Genetics, clinical features and outcomes of non-syndromic pituitary gigantism: experience of a single center from Sao Paulo, Brazil.

PURPOSE: Non-syndromic pituitary gigantism (PG) is a very rare disease. Aryl hydrocarbon receptor-interacting protein (AIP) and G protein-coupled receptor 101 (GPR101) genetic abnormalities represent important etiologic causes of PG and may account for up to 40% of these cases. Here, we aimed to characterize the clinical and molecular findings and long-term outcomes in 18 patients (15 males, three females) with PG followed at a single tertiary center in Sao Paulo, Brazil. METHODS: Genetic testing for AIP and GPR101 were performed by DNA sequencing, droplet digital PCR and array comparative genomic hybridization (aCGH). RESULTS: Pathogenic variants in the AIP gene were detected in 25% of patients, including a novel variant in splicing regulatory sequences which was present in a sporadic male case. X-LAG due to GPR101 microduplication was diagnosed in two female patients (12.5%). Of interest, these patients had symptoms onset by age 5 and 9 years old and diagnosis at 5 and 15 years, respectively. X-LAG, but not AIP, patients had a significantly lower age of symptoms onset and diagnosis and a higher height Z-score when compared to non-X-LAG. No other differences in clinical features and/or treatment outcomes were observed among PG based on their genetic background. CONCLUSION: We characterize the clinical and molecular findings and long-term outcome of the largest single-center PG cohort described so far.

A pilot study of a Community Health Agent-led type 2 diabetes self-management program using Motivational Interviewing-based approaches in a public primary care center in São Paulo, Brazil.

BACKGROUND: Rates of noncommunicable diseases (NCDs) such as type 2 diabetes are escalating in low and middle-income countries such as Brazil. Scalable primary care-based interventions are needed to improve self-management and clinical outcomes of adults with diabetes. This pilot study examines the feasibility, acceptability, and outcomes of training community health agents (CHAs) in Motivational Interviewing (MI)-based counseling for patients with poorly controlled diabetes in a primary care center in São Paulo, Brazil. METHODS: Nineteen salaried CHAs participated in 32 h of training in MI and behavioral action planning. With support from booster training sessions, they used these skills in their regular monthly home visits over a 6 month period with 57 diabetes patients with baseline HbA1cs > 7.0%. The primary outcome was patients' reports of the quality of diabetes care as measured by the Portuguese version of the Patient Assessment of Chronic Illness Care (PACIC) scale. Secondary outcomes included changes in patients' reported diabetes self-management behaviors and in A1c, blood pressure, cholesterol and triglycerides. We also examined CHAs' fidelity to and experiences with the intervention. RESULTS: Patients reported improvements over the 6 month period in quality of diabetes care received (PACIC score improved 33 (+/-19) to 68 (+/-21) (p < .001)). They reported increases in physical activity (p = .001), consumption of fruits and vegetables (p < .001) and medication adherence (p = .002), but no decreases in consumption of high-fat foods (p = .402) or sweets (p = .436). Participants had mean 6-month A1c levels 0.34% points lower than at baseline (p = .08) and improved mean LDL (-16.1 mg/dL, p = .005) and triglyceride levels (-38.725 mg/dL, p = .002). Of the 16 CHAs observed in fidelity assessments, 13 were categorized as medium- or high-performing on MI skills, while 3 were low-performing. CHAs expressed enthusiasm about learning new skills, and many described a shift from advice-giving to encouraging patients to define their own goals. CONCLUSION: In resource-scarce settings, it is essential to fully utilize existing primary care resources to stem the epidemic of diabetes and other NCDs. Our pilot results support the potential of training CHAs to incorporate effective diabetes self-management support into their routine patient encounters. TRIAL REGISTRATION: NCT02994095 12/14/2016 Registered retrospectively.

Children and adolescents living with diabetes and celiac disease. / Crianças e adolescentes que convivem com diabetes e doença celíaca.

