Från riskfaktorer till skyddsfaktorer vid diabeteskomplikationer

Diabetes. English summary

Verensokerin vaikutus verisuonistoon nuorilla tyypin 1 diabeetikoilla

Background. Patients with type 1 diabetes are at markedly increased risk of vascular complications. In this respect it is noteworthy that hyperglycaemia that is shown to cause endothelial dysfunction, has clearly been shown to be a risk factor for diabetic microvascular disease. However, the role of hyperglycaemia as a predictor of macrovascular disease is not as clear as for microvascular disease, although type 1 diabetes itself increases the risk of cardiovascular disease substantially. Furthermore, it is not known whether it is the short-term or the long-term hyperglycaemia that confers possible risk. In addition, the role of glucose variability as a predictor of complications is to a large extent unexplored. Interestingly, although hyperglycaemia increases the risk of pre-eclampsia in women with type 1 diabetes, it is unclear whether pre-eclampsia, a condition characterized by endothelial dysfunction, is also a risk factor for microvascular complication, diabetic nephropathy. Aims. This doctoral thesis investigated the role of acute hyperglycaemia and glucose variability on arterial stiffness and cardiac ventricular repolarisation in male patients with type 1 diabetes as well as in healthy male volunteers. The thesis also explored whether acute hyperglycaemia leads to an inflammatory response, endothelial dysfunction and oxidative stress. Finally, the role of pre-eclampsia, as a predictor of diabetic nephropathy in type 1 diabetes was examined. Subjects and methods. In order to study glucose variability and the daily glycaemic control, 22 male patients with type 1 diabetes, without any diabetic complications, were monitored for 72-h with a continuous glucose monitoring system. At the end of the 72-h glucose monitoring period a 2-h hyperglycaemic clamp was performed both in the patients with type 1 diabetes and in the 13 healthy age-matched male volunteers. Blood pressure, arterial stiffness and QT time were measured to detect vascular changes during acute hyperglycaemia. Blood samples were drawn at baseline (normoglycaemia) and during acute hyperglycaemia. In another patient sample, women with type 1 diabetes were followed during their pregnancy and restudied eleven years later to elucidate the role of pre-eclampsia and pregnancy-induced hypertension as potential risk factors for diabetic nephropathy. Results and conclusions. Acute hyperglycaemia increased arterial stiffness as well as caused a disturbance in the myocardial ventricular repolarisation, emphasizing the importance of a strict daily glycaemic control in male patients with type 1 diabetes. An inflammatory response was also observed during acute hyperglycaemia. Furthermore, a high mean daily blood glucose but not glucose variability per se is associated with arterial stiffness. While glucose variability in turn correlated with central blood pressure, the results suggest that the glucose metabolism is closely linked to the haemodynamic changes in male patients with uncomplicated type 1 diabetes. Notably, the results are not directly applicable to females. Finally, a history of a pre-eclamptic pregnancy, but not pregnancy-induced hypertension was associated with increased risk of diabetic nephropathy.Blodsockrets effekt på blodkärlen hos unga typ 1 diabetiker Typ 1 diabetes medför en avsevärt ökad mortalitet och morbiditet i kardiovaskulära sjukdomar. Dyslipidemi, hypertoni, övervikt och rökning är klassiska riskfaktorer, men kan inte ensamma förklara alla sjukdomsfall i denna patientgrupp. En bristfällig kontroll av glukosbalansen har däremot klart förknippats med utvecklingen av de så kallade mikrovaskulära komplikationerna (nefro-, neuro- ja retinopati), trots att dess roll som risk faktor för hjärt- och kärlsjukdomar är ännu oklar. Man har ej heller ännu kunnat klargöra ifall akut eller kronisk hyperglykemi medför en större risk för diabetiska komplikationer. Avhandlingen undersökte ifall akut hyperglykemi och en varierande daglig blodsockerbalans påverkade artärstelheten och hjärtats ledningsförmåga hos unga typ 1 diabetiker och friska kontroller. Dessutom undersöktes om en hyperglykemi inducerad inflammationsprocess delvis kunde förklara de eventuella vaskulära förändringarna. Vidare undersöktes pre-eklampsins roll som risk faktor för diabetisk nefropati hos typ 1 diabetiker. Tjugotvå rökfria män med typ 1 diabetes, utan diabetiska komplikationer deltog i undersökningen. En grupp på 13 friska män som till sin ålder motsvarade diabetikerna fungerade som kontrollgrupp. Alla försökspersoner hade normalt viktindex, normala lipidvärden samt normalt blodtryck. Den dagliga glukosbalansen registrerades hos diabetikerna under 72 timmars tid med