Central Insulin Research Articles

Sarcopenic obesity in survivors of childhood acute lymphoblastic leukemia: prevalence, risk factors, and implications for cancer survivors.

Sarcopenic obesity, characterized by increased adiposity with low skeletal muscle mass, contributes to frailty and the development of chronic disease. Data on sarcopenic obesity in survivors of childhood acute lymphoblastic leukemia (cALL) is limited. A cross-sectional study on 65 cALL survivors (7-18years, > 2years from treatment completion) was conducted on cALL survivors with the primary outcome to determine the prevalence of sarcopenic obesity. Sarcopenic obesity was defined as patients with a positive Fat Mass Index (FMI) z-score with a negative Skeletal Muscle Index (SMI) z-score, measured using a Dual-Energy Xray Absorptiometry (DXA) scan. In addition, we assessed the factors associated with sarcopenic obesity by multivariable regression analysis. The mean (± SD) age was 12.9 (± 3.2) years, the median (Interquartile Range) time since diagnosis was 6.5 (5.9;8) years, and 66% received cranial radiotherapy. Central obesity, insulin resistance, and metabolic syndrome were seen in 21.5%, 23.1%, and 21% respectively. DXA-derived body composition variables revealed higher fat percentage despite normal body mass index (BMI) and lower muscle mass compared to the general population. Sarcopenic obesity was seen in 21 (34%) of survivors. On multivariable regression analysis, age at diagnosis (OR: 0.95 (95% CI: 0.92-0.98), p = 0.02), central obesity (OR: 18.99 (95% 2.32-155.5), p = 0.006) and insulin resistance (OR: 10.2 (95% CI: 1.75-59.09), p = 0.01) were associated with sarcopenic obesity. Sarcopenic obesity, an early clinical indicator for metabolic disease despite normal BMI, was significantly worse in children diagnosed with ALL at a younger age and was associated with central obesity and insulin resistance, which may contribute to adverse outcomes later in life.

Insulin potential in preventing brain damage after traumatic brain injury: What we know.

Traumatic brain injury (TBI) is a major global cause of disability and mortality. TBI results in a spectrum of primary and secondary injuries that impact neural function and overall survival. Insulin, beyond its well-known role in regulating blood glucose levels, plays critical roles in the central nervous system (CNS). These roles include the modulation of synaptic plasticity, neurotransmitter levels, neurogenesis, and neuroprotection. Central insulin resistance, a reduced sensitivity to insulin in the brain, has been observed in TBI patients. This insulin resistance impairs insulin function in the brain and increases the risk of neurodegenerative processes. This review will delve into the central role of insulin resistance in the pathological changes observed after TBI and explore the potential benefits of insulin therapy as a treatment approach for TBI.

Insulin Resistance Is a Modifying Factor for Parkinson's Disease.

Parkinson's disease (PD) is the second most common, and the fastest-growing neurodegenerative disorder with unclear etiology in most cases. Therefore, the identification of non-genetic risk factors for PD pathology is crucial to develop effective preventative or therapeutic strategies. An increasing number of evidence suggests that central insulin resistance might have an essential role in PD pathology. Nevertheless, it is not clear whether insulin resistance arises from external factors/lifestyle, comorbidities such as type 2 diabetes or it can occur in a PD patient's brain independently from peripheral insulin resistance. We aimed to investigate insulin resistance and its role in GBA1mutation-associated PD pathogenesis and phenotype severity. Midbrain organoids, generated from induced pluripotent stem cells (iPSCs) of PD patients carrying the GBA1-N370S heterozygous mutation (GBA-PD) and healthy donors, were exposed to different insulin concentrations to modify insulin signaling function. Transcriptomics analysis was performed to explore insulin signaling gene expression patterns in GBA-PD and to find a potential target for GBA-PD-associated phenotype rescue. The insulin signaling pathway genes show dysregulation in GBA-PD. Particularly, we highlight that a knockdown of FOXO1 mitigates the loss of dopaminergic neurons and cellular death in GBA-PD. Additionally, our findings suggest a promising therapeutic potential of the anti-diabetic drug Pioglitazone in decreasing dopaminergic neuron loss associated with GBA-PD. Local insulin signaling dysfunction plays a substantial role in GBA-PD pathogenesis, exacerbating dopaminergic neuron death. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Role of Peripheral and Central Insulin Resistance in Neuropsychiatric Disorders.

