Complex rearrangement in TBC1D4 in an individual with diabetes due to severe insulin resistance syndrome.

Severe insulin resistance syndromes result from primary insulin signaling defects, adipose tissue abnormalities or other complex syndromes. Mutations in TBC1D4 lead to partial insulin signaling defects, characterized mainly by postprandial insulin resistance. We describe an individual with severe insulin-resistant diabetes unresponsive to multiple therapies, in whom exome and genome analyses identified a complex rearrangement in TBC1D4. The rearrangement was of the pattern DUP-TRP/INV-DUP, with mutational signatures suggestive of replicative repair and Alu-Alu recombination as the underlying mechanisms. TBC1D4 encodes the TBC1D4/AS160 RabGTPase activating protein (RabGAP) involved in the translocation of glucose transporter 4 (GLUT4) from the cytosol to the cell membrane. Although the precise functional mechanism underlying insulin resistance in the proband is yet to be determined, this case provides further support for the link between TBC1D4 and hereditary insulin-resistant diabetes.

Future diabetes risk can be predicted by the number of abnormal oral glucose tolerance test values during pregnancy.

AIM: To quantify the future risk of type 2 diabetes (T2D) in women with gestational diabetes (GD) based on baseline metabolic characteristics and the number of abnormal values during a 3-hour 100-g oral glucose tolerance test (OGTT). MATERIALS AND METHODS: We conducted a population-based retrospective cohort study of 10 023 pregnant women who underwent testing for GD in a large health maintenance organization in Israel using a 100-g OGTT. Glucose values were obtained at four time points, 0, 60, 120 and 180 minutes. RESULTS: We identified 9939 women who met the study criteria. Median follow-up was 3.25 (interquartile range 1.5-5.1; maximum 10.1) years. Using women without GD as reference, women with GD were at an increased risk of future T2D (hazard ratio [HR] 5.33 [95% confidence interval {CI} 3.86-7.34]). This risk increased with a greater number of abnormal OGTT values, with the highest risk seen in women with four abnormal values (HR 16.67 [95% CI 7.94-35.01]). In a multivariate model, a higher number of abnormal values, Arab ethnicity, higher body mass index, triglycerides and prepregnancy glucose were significantly associated with increased risk. Future T2D risk was also affected by the type of OGTT abnormality; an abnormal fasting value had the greatest risk, whereas an abnormal 3-hour value had the lowest risk (HR 3.61 [95% CI 2.42-5.38] vs. 1.50 [95% CI 0.93-2.43], respectively). CONCLUSIONS: GD is a heterogenous disease, with varying degrees of glucose intolerance and subsequent T2D risk. Targeting interventions to women at the highest risk may help to improve postpartum adherence and effective long-term follow-up strategies.

GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial isolated hyperparathyroidism.

Context: A germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the GCM2 [(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT Ashkenazi Jews (AJ). Objective: To evaluate the presence of the GCM2 p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management. Method: Patients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the GCM2 p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database. Results: A total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight CASR and two AP2S1 mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the GCM2 p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the GCM2 p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the GCM2 p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%. Conclusion: In contrast to previous observations, the GCM2 p.Tyr394Ser variant-associated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation.

RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies.

Immune checkpoint inhibitors (ICI) are commonly associated with thyroid immune-related adverse events, yet the mechanism has not been fully elucidated. We aimed to further explore the mechanism of ICI-induced thyroid dysfunction by assessing changes induced in the thyroid transcriptome by ICI treatment (αPD-1/αPD-L1) in a lung cancer murine model. RNA-sequencing of thyroid tissues revealed 952 differentially expressed genes (DEGs) with αPD-1 treatment (|fold-change| ≥1.8, FDR < 0.05). Only 35 DEG were identified with αPD-L1, and we therefore focused on the αPD-1 group alone. Ingenuity Pathway Analysis revealed that of 952 DEGs with αPD-1 treatment, 362 were associated with functions of cell death and survival, with predicated activation of pathways for apoptosis and necrosis (Z = 2.89 and Z = 3.21, respectively) and negative activation of pathways for cell viability and cell survival (Z = -6.22 and Z = -6.45, respectively). Compared to previously published datasets of interleukin-1ß and interferon γ-treated human thyroid cells, apoptosis pathways were similarly activated. However, unique changes related to organ inflammation and upstream regulation by cytokines were observed. Our data suggest that there are unique changes in gene expression in the thyroid associated with αPD-1 therapy. ICI-induced thyroid dysfunction may be mediated by increased tissue apoptosis resulting in destructive thyroiditis.