en glukossensor. Därefter utfördes en 2 timmars sockerbelastning åt alla försökspersoner genom att tillföra sockerlösning intravenöst. Artärstelhetsmätningar samt registrering av blodtryck och hjärtfilm gjordes före och under den akuta hyperglykemin. Dessutom togs blodprov för att mäta inflammationsmarkörer. I ett annat sampel undersöktes typ 1 diabetiker som genomgått en födsel på HUCS Kvinnoklinik under åren 1988-1996. Kvinnorna kallades för ett uppföljningsbesök inom ramen för FinnDiane (Finnish Diabetic Nephropathy Study) undersökningen (uppföljningstid ca 11 år). Under uppföljningsbesöket togs blod- och urinprov. Diabetisk nefropati bestämdes på basen av tre dygnsurinprov. Avhandlingens resultat visade att akut hyperglykemi får artärerna att stelna samt stör hjärtats ledning hos unga typ 1 diabetiker utan diabetiska komplikationer. Härtill visade sig ett högt medelglukosvärde öka artärstelheten medan en varierande daglig glukosbalans korrelerade med ett högt blodtryck. Hjärt- och blodkärlssjukdomar har associerats med en inflammationsprocess som även i denna avhandling verkade medverka i de vaskulära förändringarna. Resultaten stöder uppfattningen om en att en god kontroll av glukosbalansen är essentiell inta bara för att undvika mikrovaskulära men även hjärt- och blodkärlskomplikationer. Pre-eklampsi var en risk faktor för diabetisk nefropati hos typ 1 diabetiker. Sålunda borde läkare som sköter typ 1 diabetiker som genomgått pre-eklampsi i ett tidigt skede inleda adekvat medicinering åt dessa patienter.Verensokerin vaikutus verisuonistoon nuorilla tyypin 1 diabeetikoilla Tyypin 1 diabetekseen liittyy selkeästi lisääntynyt kuolleisuus sydän- ja verisuonitauteihin. Niin sanotut tavanomaiset sydän- ja verisuonitautien riskitekijät kuten hyperkolesterolemia, verenpainetauti, lihavuus ja tupakointi eivät kuitenkaan täysin selitä suurta kuolleisuutta tässä potilasryhmässä. Huono sokeritasapaino sen sijaan on selkeästi liitetty mikrovaskulaarisiin lisäsairauksiin (nefro-, neuro- ja retinopatiaan), mutta yksioikoinen näyttö sen osuudesta sydän- ja verisuonitautien riskitekijänä puuttuu. Ei ole myöskään selvitetty mikäli akuutti tai krooninen hyperglykemia olisi keskeisempi diabeteksen komplikaatioiden synnyssä. Tämän väitöskirjatyön tarkoituksena oli selvittää, mikäli akuutti hyperglykemia ja päivittäin vaihteleva sokeritasapaino vaikuttavat valtimojäykkyyteen ja sydämen johtumiseen nuorilla tyypin 1 diabeetikoilla sekä terveillä verrokeilla. Lisäksi tutkittiin samassa potilasryhmässä mikäli akuutti hyperglykemia aiheuttaa tulehduksellisen vasteen, mahdollisten verisuonimuutosten osaselittäjänä. Tämän lisäksi väitöskir-jatyön tarkoitus oli selvittää, lisääkö pre-eklampsia tai raskaudenaikainen verenpaineen nousu diabeettisen nefropatian esiintyvyyttä. Tutkimukseen osallistui 22 tupakoimatonta tyypin 1 diabeetikkoa, joilla ei ollut diabetekseen liittyviä komplikaatioita, sekä 13 niin ikään tupakoimatonta tervettä miestä. Kaikilla koehenkilöillä oli normaali painoindeksi, verenpaine ja normaalit kolesteroliarvot. Tyypin 1 diabeetikoilla monitoroitiin jatkuva kudossokeri 72 tunnin ajan päivittäisen sokeritasapainon selvittämiseksi. Tämän jälkeisenä aamuna verenglukoosipitoisuutta lisättiin glukoosi-infuusiolla 10 mmol/l lähtöarvoa suuremmaksi (tavoite 15 mmol/l) kahdeksi tunniksi kaikilla tutkimushenkilöillä. Sekä lähtötilanteessa että hyperglykemian aika-na valtimoiden joustavuutta tutkittiin ei-invasiivisesti applanaatiotonometrian avulla, lisäksi mitattiin verenpaine, rekisteröitiin sydänfilmi ja otettiin verikokeita tulehdusarvojen määrittämiseksi. Toisessa otoksessa tutkittiin vuosina 1988–1996 HYKS:n Naistenklinikalla synnyttäneitä tyypin 1 diabeetikoita. Synnyttäjät kutsuttiin seurantakäynnille (seuranta-aika 11 vuotta) FinnDiane-tutkimukseen (Finnish Diabetic Nephropathy Study). Seurantakäynnillä potilaille tehtiin kliininen tutkimus ja otettiin veri- ja virtsanäytteitä. Diabetes nefropatia todettiin kolmen 24 tunnin virtsankeräyksen perusteella. Tulokset osoittivat, että valtimot jäykistyvät ja sydämen johtuminen häiriintyy akuutin hyperglykemian aikana ja painottavat tyypin 1 diabeetikoiden päivittäisen verensokeritasapainon tärkeyttä. Sydän- ja verisuonitauteihin tiiviisti liitetty tulehdusprosessi vaikuttaisi olevan osaltaan selittävänä tekijänä. Lisäksi, korkea päivittäinen keskiverensokeri näyttäisi jäykistävän nuorten tyypin 1 diabeetikoiden valtimoita, kun taas päivittäin vaihteleva sokeritasapaino ja verenpaine korreloivat keskenään niin ikään korostaen tiukkaa sokeritasapainoa . Viimeiseksi raskauden aikainen pre-eklampsia ennusti diabeettisen nefropatian esiintyvyyttä. Näin ollen tyypin 1 diabeetikoita hoitavien lääkäreiden tulisi herkästi aloittaa asianmukainen lääkitys diabeettisen nefropatian ehkäisemiseksi, jos potilaalla on ollut pre-eklampsia