Insulin acts on different organs, including the brain, which helps it regulate energy metabolism. Insulin signaling plays an important role in the function of different cell types. In this review, we have summarized the key roles of insulin and insulin receptors in healthy brains and in different brain disorders. Insulin signaling, as well as insulin resistance (IR), is a major contributor in the regulation of mood, behavior, and cognition. Recent evidence showed that both peripheral and central insulin resistance play a role in the pathophysiology, clinical presentation, and management of neuropsychiatric disorders like Cognitive Impairment/Dementia, Depression, and Schizophrenia. Many human studies point out Insulin Resistance/Metabolic Syndrome can increase the risk of dementia especially Alzheimer's dementia (AD). IR has been shown to play a role in AD development but also in its progression. This review article discusses the pathophysiological pathways and mechanisms of insulin resistance in major neuropsychiatric disorders. The extent of insulin resistance can be quantified using IR biomarkers like insulin levels, HOMA-IR index, and Triglyceride glucose-body mass index (TyG-BMI) levels. IR has been shown to precede neurodegeneration. Human trials showed current treatment with certain antidiabetic drugs, as well as life style management, like weight loss and exercise for IR, have shown promise in the management of cognitive/neuropsychiatric disorders. This may pave the pathway to the development of new therapeutic approaches to these challenging disorders of dementia and psychiatric diseases. Recent clinical trials are showing some encouraging evidence for these pharmacological and nonpharmacological approaches for IR in psychiatric and cognitive disorders, even though more research is needed to apply this evidence into clinical practice. Early identification and management of IR may help as a strategy to potentially alter neuropsychiatric disorders onset as well as its progression.

Combination of Green Tea, Green Coffee, and Turmeric Extract Improve the THOC5 and AIF1, but not ACTA2 and CNN1 Gene Expression in the Aortic Tissue of Metabolic Syndrome Model

Metabolic syndrome (MetS) is a group of risk factors in the form of central obesity, insulin resistance, dyslipidemia, and hypertension, increasing oxidative stress. This pathological event leads to the development of cardiovascular disease, for instance, atherosclerosis. Besides modifiable risk factors, non-modifiable risk factors such as genetic factors also play a role in the formation of atherosclerosis in MetS conditions such as THOC5, AIF1, CNN1, and ACTA2. Recently, natural compound derivatives, such as epigallocatechin-3-gallate (EGCG), chlorogenic acid (CGA), and turmeric, have shown beneficial effects in MetS improvement. This study aimed to investigate the effect of green tea, green coffee, and turmeric extract on the expression of THOC5, AIF1, CNN1, and ACTA2 genes that contributed to atherosclerotic vasculopathy development in the MetS rat model. Twenty-five MetS rat models were grouped into 4 groups (n = 5): Standard control (SC), MetS (MetS), a combination of green tea, green coffee, and turmeric extract with treatment doses: 300/100/150 mg/BW(C1) and 400/200/250 mg/BW(C2) group. The THOC5, AIF1, CNN1, and ACTA2 expression were measured at the end of treatment periods. This study found that administering green tea, green coffee, and turmeric extract can lower the expression of THOC5, AIF1, CNN1, and ACTA2. The correlation test showed that there is a strong correlation between THOC5 and AIF1 gene expression, with positive value. In summary, the combined effects of green tea, green coffee, and curcumin extract show significant promise as a potential anti-atherosclerosis treatment by improve the THOC5 and AIF1, but not ACTA2 and CNN1 gene expression in the aortic tissue of metabolic syndrome model. HIGHLIGHTS Metabolic syndrome is a group of risk factors consist of central obesity, insulin resistance, dyslipidemia, and hypertension. Individuals with MetS have an increased risk of developing atherosclerotic cardiovascular disease. Besides modifiable risk factors, non-modifiable risk factors such as genetic factors also play a role in the formation of atherosclerosis in MetS conditions such as THOC5, AIF1, CNN1, and ACTA2. This study aimed to investigate the effect of green tea, green coffee, and turmeric extract on the expression of THOC5, AIF1, CNN1, and ACTA2 genes that contributed to atherosclerotic vasculopathy development in the MetS rat model. Administering green tea, green coffee, and turmeric extract can lower the expression of THOC5, AIF1, CNN1, and ACTA2. The correlation test showed that there is a strong correlation between THOC5 and AIF1 gene expression, with positive value. In summary, the combined effects of green tea, green coffee, and curcumin extract show significant promise as a potential anti-atherosclerosis treatment by improve the THOC5 and AIF1, but not ACTA2 and CNN1 gene expression in the aortic tissue of metabolic syndrome model. GRAPHICAL ABSTRACT

