Olefsky JM. Prospects for Research in Diabetes Mellitus. JAMA. 2001;285(5):628-632. doi:10.1001/jama.285.5.628
Author Affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, and Department of Veterans Affairs, San Diego.
Diabetes mellitus is the sixth leading cause of death in the United
States, and morbidities resulting from diabetes-related complications such
as retinopathy, kidney disease, and limb amputation cause a huge burden to
the national health care system. Identification of the genetic components
of type 1 and type 2 diabetes is the most important area of research because
elucidation of the diabetes genes will influence all efforts toward a mechanistic
understanding of the disease, its complications, and its treatment, cure,
and prevention. Also, the link between obesity and type 2 diabetes mandates
a redoubled effort to understand the genetic and behavioral contributions
Diabetes mellitus affects between 6% and 7% of the US population equating
to about 16 million people. It is projected that there will be 800 000
new cases per year and a total of 23 million affected people within 10 years.1 Diabetes occurs in all populations and age groups
but is increasing in prevalence in the elderly and in blacks, Hispanics, Native
Americans, and Asians.2 Although deaths due
to cancer, stroke, and cardiovascular disease are declining, the death rates
due to diabetes have increased by about 30% in the past 12 years (Figure 1), and life expectancy for persons
with diabetes is approximately 15 years less than in those who do not have
diabetes. Diabetes is the sixth leading cause of death in the United States
and accounted for more than 193 000 deaths in the US in 1997. However,
this is an underestimate because diabetes contributes substantially to many
deaths that are ultimately ascribed to other causes, such as cardiovascular
Due to its complications, diabetes causes an enormous national burden
of morbidity. For example, diabetic retinopathy is the leading cause of blindness
in adults aged 20 through 74 years,4 and diabetic
kidney disease accounts for 40% of all new cases of end-stage renal disease.5 Diabetes is the leading cause for amputation of limbs
in the country.6 Heart disease and strokes
occur 2 to 4 times more frequently in adults with diabetes than in those who
are healthy. Diabetes causes special problems during pregnancy, and the rate
of congenital malformations can be 5 times higher in the offspring of women
with diabetes. In aggregate diabetes mellitus costs $105 billion annually
and involves 1 of every 10 US health care dollars and 1 of every 4 Medicare
Diabetes mellitus refers to a number of disorders that share the cardinal
characteristic feature of elevated blood glucose levels. The 2 most common
general categories of this disease are termed type 1
and type 2 diabetes.8
Research has enormously increased our understanding of type 1 and type 2 diabetes,
but much more remains to be done.
Documentation that elevated blood glucose levels are a direct cause
of long-term complications of diabetes has been a major accomplishment. The
Diabetes Control and Complications Trial (DCCT)9
and the United Kingdom Prospective Diabetes Study (UKPDS)10
both showed that control of blood glucose levels as close to normal as possible
prevents and retards development of diabetic retinopathy, nephropathy, neuropathy,
and macrovascular disease. The fact that each increment of improved control
of blood glucose levels reduces complications has focused clinical and research
efforts to elucidate disease mechanisms and to design new therapies. This
insight coincided with the development of home glucose monitoring systems
that make it possible to measure blood glucose levels throughout the day and
coincided with the availability of new insulin preparations; insulin delivery
devices, such as insulin pumps; and oral antidiabetic agents.11
Likewise, fetal malformations and perinatal morbidity are now known
to be due to elevated maternal glucose levels, and blood glucose control before
and after conception can reduce these risks to normal.7(pp863-870)
As a consequence, intensive efforts are now being made to diagnose and control
glucose levels in pregnant women with diabetes. Although these advances have
certainly helped improve the lives of patients, they do not provide an answer
because most patients with diabetes do not obtain adequate blood glucose control.
Type 1 diabetes accounts for 5% to 10% of diabetes, usually occurs in
children or young adults, and was formerly termed insulin-dependent
diabetes mellitus (IDDM) or juvenile-onset diabetes.12 This disease is caused by autoimmune
destruction of the pancreatic β cells that secrete insulin.12
The process involves a smoldering destructive process that can persist for
several years and ultimately leads to failure of insulin secretion. This autoimmune
process is due to genetic and environmental factors, and many genes contribute
to the pathogenesis. During the preclinical phase, a variety of autoimmune
antibodies directed against β-cell antigens serve as markers for the
prediabetic state, allowing for early detection and possible prevention strategies.
Patients with type 1diabetes require insulin therapy for survival, but blood
glucose is still difficult to control, and most patients ultimately develop
devastating complications of this disease. The present need is for improved
means of treating type 1 diabetes until it is practical to prevent its development.
