- Email: [email protected]
Diabetes—the road ahead
Diabetes-The KARL
E. SUSSMAN, M.D.
Road Ahead
Denver, Colorado
Considerable progress has been made in the acquisition of knowledge relative to diabetes and its complications. However, areas exist wherein even greater progress can be anticipated. These include: (1) defining the genetics of diabetes; (2) the development of suitable markers for early identification of those persons at risk for developing diabetes; (3) the formulation of intervention strategies for preventing or ameliorating the phenotypic expression of diabetes; (4) improving the treatment of diabetes to achieve better control; (5) the possible use of adjunct agents to prevent the chronic complications associated with long-term diabetes; and (6) the development of possible approaches to achieving a cure for diabetes including application of the new knowledge in molecular biology to gene therapy.
otwithstanding the tremendous advances that N have accrued in diabetes research and in improving clinical care, diabetes still remains a major health problem. Diabetes mellitus is the fourth leading cause of death by disease in the United States. Those affected with diabetes face not only a shortened lifespan but also the probability of incurring acute and chronic complications. Table I lists the major recent advances in research and in the treatment of diabetes that have been identified by the National Diabetes Advisory Board. These accomplishments have mainly been attained over the past 10 years. Undoubtedly, we can anticipate even greater advances during the next decade. Table II lists the major present and future challenges in the field of diabetes that represent the focus of this particular presentation. GENETIC PREDISPOSITION TO DIABETES At present, great effort is being expended to define and delineate those factors that play a role in determining the genetic predisposition to diabetes (Table III). The purpose of this overall effort is twofold: (1) to provide a frame of reference for genetic counseling; and (2) to select persons at high risk for developing disease for consideration of possible interventions in hopes of being able to prevent the penetrance and development of manifest diabetes mellitus.
From the Veterans Administration Medical Center and the University of Colorado Health Sciences Center, Denver, Colorado. Requests for reprints should be addressed to Dr. Karl E. Sussman, Veterans Administration Medical Center, 1055 Clermont Street, Denver, Colorado 80220.
166
November
28, 1988
The American Journal of Medicine
HisToco~P~~i~i~iw ANTIGENS (HUMAN LEUKOCYTE ANTIGEN TYPING) The greatest overall advance in this area has been the discovery that certain histocompatibility antigens are quite prevalent in the patient population with insulin-dependent diabetes mellitus (IDDM; Table IV). Thus, for example, human leukocyte antigen (HLA) types DR-3 and DR-4 are present in 98 percent of the patients with IDDM. In contrast, HLA type DR-2 is decreased in the patient population with IDDM as compared with a control non-diabetic complication. DQ HLA subtypes also appear to be associated with an increased prevalence of IDDM. As markers, however, indicating an increased predisposition to diabetes, these particular HLA antigens are not all that specific. From Table IV, it is apparent that the homozygote DR-3 or DR-4 and the heterozygote DR-3/DR4 are at increased risk for the development of IDDM. Nevertheless, as shown in Table V, if HLA typing is performed in the general population, the heterozygote DR-3/DR-4 has only a one out of 42 chance of developing diabetes. The risk of developing IDDM increases substantially with positive DR-3 or DR-4 haplotypes being present in subjects with a positive family history of diabetes. In non-insulin-dependent diabetes (NIDDM), histocompatibility antigens do not provide any indication of risk for disease except in certain unique population groups. HLA-A2 has been found to be associated with
Volume 85 (suppl 5A)
SYMPOSIUM
ON DIABETES / SUSS~A~
TABLE I Major Advances in Research and Treatment of Diabetes * * * * e * 9 @ 0 * * e * * *
The association of genetic factors with both IDDM and NIDDM The discovery of animal models of IDDM The identification of insulinreceptors on the surface of cells and signalingmechanisms wlthin the cells Clarification of the mechanism and regulation of glucose iranspori and metabolism In cells The elucidation of ihe biochemical events associated with insulin synthesis and secretion The measurement of islet cell auto-antibodies in newly diagnosed IDDM patients and the identification of early markers for the prediabetic state In IDDM The production of human insulin by recombinant DNA technology Increased understanding of the roles of diet and exercise in the treatment of diabetes Improved methods for measuring and regulating blood sugar levels in patients with diabetes Laser photocoagulaiion therapy to treat diabetic retinopathy and reduce the risk of blindness Identification of the role of abnormal maternal metabolism in the Increased incidence of birth defects, and the development of strategies for pregnant women wrth diabetes ihat improve metabolic control and thereby prevent birth defects and early infant mortality Effective medications to control high blood pressure in people with diabetes Preventive and therapeutic strategies to reduce lower extremity amputations Treatment strategies to prevent periodontal disease and subsequent tooth loss Development of standards for diabetes patlent education programs to improve the quality of this component of care and to facilitate third-party reimbursement of outpatient education
Yom the National Diabetes Advisory Board: Nabonal long range plan to combat diabetes, 1987. NIH Publication No. 87-1587. Washington, D.C.: United States Department of Health ar Id Human Services, 1987.
increased prevalence of diabetes in the Pima Indians and the Xhosa tribe of South Africa. There was a small increased risk for early onset of diabetes (less than 46 years) associated with HLA-Bw22 in the Naura population, a Micronesian group. However, despite the fact that NIDDM is a genetic disorder, in the vast majority of patients with NIDDM, no association is found with diverse histocompatability antigens.
ISLET CELL ANTIBODIES In patients with IDDM, a rather sizable proportion (approximately 65 to 75 percent) will present with circulating islet cell antibodies at the time of onset of their disease. With the passage of time, however, islet cell antibodies tend to diminish and the percentage of patients with positive islet cell antibodies tends to decrease with duration of disease. Nevertheless, in high-risk persons who test positive for islet cell antibodies, the risks of developing IDDM is exceedingly high.
