Early autonomic dysfunction in type 1 diabetes : Insights into its significance and mechanisms

Diabetic autonomic neuropathy is a serious complication, associated with increased risk of morbidity and mortality, but it is perhaps the least understood of the diabetic complications. The challenge lies in the early diagnosis of this often subclinical condition, in the time window when it would still be treatable. Notably, when detected with the current diagnostic tools, diabetic autonomic neuropathy has been considered as the result of irreversible nerve damage. Reduced baroreflex sensitivity (BRS) is a sensitive marker of autonomic dysfunction, and importantly, also a prognostic marker in cardiovascular medicine. In addition to diabetes, abnormalities in the BRS also occur in conditions characterized by functional autonomic abnormalities such as myocardial infarction, heart failure, and hypertension. Accordingly, we hypothesized that early autonomic dysfunction in type 1 diabetes, as demonstrated by reduced BRS, is functional. The aim of this thesis was to elucidate the early markers of autonomic dysfunction in patients with type 1 diabetes of various durations. We reasoned that if BRS in patients with type 1 diabetes responds to slow, deep breathing, a manoeuvre shown to reduce sympathetic activity, or responds to oxygen administration, such a finding would support a functional aetiology. We also studied whether autonomic dysfunction, as established by reduced BRS, progresses alongside increasing diabetes duration to a stage where it is no longer improved by a functional manoeuvre. Moreover, we aimed to elucidate the role of BRS as a predictor of increased blood pressure (BP) level during a 5-year follow-up. We studied 117 patients with short (8.9±0.1 yrs) and 37 patients with long duration (33.7±0.5 yrs) type 1 diabetes, and a total of 73 age- and gender-matched, healthy control participants. Twelve heart-transplanted patients served as a model of cardiac denervation. An autonomic score was calculated from autonomic function tests. Spectral analysis of heart rate variability (HRV), blood pressure variability (BPV), and BRS came from recordings during normal (15/min) and slow, deep (6/min) controlled breathing. Of those with short-duration type 1 diabetes, 96 subjects were studied during a prospective visit by similar autonomic assessment as at baseline but in addition, with BRS assessed during inhalation of oxygen. In a total of 80 patients, we compared autonomic indices and ambulatory BP at baseline and follow-up. BRS was already reduced in patients with short-duration type 1 diabetes, but even more reduced in those with long duration or with increasing autonomic involvement. Slow breathing elevated the BRS to the level of control subjects at a normal breathing rate (15/min) in all patients except in those with an abnormal autonomic score. BRS also increased with oxygen during spontaneous breathing in diabetic but not in control participants, and with oxygen the difference in BRS was no longer significant. Slow breathing in normoxia restored the BRS to a similar extent as did oxygen. In the follow-up study, spontaneous BRS declined over time, but the change was not significant when adjusted for time of follow-up. Low BRS at baseline did not advance to cardiovascular autonomic neuropathy (CAN) but predicted an increase in night-time systolic BP. Furthermore, the BRS response to deep breathing at baseline predicted the increase found in 24-hour ambulatory BP. The results of this thesis indicate that even after long-duration diabetes, any abnormal BRS is at least in part of functional origin. The increased baroreflex response to oxygen supports the hypothesis of a functional reduction in parasympathetic activity occurring in patients with type 1 diabetes. The follow-up study showed that the decline in spontaneous BRS over time in patients with type 1 diabetes seems to be mainly due to normal ageing. Although early autonomic dysfunction seems functional and does not necessarily develop into autonomic