Albumin Oxidation and Albumin Glycation Discordance During Type 2 Diabetes Therapy: Biological and Clinical Implications.

Aims: Cys34 albumin redox modifications (reversible "cysteinylation" and irreversible "di/trioxidation"), besides being just oxidative stress biomarkers, may have primary pathogenetic roles to initiate and/or aggravate cell, tissue, and vascular damage in diabetes. In an exploratory "proof-of-concept" pilot study, we examined longitudinal changes in albumin oxidation during diabetes therapy. Methods: Mass spectrometric analysis was utilized to monitor changes in human serum albumin (HSA) post-translational modifications {glycation [glycated albumin (GA)], cysteinylation [cysteinylated albumin (CA) or human non-mercaptalbumin-1; reversible], di/trioxidation (di/trioxidized albumin or human non-mercaptalbumin-2; irreversible), and truncation (truncated albumin)} during ongoing therapy. Four informative groups of subjects were evaluated [type 1 diabetes (T1DM), type 2 diabetes (T2DM), prediabetes-obesity, and healthy controls] at baseline, and subjects with diabetes were followed for a period up to 280 days. Results: At baseline, T2DM was associated with relatively enhanced albumin cysteinylation (CA% total) compared with T1DM (P = 0.004), despite comparable mean hyperglycemia (P values: hemoglobin A1c = 0.09; GA = 0.09). T2DM, compared with T1DM, exhibited selectively and significantly higher elevations of all the "individual" glycated cum cysteinylated ("multimodified") albumin isoforms (P values: CysHSA+1G = 0.003; CysHSA+2G = 0.007; and CysHSA+3G = 0.001). Improvements in glycemic control and decreases in albumin glycation during diabetes therapy in T2DM were not always associated with concurrent reductions of albumin cysteinylation, and in some therapeutic situations, albumin cysteinylation worsened (glycation-cysteinylation discordance). Important differences were observed between the effects of sulfonylureas and metformin on albumin molecular modifications. Conclusions: T2DM was associated with higher oxidative (cysteinylation) and combined (cysteinylation plus glycation) albumin molecular modifications, which are not ameliorated by improved glucose control alone. Further studies are required to establish the clinical significance and optimal therapeutic strategies to address oxidative protein damage and resulting consequences in diabetes.

Metabolic and other morbid complications in congenital generalized lipodystrophy type 4.

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.

Early-onset diabetes mellitus as a presenting feature of Werner's syndrome in an Indian family.

BACKGROUND: Diabetes mellitus (DM) in children and adolescents is typically caused by type 1 DM, followed by type 2 DM and maturity-onset diabetes of the young (MODY). We report an unusual Asian Indian family in which three members presented with DM at ages 15, 20, and 30, but not fitting the typical clinical picture of type 1 DM, type 2 DM, or MODY. The primary objective was to elucidate the molecular genetic basis of DM in this family. METHODS: The proband, a 22-year-old man, had short stature, gray hair, osteoporosis, and markedly reduced subcutaneous fat on the body, especially on the extremities along with acanthosis nigricans, and developed myxoid malignant peripheral nerve sheath tumor. Detailed family history revealed multiple loops of consanguinity. The proband underwent whole-genome sequencing, and seven relatives underwent whole-exome sequencing. RESULTS: The proband and three additional family members were found to have the homozygous c.561A>G nucleotide variant of WRN RecQ-like helicase (WRN) gene consistent with the diagnosis of Werner's syndrome. The c.561A>G variant induces a new splicing site on exon 6 resulting in a truncated WRN protein, p.Lys187Trpfs*13. CONCLUSION: Our report brings to attention the onset of DM during childhood or early adulthood in patients with Werner's syndrome who typically develop type 2 DM around the age of 30-40 years. Presence of consanguinity among parents, dysmorphic features, and malignancy should prompt consideration of diagnosis of Werner's syndrome.

Marked Hypoleptinemia Precedes Overt Fat Loss in Immune Checkpoint Inhibitor-induced Acquired Generalized Lipodystrophy.

