Ludzkie koronawirusy - autor: Krzysztof Pyrć z Zakładu Mikrobiologii, Wydział Biochemii, Biofizyki i Biotechnologii, Uniwersytet Jagielloński, Kraków

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© Borgis - Postępy Nauk Medycznych 12/2016, s. 878-882 | DOI: 10.5604/08606196.1226636
*Karolina M. Nowak1, Katarzyna Romanowska-Próchnicka2, 3, Katarzyna Bornikowska1, Wojciech Zgliczyński1, Lucyna Papierska1
Oral glucose tolerance test as a screening tool in diagnostics of steroid-induced glucose intolerance – preliminary report
Doustny test obciążenia glukozą jako test przesiewowy w diagnostyce zaburzeń gospodarki węglowodanowej indukowanej przewlekłym leczeniem glikokortykosteroidami – doniesienie wstępne
1Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw
Head of Department: Professor Wojciech Zgliczyński, MD, PhD
2Department of General and Experimental Pathology, 2nd Faculty of Medicine, Medical University of Warsaw
Head of Department: Dariusz Szukiewicz, MD, PhD
3Department of Systemic Connective Tissue Diseases, Eleonora Reicher National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw
Head of Department: Professor Marzena Olesińska, MD, PhD
Streszczenie
Wstęp. Glikokortykoidy (GKS) wykorzystywane są w leczeniu wielu schorzeń, między innymi chorób układowych tkanki łącznej. Niestety, wywołują one również wiele działań niepożądanych, w tym zaburzenia metabolizmu glukozy. Z uwagi na to, że stan przedcukrzycowy i cukrzyca prowadzą do makro- i mikroangiopatii, niezmiernie ważne jest, by prawidłowo rozpoznawać i leczyć te zaburzenia. Obecne wytyczne dotyczące rozpoznawania cukrzycy u pacjentów przewlekle leczonych steroidami zalecają wykonywanie przesiewowych oznaczeń stężenia glukozy na czczo, podczas gdy GKS powodują głównie hiperglikemie poposiłkowe.
Cel pracy. Ocena przydatności doustnego testu obciążenia glukozą jako testu przesiewowego w diagnostyce zaburzeń gospodarki węglowodanowej wśród pacjentów przewlekle leczonych glikokortykosteroidami (powyżej 3 miesięcy), u których nie stwierdzono stanu przedcukrzycowego lub cukrzycy przed włączeniem do badania. Drugim celem badania było zaobserwowanie zależności pomiędzy występowaniem nieprawidłowości w metabolizmie glukozy indukowanej steroidami a czasem leczenia, dawką i rodzajem glikokortykoidu, BMI, WHR, procentową zawartością tkanki tłuszczowej (tułowia i całkowitą), HbA1c, HOMA-IR, Matsuda Index i wywiadem rodzinnym w kierunku cukrzycy.
Materiał i metody. U 30 pacjentów z układową chorobą tkanki łącznej wykonano OGTT. Wszyscy uczestnicy badania odbyli ocenę kliniczną i biochemiczną, a następnie zostali podzieleni na dwie grupy. Do grupy I zakwalifikowano 10 chorych, u których stwierdzono nieprawidłową tolerancję glukozy lub cukrzycę, a do grupy II 20 badanych z prawidłowym metabolizmem glukozy. Wykonano analizę statystyczną i porównano obie grupy, wykorzystując program STATA 13.
Wyniki. U 26% badanych stwierdzono upośledzoną tolerancję glukozy lub cukrzycę dopiero na podstawie OGTT. Nie wykazano różnic pomiędzy grupami w: czasie steroidoterapii, aktualnej dawce dobowej i rodzaju steroidu, BMI, WHR, całkowitej procentowej zawartości tkanki tłuszczowej i procentowej zawartości tkanki tłuszczowej tułowia oraz wskaźniku insulinooporności HOMA. Co zaskakujące, to w grupie z zaburzeniami tolerancji glukozy stwierdzono znamiennie niższą kumulacyjną dawkę steroidu.
