Continue to Overview - Part 2
Diabetes Mellitus: Challenges and Opportunities
Final Report and Recommendations
Overview - Part 1
Summary of Scientific Accomplishments, Gaps, and
Opportunities Identified at the Trans-NIH Symposium "Diabetes Mellitus: Challenges and
Opportunities" September 4-5, 1997, Bethesda, Maryland
Magnitude of the Health Problem
Approximately 16 million Americans have diabetes, a chronic disease that has an enormous
adverse impact on people who are afflicted, as well as a staggering economic cost to the
nation-approximately $92 billion annually, which includes direct medical costs and
indirect costs such as disability, work loss, and premature mortality. About one third of
these people are unaware that they have diabetes. There are 1,700 new cases of diabetes
diagnosed every day and 625,000 new cases diagnosed every year.
Serious health complications result from
diabetes, including eye, heart, kidney, and nerve damage. Diabetes is the leading cause of
new cases of blindness among adults 20 to 74 years of age: 12,000 to 24,000 new cases each
year. It is the leading cause of end-stage renal disease (ESRD), accounting for 19,790 new
cases in 1992. Additionally, over half of lower limb amputations in the United States
occur among persons with diabetes. The number of amputations among persons with diabetes
averaged 54,000 from 1989 to 1992. A disproportionate share of that burden is borne by
racial and ethnic minorities.
Basic research underpins many therapies developed
for diabetes: insulin pumps, various forms of insulin, and strategies for treating type 1
diabetes and numerous medications for type 2 diabetes. Even with these therapies, diabetes
remains an exceedingly difficult disease to control. The health complications that result
from uncontrolled or poorly controlled diabetes are largely responsible for the toll
diabetes takes on human health and on the health care system. Thus, effectively treating
and preventing diabetes and its complications are major goals of research.
Type 1 Diabetes
Type 1 diabetes (formerly called insulin-dependent diabetes) affects an estimated 500,000
to 750,000 Americans. The disease may occur at any age, and in some populations about 1
percent of all newborns will develop type 1 diabetes during their lives. It is usually
diagnosed in childhood or young adulthood. Daily injections of insulin are necessary to
sustain life, and compliance with this treatment regimen is often difficult, especially
for teenagers. In this form of the disease, the body's immune defense system destroys the
insulin-producing ß-cells of the pancreas-an "autoimmune" disease process.
Type 1 diabetes appears to be increasing
worldwide. Although significant progress has been made to define the illness more
completely, there is a major lack of understanding of the mechanisms involved in the
cause, treatment, and prevention of diabetes. It is unclear what type of treatment might
prevent subjects from developing overt disease. While our understanding of how children
may get type 1 diabetes has improved, there is still no therapy other than insulin or
pancreas transplantation. The challenges, opportunities, and need for research are
compelling and pressing.
Environmental factors, in combination with
genetic susceptibility, are thought to initiate the type 1 diabetes disease process.
Rigorous studies on known and unknown infectious agents and their relationship to islet
cell autoimmunity are needed. The role of genetics in autoimmune diabetes needs to be
examined in a worldwide effort to determine genetic risk and its mechanism.
Therapy for diabetes, though complex, has become
more focused in the past decade. Insight into the process of diabetes and its
complications has led to the development of improved therapeutic strategies. Metabolic
goals that result in improved longterm outcome, and the means of achieving those goals,
have been established for type 1 diabetes on the basis of high quality clinical research
such as the Diabetes Control and Complications Trial (DCCT). The largest diabetes clinical
trial to date, this study demonstrated that the complications that result from diabetes
can be prevented or reduced. This major multicenter clinical trial compared the effects of
intensive insulin therapy to the outcome of standard diabetes treatment on the
microvascular complications of type 1 diabetes. Results indicated that very carefully
controlled blood glucose levels dramatically reduce the risk of life-threatening
complications due to type 1 diabetes. The intensive metabolic control achieved in this
study reduced diabetic eye, kidney, and nerve disease by 76 percent; 3,556 percent; and 60
percent, respectively, compared with standard therapy. Clinical data on type 2 diabetes,
although not as definitive as for type 1 diabetes, support achieving and maintaining the
metabolic goal of normal blood glucose levels.
In addition to the therapies aimed at achieving
goals of glucose levels that will prevent or delay the development of long-term
complications of type 1 diabetes, other therapies have been developed and demonstrated to
ameliorate long-term complications. Treatment of hypertension and early stages of diabetic
renal dysfunction with blood-pressure-lowering agents, and specifically with
angiotensin-converting enzyme (ACE) inhibitors, and laser therapy of diabetic eye disease
and clinically significant macular edema represent two prime examples of such therapy.
