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Diabetogenic Effects of Glucocorticoid Drugs: The Knowns and The Unknowns van Raalte, D.H.

2012

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Download date: 30. Sep. 2021 Chapter 1

General Introduction and Outline of the Thesis

D.H. van Raalte and M.Diamant Chapter 1 General Introduction 12 structure and biological effects of adrenal cortex hormones’. In the same year,hormones’.same cortexadrenalwas the of cortisone In effects biological and structure Kendallshared the Nobel Prize for Physiology or Medicine in 1950 ‘for research onthe immunosuppressive effects. Tadeusz Reichstein,and PhilipShowalter Hench and Edward Calvin anti-inflammatory potent their to due diseases of number increasing an of treatment years,use ofadrenal the cortex hormones formulations was successfully introducedthe in tenderness and swellingin chronic rheumatoid [10,11]. arthritis In thefollowingpatients steroid cortisone.Indeed, cortisone treatmentreductionspectacular induced a injoint acids arebile increased,were that substances found closely related to thenoveldiscovered complains were reduced during pregnancy andjaundice,conditions in which sexsteroids and testedrheumatoidwith cortisone in patients arthritis,driven by observationsjoint that Hench addition, Addison’simprovedIn of symptomstime disease. the first the fortreatment clinic by therheumatologist PhilipShowalter Hench, a collaborator of Kendall,cortisone Mayo the in conducted trials clinical In humans. in studies first the initiate to produced was material sufficient 1948, of summer the By [9]. acid desoxycholic from cortisone producing 1946, LewisHastingsSarettIn of Merck Research Laboratories succeeded in synthetically priority thanthedevelopment of penicillinandanti-malarials[7,8]. quest forall-out large-scale synthesis of active adrenalhormone, which was given even higher oxygen deprivation at high altitudes. Although this rumor was never confirmed, it induced an circulated Luftwaffethat pilotswereadrenal taking extracts to increase their resistance to This process apparent. wasby fuelled entry into theUS theSecondWorldWar, when rumors and theneed tosmall, produce adrenocorticosteroids through synthetic methods became soon isolatedbe could of cortisone that The amount from bovine adrenalglands, however, was was alsoshown to reduce stress responses andtraumatic shockinrats [6]. cortex hormones. Not only wereeffects themetabolic of cortisone further explored, cortisone breakthrough enabled further experiments into the various physiological roles of adrenal chemist Tadeusz Reichstein [4]andtheAmerican scientist Edward Calvin Kendall[5]. This inactive form of the adrenal hormone cortisol, so called cortisone, by thePolish-born, Swiss characterized [3]. Amajoradvance wasisolation ofthe madein1936thesimultaneous with role of the adrenalcortex inintermediary and energymetabolism homeostasis was further first described in association with Addison’s disease [2]. In the following decades, the critical adrenalectomized dogs developed lower fastingglucose levels1910, hypoglycemiaIn [1]. was whenFrench1908, the in established first investigators discoveredMalloizel and Bierry that The involvementof hormones secreted by theadrenalcortex in intermediary was metabolism officially launchedasapharmacologicalagent. Figure 1. Overview of the therapeutic and adverse effects induced by glucocorticoid treatment. (See page 366 for full color figure) Chapter 1

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However, with its increasing use, it became quickly apparent that high-dose glucocorticoid (GC) treatment induced several undesired effects, ranging from salt and water retention to increased gastric acidity and psychosis. To this end, in the 1950-1960s, newer synthetic GC compounds were developed, including prednisolone and dexamethasone, which were designed to induce fewer side effects. Prednisolone, which is characterized by a 1,2 double bond market a decade later under the brand name Meticortelone. When this structure additionally in the A-ring, was first produced in 1955 by Schering Corporation and was introduced into the yielded and this compound was introduced for clinical use a year later. Although these newer undergoes 9α-fluorination, 1-dehydrogenation and 16α-methylation, dexamethasone is effects of GC treatment remain present today (Figure 1). Of these adverse effects, unfavorable formulation significantly reduced side effects as compared to cortisone, many important side changes in cardiometabolic parameters are prominent and include the development of glucose intolerance, diabetes, visceral adiposity, dyslipidemia, skeletal muscle atrophy and hypertension [12]. The mechanisms underlying these so called diabetogenic effects of GCs regarding glucose, lipid and protein metabolism were studied extensively in the 1960-1970s

