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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 5  |  Page : 897-902
New-onset diabetes after transplantation - Role of oral glucose tolerance test for diagnosis and study of risk factors

1 Department of Nephrology, Osmania General Hospital, Hyderabad, Andhra Pradesh, India
2 Department of Endocrinology, Osmania General Hospital, Hyderabad, Andhra Pradesh, India

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Date of Web Publication12-Sep-2013


To determine the role of the oral glucose tolerance test in the early detection of new-onset diabetes after transplantation (NODAT) and to compare the various risk factors and insulin kinetics in the transplant patients, we studied 41 live-related renal allograft recipients who were not diabetic before transplantation. Immunosuppression included triple drug therapy (cyclosporine, azathioprine and steroids) and rejection episodes were treated with methyl prednisolone (30 mg/kg IV × 3 days). All the study patients were subjected to an oral glucose tolerance test (OGTT) at Day 90 post-transplant and classified as having normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and NODAT as per the World Health Organization guidelines. Insulin levels were also determined at 0, ½ hour, 1 hour and 2 hours during OGTT. NODAT was noted in 29.2% of the study patients, IFG in 4.8% of the study patients and NGT in 65.8% of the study patients. All the groups had normal fasting plasma glucose, but higher than normal insulin levels, suggesting insulin resistance. The patients with overt NODAT had, in addition, low fasting insulin (insulin secretory defect). OGTT may be used for the early detection of NODAT. Although insulin resistance is detected in the majority of post-transplant patients, NODAT also reveals also an insulin secretory defect.

How to cite this article:
Sahay M, Sahay RK, Narayan G, Anuradha. New-onset diabetes after transplantation - Role of oral glucose tolerance test for diagnosis and study of risk factors. Saudi J Kidney Dis Transpl 2013;24:897-902

How to cite this URL:
Sahay M, Sahay RK, Narayan G, Anuradha. New-onset diabetes after transplantation - Role of oral glucose tolerance test for diagnosis and study of risk factors. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2021 Dec 6];24:897-902. Available from: https://www.sjkdt.org/text.asp?2013/24/5/897/118068

   Introduction Top

In an era where successful transplantation can be offered to a growing number of patients, there is an increasing concern about the complications that develop after the transplantation of a functioning allograft. One of the most significant complications in this setting is new-onset diabetes after transplantation (NODAT), because this is often unanticipated by the patient and has the potential to result in poor patient and poor graft outcomes. [1],[2]

The difficulty in interpreting NODAT stems from the varied definitions of this disease. Most definitions in the literature are derived from random glucose testing or fasting glucose levels higher than 140 mg/dL. Recently, the World Health Organization (WHO) has defined impaired glucose tolerance (IGT) as plasma glucose level higher than 140 mg/dL and clinical diabetes as plasma glucose levels higher than 200 mg/dL at the 2-hour time point during an oral glucose tolerance test (OGTT). Unfortunately, very few studies have included OGTT to determine the exact incidence of glycemic abnormalities in transplant recipients. [1] The incidence of NODAT has been variably reported to be between 3% and 40%. [3],[4],[5],[6],[7] The time lag between transplantation and the onset of glucose intolerance ranges from 2 to 6 months. [5],[6],[7]

NODAT is one such undesirable adverse effect associated not only with significant morbidity but also with a clear impact on both the patient and the graft outcomes. Several factors contribute to the development of NODAT by their effect on either insulin secretion or on insulin resistance.

The aim of this prospective study was to determine the role of OGTT in the detection of NODAT and the various risk factors and insulin kinetics involved in the development of this complication.

   Materials and Methods Top

We studied 41 consecutive non-diabetic renal allograft recipients (35 males, six females) who underwent live-related donor renal transplant at our center. Pre-transplant evaluation included an assessment of the family history of diabetes, basic kidney disease, donor source and measurement of height in cm and weight in kg. Blood pressure was measured and body mass index (BMI) was calculated as (weight in kg)/ (height in m 2 ), in addition to the waist hip ratio (WHR). Complete renal profile, lipid profile, cardiac evaluation, HLA typing and viral markers were performed. Immunosuppression included standard doses of cyclosporine, azathioprine and steroids [Table 1]. Rejections (confirmed by biopsy) were treated with methyl prednisolone (30 mg/kg IV × 3 days). The total cumulative dose of steroids at the time of analysis was calculated.
Table 1: Immunosuppressive drug dosages in the study patients.

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Follow-up of renal functions, hemogram and fasting and random blood sugar were obtained initially daily and then weekly. Liver function tests, lipid profile and cyclosporine (C2) levels (HPLC) were also performed.

For the purpose of the study, all the patients were subjected to an OGTT as recommended by the WHO at Day 90 after transplantation. Simultaneous blood samples were drawn at 0, ½ hour, 1 hour and 2 hours for estimation of the plasma glucose and serum insulin levels. Patients were classified as having normal glucose tolerance (NGT), impaired fasting glucose (IFG), IGT and NODAT based on the WHO criteria [Table 2].
Table 2: Categories of glucose intolerance as per the World Health Organization criteria.

