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Study (n = 11,140) had a
mean age of 66 years at entry and 8 years of diabetes duration. Fifty-seven
percent were men and 32% had prior macrovascular disease and a baseline
median HbA1c level of 7.2% (49). Study patients were assigned to receive
Florez et al.
intensive therapy (median HbA1c level achieved of 6.4%) or standard
therapy (median HbA1c level achieved of 7%). After a median follow-up
of 5 years, compared to the standard-therapy group those in the intensivetherapy group achieved a reduction in the incidence of nephropathy (5.2%
vs. 4.1%), although severe hypoglycemia was more common (1.5% vs.
2.7%). There were no differences in overall mortality (9.6% vs. 8.9%),
cardiovascular mortality (5.2% vs. 4.5%), or major macrovascular events
(10.6% vs. 10%). Finally, patients in the Veterans Affairs Diabetes Trial
(VADT) (n = 1,792) had a mean age of 60.4 years at entry and 11.5 years
of diabetes duration. Ninety-seven percent were men and 40% had prior
macrovascular events and a baseline mean HbA1c level of 9.4% (50). They
were assigned to receive intensive therapy (median HbA1c level achieved
of 6.9%) or standard therapy (median HbA1c level achieved of 8.4%). After
a median follow-up of 6 years, there was no significant difference in the
rate of the composite primary endpoint (MI, congestive heart failure, invasive revascularization, inoperable coronary artery disease, amputation for
ischemia, stroke, or cardiovascular death) between the intensive- and the
standard-therapy groups (25.9% vs. 29.3%, p = 0.12). Fewer cardiovascular events than expected were observed in both groups, in part because
of the aggressive management of blood pressure (reduction from 131/77 to
127/70 mmHg) and lipids (LDL-cholesterol and triglycerides fell from 106
and 157 mg/dl to 78 and 135 mg/dl, respectively, while HDL rose from 34 to
40 mg/dl) as well as lifestyle changes (40–57% exercised regularly, 60–68%
adhered to diet, and cigarette smoking was reduced from 16% to 10%) and
the increased use of antiplatelet/anticoagulants (from 76% at entry to 92% at
the end of the study). Intensive therapy was associated with lower risk of the
primary endpoint only in those with diabetes for less than 15 years and those
who had low arterial calcium (AC) scores (AC < 100). Severe hypoglycemia
requiring medical assistance was higher than expected and more frequent
in the intensive than in the standard group (21.1% vs. 9.7%, p < 0.01). In
fact, hypoglycemic events that led to impaired or loss of consciousness were
independent predictors of major cardiovascular events and cardiovascular
and total mortality.
Glycemic Goals
Based on results from clinical trials of glycemic control and the impact
on diabetic microvascular complications, recommendations for targets of
glycemic control have been put forth (1). Glycemic control is fundamental
to the management of diabetes. The HbA1c is the most accepted indicator of chronic control, reflecting fasting and postprandial glucose concentrations. The goal of therapy is to achieve an HbA1c as close to normal
Type 2 Diabetes
Table 2
Glycemic goals
HbA1c goal for patients in general <7%
HbA1c goal for the frail elderly patient <8%
Pre-prandial capillary plasma glucose∗ 90–130 mg/dl
Peak postprandial capillary plasma glucose∗ <180 mg/dl
∗ Capillary plasma glucose = fingerstick glucose.
Adapted from American Diabetes Association (1) and Brown
et al. (75).
as possible in the absence of hypoglycemia. Recommended glycemic goals
for non-pregnant individuals are shown in Table 2. Less stringent treatment
goals may be appropriate for patients with limited life expectancies and
in individuals with co-morbid conditions (51). Severe or frequent hypoglycemia is an indication for the modification of treatment regimens, including setting higher glycemic goals.
Nutrition and Physical Activity
Overweight and obesity are strongly linked to the development of
T2D and can complicate its management. Moderate weight loss improves
glycemic control and reduces CVD risk. Therefore, weight loss is an important therapeutic strategy in all overweight or obese individuals who have
T2D. All patients with diabetes should be encouraged to maintain a healthy
lifestyle by exercising and following an appropriate diet (52). The primary
approach for achieving weight loss is therapeutic lifestyle change, which
includes a reduction in energy intake and an increase in physical activity.
