Pancreas Transplantation: An insulin-free novel therapy for treating type 1 diabetes.

Dayanidhi B

Pancreas transplantation has been used as therapy for type 1 diabetes mellitus for the last 20 or more years.

A pancreas transplant is a treatment option for people with type 1 diabetes who have kidney failure or don't respond well to insulin treatment.It is the only therapy that successfully renders such patients insulin-independent and normoglycemic. However, successful transplan­tation requires subjects to be maintained on long-term immunosuppression, which increases their risk for infection and malignancy. Also, whether patients will live longer and with less morbidity using life-long immunosuppression following pancreas transplantation than when using traditional insulin therapy is uncertain. Consequently, it is difficult for the practitioner to determine which patients would benefit most from pancreas transplantation. This article will help the clinicians to have a better understanding of the role of pancreas transplantation in the treatment of their patients with type 1 diabetes.

Pancreas transplantation can be done in many ways:

Whole pancreas transplantation

In type 1 diabetic patients, the islet cells in the pancreas no longer produce insulin.  So it seems logical that giving a new pancreas to a person with type 1 diabetes would cure their disease and usually it does.

But the cure can be worse than the disease.  The body has a complex system for recognizing its own parts from foreign parts.  Doctors try to match the donor and recipient for a blood protein called human leukocyte antigen (HLA) type before performing transplantation of donor organ.  Patients with a transplanted organ compulsorily have to take immunosuppressive drugs in order to prevent the immune system from fighting the new organ.  The side effects of these drugs may be worse than the problems caused by diabetes, and the operation itself is serious.  One to two people in 10 die within a year of getting a pancreas transplant.  However, there are situations where a person has such severe complications from diabetes that having a pancreas transplant and taking these immunosuppressive drugs is no worse.  People with kidney transplants have to use these drugs anyway and so, for these people, pancreas transplants can be worthwhile.

When the transplant takes, the patient no longer has diabetes and is unlikely to get it again.  Insulin shots and frequent blood glucose testing are no longer necessary.  Restoring normal blood glucose levels may stop complications from worsening.

Pancreas transplants (roughly half of them) can be rejected.  Pancreases attached so that they drain into the bladder are rejected less often than pancreases attached in other body sites.  When a transplant fails, the person gets diabetes again.

Partial pancreas transplantation

Unfortunately, there are not enough cadaver pancreases to go around because not enough people sign up to be organ donors, and each pancreas must meet strict guidelines.  When a whole cadaver pancreas is not available, a person can receive a portion of a pancreas from a living relative.

When a patient with diabetes is receiving a kidney transplant from a living relative, it is usually beneficial to perform a partial pancreas transplant at the same time.  Since the transplanted kidney will become damaged by diabetes over time, transplanting a partial pancreas from the same donor will help control blood glucose levels and protect the new kidney from further damage. Transplant success seems higher when patients and donors are matched for HLA types, and a pancreas transplanted along with a kidney is less likely to fail than a pancreas transplanted alone.¹

Types of pancreatic transplantation:

Simultaneous kidney-pancreas transplantation

More than half of all pancreas transplants are performed along with a kidney transplant. The strategy is to give a patient a healthy kidney and a pancreas that is unlikely to contribute to diabetes-related kidney damage in the future. In most cases, the organs come from the same deceased donor.

This dual transplant appears to contribute to better survival rates for both organs. It has been reported that after five years, the survival rate for the pancreas in a simultaneous transplant is 70 percent, while the organ survival rate for other pancreas transplants is 52 percent.

Pancreas-after-kidney transplantation

Patients may also receive a pancreas transplant after a successful kidney transplant. The treatment goal is similar to a simultaneous transplant i.e., the normal insulin function of new pancreas should decrease the potential for diabetes-related kidney damage.

Pancreas-alone transplantation

Pancreas-alone transplants are performed when there is normal or near-normal kidney function. The doctor may recommend this option if the patient has frequent insulin reactions or poor blood glucose control despite the best efforts to manage the disease. According to a study published in JAMA, the Journal of the American Medical Association, in 2003, people with working kidneys who received a pancreas-alone transplant had a lower survival rate than that of people with comparable diabetes severity who followed their regular insulin and disease management treatments.