Objective To understand the experience of children and adolescents living with type 1 diabetes and celiac disease. Method This is a qualitative exploratory-descriptive study. The participants were 3 children and 2 adolescents. The data were collected by means of semi-structured interviews between January and September 2012 at the participant's residence or at the diabetic outpatient clinic of the Hospital das Clinicas, Faculty of Medicine, University of Sao Paulo in São Paulo, Brazil. The content analysis technique was used to process the data. Results The key aspect of the illness experience of the patients was their diet, but with different meanings. The children had difficulty following the diet, while the adolescents reported that they had greater difficulty coping with the social and affective aspects of their diet. Conclusion The results reinforce the importance of nurses who seek strategies, together with the patients and their families, that help minimize the difficulties of these patients, especially with regard to managing the diet imposed by both diseases.

Relationship between adherence to diet, glycemic control and cardiovascular risk factors in patients with type 1 diabetes: a nationwide survey in Brazil.

BACKGROUND: To determine the relationship between adherence to the diet reported by patients with type 1 diabetes under routine clinical care in Brazil, and demographic, socioeconomic status, glycemic control and cardiovascular risk factors. METHODS: This was a cross-sectional, multicenter study conducted between December 2008 and December 2010 in 28 public clinics in 20 Brazilian cities. The data was obtained from 3,180 patients, aged 22 ± 11.8 years (56.3% females, 57.4% Caucasians and 43.6% non-Caucasians). The mean time since diabetes diagnosis was 11.7 ± 8.1 years. RESULTS: Overall, 1,722 (54.2%) of the patients reported to be adherent to the diet without difference in gender, duration of diabetes and socioeconomic status. Patients who reported adherence to the diet had lower BMI, HbA1c, triglycerides, LDL-cholesterol, non HDL-cholesterol and diastolic blood pressure and had more HbA1c at goal, performed more frequently self-monitoring of blood glucose (p < 0.001), and reported less difficulties to follow specific schedules of diet plans (p < 0.001). Less patients who reported to be adherent were obese or overweight (p = 0.005). The quantity of food and time schedule of the meals were the most frequent complaints. Logistic regression analysis showed that ethnicity, (Caucasians, (OR 1.26 [1.09-1.47]), number of medical clinical visits in the last year (OR 1.10 [1.06-1.15]), carbohydrate counting, (OR 2.22 [1.49-3.30]) and diets recommended by diabetes societies', (OR 1.57 [1.02-2.41]) were related to greater patients' adherence (p < 0.05) and age, [adolescents (OR 0.60 [0.50-0.72]), high BMI (OR 0.58 [0.94-0.98]) and smoking (OR 0.58 [0.41-0.84]) with poor patients' adherence (p < 0.01). CONCLUSIONS: Our results suggest that it is necessary to rethink medical nutrition therapy in order to help patients to overcome barriers that impair an optimized adherence to the diet.

Electronic Glycemic Management System Improved Glycemic Control and Reduced Complications in Patients With Diabetes Undergoing Coronary Artery Bypass Surgery: A Randomized Controlled Trial.

BACKGROUND: In-hospital hyperglycemia poses significant risks for patients with diabetes mellitus undergoing coronary artery bypass graft (CABG) surgery. Electronic glycemic management systems (eGMSs) like InsulinAPP offer promise in standardizing and improving glycemic control (GC) in these settings. This study evaluated the efficacy of the InsulinAPP protocol in optimizing GC and reducing adverse outcomes post-CABG. METHODS: This prospective, randomized, open-label study was conducted with 100 adult type 2 diabetes mellitus (T2DM) patients post-CABG surgery, who were randomized into two groups: conventional care (gCONV) and eGMS protocol (gAPP). The gAPP used InsulinAPP for insulin therapy management, whereas the gCONV received standard clinical care. The primary outcome was a composite of hospital-acquired infections, renal function deterioration, and symptomatic atrial arrhythmia. Secondary outcomes included GC, hypoglycemia incidence, hospital stay length, and costs. RESULTS: The gAPP achieved lower mean glucose levels (167.2 ± 42.5 mg/dL vs 188.7 ± 54.4 mg/dL; P = .040) and fewer patients-day with BG above 180 mg/dL (51.3% vs 74.8%, P = .011). The gAPP received an insulin regimen that included more prandial bolus and correction insulin (either bolus-correction or basal-bolus regimens) than the gCONV (90.3% vs 16.7%). The primary composite outcome occurred in 16% of gAPP patients compared with 58% in gCONV (P < .010). Hypoglycemia incidence was lower in the gAPP (4% vs 16%, P = .046). The gAPP protocol also resulted in shorter hospital stays and reduced costs. CONCLUSIONS: The InsulinAPP protocol effectively optimizes GC and reduces adverse outcomes in T2DM patients' post-CABG surgery, offering a cost-effective solution for inpatient diabetes management.

