patients with psoriasis are insulin resistant
TRANSCRIPT
ORIGINAL ARTICLE
Patients with psoriasis are insulin resistant
Mette Gyldenløve, MD,a Heidi Storgaard, PhD,b Jens J. Holst, DMSc,c Tina Vilsbøll, DMSc,b
Filip K. Knop, PhD,b,c and Lone Skov, PhD, DMSca
Hellerup and Copenhagen, Denmark
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Background: Patients with psoriasis have increased risk of type 2 diabetes. The pathophysiology is largelyunknown, but it is hypothesized that systemic inflammation causes insulin resistance. Insulin sensitivity hasonly been sparsely investigated in patients with psoriasis, and previous studies have used suboptimalmethodology. The hyperinsulinemic euglycemic clamp remains the gold standard for quantifyingwhole-body insulin sensitivity.
Objective: We sought to investigate if normal glucose-tolerant patients with psoriasis exhibit impairedinsulin sensitivity.
Methods: Three-hour hyperinsulinemic euglycemic clamps were performed in 16 patients with moderateto severe, untreated psoriasis and 16 matched control subjects.
Results: The 2 groups were similar with regard to age, gender, body mass index, body composition,physical activity, fasting plasma glucose, and glycosylated hemoglobin. Mean 6 SEM psoriasis durationwas 23 6 3 years and Psoriasis Area and Severity Index score was 12.7 6 1.4. Patients with psoriasisexhibited reduced insulin sensitivity compared with control subjects (median M-value 4.5 [range 1.6-14.0]vs 7.4 [range 2.1-10.8] mg/kg/min, P = .046). There were no differences between groups in plasma glucose,insulin, C-peptide, and glucagon during the clamp.
Limitations: The classic hyperinsulinemic euglycemic clamp technique does not allow assessment ofendogenous glucose production.
Conclusion: Patients with psoriasis were more insulin resistant compared with healthy control subjects.This supports that psoriasis may be a prediabetic condition. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2015.01.004.)
Key words: hyperinsulinemic euglycemic clamp; insulin resistance/sensitivity; M-value; psoriasis; type 2diabetes.
the Department of Dermato-Allergologya and Center for
iabetes Research, Department of Medicine,b Gentofte
ospital, University of Copenhagen, Hellerup; and Novo
ordisk Foundation (NNF) Center for Basic Metabolic Research,
epartment of Biomedicine, Faculty of Health and Medical
iences, University of Copenhagen.c
orted by unrestricted grants from Fonden til Lægevidenska-
ns Fremme, Kgl. Hofbundtmager Aage Bangs Fond, Psoriasis
rskningsfonden, Robert Wehnert og Kirsten Wehnerts Fond,
d Direktør Werner Richter og hustrus legat (n = 1).
osure: Dr Holst received research funding from Novartis
= 1) and Merck (n = 2); is a member of advisory boards of
laxoSmithKline, Novo Nordisk, and Zealand Pharmaceuticals;
d consulted for Novo Nordisk. Dr Vilsbøll received research
nding from Novo Nordisk (n = 3) and Merck (n = 1); Dohme;
ceived lecture fees from or consulted for AstraZeneca,
ehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and
ompany, Merck, Novo Nordisk, Sanofi-Aventis, Takeda, and
aland Pharma; and is part of the advisory boards of
i Lilly, Boehringer Ingelheim, Bristol-Myers Squibb/
straZeneca, Novo Nordisk, Sanofi-Aventis, and Takeda.
r Knop received research funding from Sanofi-Aventis
(n = 2) and lecture fees from AstraZeneca, Boehringer
Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Gilead
Sciences, Merck, Novo Nordisk, Ono Pharmaceuticals, Sanofi-
Aventis, and Zealand Pharma; is part of the advisory boards of
Eli Lilly Denmark, Bristol-Myers Squibb/AstraZeneca, Novo
Nordisk, Sanofi-Aventis, and Zealand Pharma; and consulted
for AstraZeneca, Gilead Sciences, Novo Nordisk, Ono Pharma-
ceuticals, and Zealand Pharma. Dr Skov received consultancy
and/or speaker honoraria from Abbvie, Pfizer, Janssen-Cilag,
Merck, and Leo Pharma and is a member of the advisory Boards
of Abbvie, Pfizer, Janssen-Cilag, Merck, Eli Lilly, and Novartis.
Drs Gyldenløve and Storgaard have no conflicts of interest to
declare.
Accepted for publication January 6, 2015.
Reprint requests: Mette Gyldenløve, MD, Department of Dermato-
Allergology, Gentofte Hospital, University of Copenhagen, Niels
Andersens Vej 65, DK-2900, Hellerup, Denmark. E-mail: mette.
