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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 21  |  Issue : 1  |  Page : 59-63

Interferon-gamma: Has acromegaly and diabetes an impact on such marker?


1 Department of Microbiology, College of Science for Girls, University of Baghdad, Baghdad, Iraq
2 Department of Microbiology, College of Medicine, University of Al-Mustansiriyah, Baghdad, Iraq
3 National Diabetes Center, Al-Mustansiriyah University, Baghdad, Iraq

Date of Submission28-Sep-2021
Date of Decision08-Oct-2021
Date of Acceptance20-Oct-2021
Date of Web Publication30-Jun-2022

Correspondence Address:
Dr. Sabreen Hamodi Hamza
College of Science for Girls, University of Baghdad, Baghdad
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mj.mj_26_21

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  Abstract 

Background: Acromegaly is a rare endocrine disease, its incidence is 4-6 per million per years while its prevalence is 40-60 per million. The distinctive facial characteristics are prognathism prominent forehead, and large hands and feet. This happens after the fusion of growth plates; separating acromegaly from gigantism that occurs before growth plates are closed. Interferon-gamma was checked in (80) acromegalic patients (50% are diabetics and 50% are non-diabetics) while (40) persons were regareded as healthy control group being non-diabetic, non-acromegalic. Aim of the study: To find out impact lnterferon-gamma in diabetic acromegalic versus non-diabetic acromegalic patients.Methods: Eighty acromegalic subjects were enrolled in across sectional study by measuring the level of lnterferon-gamma in the sera of diabetics and non-diabetics as 39 are diabetics while the remaining 41 patients are non-diabetic. Result: lnterferon-gammais high among diabetic acromegalic patients when compared with non-diabetic acromegalic subjects. Conclusion: Interferon gamma is high in acromegalic diabetic patients, nondiabetic acromegalic patients, and controls (100%, 97.6%, and 97.5%, respectively). Interferon gamma is elevated in patients with acromegaly only in the age group of 30–39 years, but in those with diabetes, the elevation is noticed later within the age group of 40–49 years as if concomitant diabetes delays its elevation.

Keywords: Acromegaly, diabetic mellitus, interferon-gamma


How to cite this article:
Hamza SH, Ashoor ZF, Rahmah AM. Interferon-gamma: Has acromegaly and diabetes an impact on such marker?. Mustansiriya Med J 2022;21:59-63

How to cite this URL:
Hamza SH, Ashoor ZF, Rahmah AM. Interferon-gamma: Has acromegaly and diabetes an impact on such marker?. Mustansiriya Med J [serial online] 2022 [cited 2022 Aug 16];21:59-63. Available from: https://www.mmjonweb.org/text.asp?2022/21/1/59/349310


  Introduction Top


Acromegaly is a hormonal disorder that develops when your pituitary gland produces too much growth hormone during adulthood. When you have too much growth hormone, your bones increase in size. In childhood, this leads to increased height and is called gigantism. However, in adulthood, a change in height does not occur. Instead, the increase in bone size is limited to the bones of your hands, feet, and face, and is called acromegaly.[1] Growth hormones are involved in inhibiting the function of insulin, like inhibiting the phosphorylation of insulin receptors, among the most significant aspects of insulin production. As a result, the insulin sensitivity of the cells will decrease, encouraging peripheral glucose absorption in the periphery, and increasing resistance to the gluconeogenesis suppression ability of insulin. Hence, the increase in growth hormone production leads to the mobilization of free fatty acids and avoids insulin-induced glucose oxidation, resulting in further deterioration of insulin resistance, contributing to diabetes mellitus (DM).[2] Oral glucose tolerance test-glucose has a suppressive neuroendocrine signal which reduces GH.[3] In this test, 75 g of glucose is given at various points over a period of 120 min with GH measurements.[4] Interferon-gamma (INF-γ) reported to play a vital role in innate and adaptive immune responses. Mainly, it was found to be a vital orchestrator of immune responses to viral infections, but it was soon realized that its immune-modulating activities achieved much greater and broader levels.[5],[6] A broad range of biological functions are performed by the downstream INF-γ signaling pathway target genes, which are mainly associated with modulation of innate and adaptive immune responses in host defense against viral and bacterial infections, but are also linked to cell cycle regulation, apoptosis, and inflammation.[6] INF-γ directly controls the differentiation, activation, and homeostasis of T-helper-1 (Th1) cells in adaptive immunity; inhibits the production of Th2 cells; enhances the ability of regulatory T-cells (Treg); promotes the activity of natural killer cells; and activates inflammatory macrophages of the classic M1 subtype.[7],[8] INF-γ also plays an essential role in attracting particular effector cells to various inflammatory microenvironments by inducing various chemokines.[9]