Fructosamine and glycated hemoglobin as biomarkers of glycemic control in people with type 2 diabetes mellitus and cancer (GlicoOnco study).

INTRODUCTION: Glycemic control is important to avoid diabetes complications in individuals with cancer. There is no evidence for HbA1c and fructosamine as reliable biomarkers in these conditions. There are particularities in caring for patients with diabetes and cancer that can alter these biomarkers. OBJECTIVE: The aim of this study was to evaluate HbA1c and fructosamine as glycemic biomarkers in people with type 2 diabetes and cancer, undergoing clinical or surgical oncological treatment. METHODS: The authors conducted a single-center, retrospective analysis with people who have cancer and diabetes. Comparison of glycemic biomarkers (HbA1c, fructosamine, and Self-Monitoring of Blood Glucose [SMBG]) was performed including evaluation in individuals undergoing chemotherapy, using glucocorticoids, with anemia, hypoproteinemia or with reduced estimated Glomerular Filtration Rate (eGFR). RESULTS: There was a strong positive correlation between fructosamine and HbA1c (n = 318, r = 0.66, p < 0.001) in people with diabetes and cancer even in those under chemotherapy (n = 101, r = 0.61, p < 0.001) or using glucocorticoids (n = 96, r = 0.67, p<0.001). There was a strong correlation between HbA1c and fructosamine in subjects with anemia (n = 111, r = 0.66, p < 0.001), hypoproteinemia (n = 54, r = 0.67, p < 0.001), or with eGFR ≥ 60 mL/min/1.73 m2 (n = 189, r = 0.70, p < 0.001), and moderate correlation with hypoalbuminemia (n = 21, r = 0.54, p = 0.001) and with reduced eGFR (n = 67, r = 0.57, p < 0.001). The correlations between fructosamine and HbA1c with SMBG were moderate (n = 164, r = 0.49, p < 0.001; n = 111, r = 0.55, p < 0.001, respectively), strong in subjects undergoing chemotherapy, with hypoalbuminemia or hypoproteinemia, and at least moderate, if eGFR < 60 mL/min/1.73 m2 or with anemia. CONCLUSIONS: Fructosamine and HbA1c can be used as glycemic biomarkers in people with diabetes and cancer, even in those with anemia, hypoproteinemia, or undergoing chemotherapy.

Case report: Insulinomatosis: description of four sporadic cases and review of the literature.

The best-known etiologies of hyperinsulinemic hypoglycemia are insulinoma, non-insulinoma pancreatogenous hypoglycemic syndrome, autoimmune processes, and factitious hypoglycemia. In 2009, a disease not associated with classic genetic syndromes and characterized by the presence of multiple pancreatic lesions was described and named insulinomatosis. We present the clinical and pathologic features of four patients with the diagnosis of insulinomatosis, aggregated new clinical data, reviewed extensively the literature, and illustrated the nature and evolution of this recently recognized disease. One of our patients had isolated (without fasting hypoglycemia) postprandial hypoglycemia, an occurrence not previously reported in the literature. Furthermore, we reported the second case presenting malignant disease. All of them had persistent/recurrent hypoglycemia after the first surgery even with pathology confirming the presence of a positive insulin neuroendocrine tumor. In the literature review, 27 sporadic insulinomatosis cases were compiled. All of them had episodes of fasting hypoglycemia except one of our patients. Only two patients had malignant disease, and one of them was from our series. The suspicion of insulinomatosis can be raised before surgery in patients without genetic syndromes, with multiple tumors in the topographic investigation and in those who had persistent or recurrent hypoglycemia after surgical removal of one or more tumors. The definitive diagnosis is established by histology and immunohistochemistry and requires examination of the "macroscopically normal pancreas." Our case series reinforces the marked predominance in women, the high frequency of recurrent hypoglycemia, and consequently, a definitive poor response to the usual surgical treatment.