Type 2 Diabetes
Type 2 diabetes mellitus (formerly called non-insulin-dependent diabetes) is the most
common form of diabetes; it is responsible for more than 90 percent of cases in most
populations. It is a complicated, multifactorial disease syndrome. Type 2 diabetes has a
strong inherited component, but the susceptibility genes for the vast majority of cases
remain unknown. Although this is a genetically heterogeneous disease, once the full-blown
type 2 diabetes syndrome is established, there are common abnormalities that are observed
in most patients. There are characteristic metabolic derangements in three target organs:
the pancreatic islets, the liver, and peripheral tissues. In type 2 diabetes, multiple
defects in pancreatic islet function exist such that ß-cell insulin secretion cannot
compensate for the insulin-resistant state, and relative or absolute insulin insufficiency
exists. In the liver, increased glucose production is a characteristic feature in patients
with elevated fasting blood glucose levels. This increase in glucose output by the liver
is a significant cause of hyperglycemia. Peripheral tissues such as skeletal muscle and
adipose tissue are insulin resistant, and this is a fundamental abnormality in this
disease.
With respect to the fundamental causes of this
complex metabolic syndrome, type 2 diabetes is recognized as a polygenic disease, meaning
that multiple diabetes susceptibility genes may exist in the population at large and that
multiple genetic determinants within a single individual may contribute to the disease. In
addition to these genetic influences, environmental factors are also important
contributors to the development of diabetes. In this regard, most type 2 diabetes patients
(80 to 90 percent) are obese. Obesity and reduced physical activity are major risk factors
and causal determinants in the development of type 2 diabetes.
Insulin resistance, the impaired metabolic
responsiveness of muscle and fat to the action of insulin, is a major contributor to the
development of type 2 diabetes. Insulin resistance causes increased insulin production,
and evidence suggests that diabetes results in those individuals whose ß-cells are
incapable of continually compensating for this defect in insulin action. However, defects
in ß-cell function may be present prior to clinical onset of type 2 diabetes.
Understanding completely the molecular basis of insulin action is crucial to unraveling
the specific step or steps that are defective in insulin-resistant states. Potential roles
of fat, muscle, and liver metabolism and insulin resistance in these tissues must also be
considered as contributing factors in the development of the disease.
The recent successes in cloning of several
susceptibility genes relevant to type 2 diabetes have opened up new avenues of research.
Moreover, recent technological advances in gene typing and sequencing, as well as advances
in methods of gene mapping for complex disorders, suggest that continued investment in
genetic studies of type 2 diabetes and related disorders will likely pay great dividends.
Significant recent advances have been made in the
field of obesity research, including the discovery and cloning of the mouse leptin and
leptin receptor genes and other mouse obesity genes. All of these genes have human
counterparts whose role in human obesity is under intense investigation. The potential
relevance of this important area of ongoing research to diabetes cannot be overstated.
Therapy
Intensive treatment of type 1 diabetes is effective in improving long-term outcome.
However, it is labor intensive, difficult to implement for many patients with type 1
diabetes, and does not achieve normal levels of blood glucose. Using currently available
intensive treatment methods, the levels of glucose control attained were well above what
is considered the normal range. The implementation of intensive therapy also is limited by
the accompanying increased frequency of severe low blood glucose levels. In addition,
weight gain that accompanies intensive therapy has resulted in an increasing prevalence of
overweight diabetic patients. Finally, currently available methods are particularly
problematic in children and adolescents, which is especially troublesome since our best
clinical data support early intervention as being most effective.
The options for treatment of type 2 diabetes have
expanded in the past three years. In addition to diet, exercise, sulfonylurea drugs, and
insulin, the recent availability of new oral medications with different mechanisms of
action and the potential for numerous therapeutic combinations have provided new methods
to achieve improved blood glucose control. Each of the medications has advantages and
disadvantages, and the optimal medication regimen is unknown and may differ for each
patient. However, many patients with type 2 diabetes ultimately fail dietary therapy and
oral agents and require insulin.
In many respects, the limitations of therapy for
type 2 diabetes parallel the problems with treatment of type 1 diabetes: inadequate
methods to achieve normal blood glucose levels, undesirable side effects, levels of
compliance that are difficult to achieve, and nonaggressive application of treatment
strategies. The challenge is to refine currently available intensive therapies of type 1
and type 2 diabetes (directed at achieving normal blood glucose levels), making them more
accessible, user-friendly, and safe, and to develop new methods of therapy for both type 1
and type 2 diabetes.
In general, basic science has advanced
understanding of the progression of diabetes and its abnormal metabolism, providing the
foundation for the development of new therapies. In addition to improving the application
of established therapies, including the investigation of whether specific therapies and
combinations are more effective for specific subgroups of type 2 diabetes, general
emphasis needs to be placed on continued basic research.