neuropathy during a 5-year follow-up, the BRS and the response to deep breathing at baseline are associated with a future increase in BP. More research and a longer follow-up time will be required to fully clarify the prognostic significance of BRS in type 1 diabetes.Autonominen neuropatia eli tahdosta riippumattoman hermoston toimintahäiriö on diabeteksen liitännäissairauksista ehkä huonoiten tunnettu. Verenkiertoelimistön autonominen neuropatia on yleensä pitkään oireeton, mutta täysin oireettomanakin se lisää diabeetikoilla riskiä sairastua ja kuolla ennenaikaisesti sydän- ja verisuonitauteihin sekä saattaa ennustaa muiden liitännäissairauksien kehittymistä. Diabeettista hermosairautta on pidetty pysyvänä, rakenteellisena kudosvauriona, sillä verensokeritasapainon parantamisen lisäksi neuropatiaan ei ole löytynyt muuta tehokasta hoitoa. Autonomisen neuropatian diagnostiikka on haastavaa koska ei ole tarjolla herkkiä menetelmiä joilla toimintahäiriön voisi havaita sen ollessa vielä paranettavissa. Sykevaihtelun spektrianalyysi ja barorefleksiherkkyyden (BRS) tutkiminen ovat autonomisen hermoston toimintakokeita herkempiä menetelmiä ja mahdollistavat toimintahäiriön toteamisen varhaisemmassa vaiheessa. Toiminnallisestikin alentunut BRS on huonon ennusteen merkki useissa sydän- ja verisuonisairauksissa. On mahdollista että varhainen autonomisen hermoston toimintahäiriö on tyypin 1 diabeetikoillakin toiminnallinen ja mahdollisesti vielä palautuva. Väitöstutkimuksen tavoitteena oli selvittää autonomisen hermoston varhaisen toimintahäiriön merkkejä tyypin 1 diabeetikoilla joilla oli eri sairauden kesto. Tutkimme BRS:n vastetta toiminnallisille kokeille, hapen hengittämiselle sekä syväänhengitykselle, joista jälkimmäisen on aiemmin osoitettu vähentävän sympaattista aktivaatiota. Tutkimme myös miten alentunut BRS muuttuu diabeteksen keston myötä. Lisäksi selvitimme alentuneen BRS:n merkitystä verenpaineen kehityksessä 5 vuoden seurannassa. Tutkimme 117 tyypin 1 diabeetikkoa joilla oli lyhyt diabeteksen kesto (8.9±0.1 vuotta) ja 37 tyypin 1 diabeetikkoa joilla oli pitkä sairauden kesto (33.7±0.5 vuotta) sekä 73 tervettä verrokkihenkilöä. Autonomisen hermoston tutkimus koostui neljästä toimintakokeesta. Sykevaihtelua ja barorefleksiherkkyyttä mitattiin makuulla tehdystä leporekisteröinnistä spontaanihengityksen, ohjatun hengityksen (15/min) sekä syväänhengityksen (6/min) aikana. Verenpainetta mitattiin vuorokausirekisteröinnin avulla. Lyhyemmän aikaa diabetesta sairastaneiden ryhmä tutkittiin uudestaan 5 vuoden seurannan jälkeen. BRS oli alentunut jo lyhyemmän aikaa tyypin 1 diabetesta sairastaneilla, mutta merkittävästi matalampi pitkään sairastaneilla sekä heillä joilla oli kriteerit täyttävä autonominen neuropatia (CAN). Syväänhengityksen aikana BRS korjautui terveiden verrokkien tasolle kaikilla paitsi diabeetikoilla joilla todettiin CAN. Hapen hengitys sai tyypin 1 diabeetikoilla aikaan merkittävän nousun BRS:ssä toisin kuin verrokeilla. BRS huononi 5 vuoden seurannassa mutta kun huomioitiin fysiologinen ikään liittyvä alenema, muutos ei ollut tilastollisesti merkittävä. Lähtötilanteen alentunut BRS ei ennustanut CAN:n kehittymistä, mutta oli yhteydessä yöllisen verenpainetason nousuun seurannassa. Väitöstutkimus osoitti, että herkempiä menetelmiä käytettäessä autonomisen hermoston häiriöitä voidaan todeta jo tyypin 1 diabeteksen varhaisessa vaiheessa. Toiminnallisilla interventioilla BRS korjautui valtaosalla tyypin 1 diabeetikoista terveiden verrokkien tasolle. Näin ollen häiriö saattaa alkuvaiheessa olla ainakin osittain toiminnallinen eli palautuva ja voisi selittyä kiertäjähermon vaurion sijasta sympaattisen hermoston yliaktiviteetilla. Alentuneen BRS:n tarkempi ennustearvo tyypin 1 diabeteksessa on vielä epäselvä eikä tiedetä eteneekö se vääjäämättä jatkossa pysyvään autonomiseen neuropatiaan. Löydösten merkitys lisäsairauksien kehittymisessä vaatii vielä lisätutkimuksia ja pidempää seurantaa. Liikunnan myönteisestä vaikutuksesta BRS:een on saatu uutta tietoa viime vuosina myös diabeetikoilla