Epidemiology and risk factors of hypoglycemia in subjects with type 1 diabetes in Brazil: a cross-sectional, multicenter study.

Objective: The aim of this study was to investigate the factors associated with hypoglycemia and severe hypoglycemia (SH) in individuals with type 1 diabetes mellitus (T1D) in Brazil. Materials and Methods: This multicenter, cross-sectional study was conducted between August 2011 and August 2014 across 10 Brazilian cities. The data were obtained from 1,760 individuals with T1D. Sociodemographic and clinical characteristics related to hypoglycemic events in the previous 4 weeks were evaluated. Results: Of 1,760 individuals evaluated, 1,319 (74.9%) reported at least one episode of hypoglycemia in the previous 4 weeks. The main factors associated with hypoglycemia were lower hemoglobin A1c (HbA1c) level, better adherence to self-monitoring of blood glucose (SMBG), and higher education level. Episodes of SH were reported by 251 (19%) individuals who, compared with subjects with nonsevere hypoglycemia, received lower doses of prandial insulin and higher doses of basal insulin, in addition to reporting less frequent use of long-acting basal insulin analogs. The percentage of SH episodes was evenly distributed across all ranges of HbA1c levels, and there were no correlations between the mean number of nonsevere or severe hypoglycemic events and HbA1c values. Higher alcohol consumption and more frequent hospitalizations were independently associated with SH. Conclusion: Although individuals presenting with hypoglycemia had lower HbA1c values than those not presenting hypoglycemia, there were no correlations between the number of nonsevere hypoglycemia or SH and HbA1c values. Also, the frequency of SH was evenly distributed across all ranges of HbA1c values. Better adherence to SMBG and higher education level were associated with hypoglycemia, while alcohol consumption, higher doses of basal insulin, and more frequent hospitalizations in the previous year were associated with SH.

Effects of glucocorticoids on interstitial glucose concentrations in individuals with hematologic cancer and without known diagnosis of diabetes: a pilot study.

OBJECTIVE: To analyze interstitial glucose behavior during glucocorticoid use in non-diabetic patients receiving chemotherapy for hematologic malignancies. METHODS: Prospective pilot study carried out to assess interstitial glucose levels in 15 non-diabetic individuals with hematologic malignancies who received glucocorticoids in combination with chemotherapy. The FreeStyle Libre flash monitoring system (Abbott Diabetes Care) was used for up to 14 days to measure interstitial glucose. RESULTS: Median age and body mass index were 53 (42-61) years and 25 (23-28) kg/m2 respectively. Interstitial glucose levels >180mg/dL lasting at least one hour were detected in 60% of participants. Interstitial glucose profile parameters (median and peak interstitial glucose levels and percentage of time during which interstitial glucose levels were >180mg/dL) were significantly (p<0.01) higher during glucocorticoid use (115mg/dL, 218mg/dL and 10% respectively) than after glucocorticoid discontinuation (97mg/dL, 137mg/dL and 0% respectively). Mean interstitial glucose levels increased in the afternoon and at night during glucocorticoid use. CONCLUSION: This pilot study was the first to evaluate interstitial glucose levels in non-diabetic individuals using glucocorticoids in treatment of hematologic cancer. Glucocorticoid use during chemotherapy significantly increases interstitial glucose levels in these patients.

InsulinAPP application protocol for the inpatient management of type 2 diabetes on a hospitalist-managed ward: a retrospective study.

Introduction: We assessed metrics related to inpatient glycemic control using InsulinAPP, an application available for free in Brazil, on the hospitalist-managed ward of our hospital. Subjects and methods: We performed a retrospective study of patients with type 2 diabetes (T2D) admitted from November 2018 to October 2019. InsulinAPP recommends NPH and regular insulins three times a day, in bolus-correction or basal-bolus schemes. Parameters that included BG within range of 70-180 mg/dL, insulin treatment regimen and frequency of hypoglycemia were evaluated. Results: A total of 147 T2D individuals (23% medicine and 77% surgery) were included (mean age 62.3 ± 12.7 years, HbA1c: 8.3 ± 3.0%). The initial insulin regimen was 50% bolus-correction, 47% basal-bolus and 3% with sliding scale insulin. During hospitalization, 71% patients required a bolus-basal regimen. In the first 10 days of the protocol, 71% BG measurements were between 70-180 mg/dL and 26% patients experienced one or more episodes of hypoglycemia < 70 mg/dL, and 5% with BG < 54 mg/dL. Conclusion: The results of this retrospective study indicate the InsulinAPP application using human insulin formulations was effective and safe for the management of hyperglycemia on a hospitalist-managed ward, with more than 70% BG measurements within the therapeutic range and a low rate of hypoglycemia.