Pancreas islet cell transplantation

An experimental procedure called a pancreas islet cell transplant provides with new insulin-producing cells from a donor pancreas rather than a whole organ. As this minimally invasive procedure is improved, it may prove to be another viable option for people with type 1 diabetes.²

II. Techniques Of Pancreas And Islet Transplantation

The goal of pancreas and islet transplantation is to provide a full complement of insulin-secreting pancreatic beta cells to a recipient with type 1 diabetes. This may seem to be a simple task but the complex structural and physiological relations present in the pancreas makes it complicated. The beta cells are the predominant cell type found in pancreatic islets, and they represent about 1 % of the total pancreatic mass. The remaining 99% of the pancreas is composed of exocrine tissue that secretes digestive enzymes into the small intestine. Islets are composed of beta cells and three other types of endocrine cells: the glucagon-secreting alpha cell, the somatostatin-secreting delta cell, and the pancreatic polypeptide-secreting pp cell. To accomplish the goal of replacing the beta cells in a patient with type 1 diabetes, transplantation of isolated beta cells, isolated islets, or unmanipulated pancreatic tissue could be considered. Isolation of functional islets from the exocrine tissue has been successfully performed for more than a decade, but survival of transplanted islets has been difficult to achieve. Consequently, insertion of unmanipulated pancreatic tissue has been and remains the transplant procedure of choice for patients with type 1 diabetes.

Most pancreas transplants involve the placement of an entire cadaveric pancreas into the abdomen of a recipient, although in some cases hemipancreas grafts have been used. The most successful surgical approach has been to place the graft into the pelvis, anastamose the vasculature with the iliac artery and vein, and divert the exocrine secretions into either the urinary bladder or the native intestine (Fig. 1). Bladder drainage readily allows on-going noninvasive monitoring for graft rejection because the amount of amylase measured in the urine is high in patients with functioning pancreas grafts. If the quantity of amylase drops in the urine, graft rejection can be con­firmed by biopsy before aggressively treating the patient before the endocrine tissue fails. Complications of diverting the exocrine effluent into the urinary bladder include excessive loss of bicarbonate and fluid into the urine and hemor­rhage cystitis. If these complications cannot be overcome with medical therapy, a second operation in which the exocrine secretions are diverted into the intestines can be performed.

Much interest has been focused at the transplantation of isolated islets over the years. Most recently, the preferred route of administration has been as an intravenous injection into the umbilical vein. Islets then travel to the liver where they take up residence in the portal regions. Despite the simplicity of such an operation, islet transplantation has still not been a successful procedure. The main reason for its lack of success is uncertain, but may involve recurrence of autoimmune disease in the transplanted islets, drug toxicity, or immunological factors involved in the placement of the islets into the liver.

Fig-1: Pancreas allograft transplantation: The donor organ is placed into the pelvis with exocrine effluent diverted into the bladder. Vascular anastomoses are established with the iliac artery and vein.

III. Immunosuppression: Very Much Required

All recipients of pancreatic transplantation require life-long immunosuppression to prevent graft rejection. Pancreas transplant recipients generally receive the same types of regimens as other solid-organ recipients. All immunosup­pressive drugs carry the risk of increasing susceptibility to infections, particularly those that are viral and fungal in origin, and of malignancy. The drugs most commonly used and their individual side effects are listed in Table 1.³

IV. Surgical Complications And Survival Rates

Pancreas transplantation is associated with various surgical complications, includ­ing graft thrombosis, infection, graft pancreatitis, bleeding, and anastomotic leaks. In a retrospective evaluation of 445 consecutive transplants performed at a center in United States, 35% of recipients experienced a significant surgical complication. The risk of developing a surgical complication in the first 3 months after transplanta­tion was greater in those subjects undergoing simultaneous pancreas-kidney transplants (SPK) than in those who underwent a pancreas transplant alone (PT A) or after a kidney transplant (PAK).^3,4