13 Chapter 1 General Introduction cellular levelcellular hasledto thedevelopmentof so-calleddissociated glucocorticoid receptor Second, improvedand of GCs onthemolecular mode ofaction understandingofthe this topic hasskyrocketed duringthelastdecade(Figure 3). reduce tissue cortisol levels by targeting 11-betaHSD of type 1.The researchamount done on As such, a battery of pharmaceutical companies is currently developing compounds that may attractive therapeuticcandidate for the treatmentconsequences. of obesityanditsmetabolic models ofobesityandfrom[23]. This obesehumansmakes thehormone 1 an HSD type 11-beta dehydrogenase (HSD) type 1,were demonstrated in adipose tissue derived from rodent the inactive metabolite cortisone by enhancedactivityhydroxysteroidof theenzyme 11-beta and cardiovasculardisease [22]. Inaddition,increased tissue cortisol levels, generated from by (slightly) increased GCactivity, may contribute to visceralobesity, syndrome themetabolic chronic GCexcess.was It postulated by Björntorplow-grade that chronic stress, characterized the observation thatseveralfeatures of these conditions strikingly resemble thephenotypeof by encouraged syndrome, metabolic and obesity ‘idiopathic’ in role a play may metabolism mainly dueto two different reasons.deregulated itbecameclearthat First, (tissue) GC 15 years,the last In however, research into thediabetogenic effects ofGCs has beenrevived, butinrecentsomewhat, years, thesubjecthasreceived fullattention. shown per 5-year intervals. After 1975, the amountof research performed on thetopic declined Figure 2. about two decades(Figure 2). intensive research effects onthemetabolic of GCs, research slowed down inthisarea for and were mainly attributed to GC-induced insulin resistance [13-21].After this period of 14 (GR) agonists (Figure 4).In1985, it was discoveredGCs that exert their actions through The number of new publications on Pubmed with searchwith Pubmed on publications ofnew The number terms “glucocorticoids” “diabetes”and binding to the intracellular GR, following which this complex migrates to the nucleus, where it regulates target gene expression [24,25]. Additionally, it became clear that the anti- actions, i.e. transrepression and transactivation, respectively. This suggests that these effects inflammatory actions and dysmetabolic effects of GCs may be the result of different genomic may potentially be separated, which forms the basis of these novel GR agonists [25-32]. pharmaceutical companies and have shown promising results in disease and side effect Several compounds with a dissociated profile are currently under development by different animal models, where they reduced inflammation without altering glucose levels [33]. Figure 3. The number of new publications on Pubmed with search term “11-beta hydroxysteroid dehydrogenase” shown per decade. The number of publications on this topic has skyrocketed in the past 2 decades. Chapter 1

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Figure 4. The number of new publications on Pubmed with search term “selective glucocorticoid receptor agonists” shown per decade. In the last decade, information on the development of these novel compounds has found its way to the public domain.

