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Atypical antipsychotics increase the risk of diabetes and cardiovascular disease through their side effects of insulin resistance and weight gain. The populations for which atypical antipsychotics are used carry a baseline risk of metabolic dysregulation prior to medication which has made it difficult to fully understand whether atypical antipsychotics cause insulin resistance and weight gain directly. The purpose of this work was to conduct a systematic review and meta-analysis of atypical antipsychotic trials in healthy volunteers to better understand their effects on insulin sensitivity and weight gain. Furthermore, we aimed to evaluate the occurrence of insulin resistance with or without weight gain and with treatment length by using subgroup and meta-regression techniques. Overall, the meta-analysis provides evidence that atypical antipsychotics decrease insulin sensitivity (standardized mean difference = − 0.437, p < 0.001) and increase weight (standardized mean difference = 0.591, p < 0.001) in healthy volunteers. It was found that decreases in insulin sensitivity were potentially dependent on treatment length but not weight gain. Decreases in insulin sensitivity occurred in multi-dose studies < 13 days while weight gain occurred in studies 14 days and longer (max 28 days). These findings provide preliminary evidence that atypical antipsychotics cause insulin resistance and weight gain directly, independent of psychiatric disease and may be associated with length of treatment. Further, well-designed studies to assess the co-occurrence of insulin resistance and weight gain and to understand the mechanisms and sequence by which they occur are required. [ABSTRACT FROM AUTHOR]

Study Objective: Atypical antipsychotics cause insulin resistance that leads to an increased risk of diabetes mellitus and cardiovascular disease. Skeletal muscle is the primary tissue for uptake of glucose, and its dysfunction is considered one of the primary defects in the development of insulin resistance. Protein kinase B (AKT) plays an important role in overall skeletal muscle health and glucose uptake into the muscle. The objective of this study was to measure AKT isoform–specific gene methylation differences in the skeletal muscle of patients with bipolar disorder treated with atypical antipsychotic or mood stabilizer maintenance therapy. Design: Cross‐sectional observational study. Setting: Clinical research services center at an academic center. Patients: Thirty patients with a confirmed diagnosis of bipolar disorder who were treated with either an atypical antipsychotic (16 patients) or mood stabilizer (14 patients) at a consistent dose for at least 3 months. Interventions: A fasting skeletal muscle biopsy was performed in the vastus lateralis in each patient. Patients also underwent fasting blood sample collection and a standard 75‐g oral glucose tolerance test. Measurements and Main Results: Skeletal muscle DNA methylation near the promoter region for three genes, AKT1, AKT2, and AKT3, was measured by methylation‐sensitive high‐resolution melting. Gene methylation was analyzed based on atypical antipsychotic versus mood stabilizer maintenance therapy. Associations between gene methylation, insulin resistance, and glucose tolerance were also analyzed. In patients treated with atypical antipsychotics, AKT1 and AKT2 methylation was increased compared with patients treated with mood stabilizers (p=0.03 and p=0.02, respectively). In addition, for patients receiving atypical antipsychotics, a positive trend for AKT2 hypermethylation with increasing insulin resistance was observed, whereas for patients receiving mood stabilizers, a trend for decreased AKT2 methylation with increasing insulin resistance was observed. Conclusion: Overall, our findings suggest that the AKT gene is differentially methylated in the skeletal muscle of patients taking atypical antipsychotics or mood stabilizer maintenance therapy. These results may direct future approaches to reduce the harmful adverse effects of atypical antipsychotic treatment. [ABSTRACT FROM AUTHOR]

