Browsing by Subject "Diabetic kidney disease"

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  • Laursen, Jens Christian; Sondergaard-Heinrich, Niels; de Melo, Joana Mendes Lopes; Haddock, Bryan; Rasmussen, Ida Kirstine Bull; Safavimanesh, Farzaneh; Hansen, Christian Stevns; Storling, Joachim; Larsson, Henrik Bo Wiberg; Groop, Per-Henrik; Frimodt-Moller, Marie; Andersen, Ulrik Bjorn; Rossing, Peter (2021)
    Background: Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria. Methods: A randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R-2* (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three- and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019-004,557-92), on ClinicalTrials.gov (NCT04193566), and is completed. Findings: Between February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21-58] mg/g and an eGFR of 73 (32) ml/min/1.73m(2). The mean changes in renal cortical R-2* from baseline to six hours were for dapagliflozin -1.1 (SD 0.7) s(-1) and for placebo +1.3 (0.7) s(-1), resulting in a difference between interventions of -2.3 s(-1) [95% CI -4.0 to -0.6]; p = 0.012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events. Interpretation: A single dose of 50 mg dapagliflozin acutely improved renal cortical R-2* without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well. (C) 2021 The Author(s). Published by Elsevier Ltd.
  • Lithovius, Raija; Toppila, Iiro; Harjutsalo, Valma; Forsblom, Carol; Groop, Per-Henrik; Makinen, Ville-Petteri; FinnDiane Study Grp (2017)
    Aims/hypothesis Previously, we proposed that data-driven metabolic subtypes predict mortality in type 1 diabetes. Here, we analysed new clinical endpoints and revisited the subtypes after 7 years of additional follow-up. Methods Finnish individuals with type 1 diabetes (2059 men and 1924 women, insulin treatment before 35 years of age) were recruited by the national multicentre FinnDiane Study Group. The participants were assigned one of six metabolic subtypes according to a previously published self-organising map from 2008. Subtype-specific all-cause and cardiovascular mortality rates in the FinnDiane cohort were compared with registry data from the entire Finnish population. The rates of incident diabetic kidney disease and cardiovascular endpoints were estimated based on hospital records. Results The advanced kidney disease subtype was associated with the highest incidence of kidney disease progression (67.5% per decade, p <0.001), ischaemic heart disease (26.4% per decade, p <0.001) and all-cause mortality (41.5% per decade, p <0.001). Across all subtypes, mortality rates were lower in women compared with men, but standardised mortality ratios (SMRs) were higher in women. SMRs were indistinguishable between the original study period (19942007) and the new period (2008-2014). The metabolic syndrome subtype predicted cardiovascular deaths (SMR 11.0 for men, SMR 23.4 for women, p <0.001), and women with the high HDL-cholesterol subtype were also at high cardiovascular risk (SMR 16.3, p <0.001). Men with the low-cholesterol or good glycaemic control subtype showed no excess mortality. Conclusions/interpretation Data-driven multivariable metabolic subtypes predicted the divergence of complication burden across multiple clinical endpoints simultaneously. In particular, men with the metabolic syndrome and women with high HDL-cholesterol should be recognised as important subgroups in interventional studies and public health guidelines on type 1 diabetes.
  • Muskiet, M. H. A.; Bunck, M. C.; Heine, R. J.; Corner, A.; Yki-Järvinen, H.; Eliasson, B.; Joles, J. A.; Diamant, M.; Tonneijck, L.; van Raalte, D. H. (2019)
    Aims: To compare the effects of long-term treatment with the GLP-1RA exenatide twicedaily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. Methods: We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean +/- SD age 60 +/- 8 years, HbA1c 7.5 +/- 0.9%, eGFR 86 +/- 16 mL/min/1.73m(2), median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 mg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albuminexcretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. Results: HbA1c-reductions were similar with exenatide (mean +/- SEM -0.80 +/- 0.10%) and iGlar (-0.79 +/- 0.14%; treatment-difference 0.02%; 95% CI - 0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P <0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 +/- 2.1 mL/min/1.73 m(2); P = 0.069) and iGlar (-2.7 +/- 1.2 mL/min/1.73 m(2); P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P <0.001), but did not affect blood pressure, lipids or plasma uric acid. Conclusions: Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar. (C) 2019 Elsevier B.V. All rights reserved.