Published online February 1, 2015.
0190-9622/$36.00
� 2015 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2015.01.004
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n 20152 Gyldenløve et al
Patients with psoriasis are at increased risk ofdeveloping type 2 diabetes.1-3 The pathophysiologyis largely unknown, but it has been hypothesizedthat systemic inflammation causes reduced insulinsensitivity.4 Low insulin sensitivity, often referred toas insulin resistance, is an independent risk factorfor type 2 diabetes. In many cases, insulin
CAPSULE SUMMARY
d Patients with psoriasis have increasedrisk of type 2 diabetes. It is hypothesizedthat systemic inflammation causesinsulin resistance.
d Our data suggest that psoriasis may beassociated with insulin resistance, evenin patients who are not diabetic.
d Lifestyle interventions on modifiable,traditional diabetes risk factors (eg,physical inactivity, overweight, smoking)should be encouraged.
resistance develops earlyin the pathophysiologicalprocess leading to type 2diabetes and is often presentbefore glucose tolerancestarts to deteriorate.5,6
First described byDeFronzo et al7 in 1979, thehyperinsulinemic euglyce-mic clamp techniqueremains the gold standardfor investigating and quanti-fying whole-body insulinsensitivity in vivo.8 It is adynamic, functional testthat assesses the amountof glucose necessary to
compensate for an increased insulin level.Basically, insulin is infused at a constant rate alongwith glucose, which is continuously adjusted tomaintain euglycemia. The supraphysiological levelsof plasma insulin suppress endogenous glucose andinsulin output, and once a steady state is reached, therate of glucose infusion equals the rate of peripheralglucose disposal; this is denoted M-value. A highvalue indicates a high degree of insulin sensitivity,whereas a low value indicates insulin resistance.Insulin resistance has only been sparsely investi-gated in patients with psoriasis, and previous studieshave used suboptimal methodology.9-15 We aimed toinvestigate whether normal glucose-tolerant patientswith moderate to severe, untreated psoriasis exhibitimpaired insulin sensitivity compared with healthy,matched control subjects.
METHODSStudy protocol and informed consent
The Ethics Committee of the Capital Region ofDenmark approved the study (H-1-2011-114).Written informed consent was obtained from allparticipants before screening, and the study wasconducted according to the latest revision of theHelsinki Declaration.
SubjectsParticipants were recruited through advertising
and from the Department of Dermato-Allergology,Gentofte Hospital, University of Copenhagen.
Inclusion criteria were Psoriasis Area and SeverityIndex score above 8 and age above 18 years. Patientswere excluded in case of diabetes, prediabetes, first-degree relatives with diabetes, chronic inflammatorydiseases other than psoriasis, severe anemia, sys-temic anti-inflammatory treatment within 1 monthbefore inclusion, or current topical treatment with
steroids. Daily intake ofmedications known to influ-ence glucose metabolismwas not allowed (restrictedto asthma medicines, anti-psychotics, antidepressants,thiazides, and hormonalcontraception). Enrolled pa-tients were matched tohealthy control subjectsaccording to age, gender,and body mass index. Thecontrol subjects fulfilledthe same inclusion andexclusion criteria as the pa-tients, except for being givena diagnosis of psoriasis.
Baseline evaluationAll participants underwent a screening to
exclude undiagnosed diabetes (fasting plasmaglucose$ 7.0 mmol/L and/or glycosylated hemoglo-bin [HbA1c] $ 48 mmol/mol) or prediabetes (fastingplasma glucose 6.1-6.9 mmol/L and/or HbA1c 43-47mmol/mol). In addition, information about psoriasisduration, genetic predisposition, medical history,current medications, tobacco smoking, and alcoholhabits was recorded. Physical measurementsincluded blood pressure, weight, height, and waistand hip circumferences. Psoriasis severity wasevaluated by Psoriasis Area and Severity Index andthe Dermatology Life Quality Index questionnaire.Level of physical activity was assessed by the shortInternational Physical Activity Questionnaire andexpressed by metabolic equivalents.
Hyperinsulinemic euglycemic clampThe participants met in the morning after a
10-hour fast (including liquids, medication, andtobacco). No alcohol consumption or vigorousphysical activities was permitted 48 hours beforethe examinations, and all participants wererequested to eat a carbohydrate-rich diet theprevious 2 days. After drawing of fasting bloodsamples, a 3-hour continuous infusion ofhuman insulin (Actrapid, Novo Nordisk,Copenhagen, Denmark) was initiated at therate of 40 mU/m2/min, after a priming dose.