Immune checkpoint inhibitors (ICIs) targeting cancer cells that evade immune T-cell regulation have revolutionized the treatment of metastatic carcinomas. Unfortunately, secondary endocrinopathies associated with ICI, including adrenal insufficiency, primary hypothyroidism, autoimmune diabetes, and rarely hypoparathyroidism, are increasing. Lipodystrophy, presumably due to the autoimmune destruction of adipocytes, leading to metabolic complications, is a less recognized adverse effect of ICI therapy. We present a case of a 66-year-old Caucasian woman treated with pembrolizumab, an anti-programmed death 1 inhibitor, for metastatic lung adenocarcinoma. Fifteen months after the treatment initiation, she was found to have hyperglycemia, hyperlipidemia, and hepatic steatosis but without any evidence of autoimmune diabetes. She was also noted to have isolated buccal fat pad loss, raising suspicion of acquired lipodystrophy. Despite well-preserved subcutaneous fat over the trunk and limbs, she had undetectable serum leptin levels. Whole-body fluorodeoxyglucose (FDG)-positron emission tomography scan showed diffuse mild FDG activity throughout the subcutaneous tissue, suggesting underlying inflammation. Over the next 3 months, she developed progressive fat loss leading to generalized lipodystrophy. Adipose tissue dysfunction, secondary to ICI-induced subclinical panniculitis, precedes overt fat loss and is characterized by hypoleptinemia and metabolic abnormalities.

Dramatic elevation of LDL cholesterol from ketogenic-dieting: A Case Series.

High-fat, low carb dieting, also known as the "ketogenic diet," has increased in popularity as a rapid weight-loss tool. Previous studies describe a modest elevation in cholesterol in the average keto-diet participant without specific cardiovascular impact. We hypothesize that patients with a genetic predisposition to cholesterol metabolism dysregulation may have a disproportionate elevation in cholesterol in response to ketogenic dieting.

Pitfalls in Diagnosing Hypoglycemia Due to Exogenous Insulin: Validation and Utility of an Insulin Analog Assay.

OBJECTIVE: To overcome the limitations of commercially available insulin immunoassays which have variable detection of analog insulin and can lead to clinically discordant results and misdiagnosis in the workup of factitious hypoglycemia. PATIENTS AND METHODS: We performed analytical validation of a liquid chromatography high resolution accurate mass (LC-HRAM) immunoassay to detect insulin analogs. We completed clinical assessment using a large cohort of human serum samples from 78 unique individuals, and subsequently used the assay in the evaluation of eight individuals with high diagnostic suspicion for factitious hypoglycemia. RESULTS: The performance characteristics show that the LC-HRAM immunoassay can be applied to detect five commonly used synthetic insulin analogs (lispro, glulisine, aspart, glargine metabolite, and detemir) in human serum. Our clinical cases show that this assay could be used in the diagnosis of factitious hypoglycemia by identifying the analog insulin(s) in question. CONCLUSION: The LC-HRAM immunoassay reported here overcomes a gap in our diagnostic pathway for hypoglycemia. The results obtained from our studies suggest that this method is appropriate for use in clinical laboratories when factitious hypoglycemia is considered as a differential diagnosis.

Impaired Muscle Mitochondrial Function in Familial Partial Lipodystrophy.

CONTEXT: Familial partial lipodystrophy (FPL), Dunnigan variety is characterized by skeletal muscle hypertrophy and insulin resistance besides fat loss from the extremities. The cause for the muscle hypertrophy and its functional consequences is not known. OBJECTIVE: To compare muscle strength and endurance, besides muscle protein synthesis rate between subjects with FPL and matched controls (n = 6 in each group). In addition, we studied skeletal muscle mitochondrial function and gene expression pattern to help understand the mechanisms for the observed differences. METHODS: Body composition by dual-energy X-ray absorptiometry, insulin sensitivity by minimal modelling, assessment of peak muscle strength and fatigue, skeletal muscle biopsy and calculation of muscle protein synthesis rate, mitochondrial respirometry, skeletal muscle transcriptome, proteome, and gene set enrichment analysis. RESULTS: Despite increased muscularity, FPL subjects did not demonstrate increased muscle strength but had earlier fatigue on chest press exercise. Decreased mitochondrial state 3 respiration in the presence of fatty acid substrate was noted, concurrent to elevated muscle lactate and decreased long-chain acylcarnitine. Based on gene transcriptome, there was significant downregulation of many critical metabolic pathways involved in mitochondrial biogenesis and function. Moreover, the overall pattern of gene expression was indicative of accelerated aging in FPL subjects. A lower muscle protein synthesis and downregulation of gene transcripts involved in muscle protein catabolism was observed. CONCLUSION: Increased muscularity in FPL is not due to increased muscle protein synthesis and is likely due to reduced muscle protein degradation. Impaired mitochondrial function and altered gene expression likely explain the metabolic abnormalities and skeletal muscle dysfunction in FPL subjects.

