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SIDE NOTES ON DR.TOLINTINOS DIABETES LEC

*There is an urgent need to treat and prevent diabetes mellitus as

the prevalence of the disease continues to rise globally.
As early as Sept 2000, non medical journals like Newsweek, has
recognized Diabetes as a growing health risk short of a global
pandemic in a few years. The disease burden in all aspect of human
life caused by diabetes mellitus cannot be overemphasized.
*The rapidly increasing global prevalence of diabetes 1 is a significant
cause for concern.
The International Diabetes Federation (IDF) estimates that diabetes
currently affects 246 million people around the world. By 2025, they
predict it will affect 380 million,2 representing a doubling of the
prevalence of 194 million in 2003.3 This alarming increase of
diabetes prevalence is projected to occur because of dietary and
other lifestyle factors.3
The five countries with the largest numbers of people with diabetes
are India (40.9 million), China (39.8 million), the United States
(19.2 million), Russia (9.6 million), and Germany (7.4 million).4
The five countries with the highest diabetes prevalence are Nauru
(30.7%), United Arab Emirates (19.5%), Saudi Arabia (16.7%),
Bahrain (15.2%), and Kuwait (14.4%).2
The largest increases in diabetes prevalence will take place in
developing countries.3
*Why will Asia become the center of the new diabetes epidemic?
Reasons why Asia will become center of new epidemic in diabetes
include increased obesity, change in type of food intake and
sedentary lifestyle. Picture shows the evolution from classical food,
to modern westernized eating patterns, to more obese individuals,
especially young people.
*The Global Burden of Diabetes and Its Complications Is Increasing
Diabetes is the fourth leading cause of disease-related
death worldwide.
Over 3 million deaths yearly are tied directly to diabetes. 1
In developed countries, diabetes is the leading cause of blindness
and impaired vision among adults. Diabetes is also the most
frequent cause of nontraumatic amputation and is responsible for
over 1 million amputations each year.1
People with diabetes are at 2 to 4 times greater risk of developing
cardiovascular disease than individuals without diabetes. 1
*AusDiab Australian Diabetes, Obesity and Lifestyle Study, first
population based study in developed country to use OGTT
*An increasing incidence and prevalence of type 2 diabetes in the
young is being observed in developed countries (U.S.A., E.U.).
Sedentary lifestyle and changing eating patterns are the main
contributors, leading to increased incidence of type 2 diabetes
mellitus.
*In the UKPDS, 50% of patients had a diabetes-related complication
at diagnosis.1
Neuropathy affects around 70% of those with diabetes at the time of
diagnosis, leading to 55,00060,000 amputations in the USA each
year.2
Retinopathy, glaucoma or cataracts occur in around 10% of people
after 15 years of diabetes. Blindness affects around 2%.2
Nephropathy is the leading cause of end-stage renal disease. 2
Coronary heart disease (CHD) affects 7.520% of all people with
diabetes over 45 years of age in the USA. The risk of CHD is two to
four times higher than for those without diabetes.2
Cerebrovascular disease: the risk of stroke is two to four times
higher in people with diabetes. Fifteen percent of people with type 2
diabetes die from stroke.2
The risk of peripheral vascular disease is four to eight times higher
in people with type 2 diabetes.2
1. UK Prospective Diabetes Study Group. UKPDS 33. Lancet 1998;
352:837853.
2. World Health Organization/International Diabetes Federation. The
economics of diabetes and diabetes care: a report of the Diabetes
Health Economics Study Group. 1999 (WHO).