Wnioski. Wyniki prezentowanego badania pokazują, iż w grupie pacjentów leczonych przewlekle glikokortykoidami, opieranie diagnostyki cukrzycy jedynie na oznaczaniu stężeń glukozy na czczo jest nieprzydatne. Zaburzeń tych nie przewidują również: BMI, WHR, czas steroidoterapii, dawka i rodzaj glikokortykoidu, wskaźnik HOMA czy wywiad rodzinny w kierunku cukrzycy. Rekomendujemy wykonanie doustnego testu obciążenia glukozą u wszystkich pacjentów leczonych glikokortykoidami powyżej 3 miesięcy, gdyż w tej grupie pacjentów jest to najskuteczniejsze badanie przesiewowe.
Summary
Introduction. Glucocorticoids (GCS) are used in chronic treatment of many connective tissue diseases, however they can also cause many adverse events such as impairment in glucose metabolism. Since pre-diabetes or diabetes lead to macro- and microangiopathy it is crucial to properly detect and manage these conditions. The current guidelines recommend to screen patients chronically treated with GCS using fasting plasma glucose levels while these medicaments cause mainly postprandial hyperglycemia.
Aim. The aim of the study was to assess the usefulness of oral glucose tolerance test (OGTT) in screening of patients chronically treated with glucocorticoids without previously diagnosed pre-diabetes or diabetes. The second study’s objective was to evaluate the relation between occurrence of steroid-induced impairment in glucose metabolism and time, dose and type of steroid, BMI, WHR, HbA1c, HOMA-IR, Matsuda Index and family history of diabetes.
Material and methods. In 30 patients diagnosed with connective tissue diseases OGTT was performed. All participants underwent clinical and biochemical evaluation. Then they were divided into two groups. Group 1 (10 patients) was found to have steroid-induced IGT or diabetes and group 2 (20 patients) had normal glucose metabolism. Statistical analysis comparing two groups was performed with STATA13 software.
Results. 26% of patients had pre-diabetes or diabetes diagnosed only during OGTT. There was no difference between groups in time of treatment, type or daily dose of steroids, BMI, WHR, percentage total body or trunk fat and HOMA-IR. The statistical significance was reached for cumulative dose of steroids – it was surprisingly lower in the group with IGT.
Conclusions. The oral glucose tolerance test should be performed in every patients chronically treated with GCS as it is the only way to effectively detect the impairment in glucose metabolism.
INTRODUCTION
Oral glucocorticoids (GCS) are widely used in treatment of many diseases. Despite their unquestionable positive effects in treatment of autoimmune and inflammatory disorders they are not free from serious adverse events such as impairment in glucose metabolism (1). GCS cause hyperglycemia by several mechanisms:
– enhancing liver gluconeogenesis (rise in glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activity) (2),
– increasing the glycogen production in liver (through inactivation of glycogen phosphorylase and activation of glycogen synthetase) (2),
– reducing glucose uptake in liver, muscles and adipose tissue,
– inducing the insulin resistance and β-cells dysfunction (2, 3).
The GCS treatment can worsen the glycemic control in patients with pre-existing diabetes or pre-diabetes but can also lead to development of these conditions “de novo”. Some authors estimate the prevalence of new-onset steroid-induced diabetes on 10-20% (4) while in other four studies researchers did not find any case of this disease (5). Probably this is due to the fact that mentioned studies were carried out on patients using small doses of GCS (≤ 10 mg of prednisone) while the risk of hyperglycemia that require treatment was found to be dependent on the daily dose of steroids (OR 10.34 when using > 120 mg/d of hydrocortisone equivalent and OR 1.77 for a dose 1-39 mg/d) (6). Not only the dose but also the type of steroid is important. Patients using dexamethasone are thirty times and using prednisone four times more prone to developing impairment in glucose metabolism than patients treated with hydrocortisone (7). In the study conducted by Da Silva the risk factors for developing the new-onset diabetes after GCS were identified as the same as for type 2 diabetes: pre-diabetes, obesity, positive family history and previous gestational diabetes (5). However, the study published in 2012, comparing individuals with pre-existing type 2 diabetes and with new-onset steroid-induced diabetes, both chronically treated with GCS, gave interesting results (8). Patients with type 2 diabetes had more positive family history and macrovascular complications as well as a higher body mass index. Interestingly, the retinopathy was not observed in any of the patients with new-onset diabetes, what may suggest shorter exposure to hyperglycemia (8). This indicates that steroid-induced diabetes may be more than just simply unmasking previously existing impairment in glucose metabolism, and probably its development is dependent on other additional, probably genetic, factors.
