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Short sleep duration is associated with impaired glucose tolerance and an increased risk of diabetes. The effects of sleep restriction on insulin sensitivity have not been established. This study tests the hypothesis that decreasing nighttime sleep duration reduces insulin sensitivity and assesses the effects of a drug, modafinil, that increases alertness during wakefulness. This 12-day inpatient General Clinical Research Center study included 20 healthy men (age 20-35 years and BMI 20-30 kg/m(2)). Subjects spent 10 h/night in bed for >or=8 nights including three inpatient nights (sleep-replete condition), followed by 5 h/night in bed for 7 nights (sleep-restricted condition). Subjects received 300 mg/day modafinil or placebo during sleep restriction. Diet and activity were controlled. On the last 2 days of each condition, we assessed glucose metabolism by intravenous glucose tolerance test (IVGTT) and euglycemic-hyperinsulinemic clamp. Salivary cortisol, 24-h urinary catecholamines, and neurobehavioral performance were measured. IVGTT-derived insulin sensitivity was reduced by (means +/- SD) 20 +/- 24% after sleep restriction (P = 0.001), without significant alterations in the insulin secretory response. Similarly, insulin sensitivity assessed by clamp was reduced by 11 +/- 5.5% (P < 0.04) after sleep restriction. Glucose tolerance and the disposition index were reduced by sleep restriction. These outcomes were not affected by modafinil treatment. Changes in insulin sensitivity did not correlate with changes in salivary cortisol (increase of 51 +/- 8% with sleep restriction, P < 0.02), urinary catecholamines, or slow wave sleep. Sleep restriction (5 h/night) for 1 week significantly reduces insulin sensitivity, raising concerns about effects of chronic insufficient sleep on disease processes associated with insulin resistance.

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Populations at risk for AD show altered brain activity in the default mode network (DMN) before cognitive dysfunction. We evaluated this brain pattern in T2DM patients. We compared T2DM patients (n = 10, age = 56 ± 2.2 years, fasting plasma glucose [FPG] = 8.4 ± 1.3 mmol/L, HbA(1c) = 7.5 ± 0.54%) with nondiabetic age-matched control subjects (n = 11, age = 54 ± 1.8 years, FPG = 4.8 ± 0.2 mmol/L) using resting-state functional magnetic resonance imaging to evaluate functional connectivity strength among DMN regions. We also evaluated hippocampal volume, cognition, and insulin sensitivity by homeostasis model assessment of insulin resistance (HOMA-IR). Control subjects showed stronger correlations versus T2DM patients in the DMN between the seed (posterior cingulate) and bilateral middle temporal gyrus (β = 0.67 vs. 0.43), the right inferior and left medial frontal gyri (β = 0.75 vs. 0.54), and the left thalamus (β = 0.59 vs. 0.37), respectively, with no group differences in cognition or hippocampal size. In T2DM patients, HOMA-IR was inversely correlated with functional connectivity in the right inferior frontal gyrus and precuneus. T2DM patients showed reduced functional connectivity in the DMN compared with control subjects, which was associated with insulin resistance in selected brain regions, but there were no group effects of brain structure or cognition.

BACKGROUNDBariatric surgery is a potent therapeutic approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1-3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin.METHODSTo identify mediators of disordered metabolism in PBH, we analyzed the plasma metabolome in the fasting state and 30 and 120 minutes after mixed meal in 3 groups: PBH (n = 13), asymptomatic post-Roux-en-Y gastric bypass (post-RYGB) (n = 10), and nonsurgical controls (n = 8).RESULTSIn the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone β-hydroxybutyrate were increased by 30%-80% in PBH versus asymptomatic. Conversely, multiple amino acids (branched-chain amino acids, tryptophan) and polyunsaturated lipids were reduced by 20%-50% in PBH versus asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced 2- to 10-fold in PBH in the fasting state. Postprandially, plasma serotonin was uniquely increased 1.9-fold in PBH versus asymptomatic post-RYGB. In mice, serotonin administration lowered glucose and increased plasma insulin and GLP-1. Moreover, serotonin-induced hypoglycemia in mice was blocked by the nonspecific serotonin receptor antagonist cyproheptadine and the specific serotonin receptor 2 antagonist ketanserin.CONCLUSIONTogether these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a potential therapeutic target.FUNDINGNational Institutes of Health (NIH) grant R01-DK121995, NIH grant P30-DK036836 (Diabetes Research Center grant, Joslin Diabetes Center), and Fundação de Amparo à Pesquisa do Estado de São Paulo grant 2018/22111-2.

To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR’s mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling. Trial Registration: Clinicaltrials.gov NCT01073020. Factors underlying the effects of gastric bypass surgery on glucose homeostasis are incompletely understood. Here the authors developed and applied high-throughput mediation analysis to identify proteome/metabolome mediators of improved glucose homeostasis after to gastric bypass surgery, and report that improved glycemia was mediated by the growth hormone receptor.