Arterial Stiffness Predicts Mortality in Individuals With Type 1 Diabetes

OBJECTIVE Type 1 diabetes is accompanied by a significant burden of cardiovascular disease (CVD), which is poorly explained by traditional risk factors. We therefore aimed to explore whether arterial stiffness estimated by the augmentation index (AIx) predicts mortality in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS After baseline examination comprising pulse wave analysis by applanation tonometry alongside assessment of traditional cardiovascular risk factors, 906 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study were followed up for a median of 8.2 years (interquartile range 5.7-9.7). Associations between baseline hemodynamics, including AIx, and all-cause mortality as well as a composite of cardiovascular and/or diabetes-related mortality were investigated using multivariable Cox regression models. RESULTS The 67 individuals who died during follow-up had higher baseline AIx (median 28% [interquartile range 21-33] vs. 19% [9-27];P<0.001) compared with those alive. This association was independent of conventional risk factors (age, sex, BMI, HbA(1c), estimated glomerular filtration rate [eGFR], and previous CVD event) in Cox regression analysis (standardized hazard ratio 1.71 [95% CI 1.10-2.65];P= 0.017) and sustained in a subanalysis of individuals with chronic kidney disease. Similarly, higher AIx was associated with the composite secondary end point of cardiovascular and diabetes-related death (N= 53) after adjustments for sex, BMI, eGFR, previous CVD event, and height (standardized hazard ratio 2.30 [1.38-3.83];P= 0.001). CONCLUSIONS AIx predicts all-cause mortality as well as a composite cardiovascular and/or diabetes-related cause of death in individuals with type 1 diabetes, independent of established cardiovascular risk factors.Peer reviewe