*Diabetic microvascular complications are most commonly

manifested in the eyes, kidneys, and nerves.
Diabetic retinopathy and diabetic macular edema: Diabetes is the
leading cause of new cases of blindness in adults between the ages
of 20 and 74 years.1 After 15 years of diabetes, 2% of patients
become blind and 10% develop severe visual disability.4
Diabetic nephropathy: In end-stage renal disease, diabetes accounts
for about 35% to 40% of new cases.1 People with diabetes make up
the fastest-growing group of renal dialysis and transplant recipients. 3
Diabetic neuropathy and amputations: Diabetes is the leading cause
of nontraumatic lower-extremity amputations, accounting for 50% of
amputations in the United States. About 60% to 70% of people with
diabetes have some degree of diabetic nerve damage.4
There is also a high frequency of atherosclerosis (macrovascular
disease) leading to increased risk of stroke and/or heart attack.
Cardiovascular disease: People with diabetes are 2 to 4 times more
likely to die from heart disease than people without diabetes.
Cardiovascular disease is responsible for 50% of diabetes-related
deaths.2
Stroke: A person with diabetes is 2 to 4 times more likely to suffer a
stroke than a person without diabetes.1
*Approximately 50% of people with diabetes have some level of
diabetic retinopathy; at 20 years diabetes, this climbs to >80%.
The 4 chronic complications of diabetes shown here are classified as
either microvascular (retinopathy, neuropathy, and nephropathy) or
macrovascular (cardiovascular disease).
While microvascular complications are known to be associated with
hyperglycemia, macrovascular problems may be the result of
multiple factors, including hyperglycemia, insulin resistance,
hypertension, and hyperlipidemia.
*Key Points:
Diabetic peripheral neuropathy (DPN) is not a single entity. The
clinical manifestations of DPN can be quite variable and reflect the
specific nerves involved in any given individual. Nerve involvement
can be focal or diffuse and thus lead to localized symptoms (eg
cranial nerve palsies) or more widespread deficits (eg bilateral lower
extremity sensory loss). DPN can also involve any branch of the
peripheral nervous system including sensory, voluntary motor and
autonomic nerves, with symptoms referable to each component.
Frequently autonomic, motor and sensory defects will co-exist but
selective involvement of certain nerve fiber types has been
described. An example would be the small fiber neuropathy
(involving primarily A delta and C fibers) that can produce painful
symptoms, sometimes in the absence of physical findings or
changes in measured nerve conduction velocities.
The most common type of DPN is distal symmetric polyneuropathy
that typically starts in the feet but may progress to a stockingglove distribution in all of the extremities. Sensory symptoms
predominate in this condition but motor and autonomic dysfunction
often co-exist.
* It is estimated that 4-10% of people with diabetes will develop a
foot ulcer. In other words 80,000-200,000 Canadians with diabetes
will be affected in their lifetime.
The numbers get even worse because statistics show that 14-24%
of those persons with diabetes and foot ulcers will require
amputation (either a partial foot amputation or a leg amputation)
because the ulcer won't heal. Quality of life is another big concern
because persons suffering from a foot ulcer are often reluctant to go
out for fear of offending others with the odour. Routines are
interrupted by the need for daily dressing changes, a situation that
may mean waiting around for the visiting nurse. It is not surprising
that foot ulcers are one of the biggest fears shared by persons with
diabetes.
*Skin
The clinical symptoms and complications of skin disease are
frequently more severe in the context of diabetes.
Digestive Problems
It is estimated that between 30 to 50 percent of all people with the
gastrointestinal tract.

Sexual Dysfunction
Although there are many causes of ED, diabetes accounts for the
largest number of cases. Between 50 to 70 percent of men with
diabetes develop erectile dysfunction.
The longer a man has diabetes, the greater his chances are of
developing the condition, according to the Canadian Male Sexual
Health Council. In 12 percent of men with diabetes, erectile
dysfunction is actually the first sign of the disease.
The Thyroid Gland
Studies have shown that the incidence of hypothyroidism seems to
be increased in both people with type 1 and type 2 diabetes,
especially women over the age of 40.
*Type 2 diabetes is caused by 2 metabolic abnormalities: insulin
resistance and relative insulin deficiency. In overt type 2 both
abnormalities are present, but their contribution to the development
of hyperglycemia may vary. Some patients have more profound
insulin resistance (x-axis), others may have very severe insulin
deficiency (y-axis). On the two ends of the spectrum are patients
with isolated severe insulin deficit and minimal insulin resistance and
patients with severe insulin resistance and minimal insulin secretion
deficit. The various possibilities are shown in the hyperbolic curve in
the graph.
*The pathophysiology of hyperglycemia in type 2 diabetes involves
three main defects: (1) insulin deficiency due to insufficient
pancreatic insulin release;
(2) excess hepatic glucose output; and (3) insulin resistance
(decreased glucose uptake) in peripheral tissues (including muscle
and fat) and the liver.1-3
Two pancreatic islet cell defects contribute to this pathology:

Beta cells produce insulin, which facilitates glucose entry

into tissues.4
In type 2 diabetes mellitus, a decline in functional beta-cell
mass causes insulin deficiency, which in turn contributes to
hyperglycemia.3-5

Alpha cells produce glucagon.6 Elevated glucagon levels

promote increased hepatic glucose output.1
In type 2 diabetes mellitus, excess glucagon and diminished insulin
secretion drive hepatic glucose output and contribute to
hyperglycemia.1
*Other specific types encompasses all other rare
pathophysiologies. Number of sub-categories increases with our
improved knowledge of genetics and other aspects of glucose
metabolism. Gestational diabetes is defined as carbohydrate
intolerance with onset or first recognition during a current
pregnancy. This form of diabetes is normally treated by
gynecologists/obstetricians and diabetologist/endocrinologists
together. It may resolve after delivery, but patients should be
followed closely afterwards as diabetes may persist, and they may
be at risk of developing diabetes in the future.
*UKPDS: Reduction in HbA1c Reduced Diabetes-Related
Complications1
This prospective observational study evaluated the relationship
between exposure to hyperglycemia over time and the risk of
diabetes-related complications among participants in the UKPDS.
The analysis of incidence rates included 4585 patients, while the
analysis of relative risk included 3642 patients.1
This study demonstrated that the risk of microvascular and
macrovascular complications in type 2 diabetes is strongly
associated with the degree of hyperglycemia. 1
As shown in the graph on left, the incidence rates for any endpoint
related to diabetes increased as the HbA1c level increased.1
The lower the HbA1c levels, the lower the risk of complications. No
threshold level for any complications below which risk no longer
decreased was observed. 1
In the observational analysis of the UKPDS cohort, every 1%
decrease in HbA1c was associated with clinically important reductions
in the risk of1:
Diabetes-related death (mean risk reduction 21%, P<0.0001)
Myocardial infarction (mean risk reduction 14%, P<0.0001)
Microvascular complications (mean risk reduction 37%, P<0.0001)
Peripheral vascular disease (mean risk reduction 43%, P<0.0001)

