| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Department of Internal Medicine, Division of Endocrinology (S.T.A., I.S., M.S.Z.), Chronic Care Center for Diabetes (S.T.A.), and Department of Family Medicine (S.M.), American University Medical Center, Beirut, Lebanon
Address correspondence and requests for reprints to: Sami T. Azar, M.D., F.A.C.P., Department of Internal Medicine, Division of Endocrinology, American University of Beirut, 850 3rd Avenue 18th floor, New York, New York 10022. E-mail: sazar{at}aub.edu.lb
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Twenty-six normoalbuminuric patients with type 1 diabetes and 25 normoalbuminuric patients with type 2 diabetes were divided into three groups according to the onset of their diabetes and were compared with 27 and 15 age-matched normal subjects, respectively. We conclude that in normoalbuminuric patients serum TGF-ß levels increased at the onset of type 2 diabetes and remained elevated throughout the disease; they did not change at the onset of type1 diabetes, however, they started to decrease around 2 yr after the onset of the disease.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
In this study, we compared the levels of TGF-ß in the serum of normoalbuminuric patients with type 1 and type 2 diabetes at different stages of the duration of this disease.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
All subjects gave consent to the study. Type 1 diabetics were divided into three groups (A1, B1, and C1) where duration of diabetes in the patients was less than 2 yr, between 2 and 10 yr, and greater than 10 yr, respectively. Type 2 diabetics were also divided into three groups (A2, B2, and C2) where duration of diabetes in the patients (according to the date of the first diagnosis of hyperglycemia) was less than 2 yr, between 2 and 10 yr, and greater than 10 yr, respectively. The gender distribution and the HbA1c levels were similar in the three groups and in the controls of both type 1 and type 2 diabetes, respectively.
The subjects’ characteristics are shown in Table 1
.
|
Venous blood was collected from patients and transferred to tubes (kept on ice) without anticoagulants. After the coagulation (kept at 4 C), samples were centrifuged at 4 C (3000 rpm, for 15 min, using a refrigerated centrifuge) and the serum was transferred to a new set of polypropylene tubes. All sera were stored in a -70 C freezer until the time of the assay. TGF-ß levels were measured by a solid phase sandwich, two-site enzyme-linked immunosorbent assay, using a Promega Corp. Emax immunoassay system (Promega Corp., Madison, WI). Briefly, Nunc Maxisorp 96-well plates were coated with monoclonal anti-TGF-ß antiserum, and the plates were incubated overnight at 4 C. After washing the plates and blocking for nonspecific binding, TGF-ß standards and samples, in duplicate, were added to the appropriate wells and the plates were incubated for 6 h at room temperature. After washing the plates, polyclonal anti-TGF-ß antiserum were added to all the wells and the plates were incubated overnight at 4 C. The next day the plates were washed further and horseradish peroxidase-labeled antirat IgG was added to all the wells. The color in the plates was developed by adding TMB as the substrate, and the OD was measured at 450 nm, using an automatic plate reader.
Statistical analysis
Data are reported as mean ± SD. Scheffe’s multiple comparison test was used for analysis. A level of P < 0.05 was accepted as statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
).
|
15
yr; n = 9) were compared with TGF-ß levels in the older control
subgroup (age, >15 yr; n = 18). There was no difference in the
TGF-ß levels between the two groups (6.0 ± 0.8 vs.
5.8 ± 0.7, respectively).
In type 2 diabetes, TGF levels were, respectively, higher in group A2
(10.8 ± 2.3 ng/mL), group B2 (9.9 ± 2.8 ng/mL), and group
C2 (10.7 ± 2.2 ng/mL) than in controls (4.1 ± 0.5 ng/mL);
P < 0.05 (Fig. 2).