Tumor PD-L1 expression and molecular profiling are not associated with immune checkpoint inhibitor-induced thyroid dysfunction in advanced NSCLC patients.

Background: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), however are frequently associated with thyroid immune-related adverse events (IRAEs). We investigated the association between patient characteristics, tumor PD-L1 expression and molecular profile with the development of thyroid IRAEs in NSCLC patients. Methods: Single center, retrospective study including 107 NSCLC patients treated with PD-1/PD-L1 inhibitors from April 2016 to July 2020. All patients were euthyroid at baseline with at least two TSH measurements post-treatment initiation. The primary outcome was the difference in tumor PD-L1 expression in patients who developed any thyroid IRAEs versus those who remained euthyroid. Additional outcomes included development of overt thyroid dysfunction, the association of specific molecular alterations with thyroid IRAEs, and onset of thyroid IRAEs as a function of tumor PD-L1 expression. Results: Overall, 37 (34.6%) patients developed any thyroid dysfunction and 18 (16.8%) developed overt thyroid dysfunction. Tumor PD-L1 staining intensity was not associated with thyroid IRAEs. TP53 mutation was less likely to be associated with any thyroid dysfunction (p < 0.05) and no association was found between EGFR, ROS, ALK or KRAS mutations. There was no association between PD-L1 expression and time to develop thyroid IRAEs. Conclusion: PD-L1 expression is not associated with the development of thyroid dysfunction in advanced NSCLC patients treated with ICIs, suggesting that thyroid IRAEs are unrelated to tumor PD-L1 expression.

Efficacy and Safety of Dapagliflozin by Baseline Insulin Regimen and Dose: Post Hoc Analyses From DECLARE-TIMI 58.

OBJECTIVE: The cardiorenal benefits of adding sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy for patients on insulin, particularly those on intensive regimens that include short-acting (SA) insulin, have not been explored. RESEARCH DESIGN AND METHODS: In Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomized to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular (CV), renal, metabolic, and safety outcomes with dapagliflozin versus placebo by insulin dose and regimen were studied with Cox regression models. RESULTS: The study included 7,013 insulin users at baseline, with 4,650 (66.3%) patients on regimens including SA insulin. Insulin doses varied, with 2,443 (34.8%) patients receiving <0.5 IU/kg, 2,795 (39.9%) 0.5 to ≤1 IU/kg, and 1,339 (19.1%) >1 IU/kg. Dapagliflozin reduced CV death/hospitalization for heart failure among overall insulin users (hazard ratio [HR] 0.82 [95% CI 0.69-0.97]) and consistently in patients on insulin regimens with or without SA insulin (0.83 [0.67-1.03] and 0.78 [0.57-1.07], respectively, Pinteraction = 0.75). No heterogeneity was observed by insulin dose (Pinteraction = 0.43). The HR for major adverse CV events with dapagliflozin among insulin users (0.84 [0.74-0.97]) was similar irrespective of regimen or dose (Pinteraction = 0.75 and 0.07). Dapagliflozin reduced the rate of adverse renal outcomes overall and consistently across subgroups of insulin users. Decreases in HbA1c, weight, and systolic blood pressure with dapagliflozin were seen regardless of insulin dose or regimen. The known safety profile of dapagliflozin was unchanged in patients on intensive insulin regimens. CONCLUSIONS: The benefits and safety of dapagliflozin were maintained in high-risk patients receiving high-dose or intensive insulin regimens including SA insulin.

SGLT2 Inhibitors and Safety in Older Patients.