Antipsychotic medications demonstrate a variable range of efficacy and side effects in patients with mental illness. Research has attempted to identify biomarkers associated with antipsychotic effects in various populations. Research designs utilizing healthy volunteers may have the added benefit of measuring the effect of antipsychotics on a given biomarker (s) independent of the varied environmental and clinical factors that often accompany patient populations. The aim of this systematic review and meta‐analysis was to synthesize the current evidence of hormonal, inflammatory, and metabolic biomarker studies of antipsychotic treatment in study designs using healthy volunteers. The systematic review was performed according to established guidelines and a random effects meta‐analysis of biomarkers appearing in at least three studies was performed while biomarkers in two or less studies were qualitatively summarized. A total of 28 studies including 28 biomarkers were identified. Meta‐analyses were carried out for 14 biomarkers, showing significant effects within six biomarkers (cortisol, C‐peptide, free fatty acids, leptin, thyroid‐stimulating hormone, and prolactin). Many of these effects were associated with olanzapine, the most used antipsychotic amongst the trials, observed on sub‐analyses. When combining biomarkers into categories, some additional effects were observed, for example, when grouping inflammatory biomarkers. These findings suggest that antipsychotics exert potentially strong effects on several biomarkers of interest independent of psychiatric disease which could be used to spur future investigations, however, replication work is needed for many biomarkers included in this review. [ABSTRACT FROM AUTHOR]

Skeletal muscle insulin resistance is one of the primary contributors of type 2 diabetes (T2D). Metformin is the first-line drug for the treatment of T2D. Main known effects of metformin include inhibition of glucose production in liver and attenuation of insulin resistance in skeletal muscle. However, molecular mechanism of metformin's action in skeletal muscle is not well understood. Protein phosphatase 2A (PP2A), a major serine/threonine phosphatase, plays a pivotal role in cellular processes (e.g., signal transduction, apoptosis), and acts through dephosphorylating key signaling molecules such as AKT, AMPK, etc. However, whether or not PP2A plays a role in metformin-induced insulin sensitivity improvement in human skeletal muscle cells remains to be elucidated. In the present study, hyperinsulinemic-euglycemic clamp was performed to assess insulin sensitivity in human subjects and skeletal muscle biopsy samples were obtained. Primary human skeletal muscle cells (shown to retain metabolic characteristics of donors) were cultured from these muscle biopsies from 8 lean insulin sensitive participants (4 Female and 4 male; age: 21.4±0.8 yrs; BMI: 22.1±0.7 kg/m2; 2-hour OGTT: 96.5± 6.3 mg/dl; HbA1c: 5.3±0.1 %; fasting plasma glucose: 87.5±1.4 mg/dl; M-value; 10.9±0.8 mg/kgBW/min). The cells were expanded, differentiated into myotubes, and treated with 50µM metformin (the physiologic concentration) for 24 hours before harvesting. PP2A activity was measured by a phosphatase activity assay (Millipore). The results indicated that metformin increased the activity of PP2A in the myotubes derived from all 8 participants, and the average fold increase is 1.59±0.13 (p<0.05). These results provided the first evidence to suggest that metformin promotes activation of PP2A in human skeletal muscle cells derived from lean insulin sensitive participants, and may help to understand metformin's action in skeletal muscle in humans. Disclosure: A.H. Mestareehi: None. B. Seyoum: None. Z. Msallaty: None. A.P. Mallisho: None. X. Zhang: None. A. Kowluru: None. Z. Yi: None. Funding: American Diabetes Association (1-13-TS-27 to Z.Y.); National Institutes of Health (R01DK107666, R01DK081750 to Z.Y.), (T32HL120822 to A.H.M.); DOTS Scholars (to A.H.M., Z.Y.) [ABSTRACT FROM AUTHOR]

Context. Skeletal muscle insulin resistance is one of the primary contributors of type 2 diabetes (T2D). Metformin is the first-line drug for the treatment of T2D. The primary effects of metformin include decreasing glucose production in the liver and decreasing insulin resistance in the skeletal muscle. However, the molecular mechanism of metformin's action in skeletal muscle is not well understood. Protein phosphatase 2A (PP2A), a major serine/threonine protein phosphatase, plays a pivotal role in cellular processes, such as signal transduction, cell proliferation, and apoptosis, and acts through dephosphorylating key signaling molecules such as AKT and AMPK. However, whether PP2A plays a role in metformin-induced insulin sensitivity improvement in human skeletal muscle cells remains to be elucidated. Objective. To investigate if PP2A plays a role in metformin-induced insulin sensitivity improvement in human skeletal muscle cells. Participants. Eight lean insulin-sensitive nondiabetic participants (4 females and 4 males; age: 21.0 ± 1.0 years; BMI: 22.0 ± 0.7 kg / m 2 ; 2-hour OGTT: 97.0 ± 6.0 mg / dl ; HbA1c: 5.3 ± 0.1 % ; fasting plasma glucose: 87.0 ± 2.0 mg / dl ; M value; 11.0 ± 1.0 mg / kgBW / min). Design. A hyperinsulinemic-euglycemic clamp was performed to assess insulin sensitivity in human subjects, and skeletal muscle biopsy samples were obtained. Primary human skeletal muscle cells (shown to retain metabolic characteristics of donors) were cultured from these muscle biopsies that included 8 lean insulin-sensitive participants. Cultured cells were expanded, differentiated into myotubes, and treated with 50 μM metformin for 24 hours before harvesting. PP2Ac activity was measured by a phosphatase activity assay kit (Millipore) according to the manufacturer's protocol. Results. The results indicated that metformin significantly increased the activity of PP2A in the myotubes for all 8 lean insulin-sensitive nondiabetic participants, and the average fold increase is 1.54 ± 0.11 (P < 0.001). Conclusions. These results provided the first evidence that metformin can activate PP2A in human skeletal muscle cells derived from lean healthy insulin-sensitive participants and may help to understand metformin's action in skeletal muscle in humans. [ABSTRACT FROM AUTHOR]

