Djulis Hull Improves Insulin Resistance and Modulates the Gut Microbiota in High-Fat Diet (HFD)-Induced Hyperglycaemia

In this study, we annotated the major flavonoid glycoside, rutin, of djulis hull crude extract using a Global Natural Products Social Molecular Networking (GNPS) library and its MS/MS spectra. To evaluate the protective effect of djulis hull crude extract and rutin on glucose tolerance, we fed mice a high-fat diet (HFD) for 16 weeks to induce hyperglycaemia. These results showed that crude extract significantly decreased HFD-induced elevation in the area under the curve (AUC) of weekly random blood glucose and oral glucose tolerance tests (OGTT), homeostasis model assessment (HOMA-IR), and advanced glycation end product (AGE) levels, and significantly increased pIRS1 and Glut4 protein expression in epididymal white adipose tissue (eWAT) and liver. Furthermore, the HFD-induced reduction in the activity of glutathione peroxidase (GPx) and catalase (CAT) was reversed by crude extract. In addition, ZO-1 and occludin protein expression in the colon was markedly downregulated in HFD-fed mice, resulting in decreased intestinal permeability and lipopolysaccharide (LPS) translocation, but were restored following crude extract. Moreover, the crude extract intervention had a profound effect on the alpha diversity and microbial community in the gut microbiota. Therefore, djulis hull crude extract could improve blood glucose and increase insulin receptor sensitivity in HFD-induced hyperglycaemia, which is likely due to its modulation of the gut microbiota, preservation of the integrity of the intestinal barrier to reduce body inflammation, increased antioxidant activity, and modulation of insulin signalling.

Genomic signatures of desert adaptation at gene-rich regions in zebu cattle from the African drylands

Sudan, the largest country in Africa, acts as a corridor between North and sub-Saharan Africa along the river Niles. It comprises warm arid and semi-arid grazing lands, and it is home to the second-largest African population of indigenous livestock. Indigenous Sudanese cattle are mainly indicine/zebu (humped) type. They thrive in the harshest dryland environments characterised by high temperatures, long seasonal dry periods, nutritional shortages, and vector diseases challenges. We investigated genome diversity in six indigenous African zebu breeds sampled in Sudan (Aryashai, Baggara, Butana, Fulani, Gash, and Kenana). We adopted three genomic scan approaches to identify candidate selective sweeps regions (ZHp, FST, XP-EHH). We identified a set of gene-rich selective sweep regions shared across African and Asian zebu or unique to Sudanese zebu. In particular, African and Asian zebu candidate gene-rich regions are detected on chromosomes 2, 5 and 7. They include genes involved in immune response, body size and conformation, and stress response to heat. In addition, a 250 kb selective sweep on chromosome 16 was detected exclusively in five Sudanese zebu populations. This region spans seven genes, including PLCH2, PEX10, PRKCZ and SKI, which are involved in alternative adaptive metabolic strategies of insulin signalling, glucose homeostasis, and fat metabolism. Together, these genes may contribute to the zebu cattle resilience to heat, nutritional and water shortages. Our results highlight the putative importance of selection at gene-rich genome regions, which might be under a common regulatory genetic control, as an evolutionary mechanism for rapid adaptation to the complexity of environmental challenges.

Carpachromene Ameliorates Insulin Resistance in HepG2 Cells via Modulating IR/IRS1/PI3k/Akt/GSK3/FoxO1 Pathway