Data adjusted for age at diagnosis of diabetes, sex, ethnic group,

smoking, presence of albuminuria, systolic blood pressure, high and
low density lipoprotein cholesterol, and triglycerides.
*Current Treatment Goals for Glycemic Control
This slide reviews the treatment guidelines for diabetes
recommended by the American Diabetes Association (ADA), the
American College of Endocrinology (ACE), and the International
Diabetes Federation (IDF).
In terms of hemoglobin A1c (HbA1c), the ADA recommends a goal of
<7.0% (referenced to a nondiabetic range of 4.0%6.0%) for the
general population with diabetes, while advocating a more stringent
goal of <6.0% (or as close to normal as possible) for individual
patients, based on their risk of hypoglycemia and other factors. The
latter recommendation is based on the results of epidemiologic
studies showing a correlation between elevated glucose levels and
cardiovascular risk, and demonstrating that there is no threshold of
benefit; in other words, the closer the HbA1c is to the normal level
of 4.0% to 6.0%, the lower the risk.1
In contrast, ACE and IDF recommend a goal of less than 6.5% for all
patients (ACE: upper limit of normal = 6.0%). Both groups base
their recommendation on the epidemiologic analysis of the UK
Prospective Diabetes Study (UKPDS) data,2 which showed that the
risk for both microvascular and macrovascular complications of
diabetes increased at HbA1c values 6.5%.3,4
For preprandial glucose, the ADA recommends a therapeutic target
of 5.07.2 mmol/L (90130 mg/dL), whereas ACE and IDF suggest
using <6.0 mmol/L (<110 mg/dL) as the target.1,34
The ADA and IDF recommend that patients test their postprandial
glucose levels 12 hours after a meal. The ADA advises that
postprandial glucose values not exceed a peak value of 10.0 mmol/L
(180 mg/dL), while the IDF recommends <8.0 mmol/L (<145
mg/dL).1,4 ACE suggests that postprandial measurements be taken 2
hours after a meal and that the value should be <7.7 mmol/L (<140
mg/dL).3 ACE and IDF base their recommendations on the increased
cardiovascular risk associated with glucose values above these
levels, as well as the fact that in the nondiabetic population,
postprandial glucose levels rarely exceed 7.7 mmol/L (140 mg/dL). 3,4
*To refresh our memories, these are the treatment goals
recommended by the International Diabetes Federation and 2
American associations. It is appropriate to include country-specific
goals to replace the American goals.
The IDF and the AACE support raising the targets for patients who
cannot attain the stringent goals, whereas the ADA supports
lowering the targets for patients who are able to attain the lower
goals. ADA suggests that The HbA1c goal for the individual patient
is an HbA1c as close to normal (6%) as possible without significant
hypoglycaemia.
Glycaemic targets for children 12 years of age and pregnant
women differ from these targets.
An HbA1c of 7% corresponds to a laboratory value of 0.070. Where
possible, laboratories should standardize their HbA1c value to DCCT
levels (0.04-0.06). HbA1c target of 7.0% refers to approximately
15% above the upper limit of normal.
*A clinical study elucidated postprandial glucose, insulin, and
glucagon dynamics in patients with type 2 diabetes mellitus (n=12)
versus nondiabetic control subjects (n=11). The study also
recruited 12 patients with type 1 (juvenile) diabetes; results for this
group are not shown.1
After a large carbohydrate meal, mean plasma glucose
concentrations rose from
228 mg/100 ml to a peak of 353 mg/100 ml in patients with type 2
diabetes mellitus, compared with an increase from 84 mg/100 ml to
a peak of 137 mg/100 ml in nondiabetic subjects.1
In the 12 patients with type 2 diabetes mellitus, mean insulin values
represent measurements from five patients in the group; insulin
antibodies resulting from prior insulin therapy precluded insulin
immunoassay in the other seven patients in the group. Insulin rose
in normal subjects from a mean fasting level of 13 U/ml to a peak
of
136 U/ml at 45 minutes after the meal. The insulin response in
patients with type 2 diabetes mellitus was delayed and suppressed

in comparison, increasing from a fasting level of 21 U/ml to a peak

of only 50 U/ml at 60 minutes.1
Mean plasma glucagon levels declined significantly from the fasting
value of 126 g/ml to 90 g/ml at 90 minutes (p<0.01) in the
control group. In contrast, no significant fall in glucagon was
observed in patients with type 2 diabetes mellitus; in fact, the mean
plasma glucagon level rose slightly from the fasting level of 124
g/ml to 142 g/ml at 60 minutes and returned to 124 g/ml at
180 minutes.1
Therefore, this study showed that patients with type 2 diabetes
mellitus had a delayed and suppressed insulin response and failed to
exhibit normal postprandial declines in glucagon concentrations
despite their marked hyperglycemia. These abnormalities contribute
markedly to hyperglycemia both at the level of body tissues where
insulin is not sufficient to drive glucose uptake and at the level of
the liver where increased glucagon and decreased insulin spur the
liver to release glucose into the blood.1
*The Belfast Diet Study monitored a large cohort of patients aged
40 to 69 years (N=432) with newly diagnosed type 2 diabetes
(referred to Royal Victoria Hospital Diabetes Clinic). Patients were
monitored for 10 years while they maintained active dietary
management; drug therapy (insulin, tolbutamide, or metformin) was
instituted on the basis of weight and blood glucose according to
well-defined and uniform criteria, allowing for investigation of the
natural history and progression of type 2 diabetes. In the study,
assessment of fasting glucose and insulin levels was based on
fasting blood samples taken every three months over the first six
years of the study. These measures provided ongoing indices of
beta-cell function and insulin sensitivity.1
The investigators assessed beta-cell function and insulin sensitivity
by using Homeostasis Model Assessment (HOMA) analysis of fasting
plasma glucose (FPG) and insulin concentrations. Beta-cell function
and insulin sensitivity were expressed as percentages of values in a
lean young nondiabetic reference population.1
Patient were divided into four cohorts on the basis of the date of
failure of diet therapy:1