Table-1: Immunosuppressive drugs used in Pancreas transplantation

Drug name Commercial name Side effects

1. Prednisone Deltasone Weight gain, osteoporosis, diabetes.

2. Azathioprine Imuran Pancytopenia, nausea and vomiting.

3. Cyclosporine Neoral Nephrotoxicity.

4. Tacrolimus Prograf Nephrotoxicity, neurotoxicity, Hypertension.

5. Mycophenolate mofetil Cellcept Diarrhoea, neutropenia, fetal malformations.

For those transplantation procedures that are technically successful, there is a greater risk for subsequent loss of function due immunity. As immunosup­pressive drugs have improved over the years, the rates of rejection have decreased. The risk of immunological loss is greater in PT A cases than in the others.

With improved surgical techniques and better immunosuppression, the rates of overall graft survival and patient survival rates have improved over the years. One-year patient survival rates for those receiving transplants in the United States between 1994 and 1997 was 94% for those who received a pancreas and kidney transplant simultaneously, 95% for those who received a pancreas after a kidney transplant, and 93% for those who received a pancreas transplant alone.⁵

Currently, many patients who require a kidney transplant for diabetic nephropathy are considered candidates for a simultaneous pancreas transplant. One concern about placing a pancreas graft in such patients is the influence such a procedure may have on graft and patient survival following kidney transplanta­tion. Data from the United Network for Organ Sharing (UNOS) Registry from 1987-1996 demonstrate that the 1- and 3-year kidney graft survival rates were 90 and 68%, respectively, for patients with type 1 diabetes. In those patients who simultaneously received a pancreas and kidney grafts between 1987 and 1997, the kidney survival rates were 86 and 79%, respectively. However, in a non-randomized and retrospective evaluation of the effect of pancreas transplantation on patient survival following kidney transplant, Manske and colleagues found that the 3-year patient survival rate is lower (68 vs. 90%) in patients who received simultaneous transplants than in those patients given a kidney alone. In a separate study, Rosen and colleagues observed that patients receiving simultaneous kid­ney-pancreas grafts experience more frequent rejection episodes, more cyto­megalovirus (CMV) infections, and more wound infections, and that these complications result in more hospitalizations than are seen in patients receiving a kidney alone. These investigations raise the question of whether simultane­ous pancreas-kidney transplantation should be routinely recommended in pa­tients with type 1 diabetes and diabetic nephropathy.^6,7,8

V.Pancreas Transplantation: It’s Metabolic Consequences

Patients undergo pancreas transplantation to acquire insulin independence and avoid the long-term complications of diabetes mellitus. Insulin independence with normoglycemia occurs in more than 70% of pancreas transplant recipients at 1 year, and long-term follow-up demonstrates continued metabolic success in most subjects up to 5 years after transplantation. Following successful pan­creas transplantation, patients with systemic venous drainage of their grafts uniformly have basal hyperinsulinemia and increased insulin secretory response to intravenously administered glucose and arginine. But, the insulin secretory reserve capacity in recipients of a successful pancreas transplant is diminished, perhaps as a result of the immunosuppressive drugs used to prevent rejection. Despite this observation, some patients are at risk for the development of spontaneous hypoglycemia following pancreas transplantation, particularly after meals. In at least a few episodes, spontaneous hypoglycemia has led to serious sequelae in those patients with such problems after receiving transplants.^9,10,11

Following pancreas transplantation, patients with type 1 diabetes mellitus once again regain their ability to secrete glucagon in response to hypoglycemia, although the secretory response is less exuberant than that seen in normal volunteers. With the return of hypoglycemia-induced glucagon secretion comes a return of hypoglycemia-induced endogenous glucose production. Such observations have made pancreas transplantation a particularly attractive option for patients with severe hypoglycemic unawareness.

