-
1.
The FTO variant is associated with chronic complications of diabetes mellitus in Czech population.
Hubacek, JA, Dlouha, D, Klementova, M, Lanska, V, Neskudla, T, Pelikanova, T
Gene. 2018;:220-224
Abstract
BACKGROUND Genome-wide association studies have resulted in the identification of the FTO gene as an important genetic determinant of diabetes mellitus. The aim of this study was to confirm the role of this gene in the development of DM in the Czech-Slavonic population and to analyse whether this gene is associated with common DM complications. METHODS Two groups of patients (814 with T1DM and 848 with T2DM) and a group of healthy controls (2339 individuals) - both of Czech origin - were genotyped for the FTO rs17817449 SNP. ANOVA and logistic regression were used for the statistical evaluations. RESULTS The frequency of the GG genotype was significantly higher in T2DM (25.4% vs. 16.7%, P<0.0005) but not in T1DM patients (19.3% vs. 16.7%, P=0.20) than in controls. The increased risk of development of diabetic nephropathy was observed both for T1DM patients (GG vs. TT homozygotes, P<0.01) and T2DM patients (G carriers vs. TT homozygotes, P<0.05). FTO genotype predicted the development of diabetic neuropathy (GG vs. TT comparison; P<0.01) in the T2DM patients only. No association between FTO genotype and development of retinopathy was detected. All presented values are after adjustment for age, sex, BMI and duration of diabetes. CONCLUSIONS We confirm the association between the FTO rs17817449 SNP and susceptibility to T2DM in the Czech-Slavonic population. The same variant is associated with a spectrum of chronic complications in both types of diabetes.
-
2.
[The mechanisms and clinical potential: sodium-glucose cotransporter 2 (SGLT-2) inhibitors treating diabetic kidney disease].
Wang, YJ, Hao, CM
Sheng li xue bao : [Acta physiologica Sinica]. 2018;(6):663-669
Abstract
The employment of sodium-glucose cotransporter 2 (SGLT-2) inhibitors in the treatment of diabetes mellitus and diabetic kidney disease (DKD) becomes a hot topic in recent years. Compared with traditional glucose-lowering drugs, SGLT-2 inhibitors present distinctive advantages in renal and cardiovascular protection. The mechanisms for renal protection include attenuating glomerular hyperfiltration, lowering serum uric acid, alleviating tubular lesions and regulating intrarenal renin-angiotensin-aldosterone system (RAAS) dysfunction. In addition, the lowering blood pressure, blunting blood glucose fluctuation, increasing insulin sensitivity, optimizing energy metabolism and body fat distribution account for the cardiovascular protective effects of SGLT-2 inhibitors. However, their potential adverse reactions and safety concerns should be carefully addressed in clinical usage.
-
3.
Managing diabetic kidney disease.
Zac-Varghese, S, Winocour, P
British medical bulletin. 2018;(1):55-66
Abstract
INTRODUCTION Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD). This review covers the pillars of care essential for the management of diabetic kidney disease (DKD) including (1) early diagnosis, (2) improved glycaemic control, (3) treatment of hypertension, (4) identification and treatment of associated metabolic bone disease and (5) identification and effective management of dyslipidaemia and additional cardiovascular risk factors. SOURCES OF DATA We searched PubMed for articles using search terms: diabetic nephropathy, diabetic kidney disease, diabetes and chronic kidney disease. We used clinical guidelines from NICE, the Association of British Clinical Diabetologists (ABCD), the Joint British Societies (JBS) and the Kidney Disease: Improving Global Outcomes (KDIGO) working group. AREAS OF AGREEMENT Multiple risk factor reduction targeting glycaemic control, blood pressure control, dyslipidaemia, smoking and management of obesity is important in preventing and in managing DKD. AREAS OF CONTROVERSY Guidelines disagree on the individualized glycaemic targets for patients with diabetic kidney disease. GROWING POINTS The growing number of patients with DKD is causing increased pressure on limited primary care and specialized services. New ways of managing patients using novel technology solutions are required. AREAS TIMELY FOR DEVELOPMENT The use of novel anti-hyperglycaemic agents, particularly sodium glucose co-transporter 2 inhibitors and GLP-1 receptor agonists, has been associated with a reduction in cardiovascular disease and DKD.
-
4.
Managing the Course of Kidney Disease in Adults With Type 2 Diabetes: From the Old to the New.
