New Onset Diabetes After Transplant

Etiology

Patients who have preexisting risk factors for type 2 DM are more prone to develop NODAT. NODAT risk factors subclassify into two groups of nonmodifiable and modifiable risk factors.

Nonmodifiable Risk Factors

Age

Age is among the greatest risk factors in the development of NODAT. Studies demonstrated that the incidence of NODAT is 2.2 times higher in transplant recipients who are more than 45 years of age compared to younger adults.

Ethnicity

NODAT is more common in the Black and Hispanic population compared to the White population. This difference in the incidence of NODAT can be due to the genetic diversity and variable effects of immunosuppressive agents on various ethnicities. As an example, tacrolimus has been reported to be a more potent cause of NODAT in the Black population. 

Family History of Diabetes Mellitus and Genetic

Genetic factors are known to be important in NODAT. Based on the evidence, NODAT is more common in people with a history of diabetes in their first-degree relatives. The development of NODAT has genetic links to the alleles of human leukocyte antigen (HLA) A28, A30, B27, and Bw42. The association between single nucleotide polymorphisms (SNPs) and risk for NODAT has been documented in multiple studies. Also, studies show that the association of the R325W polymorphism in the SLC30A8 zinc transporter gene with the R/r inheritance relates to a higher risk of NODAT. Other specific gene variants which are associated with NODAT are KCNQ1, TCF7L2, KCNJ11-Kir6.2, and NFATc4. TCF7L2. These variants relate to impaired insulin secretion and an accelerated rate of gluconeogenesis. Pathogenesis of NODAT in kidney transplant recipients demonstrates a relationship to significant variations of IL-7R, IL-17E, IL-17R, and IL-17RB.

Pre-diabetes Status

Abnormal glucose tolerance is another risk factor for NODAT. Patients with pre-diabetic conditions such as fasting blood sugar levels between 90 and 100 mg/dL need to be monitored closely post-transplant and advised on lifestyle modifications to avoid weight gain, which on its own can tip the patient to develop diabetes mellitus. 

Modifiable Risk Factors

Obesity

Obesity confers a significant modifiable risk factor for the development of NODAT. It acts by upregulating of inflammatory markers and C-reactive protein levels. Adipose tissue increases the production of tumor necrosis factor-alpha (TNF-alpha), which causes defects in the phosphorylation of the glucose receptor and decreases the expression of insulin-sensitive glucose transporters. This mechanism leads to insulin resistance and DM. Furthermore, adipose tissue induces IL-6 synthesis, which is associated with glucose intolerance. Increasing in adipose tissue results in the reduction of adiponectin, a hormone that reduces the risk of DM. In transplant recipients, the level of adiponectin is low before transplant, which in turn is a risk factor to develop NODAT. 

Post-transplant Medications

Corticosteroids are traditionally associated with hyperglycemia and DM by decreasing peripheral insulin sensitivity, inhibiting pancreatic insulin production and secretion, increasing hepatic gluconeogenesis, and promoting protein degradation to free amino acids in muscles. The diabetogenic effect of corticosteroids in developing NODAT has been suggested to be related to both the dosage and the duration of therapy. In general, post-transplant steroid therapy increases the risk of NODAT by 42%. While a steroid-free regimen reduces the NODAT risk, glucose tolerance can significantly improve by reducing the daily dose of prednisone to 5 mg or lower post-transplantation. Using a higher dosage of prednisolone, such as 0.01 mg/kg/day, will increase the risk of NODAT by 5%. Calcineurin inhibitors (CNI) are given to most transplant recipients and are associated with hyperglycemia. CNI reduces the number of glucose transporter type 4 (GLUT-4) receptor molecules on the adipocytes. GLUT-4 is an insulin-regulated protein, and its task is to transport the glucose into adipocytes and striated muscle cells. A decrease in the number of GLUT-4 receptors leads to a reduction of glucose uptake by these cells, which resultant hyperglycemia. Also, CNIs decrease the pancreatic beta-cell density by interfering with the activated T-cell signaling in pancreatic beta-cells. As a result, this pathway activates the mutated genes responsible for DM and leads to reduced insulin synthesis. Studies report that the incidence of NODAT is significantly higher in patients who got treatment with tacrolimus compared to those who have had therapy with cyclosporine. Tacrolimus acts by inhibiting T-cell activity, which results in inhibition of interleukin-2 synthesis, and leads to a failure of T-cell production. Beyond the mechanism mentioned above, tacrolimus also causes hyperglycemia by reducing glucokinase activity in pancreatic islets leading to suppression of glucose-induced insulin release. The effect of tacrolimus in the development of glucose intolerance is reversible with drug discontinuation. Sirolimus is another immunosuppressant that has been associated with NODAT, especially when used in combination with CNI. There is no known recognized association between mycophenolate mofetil and azathioprine use and the development of NODAT.