Diet therapy failure years 2 to 4: 41 patients

Diet therapy failure years 5 to 7: 67 patients

Diet therapy failure years 8 to 10: 51 patients

No diet therapy failure after 10 years: 173 patients

Analysis of the complete data showed that patients continuing on
diet alone for the first 10 years after diagnosis had a small but
progressive rise in FPG, associated with an equally progressive fall in
beta-cell function, but not with a change in obesity or insulin
sensitivity. Further, it demonstrated that failure of dietary therapy
within the first 10 years was associated with higher rates of glucose
rise and beta-cell decline. Failure of dietary therapy occurred earlier
with higher initial glucose concentration, lower initial beta-cell
function, and younger age, and for patients maintained on diet alone
for 6 months, greater obesity.1
The rate of rise in FPG was inversely related to the duration of
successful dietary therapy. Following the initial fall in weight during
the first months of dietary therapy, weight was maintained in all
groups while on dietary therapy alone. Beta-cell function during the
first six years of follow-up closely mirrored the increase in FPG.
There was no difference in insulin sensitivity in any group at six
months and no change during the further course of dietary therapy.1
The two graphs on the slide, showing data for the 67 patients who
required additional treatment with either oral antihyperglycemic
therapy or insulin during years 5 to 7, demonstrate the greater
contribution of progressive beta-cell dysfunction versus insulin
sensitivity to disease progression.
Beta-cell function, which was <50% at diagnosis, continuously
declined thereafter. In contrast, insulin sensitivity remained almost
unchanged.1
*After 3 months of diet therapy 4209 newly diagnosed,
asymptomatic patients with type 2 diabetes mellitus (FPG between
6.0 and 15.0 mmol/L) were randomized to 6 years of treatment and
follow-up in the United Kingdom Prospective Diabetes Study
(UKPDS). Results indicated a steady deterioration in glucose control
and a progressive decrease in beta-cell function, irrespective of the
type of antidiabetic therapy administered.1

Patients were randomized to receive either conventional therapy

(primarily dietary therapy alone) or intensive therapy (insulin or
sulfonylurea for nonobese and obese patients, or metformin for
obese patients). Beta-cell function and insulin sensitivity were
assessed in relation to a reference group of 40 normoglycemic
subjects aged 18 to 25 years and were estimated in the subsets of
subjects who remained on their allocated therapy over six years.
Beta-cell function and insulin sensitivity were assessed using HOMA
and HOMA 2, an updated model. HOMA 2 uses specific insulin and
proinsulin concentrations and combines them to provide the
equivalent of the radioimmunoassay for insulin. 1
Beta-cell function increased significantly between baseline and year
1 in patients treated with sulfonylurea (46%78%, p<0.0001) and
patients treated with metformin
(51%66%, p<0.0003) who remained on their allocated therapy
throughout six years of follow-up. Between one and six years,
however, beta-cell function deteriorated significantly (p<0.0001) to
52% in the sulfonylurea-treated patients and to 38% in metformintreated patients. Beta-cell function in patients who remained on
conventional/dietary therapy for six years showed a slight,
statistically insignificant increase from 51% at baseline to 53% after
one year but decreased significantly (p<0.0001) to 28% from one to
six years.1
Glycosylated hemoglobin (HbA1c) levels in obese patients allocated to
intensive therapy decreased after one year of treatment but
subsequently increased in both groups between years 1 and 6.
Obese patients allocated to conventional therapy demonstrated a
progressive increase in HbA1c levels over the six-year follow-up
period.1
*This is a diagram that demonstrates how Type 2 diabetes is
believed to develop.
The green broken line represents blood sugar.
The solid black line represents beta cell function.
The broken red line represents insulin secretion by the pancreas.
The blue solid line represents insulin sensitivity of peripheral tissues.
It is believed that the first thing that goes wrong in diabetes is that
insulin sensitivity of the tissues decreases (or you can say insulin
resistance increases), shown here as the blue line starts to go down.
At this point, the patient is believed to have pre-diabetes.
The beta cells compensate for this decreased sensitivity of the
tissues by producing more insulin, shown here as the broken red line
rapidly going up at the same time the blue line rapidly goes down.
The result is blood sugar, the green broken line, goes up only
slightly.
Eventually however, the beta cells become exhausted, shown here
as the solid black line progressively going down. As progressive beta
cell failure occurs, insulin level in the blood goes down, the broken
red line goes down.
The end result is the blood sugar steadily goes up, the green dotted
line goes up. This is the uncontrolled hyperglycemia that
characterizes diabetes.
*Use of TZDs is Associated with Increased Incidence of Congestive
Heart Failure
Results from DREAM (Diabetes REduction Assessment with ramipril
and rosiglitazone Medication) and PROactive (PROspective
pioglitAzone Clinical Trial In macroVascular Events) have shown
evidence for thiazolidinedione (TZD)-associated congestive heart
failure.1,2
The aim of DREAM was to prospectively assess the ability of
rosiglitazone to prevent type 2 diabetes mellitus (T2DM) in
individuals at high risk of developing the condition. Subjects
(n=5269) with impaired fasting glucose and/or impaired glucose
tolerance and no previous cardiovascular disease were randomized
to rosiglitazone (8 mg daily; n=2365) or placebo (n=2634) and
followed for a median of 3 years.1
Although cardiovascular event rates were similar in the two groups,
14 (0.5%) participants in the rosiglitazone group and 2 (0.1%) in
the placebo group developed heart failure (P=0.01).1
The aim of PROactive (PROspective pioglitAzone Clinical Trial In
macroVascular Events) was to prospectively assess whether
pioglitazone reduced macrovascular morbidity and mortality in
patients with T2DM who had evidence of macrovascular disease.
Patients (n=5238) were randomized to pioglitazone 15 mg to 45 mg