  Materials and Methods Top


Through the period from October 2020 to March 2021, 120 patients registered in the National Diabetes Center (NDC)/Mustansiriyah University were enrolled in the study, 80 acromegalic patients (40 – diabetic and 40 – nondiabetic) and 40 healthy controls; their control was defined by achieving the goals (pituitary adenoma, size regression, IGF-1, and GH decrement down to the recommended and predefined targets). They were subdivided into subgroups according to their age, disease duration, the use of Gamma-Knife radiosurgery, concomitant diabetes, and glycemic control in diabetic patients.

Interferon-gamma was studied by the use of enzyme-linked immunosorbent assay (ELISA), and the utilized ELISA was sandwich methodology. The Micro Elisa strip plate provided in this kit has been precoated with an antibody specific to IFN-γ and study the correlation between INF-γ and other biochemical and clinical variables was studied using the suitable statistical methods.

The SPSS Statistics for Windows, version 27. 0 (SPSS Inc., Chicago, Ill., USA) was utilized to analyze the data.


  Results Top


Eighty acromegalic patients were recruited, of which 40 are diabetics and the other 40 are nondiabetics, while the control group includes 40 nondiabetic, nonacromegalic healthy persons.

All the recruited patients are registered in the NDC/Mustansiriyah University.

[Table 1] and [Figure 1] show that INF-γ is high in all acromegalic patients but only 97.6% and 97.5% of nondiabetic acromegalic patients and healthy controls, respectively.
Table 1: Interferon-gamma concentration in diabetic acromegalic, nondiabetic acromegalic, and control groups

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Figure 1: Interferon-gamma concentration in the diabetic acromegalic, nondiabetic acromegalic, and control groups

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[Table 2] shows that interferon-gamma is high among diabetic acromegalic patients followed by nondiabetic acromegalic patients and finally the control group.
Table 2: Interferon-gamma concentration in acromegalic diabetic, acromegalic nondiabetic acromegalic, and control groups according to age and gender

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Interferon-gamma is the highest in the age group of 40–49 years among the diabetic acromegalic group and 30–39 years among the nondiabetic acromegalic group and the control group.

Interferon-gamma is found to be higher in males in diabetic acromegalic, nondiabetic acromegalic patients, while in the control group, there is no gender difference.

Interferon-gamma is found to be higher in diabetic acromegalic patients in those with disease duration <10 years, but in nondiabetic acromegalic patients, it was found to be higher in those with acromegaly duration >10 years.

In diabetic acromegalic patients, INF-γ is higher in Gamma-Knife-treated diabetic acromegalic patients versus those who were not treated by Gamma-Knife. However, in nondiabetic acromegalic patients, the use of Gamma-Knife has no impact on INF-γ, as shown in [Table 3].
Table 3: Interferon-gamma concentration in diabetic acromegalic and nondiabetic acromegalic patients according to disease duration and Gamma-Knife use

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INF-γ in statin users and nonusers shows nonsignificant difference in the diabetic acromegalic, nondiabetic acromegalic, and control groups, however, it was found to be the highest in diabetic acromegalic, nonstatin users.

The level of high-density lipoprotein (HDL) has no impact on the level of INF-γ among the three groups.

High cholesterol is associated with marginal nonsignificant elevation of INF-γ in diabetic acromegalic patients only.