Preoperative Management of Endocrine, Hormonal, and Urologic Medications: Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement.

Perioperative medical management is challenging due to the rising complexity of patients presenting for surgical procedures. A key part of preoperative optimization is appropriate management of long-term medications, yet guidelines and consensus statements for perioperative medication management are lacking. Available resources utilize the recommendations derived from individual studies and do not include a multidisciplinary focus or formal consensus. The Society for Perioperative Assessment and Quality Improvement (SPAQI) identified a lack of authoritative clinical guidance as an opportunity to utilize its multidisciplinary membership to improve evidence-based perioperative care. SPAQI seeks to provide guidance on perioperative medication management that synthesizes available literature with expert consensus. The aim of this Consensus Statement is to provide practical guidance on the preoperative management of endocrine, hormonal, and urologic medications. A panel of experts with anesthesiology, perioperative medicine, hospital medicine, general internal medicine, and medical specialty experience was drawn together and identified the common medications in each of these categories. The authors then utilized a modified Delphi approach to critically review the literature and generate consensus recommendations.

Measurement of apolipoprotein B levels helps in the identification of patients at risk for hypertriglyceridemic pancreatitis.

BACKGROUND: Severe hypertriglyceridemia (HTG) is a common cause of acute pancreatitis, although even moderate HTG may elevate this risk. Identifying patients who are prone to hypertriglyceridemic pancreatitis (HTGP) can facilitate early, preventative interventions. OBJECTIVE: To examine advanced lipoprotein profile (ALP) of hypertriglyceridemic patients with and without HTGP to identify lipid and lipoprotein parameters which may help improve risk stratification. METHODS: This was a retrospective cohort study of adult patients with serum triglycerides (TGs) ≥ 500 mg/dL who underwent ALP testing. Chart reviews were conducted to identify those who developed HTGP or not. Comparisons of lipid profiles of patients with and without HTGP were performed using chi-square or rank-sum tests. ROC curves were generated to identify lipid and lipoprotein parameters which helped improve prediction of HTGP beyond serum TG levels. RESULTS: Fifty-eight subjects were included in the analysis. Twenty had at least one documented episode of HTGP. Among patients with HTGP, median serum TG concentrations were 2832 mg/dL vs. 978 mg/dL in the non-pancreatitis group (p < 0.001). Chylomicron TG/total TG, chylomicron TG/VLDL TG, chylomicron TG/apoB, total TG/total Cholesterol, and total TG/apoB were significantly higher among the pancreatitis group. Total serum TG/apoB had the best discriminant value for predicting HTGP with an AUC-ROC of 0.87 (p < 0.001). A cutoff of >10.6 was associated with a sensitivity of 90% and specificity of 75%. CONCLUSION: Measurement of serum apoB levels and calculation of serum TG/apoB ratio may help identify hypertriglyceridemic patients at risk for HTGP.

Perioperative Evaluation and Management of Endocrine Disorders.

Evaluation of endocrine issues is a sometimes overlooked yet important component of the preoperative medical evaluation. Patients with diabetes, thyroid disease, and hypothalamic-pituitary-adrenal axis suppression are commonly encountered in the surgical setting and require unique consideration to optimize perioperative risk. For patients with diabetes, perioperative glycemic control has the strongest association with postsurgical outcomes. The preoperative evaluation should include recommendations for adjustment of insulin and noninsulin diabetic medications before surgery. Recommendations differ based on the type of diabetes, the type of insulin, and the patient's predisposition to hyperglycemia or hypoglycemia. Generally, patients with thyroid dysfunction can safely undergo operations unless they have untreated hyperthyroidism or severe hypothyroidism. Patients with known primary or secondary adrenal insufficiency require supplemental glucocorticoids to prevent adrenal crisis in the perioperative setting. Evidence supporting the use of high-dose supplemental corticosteroids for patients undergoing long-term glucocorticoid therapy is sparse. We discuss an approach to these patients based on the dose and duration of ongoing or recent corticosteroid therapy. As with other components of the preoperative medical evaluation, the primary objective is identification and assessment of the severity of endocrine issues before surgery so that the surgeons, anesthesiologists, and internal medicine professionals can optimize management accordingly.