GENETIC MARKERS-AN
UNCERTAIN FUTURE
Despite the significant advances in the molecular biology of disease and the elucidation of location of various genetic defects to specific chromosomes in humans relative to diabetes, this area in our knowledge remains as one of the most challenging. It is evident that we need better markers for predicting risk of developing diabetes. It would be appropriate if the markers were critical genetic factors involved in the development and the evolution of disease. In the case of the histocompatibility antigens in IDDM, it is quite likely that certain abnormal HLA haplotypes simply indicate that there exists a genetic disorder coding for the immune system, this specific defect being located on the short arm of chromosome-6. As such, the DR-3/ DR-4 HLA types predict an increased risk for a wide variety of immune disorders. Islet cell antibodies are a much more definitive marker, but these occur probably because the disease is already in an active state of development and progression. To be sure, islet cell antibodies may antedate the onset of disease by upwards of five years, and this may provide useful information. Nevertheless, this is not equivalent to being able to predict at an early stage of life the genetic risk for developing IDDM. Recent experimental evidence suggests that histocompatibility antigens could induce November
TABLE II Present and Future Issues in Diabetes * * *
Genetic predisposition-detection Delineationof intervention strategies to prevent manifest disease Improvements in treatment-better control of metabolic disturbance, treatment made more convenient l Prevention of chronic complications 0 Improved treatment of chronic complications * Search for “cures”
TABLE III Genetic Predisposition to Diabetes Purpose-genetic counseling SelectIon of individuals at high risk for disease for posstble interventions Delineategenetic markers IDDM DR-3. DR4-Increased orevalence DR-2-Decreased prevalence DQ-Being studied NIDDM Heterogenous disorder-diverse origin Certain discrete groups-some small association with HLA type HLA-A2-Pima Indians, XhosaTribe HLA-BwZZ-Nauruan population of Micronesia Islet cell antibody: IDDM Need for better markers Markers that relate to the developmeni and evolution of the disease process
TABLE IV Relationship between HLA Typing and Relative Risk of Developing IDDM HLA Type
Relative Risk
DR.3homozygote DR.4 homozygote DR-3/DR-4 heierozygote DR3IX heterozygoie DR4IX heterozygote
15.9 33 3.3 6.3
10.5
specific destruction of beta cells of the pancreatic islet. Investigators in California produced transgenic mouse expressing both chains of the I-A gene in insulinproducing beta cells. Beta cells progressively disappeared coinciding with the development of IDDM. Relative to genetic markers indicating increased 28, 1988
The American Journal of Medicine
Volume 85 (suppl 5A)
167
TABLE V HLA Typing and the Risk of Developing IDDM General
Population
HLA Type DR.3 homozygote DR.4 homozygote DR.3/DR-4 heterozygote
FamilyHistory Positive (sib)
l/420 l/400 l/42
I 114
TABLE VI Complex Development of NIDDM (type II) Abnormal secretion of insulin l Depressed insulin release l Inability of glucose to potentiate insulinrelease by nonglucose secretagogues * Depressed glucose-induced margination of secretion granules at surface membrane of beta cells Impaired insulin action * Abnormal insulin molecule a Decreased proinsulin to insulinconversion @ Circulatingantibodies to insulin * Presence of antibodies directed at tissue receptor for insulin @ Decreased concentration [number] of insulin receptors 9 Decreased affinky of receptors for insulin @ Postreceptor defect, e.g.,impaired cellular metabolism
TABLE VII Improvements in Treatment Purpose l Strive for more effective treatment, better control of metabolic abnormalities associated with diabetes l Make treatment easier, more convenient, more palatable or tolerable Advances in improved monitoring of metabolic abnormalities a Glycosylated hemoglobin or glycosylated protein 0 Self-monitoring blood glucose Search for oral agents other than sulionylureas which induce blood glucose lowering l Oral insulin(alternative intra-nasal insulin) Insulin delivery systems * Open loop @ Closed loop
risk for the development of NIDDM, knowledge is quite lacking. The problem is that NIDDM represents a heterogenous disorder. Table VI lists the possible pathologic lesions that may account for patients having NIDDM. This list is not all-inclusive. For example, post-receptor defects probably encompass all the many biochemical steps necessary for insulin-mediated metabolic effects. Until more specific information is provided relative to possible biochemical or cellular lesions that may account for the presence of NIDDM, the use or even development of specific genetic markers will probably proceed slowly. In sum, we do not possess good candidate genes for determining which patients are going to develop NIDDM. DEVELOPMENT AND DELINEATION OF INTERVENTION STRATEGIES TO PREVENT MANIFEST DISEASE As already noted, a major reason for attempting to detect genetic markers in persons is to identify those at high risk for the development of manifest disease. In fact, even if we had precise genetic markers for IDDM and NIDDM, the possibilities for intervention at this time and the hopes of preventing or ameliorat168
November
28, 1988
The American Journal of Medicine
ing disease are really quite limited. In patients with IDDM, studies are ongoing to evaluate various agents to prevent or ameliorate disease. These largely consist of attempts at immunosuppression. Although various forms of immunotherapy are currently being evaluated (including corticosteroids, cyclosporin-A, and anti-thymocyte globulin), it has been difficult to achieve a completely normal metabolic state in patients with IDDM. Nevertheless, in some IDDM patients, it has been possible to ameliorate serious disease to the extent that insulin therapy could be discontinued. A major problem exists that current programs of immunotherapy evaluated are associated with diverse major side effects, including nephrotoxicity in the case of cyclosporin-A. In a recent study from Paris, France, the investigators demonstrated that by maintaining blood cyclosporin levels at well-defined levels, the risk of developing nephrotoxicity could be substantially prevented. These toxic or side effects preclude using these various agents other than in the setting of well-controlled clinical research protocols. Nevertheless, it is the hope that given increasing knowledge of the events that lead to the penetrance and expression of IDDM, it should be possible to intercede with appropriate agents and perhaps prevent or ameliorate disease. A form of lymphocytic choriomeningitis virus prevents diabetes in mice genetically predisposed to develop the disease. Apparently, the virus invades and inhibits T lymphocytes, particularly the helper cells, which play a role in immune destruction of the beta cells of the islets. Efforts are now ongoing to isolate the viral gene or its product to determine the factor that inhibits T helper cell immune function. Perhaps such viral products might be useful in preventing the penetrance and full expression of IDDM. In patients with NIDDM, as noted elsewhere in this symposium, it has been possible to improve or even reverse existing disease with programs of weight reduction in overweight subjects. Families with an increased prevalence of NIDDM should be counseled to strive for normal weights so as to lessen the chance of developing manifest NIDDM. It seems unlikely, given the present state of knowledge concerning NIDDM, that any more specific recommendations will be forthcoming. IMPROVEMENTS IN TREATMENT As already noted elsewhere in this symposium, the treatment of diabetes mellitus has undergone significant improvement over the past 25 years. In general, the treatment has been more effective resulting in better metabolic control (Table VII). Furthermore, the treatment has become somewhat easier, more convenient, and better targeted at achieving closer metabolic control. Two major technologic advances have aided immeasurably in our being able to help patients in better managing their disease. Glycosylated hemoglobin levels have afforded the opportunity of assessing the state of diabetic control over a prolonged interval of time. The other major advance has been the development of very sophisticated techniques allowing patients to monitor their own blood glucose levels. One can anticipate that techniques will become available for measurement of glycosylation of various other tissue or circulating proteins. Depending upon
Volume 85 (suppl 5A)
SYMPOSIURI ON DlABETESlSUSSMAN
