Search

Objective: Most individuals with lower extremity peripheral artery disease (PAD) experience symptoms other than claudication and live with undiagnosed PAD yet no tools exist to detect atypical PAD symptoms. The purpose of this study was to identify discriminating PAD symptom descriptors from a community-based sample of patients with no current diagnosis of PAD. Methods: Symptoms descriptors were obtained in a sample of 22 participants with persistent lower extremity symptoms pre/post exercise. An ankle brachial index with exercise was used to classify participants as "PAD" or "No PAD." Results: Thirteen (59%) participants had a positive ankle brachial index (<0.9, ≥20% drop postexercise, or 30 mmHg drop postexercise). Symptoms do not disappear while walking, trouble keeping up with friends/family, positive response to pain or discomfort while sitting, and pain outside of the calves and thighs were associated with a positive ankle brachial index. Conclusion: Atypical symptoms were common among study participants. Symptoms while sitting and symptoms outside of the calf and thigh were negatively associated with a positive ankle brachial index. More precise descriptions of symptom characteristics are needed to improve PAD symptom recognition. [ABSTRACT FROM AUTHOR]

The healthcare industry continues to experience high rates of burnout, turnover, and staffing shortages that erode quality care. Interventions that are feasible, engaging, and impactful are needed to improve cultures of support and mitigate harm from exposure to morally injurious events. This quality improvement project encompassed the methodical building, implementation, and testing of RECONN (Reflection and Connection), an organizational intervention designed by an interdisciplinary team to mitigate the impact of moral injury and to increase social support among nurses. This quality improvement project was conducted in a medical intensive care unit (MICU) in a rural, academic medical center. We employed an Evidence-Based Quality Improvement (EBQI) approach to design and implement the RECONN intervention while assessing the feasibility, acceptability, and preliminary effectiveness via surveys (n = 17). RECONN was found acceptable and appropriate by 70% of nurses who responded to surveys. Preliminary effectiveness data showed small to moderate effect sizes for improving social support, moral injury, loneliness, and emotional recovery. Further evaluation is warranted to establish the effectiveness and generalizability of RECONN to other healthcare settings. [ABSTRACT FROM AUTHOR]

The article examines the relationship between having an Individualized Educational Program (IEP) and emotional distress among adolescents. It investigates whether participation in activities such as sports, clubs, and community programs can reduce symptoms of emotional distress, such as depression and anxiety, in adolescents with IEPs, given their higher risk for emotional challenges compared to their peers.

This article discusses the measurement and interpretation of vitellogenin (VTG) in fish and amphibians as a biomarker for endocrine activity. The reliability and acceptability of VTG results are important for regulatory assessments of chemicals. The article highlights the variability in VTG measurements and the need for improvement in sampling, quantification, and data handling. It proposes a decision logic to assist in the interpretation of VTG measurements and calls for the development of OECD guidance on best practices for VTG assessment. The article emphasizes the importance of considering other factors and endpoints in conjunction with VTG results to determine endocrine activity. [Extracted from the article]

BACKGROUND. Postreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis. METHODS. Cross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma [beta]-hydroxybutyrate) were measured. RESULTS. Lipolysis was 2- to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%-0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%-17.1%], P < 0.0001). [beta]-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation. CONCLUSION. These data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis. TRIAL REGISTRATION. ClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897. FUNDING. National Institute of Diabetes and Digestive and Kidney Diseases, US Department of Agriculture/Agricultural Research Service 58-3092-5-001., Introduction Insulin is a hormone that signals the fed state, promoting a switch from net glucose production to net glucose uptake and shifting lipids from lipid metabolism to lipid storage. [...]

Context Childhood overnutrition is associated with increased growth and bone mineral density (BMD) vs the opposite for undernutrition. The role of insulin receptor (InsR) signaling in these phenotypes is unclear. Rare disease patients with hyperinsulinemia and impaired InsR function (homozygous [−/−] or heterozygous [+/−] INSR pathogenic variants, type B insulin resistance [TBIR]) model increased InsR signaling, while patients with intact InsR function (congenital generalized lipodystrophy, CGL) model decreased InsR signaling. Objective This work aimed to understand mechanisms whereby InsR signaling influences growth. Methods A cross-sectional comparison was conducted of CGL (N = 23), INSR −/− (N = 13), INSR +/− (N = 17), and TBIR (N = 8) at the National Institutes of Health. Main outcome measures included SD scores (SDS) for height, body mass index, insulin-like growth factor (IGF)-1, and BMD, and IGF binding proteins (IGFBP)-1 and -3. Results INSR -/− vs CGL had higher insulin (median 266 [222-457] vs 33 [15-55] mcU/mL), higher IGFBP-1 (72 350 [55 571-103 107] vs 6453 [1634-26 674] pg/mL), lower BMI SDS (−0.7 ± 1.1 vs 0.5 ± 0.9), lower height SDS (−1.9[−4.3 to −1.3] vs 1.1 [0.5-2.5]), lower BMD SDS (−1.9 ± 1.4 vs 1.9 ± 0.7), and lower IGFBP-3 (0.37 [0.19-1.05] vs 2.00 [1.45-2.67] μg/mL) (P <.05 for all). INSR +/− were variable. Remission of TBIR lowered insulin and IGFBP-1, and increased IGF-1 and IGFBP-3 (P <.05). Conclusion Patients with hyperinsulinemia and impaired InsR function exhibit impaired growth and lower BMD, whereas elevated InsR signaling (CGL) causes accelerated growth and higher BMD. These patients demonstrate that insulin action through the InsR stimulates direct anabolic effects in bone and indirect actions through the growth hormone (GH)–IGF-1 axis. TBIR patients exhibit abnormalities in the GH axis that resolve when InsR signaling is restored, supporting a causal relationship between InsR and GH axis signaling. [ABSTRACT FROM AUTHOR]