VI. Pancreas Transplantation: It’s Effect On The Complications Of Diabetes

Since the Diabetes Complications and Control Trial (DCCT) clearly demon­strated that improving glycemic control prevents the development of the microvascular complications of diabetes in patients with the type 1 form of the disease, more patients and physicians have considered the possibility of treating type 1 diabetes with pancreas transplantation. Suc­cessful pancreas transplantation produces long-standing normoglycemia without the use of parenterally administered insulin or carefully monitored food plans. Consequently, one would expect that pancreas transplantation would decrease the risk of developing diabetic complications. Unfortunately, proving that successful pancreas transplantation prevents or reverses diabetic complications has been difficult; perhaps in large part because patients have received transplants late in the course of their disease, long after the first signs of diabetic complications have appeared.

In 1988, Ramsay and colleagues published the first report documenting the effect of successful pancreas transplantation on diabetic retinopathy in a small group of patients with type 1 diabetes and established retinopathy.¹² After 2 years of successful graft function, no differences were noted in the rates at which retinopathy progressed in the eyes of successful pancreas transplant recipients as compared with the recipients of grafts that failed. Reports from other centers,^6,13 but not all¹⁴ replicated these findings and have led to the general agreement that, at least for those patients with established retinopathy, pancreatic transplantation is without obvious benefit on the progression of this complication (Table 2).

Successful pancreas transplantation may provide more benefit to patients with established diabetic neuropathy. Most studies have demonstrated that pa­tients may experience some symptomatic improvement within months of receiv­ing a successful transplant.^15,16 Scores derived from a comprehensive clinical examination do not show much improvement in most patients over time, but the inevitable deteriora­tion seen in similarly affected patients who did not undergo successful pancreatic transplantation appears to be halted. Consequently, it appears that pancreatic transplantation can halt the progression of peripheral neuropathy in patients with type 1 diabetes (see Table 2).

The effects of pancreatic transplantation on autonomic neuropathy also appear to be positive. In patients with established autonomic neuropathy, a suc­cessful pancreas transplant significantly slowed the rate at which cardiorespiratory reflex function declines during the first year. Unfortunately, the mortality rate of patients with autonomic neuropathy following unsuccessful pancreatic transplantation was very high, suggesting that patients with autonomic neuropathy may experience substantial risk at the time of transplantation, but if the graft is successful, they have a greater chance of survival.¹⁷

Recent reports on the effect of pancreatic transplantation on diabetic ne­phropathy suggest that the procedure may ultimately reverse the nephropathic lesions associated with a strong likelihood of progression to end-stage renal dis­ease. More recently, Fioretto and colleagues reported that the glomerular lesions associated with diabetic nephropathy in the native kidneys of patients with type 1 diabetes who underwent a successful pancreas transplant alone began to normal­ize after 10 years.^18,19 Taken together, these observations suggest that the nor­moglycemia imposed by a successful pancreas transplant can probably prevent the progression of diabetic nephropathy and may even reverse this complication in patients with early-stage renal disease (see Table 2).

The macro vascular complications of diabetes appear to be increased in patients with type 1 diabetes who have received a successful pancreas transplant. Morissey and colleagues reported the results of a non-randomized, retrospective controlled study in 1997 in which they found that despite the presence fewer cardiovascular risk factors before undergoing pancreas transplant, recipients of a successful pancreas and kidney transplant experienced more complications at­tributed to peripheral vascular disease in the 4 years after surgery than did a similar group of patients with type 1 diabetes who received a kidney transplant alone.²⁰ Some investigators have suggested this may be due to the hyperinsuli­nemia that invariably results from the systemic venous drainage of the pancreas graft. Interestingly, Bagdade and colleagues recently found that the recipients of successful pancreas transplants have the same pro atherogenic level of cholesterol ester transfer as patients with type 1 diabetes, suggesting that the euglycemia imposed by the transplant may not necessarily lower the atherosclerotic risk for these patients.²¹ (see Table 2)

Table 2: Effect of Successful Pancreas Transplant on the Secondary Complications of Diabetes^12,15,19,21