Background: This study profiles ceramides extracted from visceral and subcutaneous adipose tissue of human subjects by liquid chromatography‐mass spectrometry to determine a correlation with status of diabetes and gender. Methods: Samples of visceral and abdominal wall subcutaneous adipose tissue (n = 36 and n = 31, respectively) were taken during laparoscopic surgery from 36 patients (14 nondiabetic, 22 diabetic and prediabetic) undergoing bariatric surgery with a body mass index (BMI) >35 kg/m2 with ≥1 existing comorbidity or BMI ≥40 kg/m2. Sphingolipids were extracted and analyzed using liquid chromatography‐mass spectrometry. Results: After logarithm 2 conversion, paired analysis of visceral to subcutaneous tissue showed differential accumulation of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) in visceral tissue of prediabetic/diabetic female subjects, but not in males. Within‐tissue analysis showed higher mean levels of ceramide species linked to insulin resistance, such as Cer(d18:1/18:0) and Cer(d18:1/16:0), in visceral tissue of prediabetic/diabetic patients compared with nondiabetic subjects and higher content of Cer(d18:1/14:0) in subcutaneous tissue of insulin‐resistant female patients compared with prediabetic/diabetic males. Statistically significant differences in mean levels of ceramide species between insulin‐resistant African American and insulin‐resistant Caucasian patients were not evident in visceral or subcutaneous tissue. Conclusions: Analysis of ceramides is important for developing a better understanding of biological processes underlying type 2 diabetes, metabolic syndrome, and obesity. Knowledge of the accumulated ceramides/dihydroceramides may reflect on the prelipolytic state that leads the lipotoxic phase of insulin resistance and may shed light on the predisposition to insulin resistance by gender. [ABSTRACT FROM AUTHOR]