15 Chapter 1 General Introduction initiated. effects ofGCtreatmentis presented was that availablethe timewhenat ourstudies were In pathways. on theeffects ofprednisolonesensitivityfunction andinsulin on islet-cell ofvarious metabolic specificallyfocusing arthritis, rheumatoid with patients volunteersand healthy in treatment backbone, we aimed to assess the peripheral metaboliceffects of both low-and high-dose GC me In thepresent thesis, of which the PANTHEON ( GR agonists. compounds with animproved therapeutic index compared to thecurrently-availableclassic after these indicators of efficacy and safety have become available, it will be possible to design manner.dose-dependent a in effects side Onlymetabolic these reflectbiomarkers that select detailed information regardingside effects themetabolic inducedby obtain prednisolone treatmenttoand first to important highly is it agonists, GR dissociated the develop further methods and techniquesare that currentlyemployed. being Thus,inorder toto beable recent studieswiththeresultsfromobtained thoseearly studiesdueto differentresearch compare to difficult be may it ago, decades 4 than more conducted were studies many since of administration andchosen dose, severalcontrasting reports exist inthe literature. Also, addition, duetoIn thedifferences inthetypeofGCadministered, treatmentduration, mode The mechanisms by which prednisolonechanges remain inducesmetabolic largely unknown. difficulties. important however,faces compounds, novel these of development clinical The who are currently developing GRagonistswithadissociated profile. Dohme), & Sharp Merck by later and Schering-Plough by first incorporated recently (more our Top Institute PharmaProject consortium (T1.106), we collaboratedNV withOrganon universities werebrought together togoal the with developpriority medicines. In so called Pharma, inwhich theDutch government, severalDutchcompanies and all pharmaceutical TopInstitute of name the by founded was TechnologicalTopInstitute Dutch fifth the 2005, GR agonistsandwas conducted within theframework of a relatively novel organization. In The worklightseen in be this thesisshould done in developmentof the of thesedissociated 16 C-peptide concentrations obtainedfrom standardizedtests. challenge meal In function arebeta-cell described, modeling analysisusing mathematical of glucose, insulinand stress. In addressed in INS-1Ecells chapter3 chapter 2 T abolism, metabolic chapter 4 PartII mechanisms underlyingthe deleterious effectsfunction are ofGCs on beta-cell of this thesis, an overview ofthisthesis,an oftheknowledge regarding thediabetogenic side describes the effects ofGCtreatmenton pancreatic function. In islet-cell , theeffects of both acute andmore prolonged high-dose GC treatment on H in vitro ormones, insulin s , in particular the involvement, inparticular ofendoplasmic reticulum E P nsitivity andsecreti rednisolone peripher O A N l effects o )-trials form the chapter 5 N glucose , we further explored the effects of both low- and high-dose GC treatment on both alpha- and beta- cell function in healthy volunteers using both intravenous hyperglycemic clamp studies and meal challenge tests. In chapter 6, in order to further delineate the role of GR signaling in beta- cell function, we investigated the effects of single nucleotide polymorphisms (SNPs) in the GR gene on measures of beta-cell function in a cohort of 449 subjects. In chapter 7, we explored the potential of the novel class of glucose-lowering agents the glucagon-like peptide (GLP)- 1 receptor agonists to prevent the dysmetabolic effects induced by GC treatment in healthy subjects. Part III of the thesis focuses on GC-induced insulin resistance and the mechanisms that may contribute to this well-known but only partly understood side effect of GC treatment. In chapter 8, the effects of both low- and high-dose GC treatment on several aspects of intermediary metabolism is addressed. Possible mediators of GC-induced insulin resistance in skeletal muscle, including impaired sphingolipid metabolism and mitochondrial dysfunction, Chapter 1 are investigated in chapter 9. In chapter 10 the possible role of microvascular dysfunction induced by GC treatment was addressed and in chapter 11 we investigated the effects of GC treatment on adipose tissue function and adipokine secretion. In chapter 12, the role of the novel endocrine factor angiopoietin-like protein 4 in GC-induced metabolic alterations was studied, by combining an in vivo (randomized controlled trial in healthy individuals) and in 1 vitro (cell culture) approach. In part IV of this thesis, using an oral glucose tolerance test to assess both insulin secretory response and surrogate markers of insulin resistance, the diabetogenic effects of GC treatment were investigated in two different rheumatoid arthritis chapter 13, the acute effects of high-dose prednisolone treatment on glucose tolerance, insulin sensitivity and populations, allowing to study the interaction with systemic inflammation. In insulin secretion in patients with early and active rheumatoid arthritis are described, whereas in chapter 14, the effects of chronic GC treatment on glucose tolerance, insulin sensitivity and insulin secretion are assessed in patients with long-standing rheumatoid arthritis.

In the general discussion (part V, chapter 15), an overview will be presented of the pathophysiology of glucose intolerance induced by GC treatment. Additionally, implications will be discussed for the development of dissociated GR agonists. Finally, since these compounds are still under development, a proposition will be made how GC-induced diabetes may best be treated in clinical practice.

17 Chapter 1 General Introduction 16. 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. R 18

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