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Plasma glucose was estimated by the glucose oxidase method. Serum insulin was measured by immunoradiometric assays [using kits provided by Diagnostic Products Corporation (DPC), Los Angeles, CA, USA]. Insulin resistance was determined using the Homeostasis Model of Assessment (HOMA-R) and Insulin secretion by HOMA-B. HOMA-B = Insulin (mU/mL) 20/[glucose (mmol/L) - 3.5] HOMA-R = Insulin (mU/mL) glucose (mmol/L)/22.5.

   Statistical Analysis Top

The data of the NGT, IFG, IGT and NODAT patients were analyzed with regard to family history of diabetes, age, sex, basic renal disease, donor source, HLA typing, anthropometric parameters and biochemical abnormalities. The mean cyclosporine levels and the percentage of rejection episodes were compared in the three groups. The results were statistically analyzed using STATA 6.0 for windows. P-values <0.05 were considered significant.

   Results Top

There were 35 males and six females (M:F = 5.8:1) with a mean age of 27.8 ± 6.64 years (range 13-48 years). Twenty-seven (65.8%) patients had NGT, two (4.8%) patients had IGT and 12 (29.26%) patients had NODAT. None of the patients had IFG. The fasting and random plasma glucose levels were similar in the three groups. The WHR, BMI, cholesterol and low-density lipoprotein (LDL) were significantly higher in the NODAT group, while all the other investigated parameters were not significantly different between the three groups, [Table 3] and [Table 4]. One patient in the NODAT group (8.3%) and two patients in the NGT group (7.4%) had biopsy-proven acute cellular rejection. All the three groups had higher than normal insulin levels. The patients with overt NODAT had, in addition, low fasting insulin [Table 5].
Table 3: Study patients' characteristics.

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Table 4: Comparison patients with or without NODAT.

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Table 5: Insulin kinetics.

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   Discussion Top

Our results showed that OGTT was positive in a significant percentage of transplant patients without the elevation of fasting plasma glucose, and a significant percentage developed NODAT.

Increasing age (>45 years), a family history of diabetes, abnormal glucose tolerance prior to transplant and black, Hispanic and Arabic races are some of the definitely identified risk factors for NODAT. [1],[3],[4] Other factors not conclusively linked to NODAT include donor source, basic kidney disease, sex, increased BMI, transplant from a deceased kidney donor and certain HLA types, which include HLA A28, A30, B8, B18, BW15, BW42 and DW16. [7],[8],[9],[10] An association between HCV infection and the development of NODAT has been reported especially in patients on tacrolimus. [11] In our study, age, gender, donor source, basic kidney disease, viral profile and HLA type did not predict NODAT. Family history of diabetes was present only in three patients. WHR, BMI, total cholesterol and LDL were significantly higher in the abnormal glucose tolerance group.

Medications have been incriminated in the pathogenesis of NODAT. In the pre-cyclosporine era, glucose intolerance was observed in about 40% (steroid diabetes) of the patients. Corticosteroid withdrawal may decrease the incidence of NODAT, but it is complicated with a high risk of rejection, which might in turn increases the steroid requirements with subsequent increases in NODAT. [1],[4],[6],[10],[11] The use of anti-rejection therapy for acute rejection has been positively associated with NODAT, but, in our study, no such an association was found. The diabetogenic effect of cyclosporine is due to its potential to inhibit the P-450 system and thus steroid metabolism, thereby increasing steroid levels, and also by decreasing insulin production and increasing resistance to insulin action. [1] Tacrolimus is reportedly more diabetogenic, and this effect is mostly dose related and mainly attributed to decreased insulin mRNA transcription and also insulin resistance. Rapamycin has also been inconsistently linked with NODAT. Our patients, despite receiving an identical immu-nosuppression, had varying propensity to develop NODAT, suggesting that NODAT is not solely a drug-related phenomenon.

A high index of suspicion is required to diagnose NODAT. Although fasting plasma glucose has been variably quoted to be a good predictor of glucose intolerance, [12] OGTT is an early reliable marker of glucose intolerance in asymptomatic patients in our study.

Recent studies demonstrate that impaired insulin secretion and insulin resistance characterize patients with IFG, IGT and NODAT. [2],[13] Defects in insulin release indicate poor prognosis. [14] In our study, while insulin resistance was universal, only patients with an additional insulin secretory defect developed overt NODAT.

Our study showed a high incidence of NODAT. This may be due to the high baseline risk of diabetes in the Asian Indian population. [15] The National Urban Diabetes Survey (NUDS) reported that the age-standardized prevalence of type 2 diabetes was 12.1%. [16]

Asian Indians tend to have greater waist circumference and WHRs; thus, having a greater degree of central obesity with more total abdominal and visceral fat and increased insulin resistance. [17] Changes in life style have resulted in increased longevity. This has also resulted in a rapid rise in the prevalence of obesity, diabetes and heart disease. Neel's "thrifty genotype" hypothesis proposes that some genes are selected over previous millennia to allow survival in times of famine by efficiently storing all available energy during times of feast. However, these very genes result in obesity and type 2 diabetes when exposed to a constant high-energy diet. [18] From these studies, it is clear that Asian Indians are genetically predisposed to develop diabetes, and organ transplantation may further worsen the glycemic status, probably explaining the high incidence of NODAT in our young population despite the moderately high BMI.

