Variants in HSD11B1 gene modulate susceptibility to diabetes kidney disease and to insulin resistance in type 1 diabetes.

BACKGROUND AND AIM: 11ß-Hydroxysteroid dehydrogenase 1 has been implicated in insulin resistance (IR) in the setting of metabolic disorders, and single nucleotide polymorphisms (SNPs) in its encoding gene (HSD11B1) have been associated with type 2 diabetes and metabolic syndrome. In type 1 diabetes (T1D), IR has been related to the development of chronic complications. We investigated the association of HSD11B1 SNPs with microvascular complications and with IR in a Brazilian cohort of T1D individuals. MATERIALS AND METHODS: Five SNPs were genotyped in 466 T1D individuals (57% women; median of 37 years old, diabetes duration of 25 years and HbA1c of 8.4%). RESULTS: The minor allele T of rs11799643 was nominally associated with diabetic retinopathy (OR = 0.52; confidence interval [CI] 95% = 0.28-0.96; P = .036). The minor allele C of rs17389016 was nominally associated with overt diabetic kidney disease (DKD) (OR = 1.90; CI 95% = 1.07-3.37; P = .028). A follow-up study revealed that 29% of the individuals lost ≥5 mL min-1 × 1.73 m2 per year of the estimated glomerular filtration rate (eGFR). In these individuals (eGFR decliners), C allele of rs17389016 was more frequent than in non-decliners (OR = 2.10; CI 95% = 1.14-3.89; P = .018). Finally, minor allele T of rs846906 associated with higher prevalence of arterial hypertension, higher body mass index and waist circumference, thus conferring risk to a lower estimated glucose disposal rate, a surrogate marker of insulin sensitivity (OR = 1.23; CI 95% = 1.06-1.42; P = .004). CONCLUSION: SNPs in the HSD11B1 gene may confer susceptibility to DKD and to IR in T1D individuals.

Rs4862705 in the melatonin receptor 1A gene is associated with renal function decline in type 1 diabetes individuals.

Aim: The pathogenesis of chronic diabetes complications has oxidative stress as one of the major elements, and single-nucleotide polymorphisms (SNPs) in genes belonging to antioxidant pathways modulate susceptibility to these complications. Considering that melatonin is a powerful antioxidant compound, our aim was to explore, in a longitudinal cohort study of type 1 diabetes (T1D) individuals, the association of microvascular complications and SNPs in the gene encoding melatonin receptor 1A (MTNR1A). Methods: Eight SNPs in MTNR1A were genotyped in 489 T1D individuals. Besides cross-sectional analyses of SNPs with each one of the microvascular complications (distal polyneuropathy, cardiovascular autonomic neuropathy, retinopathy, and diabetic kidney disease), a longitudinal analysis evaluated the associations of SNPs with renal function decline in 411 individuals followed up for a median of 8 years. In a subgroup of participants, the association of complications with urinary 6-sulfatoxymelatonin (aMT6s) concentration was investigated. Results: The group of individuals with a renal function decline ≥ 5 mL min-1 1.73 m-2 year-1 presented a higher frequency of the A allele of rs4862705 in comparison with nondecliners, even after adjustment for confounding variables (OR = 1.84, 95% CI = 1.20-2.82; p = 0.0046). No other significant associations were found. Conclusions: This is the first study showing an association between a variant in a gene belonging to the melatonin system and renal function decline in the diabetic setting.

Distal Symmetric and Cardiovascular Autonomic Neuropathies in Brazilian Individuals with Type 2 Diabetes Followed in a Primary Health Care Unit: A Cross-Sectional Study.

The paucity of epidemiological data regarding diabetes complications in Brazil motivated us to evaluate the prevalence rates of distal symmetric polyneuropathy (DSP) and of cardiovascular autonomic neuropathy (CAN) in individuals with type 2 diabetes (T2D) followed in a primary care unit. A total of 551 individuals (59.3% women, 65 years old; diabetes duration of 10 years; HbA1c of 7.2%, medians) were included in this cross-sectional study. DSP was diagnosed by sum of the Neuropathy Symptoms Score (NSS) and Modified Neuropathy Disability Score (NDS) and by the Semmes-Weinstein monofilament. CAN was diagnosed by cardiovascular autonomic reflex tests combined with spectral analysis of heart rate variability. The prevalence rates of DSP were 6.3% and 14.3%, as evaluated by the sum of NSS and NDS and by the Semmes-Weinstein monofilament, respectively. Those with DSP diagnosed by monofilament presented longer diabetes duration, worse glycemic control and a higher stature. The prevalence rates of incipient and definitive CAN were 12.5% and 10%, respectively. Individuals with definitive CAN presented a higher frequency of hypercholesterolemia and of arterial hypertension. The higher prevalence rate of DSP with the use of the monofilament suggests that it may be a more appropriate tool to diagnose DSP in the primary care setting in Brazil.