Androgen deprivation therapy (ADT), a cornerstone of treatment for patients with locally advanced and metastatic prostate cancer, is associated with many adverse effects, including osteoporosis, sexual dysfunction, fatigue, and vasomotor symptoms. It is also associated with loss of muscle mass and increased adiposity. This change in body composition is likely the inciting event in the development of insulin resistance, an independent risk factor for diabetes mellitus and cardiovascular disease. Although the occurrence of insulin resistance during ADT has been reported, it remains unclear whether this insulin resistance is primarily hepatic or muscular. Similarly, the mechanisms that lead to insulin resistance also remain unknown. The ADT & Metabolism Study was designed to address these knowledge gaps, as the elucidation of the predominant site of insulin resistance will allow prevention strategies and the use of targeted, tissue-specific insulin-sensitizing agents in patients undergoing ADT. This prospective, mechanistic, single-center, 24-week, observational cohort study will enroll treatment-naïve adult men with prostate cancer about to undergo surgical or medical ADT for at least 24 weeks (ADT group; n = 50) and a control group of men who had undergone radical prostatectomy and are in remission (non-ADT group, n = 25). The primary outcome is to determine the site of insulin resistance (skeletal muscle or liver) using frequent sampling oral glucose tolerance test at baseline and 12 and 24 weeks after commencement of ADT (ADT group) or after enrollment in the study (non-ADT group). Secondary outcomes will assess changes in hepatic and intramyocellular fat (using magnetic resonance spectroscopy), inflammatory markers, adipokines, free fatty acids, and changes in body composition (assessed using dual-energy x-ray absorptiometry) and their correlation with the development of insulin resistance. Exploratory outcomes will include changes in muscle performance, physical function, physical activity, vitality, and sexual drive.

[This corrects the article DOI: 10.3389/fnins.2025.1516746.].

Aging is the primary risk factor for sporadic Alzheimer's disease. Chronic low-grade inflammation associated with aging drives cognitive impairment through multiple mechanisms involving oxidative stress, insulin resistance, and dysregulation of metabolic, immunologic, and hematologic systems. In a 7-month, randomized, double-blind, placebo-controlled trial (NCT04669028), we investigated the safety and activity of bezisterim, a first-in-class, oral, blood-brain barrier-permeable, anti-inflammatory agent on cognitive, molecular, biochemical, physiological, and biological aging parameters in a subset of 50 mild-to-moderate probable Alzheimer's disease participants. These participants had source-document-verified clinical measures and samples, and they completed the protocol. This study focuses on epigenetic, metabolic, biomarker, and cognitive measures in the exploratory biomarker population that completed the protocol. Bezisterim was associated with non-significant directional improvements in multiple measures of cognitive and functional performance compared to placebo, with correlations to biological age (determined by DNA methylation \"clocks\") and to metabolism, inflammation, and dementia biomarkers. In addition, clinical measures correlated with the extent of DNA methylation of certain cytosine-phosphate-guanine (CpG) sites in genes associated with metabolic inflammation and neurodegeneration. The results suggest the possible use of bezisterim to target the multifactorial processes underlying dementia. https://clinicaltrials.gov/study/NCT04669028, Identifier: NCT04669028.

IntroductionWe previously reported predictors of mortality in 1786 adults with diabetes or stress hyperglycemia (glucose>180 mg/dL twice in 24 hours) admitted with COVID-19 from March 2020 to February 2021 to five university hospitals. Here, we examine predictors of readmission.Research design and methodsData were collected locally through retrospective reviews of electronic medical records from 1786 adults with diabetes or stress hyperglycemia who had a hemoglobin A1c (HbA1c) test on initial admission with COVID-19 infection or within 3 months prior to initial admission. Data were entered into a Research Electronic Data Capture (REDCap) web-based repository, and de-identified. Descriptive data are shown as mean±SD, per cent (%) or median (IQR). Student’s t-test was used for comparing continuous variables with normal distribution and Mann-Whitney U test was used for data not normally distributed. X2 test was used for categorical variable.ResultsOf 1502 patients who were alive after initial hospitalization, 19.4% were readmitted; 90.3% within 30 days (median (IQR) 4 (0–14) days). Older age, lower estimated glomerular filtration rate (eGFR), comorbidities, intensive care unit (ICU) admission, mechanical ventilation, diabetic ketoacidosis (DKA), and longer length of stay (LOS) during the initial hospitalization were associated with readmission. Higher HbA1c, glycemic gap, or body mass index (BMI) were not associated with readmission. Mortality during readmission was 8.0% (n=23). Those who died were older than those who survived (74.9±9.5 vs 65.2±14.4 years, p=0.002) and more likely had DKA during the first hospitalization (p<0.001). Shorter LOS during the initial admission was associated with ICU stay during readmission, suggesting that a subset of patients may have been initially discharged prematurely.ConclusionsUnderstanding predictors of readmission after initial hospitalization for COVID-19, including older age, lower eGFR, comorbidities, ICU admission, mechanical ventilation, statin use and DKA but not HbA1c, glycemic gap or BMI, can help guide treatment approaches and future research in adults with diabetes.