Insulin resistance contributes to several disorders including type 2 diabetes and cardiovascular diseases. Carpachromene is a natural active compound that inhibits α-glucosidase enzyme. The aim of the present study is to investigate the potential activity of carpachromene on glucose consumption, metabolism and insulin signalling in a HepG2 cells insulin resistant model. A HepG2 insulin resistant cell model (HepG2/IRM) was established. Cell viability assay of HepG2/IRM cells was performed after carpachromene/metformin treatment. Glucose concentration and glycogen content were determined. Western blot analysis of insulin receptor, IRS1, IRS2, PI3k, Akt, GSK3, FoxO1 proteins after carpachromene treatment was performed. Phosphoenolpyruvate carboxykinase (PEPCK) and hexokinase (HK) enzymes activity was also estimated. Viability of HepG2/IRM cells was over 90% after carpachromene treatment at concentrations 6.3, 10, and 20 µg/mL. Treatment of HepG2/IRM cells with carpachromene decreased glucose concentration in a concentration- and time-dependant manner. In addition, carpachromene increased glycogen content of HepG2/IRM cells. Moreover, carpachromene treatment of HepG2/IRM cells significantly increased the expression of phosphorylated/total ratios of IR, IRS1, PI3K, Akt, GSK3, and FoxO1 proteins. Furthermore, PEPCK enzyme activity was significantly decreased, and HK enzyme activity was significantly increased after carpachromene treatment. The present study examined, for the first time, the potential antidiabetic activity of carpachromene on a biochemical and molecular basis. It increased the expression ratio of insulin receptor and IRS1 which further phosphorylated/activated PI3K/Akt pathway and phosphorylated/inhibited GSK3 and FoxO1 proteins. Our findings revealed that carpachromene showed central molecular regulation of glucose metabolism and insulin signalling via IR/IRS1/ PI3K/Akt/GSK3/FoxO1 pathway.

Comprehensive Review on Neuro-Degenerative Type 3DM

: Alzheimer disease (AD) is thought to be the metabolic illness raised by defective insulin signaling, insulin resistance, and low insulin levels in the brain, according to a growing body of research. The "Type 3 diabetes" has been postulated for AD because reduced insulin signalling has molecular and physiological consequences that are comparable to Type I and Type 2 diabetes mellitus (Type 1 DM and Type 2 DM, respectively). The similarities between type 2 diabetes and Alzheimer's disease suggest that these clinical trials might yield therapeutic benefits. However, it's important to note that lowering your risk of Alzheimer's dementia, whether you have diabetes or not, is still a multidimensional process involving factors like exercise, smoking, alcohol, food, and mental challenge. The current aim is to show the relationship between T3D and AD being based on both the processing of amyloid-β (Aβ) precursor protein toxicity and the clearance of Aβ are the result of an impaired insulin signaling. The brain's metabolism with its high lipid content and energy needs, places excess demands on mitochondria and appears more susceptible to oxidative damage than the rest of the body. Current data suggests that increased oxidative stress relates to amyloid-β (Aβ) pathology and onset of AD.

The Link between Gut Dysbiosis Caused by a High-Fat Diet and Hearing Loss

This review aims to provide a conceptual and theoretical overview of the association between gut dysbiosis and hearing loss. Hearing loss is a global health issue; the World Health Organisation (WHO) estimates that 2.5 billion people will be living with some degree of hearing loss by 2050. The aetiology of sensorineural hearing loss (SNHL) is complex and multifactorial, arising from congenital and acquired causes. Recent evidence suggests that impaired gut health may also be a risk factor for SNHL. Inflammatory bowel disease (IBD), type 2 diabetes, diet-induced obesity (DIO), and high-fat diet (HFD) all show links to hearing loss. Previous studies have shown that a HFD can result in microangiopathy, impaired insulin signalling, and oxidative stress in the inner ear. A HFD can also induce pathological shifts in gut microbiota and affect intestinal barrier (IB) integrity, leading to a leaky gut. A leaky gut can result in chronic systemic inflammation, which may affect extraintestinal organs. Here, we postulate that changes in gut microbiota resulting from a chronic HFD and DIO may cause a systemic inflammatory response that can compromise the permeability of the blood–labyrinth barrier (BLB) in the inner ear, thus inducing cochlear inflammation and hearing deficits.