Hypomagnesemia

Hypomagnesemia after transplant is another risk factor for NODAT. CNIs can induce hypomagnesemia by inhibition of the renal magnesium transporter, resulting in renal magnesium wasting.

Viral Infections

Infection and inflammation are two other factors that contribute to glucose intolerance and the development of DM. HCV infection has a diabetogenic effect by causing insulin resistance and decreasing hepatic glucose uptake and glycogenesis. Also, HCV has a cytopathic effect on pancreatic beta cells. Studies show that the incidence of NODAT is 25.6% in those who are HCV-positive, while it is 14.4% in those with no HCV infection.[3][4][5][6][7][8] Antiviral therapy has been a recommended approach before transplant, but it is still unclear whether the response to therapy can improve glycemic control. Using tacrolimus in patients with HCV aggravates the risk of NODAT. Active cytomegalovirus (CMV) infection decreases insulin secretion by impairing the pancreatic beta cells. CMV can induce the release of cytokines, which leads to apoptosis and mal-functioning of pancreatic beta-cells. As a result, CMV can predispose the patients to NODAT.[9][10][11][12]

Epidemiology

NODAT is more common in Black and Hispanic patients compared to Whites, which might be because of genetic polymorphisms among Black and Hispanic transplant recipients. NODAT incidence in the United States has been reported to be about 9.1% of patients at 3 months, 16% at 12 months, and 24% at 36 months post-transplantation. Also, NODAT has been estimated to occur in about 4 to 25% of renal transplants, 2.5 to 25% of liver transplants, 4 to 40% of heart transplants, and 30 to 35% of lung transplant recipients. The risk of NODAT increases in liver transplants if the patient has an HCV infection and can range between 40% and 60%. Some studies report the range of NODAT to be from 7 to 30% in the first year after kidney transplantation. Also, the majority of organ recipients (about 76.5%) develop NODAT in the first 3 months. After 6 months, the incidence of DM is almost the same as the patients with no transplant. Using higher doses of immunosuppressive medications after transplant correlates with a higher incidence of NODAT.[13][14][15]

Pathophysiology

The pathophysiology of NODAT is almost as same as type 2 DM: increase in insulin resistance and decrease in insulin secretion. In NODAT, insulin hyposecretion seems to have a more important role in glucose intolerance. NODAT more likely occurs in patients who have other risk factors in developing DM type 2. Immunosuppression regimen is one of the leading causes of NODAT; this acts by affecting insulin secretion and action.[16]

History and Physical

As with DM, most patients with NODAT are asymptomatic. The detection of many patients will be due to inpatient glucose monitoring and hyperglycemia on laboratory tests after transplant surgery. Hence, glucose testing is in the recommendations for post-transplant screening in all transplant patients; this can result in early detection of NODAT. Symptoms are the same as in non-transplant DM patients and include polyuria, polydipsia, polyphagia, weight loss, blurry vision, neuropathy, numbness of extremities, and symptoms of infection.  The physical exam includes vital signs, the extent of hydration, funduscopic eye exam, vascular and neurologic examinations, and a foot assessment. The physical examination findings might be unrevealing, although observable end-organ damage may occur.

Evaluation

NODAT is predictable by evaluation of the risk factors such as pre-diabetic status and obesity. Some studies suggest that assessment of preoperative insulin resistance, insulin sensitivity, and beta-cell function (c-peptide levels) may be helpful to predict NODAT but remains unconfirmed by other studies.

Guidelines that define the criteria for the diagnosis of NODAT are identical to the diagnostic criteria in DM:

• Symptoms of diabetes and random plasma glucose greater than or equal to 200 mg/dL (11.1 mmol/L)
• Fasting plasma glucose greater than or equal to 126 mg/dL (7.0 mmol/L) which requires repetition on another day
• Two-hour plasma glucose greater than or equal to 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT)

OGTT is the gold standard for NODAT diagnosis, especially in the early stages of transplantation. Because of the reduction of red blood cell survival after transplant, the diagnosis of NODAT based on HbA1c is not accurate in the first 3 months after the transplantation and is therefore not recommended. Beyond 3 months, the new hemoglobin would be synthesized and glycated for the appropriate period, and HbA1c greater than or equal to 6.5 percent can be utilized to diagnose NODAT. Even many studies don't recommend HbA1c alone as a screening tool for NODAT in the first year after transplant.[3][17][18][12][19]

Although hemoglobin A1c can be used is some patients to diagnose diabetes mellitus, in the setting of ESRD, RBC turnover makes this unreliable.