the turnover rate of the protein undergoing glycosylation, these techniques will yield information concerning the adequacy of control over varying periods of time. Thus far, there is no evidence that the rate of glycosylation of hemoglobin parallels the process of protein glycosylation contributing to the development of chronic microvascular complications. If an assay were available reflecting pathologic glycosylation of tissue proteins, we would have an endpoint that might be useful in our assessing whether our attempts at attaining close diabetic control are sufficient to prevent the development of chronic complications of diabetes. Self-monitoring blood glucose techniques have afforded patients the opportunity of determining their blood glucose levels at a given moment in time and being able to restructure their therapeutic programs based on this information. The techniques have become more convenient to use and yield more reliable information. The major issue relative to the use of these self-monitoring blood glucose techniques is, however, the question of quality control. Given the present state of the art, it is incumbent upon clinicians to determine periodically whether self-monitoring blood glucose is being performed properly, and whether the values obtained reflect blood glucose measurements measured by other techniques, for example, those in use in the clinical laboratory. Glucose monitoring reflectance meters now contain memory microchips that allow the compilation of multiple blood glucose determinations. This -information can be transferred to various computers and analyzed by diverse techniques. The patient is afforded the opportunity of observing the blood glucose level at a given moment in time, but also the compiled data can be analyzed and additional measures taken to ensure closer diabetic control. One can anticipate that the devices and techniques for measuring blood glucose levels will become more failsafe, and considering the highly competitive nature of this particular area, the cost of performing such tests should decrease. Research is ongoing to develop non-invasive techniques for measuring blood glucose levels such as those employed to measure blood oxygen tension. During the past decade, we have witnessed advances in the treatment of diabetes with hypoglycemic agents. The search still continues for the development of an oral insulin preparation. A variety of insulin preparations has been formulated that can be taken orally. Only a small amount of this insulin is absorbed by the gastrointestinal tract as most of the insulin is destroyed by the gastric juices. Intra-nasal insulin has been employed with some success in lowering blood glucose levels, and this warrants further investigation. Research is continuing to attempt to develop oral hypoglycemic agents that lower blood glucose levels by chemical pathways other than those affected by the sulfonylurea medications. Again, a number of agents have been prepared, but none of these has been notably successful. Furthermore, use of some of these potential drugs has resulted in side effects such as, among others., fatty infiltration of the liver. Open-loop insulin delivery systems have enjoyed considerable popularity. There is but little question that these insulin delivery systems result in better
diabetic control than that which can be achieved by conventional therapy alone. In combination with selfmonitoring of blood glucose, open loop insulin delivery systems have also afforded patients with diabetes flexibility in structuring therapeutic programs. The devices for delivering insulin have become more eonvenient, smaller, and involve a number of fail-safe systems to ensure the well-being of patients receiving insulin infusions. Closed-loop insulin delivery systems in which the quantity of insulin administered is attuned or regulated by the ambient blood glucose level still remain elusive. The major difficulty relative to closed-loop insulin delivery systems has been the sensing electrode that has been implanted to measure blood glucose levels. After several days, these glucose-sensing electrodes become encased in fibrous tissue and no longer yield reliable values for blood glucose levels. Tiny fiber-optic sensors, called optrodes, are currently being developed for measurement of blood components. These optrodes can be inserted into the bloodstream and are less likely to undergo corrosion. Typically, the electrode has a cavity coated with a fluorescent dye at its tip. A light beam traverses this fiber through the sensing unit and returns back up the fiber. When the sensing unit comes in contact with a specific component of the blood, the resulting fluorescence modifies the light beam so that this change can be measured. Work is ongoing to determine whether such a system would be applicable in the development of a closed-loop insulin delivery system.
November
PREVENTION, AMELIORATION, OR REVERSAL OF CHRONIC COMPLICATIONS With increasing ability to obtain tighter glycemic control, the available literature suggests that chronic complications of diabetes may occur less frequently and also be less severe. The Diabetes Control and Complications Trial should present more definitive information relative to whether better glycemic control results in decreased retinopathy. Certain questions still remain to be answered. For example, if one achieves good control but the blood glucose level is not absolutely normai, does this result in a decrease in chronic complications? Over what span of time must diabetes be controlled in order to prevent complications? Will transient or periodic elevations in blood glucose levels promote glycosylation of various proteins and therefore lead to the evolution of chronic complications? The role of genetic factors in predisposing to the development of chronic complications still remains an area of controversy. Certain clinical manifestations of the diabetic state appear to precede the onset of the abnormality in carbohydrate tolerance. This suggests that there may be certain genetic factors operative in the development and progression of complications. Various investigators have attempted to correlate the existence of certain HLA types (e.g., DR-4) to the presence of microvascular complications. There may be a statistically significant correlation but the data are not very impressive. We are seeing the increased use of adjunct agents to help prevent the progression of chronic complications of diabetes (Table VIII). Increased attention is being paid to the use of antihypertensive agents to halt the progression of retinopathy and nephropathy. Angio28, 1988
The American Journal of Medicine
Volume 85 (suppl 5A)
169
SYMPOSIUM
ON DIABETES / SUSSMAN
TABLE VIII Prevention, Amelioration, tions
or Reversal of Chronic Complica-
Tighter glycemic control Targeting of biochemical pathways contributing to chronic complications Lipid-loweringstrategies Bile sequestering agents Lovastatin Nicotinic acid Omega-3-polyunsaturated fatty acids Aldose reductase inhibitors Aminoguanidine Acetylsalicylic acid Treatment of hypertension and/or microalbuminuria angiotensin-converting enzyme inhibitors Cessation of smoking
TABLE IX improved Treatment of Chronic Complications
IMPROVED TREATMENT OF CHRONIC COMPLICATIONS
Lower extremity amputations-more selective approaches Coronary artery bypass grafts a Laser photocoagulation of diabetic retinopathy-earlier treatment being recommended
l
l
TABLE X Search for “Cures” ‘0 a * e
lmtnunosuppression Islet transplantation Pancreatic transplantation Genetic engineering
tensin-converting enzyme inhibitors are being employed to treat hypertension andior microalbuminuria. The evidence does suggest that control of hypertension with angiotensin-converting enzyme inhibitors may halt the progression of renal disease. Further studies need to be conducted’ to determine whether microalbuminuria represents a significant marker suggesting the presence of incipient renal disease that warrants treatment. The view has been advanced that microalbuminuria needs to be treated with antihypertensive agents (even in the absence of hypertension), but we lack experimental data supcarting this type of treatment. Various lipid-lowering agents and strategies are being employed in the treatment of hyperlipidemia associated with diabetes. These include the use of bilesequestering agents, lovastatin, nicotinic acid, and omega-3 polyunsaturated fatty acids (chiefly eicosatetraneoic acid). Omega-3 polyunsaturated fatty acids appear to prevent atherosclerotic cardiovascular disease possibly by raising high-density lipoprotein cholesterol levels, inhibiting thrombogenic prostaglandins, and suppressing platelet aggregation. However, a few studies suggest that these same fatty acids may worsen carbohydrate tolerance in patients with NIDDM. Aldose reductase inhibitors that suppress the polyol pathway of glucose utilization are being studied in an attempt to halt the progression of retinopathy, nephropathy, and neuropathy. A major problem with the agents developed thus far has been the fact that they possess a chemical structure similar to diphenyl170
November
28, 1988
The American Journal of Medicine
hydantoin. A significant percentage of the patients treated with these agents developed hypersensitivity reactions characterized by fever, lymphadenopathy, and dermatologic manifestations. The concept of biochemical targeting (i.e., the delineation of those biochemical pathways that contribute to the development of chronic complications and the use of agents specifically targeted to suppress or inhibit those pathways) is a new one and needs further exploration. It is conceivable that, in the circumstance in which we cannot obtain “perfect” diabetic control, we can add to our therapy by giving drugs directed at suppressing the biochemical pathways causing chronic complications, in addition to hypoglycemic medications. What needs to be assessed and evaluated is the relative safety of this type of approach in treatment. Overall risk/benefit ratios need to be weighed in this regard.