Background: Management of type 1 diabetes (T1D) involves achieving glycemic targets to avoid complications. However, despite advancements in diabetes technology and standards, achieving adequate glycemic control in children and adolescents remains a challenge. This study aims to identify factors associated with optimal glycemic targets of <7% in the T1DX-QI collaborative, a U.S. based multi-center study. Methods: The analysis included 9,991 T1D patients (1-18 years) from eight sites in the T1D Exchange Quality Improvement (T1DX-QI) database for whom electronic health record data was available with at least one completed clinic encounter between July 2017-July 2020. Results: Among those with hemoglobin A1c <7%, more were Non-Hispanic White (72% vs. 66%) and privately insured patients (59% vs. 44%) compared to patients with A1c > 7% [p<0.001]. Additional analysis showed that patients who used both continuous glucose monitor and insulin pump for diabetes management were more likely to have better glycemic control compared to those who did not use this combination. Conclusions: This study highlights real-world challenges and social disparities in achieving optimal glycemic control. A combination of CGM and insulin pump device use is beneficial for the effective management of blood glucose levels. T1Dx-QI sites are implementing best practices to improve optimal outcomes. Disclosure: O. Ebekozien: None. E. L. Ospelt: None. M. K. Kamboj: None. T1dx-qi collaborative: n/a. N. Noor: Research Support; Self; Dexcom, Inc. B. Seyoum: None. S. Majidi: Advisory Panel; Self; Companion Medical. N. Jones: Consultant; Self; Companion Medical, Medtronic. R. Mcdonough: None. J. Sanchez: None. A. Kim: None. R. Izquierdo: None. Funding: The Leona M. and Harry B. Helmsley Charitable Trust [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is highly prevalent worldwide, and its individual components obesity, diabetes, and hypertension have been identified as risk factors to develop severe coronavirus disease 2019 (COVID‐19); however, data on MetS and clinical outcomes in COVID‐19 are scarce. This study aims to determine association between MetS and severe disease outcomes, that is, mortality, need for mechanical ventilation, and intensive care unit (ICU) requirement among patients with COVID‐19. Methods: This is a retrospective multihospital cohort study on 1871 patients with confirmed COVID‐19 diagnosis. Patient data including demographics, comorbidities, body mass index (BMI), smoking, laboratory data, and the clinical course of hospitalization were collected. Multivariable regression was performed adjusting for age, sex, race, insurance, smoking, and comorbidities. Results: A total of 1871 patients (median age 66 [interquartile range, IQR 54‐75]; 965 (51.6%) males; 1494 (80%) African Americans; median BMI 29.4 kg/m2 [IQR 25‐35.8]; 573 (30.6%) patients with MetS) were included. Patients with MetS had increased mortality (odds ratio [OR], 1.40; 95% CI, 1.11‐1.75; P =.004), higher ICU admission (OR, 1.68; 95% CI, 1.36‐2.08; P <.001), and increased need for mechanical ventilation (OR, 1.90; 95% CI, 1.52‐2.37; P <.001). Among individual comorbidities, diabetes had significant association with mortality (OR, 1.30; 95% CI, 1.05‐1.63; P = 0.02), ICU admission (OR, 1.56; 95% CI, 1.27‐1.93; P <.001), and need for mechanical ventilation (OR, 1.63; 95% CI, 1.30‐2.03; P <.001). Conclusions: MetS is a better prognostic indicator for severe disease outcomes in patients with COVID‐19 than its individual components. Patients with MetS had significantly higher mortality, increased ICU admissions, and need for mechanical ventilation. [ABSTRACT FROM AUTHOR]

Insulin resistance in skeletal muscle is among the primary contributors to the development of type 2 diabetes (T2D), a leading cause of heart disease, stroke, etc. Over 26 million U.S. adults have T2D. Molecular mechanisms for skeletal muscle insulin resistance remain elusive, limiting strategies to prevent/treat T2D. Phospholipase C, gamma 1 (PLCG1, aka PLC-γ1) serves as a signal transducer of tyrosine kinases and regulates various downstream signaling pathways in vitro. PLCG1 has been shown to interact with insulin receptor (IR) via its pleckstrin homology domain and plays a significant role in insulin-stimulated glucose uptake in adipocytes. Moreover, phosphorylation of tyrosine residue 771 (pTyr771) of PLCG1 has been shown to regulate PLCG1 activity. However, no prior publication shows that PLCG1 pTyr771 is linked with insulin resistance and T2D. Previously, we observed that insulin-stimulated PLCG1 pTyr771 is impaired in skeletal muscle from subjects with T2D compared to lean controls. In the present work, we mutated Tyr771 of PLCG1 to phenylalanine, and observed reduced insulin-stimulated AKT and AS160 phosphorylation in primary human skeletal muscle cells derived from an insulin sensitive participant. To identify the upstream regulator of PLCG1, we carried out in vitro kinase assay by incubating PLCG1 with insulin receptor. PLCG1 was expressed and purified from E. coli. The insulin receptor (active cytoplasmic terminus) was expressed and purified from insect cells. After incubating PLCG1 with insulin receptor in vitro for 30 min in the presence of ATP, PLCG1 phosphorylation was determined by HPLC-ESI-MS/MS. The result demonstrated that insulin receptor phosphorylated Tyr771 of PLCG1. Western blotting using pTyr771 specific antibodies confirmed these findings. In summary, these results suggest that reduced insulin-stimulated pTyr771 may contribute to the development of insulin resistance and T2D, and the insulin receptor is an upstream regulator of PLCG1 pTyr771. Disclosure: X. Zhang: None. A.H. Mestareehi: None. B. Seyoum: None. Z. Yi: None. Funding: American Diabetes Association (1-13-TS-27 to Z.Y.); National Institutes of Health (R01DK107666, R01DK081750 to Z.Y.), (T32HL120822 to A.H.M.); DOTS Scholars (to A.H.M., Z.Y.) [ABSTRACT FROM AUTHOR]