Abbreviations used:
HbA1c: glycosylated hemoglobinHOMA-IR: insulin resistance according to the
homeostasis model assessmenttAUC: total area under the curve
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Normoglycemia (5 mmol/L) was maintained bymanually adjusting the rate of a 20% glucose infusion(Baxter, Allerød, Denmark). Blood samples weredrawn at fixed intervals for analysis of glucose,insulin, C-peptide, and insulin.
Biochemical analysesScreening blood samples were analyzed
using routine assays. Bedside plasma glucoseconcentrations were measured bedside withHemocue Glucose 201 RT analyzer (Hemocue,Vedbæk, Denmark). Serum insulin and C-peptideconcentrations were analyzed with chemilumines-cent immunometric assays (Siemens Healthcare,Ballerup, Denmark) using the ADVIA Centaur CP(Siemens Healthcare, Ballerup, Denmark). Theglucagon assay was directed against the C-terminalof the glucagon molecule and, therefore, measuredglucagon of pancreatic origin.16
Calculations and statistical analysesThe sample size was determined with a
significance level of 5%, a power of 80%, and aminimal relevant difference of 15% between groups.The SD of the primary end point (M-value) wasbased on findings from previous studies.17 Fastinglevels of glucose, insulin, C-peptide, and glucagonwere evaluated from means of �15 minute, �10minute, and 0 minute values. M-values werecalculated from the amount of glucose infusedwithin the steady-state period (t = 150-180 min)and expressed as mg/kg/min. Results from theInternational Physical Activity Questionnaire wereconverted into metabolic equivalents according toofficial guidelines (http://www.ipaq.ki.se/scoring.pdf, assessed 20 May 2014).
Statistical analyses were performed usingsoftware (SPSS Statistics 19.0, IBM Corp, Armonk,NY). Normally distributed, continuous data werepresented in means 6 SEM and compared with theindependent samples t test. Nonnormally distributeddata were given in medians and range and analyzedwith the Mann-Whitney test. The x2 test was used tocompare categorical variables presented in numbersand percentage. Excursions of glucose, insulin,C-peptide, and glucagon were assessed by 1-wayrepeatedmeasures analysis of variance and total areaunder the curve (tAUC). All tests were 2-tailed, and
P values below .05 were considered statisticallysignificant.
RESULTSDemographic and clinical data
A total of 41 subjects were screened. Ninepotential participants (7 patients and 2 controlsubjects) were excluded as they did not meet theinclusion criteria. The remaining 32 subjects allcompleted the study. The 2 groups were similarwith regard to age, gender, body mass index, bodycomposition, physical activity level, fasting plasmaglucose, andHbA1c (P[.329). Mean6 SEM psoriasisduration was 23 6 3 years and Psoriasis Area andSeverity Index score was 12.7 6 1.4.
Subject characteristics are given in Table I.
GlucosePlasma glucose concentrations did not differ
between time points (P[.393) or groups (P[.174)during the clamp.
Baseline and tAUC values are given in Table II.Excursions are illustrated in Fig 1.
Insulin, C-peptide, and glucagonFasting serum insulin and C-peptide concentra-
tions and plasma glucagon concentration werewithin the normal range and comparable betweengroups (P [ .075). There were no differencesbetween tAUCs (P [ .097) or mean curves(P [ .340). However, throughout the clamp therewas a trend toward higher C-peptide and glucagonlevels in patients with psoriasis (Fig 1, C and D).
Baseline and tAUC values are given in Table II.Excursions are illustrated in Fig 1.
Insulin sensitivity and insulin resistanceindices
Patients with psoriasis had significantly lowerM-values than control subjects (4.5 vs 7.4mg/kg/min, P = .046) (Fig 2). There was nodifference in insulin resistance according tothe updated homeostasis model assessment(HOMA-IR) between the groups.
Indices are given in Table II.