One of the major advances in the treatment of chronic complications (Table IX) has been the use of laser photocoagulation in the treatment of diabetic retinopathy. Laser treatment is effective in many patients in preventing blindness from proliferative retinopathy and macular edema. Studies suggest that early treatment may help in terms of preventing more serious retinopathy or ameliorating or reversing already existent eye disease. Patients with chronic renal disease due to diabetes are being prescribed programs of hemodialysis for the treatment of end-stage renal disease. Indeed, the disease contributing to the greatest expenditure relative to the use of hemodialysis for end-stage renal disease is diabetes. Selected patients with chronic renal disease due to diabetes are also undergoing renal transplantation. The outcome has proved to be fairly good. Survival rates have been impressive. A number of these patients experience relief of neuropathic symptoms. It has been estimated that approximately 40 to 45 percent of non-traumatic amputations in the United States involve patients with diabetes. Considerable emphasis has been placed upon preventive measures directed at ensuring better diabetic control, cessation of cigarette smoking, control of hypertension, and a greater focus on preventing injury to lower extremities. There have been major advances in the surgical approach to the treatment of diabetic vascular disease with a wide variety of very sophisticated studies being currently available to delineate the existent vascular pathology and to better select patients for diverse therapeutic maneuvers. Despite the impressive advances that have occurred during the past decade in the treatment of chronic complications, it is evident that these complications very significantly contribute to the suffering and the morbidity and mortality rates associated with diabetes mellitus. Once patients develop chronic complications of diabetes mellitus, they reach a point at which those complications tend to be somewhat irreversible. The progression of complications seems to be inexorable. Clearly, more needs to be learned about the development of chronic complications of diabetes and in particular to define this point of irreversibility in order to be able to make appropriate decisions as to
Volume 85 (suppl 5Aj
SYMPOSIUM
what therapeutic measures would be best suited for any given patient. SEARCH FOR “CURES” The search for a cure for diabetes continues (Table X). Immunosuppression has already been discussed. The point was made that thus far this approach has considerable attendant risk. Islet transplantation has been attempted in a number of medical centers. Two major problems exist relative to islet transplantation: (1) immune rejection of a foreign tissue; and (2) the possibility that even if immune rejection could be surmounted, the tissues would undergo the same destructive process that leads to the initial expression of diabetes. There has been no great success in islet transplantation in terms of normalizing blood glucose levels in patients with diabetes. To be sure, most of the patients undergoing islet transplantation are those that have serious nephropathy and are undergoing renal transplantation. The islets are being transplanted simultaneously with the kidneys beneath the renal capsule. Fetal islets have been transplanted in the hope that this tissue would be somewhat lacking in immunologic identity. In contrast to adult cells, fetal islet cells possess the ability to grow and differentiate. The hope is that the transplanted cells will continue to grow somewhat in the patient receiving this tissue. This procedure too has not enjoyed great success in restoring normal metabolism in IDDM patients. In a few selected cases, segmented or total pancreatic transplantation has resulted in normalization or i.mprovement in blood glucose levels. This is, however, a major surgical procedure, and the availability of pancreases suitable for transplantation is not all that great. Basically, we need to acquire additional knowledge concerning immunology and transplantation biology. The clinical transplantation trials of the last several years were necessary if only to reveal the depth of our ignorance. Finally., we are led to the question of whether genetic engmeering might not be effective in achieving a cure. Clearly, all the cells of the body contain the gene that could code for insulin synthesis. We will probably be able to activate the gene and have the cells synthesize insulin, but what must be accomplished is to have this insulin released from that particular cell accord-
ON DIABETES ISUSSMAN
ing to the magnitude of the blood glucose level (i.e., stimulus-secretion coupling). Whether one can insert or transfect a given cell in order to insert the capacity for stimulus-secretion coupling still remains unanswered and represents one of the great challenges relative to genetic engineering as applied to achieving a cure for diabetes. Investigators have been able to deliver functional insulin genes to normal and diabetic mice with the use of transkaryotic implantation in mice. Some of the diabetic mice had prolonged declines in serum glucose levels. Unfortunately, these animals ultimately became hypoglycemic, indicating that the regulation of insulin expression and/or the cellular elaboration of this hormone must be regulated. We have presented a brief glimpse of what might be the road ahead, based on the available knowledge. In one sense, one can not be too sanguine about the prospect of achieving a cure for diabetes. Yet, on the other hand, we have made remarkable progress in being better able to treat patients. Given the present state of the art, our goal has to be to acquire those bits and pieces of knowledge that enable us to achieve a breakthrough. For the moment, we seem to be like the child described by Walt Whitman in his work “Song of Myself” from Leaves of Grass. “A child said ‘What is the grass’ fetching it to me with full hands. How could I answer the child? I do not know what it is any more than he.” SUGGESTED READINGS
-
National Diabetes Advisory Board: The natronal long range plan to combat diabetes, 1987. NIH Publication No. 87-1587, Washington, DC: United States Department of Health and Human Services, 1987. Sussman KE, Draznin B, James WJ (eds): Clinical guide to diabetes meltitus. New York: Alan R. Liss Co., 1987. Physician’s guide to non-insulin dependent diabetes mellitus. American Diabetes Association, 1985. Consensus statement on self-monitorrng of blood glucose. Diabetes Care 1987; 10: 9599. Natronal Diabetes Data Group: Diabetes in America: diabetes data compiled 1984. NIH Pubircation 85-1468. Bethesda, Maryland: National Institute of Arthritis Diabetes and Digestive and Kidney Diseases, and United States Department of Health and Human Services, 1984. Sarvetnick N. Liaaitt -- D. Pitts SL. Hansen S. Stewart TA: insulin-deoendent diabetes mellitus induced in transgenrc mice by ectopic expression of class II MHC and interferon. gamma. Ceil 1988; 52: 773-782. Selden RF, Skoskiewicz MJ, Russell PS, Goodman HM: Regulation of insulin-gene expres sion: implications for gene therapy. N Engl J Med 1987; 317: 1067-1076.