Unfortunately, there are no available evidence based medicine data on how to detect, prevent and manage steroid-induced hyperglycemia or diabetes. The only recommendations are based on opinion of experts (9, 10). Every patient before initiating treatment with GCS should be screened to determine plasma fasting glucose. If any abnormalities are found, oral glucose tolerance test (OGTT) should be performed and depending on the result further management need to be introduced as stated in the current guidelines for diagnosis of diabetes (11-13). If GCS treatment was already initiated The European League Against Rheumatism (EULAR) recommends regular testing for plasma fasting glucose (FPG) and “standard care” (9, 10).
In American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” from 2016, in International Diabetes Federation Global Guidelines (IDF) released in 2012 or in Polish Diabetes Association Guidelines 2016 there are no separate recommendations for diagnosing and treatment of steroid-induced diabetes (11-13). This is surprising, taking into consideration fact that steroids are the most common cause of drug-induced diabetes (3). In 2003 the international guidelines concerning diagnosis and management of new-onset diabetes after transplantation ware released (14). It is recommended to determine plasma fasting glucose once a week during treatment for the first four weeks after surgery and then after 3, 6 and 12 months and once a year afterwards. However, this does not reflect the action of GCS which increase mainly postprandial glucose concentrations while fasting glucose levels are within normal range (3). In 2014 Lansang (15) proposed to diagnose the steroid-induced diabetes based on the “random plasma glucose ≥ 200 mg/dl (preferably in the afternoon or two hours after a meal) with classical symptoms of hyperglycemia” or as stated in ADA guidelines (FPG ≥ 126 mg/dl, HbA1c ≥ 6.5% or 2-hour value of glucose ≥ 200 mg/24 in OGTT) (11, 15). Still this is not much different from previous general guidelines for diagnosing diabetes (16, 17). There is a current need to create practical recommendations on how to detect diabetes in patients chronically treated with glucocorticoids, based on the wide knowledge about GCS and their effect on glucose metabolism.
AIM
The aim of the study was to evaluate the OGTT as a screening test in patients chronically treated with GCS who were not previously diagnosed with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes. The second objective was to determine the relation between occurrence of steroid-induced impairment in glucose metabolism and time, dose and type of steroid, body mass index (BMI), waist-to hip ratio (WHR), HbA1c, Homeostasis Model Assessment (HOMA-IR), Matsuda Index and family history (FH) of diabetes. The preliminary report of the study is presented.
MATERIAL AND METHODS
30 patients diagnosed with systemic connective tissue diseases admitted to the Department of Endocrinology of Centre of Postgraduate Medical Education in Warsaw were evaluated for major side effects of chronic glucocorticoid treatment.
All participants met the inclusion criteria:
– glucocorticoid treatment lasting for at least three months,
– documented lack of IFG, IGT or diabetes (according to definition of IDF 2012).
The exclusion criteria were as follows:
– pregnancy,
– diagnosed IFG, IGT or diabetes before corticoid treatment,
– corticoid treatment for less than three months,
– diagnosed hypercortisolemia before corticoid treatment,
– cancer,
– liver or renal failure.
The study was approved by the Bioethics Committee and all patients gave their written consent to participate in the study.
All participants underwent clinical and biochemical evaluation including:
– medical history of the daily, cumulative dose and type of GCS,
– waist and hip circumference – Waist-hip (WHR) was calculated,
– body composition assessment – percentage total body fat and percentage fat trunk was measured using densitometer with “Total body” option (General Electric Healthcare model Lunar Prodigy Advance). Body composition measurement with dual-energy X-ray absorptiometry (DEXA) is more accurate than body mass index to determine body fat distribution,
– weight and height – body mass index (BMI) was calculated,
– lipid profile and HbA1c%,
– OGTT – the blood samples for glucose and insulin were collected in basic state and every thirty minutes until two hours after administering 75 g of glucose (without the morning dose of steroid),
– family history of diabetes.
