Most countries’ diabetes associations recommend achieving and monitoring an HbA1c level lower than 7.0%. European guidelines recommend HbA1c <6.5% [91]. The ADA recommends <7.0% and less than 6.0% for the individual patient [92] in whom it can be safely achieved. The Canadian Diabetes Association Clinical Practice Guidelines recommend <7.0% [93].

EFFECT OF INTENSIVE INSULIN THERAPY ON HYPOGLYCEMIA COUNTERREGULATION

The major limitation of near-normoglycemia is the increased risk of hypoglycemia due to lower blood glucose levels and/or defective hypoglycemia counterregulation. The pathophysiology of glucose counterregulation was recently reviewed by Cryer [94]. Glucagon release which is reduced in early years of diabetes history [95] cannot be improved in response to hypoglycemia with islet cell transplantation into liver [96]. Thereafter, catecholamine secretion becomes the most important hypoglycemia counterregulatory hormone [95, 97], until its secretion is impaired by hypoglycemia episodes. However, hypoglycemia counterregulation is partly restored by prevention of severe hypoglycemia and decreases in the incidences of mild hypoglycemia [98, 99]. Tight metabolic control is compatible with mostly intact hormonal hypoglycemia counterregulation for up to 7 years provided there is a low incidence of hypoglycemia [100]. Hormonal counterregulation becomes progressively impaired; even meticulous prevention of insulin-induced hypoglycemia cannot totally prevent this development in type 1 diabetic patients after a diabetes duration of more than 10 years [101].

b CELL FUNCTION

Diabetes is defined by a sole defect—the loss of b cell function below a level that is adequate to maintain euglycemia. C-peptide is co-secreted with insulin in equimolar concentration by the b cell as a by-product of the enzymatic cleavage of proinsulin to insulin. Measurement of C-peptide under standardized conditions provides a sensitive and clinically valid assessment of b cell function (endogenous insulin secretion) [102]. The diagnosis of type 1 diabetes can be enhanced with fasting C-peptide below 0.3 mmol/L or glucagon-stimulated C-peptide under 0.6 nmol/L or high concentration of islet cell antibodies, although with less sensitivity and specificity [102]. Continuing C-peptide insulin secretion is important in avoiding hypoglycemia. Stimulated C-peptide levels >0.2 pmol/mL at diagnosis is a level associated with improved control [47]. Glycemic control strongly influences the decline in b cell function in type 1 diabetes. The DCCT identified a “virtuous circle” whereby residual insulin secretion resulted in better glucose control with less hypoglycemia and slower progression to vascular complications; better glucose control, in turn, prolonged b cell function [47]. The natural course of b cell destruction is heterogeneous in the decline of C-peptide. Some patients lose b cells completely soon after the onset of diabetes whereas others retain minute residual b cells over a long period [103]. In healthy subjects, C-peptide response increases with age between 19 and 78 years [104, 105]. Age is a determinant of residual insulin production at diagnosis [105, 106]. Older patients have much higher stimulated C-peptide levels

at the time of diagnosis of diabetes [107], whereas younger patients have a more rapid decline in C-peptide. As shown in the DCCT and other studies [108], there is clear evidence of clinical benefit from preserved b cell function in patients with type 1 diabetes: less retinopathy, less neuropathy, and less hypoglycemia with intensive insulin therapy [47, 48]. Potential direct effects of C-peptide include prevention and amelioration of diabetic nephropathy, and neuropathy, decreasing microalbuminuria, improved survival of renal allograft, activation of eNOS with microvasodilatory effect, and activation of transcription factor [107, 109]. The reason that b cells should persist and enhance insulin secretion is not clear.

WHOLE PANCREAS TRANSPLANTATION

Pancreas transplantation has a dramatic effect in curing the problems of hypoglycemia but with the risk of perioperative morbidity. Whole pancreas transplantation is chosen principally for the patient with end-stage renal failure who had or plans to have a kidney transplant. Procedures for whole pancreas transplantation include simultaneous pancreas-kidney transplantation (SPK), pancreas after kidney transplantation (PAK), and pancreas transplant alone (PTA). The procedures have been reviewed by Larsen [110] and by Meloche [111]. The most commonly performed is SPK with enteric drainage and systemic venous outflow. Among whole pancreas transplant procedures, patient survival at 1 and 5 years is 95 and 85%, respectively. Graft survival for whole pancreas recipients is 90, 70, and 45% at 1, 5, and 10 years after transplantation, respectively [112, 113].