VII. Pancreas Transplantation: It’s Effect On The Quality Of Life

Many patients seek a pancreas transplant in an effort to improve their quality of life. They report that the daily demands of insulin therapy and consistent nutri­tional intake, with the attendant risk of hypoglycemia and long-term complica­tions of diabetes, have a profoundly negative influence on their quality of life and that undergoing a pancreas transplant would be worth the risk of avoiding these ongoing concerns. Over the last decade, several groups have rigorously addressed the question of whether pancreatic transplantation alters the quality of life of patients with type 1 diabetes. Without exception, these studies demonstrate that those recipients of successful pancreas grafts rate their quality of life to be much higher after the transplant than before. Of interest, even the majority of patients who suffered from surgical complications and subsequently lost their graft in the first few months after transplantation report a desire to undergo a repeat pancreas transplant.²² Although these studies have all been performed in a select group of patients who actively sought a pancreas transplant, they are very consistent in demonstrating that pancreatic transplantation increases the quality of life for patients with type 1 diabetes (see Table 2).

VIII. Pancreas Transplantation: Indications And Contraindications

Pancreatic transplantation offers type 1 diabetic patients an alternative ther­apy to lifelong insulin administration. Indeed, the glycemic control provided by a successful pancreas transplant is probably superior to that provided by insulin therapy. Unfortunately, predicting which patients are at risk for developing complications, even in the face of the excellent level of glucose control that can be achieved by intensive insulin therapy, is not possible in the early stages of the disease, and the relative risks of long-term insulin therapy versus long-term immunosuppression have not been determined. Hence, clinicians and their patients are left to make their own decisions about who meets the conditions necessary to undergo a pancreas transplant.

Some clinicians recommend that patients with severe hypoglycemic una­wareness be offered pancreas transplant as an alternative therapy to insulin. Al­though successful pancreatic transplantation will usually avoid the recurrent prob­lems with severe hypoglycemia experienced by such patients, merely stepping back from the intensity of insulin therapy is usually as successful in relieving their hypoglycemic symptoms.

Patients with debilitating complications from diabetes are often referred for pancreatic transplantation in the hope that the complications will be reversed by the surgery. Unfortunately, successful transplantation cannot reverse diabetic retinopathy, has limited benefit on symptomatic peripheral neuropathy, and may not alter the course of macrovascular complications. Patients with autonomic neuropathy may experience relief of their symptoms and may be appropriately referred for a pancreas transplant, but if it is unsuccessful, these patients appear to have greater mortality than patients who never underwent the operation.

Despite all of the foregoing limitations, the effect of successful pancreas transplantation on the quality of life experienced by a patient has been well demonstrated. For this reason, it is believed that pancreas transplantation can be considered as an alternative therapy for patients with type 1 diabetes at any stage of their disease. In deciding whether a pancreas transplant is the appropriate therapy for a patient, the clinician must work with the patient and their family members to ensure that they understand all the risks and benefits associated with the operation for the individual patient. For many patients, the risk of long-term immunosuppression outweighs any benefits of a successful pancreas transplant, but for some, the risk may be considered to be minor compared with ongoing insulin injections.

Contraindications for pancreas transplantation include the existence of other conditions that make long-term survival unlikely, such as advanced malignancy or end-stage human immunodeficiency virus (HIV) infection, or substantially increased surgical risk, such as uncorrectable coronary artery disease. For patients with severe hypoglycemic unawareness, failure to work closely with a physician and health care team skilled in the management of diabetes is a relative contraindi­cation because appropriate diabetes management usually decreases if not removes the morbidity associated with this condition.^18-20

IX. Management After Transplantation

After a successful pancreatic transplantation, management focuses on appropri­ately adjusting the immunosuppressive drug regimen, monitoring for the toxicity and expected consequences of these drugs, and preparing to diagnose and treat risk factors that increase the likelihood of developing progressive diabetic compli­cations. The immunosuppressive drug regimen used will be reduced in dose over time and may eventually require the administration of fewer drugs. To appropri­ately adjust drug doses, patients must be carefully monitored for evidence of graft rejection. For patients with diversion of their pancreatic exocrine effluent into the urinary bladder, this is easily accomplished by measuring the amount of amylase in the urine. For patients with enteric drainage, early signs of rejection, such as an increase in serum lipase, can be missed, and patients may display elevated blood sugar levels as their first sign of rejection. Suspected rejection episodes are confirmed by biopsy of the graft and aggressively treated with high dose immunosuppression regimens.