Lihavuusleikkaukseen liittyvä hypoglykemia

Teema : lihavuuskirurgia. English summaryPeer reviewe

Lihavuusleikkauksen pitkäaikaisvaikutukset vitamiinien ja kivennäisaineiden imeytymiseen

Teema : lihavuuskirurgia. English summaryPeer reviewe

Tukeva diabeetikko - tapauksen ratkaisu

Terveyskeskuslääkärin vastaanotolle diabetestarkastukseen tulleella 49-vuotiaalla naisella verensokerit olivat lääkityksestä huolimatta huonolla mallilla

Weight Loss Trajectories in Healthy Weight Coaching : Cohort Study

Background: As global obesity prevalence continues to increase, there is a need for accessible and affordable weight management interventions, such as web-based programs. Objective: This paper aims to assess the outcomes of healthy weight coaching (HWC), a web-based obesity management program integrated into standard Finnish clinical care. Methods: HWC is an ongoing, structured digital 12-month program based on acceptance and commitment therapy. It includes weekly training sessions focused on lifestyle, general health, and psychological factors. Participants received remote one-on-one support from a personal coach. In this real-life, single-arm, prospective cohort study, we examined the total weight loss, weight loss profiles, and variables associated with weight loss success and program retention in 1189 adults (963 women) with a BMI >25 kg/m(2) among participants of the program between October 2016 and March 2019. Absolute (kg) and relative (%) weight loss from the baseline were the primary outcomes. We also examined the weight loss profiles, clustered based on the dynamic time-warping distance, and the possible variables associated with greater weight loss success and program retention. We compared different groups using the Mann-Whitney test or Kruskal-Wallis test for continuous variables and the chi-squared test for categorical variables. We analyzed changes in medication using the McNemar test. Results: Among those having reached the 12-month time point (n=173), the mean weight loss was 4.6% (SE 0.5%), with 43% (n=75) achieving clinically relevant weight loss (>= 5%). Baseline BMI >= 40 kg/m(2) was associated with a greater weight loss than a lower BMI (mean 6.6%, SE 0.9%, vs mean 3.2%, SE 0.6%; P=.02). In addition, more frequent weight reporting was associated with greater weight loss. No significant differences in weight loss were observed according to sex, age, baseline disease, or medication use. The total dropout rate was 29.1%. Dropouts were slightly younger than continuers (47.2, SE 0.6 years vs 49.2, SE 0.4 years; P=.01) and reported their weight less frequently (3.0, SE 0.1 entries per month vs 3.3, SE 0.1 entries per month; P Conclusions: A comprehensive web-based program such as HWC is a potential addition to the repertoire of obesity management in a clinical setting. Heavier patients lost more weight, but weight loss success was otherwise independent of baseline characteristics.Peer reviewe

Arterial function, biomarkers, carcinoid syndrome and carcinoid heart disease in patients with small intestinal neuroendocrine tumours

Purpose Carcinoid heart disease (CHD) is a life-threatening complication of carcinoid syndrome (CS) characterised by tricuspid regurgitation (TR). However, there is an unmet need for earlier diagnosis of CHD. We cross-sectionally assessed the prevalence and potential predictive or diagnostic markers for CS and CHD in a contemporary cohort of patients with small intestinal neuroendocrine tumours (SI-NETs). Methods Biochemical characteristics, hepatic tumour load, measures of arterial and endothelial function, atherosclerosis, and transthoracic echocardiography were analysed in a prospective cross-sectional setting. Results Among the 65 patients studied, 29 (45%) had CS (CS+), and 3 (5%) CHD. CS+ was characterised by significantly higher hepatic tumour load, S-5-HIAA and fP-CgA, higher frequency of diarrhoea and flushing, and more frequent PRRT compared to CS- (for all, P < 0.05). Central systolic, central mean, and central end-systolic blood pressures were significantly higher in CS+ than in CS- (for all, P < 0.05). Subjects with grades 2-4 TR had higher hepatic tumour burden, fP-CgA, and S-5-HIAA compared to those with grades 0-1 TR, but measures of vascular function did not differ. fP-CgA (P = 0.017) and S-5-HIAA (P = 0.019) but not proBNP increased significantly according to the severity of TR. Conclusion Although CS is common, the prevalence of CHD was found to be lower in a contemporary cohort of SI-NET patients than previously anticipated. Measures of arterial or endothelial function or carotid atherosclerosis do not identify subjects with mild TR. Echocardiography remains the most sensitive means to diagnose CHD in CS patients with high tumour burden and elevated CgA and 5-HIAA.Peer reviewe

