Auswahl der wissenschaftlichen Literatur zum Thema „Glucocorticoids-Induced diabetes“

Glucocorticoids are used in clinical practice for more than 50 years and are a great advance in the treatment of systemic inflammatory diseases. High doses of intravenous glucocorticoids (pulse therapy) are effective in conditions requiring rapid immunosuppression and antiinflammatory effect, such as systemic lupus erythematosus, rheumatoid arthritis, glomerulonephritis and systemic vasculitides. The advantage of this method are increased efficacy and lower rate of complications associated with prolonged administration of glucocorticoids. At the same time, glucocorticoid pulse therapy is associated with increased risk of hyperglycemia or even can be a cause of steroid-induced diabetes in patients without known hyperglycemia, as well as worsen glycemia control in patients with diabetes. Increased hepatic gluconeogenesis, inhibition of glucose uptake and metabolism in peripheral tissues and altered both receptor and post-receptor insulin action can lead to an increased serum glucose levels. In patients with inadequate compensatory reserves of pancreas, a clinical picture of diabetus mellitus can develop while treated with glucocorticoids. Blood glucose levels begin to rise 6-12 hours after the infusion of high doses of glucocorticoids. Risk factors for developing glucose intolerance and diabetes include advanced age, obesity, family history of diabetes and high cumulative doses of glucocorticoids. Glucocorticoid-induced diabetes is a common complication of pulse therapy, but exact causes are still not elucidated yet, current literature data on glucocorticoid-induced hyperglycemia are scarce.

Glucocorticoids are often used as immunosuppressant and anti-inflammatory therapy in various medical conditions. In addition to providing clinical benefits, glucocorticoids have various side effects, one of which is related to steroid-induced diabetes mellitus (SIDM). Steroid-induced diabetes mellitus can be a new onset or an exacerbation of hyperglycemia in patients who have previously been diagnosed with DM. Acute and chronic hyperglycemia due to steroids can have an impact on lengthening hospitalization, infectious complications, decreased response to therapy and increased mortality. The challenges of managing steroid-induced diabetes mellitus vary widely. Understanding of pathophysiology, risk factors, diagnosis and therapy can add insight regarding the comprehensive management of steroid-induced DM

Background: Since the COVID-19 pandemic has started, glucocorticoids have been proved to be one of the most effective lifesaving treatments for respiratory complications associated with SARS CoV-2. Aim: To review the incidence of steroid induced diabetes and the associated risk factors in COVID-19 patients. Study Design: Retrospective cohort study Place and duration of the study: Bahria International Hospital Lahore from 15th April 2020 to 31st December 2020 Methodology: Two hundred and thirty patients of COVID-19 cases treated with glucocorticoids (Dexamethasone 4mg BID) were enrolled. All known cases of pre-existing diabetes mellitus and with initial (admission) random blood glucose levels of more than 200 mg/dl were excluded. Patients labelled as glucocorticoid induced diabetes mellitus (GI-DM)met the following criteria, fasting blood glucose level of more than 126 mg/dl or a random glucose level of more than200 mg/dlon two occasions after starting these patients on steroids. Results: The glucocorticoid induced diabetes mellitus was 36 (15.65%). Multivariate logistic regression analysis revealed that older age (odds ratio 1.19, 95% confidence interval (1.02-1.36) was found to be the most profound risk factor for GI-DM. Conclusion: Glucocorticoid induced diabetes mellitus found to be associated with glucocorticoid used among COVID-19 patients especially in older ages. So, it is recommended that the treating physicians should consider this side effect of steroids especially when dealing with geriatric cases. Keywords: Hyperglycaemia, COVID-19, Steroids, SARS-CoV-2, Diabetes mellitus, Steroids induced diabetes, Glucocorticoids

Glucocorticoid-induced diabetes (GID) is a frequent metabolic complication of glucocorticoid therapy. It results from both insulin resistance and impaired insulin secretion, exacerbated by glucocorticoid use. Despite its prevalence, consensus guidelines on screening and management remain limited. GID affects approximately one in five patients receiving long-term glucocorticoid therapy. Risk factors include older age, high BMI, prediabetes, ethnicity, and high-dose systemic glucocorticoids. All patients initiated on moderate to high doses of glucocorticoids should be assessed for GID risk factors and closely monitored for the development of hyperglycemia and diabetes. In addition, glucocorticoid therapy can significantly exacerbate hyperglycemia in individuals with pre-existing diabetes, and stringent glucose monitoring is crucial. Treatment should be tailored to individual patient. Oral anti-diabetics such as metformin and sulfonylureas might be used in selected patients with mild GID. However, insulin is the primary treatment for severe hyperglycemia. Early detection and individualized management strategies are critical to mitigate GID’s impact. Further research is needed to develop consensus guidelines and optimize treatment approaches.