Phospholipase C-related catalytically inactive protein acts as a positive regulator for insulin signalling in adipocytes

Insulin signalling is tightly controlled by various factors, but the exact molecular mechanism remains incompletely understood. We previously reported that phospholipase C-related but catalytically inactive protein (PRIP) interacts with Akt, the central molecule in insulin signalling. Here, we investigated whether PRIP is involved in the regulation of insulin signalling in adipocytes. We found that insulin signalling including insulin-stimulated phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), Akt, and glucose uptake, were impaired in adipocytes from PRIP-knockout (KO) mice compared with those from wild-type (WT) mice. The amount of IR expressed on the cell-surface was decreased in PRIP-KO adipocytes. Immunoprecipitation assay showed that PRIP interacted with IR. The reduced cell-surface IR in PRIP-KO adipocytes was comparable with that in WT cells when Rab5 expression was silenced using specific siRNA. In contrast, the dephosphorylation of IRS-1 at serine residues, some of which were reported to be involved in the internalisation of IR, was impaired in cells from PRIP-KO mice. These results suggest that PRIP facilitates insulin signalling by modulating the internalisation of IR in adipocytes.

Insulin signalling in tanycytes gates hypothalamic insulin uptake and regulation of AgRP neuron activity

Insulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.

Dominant Role of PI3K p110α over p110β in Insulin and β-Adrenergic Receptor Signalling

Attribution of specific roles to the two ubiquitously expressed PI 3-kinase (PI3K) isoforms p110α and p110β in biological functions they have been implicated, such as in insulin signalling, has been challenging. While p110α has been demonstrated to be the principal isoform activated downstream of the insulin receptor, several studies have provided evidence for a role of p110β. Here we have used isoform-selective inhibitors to estimate the relative contribution of each of these isoforms in insulin signalling in adipocytes, which are a cell type with essential roles in regulation of metabolism at the systemic level. Consistent with previous genetic and pharmacological studies, we found that p110α is the principal isoform activated downstream of the insulin receptor under physiological conditions. p110α interaction with Ras enhanced the strength of p110α activation by insulin. However, this interaction did not account for the selectivity for p110α over p110β in insulin signalling. We also demonstrate that p110α is the principal isoform activated downstream of the β-adrenergic receptor (β-AR), another important signalling pathway in metabolic regulation, through a mechanism involving activation of the cAMP effector molecule EPAC1. This study offers further insights in the role of PI3K isoforms in the regulation of energy metabolism with implications for the therapeutic application of selective inhibitors of these isoforms.

Maternal hypothyroidism in rats reduces placental lactogen, lowers insulin levels and causes glucose intolerance

Hypothyroidism increases incidence of gestational diabetes mellitus (GDM) but the mechanisms responsible are unknown. This study aimed to assess the pathophysiological mechanisms by which hypothyroidism leads to glucose intolerance in pregnancy. Hypothyroidism was induced in female Sprague-Dawley rats by adding methimazole (MMI) to drinking water at moderate (MOD, MMI at 0.005% w/v) and severe (SEV, MMI at 0.02% w/v) doses from one week prior to pregnancy and throughout gestation. A non-pregnant cohort received the same dose for the same duration but were not mated. On gestational day 16 (GD16), or non-pregnant day 16 (NP16), animals were subjected to an intraperitoneal glucose tolerance test. Tissues and blood samples were collected four days later. Hypothyroidism induced a diabetic-like phenotype by GD16 in pregnant females only. Pregnant MOD and SEV females had reduced fasting plasma insulin, less insulin following a glucose load and altered expression of genes involved in insulin signalling within skeletal muscle and adipose tissue. Hypothyroidism reduced rat placental lactogen concentrations, which was accompanied by reduced percentage beta-cell cross-sectional area (CSA) relative to total pancreas CSA, and a reduced number of large beta cell clusters in the SEV hypothyroid group. Plasma triglycerides and free fatty acids were reduced due to hypothyroidism in pregnant rats, as was the expression of genes that regulate lipid homeostasis. Hypothyroidism in pregnant rats results in a diabetic-like phenotype that is likely mediated by impaired beta cell expansion in pregnancy. This pregnancy specific phenomenon is likely due to reduced placental lactogen secretion.