  • Gordin, Daniel; Saraheimo, Markku; Tuomikangas, Jaana; Soro-Paavonen, Aino; Forsblom, Carol; Paavonen, Karri; Steckel-Hamann, Birgit; Harjutsalo, Valma; Nicolaou, Loizos; Pavo, Imre; Koivisto, Veikko; Groop, Per-Henrik (2019)
    Aims Insulin possesses both vasodilatory and sympathomimetic activities. The aim was to examine the relationship between changes in insulin exposure and arterial stiffness in type 2 diabetes (T2D). Methods Patients with T2D with (n = 22) or without (n = 24) albuminuria, and non-diabetic controls (n = 25) were randomized to a crossover study having a breakfast with or without pre-meal rapid-acting insulin. Pulse wave velocity (PWV) was measured at 30 min before and at 60-min intervals up to 240 min after the breakfast. Results At baseline, both postprandial aortic (p = 0.022) and brachial (p = 0.011) PWV were higher in individuals with T2D than in healthy controls irrespective of the presence of albuminuria. In patients with albuminuria, weight-adjusted insulin dose correlated inversely with the excursion of the aortic (r = - 0.412, p = 0.006) and brachial (r = - 0.372; p = 0.014) PWV. Similarly, circulating endogenous insulin concentrations correlated inversely with the aortic (r = - 0.347, p = 0.026) and brachial (r = - 0.622, p =
  • Barlovic, Drazenka Pongrac; Tikkanen-Dolenc, Heidi; Groop, Per-Henrik (2019)
    Purpose of Review Physical activity is a fundamental part of lifestyle management in diabetes care. Although its benefits are very well recognized in the general population and in people with type 2 diabetes, much less is known about the effects of exercise in type 1 diabetes. In particular, exercise effects in relation to diabetic kidney disease (DKD) are understudied. Some uncertainties about physical activity recommendations stem from the fact that strenuous exercise may worsen albuminuria immediately after the activity. However, in middle-aged and older adults without diabetes, observational studies have suggested that physical activity is associated with a decreased risk of rapid kidney function deterioration. In this review, we focus on the role of physical activity in patients with DKD and type 1 diabetes.\ Recent Findings Hereby, we present data that show that in individuals at risk of DKD or with established DKD, regular moderate-to-vigorous physical activity was associated with reduced incidence and progression of DKD, as well as reduced risk of cardiovascular events and mortality. Summary Therefore, regular moderate-to-vigorous exercise should become a central part of the management of individuals with type 1 diabetes, in the absence of contraindications and accompanied with all needed educational support for optimal diabetes management.
  • Finndiane Study Grp; Pongrac Barlovic, Drazenka; Harjutsalo, Valma; Sandholm, Niina; Forsblom, Carol; Groop, Per-Henrik (2020)
    Aims/hypothesis Lipid abnormalities are associated with diabetic kidney disease and CHD, although their exact role has not yet been fully explained. Sphingomyelin, the predominant sphingolipid in humans, is crucial for intact glomerular and endothelial function. Therefore, the objective of our study was to investigate whether sphingomyelin impacts kidney disease and CHD progression in individuals with type 1 diabetes. Methods Individuals (n = 1087) from the Finnish Diabetic Nephropathy (FinnDiane) prospective cohort study with serum sphingomyelin measured using a proton NMR metabolomics platform were included. Kidney disease progression was defined as change in eGFR or albuminuria stratum. Data on incident end-stage renal disease (ESRD) and CHD were retrieved from national registries. HRs from Cox regression models and regression coefficients from the logistic or linear regression analyses were reported per 1 SD increase in sphingomyelin level. In addition, receiver operating curves were used to assess whether sphingomyelin improves eGFR decline prediction compared with albuminuria. Results During a median (IQR) 10.7 (6.4, 13.5) years of follow-up, sphingomyelin was independently associated with the fastest eGFR decline (lowest 25%; median [IQR] for eGFR change:
  • Esposito, Pasquale; Mereu, Roberto; De Barbieri, Giacomo; Rampino, Teresa; Di Toro, Alessandro; Groop, Per-Henrik; Dal Canton, Antonio; Bernardi, Luciano (2016)
    Cardiovascular autonomic dysfunction, evaluated as baroreflex sensitivity (BRS), could be acutely corrected by slow breathing or oxygen administration in patients with type 1 diabetes, thus suggesting a functional component of the disorder. We tested this hypothesis in patients with the type 2 diabetes with or without renal impairment. Twenty-six patients with type 2 diabetes (aged 61.0 +/- A 0.8 years, mean +/- A SEM; duration of diabetes 10.5 +/- A 2 years, BMI 29.9 +/- A 0.7 kg/m(2), GFR 68.1 +/- A 5.6 ml/min) and 24 healthy controls (aged 58.5 +/- A 1.0 years) were studied. BRS was obtained from recordings of RR interval and systolic blood pressure fluctuations during spontaneous and during slow, deep (6 breaths/min) controlled breathing in conditions of normoxia or hyperoxia (5 l/min oxygen). During spontaneous breathing, diabetic patients had lower RR interval and lower BRS compared with the control subjects (7.1 +/- A 1.2 vs. 12.6 +/- A 2.0 ms/mmHg, p <0.025). Deep breathing and oxygen administration significantly increased arterial saturation, reduced RR interval and increased BRS in both groups (to 9.6 +/- A 1.8 and 15.4 +/- A 2.4 ms/mmHg, respectively, p <0.05, hyperoxia vs. normoxia). Twelve diabetic patients affected by chronic diabetic kidney disease (DKD) presented a significant improvement in the BRS during slow breathing and hyperoxia (p <0.025 vs. spontaneous breathing during normoxia). Autonomic dysfunction present in patients with type 2 diabetes can be partially reversed by slow breathing, suggesting a functional role of hypoxia, also in patients with DKD. Interventions known to relieve tissue hypoxia and improve autonomic function, like physical activity, may be useful in the prevention and management of complications in patients with diabetes.