(n=2605) or matching placebo (n=2633), taken in addition to their

glucose-lowering drugs and other medications. The average time of
observation in the trial was 34.5 months.2
Although mortality rates from heart failure did not differ between
groups (P=0.634), there were reports of heart failure in 281 patients
(11%) in the pioglitazone group compared with 198 patients (8%) in
the placebo groups (P <0.0001).2
*Edema is Common During Treatment with Thiazolidinediones
(TZDs;
Pioglitazone)
In monotherapy studies of pioglitazone, edema was observed in
4.8% of patients receiving active treatment and 1.2% of patients
receiving placebo.1
In studies assessing pioglitazone in combination with a sulfonylurea,
edema was reported in 7.2% of patients receiving combination
treatment vs 2.1% of patients receiving only a sulfonylurea.
In combination therapy studies with metformin, edema was reported
in 6.0% of patients on combination therapy and 2.5% of patients on
metformin alone.
Edema was also observed more frequently in patients receiving
combination therapy with pioglitazone and insulin than in patients
receiving insulin alone (15.3% vs 7.0%).
*Major Adverse Events of Current Treatments for T2DM Limit
Efficacy
Adverse effects can limit the utility of any medication, and diabetes
drugs are no exception.
The most common adverse effects of the biguanide metformin are
gastrointestinal (GI) disturbances such as nausea and diarrhea; in
some patients, these effects are severe enough to cause the drug to
be discontinued. Lactic acidosis, a serious but rare side effect, has a
low rate of occurrence and is entirely preventablemetformin should
not be used in patients with renal impairment for this reason. Other
contraindications are hepatic dysfunction, congestive heart failure
(CHF), metabolic acidosis, dehydration, and alcoholism. 1
The risk of hypoglycemia and weight gain are increased with both
the sulfonylureas and the meglitinides, because these agents
increase insulin secretion independently of glucose stimulation. The
resulting hyperinsulinemia may have an adverse effect on the
cardiovascular system, although this association has been identified
only in epidemiologic studies and has not been supported by
prospective studies such as the UK Prospective Diabetes Study
(UKPDS).1
The thiazolidinediones (TZDs) rosiglitazone and pioglitazone are
primarily associated with weight gain and edema.1 Their use has also
been associated with increased rates of CHF, and they are
contraindicated in patients with this condition as well as those with
hepatic impairment.1,2 Another agent in this class, troglitazone, was
withdrawn from the market because of rare cases of idiosyncratic
hepatocellular injury. As a result, periodic liver function tests are
recommended for rosiglitazone and pioglitazone, but an association
with liver injury has not been shown with these agents.1
GI disturbancesnamely flatulence, abdominal discomfort, and
diarrheaare the primary adverse effects of the -glucosidase
inhibitors acarbose and miglitol. These effects often lead to
discontinuations.1
The only available incretin mimetic, exenatide, is likewise associated
with GI effects such as nausea, vomiting, and diarrhea. Nausea
sometimes has led to drug discontinuation.35 Although
hypoglycemia was reported in a tolerability trial, and hypoglycemia
rates were higher when exenatide was administered in combination
with a sulfonylurea or with a sulfonylurea plus metformin, there was
no increased hypoglycemia when exenatide was administered with
metformin alone.36
*Contraindications and Precautions for Current T2DM Treatments
Limit Use