The effect of metabolic syndrome in patients with type 2 diabetes mellitus: Review

A group of metabolic abnormalities known as the metabolic syndrome (MS) are typified by a number of cardiovascular risk factors that are typically linked to central fat buildup and insulin resistance. Insufficient dietary modifications and weight loss, linked to consistent physical exercise, are regarded as primary and first-choice treatments for multiple sclerosis (MS). These interventions help decrease visceral fat and belly circumference, enhance insulin sensitivity, lower plasma glucose and triglyceride concentrations, increase high-density lipoprotein levels, and ultimately lower the risk factors that lead to type 2 diabetes. The MS is a topic of study in the medical community right now since it is associated with conditions that not only have a high death rate globally but also exhibit rising occurrence. Deregulation of the proteins, fats, and carbohydrates involved in metabolism causes type 2diabetes, which can lead to reduced insulin production, insulin resistance, or a combination of the two. With 90% of cases, type 2 diabetes is the most common of the three kinds of the disease. Being a chronic and complicated illness, diabetes necessitates close medical monitoring in order to lower risks and develop control techniques. Given its rapid epidemic expansion on a global scale in recent years, it is regarded as one of the pandemics of the twenty-first century. This review was non-systematic and advanced, examining the MS in individuals with type 2 diabetes by consulting multiple literatures and analyzing some new publications.

The Effect of Laparoscopic Sleeve Gastrectomy on Body Mass Index and the Resolution of Other Metabolic Syndrome Components in Patients over 50 Years Old during a Two Year Follow-Up.

Background/Objectives: Metabolic syndrome, defined by the coexistence of central obesity, dyslipidemia, hypertension, and insulin resistance, is a significant contributor to increased cardiovascular morbidity and mortality in the aging population. We aimed to determine whether age influences the efficacy of LSG in treating obesity-related comorbidities. Methods: A retrospective analysis of lipid profiles, glycemic and clinical parameters was conducted in a group of 786 patients in two age groups (under 50 years old and over 50 years old) who underwent laparoscopic sleeve gastrectomy with follow-ups 1, 3, 6, 12 and 24 months after surgery. Results: There was a significant improvement in lipid metabolism with no significant differences between the two age groups in these parameters throughout the observation period. Furthermore, there was significant weight loss (54.82 kg vs. 54.56 kg) and BMI reductions (47.71 kg/m2 vs. 47.01 kg/m2 to 29.03 kg/m2 vs. 30.73 kg/m2). Total cholesterol decreased from 198 mg/dL to 184.9 mg/dL (<50 years old) and from 206.4 mg/dL to 193 mg/dL (>50 years old). LDL dropped from 136.2 mg/dL to 116.7 mg/dL and from 141.0 mg/dL to 121.0 mg/dL. Mean HbA1c decreased to comparable levels (5.66% vs. 5.53%). Both groups showed similar rates of remission for type 2 diabetes and hypertension. Conclusions: Our findings suggest that LSG is an effective method for treating components of metabolic syndrome regardless of age, supporting its use as a therapeutic tool for older patients.

