Beneficial Effects On Glycemic Control

As opposed to exogenous insulin-based therapy, successful pancreas transplantation reliably restores endogenous insulin secretion and uniquely maintains glucose levels in the normal range without significant hypoglycemia for many years. Many investigators have detailed the beneficial effects of pancreas transplantation on insulin secretion and carbohydrate metabolism. In a study of 96 pancreas-transplanted patients, fasting plasma glucose, hemoglobin A1c, glucose-induced insulin secretion, and arginine-induced glucagon secretion were maintained at normal levels for up to 5 yr (13). The degree of normalization of hemoglobin A1c levels is better with pancreas transplantation than with the intensive insulin-based management used in the DCCT (see Fig. 2). In a more recent study of 16 patients who had successfully undergone a pancreas transplant 10-18 yr earlier, all recipients had normal levels of fasting blood glucose, intravenous glucose tolerance, and hemoglobin A1c level (14). Fifteen of the 16 patients stated that their quality of life had improved after transplantation. This study established that concerns over long-term deterioration, as distinct from rejection, of pancreatic grafts should not be a major obstacle when deciding whether or not to recommend pancreas transplantation. These positive clinical outcomes of transplanted pancreases are impressive in their own right, but all the more so considering that the recipients are treated with immunosuppres-sive drugs that by themselves diminish P-cell function. Steroid treatment is a well-known cause of peripheral insulin resistance, which, in turn, places more secretory

Intensive Diabetes Control
Fig. 2. Comparison of hemoglobin A1c levels following successful pancreas transplantation to hemoglobin A1c levels obtained during standard and intensive therapy in the Diabetes Control and Complications Trial (DCCT). Solid line at 6% represents upper limit of normal. (Data from refs. 1 and 13.)
A1c Levels
Fig. 3. Glucagon responses during hypoglycemia induced by an insulin infusion (stepped hypo-glycemic clamp). Glucagon responses in type 1 diabetic patients are absent, whereas after successful pancreas transplantation (PTx), glucagon responses are normal. (Data from ref. 23.)

demands on the islet. In addition, glucocorticoids, calcineurin inhibitors, and mycophe-nolate mofetil also directly inhibit insulin secretion (15-22).

As mentioned earlier, patients who have had type 1 diabetes for many years typically have sluggish to absent counterregulatory hormonal responses and glucose recovery during

Hypoglycemia Counter Regulatory Response

Fig. 4. Degree of symtomotology during stepped hypoglycemic clamps in nondiabetic kidney transplant recipients, type 1 diabetic pancreas transplant recipients, control subjects, and type 1 diabetic subjects. In contrast to the diminished symptom awareness of the type 1 diabetic group, diabetic patients undergoing successful pancreas transplantation have normal symptom awareness. IDDM, insulin-dependent diabetes mellitus. (Data from ref. 24.)

Fig. 4. Degree of symtomotology during stepped hypoglycemic clamps in nondiabetic kidney transplant recipients, type 1 diabetic pancreas transplant recipients, control subjects, and type 1 diabetic subjects. In contrast to the diminished symptom awareness of the type 1 diabetic group, diabetic patients undergoing successful pancreas transplantation have normal symptom awareness. IDDM, insulin-dependent diabetes mellitus. (Data from ref. 24.)

Symptoms And Effects Type Diabetes

Fig. 5. Epinephrine responses during a hypoglycemic clamp in nondiabetic kidney transplant recipients, type 1 diabetic pancreas transplant recipients, and patients with type 1 diabetes mellitus. Secretion of epinephrine during the hypoglycemic clamp improves in successful recipients of pancreas transplantation, but does not return to normal levels. IDDM, insulin-dependent diabetes mellitus. (Data from ref. 24.)

Fig. 5. Epinephrine responses during a hypoglycemic clamp in nondiabetic kidney transplant recipients, type 1 diabetic pancreas transplant recipients, and patients with type 1 diabetes mellitus. Secretion of epinephrine during the hypoglycemic clamp improves in successful recipients of pancreas transplantation, but does not return to normal levels. IDDM, insulin-dependent diabetes mellitus. (Data from ref. 24.)

insulin-induced hypoglycemia. In recent studies, patients were subjected to progressive levels of mild hypoglycemia provided by exogenous insulin infusion. Compared to patients who did not receive a pancreas transplant, transplanted patients had normal glucagon secretion (23) (see Fig. 3) and symptom awareness (24) (see Fig. 4) and partially intact epi-

nephrine response (24) (see Fig. 5) during hypoglycemia. Studies such as these have established that successful transplantation provides better control of glycemia than exogenous insulin treatment without running the risk of recurrent, serious hypoglycemia, and consequent diminished counterregulatory hormone secretion and symptom awareness.

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