Altered Plasma Levels of Nerve Growth Factor and Transforming Growth Factor-β2 in Type-1 Diabetes Mellitus

doi:10.1006/brbi.1999.0554

Brain, Behavior, and Immunity

Volume 13, Issue 4, December 1999, Pages 361-366

https://doi.org/10.1006/brbi.1999.0554 Get rights and content

Abstract

Nerve growth factor (NGF) and transforming growth factor-β2 (TGF-β2) are cytokines which have known immunological effects. An elevated level of NGF has been reported in certain autoimmune diseases, whereas TGF-β2 is an immunosuppressor which is known to play a role in regulating cell proliferation. A role of this cytokine has been proposed in the pathogenesis of type-1 diabetes mellitus (IDDM), but no clinical studies have yet measured its serum level in this disease. In this study we measured the levels of NGF and TGF-β2 in the sera of patients with IDDM (n = 26) and values were compared to those of age-matched normal subjects (n = 27) and also to patients with type-2 diabetes mellitus (NIDDM) (n = 26) with similar HbA1c levels and an equal duration of diabetes. Serum NGF levels were significantly elevated in IDDM patients compared to those of age-matched controls (p < .001) and NIDDM controls (p < .01). TGF-β2 levels were lower in IDDM patients when compared with the healthy control (p < .001) and the NIDDM control (p < .05). There was no correlation between the levels of NGF and TGF-β2. The duration of diabetes and the level of HbA1c did not affect the NGF and TGF-β2 levels in the IDDM patients. We conclude that an increase in NGF and a suppression in TGF-β2 levels are present in patients with type-1 diabetes mellitus and that both cytokines may play independent roles in the pathogenesis of this disease.

References (28)

P. Fernyhough et al.
Deficits in sciatic nerve neuropeptide content coincide with a reduction in target tissue nerve growth factor messenger RNA in streptozotocin-diabetic rats: effects of insulin treatment
Neuroscience
(1994)
J.J. Letterio et al.
TGF-β: A critical modulator of immune cell function
Clin. Immunol. Immunopathol.
(1997)
A. Schattner
Lymphokines in autoimmunity—A critical review
Clin. Immunol. Immunopathol.
(1994)
R. Tisch et al.
Insulin-dependent diabetes mellitus
Cell
(1996)
M. Torcia et al.
Nerve growth factor is an autocrine survival factor for memory B-lymphocytes
Cell
(1996)
G. Wolf et al.
High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-beta
Kidney Int.
(1992)
S. Bonini et al.
Circulating nerve growth factor levels are increased in humans with allergic diseases and asthma
Proc. Natl. Acad. Sci. USA
(1996)
L. Bracci-Laudiero et al.
Multiple sclerosis patients express increased levels of nerve growth factor in cerebrospinal fluid
Neurosci. Lett.
(1992)
J.A. Bruijn et al.
Transforming growth factor β and the glomerular extracellular matrix in renal pathology
J Lab. Clin. Med.
(1994)
D.B. Constam et al.
Differential expression of transforming growth factor-β 1, β 2 and β 3 by glioblastoma cells, astrocytes and microglia
J. Immunol.
(1992)

E. Dicou et al.

Increased frequency of NGF in sera of rheumatoid arthritis and systemic lupus erythematosus patients

Neuroreport

(1993)

P.B. Ehihard et al.

Expression of nerve growth factor and nerve growth factor tyrosine kinase Trk in activated CD4-positive T cell clones

Proc. Natl. Acad. Sci. USA

(1993)

V. Faradji et al.

Low serum levels of nerve growth factor in diabetic neuropathy

Acta Neurol. Scand.

(1990)

Cited by (29)