Management of hypertriglyceridemia.

Hypertriglyceridemia is one of the most common lipid abnormalities encountered in clinical practice. Many monogenic disorders causing severe hypertriglyceridemia have been identified, but in most patients triglyceride elevations result from a combination of multiple genetic variations with small effects and environmental factors. Common secondary causes include obesity, uncontrolled diabetes, alcohol misuse, and various commonly used drugs. Correcting these factors and optimizing lifestyle choices, including dietary modification, is important before starting drug treatment. The goal of drug treatment is to reduce the risk of pancreatitis in patients with severe hypertriglyceridemia and cardiovascular disease in those with moderate hypertriglyceridemia. This review discusses the various genetic and acquired causes of hypertriglyceridemia, as well as current management strategies. Evidence supporting the different drug and non-drug approaches to treating hypertriglyceridemia is examined, and an easy to adopt step-by-step management strategy is presented.

Glycemic Outcomes of Use of CLC Versus PLGS in Type 1 Diabetes: A Randomized Controlled Trial.

OBJECTIVE: Limited information is available about glycemic outcomes with a closed-loop control (CLC) system compared with a predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS: After 6 months of use of a CLC system in a randomized trial, 109 participants with type 1 diabetes (age range, 14-72 years; mean HbA1c, 7.1% [54 mmol/mol]) were randomly assigned to CLC (N = 54, Control-IQ) or PLGS (N = 55, Basal-IQ) groups for 3 months. The primary outcome was continuous glucose monitor (CGM)-measured time in range (TIR) for 70-180 mg/dL. Baseline CGM metrics were computed from the last 3 months of the preceding study. RESULTS: All 109 participants completed the study. Mean ± SD TIR was 71.1 ± 11.2% at baseline and 67.6 ± 12.6% using intention-to-treat analysis (69.1 ± 12.2% using per-protocol analysis excluding periods of study-wide suspension of device use) over 13 weeks on CLC vs. 70.0 ± 13.6% and 60.4 ± 17.1% on PLGS (difference = 5.9%; 95% CI 3.6%, 8.3%; P < 0.001). Time >180 mg/dL was lower in the CLC group than PLGS group (difference = -6.0%; 95% CI -8.4%, -3.7%; P < 0.001) while time <54 mg/dL was similar (0.04%; 95% CI -0.05%, 0.13%; P = 0.41). HbA1c after 13 weeks was lower on CLC than PLGS (7.2% [55 mmol/mol] vs. 7.5% [56 mmol/mol], difference -0.34% [-3.7 mmol/mol]; 95% CI -0.57% [-6.2 mmol/mol], -0.11% [1.2 mmol/mol]; P = 0.0035). CONCLUSIONS: Following 6 months of CLC, switching to PLGS reduced TIR and increased HbA1c toward their pre-CLC values, while hypoglycemia remained similarly reduced with both CLC and PLGS.

Association between hyperlipidemia and mortality after incident acute myocardial infarction or acute decompensated heart failure: a propensity score matched cohort study and a meta-analysis.