SGLT2 inhibitors (SGLT2i) are effective in the management of diabetes and in reducing adverse cardiovascular and renal outcomes. Randomized clinical trials demonstrated safety and tolerability in older adults. Adverse effects associated with SGLT2i are impacted by patient frailty, comorbidities, and concomitant medication use and, therefore, must be thoroughly evaluated before initiating treatment. The risk of volume depletion, hypoglycemia, genital infections, and diabetic ketoacidosis can be minimized by appropriate patient selection, patient education, and early symptom recognition. Limited data exists regarding the risk of urinary tract infections, fractures, and amputations in the elderly treated with SGLT2i and routine monitoring is recommended.

Consistency of Thyroid Imaging Reporting and Data System Reporting in Community-Based Imaging Centers Versus a Large Tertiary Hospital.

OBJECTIVE: In our country, thyroid nodules are sonographically evaluated in health maintenance organization (HMO) imaging centers, and patients are referred to tertiary hospitals for ultrasound-guided fine-needle aspiration (FNA) biopsy when indicated. We evaluated the concordance in Thyroid Imaging Reporting and Data System (TI-RADS) classification reporting between these sites. METHODS: We conducted a retrospective cohort study reviewing the sonographic features of thyroid nodules evaluated both at the HMO and a large tertiary center between January 2018 and December 2019. The primary outcome was concordance between the TI-RADS classification at both sites. Additional endpoints included correlation of TI-RADS to the Bethesda category following FNA and correlation of TI-RADS with malignancy on final pathology at each site. RESULTS: The records of 336 patients with 370 nodules were reviewed. The level of concordance was poor (19.8%), with 277 (74.8%) nodules demonstrating higher TI-RADS and 20 (5.4%) lower TI-RADS at the HMO compared to the hospital (P < .001; weighted κ = 0.120). FNA results were available for 236 (63.8%) nodules. The Bethesda category strongly correlated with the hospital TI-RADS (P < .001), yet not with HMO TI-RADS (P = .123). In the surgically removed 57 nodules, a strong correlation was identified between the malignancy on final pathology and TI-RADS documented at the hospital (P < .001), yet not at the HMO (P = .259). CONCLUSIONS: There is poor agreement between TI-RADS classification on ultrasound performed in the HMO compared to a tertiary hospital. The hospital's TI-RADS strongly correlated with the Bethesda category and the final risk of malignancy, unlike the HMO.

[IMMUNE CHECKPOINT INHIBITOR-INDUCED DIABETES MELLITUS].

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have transformed the care of cancer patients, providing therapeutic options for advanced malignancies considered otherwise untreatable. However, these agents have been associated with immune-related adverse events (irAEs). ICI-induced diabetes (ICI-DM) is a rare complication of programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor therapy (~1%) and can be life-threatening, as patients often present with severe hyperglycemia and in diabetic ketoacidosis. We describe two patients with rapid-onset diabetes mellitus associated with anti PD-1 therapy followed by an in-depth review of the literature. We discuss the clinical presentation, potential mechanisms and optimal management of patients with ICI-DM. As ICI use continues to expand across a wide variety of malignancies, clinicians must be aware of this potentially life-threatening irAE to prevent significant morbidity and mortality.

PD-L1 EXPRESSION IN NORMAL ENDOCRINE TISSUES IS NOT INCREASED DESPITE HIGH INCIDENCE OF PD-1 INHIBITOR-ASSOCIATED ENDOCRINOPATHIES.