Nerve growth factor in metabolic complications and Alzheimer's disease: Physiology and therapeutic potential
2020, Biochimica et Biophysica Acta - Molecular Basis of Disease
Citation Excerpt :
Elevated NGF levels are observed in adult T2DM women compared with non-diabetic women [30]. When comparing T1DM with T2DM patients with similar durations of hyperglycemia and HbA1c levels, T1DM patients tend to have higher NGF levels than those with T2DM [62]. Overall, diabetes is accompanied with elevated NGF levels.
As the population ages, obesity and metabolic complications as well as neurological disorders are becoming more prevalent, with huge economic burdens on both societies and families. New therapeutics are urgently needed. Nerve growth factor (NGF), first discovered in 1950s, is a neurotrophic factor involved in regulating cell proliferation, growth, survival, and apoptosis in both central and peripheral nervous systems. NGF and its precursor, proNGF, bind to TrkA and p75 receptors and initiate protein phosphorylation cascades, resulting in changes of cellular functions, and are associated with obesity, diabetes and its complications, and Alzheimer's disease. In this article, we summarize changes in NGF levels in metabolic and neuronal disorders, the signal transduction initiated by NGF and proNGF, the physiological and pathophysiological relevance, and therapeutic potential in treating chronic metabolic diseases and cognitive decline.
Changes of regulatory T cells, transforming growth factor-beta and interleukin-10 in patients with type 1 diabetes mellitus: A systematic review and meta-analysis
2016, Clinical Immunology
Citation Excerpt :
In animal models, CD4+ CD25+ T cells can prevent murine T1DM [49], an important finding confirmed by at least two clinical trials of human T1DM [51,52]. In recent years, the relationship between Treg, IL-10, TGF-β and T1DM were inventively studied in researchers of Brusko [53], Kukreja [25], Asmaa Mohamed Zahran [54], J. M. Lawson [29], Maria Jesus [38], T.-T. Yang [55] Dai Yang-li [40], Jolanta Mysliwska [56], M. Andrade [57], Sami T. Azar [45], Katarzyna Zorena [46] and so on. However, there is still no agreement due to the small sample sizes in these case-control studies.
Regulatory T lymphocyte cells (Treg) associated with interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) have implicated in the development of type 1 diabetes mellitus (T1DM), yet the existing evidence remains unclear. Hereby we performed a systematic review and meta-analysis to characterize the changes in T1DM patients. A total of 1407 T1DM patients and 1373 healthy controls from 40 case-control studies were eventually included in the pooling analysis. Compared with the controls, T1DM patients had decreased frequency of CD4⁺ CD25⁺ Treg (p = 0.0003), CD4⁺ CD25⁺ Foxp3⁺ Treg (p = 0.020), and the level of TGF-β (p = 0.030). Decrease in IL-10 (p = 0.14) was not significant. All the changes remained significant when the studies with low NOS scores and publication bias were excluded. In conclusion, peripheral Treg and serum TGF-β are reduced in type 1 diabetes mellitus whereas changes in serum IL-10 are not significant.
Relationship between growth factors and its implication in the pathogenesis of leprosy
2014, Microbial Pathogenesis
Citation Excerpt :
It is estimated that more than one-fourth of all leprosy patients present some degree of disability; of these, about half have grade 2 disabilities, which corresponds to permanent neurological damage [52]. Several studies investigating systemic diseases such as diabetes mellitus and osteoarthritis have demonstrated an interaction between NGF and TGF-β [53,54]. Neurotrophins play a key role in the differentiation and survival of nerve cells [55].
Leprosy is a chronic infectious disease caused by Mycobacterium leprae which affects the skin and peripheral nervous system. The immune response of the host determines the clinical course of the disease. The tuberculoid form is the result of high cell-mediated immunity characterized by a Th1 response, whereas the lepromatous form is characterized by low cell-mediated immunity and a Th2 humoral response. The neural damage established produces marked changes in the expression of growth factors such as nerve growth factor (NGF) and its receptors (NGF-R). The expression of NGF, associated with the expression of Th1 and Th2 cytokines, might be involved in the tissue damage caused by the bacillus. Therefore, the objective of this study was to correlate the immunoexpression patterns of NGF and NGF-R in the different clinical forms of leprosy, and to associate the findings with the in situ expression of TGF-β and clinical classification of the disease. TGF-β, NGF and NGF-R immunoexpression was analyzed by immunohistochemistry in paraffin-embedded material. Most patients were males with a mean age of 40.7 years. TGF-β levels were significantly higher in the lepromatous forms. No significant difference in the immunoexpression of NGF or NGF-R was observed between the clinical forms, but expression tended to be higher at the lepromatous pole. There was a significant positive correlation between NGF and NGF-R in the different clinical forms of leprosy. A significant positive correlation was observed between NGF, NGF-R and TGF-β. It can be concluded that, even existing evidence on the role of these molecules in the clinical spectrum of leprosy.
Serum and Tear Levels of Nerve Growth Factor in Diabetic Retinopathy Patients
2008, American Journal of Ophthalmology
Citation Excerpt :
Tear film BUT correlated with tear NGF concentration (r = 0.566) but not with serum NGF concentration (r = 0.242; P = .361). Recent reports show that NGF expression is increased under conditions such as insulin-dependent diabetes melitus10 and high glucose levels,11 which is relevant to the development of neuropathy.12 Furthermore, NGF is reported to modulate angiogenesis in cutaneous wound healing,13 to stimulate VEGF production in streptozotocin-induced diabetic mice,7 and to be elevated under ischemic conditions.14
To measure serum and tear nerve growth factor (NGF) concentrations in diabetic retinopathy (DR) patients to determine whether the NGF correlated with parameters associated with DR.
Cross-sectional comparative study.
The study enrolled 254 DR patients and 71 nondiabetic controls. Patient demographic characteristics and diabetic parameters, including blood sugar levels, HbA1c, liver and renal function, were evaluated in two separate university hospitals. Serum and tear NGF concentrations and the ratio of NGF to total protein (TP) in serum and tear fluid were determined.
Serum and tear NGF levels were found to be higher in proliferative diabetic retinopathy (PDR) patients (98.7 ± 12.1 ng/ml in serum, 45.6 ± 6.3 ng/ml in tear) than in nondiabetic controls (18.5 ± 6.1 ng/ml in serum and 8.3 ± 4.7 ng/ml in tear) and nonproliferative diabetic retinopathy (NPDR) patients (26.6 ± 5.1 ng/ml in serum and 8.6 ± 4.2 ng/ml in tear; p < .001 for both serum and tear differences). Similarly, NGF levels were higher in PDR patients than in controls and NPDR patients after adjusting for possible confounding factors such as age, gender, serum blood urea nitrogen, creatinine, and diabetic parameters. In addition, the NGF-to-TP ratio for both serum and tear fluid was higher in the PDR group compared with the control and NPDR groups. NGF levels correlated well with diabetes duration, HbA1c, and blood sugar levels and diabetic nephropathy.
NGF concentration may be a good parameter for evaluating DR status. In addition, serum and tear NGF concentrations correlated strongly, indicating that tear fluid assays may offer an effective, accurate, and noninvasive option for NGF measurement.
Serum neurotrophins-A study on the time course and influencing factors in a large old age sample
2007, Neurobiology of Aging
The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important mediators of brain and neuronal development, the maintenance of homeostatic conditions in the adult nervous system, and the complex interplay of central and peripheral physiological and pathophysiological factors. To date there are few studies examining blood concentrations of neurotrophic factors in large samples of healthy and diseased individuals and no published study specifically addresses peripheral BDNF and NGF levels in late life. Using improved highly sensitive and specific fluorometric two-site enzyme-linked immunosorbent assays we examined BDNF (n = 465) and NGF (n = 175) serum levels in a large cohort of elderly individuals (age range: 70–103 years). Neither BDNF nor NGF serum levels proved to be normally distributed, indicating that previously published studies with small sample sizes using parametric testing may be misleading. A significant correlation was found between BDNF and platelet count (r = 0.344, p < 0.01), age and BDNF protein (r = −0.101, p = 0.029) and BDNF and NGF serum levels (r = 0.152, p = 0.04). No other major influencing factors were found including gender, depression, and dementia.
Diabetic neuropathy and nerve regeneration
2003, Progress in Neurobiology
Diabetic neuropathy is the most common peripheral neuropathy in western countries. Although every effort has been made to clarify the pathogenic mechanism of diabetic neuropathy, thereby devising its ideal therapeutic drugs, neither convinced hypotheses nor unequivocally effective drugs have been established. In view of the pathologic basis for the treatment of diabetic neuropathy, it is important to enhance nerve regeneration as well as prevent nerve degeneration. Nerve regeneration or sprouting in diabetes may occur not only in the nerve trunk but also in the dermis and around dorsal root ganglion neurons, thereby being implicated in the generation of pain sensation. Thus, inadequate nerve regeneration unequivocally contributes to the pathophysiologic mechanism of diabetic neuropathy. In this context, the research on nerve regeneration in diabetes should be more accelerated. Indeed, nerve regenerative capacity has been shown to be decreased in diabetic patients as well as in diabetic animals. Disturbed nerve regeneration in diabetes has been ascribed at least in part to all or some of decreased levels of neurotrophic factors, decreased expression of their receptors, altered cellular signal pathways and/or abnormal expression of cell adhesion molecules, although the mechanisms of their changes remain almost unclear. In addition to their steady-state changes in diabetes, nerve injury induces injury-specific changes in individual neurotrophic factors, their receptors and their intracellular signal pathways, which are closely linked with altered neuronal function, varying from neuronal survival and neurite extension/nerve regeneration to apoptosis. Although it is essential to clarify those changes for understanding the mechanism of disturbed nerve regeneration in diabetes, very few data are now available. Rationally accepted replacement therapy with neurotrophic factors has not provided any success in treating diabetic neuropathy. Aside from adverse effects of those factors, more rigorous consideration for their delivery system may be needed for any possible success. Although conventional therapeutic drugs like aldose reductase (AR) inhibitors and vasodilators have been shown to enhance nerve regeneration, their efficacy should be strictly evaluated with respect to nerve regenerative capacity. For this purpose, especially clinically, skin biopsy, by which cutaneous nerve pathology including nerve regeneration can be morphometrically evaluated, might be a safe and useful examination.