The role of prolactin levels in metabolic syndrome: a systematic review

Introduction and purpose: Prolactin is primarily associated with lactation and gonadal function, but it also has metabolic effects. Recent research shows prolactin's role in food intake, body weight, glucose, and lipid profile. Both low and excessive prolactin levels can lead to metabolic dysfunctions such as metabolic syndrome, type 2 DM, and dyslipidemia. Dopamine agonists, like cabergoline, used to treat hyperprolactinemia, may help balance metabolic homeostasis, likely due to their effect on prolactin. This study aims to synthesize current research on prolactin's metabolic effects, focusing on metabolic syndrome.State of knowledge: Metabolic syndrome is a cluster of dysfunctions like central obesity, atherogenic dyslipidemia, hypertension, and insulin resistance. It increases the risk of diabetes and cardiovascular diseases, affecting a quarter of the European population. Different combinations of metabolic syndrome components require various treatment approaches. New research focuses on prolactin and dopamine agonists in its pathogenesis and treatment.Materials and methods: This literature review is based on PubMed materials using keywords “prolactin,” “hyperprolactinemia,” “hypoprolactinemia,” “metabolic syndrome,” “diabetes mellitus,” “obesity.”Conclusions: This study highlights prolactin's importance in metabolic homeostasis, finding a positive correlation between both low and high prolactin levels and metabolic syndrome. However, gender differences and the pathogenesis of metabolic disorders should be further explored.

PTPRJ is a negative regulator of insulin signaling in neuronal cells, impacting protein biosynthesis, and neurite outgrowth.

Central insulin resistance has been linked to the development of neurodegenerative diseases and mood disorders. Various proteins belonging to the enzyme family of protein tyrosine phosphatases (PTPs) act as inhibitors of insulin signaling. Protein tyrosine phosphatase receptor type J (PTPRJ) has been identified as a negative regulator in insulin signaling in the periphery. However, the impact of PTPRJ on insulin signaling and its functional role in neuronal cells is largely unknown. Therefore, we generated a Ptprj knockout (KO) cell model in the murine neuroblast cell line Neuro2a by CRISPR-Cas9 gene editing. Ptprj KO cells displayed enhanced insulin signaling, as shown by increased phosphorylation of the insulin receptor (INSR), IRS-1, AKT, and ERK1/2. Further, proximity ligation assays (PLA) revealed both direct interaction of PTPRJ with the INSR and recruitment of this phosphatase to the receptor upon insulin stimulation. By RNA sequencing gene expression analysis, we identified multiple gene clusters responsible for glucose uptake and metabolism, and genes involved in the synthesis of various lipids being mainly upregulated under PTPRJ deficiency. Furthermore, multiple Ca2+ transporters were differentially expressed along with decreased protein biosynthesis. This was accompanied by an increase in endoplasmic reticulum (ER) stress markers. On a functional level, PTPRJ deficiency compromised cell differentiation and neurite outgrowth, suggesting a role in nervous system development. Taken together, PTPRJ emerges as a negative regulator of central insulin signaling, impacting neuronal metabolism and neurite outgrowth.

Depression, higher level of tension induction, and impaired coping strategies in response to stress in women with PCOS correlate with clinical and laboratory indices of hyperandrogenism and not with central obesity and insulin resistance.

to examine the mental condition, self-esteem, and ways of coping with stress in women with PCOS compared to age and BMI-matched healthy controls and to correlate them with clinical and laboratory hyperandrogenism, central obesity, and IR. 42 women with PCOS and 39 controls were assessed for the above-mentioned psychological measures and correlated with serum hormonal and metabolic parameters. Compared to controls, women with PCOS had more symptoms of depression (p = 0.026), a higher level of tension induction (p = 0.032), were more prone to alcohol consumption (p = 0.015), and were less likely to use the strategy of active coping in stressful situations (p = 0.014) and to seek instrumental (p = 0.048) and emotional support (p = 0.043). The presence of hirsutism correlated negatively with the level of emotional induction (R = -0.32, p < 0.05), and androgenic alopecia positively with the hedonistic tone (R = 0.36, p < 0.05). Serumtestosterone (TST) correlated positively with the likelihood of seeking instrumental support in stressful situations (R = 0.31, p < 0.05) and with emotional focus (R = 0.34, p < 0.05). Serum androstenedione (A4-dione) correlated negatively with the escape behavior (R = -0.32, p < 0.05). No correlations were found between waist circumference and IR with the studied psychological measures. Women with PCOS are characterized by depression, higher levels of tension induction, and impaired coping strategies in stressful situations, which correlate with clinical and laboratory indices of hyperandrogenism and not with central obesity and IR.

Sex difference in the association between creatinine-to-cystatin C ratio and metabolic syndrome among Chinese adults.