Diet consistency modification improves postprandial glycemic and gastroparesis symptoms.

Abstract: Diabetic gastroparesis (DGP) is an autonomic neuropathy resulting from long-standing poorly controlled diabetes, and it is also linked to fluctuations in glycemic control due to variability on nutrient absorption. Objectives: Considering the scarcity of information, the aim of this study was to identify the impact of modifications on diet consistency on post-prandial glucose variability using a continuous glucose monitoring (CGM) and its effect on the perception and severity of gastrointestinal symptoms. Methods: This proof-of-concept study was carried out in a cross-sectional cohort of six individuals with type 1 diabetes mellitus with confirmed diagnosis of DGP. Two types of diet were used to evaluate glycemic control and DGP symptoms, general consistency standard meal (SD) and modified consistency test diet (MD), associated with an application of rapid acting insulin at the time of food intake. Glycemic control was evaluated by CGM, and the Gastroparesis Cardinal Symptom Index (GCSI) was applied after meals. Results: The CGM curve was different for MD + insulin and SD + insulin. There was a smaller increment of interstitial glucose with 2 h after MD + insulin, returning almost to the basal level 4 h later. Patients scored significantly lower GCSI after MD + insulin compared to the same index after they received SD + insulin. Moreover, there was a decrease in important clinical scores present in the index, like: "Not able to finish meal", "Loss of appetite" and "Stomach or belly feels larger". Conclusion: This study showed that a modified diet can improve postprandial glycemic excursion and the perception and severity of gastroparesis symptoms. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-01117-w.

Association of genetic variants in the promoter region of genes encoding p22phox (CYBA) and glutamate cysteine ligase catalytic subunit (GCLC) and renal disease in patients with type 1 diabetes mellitus.

BACKGROUND: Oxidative stress is recognized as a major pathogenic factor of cellular damage caused by hyperglycemia. NOX/NADPH oxidases generate reactive oxygen species and NOX1, NOX2 and NOX4 isoforms are expressed in kidney and require association with subunit p22phox (encoded by the CYBA gene). Increased expression of p22phox was described in animal models of diabetic nephropathy. In the opposite direction, glutathione is one of the main endogenous antioxidants whose plasmatic concentrations were reported to be reduced in diabetes patients. The aim of the present investigation was to test whether functional single nucleotide polymorphisms (SNPs) in genes involved in the generation of NADPH-dependent O2•⁻ (-675 T → A in CYBA, unregistered) and in glutathione metabolism (-129 C → T in GCLC [rs17883901] and -65 T → C in GPX3 [rs8177412]) confer susceptibility to renal disease in type 1 diabetes patients. METHODS: 401 patients were sorted into two groups according to the presence (n = 104) or absence (n = 196) of overt diabetic nephropathy or according to glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease (MDRD) equation: ≥ 60 mL (n = 265) or < 60 mL/min/1.73 m² (n = 136) and were genotyped. RESULTS: No differences were found in the frequency of genotypes between diabetic and non-diabetic subjects. The frequency of GFR < 60 mL/min was significantly lower in the group of patients carrying CYBA genotypes T/A+A/A (18.7%) than in the group carrying the T/T genotype (35.3%) (P = 0.0143) and the frequency of GFR < 60 mL/min was significantly higher in the group of patients carrying GCLC genotypes C/T+T/T (47.1%) than in the group carrying the C/C genotype (31.1%) (p = 0.0082). Logistic regression analysis identified the presence of at least one A allele of the CYBA SNP as an independent protection factor against decreased GFR (OR = 0.38, CI95% 0.14-0.88, p = 0.0354) and the presence of at least one T allele of the GCLC rs17883901 SNP as an independent risk factor for decreased GFR (OR = 2.40, CI95% 1.27-4.56, p = 0.0068). CONCLUSIONS: The functional SNPs CYBA -675 T → A and GCLC rs17883901, probably associated with cellular redox imbalances, modulate the risk for renal disease in the studied population of type 1 diabetes patients and require validation in additional cohorts.