Oral Antidiabetic Agents
A variety of antidiabetic pharmaceutical agents for the treatment of
T2D are available, which target different mechanisms in the underlying pathogenesis of the disease (53–56) (Fig. 2). There are five categories of oral agents on the market, which can be used initially in most
cases of T2D, until insulin deficiency becomes severe and insulin replacement is required. Sulfonylureas and the glitinides (repaglinide, nateglinide) are insulin secretagogues that stimulate release of insulin from the
β-cells of the pancreas. Metformin, a biguanide, improves insulin sensitivity chiefly by reducing insulin resistance in the liver, thereby decreasing
hepatic glucose production. The thiazolidinediones (rosiglitazone, pioglitazone) improve insulin sensitivity primarily in the muscle, thereby increasing
peripheral uptake and utilization of glucose. The α-glucosidase inhibitors
(acarbose) prevent the breakdown of carbohydrates to glucose in the gut, by
Florez et al.
Increased by:
Impaired insulin secretion
Glucose absorption
Decreased by:
α -glucosidase
Decreased by:
glucose uptake
Gastric emptying
Decreased by:
Increased by:
Fig. 2. Antidiabetic agents and their mechanisms of action. The variety of antidiabetic
agents for the treatment of type 2 diabetes target different mechanisms in the underlying
pathogenesis of the disease. Sulfonylureas and the glitinides (repaglinide, nateglinide)
are insulin secretagogues that stimulate release of insulin from the pancreas. Metformin,
a biguanide, improves insulin sensitivity chiefly by reducing insulin resistance in the
liver, thereby decreasing hepatic glucose production. The thiazolidinediones (rosiglitazone, pioglitazone) improve insulin sensitivity primarily in the muscle, thereby increasing peripheral uptake and utilization of glucose. The α-glucosidase inhibitors (acarbose,
precose) prevent the breakdown of carbohydrates to glucose in the gut, by inhibiting the
enzymes that catalyze this process, thereby delaying carbohydrate absorption. Insulin
and insulin analogs increase insulin levels in the presence of declining β-cell function
and diminished endogenous insulin secretion. Exenatide and the synthetic amylin, pramlintide exploit novel mechanisms related to effects on glucagon secretion, gastric emptying, and satiety. (From DeFronzo (53). Reprinted from Annals of Internal Medicine
with permission from American College of Physicians.)
inhibiting the enzymes that catalyze this process, thereby delaying carbohydrate absorption. Sitagliptin, a dipeptidyl-peptidase (DPP)-IV inhibitor, is
an agent that reduces blood glucose with less risk of hypoglycemia. Metformin is recommended as first choice for pharmacologic treatment and has
good efficacy to lower HbA1c by approximately 1–1.5% as monotherapy
(57). However, most patients will eventually require treatment with combinations of oral medications with different mechanisms of action simultaneously in order to attain adequate glycemic control. Table 3 lists the available
classes of oral antidiabetic medications, their mechanisms of action, and side
Type 2 Diabetes
Table 3
Available oral antidiabetic agents
Drug class
α-Glucosidase inhibitors
Mechanism of action
Stimulate insulin
Suppress hepatic glucose
production (major)
Improve insulin
sensitivity in target
tissues (minor)
Improve insulin
sensitivity in target
tissues (major)
Suppress hepatic glucose
production (minor)
Delay carbohydrate
absorption from the
Major side effects
Weight gain
GI side effects Lactic
acidosis (rare)
Weight gain
Edema Congestive heart
Flatulence or abdominal
Adapted and summarized from Florez et al. (56).
Injectable Therapy
Injectable agents for treatment of insulin-deficient T2D include traditional insulin preparations, newer insulin analogs, amylin, and incretin
mimetics (see Fig. 2). Insulin and the insulin analogs increase circulating
insulin levels in the presence of declining β-cell function and diminished
endogenous insulin secretion. Insulin and analogs, available in both longacting and rapid-acting formulations, can be used in combination with oral
agents in T2D or as insulin replacement therapy in long-standing, insulindeficient T2D (56). Therecent additions to the market, the incretin mimetic
exenatide and the synthetic amylin, pramlintide, exploit novel mechanisms
related to effects on glucagon secretion, gastric emptying, and satiety to
improve glycemic control (58, 59).
