Regulation Of Glucose Homeostasis Research Articles

For Flux Sake: Isotopic Tracer Methods of Monitoring Human Carbohydrate Metabolism During Exercise.

Isotopic tracers can reveal insights into the temporal nature of metabolism and track the fate of ingested substrates. A common use of tracers is to assess aspects of human carbohydrate metabolism during exercise under various established models. The dilution model is used alongside intravenous infusion of tracers to assess carbohydrate appearance and disappearance rates in the circulation, which can be further delineated into exogenous and endogenous sources. The incorporation model can be used to estimate exogenous carbohydrate oxidation rates. Combining methods can provide insight into key factors regulating health and performance, such as muscle and liver glycogen utilization, and the underlying regulation of blood glucose homeostasis before, during, and after exercise. Obtaining accurate, quantifiable data from tracers, however, requires careful consideration of key methodological principles. These include appropriate standardization of pretrial diet, specific tracer choice, whether a background trial is necessary to correct expired breath CO2 enrichments, and if so, what the appropriate background trial should consist of. Researchers must also consider the intensity and pattern of exercise, and the type, amount, and frequency of feeding (if any). The rationale for these considerations is discussed, along with an experimental design checklist and equation list which aims to assist researchers in performing high-quality research on carbohydrate metabolism during exercise using isotopic tracer methods.

SON-light activation of glucose regulation

Body temperature maintenance is an important regulator of glucose homeostasis. In this issue of Cell, Meng etal. discover a regulatory axis in which light activation of photoreceptive retinal ganglia stimulates the supraoptic nucleus (SON) to inhibit brown adipose tissue (BAT) thermogenesis and impair glucose homeostasis. This could explain the impact of constant light exposure on metabolism.

Pancreatic Islet Biobanking Facilities in India: The Need of the Hour to Deal with Diabetes?

Endocrine pancreas regulates glucose homeostasis and prevents diabetes. Type-1 diabetes is characterized by destruction of the insulin secreting β-cells within the endocrine pancreatic islets, resulting in lower insulin release. People with type-1 diabetes can be transplanted with pancreatic islets obtained from deceased donors which restores the β-cell function. There are around 70 human islet isolation centers around the world which mostly collect endocrine pancreas from deceased donors. They assess the islet yield, functionality, viability, secretory capacity, and purity for transplantation and distribute this to donors. They also distribute a part of the pancreatic tissue for research, so that the cellular mechanisms in the human pancreatic tissue can be understood. This is crucial since human islet tissue has a unique cytoarchitecture compared to murine counterparts and therefore islet research with murine islets does not give complete picture of diabetes in humans. India is poised to take the mantle of the diabetes capital of the world in the near future. Despite this, there are no human islet isolation centers which can facilitate islet transplantation and diabetes research in India. This article highlights the glaring gap in the current infrastructure for diabetes care and provides critical insights into the role and potential of setting up islet tissue banks in the most populous country of the world.

Trans-palmitoleic acid, a dairy fat biomarker, stimulates insulin secretion and activates G protein-coupled receptors with a different mechanism from the cis isomer.

Dietary trans-palmitoleic acid (trans 16:1n-7, tPOA), a biomarker for high-fat dairy product intake, has been associated with a lower risk of type 2 diabetes mellitus (T2DM) in some cross-sectional and prospective epidemiological studies. Here, we investigated the insulin secretion-promoting activity of tPOA and compared them with the effects evoked by the cis-POA isomer (cPOA), an endogenous lipokine biosynthesized in the liver and adipose tissue, and found in some natural food sources. The debate about the positive and negative relationships of those two POA isomers with metabolic risk factors and the underlying mechanisms is still going on. Therefore, we examined the potency of both POA isomers to potentiate insulin secretion in murine and human pancreatic β cell lines. We also investigated whether POA isomers activate G protein-coupled receptors proposed as potential targets for T2DM treatment. We show that tPOA and cPOA augment glucose-stimulated insulin secretion (GSIS) to a similar extent; however, their insulin secretagogue activity is associated with different signaling pathways. We also performed ligand docking and molecular dynamics simulations to predict the preferred orientation of POA isomers and the strength of association between those two fatty acids and GPR40, GPR55, GPR119, and GPR120 receptors. Overall, this study provides insight into the bioactivity of tPOA and cPOA toward selected GPCR functions, indicating them as targets responsible for the insulin secretagogue action of POA isomers. It reveals that both tPOA and cPOA may promote insulin secretion and subsequently regulate glucose homeostasis.

RANKL inhibition: a new target of treating diabetes mellitus?