Metabolic syndrome (MetS), characterized by central obesity, insulin resistance, dyslipidemia, and hypertension, affects 20-25% of the global population. The creatinine-to-cystatin C ratio (CCR) is an indicator of skeletal muscle mass. While CCR may play a role in MetS development, sex differences in these associations are not fully understood. Therefore, this study aimed to investigate how CCR levels are associated with MetS in a Chinese adult population, focusing on possible sex disparities. We conducted a retrospective cross-sectional analysis of 9,376 adults from Xiamen Chang Gung Hospital between 2014 to 2016. We examined the relationship between CCR and MetS, adjusting for cardiometabolic risk factors. The prevalence of MetS was 24.7% in males and 18.0% in females. Interestingly, we observed significant sex differences in the association between CCR quartiles and MetS. Females in the lowest CCR quartile had a significantly higher risk of MetS (odds ratio=1.84). Receiver operating characteristic curve analysis revealed acceptable diagnostic power of CCR for MetS in females (area under the curve=0.65) but not in males. Our findings suggest that CCR is an independent risk factor for MetS in females, highlighting the importance of sex-specific assessments when evaluating MetS risk.

Effects of chronic treatment with metformin on brain glucose hypometabolism and central insulin actions in transgenic mice with tauopathy

Brain glucose hypometabolism and insulin alterations are common features of many neurological diseases. Herein we sought to corroborate the brain glucose hypometabolism that develops with ageing in 12-months old Tau-VLW transgenic mice, a model of tauopathy, as well as to determine whether this model showed signs of altered peripheral glucose metabolism. Our results demonstrated that 12-old months Tau mice exhibited brain glucose hypometabolism as well as basal hyperglycemia, impaired glucose tolerance, hyperinsulinemia, and signs of insulin resistance. Then, we further studied the effect of chronic metformin treatment (9 months) in Tau-VLW mice from 9 to 18 months of age. Longitudinal PET neuroimaging studies revealed that chronic metformin altered the temporal profile in the progression of brain glucose hypometabolism associated with ageing. Besides, metformin altered the content and/or phosphorylation of key components of the insulin signal transduction pathway in the frontal cortex leading to significant changes in the content of the active forms. Thus, metformin increased the expression of pAKT-Y474 while reducing pmTOR-S2448 and pGSK3β. These changes might be related, at least partially, to a slow progression of ageing, neurological damage, and cognitive decline. Metformin also improved the peripheral glucose tolerance and the ability of the Tau-VLW mice to maintain their body weight through ageing. Altogether our study shows that the tau-VLW mice could be a useful model to study the potential interrelationship between tauopathy and central and peripheral glucose metabolism alterations. More importantly our results suggest that chronic metformin treatment may have direct beneficial central effects by post-transcriptional modulation of key components of the insulin signal transduction pathway.

WNKs regulate mouse behavior and alter central nervous system glucose uptake and insulin signaling.

Certain areas of the brain involved in episodic memory and behavior, such as the hippocampus, express high levels of insulin receptors and glucose transporter-4 (GLUT4) and are responsive to insulin. Insulin and neuronal glucose metabolism improve cognitive functions and regulate mood in humans. Insulin-dependent GLUT4 trafficking has been extensively studied in muscle and adipose tissue, but little work has demonstrated either how it is controlled in insulin-responsive brain regions or its mechanistic connection to cognitive functions. In this study, we demonstrate that inhibition of WNK (With-No-lysine (K)) kinases improves learning and memory in mice. Neuronal inhibition of WNK enhances in vivo hippocampal glucose uptake. Inhibition of WNK enhances insulin signaling output and insulin-dependent GLUT4 trafficking to the plasma membrane in mice primary neuronal cultures and hippocampal slices. Therefore, we propose that the extent of neuronal WNK kinase activity has an important influence on learning, memory and anxiety-related behaviors, in part, by modulation of neuronal insulin signaling.

Effect of acute intranasal insulin administration on muscle sympathetic nerve activity in healthy young adults.