The pharmacoepigenetics of antipsychotic treatment in severe mental illness is a growing area of research that aims to understand the interface between antipsychotic treatment and genetic regulation. Pharmacoepigenetics may some day assist in identifying treatment response mechanisms or become one of the components in the implementation of precision medicine. To understand the current evidence regarding the effects of antipsychotics on DNA methylation a systematic review with qualitative synthesis was performed through Pubmed, Embase and Psychinfo from earliest data to June 2019. Studies were included if they analyzed DNA methylation in an antipsychotic‐treated population of patients with schizophrenia or bipolar disorder. Data extraction occurred via a standardized format and study quality was assessed. Twenty‐nine studies were identified for inclusion. Study design, antipsychotic type, sample source, and methods of DNA methylation measurement varied across all studies. Eighteen studies analyzed methylation in patients with schizophrenia, four studies in patients with bipolar disorder, and seven studies in a combined sample of schizophrenia and bipolar disorder. Twenty‐two studies used observational samples whereas the remainder used prospectively treated samples. Six studies assessed global methylation, five assessed epigenome‐wide, and 15 performed a candidate epigenetic study. Two studies analyzed both global and gene‐specific methylation, whereas one study performed a simultaneous epigenome‐wide and gene‐specific study. Only three genes were analyzed in more than one gene‐specific study and the findings were discordant. The state of the pharmacoepigenetic literature on antipsychotic use is still in its early stages and uniform reporting of methylation site information is needed. Future work should concentrate on using prospective sampling with appropriate control groups and begin to replicate many of the novel associations that have been reported. [ABSTRACT FROM AUTHOR]

We would like to comment on the recently published article titled: "Circulating Vitamin D levels status and clinical prognostic indices in COVID-19 patients" by Ricci et al. The authors grouped the patients into two groups according to the vitamin D levels measured at the time of admission into the hospital and reported that lower vitamin D levels are associated with elevated D-dimer and IL-6 levels, low CD4/CD8 ratio and compromised clinical findings with elevated LIPI and SOFA scores. However, review of recent literature shows this association to be debatable. The 25-hydroxyvitamin D levels in the initial phase of critical illness have been reported to drop rapidly and hence consideration of the time of measurement from symptom onset would have enhanced the clinical relevance of these findings. Inferred association between vitamin D levels and disease severity based on SOFA score in COVID-19 patients, needs to be further explored in the light of the recent literature which casts doubt on using SOFA score at admission to predict mortality in COVID-19. [ABSTRACT FROM AUTHOR]