Motivational Interview to improve vascular health in Adolescents with poorly controlled type 1 Diabetes (MIAD) : a randomized controlled trial

Introduction We studied if motivational interviewing (MI) added to standard educational care (SEC) improves vascular health in adolescents with poorly controlled type 1 diabetes. Research design and methods 47 adolescents with type 1 diabetes of at least 2 years duration and hemoglobin A1c >75 mmol/mol (>9.0%) on two visits were randomized to MI+SEC or SEC. We also compared vascular health parameters of patients with type 1 diabetes at trial baseline with a group of healthy historical controls matched for age and body size. Results 39 adolescents (20 MI+SEC) completed the vascular health study. At 12 months, parameter changes were not statistically significantly different between MI+SEC and SEC (carotid-femoral pulse wave velocity (cfPWV): mean difference 0.052 m/s (95% CI -0.395 to 0.500, p=0.81); carotid-radial PWV (crPWV): 0.118 m/s (95% to 0.478 to 0.713, p=0.69), carotid intima-media thickness (IMT): 0.002 mm (95% CI -0.37 to 0.40, p=0.93), systolic blood pressure (BP) z-score: 0.495 (95% CI -0.099 to 1.09, p=0.10). At baseline, duration of type 1 diabetes was associated with radial IMT (r=0.430, p=0.007) and cfPWV (r=0.373, p=0.018), and carotid, femoral and brachial IMT were correlated with continuous glucose monitoring (CGM) SD (r=0.440, p=0.017; r=0.377, p=0.048; r=0.387, p=0.038). There was an inverse association between CGM time-in-range (3.9-10.0 mmol/L) and crPWV (r=-0.476, p=0.022) changes. Systolic BP change was associated with body mass index change (r=0.374, p=0.019) and IMT change (r=0.461, p=0.016 for carotid IMT; r=0.498, p=0.010 for femoral IMT). PWVs were higher and common carotid compliance lower among patients with type 1 diabetes at baseline compared with healthy controls, but no other differences were found. Conclusion There was no effect of MI added to SEC on vascular health parameters. Although disease duration and glycemic control were associated with vascular health at baseline, there were only limited associations between glycemic control and vascular health parameter changes. Vascular health parameter changes were interrelated suggesting clustering of cardiovascular risk.Peer reviewe

Karotispoukaman aktivaatio hoitoresistentin kohonneen verenpaineen hoidossa

English summaryPeer reviewe

The Long-Term Incidence of Hospitalization for Ketoacidosis in Adults with Established T1D-A Prospective Cohort Study

CONTEXT: The long-term natural history of diabetic ketoacidosis (DKA) and its risk factors are poorly understood. OBJECTIVE: To determine the long-term incidence and predictors of DKA in adults with longstanding type 1 diabetes (T1D). DESIGN: All hospitalizations and deaths due to DKA between 1996 and 2016 were identified in 4758 adults with T1D from the Finnish Diabetic Nephropathy Study (FinnDiane), and a cohort of 16 224 adults with T1D from the Finnish general population. RESULTS: Between 1996 and 2015, there were 1228 DKA events in the FinnDiane participants (1.4/100 person-years) and 4914 DKA events (1.8/100 person-years) in adults with T1D from the general population. The majority were hospitalized only once. There was a modest increase in the frequency of DKA in the FinnDiane over the follow-up (~2.4%/year [95% CI, 0.3-4.5%]; P = 0.03). Predictors of DKA were glucose control, CSII, smoking and alcohol consumption, and raised high-density lipoprotein cholesterol and triacylglycerides. Diabetic nephropathy and renal impairment were associated with DKA; patients with end-stage renal disease, macroalbuminuria, and microalbuminuria had 2.09-fol (95% CI, 1.40-3.12), 1.65-fold (95% CI, 1.23-2.19), and 0.87-fold (95% CI, 0.61-1.24) risk of DKA compared with patients with normal albumin excretion rate, respectively. Patients with an estimated glomerular filtration ratePeer reviewe