Accumulating evidence demonstrates the link between glucose and bone metabolism. The receptor activator of nuclear factor-kB ligand (RANKL)/the receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) axis is an essential signaling axis maintaining the balance between bone resorption and bone formation. In recent years, it has been found that RANKL and RANK are distributed not only in bone but also in the liver, muscle, adipose tissue, pancreas, and other tissues that may influence glucose metabolism. Some scholars have suggested that the blockage of the RANKL signaling may protect islet β-cell function and prevent diabetes; simultaneously, there also exist different views that RANKL can improve insulin resistance through inducing the beige adipocyte differentiation and increase energy expenditure. Currently, the results of the regulatory effect on glucose metabolism of RANKL remain conflicting. Denosumab (Dmab), a fully human monoclonal antibody that can bind to RANKL and prevent osteoclast formation, is a commonly used antiosteoporosis drug. Recent basic studies have found that Dmab seems to regulate glucose homeostasis and β-cell function in humanized mice or in vitro human β-cell models. Besides, some clinical data have also reported the glucometabolic effects of Dmab, however, with limited and inconsistent results. This review mainly describes the impact of the RANKL signaling pathway on glucose metabolism and summarizes clinical evidence that links Dmab and DM to seek a new therapeutic strategy for diabetes.

Celastrol targets the ChREBP-TXNIP axis to ameliorates type 2 diabetes mellitus

BackgroundsThioredoxin-interacting protein (TXNIP) plays a pivotal role in regulation of blood glucose homeostasis and is an emerging therapeutic target in diabetes and its complications. Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium wilfordii Hook F, can reduce insulin resistance and improve diabetic complications. PurposeThis study aimed to untangle the mechanism of celastrol in ameliorating type 2 diabetes (T2DM) and evaluate its potential benefits as an anti-diabetic agent. Methodsdb/db mice was used to evaluate the hypoglycemic effect of celastrol in vivo; Enzyme-linked immunosorbent assay (ELISA) and 2-NBDG assay were used to detect the effect of celastrol on insulin secretion and glucose uptake in cells; Western blotting, quantitative reverse transcription PCR (RT-qPCR) and immunohistological staining were used to examine effect of celastrol on the expression of TXNIP and the carbohydrate response element-binding protein (ChREBP). Molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive targets stability assay (DARTS) and mass spectrometry were used to test the direct binding between celastrol and ChREBP. Loss- and gain-of-function studies further confirmed the role of ChREBP and TXNIP in celastrol-mediated amelioration of T2DM. ResultsCelastrol treatment significantly reduced blood glucose level, body weight and food intake, and improved glucose tolerance in db/db mice. Moreover, celastrol promoted insulin secretion and improved glucose homeostasis. Mechanistically, celastrol directly bound to ChREBP, a primary transcriptional factor upregulating TXNIP expression. By binding to ChREBP, celastrol inhibited its nuclear translocation and promoted its proteasomal degradation, thereby repressing TXNIP transcription and ultimately ameliorating T2DM through breaking the vicious cycle of hyperglycemia deterioration and TXNIP overexpression. ConclusionCelastrol ameliorates T2DM through targeting ChREBP-TXNIP aix. Our study identified ChREBP as a new direct molecular target of celastrol and revealed a novel mechanism for celastrol-mediated amelioration of T2DM, which provides experimental evidence for its possible use in the treatment of T2DM and new insight into diabetes drug development for targeting TXNIP.

Efficacy and safety of novel dual glucokinase activator dorzagliatin in type-2 diabetes A meta-analysis