Systemic insulin increases muscle sympathetic nerve activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans remains unknown. Herein, we hypothesized intranasal insulin administration would increase MSNA and BP in healthy young adults. Participants were assigned to time control [TC, n = 13 (5 females/8 males), 28 ± 1 yr] or 160 IU of intranasal insulin administered over 5 min [n = 15 (5 females/10 males), 26 ± 2 yr]; five (1 female/4 males) participants completed both conditions. MSNA (fibular microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) were assessed at baseline, and 15 and 30 min following insulin administration. Leg vascular conductance [LVC = (LBF ÷ mean BP) × 100] was calculated. Venous insulin and glucose concentrations remained unchanged throughout (P > 0.05). Following intranasal insulin administration, MSNA (burst frequency; baseline = 100%; minute 15, 121 ± 8%; minute 30, 118 ± 6%; P = 0.009, n = 7) and mean BP (baseline = 100%; minute 15, 103 ± 1%; minute 30, 102 ± 1%; P = 0.003) increased, whereas LVC decreased (baseline = 100%; minute 15, 93 ± 3%; minute 30, 99 ± 3%; P = 0.03). In contrast, MSNA, mean BP, and LVC were unchanged in TC participants (P > 0.05). We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA and BP and decreases LVC. These results enhance mechanistic understanding of the sympathetic and peripheral hemodynamic response to insulin.NEW & NOTEWORTHY Systemic insulin increases muscle sympathetic nerve activity (MSNA) via central actions within the brainstem and peripheral activation of the arterial baroreflex. In the absence of peripheral insulin action, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans was unknown. We provide the first evidence that intranasal insulin administration increases MSNA and blood pressure and reduces leg vascular conductance. These results enhance mechanistic understanding of the sympathetic and hemodynamic response to insulin.

Muscle Sympathetic Action Potential Firing Patterns Following Intranasal Insulin Administration in Healthy Adults

Objective: Systemic insulin increases muscle sympathetic nervous system activity (MSNA) in healthy adults by augmenting firing frequency of medium-sized sympathetic action potentials (AP) and recruiting previously latent, larger axons. Whether these neural coding patterns are due to central or peripheral effects of insulin is unclear. We examined the impact of elevated central insulin on AP firing patterns in healthy adults. We hypothesized intranasal insulin administration, which increases central insulin levels, would increase MSNA via elevated firing frequency of APs and recruitment of previously latent, larger axons. Methods: Ten participants were assigned to time control [TC, n=6 (3M/3F)] or 160 IU of intranasal insulin [n=4 (3M/1F)] administered over 5 min. MSNA (fibular microneurography) was assessed at baseline and for 30 min following insulin administration. Sympathetic APs were identified using a matched mother wavelet and continuous wavelet transform. APs were divided into the proportion of those firing in small, medium, or large amplitude clusters. AP firing frequency, percent of APs firing within an MSNA burst (synchronous), and the probability of clusters firing more than once within an MSNA burst were identified. Data are reported as median (interquartile range). Results: MSNA burst frequency increased 15 min after intranasal insulin administration [24(20) to 31(23) bursts/min, p=0.03]. At this time, the percent of synchronous APs [72(27) to 90(24)%, p=0.02] and the probability of medium-sized AP clusters firing more than once within an MSNA burst [13(14) to 19(17)%, p=0.03] increased. No changes in MSNA burst frequency [23(14) to 25(13) bursts/min, p=0.27], percent of synchronous APs [74(15) to 75(34), p=0.48], nor firing probability of medium-sized AP clusters [6(12) to 8(7)%, p=0.97] occurred in TC. The total number of detected clusters did not change in either group (p&gt;0.05). Conclusions: Intranasal insulin increases MSNA burst frequency due to a higher percent of synchronous APs, particularly medium-sized AP clusters; however, we did not observe recruitment of latent, larger axons. These exploratory data highlight potential differences in the sympathetic response to central versus peripheral insulin exposure in healthy adults. CAFNR Joy of Discovery (JKL, JP). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of Peripheral Versus Central Insulin on Cerebrovascular Compliance in Healthy Young Adults