Kohti tyypin 2 diabeetikon yksilöllistä hyperglykemian hoitoa

Teema : Diabetes avoterveydenhuollossa. English summaryPeer reviewe

Resistant Hypertension and Risk of Adverse Events in Individuals With Type 1 Diabetes : A Nationwide Prospective Study

OBJECTIVE To estimate the risk of diabetic nephropathy (DN) progression, incident coronary heart disease (CHD) and stroke, and all-cause mortality associated with resistant hypertension (RH) in individuals with type 1 diabetes stratified by stages of DN, renal function, and sex. RESEARCH DESIGN AND METHODS This prospective study included a nationally representative cohort of individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study who had purchases of antihypertensive drugs at (+/- 6 months) baseline visit (1995-2008). Individuals (N= 1,103) were divided into three groups:1) RH,2) uncontrolled blood pressure (BP) but no RH, and3) controlled BP. DN progression, cardiovascular events, and deaths were identified from the individuals' health care records and national registries until 31 December 2015. RESULTS At baseline, 18.7% of the participants had RH, while 23.4% had controlled BP. After full adjustments for clinical confounders, RH was associated with increased risk of DN progression (hazard ratio 1.95 [95% CI 1.37, 2.79],P= 0.0002), while no differences were observed in those with no RH (1.05 [0.76, 1.44],P= 0.8) compared with those who had controlled BP. The risk of incident CHD, incident stroke, and all-cause mortality was higher in individuals with RH compared with those who had controlled BP but not beyond albuminuria and reduced kidney function. Notably, in those with normo- and microalbuminuria, the risk of stroke remained higher in the RH compared with the controlled BP group (3.49 [81.20, 10.15],P= 0.02). CONCLUSIONS Our findings highlight the importance of identifying and providing diagnostic and therapeutic counseling to these very-high-risk individuals with RH.Peer reviewe

Oxygen-induced impairment in arterial function is corrected by slow breathing in patients with type 1 diabetes

Hyperoxia and slow breathing acutely improve autonomic function in type-1 diabetes. However, their effects on arterial function may reveal different mechanisms, perhaps potentially useful. To test the effects of oxygen and slow breathing we measured arterial function (augmentation index, pulse wave velocity), baroreflex sensitivity (BRS) and oxygen saturation (SAT), during spontaneous and slow breathing (6 breaths/min), in normoxia and hyperoxia (5 L/min oxygen) in 91 type-1 diabetic and 40 age-matched control participants. During normoxic spontaneous breathing diabetic subjects had lower BRS and SAT, and worse arterial function. Hyperoxia and slow breathing increased BRS and SAT. Hyperoxia increased blood pressure and worsened arterial function. Slow breathing improved arterial function and diastolic blood pressure. Combined administration prevented the hyperoxia-induced arterial pressure and function worsening. Control subjects showed a similar pattern, but with lesser or no statistical significance. Oxygen-driven autonomic improvement could depend on transient arterial stiffening and hypertension (well-known irritative effect of free-radicals on endothelium), inducing reflex increase in BRS. Slow breathing-induced improvement in BRS may result from improved SAT, reduced sympathetic activity and improved vascular function, and/or parasympathetic-driven antioxidant effect. Lower oxidative stress could explain blunted effects in controls. Slow breathing could be a simple beneficial intervention in diabetes.Peer reviewe