The drugs used to suppress rejection are known to increase the risk of infection and malignancy, and management after transplant requires careful moni­toring for these events. Viral infections, particularly with CMV, are common after a pancreas transplant, and most centers routinely use antiviral drugs as prophylaxis in the early postoperative period. Transplant patients receiving im­munosuppressive therapy who present with fever or other signs of infection need aggressive and comprehensive evaluation and treatment to prevent serious com­plications. Over time, patients on an immunosuppression regimen are at risk to develop many malignancies, particularly lymphoma and basal cell carcinoma. Careful evaluation of signs or symptoms of malignancy will allow early identifica­tion and treatment of these conditions.

After a successful pancreas transplant, patients remain at risk for the conse­quences of their diabetic complications. Retinopathy is unaffected by transplant and patients with advanced disease at the time of surgery will require ongoing ophthalmologic care. Patients with existing diabetic nephropathy who do not undergo a kidney transplant at the time of their pancreas surgery may experience a rapid drug-induced worsening of their renal function and must be carefully monitored. Although some improvement in peripheral neuropathy can be ex­pected after a successful transplant, patients still remain at risk for serious foot injury and must be instructed to continue to care for their feet. Macrovascular disease remains a big problem after transplant and may even increase. Conse­quently, attention to cardiovascular risk factors, such as lipids, smoking, and blood pressure, remain important parts of the long-term management of patients after successful pancreas transplantation.^3-8

X. Conclusion

Thus, pancreas transplants are safest in type 1 diabetic patients who do not have heart or blood vessel disease.  Before a patient goes for a transplant, the doctor checks the circulatory system to see if it is healthy enough to risk the operation. Immunosuppressive drugs are hard on the body, but people who get transplants must take these drugs the rest of their lives.  A recent study (JAMA, 2003) has indicated that, for patients with functioning kidneys, survival rates of patients who receive pancreas-only transplants are worse than the survival rates of patients who manage their diabetes with conventional therapy (insulin, diet, etc.).  Therefore, the decision to have a pancreas-only transplant should be very carefully considered by both the patient and physician.  Because of the lower survival rates seen with pancreas-only transplants, and because a pancreas transplanted along with a kidney is less likely to fail than a pancreas transplanted alone, pancreas transplants are nearly always done only in people with type 1 diabetes who are getting or already have a transplanted kidney.

References:

1. Pancreas transplantation. American Diabetic Association (ADA). Available at - http://diabetes.org/type-1-diabetes/pancreas-transplants.jsp. Accessed on 10 Aug 2007.

2. Pancreas transplant: An insulin-free treatment for type 1 diabetes. By Mayo Clinic Staff (Dec 2005). Available at: http://www.mayoclinic.com/health/pancreas-transplant/DA00047. Accessed on 10 Aug 2007.

3. R Gruessner, D Sutherland, E Troppmann, N Hakim, D Dunn, A Gruessner. The surgical risk of pancreas transplantation in the cyclosporine era: an overview. J Am Coli Surg 185:128-144, 1997.

4. C Troppmann, A Gruessner, D Dunn, D Sutherland, R Gruessner. Surgical complica­tions requiring early relaparotomy after pancreas transplantation. Ann Surg 227: 255-268, 1998.

5. A Gruessner, D Sutherland. Pancreas transplants for United States (US) and non­US cases as reported to the International Pancreas Transplant Registry (IPTR) and to the United Network for Organ Sharing (UNOS). In: CA, Terasaki, ed. Clinical Transplants. Los Angeles, CA: UCLA Tissue Typing Laboratory, 1997:45-59.

6. M Cecka, PI Teraski, eds. Clinical Transplants-1996. Los Angeles: UCLA Tissue Typing Laboratory, 1997.

7. C Manske, Y Wang, W Thomas. Mortality of cadaveric kidney transplantation versus combined kidney-pancreas transplantation in diabetic patients. Lancet 346: 1658-1662, 1995.