Despite well-publicized goals and
"standards" of therapy, many of which are supported by high-quality research
data, the implementation of the therapies and the achievement of goals has been limited at
best. Metabolic control in type 1 and type 2 diabetes remains substandard, and the
frequency of recommended examinations (feet, eyes, and measurements of blood glucose,
lipid status, and kidney function) is inadequate. Generally, diabetes and its
complications are not aggressively treated. The treatment of diabetes, unlike treatment
for many other diseases, requires extensive patient involvement and affects most aspects
of daily activity and lifestyle. Behavioral research has already identified key variables
associated with adherence to treatment regimens, strategies for improving patient-provider
interactions, and self-management skills that can promote adherence. In addition,
assessment tools that can identify barriers to adherence in individual patients and
treatment strategies to lower these barriers have been developed.
A major challenge is to improve application of
currently available therapies to enhance the long-term health of diabetes patients.
Insight into the behavioral barriers that prevent application of effective therapies and
the development of means to lower those barriers will help implement current and future
therapies.
Microvascular Complications:
Diabetic Eye Disease, Kidney Disease, and Nerve Disease
In the 1990s, the central therapeutic problem in diabetes is prevention and treatment of
its chronic complications. In the United States, diabetic eye disease is the leading cause
of new blindness in people age 20 to 74 years. Diabetic kidney disease (nephropathy)
accounts for 35 percent of all new cases of end-stage renal disease. People with diabetes
are the fastest growing group of renal dialysis and transplant recipients. Over 60 percent
of people with diabetes are affected by diabetic nerve disease, which causes a variety of
disorders. Approximately 60 percent of people with type 2 diabetes have hypertension.
Accelerated lower extremity artery disease in conjunction with diabetic nerve disease
makes diabetes account for 50 percent of all non-traumatic amputations in the United
States.
The DCCT demonstrated that a sensitive and
relatively stable indicator of blood glucose concentration (hemoglobin A1c) is the
dominant predictor of diabetic eye, kidney, and nerve disease and that intensive therapy
to reduce hemoglobin A1c in people with type 1 diabetes can reduce the appearance and
progression of these complications. While several mechanisms by which high blood glucose
causes small blood vessel and nerve damage have been identified, the interrelationships
among the mechanisms that may cause diabetes complications have not been systematically
studied. Different mechanisms may play a dominant role at different stages or in different
cell types of target tissues. Also, development of interventions for modifying known
pathways to complications is limited.
The possibly complex genetic nature of
susceptibility to complications could make certain genetic studies of families very
challenging. At present, there is considerable evidence for a genetic basis for
susceptibility to diabetic kidney disease. Despite this progress, many challenges remain.
For example, data to support a genetic predisposition for diabetic eye disease are very
limited. For diabetic nerve disease, very few family studies have been conducted.
Diabetic Eye Disease: The DCCT
demonstrated that reducing high blood glucose levels can reduce the incidence and
progression of diabetic eye disease in type 1 diabetics, and smaller studies suggest that
the same is true for type 2 diabetics. Laser therapy (photocoagulation) is highly
effective in reducing the risk of blindness if treatment occurs early enough. High blood
pressure is known to be an independent risk factor for diabetic eye disease, and another
study suggests that blood-pressure-lowering medications may have a protective effect. High
blood cholesterol may be an additional risk factor.
While many advances have been made, there are
significant challenges to progress in this area. The initiating mechanism for background
diabetic eye disease is not clear. The role of growth hormone and other growth factors in
the process of diabetic eye disease remains to be fully evaluated. Promising drug
therapies for the treatment and prevention of eye disease are limited by the lack of
efficient means of selective drug delivery to the eye. Fifty percent of diabetic patients
do not receive appropriate eye care, resulting in unnecessary vision loss.
Diabetic Kidney Disease: The DCCT
demonstrated that decreasing high blood glucose levels reduces the incidence and
progression of diabetic kidney disease in type 1 patients. Studies suggest that genetic
influences play a critical role in determining which patients progress to kidney failure
(ESRD). In animal models, various manifestations of diabetic kidney disease can be
prevented.
The results of a recent clinical trial
demonstrated that the drug captopril, an ACE inhibitor, reduced the rate of kidney failure
and death in persons with type 1 diabetes and kidney disease. ACE inhibitors are thought
to target and reduce elevated blood pressure in the vessels of the diabetic kidney and
thereby prevent the damage that leads to kidney failure. In this study, half of the
patients with type 1 diabetes took captopril and the other half took a placebo. High blood
pressure was treated in both groups. Researchers found that patients on captopril had a 50
percent reduced risk of death and kidney failure and, as a group, a 48 percent reduced
risk of doubling serum creatinine. Serum creatinine is used to estimate kidney function
and time to kidney failure; doubling represents a 50 percent loss of function. The study
showed that patients with more advanced kidney disease experienced the greatest benefits.
