Type 1 diabetes mellitus: the best of times... the worst of times

Incidence increasing worldwide, despite improved understanding of its etiology.

Issue: July 2006

ByMark A. Sperling, MD

Mark A. Sperling, MD [photo]
Mark A. Sperling

Type 1 diabetes mellitus, a member of the family of autoimmune diseases, remains a vexing problem for affected patients and their care providers.

On the one hand, advances in our theoretical and practical knowledge concerning the etiology and treatment of this disease have made this the best of times. Improved metabolic control of glucose and lipid disturbances has been proven beyond reasonable doubt to decrease the risk of microvascular complications such as nephropathy, neuropathy and retinopathy, and to a lesser extent macrovasular complications such as coronary artery disease and lower limb amputations. These results were amply demonstrated in the Diabetes Control and Complications Trial (DCCT), and those who maintained strict control still benefited by having fewer complications many years after discontinuation of the trial.

Best of times

The marked improvements in care have been enabled by a number of developments. First, the availability of newer insulin preparations designed to provide a basal-bolus pattern permits a patient to more closely mimic the normal insulin secretory profile. Included in this category is the rapidly improving technology of insulin delivery via programmable pumps of increasing sophistication. These devices are becoming linked to implantable but currently short-term glucose sensors that provide minute-to-minute information, in real time, of glucose concentration. Hence, this technology permits manual adjustment and control of insulin delivery. In the not too distant future, it is hoped that such a system could provide a “closed loop” auto feedback control for subcutaneous insulin delivery. Several prototypes are in development and one has recently been approved by the FDA, as reported in the May issue of Endocrine Today.

A second factor in improving metabolic control is the recognition that a team approach — including physician specialists, educators and dietitians who carefully monitor glycemic control, eye changes and microalbuminuria — can significantly decrease the rate and progression of diabetic complications, even with currently available treatment options.

Third, an increasing investment in basic research is providing a better understanding of the etiology and progression of this disease and the means to predict its onset. Two landmark trials, the Diabetes Prevention Trial-1 (DPT-1) and European Nicotinamide Diabetes Intervention Trial (ENDIT), succeeded in correctly predicting first-degree relatives of patients with T1DM who were likely to develop clinical disease themselves, but both interventions failed to prevent the disease.

Nevertheless, an important benefit was the demonstration that such large, multicenter, cross-national studies could be performed. In the United States, TrialNet is a consortium of participating institutions that investigate the potential to prevent T1DM by various strategies. Vitamin D, now known to be a potent immunomodulator and the monoclonal antibody to CD20 (a marker on B lymphocytes believed to be important in presenting antigen to T-cells that ultimately cause islet cell destruction), are both being investigated via TrialNet Centers.

Finally, the dream to cure T1DM was rekindled by the initial early success of islet cell transplantation via the so-called Edmonton protocol, and by the hope that lessons learned from this and other basic science approaches may eventually result in stem cell therapy as a means to cure the disease or arrest it in its earliest stages.

So much for the outline of the best of times.

Worst of times

It is regrettably also the worst of times. Most disturbing is the fact that the incidence of T1DM is increasing worldwide, with the greatest increase in those aged younger than 5 years. In Finland, the country with the highest incidence in the world (approximately 45 cases year per 100,000 people < 18 years old) the overall incidence has increased threefold over the past 50 years, with an average increase of 2.4% per year.

Similar trends are reported throughout the world. This remarkable increase cannot be explained solely by transmission of genes, implying the participation of environmental factors, the nature of which are unknown. Nevertheless, several environmental factors are currently in vogue and being explored, including exposure to cow’s milk protein, pancreatropic viral illnesses as triggers to an autoimmune response, molecular mimicry of antibody responses that cross-react with islet cell components, environmental pollutants and the so-called “hygiene hypothesis.”

The hygiene hypothesis postulates that our immune responses have been directed at self as a result of immunization and better living conditions, which have reduced or eliminated external stimuli to the immune system. Although we recognize genetic predisposition as a major contributor, and newer genes for predisposition to type 1 diabetes are likely to be discovered in the next decade, the rate of concordance in identical twins is only 30% to 50%; indicating that 50% to 70% of the time, only one identical twin is affected by T1DM. This implies that environmental factors may be more important than the genes themselves. The nature of these environmental factors, however, are unknown.