New methods to achieve tight glucose control are needed that are practical
and can be administered to all persons with type 1 diabetes, including methods
of insulin delivery, better forms of insulin, and practical, affordable methods
of noninvasive self monitoring that can be coupled to patient-specific insulin
treatment regimens. Cure of diabetes will require permanent replacement of
lost β-cell function, which could involve islet cell transplantation,
regeneration of β cells, or development of immortalized insulin secreting
cell line. The ultimate aim in preventing disease onset will require a major
multidisciplinary effort to identify the genes that predispose to type 1 diabetes
and to identify the interacting environmental factors that trigger the disease.
A thorough understanding of the cellular and molecular causes of the autoimmune
destructive process will also be necessary.
Type 2 diabetes accounts for 90% to 95% of all patients with diabetes
and is increasing in prevalence, especially in minority populations.13 Type 2 diabetes is a heterogeneous, polygenic disorder,
and the responsible genes have been identified in selected subtypes of this
disease.7(pp691-705) Multiple diabetes genes
exist, and more than 1 gene is likely to be involved in an individual patient.
Some of the known environmental factors are obesity, a sedentary lifestyle,
and aging. Obesity probably is the major environmental factor contributing
to the increasing incidence of type 2 diabetes, and some of the hormonal,
genetic, and environmental factors that predispose to obesity have been identified.
Insulin resistance is a characteristic metabolic defect in the great
majority of patients with type 2 diabetes, and this defect can be demonstrated
in the prediabetic state many years prior to the development of hyperglycemia.14 As a consequence of insulin resistance, the β
cell produces increased amounts of insulin, and, if sufficient, the compensatory
hyperinsulinemia maintains glucose levels within the normal range (Figure 2). In those individuals destined
to develop diabetes, β-cell function eventually declines, and relative
insulin insufficiency occurs.15 Thus, insulin
resistance combined with β-cell failure leads to the decompensated hyperglycemic
A number of the molecular steps in the insulin action cascade have been
identified, and several components of the β-cell insulin secretion pathway
have been elucidated. Researchers are beginning to understand the complex
heterogeneous, genetic determinants of type 2 diabetes susceptibility. Efforts
to understand genetic variation, gene expression profiling, and the interaction
between genetic factors and environmental triggers must be intensified. This
information will reveal new targets for pharmacologic intervention. Researchers
also must continue work to understand the basic mechanisms that cause insulin
resistance and limitation of compensatory insulin secretion. Truly effective
treatments for type 2 diabetes will only come about when drugs are developed
to target and correct the 2 underlying defects.
Obesity is the major environmental risk factor promoting the rise in
type 2 diabetes incidence, and obesity is an increasing problem in the United
States. The genetic and environmental factors that control food intake and
energy expenditure must be identified so that we can improve the ability to
effect beneficial lifestyle changes and eventually develop drugs to treat
obese patients who are refractory to lifestyle modifications.
Much has been learned about the basic biology, epidemiology, and treatment
of diabetes, and extraordinary opportunities exist to understand, treat, cure,
and prevent diabetes. Coupled with these opportunities are substantial challenges
and hurdles. The Diabetes Research Working Group3
has identified several research areas that present unique opportunities for
major advances and changes that will have to be made in the scientific infrastructure
to implement this research endeavor.
Identification of the genetic components of types 1 and 2 diabetes is
the single most important area of research because elucidation of the diabetes
genes (alleles) will influence all efforts toward a mechanistic understanding
of the disease, its complications, and its treatment, cure, and prevention.
Completion of the Human Genome Project, the identification of a large number
of single nucleotide polymorphisms—which will make genome-wide association
studies for complex multigenic diseases feasible—the availability of
new technologies such as DNA gene chips and genetic manipulation of animals
have provided a solid foundation for rapid and tremendous advances in the
study of diabetes genetics.
The new knowledge and technology are available for application to diabetes
research, and a rigorous, multidisciplinary, well-funded effort is needed
to achieve these goals. Increased funding for individual scientists should
be a cornerstone of this approach, but new enhancements to the scientific
infrastructure are equally important. A multidisciplinary approach will require
coordination of many centers and different disciplines to identify the diabetes
genes. This will necessitate the establishment and availability of repositories
of DNA samples from phenotypically well-characterized diabetes patients spanning
a number of ethnic groups. A coordinating and planning agency should be established
to bring together and integrate the efforts of the National Institutes of
Health and of nongovernment organizations such as the American Diabetes Association
and Juvenile Diabetes Foundation International so that information is broadly
disseminated as rapidly as possible. Once the diabetes genes are identified,
it will be necessary to deal with the ethical, legal, and social issues involved
in the availability of such information.