DISCUSSIONIn this study we found that normal glucose-
tolerant patients with moderate to severepsoriasis had significantly reduced insulinsensitivity compared with age-, gender-, and bodymass indexematched healthy control subjects.Furthermore, C-peptide and glucagon levels duringthe hyperinsulinemic euglycemic clamp tended to behigher in the psoriasis group. Taken together, this
Table I. Subject characteristics
Patients with psoriasis, n = 16 Control subjects, n = 16 P value
DemographicsAge, y 44 6 4 44 6 4 .982Men 13 (81) 13 (81) 1.000Caucasian 16 (100) 16 (100) 1.000Psoriasis duration, y 23 6 3 N/A N/ACurrent smoking 7 (50) 1 (6) .006*
Clinical dataSystolic blood pressure, mm Hg 140 6 5 137 6 4 .736Diastolic blood pressure, mm Hg 86 6 4 90 6 2 .503Resting heart rate, beats/min 77 6 4 65 6 4 .036*BMI, kg/m2 26.7 6 1.0 26.2 6 0.6 .669Waist circumference, cm 96 6 3 92 6 3 .329Hip circumference, cm 100 6 2 99 6 2 .600Waist-hip ratio 1.0 6 0.0 0.9 6 0.0 .333PASI score 12.7 6 1.4 N/A N/ADLQI score 6 6 1 N/A N/A
Biochemical dataFasting plasma glucose, mmol/L 5.5 6 0.1 5.5 6 0.1 .726HbA1c, mmol/mol 31.7 6 1.2 30.9 6 0.7 .596hs-CRP, mg/L 5.4 6 1.7 1.8 6 0.4 .048*ALT, U/L 30.5 6 3.7 28.0 6 1.9 .553AST, U/L 33.5 6 2.1 33.0 6 2.2 .887Total cholesterol, mmol/L 4.9 6 0.3 4.7 6 0.3 .625HDL, mmol/L 1.3 6 0.1 1.3 6 0.1 .688LDL, mmol/L 2.7 6 0.3 2.9 6 0.3 .663Triglycerides, mmol/L 1.9 6 0.2 1.2 6 0.2 .016*
Continuous data are presented in mean 6 SEM, categorical data in numbers and percentage.
ALT, Alanine transaminase; AST, aspartate transaminase; BMI, body mass index; DLQI, Dermatology Life Quality Index; HbA1c, glycosylated
hemoglobin; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; N/A, not applicable;
PASI, Psoriasis Area and Severity Index.
*P value\ .05.
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supports the notion that psoriasis per se constitutes aprediabetic condition.
Strengths of this study include the careful selec-tion and matching of the 2 groups. A methodologicalweakness is that the classic hyperinsulinemiceuglycemic clamp technique does not allowassessment of endogenous glucose production.Although inhibited by hyperinsulinemia, a smallresidual glycogenolytic and/or gluconeogenicactivity can theoretically persist during the clamp,particularly in insulin-resistant individuals. Weinfused human insulin at a rate of 40 mU/m2/min,as it is considered to be the common standardand sufficient to turn off the endogenous insulinproduction18,19 and the endogenous glucoseproduction, even in very insulin-resistant personswith type 2 diabetes.20
In many patients with type 2 diabetes, insulinresistance precedes the diabetic state and may,therefore, be considered an early feature of thedisease.21,22 Under normal physiological conditions,insulin is secreted from the pancreatic beta cells inresponse to food intake. Insulin directly stimulates
glucose uptake in the peripheral target tissues, inparticular skeletal muscle, and simultaneouslysuppresses hepatic glucose output. Defects in anyof these actions will tend to raise the plasma glucose,which is initially compensated for by an increasedinsulin secretion rate. At some point, the beta cellsare no longer capable of increasing the insulinsecretion, and accordingly, fasting and postprandialglucose values begin to rise.22,23 The final stages oftype 2 diabetes development are characterized by adecrease in insulin secretion, further increments inplasma glucose, and finally, overt diabetes. It isindisputable that both insulin resistance andbeta cell dysfunction represent common patho-physiological traits of type 2 diabetes. However,their temporal relation and relative contributionsto the development of type 2 diabetes remaincontroversial.24
A small number of clinical studies haveinvestigated insulin sensitivity in patients withpsoriasis.9-13,15,25 Overall, the results point toward astate of insulin resistance, but the studies are difficultto compare because of methodological differences.
Table II. Glucose, insulin, C-peptide, glucagon, and indices
Patients with psoriasis, n = 16 Control subjects, n = 16 P value
GlucoseBaseline, mmol/L 5.1 6 0.1 4.9 6 0.1 .404tAUC0-180 min, min 3 mmol/L 834 6 23 885 6 10 .214tAUCsteady-state, 30 min, min 3 mmol/L 145 6 2 148 6 2 .057
InsulinBaseline, pmol/L 66 6 8 52 6 7 .213tAUC0-180 min, min 3 pmol/L 81,261 6 6082 79,586 6 3637 .815tAUCsteady-state, 30 min, min 3 pmol/L 14,801 6 1129 14,247 6 847 .697
C-peptideBaseline, pmol/L 490 6 50 376 6 33 .075tAUC0-180 min, min 3 pmol/L 82,474 6 9082 66,180 6 8604 .203tAUCsteady-state, 30 min, min 3 pmol/L 12,718 6 1740 10,257 6 1713 .322
GlucagonBaseline, pmol/L 12 6 1 11 6 1 .249tAUC, min 3 pmol/L 1270 6 181 904 6 113 .097tAUCsteady-state, 30 min, min 3 pmol/L 148 6 27 86 6 15 .057
IndicesM-value 4.5 (1.6-14.0) 7.4 (2.1-10.8) .046*HOMA2-IR 1.2 6 0.1 1.0 6 0.1 .215IPAQ score, METs 1524 (0-9492) 1420 (229-6426) .485
Normally distributed data are presented in mean 6 SEM, nonnormally distributed data in median and range.