Goldenberg, RM, Berall, M, Chan, CTM, Cherney, DZI, Lovshin, JA, McFarlane, PA, Senior, PA, Verma, S, Weinstein, JJ
Canadian journal of diabetes. 2018;(3):325-334
Abstract
Diabetic kidney disease (DKD) is a group of chronic kidney diseases that is associated with significant cardiovascular as well as all-cause morbidity and mortality. Although DKD is often progressive in nature, its evolution can be modified by intensive management of glycemia and blood pressure and inhibition of the renin-angiotensin-aldosterone system. This review provides an overview of how multifactorial interventions can provide renal protection and includes a discussion of the nonglycemic effects of incretin-based diabetes therapies (glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors) and sodium-glucose cotransporter-2 inhibitors within the kidney in patients with type 2 diabetes.
-
5.
The Relationship between Generalized and Abdominal Obesity with Diabetic Kidney Disease in Type 2 Diabetes: A Multiethnic Asian Study and Meta-Analysis.
Man, REK, Gan, ATL, Fenwick, EK, Gupta, P, Wong, MYZ, Wong, TY, Tan, GSW, Teo, BW, Sabanayagam, C, Lamoureux, EL
Nutrients. 2018;(11)
Abstract
This study examined the associations of body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR) and waist-height ratio (WHtR) with diabetic kidney disease (DKD) in a clinical sample of Asian patients with type 2 diabetes (T2DM); substantiated with a meta-analysis of the above associations. We recruited 405 patients with T2DM (mean (standard deviation (SD)) age: 58 (7.5) years; 277 (68.4%) male; 203 (50.1%) with DKD) from a tertiary care centre in Singapore. DKD was defined as urinary albumin-creatinine ratio >3.3 mg/mmoL and/or estimated glomerular filtration rate <60 mL/min/1.73 m². All exposures were analysed continuously and categorically (World Health Organization cut-points for BMI and WC; median for WHR and WHtR) with DKD using stepwise logistic regression models adjusted for traditional risk factors. Additionally, we synthesized the pooled odds ratio of 18 studies (N = 19,755) in a meta-analysis of the above relationships in T2DM. We found that overweight and obese persons (categorized using BMI) were more likely to have DKD compared to under/normal weight individuals, while no associations were found for abdominal obesity exposures. In meta-analyses however, all obesity parameters were associated with increased odds of DKD. The discordance in our abdominal obesity findings compared to the pooled analyses warrants further validation via longitudinal cohorts.
-
6.
Effects of High-dose Vitamin E Supplementation on Markers of Cardiometabolic Risk and Oxidative Stress in Patients with Diabetic Nephropathy: a Randomized Double-blinded Controlled Trial.
Aghadavod, E, Soleimani, A, Hamidi, G, Keneshlou, F, Heidari, A, Asemi, Z
Iranian journal of kidney diseases. 2018;(3):156-162
Abstract
INTRODUCTION Patients with diabetic nephropathy (DN) may benefit from vitamin E's antilipid and antioxidant activities. This study aimed to evaluate the effects of high-dose vitamin E supplementation on markers of cardiometabolic risk and oxidative stress in patients with DN. MATERIALS AND METHODS This randomized controlled trial was carried out on 54 patients with DN that were randomly divided into 2 groups to receive vitamin E supplement (800 IU/d) or placebo for 12 weeks. Fasting blood samples were obtained at baseline and after the 12-week intervention to determine markers of cardiometabolic risk and oxidative stress. RESULTS Vitamin E supplementation, compared with the placebo, resulted in a significant reduction in serum total cholesterol (-14.3 ± 29.9 mg/dL versus -0.8 ± 13.1 mg/L, P = .03), low-density lipoprotein cholesterol (-16.4 ± 28.5 mg/dL versus 0.1 ± 17.2 mg/L, P = .01), and ratio of total cholesterol to high-density lipoprotein cholesterol ratio (-0.5 ± 0.7 versus 0.1 ± 0.5, P = .001), and a significant elevation in vitamin E levels (39.7 ± 12.4 nmol/mL versus -0.5 ± 1.3 nmol/mL, P < .001) and high-density lipoprotein cholesterol levels (1.4 ± 3.7 versus -2.1 ± 5.1 mg/L, P = .006). It also resulted in a significant elevation in plasma glutathione levels. CONCLUSIONS Our study demonstrated that high-dose vitamin E supplementation for 12 weeks had favorable effects on lipid profile and glutathione levels of patients with DN, except for triglycerides, very low-density lipoprotein cholesterol, nitric oxide, and total antioxidant capacity levels.
-
7.
AGE Content of a Protein Load Is Responsible for Renal Performances: A Pilot Study.