OBJECTIVE: Treatment with immune-checkpoint inhibitors often results in endocrine immune-related adverse events (irAEs), affecting the pituitary, thyroid, adrenal, and parathyroid glands and pancreas. The mechanism underlying the endocrine irAEs has not been fully elucidated, and it remains unclear why endocrine organs are so commonly affected. In the present study, we evaluated immunostaining patterns of programmed death-ligand 1 (PD-L1) in normal endocrine tissues to determine whether increased expression may explain the predilection of endocrinopathies in patients treated with programmed cell death-1 inhibitors. METHODS: Normal formalin-fixed paraffin-embedded endocrine tissues (pituitary, thyroid, adrenal, pancreas, and parathyroid) were collected from our hospital's pathology tissue archive. The tissues were assessed for membranous and cytoplasmic PD-L1 immunostaining using the Dako 22C3 pharmDx assay on an automated staining platform. RESULTS: We examined 49 endocrine tissues, including 12 thyroid, 5 pancreatic, 17 adrenal, 5 parathyroid, and 10 pituitary samples. Samples with less than 1% membranous PD-L1-positive cells were considered negative, while those with more than 1% of PD-L1 membranous staining were considered positive. Immunostaining result of immune-related cells was also evaluated, considering the cytoplasmic PD-L1-positive cells with the same cutoff of 1%. None of the endocrine tissues demonstrated PD-L1 positivity higher than 1% in the relevant cells. CONCLUSION: While our results do not suggest a role of PD-L1 expression in the pathogenesis of endocrine irAEs, they may serve as a basis for future studies further investigating the mechanisms of autoimmune, inflammatory, or malignant endocrine conditions.

Impact of flash glucose monitoring on glucose control and hospitalization in type 1 diabetes: A nationwide cohort study.

BACKGROUND: We evaluated the impact of flash continuous glucose monitoring (FCGM) on glycemic control and healthcare burden in a large real-world cohort of patients with type 1 diabetes (T1D) initiating FCGM technology. METHODS: In this retrospective cohort study, we included adults (age ≥18 years) with T1D from a large Health Maintenance Organization in Israel, who initiated FCGM during 2018. Primary outcomes included change in HbA1c ≥3 months following FCGM commencement and change in rate of internal-medicine hospitalization. Additional outcomes included changes in glucose test strip purchases, diabetes related outpatient health care visits and hospitalization for diabetic ketoacidosis (DKA) and/or severe hypoglycemia. RESULTS: The study included 3490 patients, followed for a median of 14 (inter-quartile range 11-15) months after FCGM commencement. Among 2682 patients with an HbA1c measured both at baseline and ≥3 months after FCGM initiation, average HbA1c declined from 8.1% ± 1.46% to 7.9% ± 1.31% (P < .001) at first measurement and was maintained during follow up. Specifically, in those with HbA1c ≥8%, a mean decline of 0.5% (P < .001) was observed. A clinically significant HbA1c reduction of ≥0.5% was experienced by 25.5% of the patients. The rate of internal medicine hospitalization, visits to primary care, or visits to endocrine/diabetes specialists in the period following FCGM commencement vs the 6 months prior was significantly reduced (P < .001). Hospitalization for DKA and/or hypoglycemia declined as well (P = .004). CONCLUSIONS: FCGM was associated with significant and durable improvement in glycemic control as well as reduced consumption of healthcare services.

Active Surveillance of Thyroid Microcarcinoma-Can This Approach Be Safely Implemented Worldwide?

The incidence of thyroid cancer has been increasing exponentially worldwide, mainly due to increased detection of small papillary thyroid microcarcinomas (PTMCs). Given the indolent nature of the disease, active surveillance (AS) has been suggested as an alternative approach to immediate surgery in the management of low-risk PTMCs. The decision to proceed with AS must take into account patient characteristics, tumor characteristics, and medical team characteristics. In this review, we discuss the rationale and evidence to support AS, as well as important considerations and limitations to implementing this approach for PTMC worldwide.

Immune Checkpoint Inhibitor-induced Thyroid Dysfunction Is Associated with Higher Body Mass Index.