A recent economic analysis determined that the use of captopril in diabetic nephropathy
would provide significant savings in health care costs; in addition, it would result in
savings in indirect costs, which reflect the broader social benefit.
There are many challenges for research in this
area. Current clinical indicators for the development of diabetic kidney disease are
either not specific or not sensitive enough for genetic studies or intervention studies.
Molecular aspects of the disease process are largely unknown. The strong genetic factors
underlying diabetic kidney disease are currently unknown. The reasons for reduced survival
of people with diabetes and ESRD treated with dialysis are not known.
Diabetic Nerve Disease: Diabetes affects
many parts of both the peripheral and autonomic nervous systems. Autonomic neuropathy
contributes to abnormal function of the gastrointestinal and genitourinary systems, which
in turn contributes substantially to the morbidity of diabetes. Peripheral neuropathy
causes pain as well as sensory loss that contributes to damage to the feet and lower
extremities and can lead ultimately to amputation. The DCCT established unequivocally that
the intensively treated group had an overall incidence reduction of 64 percent in nerve
damage. Thus, intensive control is important in treating diabetes to prevent or delay
nerve damage. In addition, therapies directed specifically at preventing or reversing
neuropathy are under investigation. Further information is needed to understand the
mechanisms underlying diabetic neuropathy, including the roles of glucose toxicity and
microangiopathy in pathogenesis.
There is no defined area within NIH having
diabetic nerve disease as its primary focus, and the challenges in this area are many. The
potential interrelationships among mechanisms implicated in nerve damage caused by high
blood glucose levels are not understood, and molecular aspects of the disease process are
largely unknown. Standardized measures of small nerve fiber sensory perception are
unsatisfactory. The clinical potential of medications showing promise in laboratory
animals is unknown. Mechanisms by which chronic, repeated high and low blood glucose
levels may damage the nervous system have not been systematically studied.
Macrovascular Complications
Heart disease (coronary artery disease caused by the build-up of fat deposits on artery
walls) is the leading cause of death in patients with type 2 diabetes and contributes to a
tragically shortened lifespan for people with type 1 and type 2 diabetes. More than 80
percent of people with diabetes die of some form of heart or blood vessel disease.
However, relatively little is known about the progression of disease of the large blood
vessels in the setting of diabetes. Many traditional risk factors for coronary artery
disease- such as high blood pressure, low high-density lipoprotein (HDL) cholesterol, and
high triglycerides-are increased in type 2 diabetes, but other factors contribute to the
enhanced prevalence of coronary artery disease. High blood glucose levels have emerged as
one encompassing factor that affects nearly all these factors.
Six clinical trials have demonstrated a
relationship between coronary artery disease events and mortality and glucose control.
However, these studies have almost uniformly excluded diabetic patients from
participation; direct data on the benefits and risks of specific therapies focused on
heart disease and its risk factors in diabetes are lacking. A major unanswered question is
whether increasing insulin levels with externally administered insulin affects the
potential for developing atherosclerosis. In three early large- population studies,
increased insulin production was identified as an independent risk factor for coronary
artery disease. A key issue now is how controlling blood glucose levels with insulin or
other approaches in the presence of insulin resistance would affect vascular injury.
Nevertheless, when it comes to the treatment of cardiovascular disease risk factors, the
current consensus is to treat patients with diabetes more aggressively than nondiabetic
patients.
One new oral drug for type 2 diabetes suppresses
glucose production by the liver and has a modest effect to improve insulin action in
muscle. It decreases circulating low- density lipoprotein (LDL) cholesterol and
triglyceride levels and has a slight effect to increase HDL cholesterol, and is associated
with weight loss and improvement in insulin resistance. Previous oral diabetes
medications, which stimulate pancreatic insulin secretion, have been available for many
years for the treatment of type 2 diabetes. They increase circulating insulin levels and
are associated with weight gain. In addition, they can induce vascular constriction, which
may adversely affect the coronary arteries of patients with atherosclerotic disease.
Another new oral medication for type 2 diabetes is an insulin-sensitizing agent that
improves glucose uptake into muscle and reverses many components of the insulin-resistance
syndrome such as high blood triglyceride level, low HDL cholesterol, hypertension, and
high fatty acids levels. Research indicates that this class of agents could have vascular
protective effects. Since it is now possible to individualize therapy targeted at glucose
control, it is critical to investigate the optimal therapeutic strategies for prediabetic
and diabetic patients who are at marked increased risk for coronary artery disease.
Continue to Overview - Part 2
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