HOMA2-IR, Insulin resistance according to the updated homeostasis model assessment; IPAQ, International Physical Activity Questionnaire;
METs, metabolic equivalents; tAUC, total area under the curve.
*P value\ .05.
Fig 1. Glucose (A), insulin (B), C-peptide (C), and glucagon (D) concentrations, and glucoseinfusion rates (GIR) (E) in patients with psoriasis (closed symbols) and healthy control subjects(open symbols) during a 3-hour hyperinsulinemic euglycemic clamp. Data points representmean 6 SEM values.
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Most authors have calculated insulin resistanceaccording to the homeostasis model assessment,which is obtained from paired fasting values ofglucose and insulin.9,11-13,15 The reproducibility of
HOMA-IR is rather poor.26 Also, because fastinglevels of glucose and insulin are determined by theendogenous glucose production of the liver (and to asmall extent the kidneys), many researchers argue
Fig 2. Box plots showing insulin sensitivity (M-values) inhealthy control subjects (left) and patients with psoriasis(right) during a 3-hour hyperinsulinemic euglycemicclamp.
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that HOMA-IR reflects hepatic insulin sensitivity andonly to a lesser extent insulin sensitivity in muscle.27
This might explain the lack of differences inHOMA-IR between patients and healthy controlsubjects in the current study. In addition to calcu-lating HOMA-IR, 2 research groups have performedinsulin tolerance tests in a matched setting.10,14
Results are conflicting, and the technique is rarelyused in diabetes research.8 To our knowledge, only 1study has previously assessed insulin sensitivity inpatients with psoriasis using the gold standard. In2012, Kofoed et al12 performed 2-hour hyperinsuli-nemic euglycemic clamps in 9 psoriatic patients andfound no differences in M-values before and after 12weeks of antietumor necrosis factor-alfa therapy. Asthe focus of that study was to examine a potentialtreatment effect, and not to describe insulinsensitivity per se, the patients were enrolledirrespective of diabetes risk factors and currentmedical treatments, and there was no control group.This and other important methodological differencesmake comparisons between the 2 studies difficult.
Why did psoriatic patients in this study displayimpaired insulin sensitivity? Firstly, psoriasisand type 2 diabetes might share common geneticbackground.28-30 Another explanation for insulinresistance in patients with psoriasis can be thepresence of chronic inflammation. Psoriasis ischaracterized by a dysregulation of the innateimmune system31 and raised levels of cytokinesplay an essential role in the pathogenesis of notonly psoriasis, but also in type 2 diabetes by
promoting insulin resistance.32,33 The low-gradeinflammation in psoriasis is, eg, reflected by elevatedlevels of high-sensitivity C-reactive protein, whichhas been linked to increased risk of type 2 diabetes ina recent meta-analysis.34
Despite careful selection and matching of theenrolled participants, the result of this study may beconfounded by diabetes risk factors. Thus, theprevalence of current smoking and hypertriglycer-idemia were significantly increased in the psoriasisgroup. A recent report from the US Department ofHealth and Human Services concluded that the riskof developing type 2 diabetes is up to 40% higheramong smokers than nonsmokers.35 Likewise, someevidence suggests that hypertriglyceridemia mayconstitute an independent risk factor for insulinresistance.36 Finally, despite normal fasting plasmaglucose and HbA1c, some of the participants mighthave had glucose abnormalities, which could havebeen revealed by an oral glucose tolerance test at thescreening.
In conclusion, our data indicate the presence ofinsulin resistance in normal glucose-tolerant patientswith moderate to severe psoriasis. Thus, theincreased risk of type 2 diabetes in patients withpsoriasis appears to include glucometabolic defectslinked to psoriasis itself. These results will have to beconfirmed in larger controlled studies. Also, furtherresearch is needed to characterize the nature of theinsulin resistance associated with psoriasis, and touncover responsible mechanisms.
We wish to thank the participants for spending timewith this project, and laboratory technicians Mie Mouritzenand Anni Olsen from Department of Dermato-Allergology,Gentofte Hospital, University of Copenhagen, for theirvaluable assistance.
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