Contraindications to transplantation of any type include active malignancy or infection, psychiatric disease which could decompensate after a large surgery, and subjects’ inability or unwillingness to take immunosuppressant medications regularly. In successful pancreas transplantation, hypoglycemia-induced glucagon secretion and hepatic glucose production are normalized [114]. Common complications and technical failures include thrombosis, bleeding, leak (6.5%), auto-rejection (12%), and CMV infection (10%) [112, 113].

EFFECT OF SPK TRANSPLANTATION ON DIABETIC RETINOPATHY

Advances in the technical aspects of SPK transplantation which have gradually improved patient and graft survival have lead to investigations of the effect of pancreas transplantation (with normalization or near-normalization of HbA1c) on secondary diabetic complications. The results of investigations of the effect of euglycemia on retinopathy following pancreas transplant can be broadly subdivided as follows:

1.No benefit [115–124]

2.Limited benefit [125–130]

3.Stable for 5 years [131]

4.Significant benefit in the latest publications [132, 133]

The control group has often been too small to be compared statistically with the treatment group. Treatment groups have been controlled for immunosuppression (failed pancreas graft, kidney transplant) or for functioning graft (nontransplanted exogenous

insulin-treated patients with type 1 diabetes). There have been no reports of a beneficial or adverse effect of immunosuppressives on retinal microvasculature. The inclusion of a steroid in an immunosuppressive regimen increases the prevalence of cataracts. Studies on diabetic retinopathy have been difficult to interpret because of the predominance of advanced proliferative retinopathy with high prevalence of scatter laser treatment. Candidates for pancreas and kidney transplants are usually persons who are approaching end-stage renal failure or are undergoing renal dialysis after about 22 years duration of disease. Eyes that worsen develop vitreous hemorrhage, traction retinal detachment, neovascular glaucoma, or have persistent neovascularization requiring more scatter laser treatment. It may not be possible to separate the effects of normoglycemia from those of scatter laser treatment. Normoglycemia has a beneficial effect on reducing the risk of severe NPDR and early proliferative retinopathy [25, 33]. In a study of the influence of glycemic control on the initial response to scatter laser treatment in patients with high-risk PDR, Kotoula et al. [134] reported that good metabolic control (HbA1c < 8%) before, during, and after treatment was associated with greater regression of proliferative retinopathy following scatter laser treatment.

An early report from Ramsay et al. [124] evaluated retinopathy using seven-field stereo fundus photography in 22 subjects (34 eyes) who had undergone successful pancreas transplantation and 16 subjects (28 eyes) with failed pancreas transplantation. In the study group, 10 of 22 patients were blind in one eye, and the average grade of retinopathy pretransplant was P6 (elevated neovascularization). Both groups had been treated with scatter laser (44% eyes, study group; 78% eyes, control group). In the study group, after a follow-up of mean 24 months, 19 eyes (56%) were unchanged and 15 eyes (44%) progressed by two or more grades (5 were laser-treated) compared with the control group in which 13 eyes (46%) were unchanged, 14 (56%) progressed, and 1 (4%) improved. One 16-year-old subject with HbA1c ³16% progressed from mild NPDR to PDR within 6 months of successful pancreas transplantation suggesting accelerated retinopathy associated with profound reduction in HbA1c. Wang et al. [116] compared the progress of diabetic retinopathy in 51 subjects with type 1 diabetes who had undergone successful kidney and pancreas transplantation with 21 subjects who had undergone successful renal transplant alone. In both groups, the prevalence of scatter laser treatment was 72%. An evaluation was made on a side-by-side comparison and grading of seven-field stereo fundus photographs taken weeks before transplantation and again 1 year later. They reported that in the 1 year follow-up, near-normalization of glycemia (mean HbA1c 6.4%) associated with successful transplantation did not accelerate retinopathy nor has a beneficial effect on the progression of advanced retinopathy. Pearce et al. [131] found that more than 90% of 17 subjects (33 eyes) examined 5 years after successful SPK had stable retinopathy defined as absence of need for laser treatment. In this series, 25 of 33 eyes had received scatter laser treatment prior to transplantation. Marchetti et al. [127] reported a series of 28 PTA (without controls) followed for 6–24 months with clinical and photographic documentation in which diabetic retinopathy improved in 58.8%, stabilized in 35.3%, and worsened in 5.9%. Improvement was defined as regression to a lower retinopathy grade in the nonproliferative group and a significant reduction of retinal lesions in the proliferative and laser-treated group. Chow et al. [115] examined 46 patients after successful SPK