Objective: Vascular compliance is an essential component of cerebral blood flow regulation. Prior work has shown cerebral vasodilation (elicited by hypercapnia) reduces cerebrovascular compliance (Ci); however, this work has yet to be translated to other vasoactive compounds. Insulin has important vasodilatory effects in the peripheral circulation, but less is known about the role of insulin in cerebrovascular control. Herein, we hypothesized both peripheral (intravenous) and central (intranasal) insulin administration would increase indices of cerebral blood flow and reduce Ci in healthy young adults. Methods: Twenty-five healthy young adults (8 female; 26±7 yrs, 25±3 kg/m2) were assigned to two separate protocols (NCT05244694, NCT05153395). Middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound) was measured at baseline and under two study conditions: 1) at the end of a 60 min hyperinsulinemic euglycemic infusion, and 2) 60 min following 160 IU of intranasal insulin. Indices of Ci were calculated using a modified Windkessel model applied to blood pressure (finger photoplethysmography) and corresponding MCAv waveforms collected over a 5-min period (10 waveforms) at baseline and during the aforementioned insulin conditions. Results: Blood glucose remained unchanged throughout both protocols (both p&gt;0.05). MCAv was maintained over time under both insulin conditions (protocol 1: 60±13 to 62±17 cm/s, p=0.635; protocol 2: 58±9 to 53±14 cm/s, p=0.146). In contrast, Ci decreased (0.00028±0.00010 to 0.00021±0.00007 cm/s/mmHg, p=0.010) from baseline during peripheral (intravenous) insulin administration. No change in Ci (0.00049±0.00025 to 0.00040±0.00018 cm/s/mmHg, p=0.189) were observed following intranasal insulin administration. Conclusions: Contrary to our hypothesis, there was no effect of peripheral or central insulin administration on resting MCAv in healthy young adults. However, intravenous (but not intranasal) insulin reduced Ci by approximately 25% from baseline values. These findings advance our understanding of cerebrovascular control mechanisms during insulin exposure and provide the opportunity to extend this work to diseased states characterized by insulin resistance, including diabetes. CAFNR Joy of Discovery (JKL, JP). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Diabetes mellitus, metabolic syndrome, and sleep disorders: An underestimated relationship

Abstract Diabetes mellitus (DM) is the most prevalent endocrine disorder globally. DM is under-evaluated and less efficiently managed in terms of ruling out comorbid conditions associated with it and predisposing factors resulting in poor outcomes. Sleep disorders are more common than usually diagnosed due to less awareness in the community regarding the importance of timely diagnosis and the impact of interventions related to proper sleep hygiene and sleep structure. Obstructive sleep apnea (OSA) is independently associated with cardiovascular and cardiometabolic risk in several large epidemiological studies. OSA leads to several physiological disturbances, such as intermittent hypoxia, sleep fragmentation, and an increase in autonomic tone. Metabolic syndrome (MS) is an adverse outcome that is typically associated with obesity. It is a cluster of metabolic risk factors for type 2 DM (T2DM) and cardiovascular diseases (CVDs), including central obesity, hypertension, hyperglycemia, insulin resistance, and dyslipidemia. T2DM is often associated with OSA, and a bidirectional relationship may exist between the two diseases, mediated by both weight- and physiology-dependent mechanisms. OSA is highly associated with T2DM, and treatment of OSA may have a positive impact on the cardiometabolic profile. In this review, we have attempted to summarize the impact of sleep disorders on MS and DM, and vice versa, with special emphasis on newer medical options in the management of DM and cardiometabolic syndrome.

Which aspects of education are health protective? a life course examination of early education and adulthood cardiometabolic health in the 30-year study of early child care and Youth Development (SECCYD)