|
There was no correlation between the levels of serum TGF-ß and the level of HbA1c in neither type 1 nor type 2 diabetes.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
In type 2 diabetes, insulin resistance, followed by defective insulin secretion, seems to be present in most patients; however, TGF-ß and other cytokines do not seem to play a major role in the disease process (5). Contrary to type 1 diabetes, we found an elevated level of plasma TGF-ß in patients with type 2 diabetes irrespective of the duration of disease. One explanation of the high TGF-ß levels is the relative state of hyperglycemia that increases TGF-ß levels. Our type 2 diabetic patients had a higher blood glucose level than the normal controls, which may explain their higher serum TGF-ß levels. One study demonstrated an elevated TGF-ß level in type 2 diabetes patients and a correlation between the TGF-ß levels and HBA1c levels (6); however, in contradistinction to this previous report, we did not find a correlation between the level of TGF-ß and the HbA1c.
The changes in TGF-ß cannot be attributed to changes in the kidney function because all the patients were normoalbuminuric and did not suffer from any form of kidney disease. In several studies involving human and experimental diabetic nephropathy, expression of TGF-ß has always been found to be elevated and the altered production of this cytokine has been implicated in the pathogenesis of glomerulosclerosis of diabetic nephropathy (7, 8, 9). TGF-ß was increased in the glomeruli of patients with nephropathy and it seems to play a key role in the pathogenesis of basement membrane thickening and extracellular matrix accumulation (9).
Type 1 diabetes, unlike type 2 diabetes, is an autoimmune condition resulting from a cell-mediated immune destruction of pancreatic ß cells (1). Whether TGF-ß plays a role in the pathogenesis of type 1 diabetes remains speculative. However, several workers have described an immunosuppressive role for this cytokine. For example, immunosuppression on a murine major histocompatibility complex class II-restricted T lymphocyte clone was mediated by TGF-ß1, -ß2, and -ß3. In gene-knockout transgenic mice in which the gene locus for the TGF-ß1 isoform was selectively deleted, these animals manifested an autoimmune-like disorder (10). The proper production and interaction between different cytokines as immune effector molecules contributes toward a well-balanced immune response, which, if upset, can have serious consequences in the pathogenesis of autoimmune disease (3). The pathogenesis of the autoimmune disturbances in type 1 diabetes remains obscure. There is, however, a complex interplay among genetic, immune, and hormonal factors. In this study, we demonstrated a late suppression in TGF-ß levels in the serum of patients with type 1 diabetes. Overwhelming evidence, from human and animal models of type 1 diabetes, has indicated a crucial role for this cytokine in the initiation and propagation of the disease (11). This is supported by the findings that TGF-ß1 and its highly homologous isoforms TGF-ß2 and TGF-ß3 are typical multifunctional cytokines, which play a crucial role in regulating not only cell proliferation, but also in modulating immune cell function (4).
The relative delayed suppression of TGF-ß in type 1 diabetes does not seem to be affected by diabetes control, and the results of this study would not have been different if the patients had better diabetes control because the extent of hyperglycemia of group A1 was similar to that of groups B1 and C1. However, the hyperglycemia in group A1 may have relatively increased the level of TGF-ß in this group to become similar to that of the control group. As such, one may speculate that, in early type 1 diabetes, serum TGF-ß levels start declining but are masked by the hyperglycemia that is usually present. Later on, and after a duration of disease more than 2 yr, the TGF-ß suppression becomes more profound, which leads to less evident stimulation by hyperglycemia.
We conclude that this low level of TGF-ß in type 1 diabetes patients may contribute to the immune alteration in this disease leading to a lack of immunosuppression and, more important, to the propagation and maintenance of the disease. In type 2 diabetes the elevation of plasma TGF may only reflect the state of hyperglycemia and may not have a contributory role in the pathogenesis of this disease.
|
Footnotes |
|---|
Received May 30, 2000.
Revised August 14, 2000.
Accepted September 1, 2000.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  B. F. Schrijvers, A. S. De Vriese, and A. Flyvbjerg From Hyperglycemia to Diabetic Kidney Disease: The Role of Metabolic, Hemodynamic, Intracellular Factors and Growth Factors/Cytokines Endocr. Rev., December 1, 2004; 25(6): 971 - 1010. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