Context The effects of leptin, an adipocyte-derived hormone that signals overall energy sufficiency, can only be studied in leptin-deficient conditions. In patients with lipodystrophy, a rare disease and unique model of leptin deficiency, treatment with recombinant leptin (metreleptin) improves glycemia and decreases energy expenditure. We hypothesized that these improvements might be mediated by reduced gluconeogenesis (GNG), an energy-requiring process. Objective To determine the effects of metreleptin on GNG and GNG substrates. Methods This was a single-arm prospective study of metreleptin administration in 15 patients with lipodystrophy, 9 of whom had data on GNG (NIH, 2013-2018). We analyzed total GNG, insulin-mediated suppression of GNG, glycerol, palmitate, alanine, lactate, peripheral and hepatic insulin sensitivity, and markers of glycemia (eg, HbA1c, glucose, fasting insulin). Results Metreleptin administration decreased basal GNG, increased insulin-mediated suppression of GNG, and improved insulin sensitivity and markers of glycemic control. Metreleptin reduced carbon sources for GNG, including plasma alanine and lactate, and rate of appearance (Ra) of glycerol, and decreased Ra of palmitate, a driver of GNG. Glycerol and palmitate Ra correlated with GNG prior to but not during metreleptin administration. Alanine strongly correlated with GNG both before and during metreleptin administration. Conclusions Metreleptin treatment in patients with lipodystrophy reduced GNG likely through decreased availability of carbon sources for gluconeogenesis, such as alanine, lactate, and glycerol. Associations between alanine and GNG persisted after metreleptin treatment while correlations with glycerol and palmitate Ra did not persist, suggesting reduced importance of lipolysis as a driver of GNG in the leptin-replete state. [ABSTRACT FROM AUTHOR]

Background and Aims: Fatty liver is common in obesity as well as in partial lipodystrophy (PL) syndromes, characterized by deficient adipose tissue. Insulin resistance is key to fatty liver pathogenesis in both entities. We aimed to compare the contributions of insulin resistance and adipose tissue to hepatic steatosis in PL and non‐syndromic, obesity‐associated non‐alcoholic fatty liver disease (NS‐NAFLD). Methods: In a cross‐sectional comparison of people with NS‐NAFLD (N = 73) and PL (N = 27), liver fat was measured by FibroScan® controlled attenuation parameter (CAP) and insulin resistance by HOMA‐IR, Adipo‐IR, and NMR‐based LP‐IR. Results: Insulin resistance was greater in PL versus NS‐NAFLD by HOMA‐IR (p = 0.005), Adipo‐IR (p = 0.01) and LP‐IR (p = 0.05) while liver fat was comparable (304 vs. 324 dB/m, p = 0.12). Liver fat correlated with HOMA‐IR in both groups, but CAP values were lower by 32 dB/m in PL compared with NS‐NAFLD for any given HOMA‐IR. In contrast, Adipo‐IR and LP‐IR correlated with CAP only in the NS‐NAFLD group, suggesting different pathways for fat accumulation. Plasma free fatty acids, reflecting substrate input from the adipose tissue, were comparable between groups. However, the levels of β‐hydroxybutyrate, a marker of β‐oxidation, and large triglyceride‐rich lipoprotein particles, a marker of VLDL secretion, were both higher in PL (p < 0.001 for both). Conclusion: Liver fat content was comparable in subjects with PL‐associated NAFLD and NS‐NAFLD, despite worse insulin resistance in partial lipodystrophy. Our data demonstrate higher triglyceride oxidation and export in PL, suggesting a compensatory shift of fat from liver storage into the circulation that does not occur in NS‐NAFLD. [ABSTRACT FROM AUTHOR]

BACKGROUND. Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS. Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS. With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION. Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake. TRIAL REGISTRATION. ClinicalTrials.gov NCT01778556 FUNDING. This research was supported by the intramural research program of the NIDDK., Introduction Leptin is an adipocyte-derived hormone that signals overall body energy sufficiency (1) and acute energy balance (2). Leptin-deficient states, such as starvation or mutations in the leptin gene, lead [...]