CONTEXT: Obesity is a proinflammatory metabolic state that may play a role in the development of immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy. OBJECTIVE: To characterize the association between body mass index (BMI) and thyroid irAEs. METHODS: We performed a single-center, retrospective analysis of 185 cancer patients treated with anti-PD-1/L1 from January 2014 to December 2018. Patients with normal thyroid function at baseline and available BMI were included. MAIN OUTCOME MEASURES: The primary endpoint was difference in BMI in patients who developed overt thyroid dysfunction versus those who remained euthyroid following anti-PD-1/L1 initiation. Additional endpoints included any (overt or subclinical) thyroid dysfunction, overt thyrotoxicosis or overt hypothyroidism, and time to development of dysfunction according to BMI. RESULTS: Any thyroid dysfunction developed in 72 (38.9%) patients and 41 (22.1%) developed overt thyroid dysfunction. Mean BMI was higher in those with overt thyroid dysfunction versus euthyroid (27.3 ±â€…6.0 vs 24.9 ±â€…4.5, P = .03). Development of overt thyrotoxicosis versus remaining euthyroid was associated with higher BMI (28.9 ±â€…5.9 vs 24.9 ±â€…4.5; P < .01), whereas overt hypothyroidism was not (26.7 ±â€…5.5 vs 24.9 ±â€…4.5, P = .10). Overt thyrotoxicosis developed within 57.5 (interquartile range [IQR] 31.8-78.8) days of treatment in the low-normal BMI group, 38.0 (IQR 26.8-40.5) days in the overweight group, and 23.0 (IQR 21.0-28.0) days in the obese group (P = .02). CONCLUSIONS: Patients treated with PD-1/L1 inhibitors were more likely to develop thyroid irAEs, specifically overt thyrotoxicosis, with increasing BMI. Overt thyrotoxicosis occurred earlier in obese versus leaner patients. These data highlight the complex interplay between obesity and immune response in immune checkpoint inhibitor-treated patients.

Role of Cannulated Prolactin Test in Evaluation of Hyperprolactinemia - A Retrospective Study.

OBJECTIVE: While guidelines propose a single elevated prolactin measurement drawn without excess venipuncture stress as sufficient for diagnosing hyperprolactinemia, this may lead to unnecessary evaluation in the setting of stress-induced hyperprolactinemia. In this study, we aimed to define the role of the cannulated prolactin test in confirming hyperprolactinemia. METHODS: We conducted a retrospective review of 757 patients with unexplained hyperprolactinemia who performed a cannulated prolactin test in a community-based referral endocrine clinic between 2000-2015. The prolactin test consisted of "test-baseline" levels taken at rest (T0), and cannulated measurements at 60 and 90 minutes (T60 and T90) without repeated venipuncture. The most recent prolactin level performed prior to the test (referral-prolactin) was collected. RESULTS: Referral-prolactin was available for 621 (82%) patients, of whom 324 (52.2%) normalized at T0. The probability of normoprolactinemia at T0 was 50% if referral-prolactin was 2.0-fold the upper-limit-of-normal (ULN), yet only 5% if referral-prolactin was 5.0-fold the ULN. Of the 359 patients with hyperprolactinemia at T0, prolactin normalized at T60 and/or T90 in 99 (27.6%) patients. The probability of normoprolactinemia was low (<5%) in those with T0 prolactin levels >2.4-fold ULN. Overall, of 757 prolactin tests performed, only 260 (34.3%) patients had persistent hyperprolactinemia. CONCLUSION: Patients with referral-prolactin levels >5.0-fold the ULN, or a rested-prolactin (T0) >2.4-fold the ULN are unlikely to normalize during the cannulated test and consideration should be made to proceed directly with pituitary imaging. In patients with prolactin levels below these thresholds, the cannulated prolactin test may considerably reduce unnecessary investigations, treatment, and cost.

Association of Inpatient Glucose Measurements With Amputations in Patients Hospitalized With Acute Diabetic Foot.

CONTEXT: The association of inpatient glucose measurements with amputations in patients admitted with acute diabetic foot has not been described. OBJECTIVE: To evaluate the relationship of hyperglycemia, hypoglycemia, and glucose variability during hospitalization with amputations in patients hospitalized with acute diabetic foot. DESIGN: Retrospective cohort study. SETTING: Academic tertiary hospital. PATIENTS: We reviewed demographic, clinical, laboratory, and point-of-care glucose data in patients hospitalized with acute diabetic foot in the Diabetic Foot Unit during 2015 through 2017. MAIN OUTCOME MEASURES: The primary outcomes were any or major amputations during hospitalization. Secondary outcomes included length of hospitalization and in-hospital mortality. RESULTS: During the study period, 418 patients were hospitalized in the Diabetic Foot Unit and 45,496 glucose measurements were taken. Patients experiencing any hyperglycemia and any or severe hypoglycemia were more likely to undergo any or major amputations during hospitalization. High glycemic variability was associated with major amputations. Peripheral vascular disease (PVD), high Wagner score, and hypoglycemia were independent predictors of amputations. Older age, PVD, previous amputation, elevated white blood cell level, high Wagner score, and hypoglycemia were independent predictors of major amputations. CONCLUSIONS: In-patient hypoglycemia emerged as an independent risk factor for any and major amputations. Although it is unclear whether hypoglycemia directly contributes to adverse outcomes or is simply a biomarker of disease severity, efforts to minimize in-hospital hypoglycemic events are warranted.