Patient-derived progenitor cell (PC) dysfunction is severely impaired in diabetes, but the molecular triggers that contribute to mechanisms of PC dysfunction are not fully understood. Methylglyoxal (MGO) is one of the highly reactive dicarbonyl species formed during hyperglycemia. We hypothesized that the MGO scavenger glyoxalase 1 (GLO1) reverses bone marrow-derived PC (BMPC) dysfunction through augmenting the activity of an important endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α (IRE1α), resulting in improved diabetic wound healing. BMPCs were isolated from adult male db/db type 2 diabetic mice and their healthy corresponding control db/+ mice. MGO at the concentration of 10 µmol/L induced immediate and severe BMPC dysfunction, including impaired network formation, migration, and proliferation and increased apoptosis, which were rescued by adenovirus-mediated GLO1 overexpression. IRE1α expression and activation in BMPCs were significantly attenuated by MGO exposure but rescued by GLO1 overexpression. MGO can diminish IRE1α RNase activity by directly binding to IRE1α in vitro. In a diabetic mouse cutaneous wound model in vivo, cell therapies using diabetic cells with GLO1 overexpression remarkably accelerated wound closure by enhancing angiogenesis compared with diabetic control cell therapy. Augmenting tissue GLO1 expression by adenovirus-mediated gene transfer or with the small-molecule inducer trans-resveratrol and hesperetin formulation also improved wound closure and angiogenesis in diabetic mice. In conclusion, our data suggest that GLO1 rescues BMPC dysfunction and facilitates wound healing in diabetic animals, at least partly through preventing MGO-induced impairment of IRE1α expression and activity. Our results provide important knowledge for the development of novel therapeutic approaches targeting MGO to improve PC-mediated angiogenesis and tissue repair in diabetes. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa keratitis is characterized by severe corneal ulceration and may lead to blindness if not treated properly in a timely manner. Although the roles of the IL-1 subfamily of cytokines are well established, as a newly discovered subfamily, IL-36 cytokine regulation, immunological relevance, and relation with IL-1 cytokines in host defense remain largely unknown. In this study, we showed that P. aeruginosa infection induces the expression of IL-36α and IL-36γ, as well as IL-1β and secreted IL-1Ra (sIL-1Ra), but not IL-36Ra. Downregulation of IL-1Ra increases, whereas downregulation of IL-36Ra decreases the severity of P. aeruginosa keratitis. IL-1R and IL-36Ra downregulation have opposing effects on the expression of IL-1β, sIL-1Ra, IL-36γ, S100A8, and CXCL10 and on the infiltration of innate immune cells. Administration of recombinant IL-1Ra improved, whereas IL-36Ra worsened the outcome of P. aeruginosa keratitis. Local application of IL-36γ stimulated the expression of innate defense molecules S100A9, mouse β-defensin 3, but suppressed IL-1β expression in B6 mouse corneas. IL-36γ diminished the severity of P. aeruginosa keratitis, and its protective effects were abolished in the presence of S100A9 neutralizing Ab and partially affected by CXCL10 and CXCR3 neutralizations. Thus, our data reveal that IL-1Ra and IL-36Ra have opposing effects on the outcome of P. aeruginosa keratitis and suggest that IL-36 agonists may be used as an alternative therapeutic to IL-1β-neutralizing reagents in controlling microbial keratitis and other mucosal infections. [ABSTRACT FROM AUTHOR]

Context An extensive body of literature indicates a relationship between insulin resistance and the up-regulation of the kynurenine pathway, i.e. the preferential conversion of tryptophan to kynurenine, with subsequent overproduction of diabetogenic downstream metabolites, such as kynurenic acid. Case description We have measured the concentration of kynurenine pathway metabolites (kynurenines) in the brain and pancreas of two young (27 and 28 yrs) insulin resistant, normoglycemic subjects (M-values 2 and 4 mg/kg/min, respectively) using quantitative C-11-alpha-methyl-tryptophan PET/CT imaging. Both subjects underwent a preventive 12-week metformin treatment regimen (500 mg daily) prior to the PET/CT study. Whereas treatment was successful in one of the subject (M-value increased from 2 to 12 mg/kg/min), response was poor in the other subjects (M-value changed from 4 to 5 mg/kg/min). Brain and pancreas concentrations of kynurenines observed in the responder were similar to that in a healthy control subject, whereas kynurenines determined in the non-responder were about 25% higher and similar to those found in a severely insulin resistant patient. Consistent with this outcome, M-values were negatively correlated with both kynurenic acid levels (R 2 = 0.68, p = 0.09) as well as with the kynurenine to tryptophan ratio (R 2 = 0.63, p = 0.11). Conclusion The data indicates that kynurenine pathway metabolites are increased in subjects with insulin resistance prior to overt manifestation of hyperglycemia. Moreover, successful metformin treatment leads to a normalization of tryptophan metabolism, most likely as a result of decreased contribution from the kynurenine metabolic pathway. [ABSTRACT FROM AUTHOR]