November 28, 1988
The American Journal of Medicine
Volume 85 (suppl 5A)
I.71
E. SUSSMAN, M.D.
Road Ahead
Denver, Colorado
Considerable progress has been made in the acquisition of knowledge relative to diabetes and its complications. However, areas exist wherein even greater progress can be anticipated. These include: (1) defining the genetics of diabetes; (2) the development of suitable markers for early identification of those persons at risk for developing diabetes; (3) the formulation of intervention strategies for preventing or ameliorating the phenotypic expression of diabetes; (4) improving the treatment of diabetes to achieve better control; (5) the possible use of adjunct agents to prevent the chronic complications associated with long-term diabetes; and (6) the development of possible approaches to achieving a cure for diabetes including application of the new knowledge in molecular biology to gene therapy.
otwithstanding the tremendous advances that N have accrued in diabetes research and in improving clinical care, diabetes still remains a major health problem. Diabetes mellitus is the fourth leading cause of death by disease in the United States. Those affected with diabetes face not only a shortened lifespan but also the probability of incurring acute and chronic complications. Table I lists the major recent advances in research and in the treatment of diabetes that have been identified by the National Diabetes Advisory Board. These accomplishments have mainly been attained over the past 10 years. Undoubtedly, we can anticipate even greater advances during the next decade. Table II lists the major present and future challenges in the field of diabetes that represent the focus of this particular presentation. GENETIC PREDISPOSITION TO DIABETES At present, great effort is being expended to define and delineate those factors that play a role in determining the genetic predisposition to diabetes (Table III). The purpose of this overall effort is twofold: (1) to provide a frame of reference for genetic counseling; and (2) to select persons at high risk for developing disease for consideration of possible interventions in hopes of being able to prevent the penetrance and development of manifest diabetes mellitus.
From the Veterans Administration Medical Center and the University of Colorado Health Sciences Center, Denver, Colorado. Requests for reprints should be addressed to Dr. Karl E. Sussman, Veterans Administration Medical Center, 1055 Clermont Street, Denver, Colorado 80220.
166
November
28, 1988
The American Journal of Medicine
HisToco~P~~i~i~iw ANTIGENS (HUMAN LEUKOCYTE ANTIGEN TYPING) The greatest overall advance in this area has been the discovery that certain histocompatibility antigens are quite prevalent in the patient population with insulin-dependent diabetes mellitus (IDDM; Table IV). Thus, for example, human leukocyte antigen (HLA) types DR-3 and DR-4 are present in 98 percent of the patients with IDDM. In contrast, HLA type DR-2 is decreased in the patient population with IDDM as compared with a control non-diabetic complication. DQ HLA subtypes also appear to be associated with an increased prevalence of IDDM. As markers, however, indicating an increased predisposition to diabetes, these particular HLA antigens are not all that specific. From Table IV, it is apparent that the homozygote DR-3 or DR-4 and the heterozygote DR-3/DR4 are at increased risk for the development of IDDM. Nevertheless, as shown in Table V, if HLA typing is performed in the general population, the heterozygote DR-3/DR-4 has only a one out of 42 chance of developing diabetes. The risk of developing IDDM increases substantially with positive DR-3 or DR-4 haplotypes being present in subjects with a positive family history of diabetes. In non-insulin-dependent diabetes (NIDDM), histocompatibility antigens do not provide any indication of risk for disease except in certain unique population groups. HLA-A2 has been found to be associated with
Volume 85 (suppl 5A)
SYMPOSIUM
ON DIABETES / SUSS~A~
TABLE I Major Advances in Research and Treatment of Diabetes * * * * e * 9 @ 0 * * e * * *
The association of genetic factors with both IDDM and NIDDM The discovery of animal models of IDDM The identification of insulinreceptors on the surface of cells and signalingmechanisms wlthin the cells Clarification of the mechanism and regulation of glucose iranspori and metabolism In cells The elucidation of ihe biochemical events associated with insulin synthesis and secretion The measurement of islet cell auto-antibodies in newly diagnosed IDDM patients and the identification of early markers for the prediabetic state In IDDM The production of human insulin by recombinant DNA technology Increased understanding of the roles of diet and exercise in the treatment of diabetes Improved methods for measuring and regulating blood sugar levels in patients with diabetes Laser photocoagulaiion therapy to treat diabetic retinopathy and reduce the risk of blindness Identification of the role of abnormal maternal metabolism in the Increased incidence of birth defects, and the development of strategies for pregnant women wrth diabetes ihat improve metabolic control and thereby prevent birth defects and early infant mortality Effective medications to control high blood pressure in people with diabetes Preventive and therapeutic strategies to reduce lower extremity amputations Treatment strategies to prevent periodontal disease and subsequent tooth loss Development of standards for diabetes patlent education programs to improve the quality of this component of care and to facilitate third-party reimbursement of outpatient education
Yom the National Diabetes Advisory Board: Nabonal long range plan to combat diabetes, 1987. NIH Publication No. 87-1587. Washington, D.C.: United States Department of Health ar Id Human Services, 1987.
increased prevalence of diabetes in the Pima Indians and the Xhosa tribe of South Africa. There was a small increased risk for early onset of diabetes (less than 46 years) associated with HLA-Bw22 in the Naura population, a Micronesian group. However, despite the fact that NIDDM is a genetic disorder, in the vast majority of patients with NIDDM, no association is found with diverse histocompatability antigens.
ISLET CELL ANTIBODIES In patients with IDDM, a rather sizable proportion (approximately 65 to 75 percent) will present with circulating islet cell antibodies at the time of onset of their disease. With the passage of time, however, islet cell antibodies tend to diminish and the percentage of patients with positive islet cell antibodies tends to decrease with duration of disease. Nevertheless, in high-risk persons who test positive for islet cell antibodies, the risks of developing IDDM is exceedingly high.