BASELINE TSH LEVEL IS ASSOCIATED WITH RISK OF ANTI-PD-1-INDUCED THYROID DYSFUNCTION.

Objective: To characterize anti-programmed cell death 1 (PD-1)-induced thyroid immune-related adverse events (irAEs) in metastatic melanoma patients treated at our institution and to identify risk factors associated with their development. Methods: We reviewed the files of 154 patients with metastatic melanoma treated with PD-1 inhibitors at a single institution from November 1, 2011, to February 28, 2017. The association of thyroid irAEs within 120 days posttreatment initiation with age, gender, melanoma characteristics, treatment protocol, and baseline thyroid-stimulating hormone (TSH) was examined. Results: Overall, 42.4% developed thyroid dysfunction following treatment, including 20.2% (20/99) subclinical thyroid dysfunction, 13.1% (13/99) overt hypothyroidism, and 9.1% (9/99) overt hyperthyroidism. Of those that developed overt hyperthyroidism, 8 progressed to overt hypothyroidism, consistent with thyroiditis. Age, gender, melanoma characteristics, or treatment protocol did not modify the risk of developing thyroid irAEs. Higher baseline TSH was observed in patients who developed overt hypothyroidism versus hyperthyroidism versus those who remained euthyroid (P = .05). A pretreatment TSH >2.19 mIU/mL was associated with an increased risk of overt thyroid dysfunction (odds ratio, 3.46; 95% confidence interval, 1.2 to 9.8). Conclusion: Thyroid dysfunction following treatment with PD-1 inhibitors is common, and patients with a higher baseline TSH appear to be at increased risk. Such patients may benefit from closer monitoring of their thyroid function following initiation of anti PD-1 agents. Abbreviations: CTLA-4 = cytotoxic T-lymphocyte antigen 4; FT3 = free triiodothyronine; FT4 = free thyroxine; irAE = immune-related adverse event; PD-1 = programmed cell death 1; TFT = thyroid function test; TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone.

Acute renal outcomes with sodium-glucose co-transporter-2 inhibitors: Real-world data analysis.

AIM: To assess the possible risk of acute kidney injury (AKI) with the use of sodium-glucose co-transporter-2 inhibitors (SGLT2-i) as well as changes in estimated glomerular filtration rate (eGFR), hospitalizations and mortality in a real-world setting. MATERIALS AND METHODS: Included in this historical cohort study were patients with type 2 diabetes in a large health organization in Israel who initiated therapy with SGLT2-i or dipeptidyl peptidase-4 inhibitors (DPP-4i) during 1 April 2015 to 30 June 2017. We collected data on serum creatinine measurements taken between 180 days prior to and 24 weeks after therapy initiation. Study endpoints included ≥30% reduction in eGFR, hospitalization with AKI, any hospitalization and all-cause mortality. RESULTS: Overall 6418 and 5604 patients initiated SGLT2-i and DPP-4i, respectively. Baseline mean (SD) eGFR was higher among the SGLT2-i group compared with the DPP-4i group (88.3 [17.4] and 82.8 [23.7], respectively) but were similar when stratifying by chronic kidney disease (CKD) stages. The adjusted odds ratio (OR) (95% confidence interval [CI]) for ≥30% reduction in eGFR with SGLT2-i versus DPP4-i was 0.70 (0.49-1.00) and ORs ranged from 1.97 (0.62-6.26) to 0.45 (0.21-0.99) in patients with baseline eGFR 30 to 45 and ≥90 mL/min/1.73 m2 , respectively. Risks of AKI (OR = 0.47, 95% CI 0.27-0.80), hospitalization (OR = 0.66, 95% CI 0.56-0.78) or all-cause mortality (OR = 0.43, 95% CI 0.20-0.95) were lower in patients initiating SGLT2-i versus DPP-4i. CONCLUSIONS: This real-world data analysis supports reassuring findings from previous randomized clinical trials showing no increased AKI risk among SGLT2-i users. Nevertheless, because of the more prominent decrease in eGFR in patients with moderate CKD, cautious use of SGLT2-i in patients with reduced eGFR is advised.

