Comparison of Whole Pancreas and Pancreatic Islet Transplantation in Controlling Nephropathy and Metabolic Disorders of Diabetes

Abstract

To compare the long-term effectiveness of whole pancreas transplantation and pancreatic islet transplantation in controlling the metabolic disorders and preventing the kidney lesions of alloxan diabetes, metabolic and morphologic studies were performed in four groups of rats: (1) NC-116 nondiabetic controls; (2) DC-273 untreated alloxan-diabetic controls; (3) PDT-182 rats that received syngeneic pancreaticoduodenal transplants not long after induction of diabetes with alloxan; and (4) IT-92 rats that received an intraportal injection of at least 1500 and usually 2000 syngeneic pancreatic islets soon after induction of diabetes with alloxan. Each month for 24 months after diabetes was well established, body weight and plasma concentrations of glucose and insulin were measured, and five lesions were scored by light microscopy in 50 glomeruli and related tubules in each kidney by a "blind" protocol: glomerular basement membrane thickening, mesangial enlargement, Bowman's capsule thickening, Armanni-Ebstein lesions of the tubules, and tubular protein casts. There were progressive and highly significant increases in the incidence and severity of all five kidney lesions in the diabetic control rats compared with the nondiabetic control rats. No significant differences were found between the kidneys of Group PDT and those of Group NC, demonstrating that whole pancreas transplantation prevented all of the diabetic kidney lesions throughout the 2-year study period. In contrast, within 3-9 months after pancreatic islet transplantation and thereafter, the incidence and severity of the five diabetic kidney lesions were similar in Group IT and Group DC. Whole pancreas transplantation produced precise metabolic control of diabetes throughout the 24 months of study, whereas pancreatic islet transplantation did not accomplish complete metabolic control, particularly beyond the first several months after transplantation. The difference in the completeness of metabolic control achieved by the two types of transplants is the most likely explanation for their sharp difference in effectiveness in preventing diabetic nephropathy.

The effect of insulin treatment and of islet transplantation on the resistance artery function in the STZ‐induced diabetic rat

“…Several studies of islet transplantation in diabetic rats have been performed demonstrating the potential to reverse the diabetic state and associated microvascular complications (Mauer et al, 1975;Orloff et al, 1987;Schmidt 1983). One such study reported that the development of nerve fibre abnormalities could be prevented if islets were transplanted soon after the onset of diabetes.…”

“…However, optimal diabetic control remains a practical impossibility in many diabetics, since even the most meticulous form of insulin therapy cannot accurately mimic the more precise and subtle blood glucose control afforded by a working pancreas. At present this can be achieved only by the transplantation of islets of Langerhans, or whole pancreas (Orloff et al, 1987; to replace the function of the damaged beta cells.…”

The long-term metabolic function of intraportal and renal subcapsular islet isografts and the effect on glomerular basement membrane thickness in rats

“…In one study by Orloff et al [18] the initial intraportal islet graft and subsequent function may have been inadequate. In a second study by Hiller et al [19], both intraportal and renal subcapsular grafts of 1800 islets appeared to show good early function but the intraportal grafts began to fail at 6 months.…”

“…Some authors have used light microscopic assessment [18], but Hirose et at. [26] have shown that light microscopic analysis is unreliable, and that the only reliable index of diabetic nephropathy in the rat is glomerular basement membrane thickening measured by the orthogonal intercept method on electron microscopic sections.…”

“…Interestingly, despite the fact that numerous experiments in diabetic rodents (both rats and mice) have documented the metabolic efficiency of islet transplantation and its effect on diabetic complications, most of these favourable reports have only examined short-term function. A longer-term study of islet transplantation in comparison to vascularized pancreas transplantation in the rat suggested that the islet grafts eventually failed and did not prevent long-term development of complications [18], and a further report suggested that long-term failure of islets might be related to the use of the intraportal transplantation site [19].…”