Other Strategies for Reduction of Comorbidities and Complications
In addition to hyperglycemia, individuals with T2D often have a constellation of other metabolic abnormalities which increase their CVD risk
(60–64). Risk determinants of CVD include the presence or absence
of coronary heart disease (CHD), other clinical forms of atherosclerotic
disease, and the major risk factors: high LDL cholesterol, cigarette smoking,
hypertension, low HDL cholesterol, family history of premature CHD
(defined as a relative with CHD younger than 65 years for women and 55
Florez et al.
years for men), and age (men ≥ 45 years, women ≥ 55 years). It is important to point out that diabetes is considered to be a CHD equivalent, so the
goal for LDL cholesterol is <100 mg/dl. Based on these risk determinants,
the Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III) identifies three categories
of risk that modify the goals and modalities of LDL-lowering therapy (65)
(Tables 4 and 5). In very high-risk persons, an LDL-C goal of <70 mg/dl is a
therapeutic option on the basis of available clinical trial evidence (66). The
justification for the more aggressive LDL targets in patients with diabetes
with CVD is based on three large statin-outcome trials: the Heart Protection
Study (HPS), the Treating to New Targets (TNT) Study, and the Incremental
Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL) Study,
which also identified the diabetic subgroup as a cohort of patients with high
residual risk even on statin therapy (67–69).
Table 4
ATP III classification of LDL, total, and HDL
cholesterol (mg/dl).∗
LDL cholesterol
Borderline high
Very high
Total cholesterol
Borderline high
HDL cholesterol
∗ ATP indicates Adult Treatment Panel; LDL –
low-density lipoprotein; HDL – high-density lipoprotein.
Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III) (65).
Risk reduction strategies have been demonstrated to be highly effective
in a number of studies (70). The MICRO-HOPE Study included 3,577 individuals with diabetes, with and without hypertension, and compared the
cardiovascular event rates with the angiotensin-converting enzyme (ACE)
inhibitor, ramipril, vs. placebo (71). The results showed that treatment with
Type 2 Diabetes
Table 5
Three categories of risk that modify LDL cholesterol goals
Risk category
CHD and CHD risk
Multiple (2+) risk factors
0–1 risk factor
LDL goal (mg/dl)
CHD indicates coronary heart disease. Diabetes is a CHD equivalent.
Adapted from Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel III) (65).
ramipril lowered the risk of the primary outcome of combined MI, stroke,
or CVD mortality by 25%, MI by 22%, stroke by 33%, and cardiovascular
death by 37%. Lowering serum cholesterol has been demonstrated in many
studies to be effective at reducing CVD risks, both as primary and secondary
prevention. Recent studies have questioned whether even more aggressive
LDL-cholesterol lowering in high-risk individuals should be the appropriate
target of such treatment (67, 72).
An important study used a focused, multifactorial intervention with strict
targets and individualized risk assessment in patients with T2D and microalbuminuria who were at increased risk for macrovascular and microvascular
complications (73, 74). These data suggest that a long-term, targeted, intensive intervention involving multiple risk factors reduces the risk of both cardiovascular and microvascular events by about 50% among these patients.
The advantages of a multifactorial approach to the reduction of cardiovascular risk are obvious. The challenge remains to ensure that this approach can
be widely adopted.
Management of Diabetes in the Older Adult
The degree of benefit controlling blood glucose, lipids, and blood pressure in older adults with diabetes to reduce microvascular and macrovascular
complications may depend on the patient’s life expectancy, functional status,
and comorbidities (75). The heterogeneity of this population is a key consideration for clinicians developing intervention strategies and establishing
clinical targets. The goals of physicians and other providers caring for the
elderly diabetic patient should be to optimize glycemic control and reduce
associated cardiovascular risk factors in an effort to maximize long-term
quality of life. On the other hand, for frail older adults, particularly those
with severe comorbidities and disabilities, aggressive management is not
likely to provide benefit and may even result in harm as a consequence of
frequent hypoglycemia associated with aggressive glycemic control (56).
Florez et al.
In the management of diabetes in older adults, it is necessary to assess
for the presence of geriatric syndromes, a group of conditions associated
with functional decline and disability that are more prevalent in the elderly.