Validity of diagnostic codes and estimation of prevalence of diabetic foot ulcers using a large electronic medical record database.

AIMS: To assess the validity of the diagnostic codes relating to diabetic foot ulcer (DFU) in the electronic medical records of a large integrated care provider and to assess the prevalence of DFU among its members. MATERIALS AND METHODS: Data were obtained from the diabetes registry of Maccabi Healthcare Services (MHS), a 2.1-million-member sick-fund in Israel, which included 125 665 patients in 2015. We randomly selected and reviewed ~400 patient files from each of the following categories during study period: (1) had a diagnostic code of DFU; (2) had a diagnostic code, or clinical condition suggestive of DFU including: leg-ulcer, amputation, DFU in quartiles proximate to 2015 or abnormality reported by nurse; (3) patients at high risk for DFU (age > 35 and one of the following: peripheral artery disease, neuropathy, DFU during 2011-2014, eGFR<30 mL/min/m2 or foot deformity). The patients' charts were reviewed by study physicians, and DFU was validated or refuted. RESULTS: Relying upon diagnostic codes entered by physicians, the positive predictive value (PPV) was 73.1% (95% CI 67.6-78.2), and the sensitivity was 48.2% (95% CI 45.8-50.7%). The PPV of the diagnostic codes listed by podiatrists were significantly lower, while that of codes listed by nurses was higher but with lower sensitivity. The estimated annual prevalence of DFU in the diabetes registry of MHS was 1.2% (95%CI 1.0-1.5%). CONCLUSIONS: Diagnostic codes alone cannot be used reliably to create a DFU registry. Nevertheless, the data collected provide an estimate of the prevalence of DFU among patients included in the MHS diabetes registry.

Resveratrol Improves Vascular Function and Mitochondrial Number but Not Glucose Metabolism in Older Adults.

BACKGROUND: Resveratrol, a plant-derived polyphenol, has been reported to improve glucose metabolism and vascular function and to extend life span in animal models, but studies in humans have been inconclusive. METHODS: In a randomized, double-blind crossover study, we treated older glucose-intolerant adults (n = 30) with resveratrol (2-3 g/daily) or placebo, each for 6 weeks. A standard mixed-meal test was used to assess insulin sensitivity (Matsuda index) and secretion (C-peptide deconvolution) and vascular function by reactive hyperemia peripheral arterial tonometry. Skeletal muscle samples were obtained for gene expression using RNA-Seq analysis and to assess mitochondrial morphology. RESULTS: There were no changes in glucose tolerance, insulin sensitivity, weight, blood pressure, or lipid profile following resveratrol treatment. Fasting reactive hyperemia index improved with resveratrol (2.02 ± 0.2 vs 1.76 ± 0.02, p = .002). RNA-Seq analysis yielded 140 differentially expressed transcripts (corrected p-value ≤ .05), predominantly associated with mitochondrial genes and noncoding RNA. Ingenuity Pathway Analysis confirmed that mitochondrial dysfunction (p = 2.77 × 10-12) and oxidative phosphorylation (p = 1.41 × 10-11) were the most significantly perturbed pathways. Mitochondrial number, but not size, was increased. CONCLUSIONS: Resveratrol treatment of older adults with impaired glucose regulation may have beneficial effects on vascular function, but not glucose metabolism or insulin sensitivity. Changes in gene expression suggest effects similar to those observed with caloric restriction, which has been shown to increase life and health span in animal models, although its significance for humans is uncertain. Future human studies should address the appropriate dose range and low bioavailability of resveratrol.