Allelic variations in genes belonging to glutathione system increase proliferative retinopathy risk in type 1 diabetes individuals.

AIMS: Given the participation of oxidative stress in the pathogenesis of diabetic complications, we evaluated, in type 1 diabetes (T1D) individuals, the association between diabetic retinopathy (DR) and functional single nucleotide polymorphisms (SNPs) in regulatory regions of two genes belonging to the antioxidant glutathione (GSH) system: rs17883901 in GCLC and rs713041 in GPX4. METHODS: A cross-sectional case-control study included 288 individuals (61% women, 34[±11] years old, diabetes duration of 22[±9] years, mean [±SD]) sorted according to DR stages: absence of DR (ADR), non-proliferative DR (NPDR) and proliferative DR (PDR). SNPs were genotyped by real-time PCR using fluorescent labelled probes. Logistic regression models with adjustment for confounding covariates were employed. RESULTS: The presence of at least one T-allele of rs17883901 in GCLC was an independent risk factor for PDR (OR 4.13, 95% CI 1.38-13.66, p = 0.014) in a polytomous regression model (PDR versus ADR). The presence of at least one T-allele of rs713041 in GPX4 conferred protection against PDR (OR 0.30, 95% CI 0.11-0.80, p = 0.017) in female T1D individuals. CONCLUSION: The functional SNPs rs17883901 and rs713041 modulate the risk for PDR in the studied population of T1D individuals, widening the spectrum of candidate genes for this complication.

Identification and performance of multiple clinical and laboratorial risk factors for diagnosis of cardiac autonomic neuropathy in type 1 diabetes patients.

PURPOSE: The incidence of cardiac autonomic neuropathy (CAN) in patients with type 1 diabetes (T1D) is frequently underestimated. Individuals with T1D and CAN have an increased mortality risk, mainly from cardiovascular causes. The objectives of the present study were to assess the clinical and laboratory characteristics associated with CAN in patients with T1D and verify the ability of multiple clinical factors to help identify patients with this condition. METHODS: 102 patients with T1D were evaluated for CAN using standardized cardiovascular reflex testing. Clinical characteristics were used to compute a numerical score for CAN diagnosis and a ROC curve elaborated for assessment of the best cutoff to predict CAN. This score was then applied to the second sample of 120 patients. The sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: Prevalence of CAN was around 35% in the first sample of patients and just below 20% in the second sample. Hypertension, total cholesterol, triglycerides, postprandial sweating, diastolic blood pressure, abnormal right and left 10 g monofilament, retinopathy, and nephropathy were considered independent predictors of CAN. The CAN-score cut-off was 16.88. This yielded a sensitivity of 50%, specificity 73.8%, positive predictive value 22.9%, and negative predictive value 90.5%. CONCLUSION: The use of a subset of clinical and laboratory characteristics can be more accessible than the cardiac reflex tests and more accurate than a single isolated characteristic.

Genetic variants in DNMT1 and the risk of cardiac autonomic neuropathy in women with type 1 diabetes.

AIMS/INTRODUCTION: Epigenetics participate in the pathogenesis of metabolic memory, a situation in which hyperglycemia exerts prolonged deleterious effects even after its normalization. We tested the hypothesis that genetic variants in an epigenetic gene could predispose to diabetes complications. MATERIAL AND METHODS: We assessed the frequency of five single-nucleotide polymorphisms in the gene encoding deoxyribonucleic acid methytransferase 1 (DNMT1; rs8112895, rs7254567, rs11085721, rs17291414 and rs10854076), and their associations with diabetic kidney disease, retinopathy, distal polyneuropathy and autonomic cardiovascular neuropathy in 359 individuals with long-term type 1 diabetes. RESULTS: None of the single-nucleotide polymorphisms studied was significantly associated with the presence of chronic complications in the overall population. However, after sex stratification, the minor allele C of rs11085721 conferred risk for cardiovascular neuropathy in women after adjustment for confounding variables (odds ratio 2.32; 95% confidence interval 1.26-4.33; P = 0.006). CONCLUSIONS: The fact that heterozygous mutations in DNMT1 are associated with hereditary sensory autonomic neuropathy provides plausibility to the present finding. If confirmed in independent samples, it suggests that genetic variants in epigenetic genes might predispose to more or fewer epigenetic changes in the face of similar metabolic derangements triggered by hyperglycemia, constituting the "genetics of epigenetics" for microvascular diabetes complications.