Two insulin resistance indexes which have a good correlation with euglycemic insulin clamp were calculated (18, 19):
1. HOMA-IR = glucose x insulin / 405 (glucose mg/dl; insulin μIU/ml).
2. Matsuda Index (18): http://mmatsuda.diabetes-smc.jp/MIndex.html – the area under the curve is calculated using insulin and glucose samples from 0, 30, 60, 90 and 120 minutes of OGTT. The whole body insulin resistance is defined as equal or lower than 2.5.

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Piśmiennictwo
1. Nowak KM, Papierska L: Prevention and monitoring of the side effects of chronic corticosteroid therapy. Post Nauk Med 2014; XXVII(12): 852-859.
2. Schäcke H, Döcke WD, Asadullah K: Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 2002 Oct; 96(1): 23-43.
3. van Raalte DH, Diamant M: Steroid diabetes: from mechanism to treatment? Neth J Med 2014 Feb; 72(2): 62-72.
4. Angelopoulos TP, Tentolouris NK, Bertsias GK, Boumpas DT: Steroid-induced diabetes in rheumatologic patients. Clin Exp Rheumatol 2014 Jan-Feb; 32(1): 126-130.
5. Da Silva JA, Jacobs JW, Kirwan JR et al.: Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis 2006; 65: 285.
6. Gurwitz JH, Bohn RL, Glynn RJ et al.: Glucocorticoids and the risk for initiation of hypoglycemic therapy. Arch Intern Med 1994; 154: 97.
7. Liapi C, Chrousos GP: Glucocorticoids. [In:] Yaffe SJ, Arands JV (eds.): Pediatric pharmacology. Saunders, Philadelphia 1992: 466.
8. Simmons LR, Molyneaux L, Yue DK, Chua EL: Steroid-induced diabetes: is it just unmasking of type 2 diabetes? ISRN Endocrinol 2012; 2012: 910905.
9. Hoes JN, Jacobs JW, Boers M et al.: EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 2007; 66: 1560
10. Van der Goes MC, Jacobs JWG, Boers M et al.: Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice. Ann Rheum Dis 2010 Nov; 69(11): 1913-1919.
11. American Diabetes Association: Standards of Medical Care in Diabetes – 2016. Diabetes Care 2016; 39 (suppl. 1): S1-S2.
12. International Diabetes Federation, 2012. Global Guidelines for type 2 diabetes.
13. PTD: Zalecenia kliniczne dotyczące postępowania u chorych na cukrzycę 2016 (Clinical Recommendations for the management in patients with diabetes). Clinical Diabetology 2016; tom 5, supl. A.
14. Davidson J, Wilkinson A, International Expert Panel on New-Onset Diabetes after Transplantation: New-onset diabetes after transplantation: 2003 international consensus guidelines. Transplantation 2003; 75(10): SS3-SS24.
15. Lansang MC, Hustak LK: Glucocorticoid-induced diabetes and adrenal suppression: how to detect and manage them. Cleve Clin J Med 2011 Nov; 78(11): 748-756. 10.3949/ccjm.78a.10180.
16. International Diabetes Federation, 2005. Global Guideline for Type 2 Diabetes.
17. American Diabetes Association: Standards of Medical Care in Diabetes – 2013. Diabetes Care 2013 Jan; 36 (suppl. 1): S11-S66
18. Sarafidis PA, Lasaridis AN, Nilsson PM et al.: Validity and reproducibility of HOMA-IR, 1/HOMA-IR, QUICKI and McAuley’s indices in patients with hypertension and type II diabetes. J Hum Hypertens 2007 Sep; 21(9): 709-716.
19. Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulinclamp. Diabetes Care 1999 Sep; 22(9): 1462-1470.
otrzymano: 2016-11-03
zaakceptowano do druku: 2016-11-30

Adres do korespondencji:
*Karolina M. Nowak
Department of Endocrinology Centre of Postgraduate Medical Education Bielański Hospital
Cegłowska 80, 01-809 Warszawa
tel. +48 (22) 569-05-29
klinendo@cmkp.edu.pl

Postępy Nauk Medycznych 12/2016
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