We conclude that NODAT is not an inferquent metabolic complication following transplantation and can occur very early in the post-transplant period. The risk for developing NODAT may be higher in populations with an increased background risk for diabetes. Routine OGTT is essential for the early diagnosis of NODAT. Insulin secretory defect, in addition to insulin resistance, is associated with NODAT.

   References Top

1.Davidson J, Wilkinson AH. New-onset diabetes after transplantation 2003 international consensus guidelines: an endocrinologist's view. Diabetes Care 2004;27(3):805-12  Back to cited text no. 1
2.Cosio FG, Pesavento TE, Kim S, Osei K, Henry M, Ferguson RM. Patient survival after renal transplantation: IV. Impact of post-transplant diabetes. Kidney Int 2002;62:1440-6.  Back to cited text no. 2
3.von Kiparski A, Frei D, Uhlschmid G, Largiader F, Binswanger U. Post-transplant diabetes mellitus in renal allograft recipients: A matched-pair control study. Nephrol Dial Transplant 1990;5:220-5.  Back to cited text no. 3
4.Johny KV, Nampoory MR, Costandi JN, et al. High incidence of post-transplant diabetes mellitus in Kuwait. Diabetes Res Clin Pract 2002;55:123-30.  Back to cited text no. 4
5.Onwubalili JK, Obineche EN. High incidence of post-transplant diabetes mellitus in a singlecentre study. Nephrol Dial Transplant 1992; 7:346-9.  Back to cited text no. 5
6.Saxena S, Dash SC, Guleria S, et al. New onset Diabetes after transplant in live related renal allograft recipients: A single centre experience. J Assoc Physicians India 1996;44:472, 477-9.  Back to cited text no. 6
7.Rao M, Jacob CK, Shastry JC. Post-renal transplant diabetes mellitus--a retrospective study. Nephrol Dial Transplant 1992;7:1039-42.  Back to cited text no. 7
8.Navasa M, Bustamante J, Marroni C, et al. Diabetes mellitus after liver transplantation: Prevalence and predictive factors. J Hepatol 1996;25:64-71.  Back to cited text no. 8
9.Cosio FG, Pesavento TE, Osei K, Henry ML, Ferguson RM. Post-transplant diabetes mellitus: Increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int 2001;59:732-7.  Back to cited text no. 9
10.Markell MS. Post-transplant diabetes: Incidence, relationship to choice of immunosuppressive drugs, and treatment protocol. Adv Ren Replace Ther 2001;8:64-9.  Back to cited text no. 10
11.van Duijnhoven EM, Christiaans MH, Boots JM, Goossens VJ, Undre NA, van Hooff JP. A late episode of post-transplant diabetes mellitus during active hepatitis C infection in a renal allograft recipient using tacrolimus. Am J Kidney Dis 2002;40:195-201.  Back to cited text no. 11
12.EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.5.4. Post-transplant diabetes mellitus. Nephrol Dial Transplant 2002;17 (Suppl 4):28.  Back to cited text no. 12
13.Midtvedt K, Hartmann A, Hjelmesaeth J, Lund K, Bjerkely BL. Insulin resistance is a common denominator of post-transplant diabetes mellitus and impaired glucose tolerance in renal transplant recipients. Nephrol Dial Transplant 1998;13:427-31.  Back to cited text no. 13
14.Hjelmesaeth J, Hagen M, Hartmann A, Midtvedt K, Egeland T, Jenssen T. The impact of impaired insulin release and insulin resistance on glucose intolerance after renal transplantation. Clin Transplant 2002;16:389-96.  Back to cited text no. 14
15.Mohan V, Sandeep S, Deepa R, Shah B, Varghese C. Epidemiology of type 2 diabetes:Indian scenario. Indian J Med Res 2007;125: 217-30.  Back to cited text no. 15
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16.Ramachandran A, Snehalatha C, Kapur A, et al. Diabetes Epidemiology Study Group in India (DESI). High prevalence of diabetes and impaired glucose tolerance in India: National Urban Diabetes Survey. Diabetologia 2001;44: 1094-101.  Back to cited text no. 16
17.Yajnik CS, Fall CH, Coyaji KJ, et al. Neonatal anthropometry: The thin-fat Indian baby. The Pune Maternal Nutrition Study. Int J Obes Relat Metab Disord 2003;27:173-80.  Back to cited text no. 17
18.Neel JV, Weder AB, Julius S. Type II diabetes, essential hypertension, and obesity as "syndromes of impaired genetic homeostatis" the "thrifty genotype" hypothesis enter the 21 st century. Perspect Biol Med 1998;42:44-74.  Back to cited text no. 18

Correspondence Address:
Manisha Sahay
Department of Nephrology, Osmania General Hospital, Hyderabad, Andhra Pradesh
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DOI: 10.4103/1319-2442.118068

PMID: 24029252

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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