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Brief CommunicationAltered Plasma Levels of Nerve Growth Factor and Transforming Growth Factor-β2 in Type-1 Diabetes Mellitus

Abstract

Neuroscience

Clin. Immunol. Immunopathol.

Clin. Immunol. Immunopathol.

Cell

Cell

Kidney Int.

Circulating nerve growth factor levels are increased in humans with allergic diseases and asthma

Proc. Natl. Acad. Sci. USA

Multiple sclerosis patients express increased levels of nerve growth factor in cerebrospinal fluid

Neurosci. Lett.

Transforming growth factor β and the glomerular extracellular matrix in renal pathology

J Lab. Clin. Med.

Differential expression of transforming growth factor-β 1, β 2 and β 3 by glioblastoma cells, astrocytes and microglia

J. Immunol.

Increased frequency of NGF in sera of rheumatoid arthritis and systemic lupus erythematosus patients

Neuroreport

Expression of nerve growth factor and nerve growth factor tyrosine kinase Trk in activated CD4-positive T cell clones

Proc. Natl. Acad. Sci. USA

Low serum levels of nerve growth factor in diabetic neuropathy

Acta Neurol. Scand.

Brief Communication
Altered Plasma Levels of Nerve Growth Factor and Transforming Growth Factor-β2 in Type-1 Diabetes Mellitus