These syndromes and the different comorbidities in the elderly make the
management of diabetes in this population a challenging task. Common geriatric syndromes in older adults with diabetes include depression, cognitive
impairment/dementia, urinary incontinence, falls, and polypharmacy (75).
Diabetes is associated with depression in the elderly and mood disorders
may lead to worsening of glycemic control and more diabetic complications.
Hyperglycemia is associated with a greater risk for cognitive impairment,
especially Alzheimer’s disease (AD) and vascular dementia. It is known that
the longer the duration of diabetes, the higher the prevalence of dementia
and also that those treated with insulin are at higher risk. Urinary incontinence can be exacerbated because of poor glycemic control and/or because
of comorbidities like heart failure and prostate disease or by medicationrelated side effects. All elderly diabetic patients should be screened for falls,
since comorbidities, diabetic neuropathy, and medications may increase the
risk of falls. Many older adults with diabetes use five or more medications (a
common definition of polypharmacy), which may or may not be appropriately prescribed and may interact with other medications or with a disease
Psychosocial Screening
Basic assessment of psychosocial status should be included as part of
the medical management of diabetes. Psychosocial screening should include
patient attitudes about illness, expectations for medical care and outcomes,
affect/mood, general and diabetes-related quality of life, available resources
(financial, social, and emotional), and psychiatric history. It is best to incorporate psychological assessment into routine care rather than wait for identification of a specific problem or deterioration in psychological status.
Opportunities for screening of psychosocial status occur at diagnosis, during
regularly scheduled management visits, during hospitalizations, at discovery
of complications, or at the discretion of the clinician when problems in glucose control or adherence are suspected or identified.
Standards of care for diabetes recommended by the American Diabetes
Association are revised periodically and published yearly in the journal
Diabetes Care. The implementation of the standards of care has been
suboptimal in most clinical settings. A report from the National Health
and Nutrition Education Survey (NHANES) 1999–2000 and NHANES III
Type 2 Diabetes
surveys demonstrated that only 37% of US adults with diabetes achieved an
HbA1c of <7%, only 36% had a blood pressure < 130/80 mmHg, and only
48% had a cholesterol < 200 mg/dl (76). Only 7.3% had overall “good control,” i.e., attained target goals for all vascular risk factors. Another study
addressing quality of diabetes care in the United States showed that during
1988–1995 there was a gap between recommended diabetes care (HbA1c <
7%, annual dilated eye exam, annual foot exam, evaluation for urine albumin
or protein excretion, achieving blood pressure and lipid goals), and the care
that patients actually received (77). In that study, only 28.8% of diabetics
even had an HbA1c measurement, 63.3% reported a dilated eye exam, and
54.8% had had a foot exam within the previous year. Eighteen percent of
these diabetic individuals had an HbA1c > 9.5%.
While many interventions to improve adherence to the recommended
standards have been implemented, providing uniformly effective diabetes
care remains a challenge. Education of health professionals and patients
alike is one key to better success. Improved access to health care and education for all is critical. Multidisciplinary teams are ideal to provide care
for people with chronic conditions like diabetes and to encourage patients
to be involved in appropriate disease self-management. Cooperative efforts
between health care providers, health policy experts, public health officials
and patients are needed to change the climate and outcomes for individuals
with diabetes and at risk for diabetes in the United States (Table 6).
Table 6
Summary of recommendations for adults with diabetes
Glycemic control
Preprandial capillary plasma glucose
Peak postprandial capillary plasma glucose†
Blood pressure
90–130 mg/dl (5.0–7.2 mmol/l)
<180 mg/dl (<10.0 mmol/l)
<130/80 mmHg
<100 mg/dl (<2.6 mmol/l)
<150 mg/dl (<1.7 mmol/l)
>40 mg/dl (>1.1 mmol/l)§
∗ HbAlc goal for selected individual patients (those with short duration of diabetes, long
life expectancy, and no significant cardiovascular disease) may be lower than the general
goal if this can be achieved without significant hypoglycemia or other adverse effects of
treatment. Conversely, less stringent HbA1c goal may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advance microvascular or macrovascular complications, extensive comorbid conditions, or frail elderly patients.
HbA1c, hemoglobin A1c; LDL, low density lipoprotein; HDL, high density lipoprotein
(Adapted from: American Diabetes Association) (1).
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