BackgroundPast research describes robust associations between education and health, yet findings have generally been limited to the examination of education as the number of years of education or educational attainment. Little is known about the specific features or processes underpinning education that are health protective. The objective of the current study was to address this gap by examining specific aspects of early education pertaining to student characteristics and experiences, as well as features of the classroom environment, in predicting cardiometabolic health in adulthood.MethodsSubjects were 1364 participants in the NICHD Study of Early Child Care and Youth Development (SECCYD, 1991–2009) and recent SECCYD 30-year follow-up, the Study of Health in Early and Adult Life (SHINE, 2018–2022). Models examined individual education indicators (student social skills, student-teacher relationship quality, and classroom emotional and instructional quality in the period of elementary school and student academic performance between ages 54 months and 15 years) in relation to a composite of cardiometabolic risk in adulthood (ages 26–31), reflecting central adiposity, blood pressure, insulin resistance, inflammation, and dyslipidemia. Models were adjusted for key explanatory factors including socio-demographics, infant characteristics, parental socioeconomic status (SES), and child health status. Follow-up analyses were performed to test potential mediators of early education effects on adult health, including adult SES (educational attainment, household income) and health behaviors (diet quality, activity level, sleep duration, smoking).ResultsIn adjusted models, results showed greater student social skills, indexed by a mean of annual teacher ratings between kindergarten and 6th grade, predicted lower cardiometabolic risk in adulthood (β=-0.009, p <.05). In follow-up analyses, results showed the protective effect of student social skills on cardiometabolic risk may be mediated by adult income (β=-0.0014, p <.05) and diet quality (β=-0.0031, p <.05). Effects of the other early education indicators were non-significant (ps > 0.05).ConclusionsFindings point to the potential significance of early student social competence as a link to long-term health, possibly via the acquisition of resources needed for the maintenance of health, as well as through engagement in health behaviors supporting healthy eating. However, more research is needed to replicate these findings and to elaborate on the role of early student social competence and the pathways explaining its effects on cardiometabolic health in adulthood.

Exploring the Pathophysiology of ATP-Dependent Potassium Channels in Insulin Resistance.

Ionic channels are present in eucaryotic plasma and intracellular membranes. They coordinate and control several functions. Potassium channels belong to the most diverse family of ionic channels that includes ATP-dependent potassium (KATP) channels in the potassium rectifier channel subfamily. These channels were initially described in heart muscle and then in other tissues such as pancreatic, skeletal muscle, brain, and vascular and non-vascular smooth muscle tissues. In pancreatic beta cells, KATP channels are primarily responsible for maintaining the membrane potential and for depolarization-mediated insulin release, and their decreased density and activity may be related to insulin resistance. KATP channels' relationship with insulin resistance is beginning to be explored in extra-pancreatic beta tissues like the skeletal muscle, where KATP channels are involved in insulin-dependent glucose recapture and their activation may lead to insulin resistance. In adipose tissues, KATP channels containing Kir6.2 protein subunits could be related to the increase in free fatty acids and insulin resistance; therefore, pathological processes that promote prolonged adipocyte KATP channel inhibition might lead to obesity due to insulin resistance. In the central nervous system, KATP channel activation can regulate peripheric glycemia and lead to brain insulin resistance, an early peripheral alteration that can lead to the development of pathologies such as obesity and Type 2 Diabetes Mellitus (T2DM). In this review, we aim to discuss the characteristics of KATP channels, their relationship with clinical disorders, and their mechanisms and potential associations with peripheral and central insulin resistance.

Evidence based lifestyle interventions in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine condition which affects up to 13% of reproductive-aged women and is associated with reproductive, metabolic and psychological features. Women with PCOS have a higher prevalence of longitudinal weight gain in population-based cohort studies compared to women without PCOS. On meta-analysis, women with PCOS also have an increased prevalence of overweight, obesity and central obesity, compared with controls. PCOS is therefore associated with an elevated prevalence of overweight and obesity which further worsen metabolic, reproductive and psychological dysfunction. Given the association between overweight and obesity and metabolic, reproductive and psychological dysfunction in women, weight management is a logical treatment strategy. This can be defined as prevention of excess weight gain, achieving a modest weight loss and sustaining a reduced weight long-term. This is best achieved through lifestyle management which traditionally refers to a complex multidisciplinary approach that combines dietary modification, physical activity and behavioural interventions. Lifestyle interventions and modest weight loss (5-10% of initial body weight) are associated with improvements in outcomes including central adiposity, hyperandrogenism, insulin resistance and cardiovascular risk factors. In PCOS specifically for dietary interventions, the majority of evidence indicates no differences between dietary approaches Lifestyle management advice should therefore follow general population guidance which states that lifestyle intervention can be achieved through a variety of dietary approaches providing these are tailored to dietary preferences and ensure the nutritional and health status of the individual patient with referral to a nutrition professional where possible. These recommendations are summarised in the 2023 International Evidence-based Guidelines on the Assessment and Management of PCOS. 1 These guidelines are now being translated and implemented internationally.