Type 1 diabetes mellitus (T1DM) usually begins in childhood and adolescence and causes lifelong damage to several major organs including the brain. Despite increasing evidence of T1DM-induced structural deficits in cortical regions implicated in higher cognitive and emotional functions, little is known whether and how the structural connectivity between these regions is altered in the T1DM brain. Using inter-regional covariance of cortical thickness measurements from high-resolution T1-weighted magnetic resonance data, we examined the topological organizations of cortical structural networks in 81 T1DM patients and 38 healthy subjects. We found a relative absence of hierarchically high-level hubs in the prefrontal lobe of T1DM patients, which suggests ineffective top-down control of the prefrontal cortex in T1DM. Furthermore, inter-network connections between the strategic/executive control system and systems subserving other cortical functions including language and mnemonic/emotional processing were also less integrated in T1DM patients than in healthy individuals. The current results provide structural evidence for T1DM-related dysfunctional cortical organization, which specifically underlie the top-down cognitive control of language, memory, and emotion.

Rosiglitazone Improves Insulin Sensitivity and Lowers Blood Pressure in Hypertensive Patients Annaswamy Raji , MD , Ellen W. Seely , MD , Shannon A. Bekins , BA , Gordon H. Williams , MD and Donald C. Simonson , MD From the Endocrine-Hypertension Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts Abstract OBJECTIVE —To examine the effect of rosiglitazone on insulin resistance and blood pressure in patients with essential hypertension, classified based on abnormalities of their renin-angiotensin system. RESEARCH DESIGN AND METHODS —A total of 24 hypertensive nondiabetic patients (age 58 ± 6 years, BMI 30 ± 5 kg/m 2 ) were studied before and after rosiglitazone treatment. After 2 weeks off antihypertensive medication, subjects received a euglycemic-hyperinsulinemic clamp (40 mU · m −2 · min −1 ) with 6,6-[ 2 H 2 ]glucose infusion, ambulatory blood pressure monitoring, and blood tests for cardiovascular risk factors. Subjects were then placed on rosiglitazone (4 mg orally b.i.d.) and their usual antihypertensive medications (but not ACE inhibitors) for 16 weeks, and baseline tests were repeated. RESULTS —There was no change in fasting plasma glucose (83 ± 2 vs. 82 ± 2 mg/dl, P = 0.60), but fasting insulin decreased (16.1 ± 1.4 vs. 12.5 ± 0.9 μU/ml, P < 0.01). Total glucose disposal during the clamp increased (5.0 ± 0.4 vs. 5.9 ± 0.5 mg · kg −1 · min −1 , P < 0.001), with no change in suppression of hepatic glucose output. There were significant decreases in mean 24-h systolic (138 ± 2 vs. 134 ± 2 mmHg, P < 0.02) and diastolic (85 ± 2 vs. 80 ± 2 mmHg, P < 0.0001) blood pressure, and the decline in systolic blood pressure was correlated with the improvement in insulin sensitivity ( r = 0.59, P < 0.005). Triglycerides (135 ± 16 vs. 89 ± 8 mg/dl, P < 0.01), LDL cholesterol (129 ± 6 vs. 122 ± 8 mg/dl, P = 0.18), and HDL cholesterol (51 ± 3 vs. 46 ± 3 mg/dl, P < 0.02) all decreased, with no change in the LDL-to-HDL ratio. Plasminogen activator inhibitor-1 and C-reactive protein also declined significantly. CONCLUSIONS —Rosiglitazone treatment of nondiabetic hypertensive patients improves insulin sensitivity, reduces systolic and diastolic blood pressure, and induces favorable changes in markers of cardiovascular risk. Insulin sensitizers may provide cardiovascular benefits when used in the treatment of patients with hypertension. ABPM, ambulatory blood pressure monitor CRP, C-reactive protein GCRC, General Clinic Research Center LR, low renin NM, nonmodulator PAI-1, plasminogen activator inhibitor 1 PPAR, peroxisome proliferator-activated receptor TZD, thiazolidinedione Footnotes Address correspondence and reprint requests to Annaswamy Raji, MD, Endocrine-Hypertension Division, Brigham and Women’s Hospital, 221 Longwood Ave., Boston, MA 02115. E-mail: arajiapartners.org . Received for publication 30 July 2002 and accepted in revised form 3 October 2002. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. DIABETES CARE