Impact of Islet Cell Transplantation on Diabetic Retinopathy in Type 1 Diabetes

INTENSIVE DIABETES THERAPY HAS LONG-TERM BENEFICIAL EFFECTS

ON THE RISK OF CARDIOVASCULAR DISEASE AND MORTALITY

QUALITY OF LIFE MEASURE

“METABOLIC MEMORY”: A PHENOMENON PRODUCING A LONG-TERM

BENEFICIAL INFLUENCE OF EARLY METABOLIC CONTROL ON CLINICAL

OUTCOMES

RECENT DECREASE OF ANNUAL INCIDENCE AND PREVALENCE

OF RETINOPATHY

NEED FOR A MORE PHYSIOLOGIC GLYCEMIC CONTROL REGIMEN

EFFECT OF INTENSIVE INSULIN THERAPY ON HYPOGLYCEMIA

COUNTERREGULATION

b CELL FUNCTION

WHOLE PANCREAS TRANSPLANTATION

EFFECT OF SPK TRANSPLANTATION ON DIABETIC RETINOPATHY

ISLET CELL TRANSPLANTATION

ADVERSE EFFECTS OF CHRONIC IMMUNOSUPPRESSION

EFFECT OF ISLET CELL TRANSPLANTATION ON RETINOPATHY

REFERENCES

Keywords Wisconsin Epidemiologic Study of Diabetic Retinopathy • Diabetes Control and Complications Trial • Intensive insulin therapy • Diabetes Quality of Life Measure • Metabolic memory • Pancreas transplantation • Islet cell transplantation

INTRODUCTION

Diabetes Mellitus is a risk factor for other diseases, often termed complications, which impose a large and expanding healthcare problem. Type 1 diabetes accounts for about 10% of all cases of diabetes. Currently, there is a global increase in incidence of 3% per year [1], and it is predicted that the incidence will be 40% higher in 2010 than in 1998 [2]. It can be confronted today because of increased emphasis on intensive control of glycemia and control of blood pressure and lipids. The morbidity of diabetes includes blindness from retinopathy (the leading cause of new cases of legal blindness in North America in people in the age group 20–74 years [3]), end-stage renal disease, cardiovascular disease, and lower extremity amputations. In any individual, these complications are markers of the severity of the disease. In type 1 diabetes, amputation and poor visual acuity are significantly associated with mortality [4]. Epidemiology contributes to the etiology of type 1 and type 2 diabetes by refining the diagnosis and identifying and quantifying the risk factors for diabetic complications. A landmark clinical trial and observational follow-up of the efficacy of medical treatment, the Diabetes Control and Complications Trial (DCCT) [5]/Epidemiology of Diabetes Intervention and Complications (EDIC) Study [6], extended the findings of the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) [7] to show beyond all doubt that diabetic microvascular

and macrovascular complications can be diminished or modified through the use of intensive insulin therapy to lower HbA1c concentrations. The study also established a causal role of hyperglycemia in the development and progression of the complications. In some centers, annual incidence rates and prevalence of the complications of retinopathy are now decreasing following translation of the DCCT findings into clinical practice. Despite the benefits of improved blood glucose control in (1) reducing the incidence and progression of retinopathy, renal disease and neuropathy, (2) diminishing the risk of cardiovascular disease, and (3) increasing life expectancy, many patients fail to achieve their glycemic targets. Those who maintain good blood glucose control endure for a lifetime the burden of a rigid lifestyle to avoid hypoglycemia. This chapter focuses on the relationship between hyperglycemia and retinal microvascular disease and the benefits and adverse effects of intensive insulin therapy to provide the rationale for pancreas islet cell transplantation, an evolving treatment aimed at the lowest HbA1c that can be safely achieved to minimize long-term diabetic complications.

WHAT IS THE ASSOCIATION BETWEEN GLYCEMIA AND THE ONSET AND PROGRESSION OF RETINOPATHY, MACULAR EDEMA,

AND PROLIFERATIVE RETINOPATHY IN TYPE 1 DIABETES?