and 8 patients with failed SPK (functioning kidney). Sixty-eight of 82 eyes (83%) had undergone scatter or focal laser treatment. Seventy-five percent of eyes in each group remained stable. In the SPK group, 14% improved and 10% progressed from no diabetic retinopathy to NPDR (2 eyes), or progressed from NPDR to active proliferation (4 eyes), or progressed from inactive to active proliferation (12 eyes). Six eyes developed macular edema. Koznarova et al. [125] compared 43 normoglycemic SPK patients with 45 control patients, who either failed SPK or kidney transplants. On the basis of examinations before and 1 year posttransplantation, the rates of improvement, stabilization, and deterioration in the normoglycemic group were 21.3, 61.7, and 17.0%, respectively and, in the control group, 6.1, 48.8, and 45.1%, respectively. Almost 80% of eyes in each group had been treated with laser. Giannarelli et al. [132] followed 48 patients for median 17 months after successful SPK and a control group of 43 patients with type 1 diabetes. In the NPDR SPK group (12 patients), 42% improved, 25% did not change, and 33% progressed by one grade. In the laser-treated/proliferative retinopathy (LT/PDR) SPK group (36 patients), 97% did not change and one patient (3%) worsened. In the LT/PDR group, the number of improved/stabilized patients was significantly higher in the transplanted group than in the control group. Giannarelli et al. [133] studied the course of retinopathy in 30 PTA recipients and in 35 nontransplanted matched type 1 diabetic patients for 30 months. In both groups, the prevalence of laser treatment and/or proliferative retinopathy was 67%. In the NPDR PTA group, 50% of patients improved by one grade and 50% showed no change. In the LT/PDR PTA group, stabilization was observed in 86% of cases, whereas worsening of retinopathy occurred in 14% of patients. In the NPDR control group, retinopathy improved in 20% of patients, remained unchanged in 10%, and worsened in 70%. In the LT/PDR control group, retinopathy did not change in 43% and deteriorated in 57%. Macular edema in four PTA patients at baseline resolved at follow-up. Despite a relatively short followup, successful PTA positively affected the course of retinopathy. However, one PTA and one control patient developed neovascular glaucoma. In both of Giannarelli’s studies [130, 131], examinations were masked. Fundus photographs were graded using the EURODIAB Study classification of severity of retinopathy.

Studies on the course of diabetic retinopathy following whole pancreas transplantation have not been designed to investigate the transient early worsening of retinopathy that was found within 12 months of baseline in the DCCT and in the earlier studies [31]. Such occurrences might be expected in the presence of similar important risk factors such as higher level of HbA1c before treatment and its greater reduction with treatment during the first 6 months after transplantation (odds ratio 1.6 for each percent point decrease). Longer duration of diabetes and more severe retinopathy are risk factors when worsening is measured by the development of soft exudates or IRMA, but not when defined as progression of three or more steps on the retinopathy scale. One can also question whether or not the time to recovery from worsening will follow the 50% recovery rate within 6–12 months found in the DCCT and whether or not subsequent progression will be found in 50% of the patients. Large decrease in HbA1c is a risk factor for the development of clinically important outcomes such as severe nonproliferative retinopathy, proliferative retinopathy, and clinically significant macular edema. In the DCCT, the long-term benefits greatly outweighed the risk of early worsening.