8. C Rosen, P Frohnert, J Velosa, D Engen, S Sterioff. Morbidity of pancreas transplan­tation during cadaveric renal transplantation. Transplantation 51:123-127, 1991.

9. R Robertson, D Sutherland, D Kendall, A Teuscher, R Gruessner, A Gruessner. Metabolic complications of long-term successful pancreas transplant in type I diabe­tes. J Invest Med 44:549-555, 1996.

10.  P Diem, M Abid, J Redmon, E Sutherland, R Robertson. Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type I diabetic recipients. Diabetes 39:534-540, 1990.

11.  A Teuscher, E Seaquist, R Robertson. Diminished insulin secretory reserve in diabetic pancreas transplant and non-diabetic kidney transplant recipients. Diabetes 43: 593-598, 1994.

12.  R Ramsay, F Goetz, D Sutherland, S Mauer, L Robison, H Cantrill, W Knobloch, J Najarian. Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med 318:208-214, 1988.

13.  A Scheider, E Meyer-Schwickerath, J Nusser, W Land, R Landgraf. Diabetic retinop­athy and pancreas transplantation: a 3-year follow-up. Diabetologia 34(suppl 1): S95-S99.

14.  A Konigsrainer, K Miller, W Steurer, G Kieselbach, C Aichberger, D Ofner, R Margreiter. Does pancreas transplantation influence the course of diabetic retinopa­thy? Diabetologia 34(suppl 1): S86-S88, 1991.

15.  X Navarro, D Sutherland, W Kennedy. Long-term effects of pancreatic transplanta­tion on diabetic neuropathy. Ann Neurol 42:727-736, 1997.

16.  S Martinenghi, G Comi, G Galardi, G Di Carlo, V Di Carlo, G Pozza, A Secchi. Amelioration of nerve conduction velocity following simultaneous kidney/pancreas transplantation is due to the glycaemic control provided by the pancreas. Diabetologia 40:1110-1112,1997.

17.  X Navarro, W Kennedy, D Sutherland. Autonomic neuropathy and survival in diabe­tes mellitus: effects of pancreas transplantation. Diabetologia 34(suppl 1): S 108-S 112, 1991.

18.  R Bilous, S Mauer, D Sutherland, J Najarian, F Goetz, MW Steffes. The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med 321:80-85, 1989.

19.  P Fioretto, MW Steffes, DER Sutherland, FC Goetz, M Mauer. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339:115-117,1998.

20.  P Morrissey, D Shaffer, A Monaco, P Conway, P Madras. Peripheral vascular disease after kidney-pancreas transplantation in diabetic patients with end-stage renal dis­ease. Arch Surg 132:358-362, 1997.

21.  J Bagdade, A Teuscher, M Ritter, R Eckel, R Robertson. Alterations in cholesteryl ester transfer, lipoprotein lipase, and lipoprotein composition after combined pan­creas-kidney transplantation. Diabetes 47:113-118, 1998.

22.  C Zehrer, C Gross. Quality of life of pancreas transplant recipients. Diabetologia 34:S145-S149, 1991.

About Authors:

Dayanidhi B

M.Pharm (Pharmacology), School of Pharmacy and Technology Management, NMIMS University, V.L. Mehta Road, Vile Parle (W), Mumbai – 400 056, Maharashtra, India.

Sateesh B

Lecturer (Pharmacology), School of Pharmacy and Technology Management, NMIMS University, V.L. Mehta Road, Vile Parle (W), Mumbai – 400 056, Maharashtra, India.

Dr. Meena C

Associate Professor ((Pharmacology), School of Pharmacy and Technology Management, NMIMS University, V.L. Mehta Road, Vile Parle (W), Mumbai – 400 056, Maharashtra,India.

Dr. Addepalli V

H.O.D ((Pharmacology & Clinical pharmacy), School of Pharmacy and Technology Management, NMIMS University, V.L. Mehta Road, Vile Parle (W), Mumbai – 400 056, Maharashtra, India.