A second troublesome factor for those involved in the care of children with T1DM is the persistence of diabetic ketoacidosis (DKA), a potentially fatal complication in 25% to 40% of children at diagnosis. At our institution and at similar institutions throughout the country, there seems to be no decrease in the incidence of DKA at diagnosis of childhood diabetes over the past 20 years. This is troublesome because the symptoms of T1DM, such as increased urination, bedwetting, increased thirst, weight loss and lethargy are well known, and hyperglycemia is easily documented by readily available devices that measure blood glucose in the office. That intense education of the public, teachers and caregivers can reduce this unacceptable incidence of DKA at presentation has been amply documented. Somehow, we must educate the public, teachers and primary care providers to think of diabetes mellitus when the classic symptoms first appear or in any sick child for whom no obvious explanation is apparent. Early recognition before the onset of DKA would eliminate cerebral edema, a potentially fatal complication that affects approximately 0.5% to 1% of all children with DKA. Newer insights into the mechanisms causing cerebral edema in DKA offer potential for treating this complication, but clearly, preventing DKA is the more feasible choice.

A third concern is that although mortality, end-stage renal disease and neuropathy are clearly declining, other complications, most notably coronary artery disease and proliferative retinopathy, have not been appreciably declining over the same timeframe. Because the DCCT clearly demonstrated that progression of retinopathy was linked to control, some consider that the lack of decline in proliferative retinopathy reflects a combination of genetic predisposition as well as our prior inability to regulate the metabolic abnormalities of T1DM.

Fourthly, it is increasingly being appreciated that the autoimmune destruction of the islet results not only in insulin deficiency but also in disturbances of the other secretions of islet cells, notably amylin, glucagon, pancreatic polypeptide and possibly others involved in metabolic regulation. Moreover, it is being increasingly appreciated that these islet hormones are secreted directly into the portal vein, perfectly attuned to the content and type of food intake that ultimately is also absorbed by the portal vein. Clearly, this degree of integration between islet secretion and food intake cannot be duplicated by subcutaneous injection of insulin alone, even if delivered by the most sophisticated pump algorithm. This appreciation is spawning new research to add amylin and incretins, factors that may enhance insulin secretion and action in a more physiological manner. Although the primary beneficiaries to date have been adults with type 2 diabetes, the results of adding amylin to patients with type 1 diabetes are encouraging and are likely to play an increasingly significant role in therapy.

Finally, there is concern that the hope invested in heterologous islet transplantation as a means to “cure” is not bearing the expected return on investment. Initially highly promising, the complications of this procedure, the use of potent immnosuppressants, and the overall five-year outcomes preclude general use of this technique for children with T1DM. Even if, or when, perfected, islet transplantation will be hampered by lack of sufficient islets and islet donors to meet the needs of the half milltion to 1 million patients with T1DM in the U.S. alone. Hence, there is urgent need to expand research on stem-cell biology to cure T1DM. Although daunting, the challenge is not insurmountable.

Concluding remarks

As I reflect on these “worst of times” and “best of times,” I am convinced that the positive developments accomplished to date and on the horizon far outweigh the negative ones. Insulin was only discovered approximately 80 years ago, human insulin was made available for treatment only about 20 years ago, and “designer” insulins that provide basal-bolus regimens are still being developed.

The next five to 10 years are likely to yield important new information on improved therapy via additives such as amylin and other incretins. The biggest benefit on the immediate horizon will be integration of continuous glucose monitoring with insulin pump systems for autoregulation of insulin delivery. The paradigms will have to allow for the delay between blood glucose and tissue fluid glucose concentrations, as well as for the rate of change in glucose concentration and not only the absolute value at which some action such as increasing or decreasing insulin delivery should take place.

On the theoretical side, a better understanding of the molecular biology of diabetes and its complications including its genetic predispositions may usher in a new era of specific therapies. This may take 20 years, but it is conceivable that we will learn to modulate the immune response, a task that would be made easier by identifying the environmental triggers that must be operative.

I believe in this positive and realistic message, and it is a message I convey to my patients and my students.

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Mark A. Sperling, MD, is Professor and Chair Emeritus of the Department of Pediatrics, University of Pittsburgh School of Medicine, and Division of Endocrinology, Metabolism and Diabetes Mellitus, Children’s Hospital of Pittsburgh. He is also a member of Endocrine Today’s Editorial Advisory Board.