OBJECTIVE: To examine the effect of HLP, defined as having a pre-existing or a new in-hospital diagnosis based on low density lipoprotein cholesterol (LDL-C) level ≥100 mg/dL during index hospitalisation or within the preceding 6 months, on all-cause mortality after hospitalisation for acute myocardial infarction (AMI) or acute decompensated heart failure (ADHF) and to determine whether HLP modifies mortality associations of other competing comorbidities. A systematic review and meta-analysis to place the current findings in the context of published literature. DESIGN: Retrospective study, 1:1 propensity-score matching cohorts; a meta-analysis. SETTING: Large academic centre, 1996-2015. PARTICIPANTS: Hospitalised patients with AMI or ADHF. MAIN OUTCOMES AND MEASURES: All-cause mortality and meta-analysis of relative risks (RR). RESULTS: Unmatched cohorts: 13 680 patients with AMI (age (mean) 68.5 ± (SD) 13.7 years; 7894 (58%) with HLP) and 9717 patients with ADHF (age, 73.1±13.7 years; 3668 (38%) with HLP). In matched cohorts, the mortality was lower in AMI patients (n=4348 pairs) with HLP versus no HLP, 5.9 versus 8.6/100 person-years of follow-up, respectively (HR 0.76, 95% CI 0.72 to 0.80). A similar mortality reduction occurred in matched ADHF patients (n=2879 pairs) with or without HLP (12.4 vs 16.3 deaths/100 person-years; HR 0.80, 95% CI 0.75 to 0.86). HRs showed modest reductions when HLP occurred concurrently with other comorbidities. Meta-analyses of nine observational studies showed that HLP was associated with a lower mortality at ≥2 years after incident AMI or ADHF (AMI: RR 0.72, 95% CI 0.69 to 0.76; heart failure (HF): RR 0.67, 95% CI 0.55 to 0.81). CONCLUSIONS: Among matched AMI and ADHF cohorts, concurrent HLP, compared with no HLP, was associated with a lower mortality and attenuation of mortality associations with other competing comorbidities. These findings were supported by a systematic review and meta-analysis.

Sirolimus Therapy Is Associated with Elevation in Circulating PCSK9 Levels in Cardiac Transplant Patients.

Sirolimus used in transplantation is often associated with hypercholesterolemia. We measured serum lipid and PCSK9 levels in 51 heart transplant recipients who had their immunosuppressive therapy switched from calcineurin inhibitors to sirolimus. The switch resulted in a 23% increase in LDL cholesterol, and 46% increase in triglycerides and PCSK9 levels increased from 316 ± 105 ng/mL to 343 ± 107 ng/mL (p = 0.04), however the change in PCSK9 levels did not correlate with an increase in lipid levels (p = 0.2). To investigate the mechanism for the variability in the change in PCSK9 levels, lymphoblastoid cell lines were incubated with both sirolimus and everolimus, resulting in a 2-3 fold increase in PCSK9 expression and protein levels in mTOR inhibitor sensitive but not in mTOR inhibitor resistant cell lines. This first in human study demonstrates that sirolimus therapy is associated with elevation in PCSK9 levels which is not associated with sirolimus-induced hypercholesterolemia.

Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial.

AIM: To evaluate the effect of alirocumab on frequency of standard apheresis treatments [weekly or every 2 weeks (Q2W)] in heterozygous familial hypercholesterolaemia (HeFH). METHODS AND RESULTS: ODYSSEY ESCAPE (NCT02326220) was a double-blind study in 62 HeFH patients undergoing regular weekly or Q2W lipoprotein apheresis. Patients were randomly assigned (2:1, respectively) to receive alirocumab 150 mg (n = 41) or placebo (n = 21) Q2W subcutaneously for 18 weeks. From day 1 to week 6, apheresis rate was fixed according to the patient's established schedule; from weeks 7 to 18, apheresis rate was adjusted based on the patient's low-density lipoprotein cholesterol (LDL-C) response in a blinded fashion. Apheresis was not performed when the LDL-C value was ≥30% lower than the baseline (pre-apheresis) value. The primary efficacy endpoint was the rate of apheresis treatments over 12 weeks (weeks 7-18), standardized to number of planned treatments. In the alirocumab group the least square (LS) mean ± SE (95% confidence interval [CI]) per cent change in pre-apheresis LDL-C from baseline at week 6 was -53.7 ± 2.3 (-58.2 to - 49.2) compared with 1.6 ± 3.1 (-4.7 to 7.9) in the placebo group. The primary efficacy endpoint showed statistically significant benefit in favour of alirocumab (Hodges-Lehmann median estimate of treatment difference: 0.75; 95% CI 0.67-0.83; P < 0.0001). Therefore, alirocumab-treated patients had a 0.75 (75%) additional reduction in the standardized rate of apheresis treatments vs. placebo-treated patients. During this period, 63.4% of patients on alirocumab avoided all and 92.7% avoided at least half of the apheresis treatments. Adverse event rates were similar (75.6% of patients on alirocumab vs. 76.2% on placebo). CONCLUSIONS: Lipoprotein apheresis was discontinued in 63.4% of patients on alirocumab who were previously undergoing regular apheresis, and the rate was at least halved in 92.7% of patients. Alirocumab was generally safe and well tolerated.