Targeted massively parallel sequencing for congenital generalized lipodystrophy.

OBJECTIVE: Our aim is to establish genetic diagnosis of congenital generalized lipodystrophy (CGL) using targeted massively parallel sequencing (MPS), also known as next-generation sequencing (NGS). METHODS: Nine unrelated individuals with a clinical diagnosis of CGL were recruited. We used a customized panel to capture genes related to genetic lipodystrophies. DNA libraries were generated, sequenced using the Illumina MiSeq, and bioinformatics analysis was performed. RESULTS: An accurate genetic diagnosis was stated for all nine patients. Four had pathogenic variants in AGPAT2 and three in BSCL2. Three large homozygous deletions in AGPAT2 were identified by copy-number variant analysis. CONCLUSION: Although we have found allelic variants in only 2 genes related to CGL, the panel was able to identify different variants including deletions that would have been missed by Sanger sequencing. We believe that MPS is a valuable tool for the genetic diagnosis of multi-genes related diseases, including CGL.

Association between health literacy and glycemic control in elderly patients with type 2 diabetes and modifying effect of social support.

OBJECTIVE: To investigate the association between inadequate functional health literacy, considering the Short Assessment of Health Literacy for Portuguese-speaking Adults, and glycemic control in elderly patients with type 2 diabetes, and to examine this association in low social support settings, according to Medical Outcomes Study . METHODS: Cross-sectional study conducted at the diabetes referral center of a university hospital. Participants were recruited among type 2 diabetes patients aged 60 years or older, between May 2013 and November 2014. The primary outcome was the most recent glycated hemoglobin value measured within the last 6 months. RESULTS: A total of 398 elderly patients with type 2 diabetes were evaluated. Of these, 232 were not eligible to participate. The final sample comprised 166 participants. Hierarchical multiple linear regression was performed. The following variables were entered in three blocks: sociodemographic characteristics, clinical variables and health literacy scores. Regression analysis of the interaction between health literacy and social support as a determinant of glycemic control was also performed. Mean age of subjects was 68.0 years (standard deviation of 5.9). Mean glycated hemoglobin value was 8.5% (standard deviation of 1.4). Short assessment of health literacy for Portuguese speaking adults score was independently associated with glycated hemoglobin (B=-0.059; p=0.043). The interaction between social support and health literacy score (p=0.003) was a determinant of glycemic control. CONCLUSION: Health literacy is associated with glycemic control. Social support may modify the relation between health literacy and glycemic control.

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.

Insulin Glargine U100 Improved Glycemic Control and Reduced Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease Stages 3 and 4.

PURPOSE: Glycemic control in patients with chronic kidney disease (CKD) is particularly hard to achieve because of a slower insulin degradation by the kidney. It might modify the long-acting insulin analogue pharmacokinetics, increasing its time-action and the risk of hypoglycemia. However, because this insulin has no peak action, it might be a more tolerable approach to patients with CKD. This hypothesis remains to be tested, because no study has thus far examined the efficacy and safety profile of long-acting basal analogues in patients with significant loss of renal function. The purpose of this study was to compare the glycemic response to treatment with glargine U100 or neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus (T2DM) and CKD stages 3 and 4. METHODS: Thirty-four patients were randomly assigned to glargine U100 or NPH insulin after a 2-way crossover open-label design. The primary end point was the difference in glycosylated hemoglobin (HbA1c) and in the number of hypoglycemic events between weeks 1 and 24, whereas secondary end points included changes in glycemic patterns, weight and body mass index, and total daily dose of insulin. HbA1c was determined by ion-exchange HPLC, and hypoglycemia was defined as glucose concentration of 54 mg/dL (3.0 mmol/L) detected by self-monitoring of plasma glucose or continuous glucose monitoring. FINDINGS: After 24 weeks, mean HbA1c decreased on glargine U100 treatment (-0.91%; P < 0.001), but this benefit was not observed for NPH (0.23%; P = 0.93). Moreover, incidence of nocturnal hypoglycemia was 3 times lower with glargine than with NPH insulin (P = 0.047). IMPLICATIONS: Our results found that insulin glargine U100 could be effective, once it improved glycemic control, reducing HbA1c with fewer nocturnal hypoglycemia episodes compared with NPH insulin in this population. These clinical benefits justify the use of basal insulin analogues, despite their high cost to treat patients with T2DM and CKD stages 3 and 4. Clinical Trials identifier: NCT02451917.