Glutathione peroxidase 4 functional variant rs713041 modulates the risk for cardiovascular autonomic neuropathy in individuals with type 1 diabetes.

Cardiac autonomic neuropathy is a neglected diabetic chronic complication for which genetic predictors are rarely reported. Oxidative stress is implicated in the pathogenesis of microvascular complications, and glutathione peroxidase 4 is involved in the detoxification of peroxides and of reactive oxygen species. Thus, the association of a functional variant in the gene encoding glutathione peroxidase 4 (rs713041) with this diabetic complication was investigated in 341 individuals with type 1 diabetes evaluated for cardiac autonomic neuropathy status (61.7% women, 34 [27-42] years old; diabetes duration: 21 [15-27] years; HbA1c: 8.3% [7.4-9.4]; as median [interquartile interval]). Cardiac autonomic neuropathy was present in 29% of the participants. There was an inverse association of the minor T allele of rs713041 with cardiac autonomic neuropathy (odds ratio = 0.39; 95% confidence interval = 0.17-0.90; p = 0.0271) after adjustment for potential confounders. The functional glutathione peroxidase 4 variant rs713041 modulated the risk for cardiac autonomic neuropathy in the studied population with type 1 diabetes.

Thioredoxin interacting protein expression in the urinary sediment associates with renal function decline in type 1 diabetes.

AIMS: Thioredoxin interacting protein (TXNIP), an inhibitor of antioxidant thioredoxin (Trx), is upregulated by hyperglycemia and implicated in pathogenesis of diabetes complications. We evaluated mRNA expressions of genes encoding TXNIP and Trx (TXN) in urinary sediment and peripheral blood mononuclear cells (PBMC) of type 1 diabetes (T1D) patients with different degrees of chronic complications. METHODS: qPCR was employed to quantify target genes in urinary sediment (n = 55) and PBMC (n = 161) from patients sorted by presence or absence of diabetic nephropathy (DN), retinopathy, peripheral and cardiovascular neuropathy; 26 healthy controls and 13 patients presenting non-diabetic nephropathy (focal and segmental glomerulosclerosis, FSGS) were also included. RESULTS: Regarding the urinary sediment, TXNIP (but not TXN) expression was higher in T1D (p = 0.0023) and FSGS (p = 0.0027) patients versus controls. Expressions of TXNIP and TXN were higher, respectively, in T1D patients with versus without DN (p = 0.032) and in those with estimated glomerular filtration rate (eGFR) < 60 versus ≥60 mL/min/1.73 m(2) (p = 0.008). eGFR negatively correlated with TXNIP (p = 0.04, r = -0.28) and TXN (p = 0.04, r = -0.30) expressions. T1D patients who lost ≥5 mL/min/1.73 m(2) yearly of eGFR presented higher basal TXNIP expression than those who lost <5 mL/min/1.73 m(2) yearly after median follow-up of 24 months. TXNIP (p < 0.0001) and TXN (p = 0.002) expressions in PBMC of T1D patients were significantly higher than in controls but no differences were observed between patients with or without chronic complications. CONCLUSIONS: TXNIP and TXN are upregulated in urinary sediment of T1D patients with diabetic kidney disease (DKD), but only TXNIP expression is associated with magnitude of eGFR decline.

New digital tool to facilitate subcutaneous insulin therapy orders: an inpatient insulin dose calculator.

BACKGROUND: Inpatient hyperglycemia is associated with adverse outcomes in hospitalized patients, with or without known diabetes. The adherence to American College of Endocrinology and American Diabetes Association guidelines recommendations for inpatient glycemic control is still poor, probably because of their complexity and fear of hypoglycemia. OBJECTIVE: To create software system that can assist health care providers and hospitalists to manage the insulin therapy orders and turn them into a less complicated issue. METHODS: A software system was idealized and developed, according to recommendations of major consensus and medical literature. RESULTS: HTML software was developed to be readily accessed from a workstation, tablet or smartphone. Standard initial daily total dose of insulin was 0.4 units/kg and could be modified by distinct factors, such as chronological age, renal and liver function, and high dose corticosteroids use. Insulin therapy consisted of basal, prandial and correction insulin according to nutritional support, glycemic control and outpatient treatment for diabetes. Human insulin or insulin analogues could be options for insulin therapy. Sensitivity factor was based on 1800 Rule for rapid-acting insulin and the 1500 Rule for short-acting insulin. Insulin-naïve patients with initial BG level less than 250 mg/dL were considered to have an initial step-wise approach with prandial and correction insulin. The calculator system has allowed insulin dose readjustments periodically, according to daily average blood glucose measurements. CONCLUSION: We developed software that can be a useful tool for all public hospitals, where generally human insulin is the only available.