Glucocorticoid-induced muscle atrophy is characterized by fast-twitch or type II muscle fiber atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. Muscle proteolysis, in particular through the ubiquitin– proteasome system (UPS), is considered to play a major role in the catabolic action of glucocorticoids. The stimulation by glucocorticoids of the UPS is mediated through the increased expression of several atrogenes (‘genes involved in atrophy’), such as atrogin-1 and MuRF-1, two ubiquitin ligases involved in the targeting of protein to be degraded by the proteasome machinery. Glucocorticoids also exert an anti-anabolic action by blunting muscle protein synthesis. These changes in protein turnover may result from changes in the production of two growth factors which control muscle mass, namely IGF-I and myostatin respectively anabolic and catabolic toward the skeletal muscle. The decreased production of IGF-I as well as the increased production of myostatin have been both demonstrated to contribute to the muscle atrophy caused by glucocorticoids. At the molecular level, IGF-I antagonizes the catabolic action of glucocorticoids by inhibiting, through the PI3-kinase/Akt pathway, the activity of the transcription factor FOXO, a major switch for the stimulation of several atrogenes. These recent progress in the understanding of the glucocorticoid-induced muscle atrophy should allow to define new therapies aiming to minimize this myopathy. Promising new therapeutic approaches for treating glucocorticoid-induced muscle atrophy are also presented in this review.

Abstract Background Hyperglycemia or diabetes is a well-known side effect of treatment with glucocorticoids. In patients with brain tumors, glucocorticoids are widely used to treat symptoms of peritumoral edema. We conducted a retrospective study of patients with suspected brain tumor to determine the incidence of and risk factors for glucocorticoid-induced diabetes. Methods This was a retrospective study of patients referred with suspected brain tumor to a neurological department, using data from a clinical database, electronic medical records, the laboratory system, and the pathology information bank. . Nondiabetic patients with a neuroimaging-verified brain tumor treated with high-dose glucocorticoid and monitored with glucose measurements were included in the study. Results Among 809 patients referred with suspected brain tumor, 171 were eligible for the study. Thirty-eight (22%) patients developed glucocorticoid-induced diabetes, defined as 2 glucose measurements ≥200 mg/dl (11.1 mmol/l) within the first week of treatment, and 4 of the patients were treated with insulin. The majority of patients with glucocorticoid-induced diabetes were identified on days 2, 3, and 4, and glucose levels were highest in the afternoon and evening. We were not able to identify any risk factors for glucocorticoid-induced diabetes and glucocorticoid-induced diabetes had no influence on survival in our cohort. Conclusions Glucocorticoid-induced diabetes is frequent in the first 7 days of treatment in patients with brain tumors. The results emphasize the need for screening for glucocorticoid-induced diabetes in this group of patients to avoid comorbidity expected to arise from hyperglycemia.

Glucocorticoids represent frequently recommended and often indispensable immunosuppressant and anti-inflammatory agents prescribed in various medical conditions. Despite their proven efficacy, glucocorticoids bear a wide variety of side effects among which steroid induced hyperglycaemia (SIHG) is among the most important ones. SIHG, potentially causes new-onset hyperglycaemia or exacerbation of glucose control in patients with previously known diabetes. Retrospective data showed that similar to general hyperglycaemia in diabetes, SIHG in the hospital and in outpatient settings detrimentally impacts patient outcomes, including mortality. However, recommendations for treatment targets and guidelines for in-hospital as well as outpatient therapeutic management are lacking, partially due to missing evidence from clinical studies. Still, SIHG caused by various types of glucocorticoids is a common challenge in daily routine and clinical guidance is needed. In this review, we aimed to summarize clinical evidence of SIHG in inpatient care impacting clinical outcome, establishment of diagnosis, diagnostic procedures and therapeutic recommendations.