Acquired Lipodystrophy Associated With Nivolumab in a Patient With Advanced Renal Cell Carcinoma.

CONTEXT: Lipodystrophy syndromes are rare disorders characterized by the selective loss of adipose tissue. We aimed to report a case of acquired generalized lipodystrophy possibly associated with nivolumab. CASE DESCRIPTION: A woman was referred to our Endocrinology Department for uncontrolled diabetes mellitus. At 50 years of age, she was diagnosed with type 2 diabetes after a routine laboratory test and her diabetes was well controlled with low doses of metformin. In 2010, she was diagnosed with clear cell renal carcinoma. The cancer progressed in the following years, leading to the initiation of treatment with nivolumab in 2017. Two months later she presented with facial lipoatrophy, with loss of the buccal fat pads and prominent zygomatic arch. Her neck, shoulders, arms, and buttocks were also affected. Her diabetes control worsened. She received maximal doses of metformin and pioglitazone and was administered 1.5 units/kg/d insulin. Subcutaneous biopsy of medial surface of the arm revealed chronic lobular panniculitis. Despite nivolumab's possible involvement in the onset of lipodystrophy, the maintenance of nivolumab therapy was justified by the observed reduction in the progression of the cancer, combined with the lack of an alternative chemotherapy. The therapy was withdrawn after 8 months of treatment because of grade 3 hepatitis. CONCLUSION: Anti-PD1 therapy has great potential. Early recognition of the onset of unusual collateral effects is important to improve decision making regarding the treatment of patients with tumors.

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.

Targeted sequencing identifies novel variants in common and rare MODY genes.

BACKGROUND: Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. To date, mutations in 11 genes have been frequently associated with this phenotype. In Brazil, few cohorts have been screened for MODY, all using a candidate gene approach, with a high prevalence of undiagnosed cases (MODY-X). METHODS: We conducted a next-generation sequencing target panel (tNGS) study to investigate, for the first time, a Brazilian cohort of MODY patients with a negative prior genetic analysis. One hundred and two patients were selected, of which 26 had an initial clinical suspicion of MODY-GCK and 76 were non-GCK MODY. RESULTS: After excluding all benign and likely benign variants and variants of uncertain significance, we were able to assign a genetic cause for 12.7% (13/102) of the probands. Three rare MODY subtypes were identified (PDX1/NEUROD1/ABCC8), and eight variants had not been previously described/mapped in genomic databases. Important clinical findings were evidenced in some cases after genetic diagnosis, such as MODY-PDX1/HNF1B. CONCLUSION: A multiloci genetic approach allowed the identification of rare MODY subtypes, reducing the large percentage of MODY-X in Brazilian cases and contributing to a better clinical, therapeutic, and prognostic characterization of these rare phenotypes.

Case Report of Acquired Generalized Lipodystrophy Associated With Common Variable Immunodeficiency.

Context: Acquired generalized lipodystrophy (AGL), a rare disorder characterized by loss of subcutaneous adipose tissue, is estimated to occur in association with autoimmune diseases in ~25% of the cases. Common variable immunodeficiency (CVI) is a condition known for its strong association with autoimmune diseases often occurring with negative autoantibodies. To the best of our knowledge, we describe the first known case of AGL in a patient with CVI. Case Description: A 24-year-old man was referred to our center with hyperglycemia, hypertriglyceridemia, hepatomegaly, and a clear pattern of generalized fat loss. AGL had been diagnosed on the basis of the clinical and laboratory findings. Because of the presence of associated hypogammaglobulinemia, a diagnosis of CVI was subsequently established. Conclusions: We propose that AGL be added to the list of possible diseases associated with CVI and, owing to the similar clinical presentation with type 1 diabetes mellitus, be included in the differential diagnosis of this condition, which is present in 1.5% of patients with CVI.