All of the available therapeutics for type 2 diabetes mellitus (T2DM)

have contraindications or other limitations to use, as indicated by
package inserts.1
Metformin should not be used in patients with renal impairment, in
case of lactic acidosis. Other contraindications are hepatic
dysfunction, congestive heart failure (CHF), metabolic acidosis,
dehydration, and alcoholism.2
The thiazolidinediones (TZDs) rosiglitazone and pioglitazone have
been associated with increased rates of CHF, and they are
contraindicated in patients with this condition as well as in those
with hepatic impairment, while in patients with normal liver function
periodic liver function tests are recommended.2,3
Periodic liver function tests are also recommended for patients
receiving the glucosidase inhibitors acarbose and miglitol, and
these agents are not recommended in severe renal impairment. 2
*Summary of Diabetic Pathophysiologies
Islet-cell dysfunction
Dysfunction of both beta cells (insulin production) and alpha cells
(glucagon production) occur
Dysfunction begins years before diagnosis of type 2 diabetes
Dysfunction is progressive both before and after diagnosis
Incretin defects contribute to islet cell dysfunction
Insulin Resistance
Insulin resistance begins years before diagnosis
After diagnosis of type 2 diabetes there is little worsening of insulin
resistance
Insulin resistance reduces glucose uptake and utilization
Hepatic Glucose Overproduction
Overproduction is a result of islet-cell dysfunction and insulin
resistance
*An oral glucose load results in a greater insulin response than the
response caused by an intravenous glucose load matched to produce
a similar glycemic profile. This phenomenon is termed the incretin
effect because it is attributable
to the release of incretin hormones that occurs after oral but not
intravenous administration of glucose.1-3
Studies in humans and animal models have shown that the incretin
hormones
GLP-1 and GIP are believed to account for almost the entire incretin
effect that facilitates disposal of ingested nutrients. 2
A clinical study showed that the incretin effect was diminished in
patients with
type 2 diabetes (n=14) compared with metabolically healthy control
subjects (n=8).4
As shown on the graphs, glucose profiles were closely mimicked at
similar levels after oral versus intravenous glucose administration. 4
This matching of intravenous glucose loads to oral glucose loads
after ingestion was achieved in both control subjects and patients
with diabetes.4
Beta-cell secretory responses, reflected by increases in plasma
levels of immunoreactive (IR) insulin, are shown on the bottom
graphs in the slide. These graphs show that plasma IR insulin peaks
were delayed and diminished in patients with type 2 diabetes.
Although insulin levels were greater after oral glucose ingestion
versus intravenous administration in both groups, the incretin effects
were markedly less pronounced in diabetic patients.4
*The presence of nutrients in the gastrointestinal tract rapidly
stimulates the release of incretins: GLP-1 from L cells located
primarily in the distal gut (ileum and colon), and GIP from K cells in
the proximal gut (duodenum).1,2
Collectively, these incretins exert several beneficial actions, including
stimulating the insulin response in pancreatic beta cells and reducing
glucagon production from pancreatic alpha cells when glucose levels
are elevated.3,4 Increased insulin levels improve glucose uptake by
peripheral tissues; the combination of increased insulin and
decreased glucagon reduces hepatic glucose output.5