Something that attracts attention is the significant reduction of INF-γ in diabetic acromegalic patients when their triglyceride is high, thus increasing triglyceride is associated with reduction of INF-γ (P = 0.017), as shown in [Table 4].
Table 4: Interferon-gamma concentration in diabetic acromegalic, nondiabetic acromegalic, and control groups in relation to statin use and lipid profile

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  Discussion Top


Interferon-gamma is the highest in diabetic acromegalic patients, thus it was found that both diseases augment the level of INF-γ. Being acromegalic but nondiabetic did not reduce such high INF-γ level; this may be attributed to the high cytokine levels, particularly interleukin-10.[10],[11]

However, the results are not in line with Wolters et al.[12] who found that there is no significant elevation of INF-γ in acromegalic patients.

Interferon-gamma is the highest in the presence of diabetes and acromegaly followed by acromegaly then the control. The studies on INF-γ in DM are really scarce, but it has been stated that INF-γ may be a predictor of the development of foot ulcer in diabetics and correlates positively with diabetes duration.[13]

Good glycemic control is found to be associated with higher levels of INF-γ reflecting better immune response and reducing the chance of infections.[14]

The immune system may have an impact on the pathogenesis and progression of acromegaly as it has been found that somatostatin, GH, and IGF-1 receptors are present on thymic cells and may have a role in immune differentiation.[15]

Male gender is associated with the higher INF-γ versus female gender in acromegalic diabetic patients followed by acromegalic nondiabetic patients, but there is no gender difference in the control group. The studies on INF-γ were reflective of its effect on atherosclerotic lesions in experimental animals as INF-γ deficiency in male mice results in progression of atherosclerotic lesions, but this is not true in female mice as INF-γ deficiency is not shown to result in any impact on atherosclerotic lesions, so the effect is strictly restricted to males.[16]

Overweight patients have the highest level of INF-γ among all studied patients and control, cytokines as INF-γ are known to be high in obese patients and may predict progression of the atherosclerotic lesion.[17]

The duration of disease has its impact on INF-γ in the enrolled patients, thus longer duration of acromegaly in diabetic acromegalic patients is associated with high INF-γ, but in acromegalic nondiabetics, the reverse is true as the presence of diabetes results in progressive elevation of INF-γ years by years. Diabetes and acromegaly result in high INF-γ in statin users, thus statin may cause an increment in INF-γ in diabetic acromegalic. Statin is known to suppress INF-γ production in cell lines, and it has been postulated that statin augments the action of immunosuppressive agents in patients with organ transplantation.[18]

HDL is found to have no impact on INF-γ level. The studies on such correlation are not available, however, the correlation between IGF-1 and HDL is found to be positive in type 2 diabetic patients.[19]


  Conclusion Top


  • Interferon-gamma is high in acromegalic diabetic patients, nondiabetic acromegalic patients, and controls (100%, 97.6%, and 97.5%, respectively)
  • Interferon-gamma is elevated in patients with acromegaly only in the age group of 30–39 years, but in those with diabetes, the elevation is noticed later within the age group of 40–49 years as if concomitant diabetes delays its elevation
  • Interferon-gamma is high in acromegalic patients but higher when there is concomitant diabetes
  • Longer duration of acromegaly is associated with higher INF-γ, and the use of Gamma-Knife radiosurgery is shown to increase INF-γ in acromegalic patients, provided that they are diabetics
  • In diabetic acromegalic patients, INF-γ is found to be high in nonstatin users, but the difference from statin users is marginal.