Normand, G, Lemoine, S, Villien, M, Le Bars, D, Merida, I, Irace, Z, Troalen, T, Costes, N, Juillard, L
Diabetes care. 2018;(6):1292-1294
Abstract
OBJECTIVE Chronic kidney disease is associated with higher morbidity and mortality in patients with diabetes. A low-protein diet is recommended to slow diabetic nephropathy progression because each protein load leads to renal hemodynamic variations. The aim of our study was to evaluate whether the advanced glycation end products (AGE) content of a protein load is responsible for the protein-induced renal hemodynamic variations in humans. RESEARCH DESIGN AND METHODS Ten healthy subjects were assigned to a high-protein (1 g/kg) low-AGE (3,000 kU AGE) versus high-AGE (30,000 kU AGE) meal. Renal perfusion, oxygen consumption, and oxygen content were measured before and 120 min after each meal. RESULTS Renal perfusion (3.2 ± 0.5 vs. 3.8 ± 0.4 mL/min/g; P = 0.0002) and oxygen consumption (0.3 ± 0.04 vs. 0.4 ± 0.08 min-1; P = 0.005) increased significantly after the high-AGE meal compared with the low-AGE meal. CONCLUSIONS Our results suggest that the AGE content of a protein load is responsible for renal hemodynamic modifications. Therefore, prevention of diabetic nephropathy progression could aim predominantly at reducing food AGE content.
-
8.
A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.
Taira, M, Imamura, M, Takahashi, A, Kamatani, Y, Yamauchi, T, Araki, SI, Tanaka, N, van Zuydam, NR, Ahlqvist, E, Toyoda, M, et al
PloS one. 2018;(12):e0208654
Abstract
To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10(-4)) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10(-10). We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10(-10)). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.
-
9.
Precision medicine in diabetes and diabetic kidney disease: Regulatory considerations.
Mol, PGM, Thompson, A, Heerspink, HJL, Leufkens, HGM
Diabetes, obesity & metabolism. 2018;(Suppl Suppl 3):19-23
-
-
Free full text
-
Abstract
Over the past 15 years, three new classes of drugs, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium glucose cotransporter-2 (SGLT-2) inhibitors have been approved to treat type 2 diabetes based on effects on glycemic control. Although large randomized controlled trials have played an important role in characterizing the efficacy and safety of these agents on a population level, questions remain about how best to individualize therapy and target the "right" medicine to the "right" patient. In contrast, few medicines have been approved to treat diabetic kidney disease and initiatives have been launched on both sides of the Atlantic to facilitate the development of effective personalized medicines for the treatment of diabetic kidney disease. Increasingly, "omics," imaging and other biomarkers will be used to match patients with therapies to which they are likely to respond best. This review addresses regulatory considerations related to precision medicine, draws lessons learned from other therapeutic areas and discusses efforts undertaken by the European (EMA) and United States (FDA) to facilitate the development of such therapies. Moving forward, an integrated approach that makes use of predictive preclinical models, innovative trial designs, observational "real-world" data and novel statistical methodologies will likely be needed to complement inherently smaller RCTs conducted in more selected populations. Patient involvement will also be critical. Regulatory agencies are ready to engage in such approaches.
-
10.
Sodium-glucose Cotransporter 2 Inhibitors: Nephroprotective Impact on Diabetic Kidney Disease.
Stavropoulos, K, Imprialos, KP, Stavropoulos, N, Bouloukou, S, Kerpiniotis, G, Dimitriadis, K, Tsioufis, C, Doumas, M
Cardiovascular & hematological disorders drug targets. 2018;(2):120-126
Abstract
BACKGROUND Diabetic nephropathy is a crucial microvascular complication of diabetes mellitus that is associated with elevated cardiovascular risk. SGLT-2 inhibitors are a new class of hypoglycemic drugs that positively affect several risk factors of cardiorenal damage. OBJECTIVES The study aimed to review and critically discuss available data on the association of SGLT-2 inhibitors treatment with kidney function, progress of diabetic kidney disease, and renal related outcomes, as well to unveil potential mechanisms of action that mediate such effects. METHOD We conducted a comprehensive search of the literature on the renal related effects of SGLT-2 inhibitors, to compose a narrative mini-review. RESULTS The administration of SGLT-2 inhibitors was observed to exert beneficial effects on a wide cluster of risk factors of chronic kidney disease, such as hyperglycemia, blood pressure, serum uric acid, and body weight. Data from the first two large, randomized, clinical trials of SGLT-2 inhibitors conducted to address the renal related outcomes of SGLT-2 inhibitors suggest substantial benefits on estimated glomerular filtration rate decline and albuminuria. CONCLUSION The initial data suggest clinically meaningful benefits of the SGLT-2 inhibitors in diabetic patients in relevance with chronic kidney disease. Future, well-designed randomised clinical trials need to be further investigated such as nephroprotective outcomes, that if confirmed, could lead to new perspectives in the management of diabetic nephropathy.