ABSTRACT In several species, glucocorticoids act directly on the pituitary gonadotroph to suppress the gonadotrophin-releasing hormone (GnRH)-induced secretion of the gonadotrophins, especially LH. A mechanism for this action of these adrenal steroids has not been established, but it appears that the glucocorticoids influence LH release by acting on one or more post-receptor sites. This study investigated whether glucocorticoids disrupt GnRH-induced LH release by altering the liberation of arachidonic acid from plasma membrane phospholipids, a component of GnRH-induced LH release. Using perifused ovine pituitary tissue, it was established that exposure of gonadotrophs to 1–1000 nmol cortisol/l for 4 h or longer significantly reduced GnRH-stimulated LH release with the maximal inhibitory effect being observed after 6 h of exposure to cortisol. This suppressive effect of cortisol could be reversed by administration of arachidonic acid, which in its own right could stimulate LH release from ovine pituitary tissue. Furthermore, the inhibitory effect of cortisol on GnRH-stimulated LH release could be directly correlated with decreased pituitary responsiveness to GnRH-stimulated arachidonic acid liberation, consistent with our hypothesis that glucocorticoids can suppress GnRH-induced secretion of LH by reducing the amount of arachidonic acid available for the exocytotic response of GnRH. Journal of Endocrinology (1991) 131, 87–94

Une exposition excessive aux glucocorticoïdes (GC), comme observée chez les patients recevant une corticothérapie, peut entraîner un dysfonctionnement des cellules β et un diabète chez jusqu'à 40% des patients. Dans l'obésité, une surexposition locale au cortisol secondaire à une altération du métabolisme du cortisol contribue à l'apparition du diabète. Des doses élevées de GC comme la dexaméthasone (DEX) inhibent la sécrétion d'insuline stimulée par le glucose (SISG), mais les effets de doses plus faibles et des autres GC, tels que l'hydrocortisone (HC) et la prednisone (PRED), restent peu étudiés. L'enzyme 5α-réductase de type 1 (SRD5A1) est une enzyme cruciale pour la dégradation des GC, modulant ainsi leur biodisponibilité. L'inhibition de SRD5A1 est associée à une altération de la sensibilité à l'insuline et à un risque accru de diabète. La première partie de ma thèse étudie l'impact de doses "thérapeutiques faibles" de PRED (équivalentes à 5 à 10 mg par voie orale) et d'autres GC sur la SISG étudiée par périfusion dans des îlots isolés de pancréas humains. Tous les GCs diminuent significativement la SISG, la DEX ayant un impact plus important que la PRED et l'HC. L'IMC, l'âge ou le sexe n'influencent pas significativement l'impact de la PRED sur la sécrétion d'insuline. La deuxième partie du travail caractérise le métabolisme des GC dans les îlots humains. SRD5A1 est la seule réductase A-ring dans les îlots, et son expression, ainsi que celle de HSD11B1, est localisée dans les cellules β des îlots. Nous avons démontré l'existence d'un métabolisme intracrine du cortisol dans des cultures primaires d’îlots humains. L’expression de HSD11B1 et SRD5A1 est significativement diminuée dans les îlots des donneurs atteints de DT2 par rapport aux donneurs normoglycémiques. La dernière partie visait à prouver que la diminution de la biodisponibilité du cortisol via la surexpression de SRD5A1 dans les îlots humains atténue l'effet inhibiteur des GC sur la SISG. La surexpression de SR5DA1 a permis d’atténuer l'impact de l'HC sur la première phase de la SISG, mais pas de la PRED. En conclusion, même à faibles doses, les GC altèrent la SISG. La diminution de l'expression de SRD5A1 dans les îlots peut contribuer au développement du diabète dans un contexte métabolique. La surexpression de SRD5A1 protège contre l'impact délétère du cortisol sur la SISG. Ces résultats supportent le rôle de SRD5A1 dans la surexposition locale au cortisol et le développement du diabète. Cependant, l'augmentation de l'activité de SRD5A1 ne semble pas efficace pour protéger contre les complications métaboliques induites par la corticothérapie. D'autres aspects de la fonction des cellules β, en particulier la viabilité cellulaire, vont être étudiés. Par ailleurs, le bénéfice potentiel de SRD5A1 dans la modulation de la résistance à l'insuline et de la stéatose hépatique doivent être étudiés. Ces études complémentaires permettront de mieux comprendre le potentiel du gène SRD5A1 dans la modulation de la résistance à l'insuline et de la maladie du foie gras
Excessive glucocorticoid (GC) exposure, as seen in patients receiving GC therapy, can lead to β-cell dysfunction and diabetes in up to 40% of the cases. In obesity, increased local cortisol exposure due to altered metabolism contributes to diabetes onset. High doses of GCs like dexamethasone (DEX) are known to inhibit glucose-stimulated insulin secretion (GSIS), but the effects of lower doses and other GCs, such as hydrocortisone (HC) and prednisone (PRED), remain underexplored. The enzyme 5α-reductase type 1 (SRD5A1) is a crucial enzyme for GC degradation, modulating their bioavailability. Inhibition or knockout of SRD5A1 is associated with impaired insulin sensitivity and increased diabetes risk. This first part of my thesis investigates the impact of “low therapeutic” doses of PRED (equivalent to 5 to 10 mg administrated orally) and other GCs on glucose stimulated insulin secretion (GSIS). We showed that PRED significantly decreases GSIS, with DEX having a worse effect compared to PRED and HC. BMI, age, or sex do not significantly influence the direct impact of PRED on insulin secretion. The second part of the work aimed to characterize GC metabolism in human islets. SRD5A1 is the only A-ring reductase expressed in islets, and its expression, along with HSD11B1, is localized within the β-cells of human islets. We demonstrated evidence of intracrine metabolism of cortisol in intact primary human islets cultured under dynamic experimental settings. Expression data reveals significantly diminished expression of both HSD11B1 and SRD5A1 in T2D donors compared to normoglycemic donors. The last part aimed to provide proof of concept that decreased cortisol bioavailability via the overexpression of SRD5A1 in human islets mitigates the inhibitory effect of GCs on GSIS. SR5DA1 overexpression attenuated the impact of HC on the first phase of insulin secretion, but not the PRED impact. To conclude, even at low doses, GCs impair GSIS. The decrease in SRD5A1 expression in islets may contribute to the development of diabetes in metabolic context. SRD5A1 overexpression protects against the deleterious impact of cortisol on GSIS, providing additional evidence to support the enzyme's role in local cortisol overexposure and the development of diabetes. However, increasing SRD5A1 activity may not be an effective approach to protect against metabolic complications induced by GC therapy. Other aspects of β-cell function, especially cell viability, need to be studied. Moreover, the potential benefits of SRD5A1 in modulating insulin resistance and fatty liver disease should be investigated. These further studies will provide more insight into the potential of SRD5A1 as a therapeutic target