GENETIC MARKERS-AN
UNCERTAIN FUTURE
Despite the significant advances in the molecular biology of disease and the elucidation of location of various genetic defects to specific chromosomes in humans relative to diabetes, this area in our knowledge remains as one of the most challenging. It is evident that we need better markers for predicting risk of developing diabetes. It would be appropriate if the markers were critical genetic factors involved in the development and the evolution of disease. In the case of the histocompatibility antigens in IDDM, it is quite likely that certain abnormal HLA haplotypes simply indicate that there exists a genetic disorder coding for the immune system, this specific defect being located on the short arm of chromosome-6. As such, the DR-3/ DR-4 HLA types predict an increased risk for a wide variety of immune disorders. Islet cell antibodies are a much more definitive marker, but these occur probably because the disease is already in an active state of development and progression. To be sure, islet cell antibodies may antedate the onset of disease by upwards of five years, and this may provide useful information. Nevertheless, this is not equivalent to being able to predict at an early stage of life the genetic risk for developing IDDM. Recent experimental evidence suggests that histocompatibility antigens could induce November
TABLE II Present and Future Issues in Diabetes * * *
Genetic predisposition-detection Delineationof intervention strategies to prevent manifest disease Improvements in treatment-better control of metabolic disturbance, treatment made more convenient l Prevention of chronic complications 0 Improved treatment of chronic complications * Search for “cures”
TABLE III Genetic Predisposition to Diabetes Purpose-genetic counseling SelectIon of individuals at high risk for disease for posstble interventions Delineategenetic markers IDDM DR-3. DR4-Increased orevalence DR-2-Decreased prevalence DQ-Being studied NIDDM Heterogenous disorder-diverse origin Certain discrete groups-some small association with HLA type HLA-A2-Pima Indians, XhosaTribe HLA-BwZZ-Nauruan population of Micronesia Islet cell antibody: IDDM Need for better markers Markers that relate to the developmeni and evolution of the disease process
TABLE IV Relationship between HLA Typing and Relative Risk of Developing IDDM HLA Type
Relative Risk
DR.3homozygote DR.4 homozygote DR-3/DR-4 heierozygote DR3IX heterozygoie DR4IX heterozygote
15.9 33 3.3 6.3
10.5
specific destruction of beta cells of the pancreatic islet. Investigators in California produced transgenic mouse expressing both chains of the I-A gene in insulinproducing beta cells. Beta cells progressively disappeared coinciding with the development of IDDM. Relative to genetic markers indicating increased 28, 1988
The American Journal of Medicine
Volume 85 (suppl 5A)
167
TABLE V HLA Typing and the Risk of Developing IDDM General
Population
HLA Type DR.3 homozygote DR.4 homozygote DR.3/DR-4 heterozygote
FamilyHistory Positive (sib)
l/420 l/400 l/42
I 114
TABLE VI Complex Development of NIDDM (type II) Abnormal secretion of insulin l Depressed insulin release l Inability of glucose to potentiate insulinrelease by nonglucose secretagogues * Depressed glucose-induced margination of secretion granules at surface membrane of beta cells Impaired insulin action * Abnormal insulin molecule a Decreased proinsulin to insulinconversion @ Circulatingantibodies to insulin * Presence of antibodies directed at tissue receptor for insulin @ Decreased concentration [number] of insulin receptors 9 Decreased affinky of receptors for insulin @ Postreceptor defect, e.g.,impaired cellular metabolism
TABLE VII Improvements in Treatment Purpose l Strive for more effective treatment, better control of metabolic abnormalities associated with diabetes l Make treatment easier, more convenient, more palatable or tolerable Advances in improved monitoring of metabolic abnormalities a Glycosylated hemoglobin or glycosylated protein 0 Self-monitoring blood glucose Search for oral agents other than sulionylureas which induce blood glucose lowering l Oral insulin(alternative intra-nasal insulin) Insulin delivery systems * Open loop @ Closed loop
risk for the development of NIDDM, knowledge is quite lacking. The problem is that NIDDM represents a heterogenous disorder. Table VI lists the possible pathologic lesions that may account for patients having NIDDM. This list is not all-inclusive. For example, post-receptor defects probably encompass all the many biochemical steps necessary for insulin-mediated metabolic effects. Until more specific information is provided relative to possible biochemical or cellular lesions that may account for the presence of NIDDM, the use or even development of specific genetic markers will probably proceed slowly. In sum, we do not possess good candidate genes for determining which patients are going to develop NIDDM. DEVELOPMENT AND DELINEATION OF INTERVENTION STRATEGIES TO PREVENT MANIFEST DISEASE As already noted, a major reason for attempting to detect genetic markers in persons is to identify those at high risk for the development of manifest disease. In fact, even if we had precise genetic markers for IDDM and NIDDM, the possibilities for intervention at this time and the hopes of preventing or ameliorat168
November
28, 1988
The American Journal of Medicine
ing disease are really quite limited. In patients with IDDM, studies are ongoing to evaluate various agents to prevent or ameliorate disease. These largely consist of attempts at immunosuppression. Although various forms of immunotherapy are currently being evaluated (including corticosteroids, cyclosporin-A, and anti-thymocyte globulin), it has been difficult to achieve a completely normal metabolic state in patients with IDDM. Nevertheless, in some IDDM patients, it has been possible to ameliorate serious disease to the extent that insulin therapy could be discontinued. A major problem exists that current programs of immunotherapy evaluated are associated with diverse major side effects, including nephrotoxicity in the case of cyclosporin-A. In a recent study from Paris, France, the investigators demonstrated that by maintaining blood cyclosporin levels at well-defined levels, the risk of developing nephrotoxicity could be substantially prevented. These toxic or side effects preclude using these various agents other than in the setting of well-controlled clinical research protocols. Nevertheless, it is the hope that given increasing knowledge of the events that lead to the penetrance and expression of IDDM, it should be possible to intercede with appropriate agents and perhaps prevent or ameliorate disease. A form of lymphocytic choriomeningitis virus prevents diabetes in mice genetically predisposed to develop the disease. Apparently, the virus invades and inhibits T lymphocytes, particularly the helper cells, which play a role in immune destruction of the beta cells of the islets. Efforts are now ongoing to isolate the viral gene or its product to determine the factor that inhibits T helper cell immune function. Perhaps such viral products might be useful in preventing the penetrance and full expression of IDDM. In patients with NIDDM, as noted elsewhere in this symposium, it has been possible to improve or even reverse existing disease with programs of weight reduction in overweight subjects. Families with an increased prevalence of NIDDM should be counseled to strive for normal weights so as to lessen the chance of developing manifest NIDDM. It seems unlikely, given the present state of knowledge concerning NIDDM, that any more specific recommendations will be forthcoming. IMPROVEMENTS IN TREATMENT As already noted elsewhere in this symposium, the treatment of diabetes mellitus has undergone significant improvement over the past 25 years. In general, the treatment has been more effective resulting in better metabolic control (Table VII). Furthermore, the treatment has become somewhat easier, more convenient, and better targeted at achieving closer metabolic control. Two major technologic advances have aided immeasurably in our being able to help patients in better managing their disease. Glycosylated hemoglobin levels have afforded the opportunity of assessing the state of diabetic control over a prolonged interval of time. The other major advance has been the development of very sophisticated techniques allowing patients to monitor their own blood glucose levels. One can anticipate that techniques will become available for measurement of glycosylation of various other tissue or circulating proteins. Depending upon
Volume 85 (suppl 5A)
SYMPOSIURI ON DlABETESlSUSSMAN