Weight Loss Trajectories in Healthy Weight Coaching: Cohort Study

BACKGROUNDAs global obesity prevalence continues to increase, there is a need for accessible and affordable weight management interventions, such as web-based programs.OBJECTIVEThis paper aims to assess the outcomes of healthy weight coaching (HWC), a web-based obesity management program integrated into standard Finnish clinical care.METHODSHWC is an ongoing, structured digital 12-month program based on acceptance and commitment therapy. It includes weekly training sessions focused on lifestyle, general health, and psychological factors. Participants received remote one-on-one support from a personal coach. In this real-life, single-arm, prospective cohort study, we examined the total weight loss, weight loss profiles, and variables associated with weight loss success and program retention in 1189 adults (963 women) with a BMI >25 kg/m² among participants of the program between October 2016 and March 2019. Absolute (kg) and relative (%) weight loss from the baseline were the primary outcomes. We also examined the weight loss profiles, clustered based on the dynamic time-warping distance, and the possible variables associated with greater weight loss success and program retention. We compared different groups using the Mann-Whitney test or Kruskal-Wallis test for continuous variables and the chi-squared test for categorical variables. We analyzed changes in medication using the McNemar test.RESULTSAmong those having reached the 12-month time point (n=173), the mean weight loss was 4.6% (SE 0.5%), with 43% (n=75) achieving clinically relevant weight loss (≥5%). Baseline BMI ≥40 kg/m² was associated with a greater weight loss than a lower BMI (mean 6.6%, SE 0.9%, vs mean 3.2%, SE 0.6%; P=.02). In addition, more frequent weight reporting was associated with greater weight loss. No significant differences in weight loss were observed according to sex, age, baseline disease, or medication use. The total dropout rate was 29.1%. Dropouts were slightly younger than continuers (47.2, SE 0.6 years vs 49.2, SE 0.4 years; P=.01) and reported their weight less frequently (3.0, SE 0.1 entries per month vs 3.3, SE 0.1 entries per month; PCONCLUSIONA comprehensive web-based program such as HWC is a potential addition to the repertoire of obesity management in a clinical setting. Heavier patients lost more weight, but weight loss success was otherwise independent of baseline characteristics.</p

Arterial stiffness and vascular complications in patients with type 1 diabetes: The finnish diabetic nephropathy (FinnDiane) study

While patients with type 1 diabetes (T1D) are known to suffer from early cardiovascular disease (CVD), we examined associations between arterial stiffness and diabetic complications in a large patient group with T1D.This study included 807 subjects (622 T1D and 185 healthy volunteers (age 40.6 ± 0.7 versus 41.6 ± 1.2 years; P = NS)). Arterial stiffness was measured by pulse wave analysis from each participant. Furthermore, information on diabetic retinopathy, nephropathy, and CVD was collected. The renal status was verified from at least two out of three urine collections.Patients with T1D without signs of diabetic nephropathy had stiffer arteries measured as the augmentation index (AIx) than age-matched control subjects (17.3% ± 0.6% versus 10.0% ± 1.2%; P0.001). Moreover, AIx (OR 1.08; 95% CI 1.03-1.13; P = 0.002) was associated with diabetic laser-treated retinopathy in patients with normoalbuminuria in a multivariate logistic regression analysis. The same was true for AIx and diabetic nephropathy (1.04 (1.01-1.08); P = 0.004) as well as AIx and CVD (1.06 (1.00-1.12); P = 0.01) in patients with T1D.Arterial stiffness was associated with microvascular and macrovascular complications in patients with T1D