Data from the WESDR, initiated in 1979–1980, identified important independent predictors of the incidence and progression of retinopathy and decreased survival [7, 8]. The study examined a sample selected from 10,135 people consisting of (1) people with diabetes developing before age 30 and taking insulin (defined as the equivalent of type 1 diabetes) and (2) people with diabetes developing after age 30 either taking insulin or not taking insulin stratified by duration of disease (defined as the equivalent of type 2 diabetes). A total of 995 persons with type 1 diabetes participated at baseline and at least one of the four follow-up examinations (including fundus photography) at 4, 10, 14, and 25 years, or died before the first follow-up examination [9–14]. This study population underwent examinations that followed a similar protocol, structured interview about medications, and objective masked recording of retinopathy using seven-standard field stereoscopic fundus photographs with a validated grading protocol modified from the Early Treatment Diabetic Retinopathy Study (ETDRS) adaptation of the modified Airlie House classification of diabetic retinopathy [15, 16] and evaluated for interand intraobserver errors.

With respect to the overall 25-year incidence of any retinopathy (97%), rates of progression of retinopathy (83%), progression to proliferative retinopathy (42%), improvement in retinopathy (18%), incidence of macular edema (29%), and incidence of clinically significant macular edema (17%), the strongest most consistent risk factor relationships throughout the study were with glycemia [10, 14]. In those multivariate models that included accurate baseline retinopathy severity level and baseline HbA1c, the duration of diabetes was not an independent risk factor for progression [17, 18]. The finding of a stepwise relationship between increasing HbA1c levels and increase in progression of retinopathy suggested a possible benefit in the reduction of risk of progression of retinopathy by lowering blood glucose at any level of hyperglycemia found within the population, at any time during the course of diabetes and at any level of severity before the onset of proliferative retinopathy [19].

Preliminary reports of small randomized controlled clinical trials of glycemic control recorded that after 8–12 months of follow-up, the frequency of deterioration of background retinopathy was greater in the group treated with an insulin pump than in the conventionally treated group [20, 21], especially in patients with the best glycemic control [20]. However, after 2 years of treatment, improvement of retinopathy was more frequent among patients treated with continuous subcutaneous insulin infusion (CSII) than among patients treated conventionally, although the difference was marginal [22–24]. The results of these studies and the findings of the WESDR prompted the need for larger longer controlled clinical trials of treatment in type 1 diabetes to provide unequivocal evidence as to whether or not intensive glycemic control aimed at lower levels of glycemia would reduce the development and progression of retinopathy. The Stockholm Diabetes Intervention Study (SDIS) evaluated the effect of intensified (mean HbA1c 7.1%) compared with standard treatment (mean HbA1c 8.5%) in people with type 1 diabetes. After 7.5 years of follow-up, intensified therapy reduced the risk of progression of nonproliferative retinopathy and retarded the development of “serious retinopathy” (proliferative retinopathy or macular edema requiring immediate photocoagulation) by an absolute amount of 25% [25]. The results of this trial and five other studies of more than 2 years duration were combined in a meta-analysis that confirmed that intensive therapy reduced progression of diabetic retinopathy in people with type 1 diabetes [26].

WHAT ARE THE BENEFITS AND RISKS OF REDUCING BLOOD GLUCOSE?

The DCCT was designed to assess whether an intensive treatment regimen aimed at achieving blood glucose values as close to the nondiabetic range as possible would affect the rates of onset and progression, or regression, of early retinal, renal, and neurological complications over time in insulin-dependent diabetes mellitus when compared with conventional treatment [5]. The study was performed before other potential confounding factors such as antihypertensives, blockers of the renin-angiotensin system, and lipidlowering agents came into common use. It was a multicenter randomized prospective study (1983–1989) which involved 1,441 patients in good general health, aged 13–39 years and no severe complications and medical conditions, who were randomly assigned to receive either conventional or intensive insulin treatment [6]. The primary prevention group (n = 726) had duration of diabetes less than 5 years, while the secondary prevention group (n = 715) had duration of diabetes 1–15 years.

The conventional therapy group injected insulin without daily adjustments, once or twice daily and tested either urine or blood glucose daily, and received education about exercise and diet. The goals were (1) absence of symptoms of hyperglycemia, (2) absence of ketonuria, (3) maintenance of normal growth development and ideal body weight, and (4) freedom from frequent or severe hypoglycemia. The intensive therapy group received treatment with a three or more times daily insulin regimen either by injection or insulin pump with doses adjusted on the basis of self-monitored blood glucose measurements (four or more per day) and diet and exercise under the direction of an expert team. The regimen was adjusted by telephone contact and examinations