Early detection of NODAT is helpful as it reduces the risk and complications of DM. The recommendation is for post-transplantation screening for NODAT in all patients undergoing solid organ transplants. Transplantation centers perform the screening tests weekly in the first month and continue screening at months 3, 6, and 12 post-transplantation. After the first year, the risk of NODAT is lower, and the recommendation is for yearly screening.[8]

Treatment / Management

Some of the factors that induce post-transplant hyperglycemia are postoperative surgical stress, pain, and high doses of immunosuppressants. Early detection of hyperglycemia is crucial because early optimization of inpatient plasma glucose has a beneficial effect on the long-term patient and graft survival. The goal for management is adequate glycemic control to minimize hyperglycemia complications. The first steps for glycemic control should focus on non-pharmacological factors that elevate blood glucose. These steps include switching from more diabetogenic immunosuppressants to the less diabetogenic ones or alter the dose of the immunosuppressants with the view of optimizing glycemic control, e.g., reducing corticosteroid dose. Sometimes by simply tapering the corticosteroids soon after transplant can control without medical therapy.

However, clinicians should be thoughtful about the possibility of acute rejection. If lifestyle modification and immunosuppressants adjustment are insufficient to control hyperglycemia, then pharmacotherapy should be initiated. Significant numbers of the patients require insulin therapy to manage postoperative hyperglycemia while in the hospital. In hospitalized patients, as a result of frequent changes in immunosuppressants doses and varying nutritional intake, fluctuations of blood glucose levels are common. Intravenous (IV) insulin is a good initial choice since it is easily titratable, which results in tight plasma glucose control and is safe, particularly post-transplant when graft function is still unstable. Choosing between insulin and oral hypoglycemic agents depends on the severity of hyperglycemia. Based on the IV insulin infusion requirement, subcutaneous insulin doses can be calculated after proper glycemic control or discharge. Oral hypoglycemic therapy at the time of discharge is an option in patients who required low-dose insulin therapy in the inpatient setting. There are no known drug-drug interactions between immunosuppressants and oral antidiabetic agents. 

Metformin is one of the more popular agents which improves insulin sensitivity. Often the glomerular filtration rate increases adequately with well-functioning grafts so it can be used safely for most patients and is the first-line oral agent in NODAT management. Sulfonylureas enhance insulin secretion and are used in NODAT extensively. Their side effects can be post-transplant weight gain and hypoglycemia. Thiazolidinediones are selective agonists of the peroxisomal proliferator-activated receptor gamma and improve glucose tolerance and insulin sensitivity in NODAT. Thiazolidinediones are contraindicated in congestive heart failure and should be used with caution if there is graft malfunction. Repaglinide is a safe drug among the meglitinides and acts by inducing insulin secretion. Dipeptidyl peptidase-4 (DPP-4) antagonists act by inhibiting the degradation of glucagon-like peptide 1, which results in pancreatic insulin secretion. Among the DPP-4 antagonists, sitagliptin is a good choice in NODAT. Using incretin-based therapy such as vildagliptin and sitagliptin needs to be avoided in liver impairment and renal insufficiency; their safety in NODAT is still under study.

Because patients with transplants are at increased risk of hypoglycemia and frequently have a concurrent history of heart disease, guidelines recommend an HbA1c goal of 7 to 7.5% in these patients. Studies demonstrated that in patients with hypertension and congestive heart failure, using ACEIs or ARBs has a significant role in reducing the incidence of NODAT. Treatment of infections such as HCV should be a consideration before transplant.[20][18][8][7][12](B2)

Differential Diagnosis

• Diabetes mellitus
• Stress hyperglycemia

Prognosis

NODAT outcome is affected by different factors, including the type of organ transplant, age, obesity, other cardiovascular risk factors, and immunosuppressants. Studies show a higher mortality rate in patients with NODAT compared to those with type 2 DM. NODAT decreases patient survival by increasing both cardiovascular events and the risk of infections. NODAT is associated with a higher prevalence of rejection and post-transplant renal failure. Studies showed that graft survival in patients with NODAT was 48%, while it was 70% in a patient without NODAT. Also, studies demonstrate that in kidney transplant recipients, cardiovascular events are 2 to 3 fold more in NODAT in comparison with other patients. Additionally, diabetic microvascular complications develop rapidly in patients with NODAT than traditional DM.[21][22][18]

Complications

NODAT can cause similar complications to traditional DM, including neuropathy, ophthalmopathy, nephropathy, ketoacidosis, and episodes of hypoglycemia. Even though these manifestations are similar to DM, the rate at which they occur is remarkably accelerated. Other than the increased risk of transplant rejection, there is a higher incidence of infection and late cardiovascular events, which leads to a higher mortality rate.[16][2][13]