Since type 1 diabetes is an autoimmune disease, the mechanisms underlying
this process must be thoroughly understood. Expanded efforts are needed to
identify the environmental triggers and how they interact with the genetic
predispositions. The basic cell biology of the immune destructive process
must be solved, and the specific β-cell autoantigens must be identified.
Hopefully this will lead to development of highly specific immunosuppressive
agents that will produce relatively few adverse effects.
Insulin resistance and impaired insulin secretion are the key metabolic
defects in type 2 diabetes. Increased efforts are necessary to dissect the
molecular components involved in insulin signaling, insulin secretion, and β-cell
growth and development. This research coupled with the efforts to identify
the diabetes genes, will provide a mechanistic understanding of the specific
defects in these pathways in type 2 diabetes, which should lead to the development
of more specific, and more effective, pharmaceutical agents directed against
defined molecular targets.
It is also essential to redouble efforts to understand the genetic and
behavioral contributions to obesity. Excess body weight is a widespread and
increasing problem in the United States and contributes to the high and increasing
incidence of type 2 diabetes. A thorough understanding of basic mechanisms
will enhance development of new methods of prevention and treatment. To facilitate
the country's ability to make rapid progress in these areas of scientific
opportunity, the Diabetes Research Working Group has recommended changes in
the infrastructure. These include the following:
Create new mechanisms and modify existing programs
to maximize recruitment, training, and career development of diabetes investigators.
Substantially strengthen and enhance National Institutes
of Health–sponsored diabetes centers by increasing the funding levels
and expanding their mission.
Create new regional centers for advanced technologies
required for metabolic and functional imaging studies, such as nuclear magnetic
resonance and positron emission tomography.
Enhance efforts to develop and characterize small-
and large-animal models of type 1 and type 2 diabetes and establish regional
centers for these animal models.
Expand procurement of human tissues, DNA samples,
and organs for diabetes research.
If aggressive efforts across the broad front of diabetes research are
accompanied by increased research funding in the areas of exceptional opportunity,
the future does indeed look promising and it is likely that major accomplishments
over the next 25 years will change the picture of diabetes prevention, treatment,
and cure. (Figure 3)
For patients with type 1 diabetes, the procedures of cadaveric islet
cell transplants will be largely perfected so that this can be performed either
without the need for immunosuppression or with the use of specific highly
focused immunosuppressive agents that will produce minimal adverse effects.
However, that supply of freshly isolated human islets will be insufficient
to provide transplants for all patients with type 1 diabetes. Replenishable
sources of β cells for replacement could be derived from xenografts,
possibly from genetically modified animals, or by creating a relatively inexhaustible,
functional insulin secreting β–cell line. Such cell lines will
be developed by learning to expand and grow large amounts of β cells
from progenitor cells or by genetically engineering immortalized β cells.
Identification of the genes that predispose to type 1 diabetes will
make it possible to identify individuals destined to develop the disease.
Coupled with the elucidation of the basic immunologic mechanisms that cause
autoimmune β-cell destruction and the development of specific targeted
treatments to interrupt this process, the prevention of type 1 diabetes will
become a reality. On the way to reaching these goals, substantial advances
in glucose monitoring and insulin delivery mechanisms, which will lead to
patient-specific treatment algorithms, will improve the outlook for patients
with type 1 diabetes.
The genes responsible for the predisposition to type 2 diabetes and
the mechanisms by which environmental factors bring out this predisposition
will be identified. In parallel with this genetic information, identification
of the cellular defects responsible for insulin resistance and impaired insulin
secretion in type 2 diabetes will lead to development of new drugs that will
be specific for defined molecular targets and that will be relatively free
of unwanted adverse effects. This should include new ways to prevent or treat
obesity. Once the predisposing diabetes genes are identified, it will be a
straightforward matter to genotype individuals for diabetes susceptibility.
The availability of new pharmaceutical treatments, together with the ability
to predict diabetes susceptibility will provide a sound basis for early intervention
and will lead to the prevention of type 2 diabetes in susceptible individuals.
If an appropriate health care delivery system can disseminate these new therapeutic
modalities to all diabetic patients, then control or prevention of diabetes
will be a reality. In this event, the burden of diabetes complications will
gradually diminish and ultimately disappear. Advances in methods of gene therapy
may make genetic interventions a reality for this disorder.
The surest way to treat diabetic complications is to prevent them by
glycemic control in patients with established diabetes or preferably by prevention
of diabetes. While moving toward these goals over the next 25 years, it is
critical to improve treatment and prevention of the microvascular and macrovascular
complications of diabetes because these complications account for the excessive
morbidity and mortality associated with this disease.
All of these predictions are fully achievable if adequate resources
(financial and human) are applied to the field of diabetes. With appropriate
effort, future generations could be freed from the scourge of diabetes.