Insulin resistance, which plays a central role in the pathogenesis of type 2 diabetes (T2D), is an early indicator that heralds the occurrence of T2D. It is imperative to understand the metabolic changes that occur at the cellular level in the early stages of insulin resistance. The objective of this study was to determine the pattern of circulating lactate levels during oral glucose tolerance test (OGTT) and hyperinsulinemic euglycemic clamp (HIEC) study in normal nondiabetic subjects. Lactate and glycerol were determined every 30 minutes during OGTT and HIEC on 22 participants. Lactate progressively increased throughout the HIEC study period (P<0.001). Participants with BMI < 30 had significantly higher mean M-values compared to those with BMI ≥ 30 at baseline (P<0.05). This trend also continued throughout the OGTT. In addition, those with impaired glucose tolerance test (IGT) had significantly higher mean lactate levels compared to those with normal glucose tolerance (P<0.001). In conclusion, we found that lactate increased during HIEC study, which is a state of hyperinsulinemia similar to the metabolic milieu seen during the early stages in the development of T2D. [ABSTRACT FROM AUTHOR]

Atypical antipsychotics (AAP) are used in the treatment of severe mental illness. They are associated with several metabolic side effects including insulin resistance. The skeletal muscle is the primary tissue responsible for insulin-stimulated glucose uptake. Dysfunction of protein regulation within the skeletal muscle following treatment with AAPs may play a role in the associated metabolic side effects. The objective of this study was to measure protein abundance in the skeletal muscle of patients on long-term AAP or mood stabilizer treatment. Cross-sectional muscle biopsies were obtained from patients with bipolar disorder and global protein abundance was measured using stable isotope labeling by amino acid (SILAC) combined with high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Sixteen patients completed muscle biopsies and were included in the proteomic analyses. A total of 40 proteins were significantly different between the AAP group and the mood stabilizer group. In-silico pathway analysis identified significant enrichment in several pathways including glucose metabolism, cell cycle, apoptosis, and folate metabolism. Proteome abundance changes also differed based on protein biological processes and function. In summary, significant differences in proteomic profiles were identified in the skeletal muscle between patients on AAPs and mood stabilizers. Future work is needed to validate these findings in prospectively sampled populations. [ABSTRACT FROM AUTHOR]

Insulin receptor substrate 1 (IRS1) is a key mediator of insulin signal transduction. Perturbations involving IRS1 complexes may lead to the development of insulin resistance and type 2 diabetes (T2D). Surprisingly little is known about the proteins that interact with IRS1 in humans under health and disease conditions. We used a proteomic approach to assess IRS1 interaction partners in skeletal muscle from lean healthy control subjects (LCs), obese insulin-resistant nondiabetic control subjects (OCs), and participants with T2D before and after insulin infusion. We identified 113 novel endogenous IRS1 interaction partners, which represents the largest IRS1 interactome in humans and provides new targets for studies of IRS1 complexes in various diseases. Furthermore, we generated the first global picture of IRS1 interaction partners in LCs, and how they differ in OCs and T2D patients. Interestingly, dozens of proteins in OCs and/or T2D patients exhibited increased associations with IRS1 compared with LCs under the basal and/or insulin-stimulated conditions, revealing multiple new dysfunctional IRS1 pathways in OCs and T2D patients. This novel abnormality, increased interaction of multiple proteins with IRS1 in obesity and T2D in humans, provides new insights into the molecular mechanism of insulin resistance and identifies new targets for T2D drug development. [ABSTRACT FROM AUTHOR]

Lipasin (also known as C19ORF80, RIFL, ANGPTL8 and betatrophin) is a newly discovered circulating factor that regulates lipid metabolism and promotes pancreatic β-cell proliferation. Whether circulating levels of lipasin in humans are altered in a) type 2 diabetes; b) obesity and c) the postprandial state, however, is unknown. The current study aimed to compare serum lipasin levels in those who were a) non-diabetic (N = 15) or diabetic (BMI- and age-matched; N = 14); b) lean or obese (N = 53 totally) and c) fasting and 2 hours following a defined meal (N = 12). Serum lipasin levels were determined by the enzyme-linked immunosorbent assay. Lipasin levels [mean±SEM] were increased by more than two fold (P<0.001) in the diabetic patients (5.56 ± 0.73 ng/mL) as compared to the control subjects (2.19 ± 0.24 ng/mL). Serum lipasin levels were positively correlated with BMI (rho = 0.49, P , 0.001), and showed a 35% increase 2 hours following a defined meal (P = 0.009). Therefore, lipasin/betatrophin is nutritionally-regulated hepatokine that is increased in human type 2 diabetes and obesity. [ABSTRACT FROM AUTHOR]