Synthetic glucocorticoids are used in a wide variety of disorders including autoimmune, pulmonary, and gastrointestinal diseases, as well as in patients following organ transplantation and with malignancies. Although the indications for glucocorticoids in these various conditions are clear, their use is fraught with a host of potential side effects. In particular, glucocorticoids are detrimental to bone and glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis (1). Despite the fact that glucocorticoids can cause bone loss and fractures, many patients receiving or initiating long-term glucocorticoid therapy are not evaluated for their skeletal health. Furthermore, patients often do not receive specific preventive or therapeutic agents when indicated. New knowledge of the pathophysiological mechanisms underlying GIO has been accompanied by the availability of effective strategies to prevent and treat GIO (1).

Glucocorticoid-induced osteoporosis (GIO), the most frequent form of secondary osteoporosis, is caused by chronic exposure to glucocorticoid excess. Glucocorticoids have several direct and indirect effects on the skeleton making multifactorial the pathogenesis of GIO. Fragility fractures occur early in GIO and antiosteoporotic drugs along with calcium and vitamin D should be started soon after exposure to glucocorticoid excess. Despite several guidelines and consensus recommendations stating that patients are at a remarkably increased fracture risk, little attention is paid to this risk and guidelines are frequently not applied in real-life clinical practice. This chapter deals with the pathophysiological, clinical, and therapeutic aspects of exogenous and endogenous GIO.

A 64-year-old Caucasian male with no previous history of diabetes presented with nausea, vomiting, fatigue, increased urination, and thirst over the 3 days before presentation, along with worsening of his mental status. He was being treated with pembrolizumab (monoclonal antibody targeting programmed cell death receptor-1 [PD-1]) infusions for advanced lung cancer. His most recent dose was 3 days before presentation, and his first dose was 24 days prior. He had a normal BMI (24.8 kg/m2), and the only pertinent past medical history was hypertension before the diagnosis of lung cancer. He has a 40–pack-year history of smoking. He had not been treated with glucocorticoids recently.