the turnover rate of the protein undergoing glycosylation, these techniques will yield information concerning the adequacy of control over varying periods of time. Thus far, there is no evidence that the rate of glycosylation of hemoglobin parallels the process of protein glycosylation contributing to the development of chronic microvascular complications. If an assay were available reflecting pathologic glycosylation of tissue proteins, we would have an endpoint that might be useful in our assessing whether our attempts at attaining close diabetic control are sufficient to prevent the development of chronic complications of diabetes. Self-monitoring blood glucose techniques have afforded patients the opportunity of determining their blood glucose levels at a given moment in time and being able to restructure their therapeutic programs based on this information. The techniques have become more convenient to use and yield more reliable information. The major issue relative to the use of these self-monitoring blood glucose techniques is, however, the question of quality control. Given the present state of the art, it is incumbent upon clinicians to determine periodically whether self-monitoring blood glucose is being performed properly, and whether the values obtained reflect blood glucose measurements measured by other techniques, for example, those in use in the clinical laboratory. Glucose monitoring reflectance meters now contain memory microchips that allow the compilation of multiple blood glucose determinations. This -information can be transferred to various computers and analyzed by diverse techniques. The patient is afforded the opportunity of observing the blood glucose level at a given moment in time, but also the compiled data can be analyzed and additional measures taken to ensure closer diabetic control. One can anticipate that the devices and techniques for measuring blood glucose levels will become more failsafe, and considering the highly competitive nature of this particular area, the cost of performing such tests should decrease. Research is ongoing to develop non-invasive techniques for measuring blood glucose levels such as those employed to measure blood oxygen tension. During the past decade, we have witnessed advances in the treatment of diabetes with hypoglycemic agents. The search still continues for the development of an oral insulin preparation. A variety of insulin preparations has been formulated that can be taken orally. Only a small amount of this insulin is absorbed by the gastrointestinal tract as most of the insulin is destroyed by the gastric juices. Intra-nasal insulin has been employed with some success in lowering blood glucose levels, and this warrants further investigation. Research is continuing to attempt to develop oral hypoglycemic agents that lower blood glucose levels by chemical pathways other than those affected by the sulfonylurea medications. Again, a number of agents have been prepared, but none of these has been notably successful. Furthermore, use of some of these potential drugs has resulted in side effects such as, among others., fatty infiltration of the liver. Open-loop insulin delivery systems have enjoyed considerable popularity. There is but little question that these insulin delivery systems result in better
diabetic control than that which can be achieved by conventional therapy alone. In combination with selfmonitoring of blood glucose, open loop insulin delivery systems have also afforded patients with diabetes flexibility in structuring therapeutic programs. The devices for delivering insulin have become more eonvenient, smaller, and involve a number of fail-safe systems to ensure the well-being of patients receiving insulin infusions. Closed-loop insulin delivery systems in which the quantity of insulin administered is attuned or regulated by the ambient blood glucose level still remain elusive. The major difficulty relative to closed-loop insulin delivery systems has been the sensing electrode that has been implanted to measure blood glucose levels. After several days, these glucose-sensing electrodes become encased in fibrous tissue and no longer yield reliable values for blood glucose levels. Tiny fiber-optic sensors, called optrodes, are currently being developed for measurement of blood components. These optrodes can be inserted into the bloodstream and are less likely to undergo corrosion. Typically, the electrode has a cavity coated with a fluorescent dye at its tip. A light beam traverses this fiber through the sensing unit and returns back up the fiber. When the sensing unit comes in contact with a specific component of the blood, the resulting fluorescence modifies the light beam so that this change can be measured. Work is ongoing to determine whether such a system would be applicable in the development of a closed-loop insulin delivery system.
November
PREVENTION, AMELIORATION, OR REVERSAL OF CHRONIC COMPLICATIONS With increasing ability to obtain tighter glycemic control, the available literature suggests that chronic complications of diabetes may occur less frequently and also be less severe. The Diabetes Control and Complications Trial should present more definitive information relative to whether better glycemic control results in decreased retinopathy. Certain questions still remain to be answered. For example, if one achieves good control but the blood glucose level is not absolutely normai, does this result in a decrease in chronic complications? Over what span of time must diabetes be controlled in order to prevent complications? Will transient or periodic elevations in blood glucose levels promote glycosylation of various proteins and therefore lead to the evolution of chronic complications? The role of genetic factors in predisposing to the development of chronic complications still remains an area of controversy. Certain clinical manifestations of the diabetic state appear to precede the onset of the abnormality in carbohydrate tolerance. This suggests that there may be certain genetic factors operative in the development and progression of complications. Various investigators have attempted to correlate the existence of certain HLA types (e.g., DR-4) to the presence of microvascular complications. There may be a statistically significant correlation but the data are not very impressive. We are seeing the increased use of adjunct agents to help prevent the progression of chronic complications of diabetes (Table VIII). Increased attention is being paid to the use of antihypertensive agents to halt the progression of retinopathy and nephropathy. Angio28, 1988
The American Journal of Medicine
Volume 85 (suppl 5A)
169
SYMPOSIUM
ON DIABETES / SUSSMAN
TABLE VIII Prevention, Amelioration, tions
or Reversal of Chronic Complica-
Tighter glycemic control Targeting of biochemical pathways contributing to chronic complications Lipid-loweringstrategies Bile sequestering agents Lovastatin Nicotinic acid Omega-3-polyunsaturated fatty acids Aldose reductase inhibitors Aminoguanidine Acetylsalicylic acid Treatment of hypertension and/or microalbuminuria angiotensin-converting enzyme inhibitors Cessation of smoking
TABLE IX improved Treatment of Chronic Complications
IMPROVED TREATMENT OF CHRONIC COMPLICATIONS
Lower extremity amputations-more selective approaches Coronary artery bypass grafts a Laser photocoagulation of diabetic retinopathy-earlier treatment being recommended
l
l
TABLE X Search for “Cures” ‘0 a * e
lmtnunosuppression Islet transplantation Pancreatic transplantation Genetic engineering
tensin-converting enzyme inhibitors are being employed to treat hypertension andior microalbuminuria. The evidence does suggest that control of hypertension with angiotensin-converting enzyme inhibitors may halt the progression of renal disease. Further studies need to be conducted’ to determine whether microalbuminuria represents a significant marker suggesting the presence of incipient renal disease that warrants treatment. The view has been advanced that microalbuminuria needs to be treated with antihypertensive agents (even in the absence of hypertension), but we lack experimental data supcarting this type of treatment. Various lipid-lowering agents and strategies are being employed in the treatment of hyperlipidemia associated with diabetes. These include the use of bilesequestering agents, lovastatin, nicotinic acid, and omega-3 polyunsaturated fatty acids (chiefly eicosatetraneoic acid). Omega-3 polyunsaturated fatty acids appear to prevent atherosclerotic cardiovascular disease possibly by raising high-density lipoprotein cholesterol levels, inhibiting thrombogenic prostaglandins, and suppressing platelet aggregation. However, a few studies suggest that these same fatty acids may worsen carbohydrate tolerance in patients with NIDDM. Aldose reductase inhibitors that suppress the polyol pathway of glucose utilization are being studied in an attempt to halt the progression of retinopathy, nephropathy, and neuropathy. A major problem with the agents developed thus far has been the fact that they possess a chemical structure similar to diphenyl170
November
28, 1988
The American Journal of Medicine
hydantoin. A significant percentage of the patients treated with these agents developed hypersensitivity reactions characterized by fever, lymphadenopathy, and dermatologic manifestations. The concept of biochemical targeting (i.e., the delineation of those biochemical pathways that contribute to the development of chronic complications and the use of agents specifically targeted to suppress or inhibit those pathways) is a new one and needs further exploration. It is conceivable that, in the circumstance in which we cannot obtain “perfect” diabetic control, we can add to our therapy by giving drugs directed at suppressing the biochemical pathways causing chronic complications, in addition to hypoglycemic medications. What needs to be assessed and evaluated is the relative safety of this type of approach in treatment. Overall risk/benefit ratios need to be weighed in this regard.