Recommendation

A well-designed prospective study enrolled higher number of acromegalic patients is highly recommended to find out then impact of INF-γ on the progression of acromegaly and its mortality to find out a modality of therapy that modulates the level of this molecule in the fruitful way.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Melmed S. Medical progress: Acromegaly. N Engl J Med 2006;355:2558-73.  Back to cited text no. 1
    
2.
Olarescu NC, Bollerslev J. The impact of adipose tissue on insulin resistance in acromegaly. Trends Endocrinol Metab 2016;27:226-37.  Back to cited text no. 2
    
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Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest 2009;119:3189-202.  Back to cited text no. 3
    
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Cordero RA, Barkan AL. Current diagnosis of acromegaly. Rev Endocr Metab Disord 2008;9:13-9.  Back to cited text no. 4
    
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Pestka S, Krause CD, Walter MR. Interferons, interferon-like cytokines, and their receptors. Immunol Rev 2004;202:8-32.  Back to cited text no. 5
    
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Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: An overview of signals, mechanisms and functions. J Leukoc Biol 2004;75:163-89.  Back to cited text no. 6
    
7.
Wang Z, Hong J, Sun W, Xu G, Li N, Chen X, et al. Role of IFN-gamma in induction of Foxp3 and conversion of CD4+ CD25- T cells to CD4+ Tregs. J Clin Invest 2006;116:2434-41.  Back to cited text no. 7
    
8.
Curtsinger JM, Agarwal P, Lins DC, Mescher MF. Autocrine IFN-γ promotes naive CD8 T cell differentiation and synergizes with IFN-α to stimulate strong function. J Immunol 2012;189:659-68.  Back to cited text no. 8
    
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Pak-Wittel MA, Yang L, Sojka DK, Rivenbark JG, Yokoyama WM. Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection. Proc Natl Acad Sci U S A 2013;110:E50-9.  Back to cited text no. 9
    
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Kooijman R, Coppens A. Insulin-like growth factor-I stimulates IL-10 production in human T cells. J Leukoc Biol 2004;76:862-7.  Back to cited text no. 10
    
11.
Amado A, Araújo F, Carvalho D. Cardiovascular risk factors in acromegaly: What's the impact of disease control? Exp Clin Endocrinol Diabetes 2018;126:505-12.  Back to cited text no. 11
    
12.
Wolters TL, van der Heijden CD, van Leeuwen N, Hijmans-Kersten BT, Netea MG, Smit JW, et al. Persistent inflammation and endothelial dysfunction in patients with treated acromegaly. Endocr Connect 2019;8:1553-67.  Back to cited text no. 12
    
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Hammad R, Elmadbouly AA, Ahmad IH, Mohammed SA, Farouk N, Futooh Z, et al. T-natural killers and interferon gamma/interleukin 4 in augmentation of infection in foot ulcer in type 2 diabetes. Diabetes Metab Syndr Obes 2021;14:1897-908.  Back to cited text no. 13
    
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Foss-Freitas MC, Foss NT, Donadi EA, Foss MC. Effect of metabolic control on interferon-gamma and interleukin-10 production by peripheral blood mononuclear cells from type 1 and type 2 diabetic patients. Braz J Med Biol Res 2007;40:671-7.  Back to cited text no. 14
    
15.
Colao A, Ferone D, Marzullo P, Lombardi G. Acromegaly and immune function. In: Neuroimmune Biology. Vol. 2. Amsterdam, Netherlands: Elsevier; 2002. p. 247-57.  Back to cited text no. 15
    
16.
Whitman SC, Ravisankar P, Daugherty A. IFN-gamma deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E-/- mice. J Interferon Cytokine Res 2002;22:661-70.  Back to cited text no. 16
    
17.
Abdulrahman AT, Al-Barzinji RM. Estimation of interferon gamma and some inflammatory atherogenic biomarkers levels in obese coronary atherosclerotic patients. Zanco J Med Sci 2020;24:205-12.  Back to cited text no. 17
    
18.
Mach F. Statins as immunomodulatory agents. Circulation 2004;109:I15-7.  Back to cited text no. 18
    
19.
Yen CJ, Lin SL, Huang KT, Lin RH. Age-associated changes in interferon-gamma and interleukin-4 secretion by purified human CD4+ and CD8+ T cells. J Biomed Sci 2000;7:317-21.  Back to cited text no. 19
    


    Figures

  [Figure 1]
 
 
    Tables

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



 

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