One of the major advances in the treatment of chronic complications (Table IX) has been the use of laser photocoagulation in the treatment of diabetic retinopathy. Laser treatment is effective in many patients in preventing blindness from proliferative retinopathy and macular edema. Studies suggest that early treatment may help in terms of preventing more serious retinopathy or ameliorating or reversing already existent eye disease. Patients with chronic renal disease due to diabetes are being prescribed programs of hemodialysis for the treatment of end-stage renal disease. Indeed, the disease contributing to the greatest expenditure relative to the use of hemodialysis for end-stage renal disease is diabetes. Selected patients with chronic renal disease due to diabetes are also undergoing renal transplantation. The outcome has proved to be fairly good. Survival rates have been impressive. A number of these patients experience relief of neuropathic symptoms. It has been estimated that approximately 40 to 45 percent of non-traumatic amputations in the United States involve patients with diabetes. Considerable emphasis has been placed upon preventive measures directed at ensuring better diabetic control, cessation of cigarette smoking, control of hypertension, and a greater focus on preventing injury to lower extremities. There have been major advances in the surgical approach to the treatment of diabetic vascular disease with a wide variety of very sophisticated studies being currently available to delineate the existent vascular pathology and to better select patients for diverse therapeutic maneuvers. Despite the impressive advances that have occurred during the past decade in the treatment of chronic complications, it is evident that these complications very significantly contribute to the suffering and the morbidity and mortality rates associated with diabetes mellitus. Once patients develop chronic complications of diabetes mellitus, they reach a point at which those complications tend to be somewhat irreversible. The progression of complications seems to be inexorable. Clearly, more needs to be learned about the development of chronic complications of diabetes and in particular to define this point of irreversibility in order to be able to make appropriate decisions as to
Volume 85 (suppl 5Aj
SYMPOSIUM
what therapeutic measures would be best suited for any given patient. SEARCH FOR “CURES” The search for a cure for diabetes continues (Table X). Immunosuppression has already been discussed. The point was made that thus far this approach has considerable attendant risk. Islet transplantation has been attempted in a number of medical centers. Two major problems exist relative to islet transplantation: (1) immune rejection of a foreign tissue; and (2) the possibility that even if immune rejection could be surmounted, the tissues would undergo the same destructive process that leads to the initial expression of diabetes. There has been no great success in islet transplantation in terms of normalizing blood glucose levels in patients with diabetes. To be sure, most of the patients undergoing islet transplantation are those that have serious nephropathy and are undergoing renal transplantation. The islets are being transplanted simultaneously with the kidneys beneath the renal capsule. Fetal islets have been transplanted in the hope that this tissue would be somewhat lacking in immunologic identity. In contrast to adult cells, fetal islet cells possess the ability to grow and differentiate. The hope is that the transplanted cells will continue to grow somewhat in the patient receiving this tissue. This procedure too has not enjoyed great success in restoring normal metabolism in IDDM patients. In a few selected cases, segmented or total pancreatic transplantation has resulted in normalization or i.mprovement in blood glucose levels. This is, however, a major surgical procedure, and the availability of pancreases suitable for transplantation is not all that great. Basically, we need to acquire additional knowledge concerning immunology and transplantation biology. The clinical transplantation trials of the last several years were necessary if only to reveal the depth of our ignorance. Finally., we are led to the question of whether genetic engmeering might not be effective in achieving a cure. Clearly, all the cells of the body contain the gene that could code for insulin synthesis. We will probably be able to activate the gene and have the cells synthesize insulin, but what must be accomplished is to have this insulin released from that particular cell accord-
ON DIABETES ISUSSMAN
ing to the magnitude of the blood glucose level (i.e., stimulus-secretion coupling). Whether one can insert or transfect a given cell in order to insert the capacity for stimulus-secretion coupling still remains unanswered and represents one of the great challenges relative to genetic engineering as applied to achieving a cure for diabetes. Investigators have been able to deliver functional insulin genes to normal and diabetic mice with the use of transkaryotic implantation in mice. Some of the diabetic mice had prolonged declines in serum glucose levels. Unfortunately, these animals ultimately became hypoglycemic, indicating that the regulation of insulin expression and/or the cellular elaboration of this hormone must be regulated. We have presented a brief glimpse of what might be the road ahead, based on the available knowledge. In one sense, one can not be too sanguine about the prospect of achieving a cure for diabetes. Yet, on the other hand, we have made remarkable progress in being better able to treat patients. Given the present state of the art, our goal has to be to acquire those bits and pieces of knowledge that enable us to achieve a breakthrough. For the moment, we seem to be like the child described by Walt Whitman in his work “Song of Myself” from Leaves of Grass. “A child said ‘What is the grass’ fetching it to me with full hands. How could I answer the child? I do not know what it is any more than he.” SUGGESTED READINGS
-
National Diabetes Advisory Board: The natronal long range plan to combat diabetes, 1987. NIH Publication No. 87-1587, Washington, DC: United States Department of Health and Human Services, 1987. Sussman KE, Draznin B, James WJ (eds): Clinical guide to diabetes meltitus. New York: Alan R. Liss Co., 1987. Physician’s guide to non-insulin dependent diabetes mellitus. American Diabetes Association, 1985. Consensus statement on self-monitorrng of blood glucose. Diabetes Care 1987; 10: 9599. Natronal Diabetes Data Group: Diabetes in America: diabetes data compiled 1984. NIH Pubircation 85-1468. Bethesda, Maryland: National Institute of Arthritis Diabetes and Digestive and Kidney Diseases, and United States Department of Health and Human Services, 1984. Sarvetnick N. Liaaitt -- D. Pitts SL. Hansen S. Stewart TA: insulin-deoendent diabetes mellitus induced in transgenrc mice by ectopic expression of class II MHC and interferon. gamma. Ceil 1988; 52: 773-782. Selden RF, Skoskiewicz MJ, Russell PS, Goodman HM: Regulation of insulin-gene expres sion: implications for gene therapy. N Engl J Med 1987; 317: 1067-1076.
November 28, 1988
The American Journal of Medicine
Volume 85 (suppl 5A)
I.71