Background & aimsGlucokinase has a critical role in regulating glucose homeostasis in humans, and has been a target for diabetes drug development since 1990s. Dorzagliatin is a novel allosteric dual glucokinase activator targeting both pancreatic and hepatic glucokinase. No meta-analysis has analysed the efficacy and safety of dorzagliatin in type-2 diabetes (T2DM). We undertook this meta-analysis to address this knowledge-gap. MethodsElectronic databases were searched for RCTs involving T2DM patients receiving dorzagliatin in intervention arm, and placebo/active comparator in control arm. Primary outcome was to evaluate changes in HbA1c. Secondary outcomes were to evaluate alterations in blood glucose parameters, lipids, insulin-resistance and adverse events. ResultsFrom initially screened 17 articles, data from 3 RCTs (1333 patients) was analysed. Over 12–24 weeks use, dorzagliatin had significantly higher lowering of HbA1c [MD -0.66% (95%CI: −0.74 to −0.59); P < 0.01; I2 = 99%], fasting glucose [MD -32.03 mg/dl (95%CI: 45.12 to −18.94); P < 0.01; I2 = 100%], 2-h post-prandial glucose [MD -43.49 mg/dl (95%CI: −46.26 to −40.72); P < 0.01; I2 = 90%] along with greater number of patients achieving HbA1c<7% [OR 6.01 (95% CI: 2.50–14.46); P < 0.01; I2 = 83%], as compared to placebo. Dorzagliatin was associated with significant elevation of triglycerides [MD 0.43 mmol/L (95%CI:0.30–0.56); P < 0.01; I2 = 0%], greater occurrence of hyperlipidaemia [RR 1.52 (95% CI:1.05–2.18); P = 0.03; I2 = 0%], and increase in body-weight [MD 0.40 kg (95%CI:0.06–0.75); P = 0.03; I2 = 0%], compared to placebo. The occurrence of total-adverse-events [RR 1.43 (95%CI:1.11–1.83); P < 0.01; I2 = 0%] but not severe adverse-events [RR 0.92 (95%CI:0.54–1.57); P = 0.76; I2 = 0%] was significantly higher with dorzagliatin. ConclusionDorzagliatin has good glycaemic efficacy and well tolerated over 6-months use. Mild increase in body-weight, serum triglycerides and overall adverse events remain issues of concern warranting further evaluation in longer clinical trials with active controls.

The association of serum visfatin in women with polycystic ovary syndrome: A case-control study

Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy among women of reproductive age. Visfatin is an adipokine secreted by fat tissue and macrophages involved in regulating glucose homeostasis, adipose tissue inflammation, chronic systemic inflammation, cardiovascular disease and endothelial dysfunction. The study sample (100 patients) includes 50 PCOS women and 50 control matched for age and body mass index (BMI). The women with PCOS were divided into obese or overweighed according to BMI ≥ 25 Kg/m2 and non-obese BMI ≤ 25 Kg/m2. The control group was also divided into obese and non-obese. The results showed that serum visfatin was significantly increased in obese women with POCS compared to obese control (5.61 ± 1.27 ng/mL vs. 0.48 ±0.28 ng/mL) and in non-obese women with polycystic ovarian syndrome compared to non-obese control (5.22± 1.36 ng/mL vs. 0.33± 0.26 ng/mL). These findings might suggest that visfatin could play a role in pathogenesis and the long-term consequences of PCOS. Keywords: visfatin; polycystic ovarian syndrome; body mass index; obese women

Loss of glyoxalase 2 alters the glucose metabolism in zebrafish

Glyoxalase 2 is the second enzyme of the glyoxalase system, catalyzing the detoxification of methylglyoxal to d-lactate via SD-Lactoylglutathione. Recent in vitro studies have suggested Glo2 as a regulator of glycolysis, but if Glo2 regulates glucose homeostasis and related organ specific functions in vivo has not yet been evaluated. Therefore, a CRISPR-Cas9 knockout of glo2 in zebrafish was created and analyzed. Consistent with its function in methylglyoxal detoxification, SD-Lactoylglutathione, but not methylglyoxal accumulated in glo2−/− larvae, without altering the glutathione metabolism or affecting longevity. Adult glo2−/− livers displayed a reduced hexose concentration and a reduced postprandial P70–S6 kinase activation, but upstream postprandial AKT phosphorylation remained unchanged. In contrast, glo2−/− skeletal muscle remained metabolically intact, possibly compensating for the dysfunctional liver through increased glucose uptake and glycolytic activity. glo2−/− zebrafish maintained euglycemia and showed no damage of the retinal vasculature, kidney, liver and skeletal muscle. In conclusion, the data identified Glo2 as a regulator of cellular energy metabolism in liver and skeletal muscle, but the redox state and reactive metabolite accumulation were not affected by the loss of Glo2.

Disease progression promotes changes in adipose tissue signatures in type 2 diabetic (db/db) mice: The potential pathophysiological role of batokines

Unlike the white adipose tissue (WAT) which mainly stores excess energy as fat, brown adipose tissue (BAT) has become physiologically important and therapeutically relevant for its prominent role in regulating energy metabolism. The current study makes use of an established animal model of type 2 diabetes (T2D) db/db mice to determine the effect of the disease progression on adipose tissue morphology and gene regulatory signatures. Results showed that WAT and BAT from db/db mice display a hypertrophied phenotype that is consistent with increased expression of the pro-inflammatory cytokine, tumor necrosis factor-alpha (Tnf-α). Moreover, BAT from both db/db and non-diabetic db/+ control mice displayed an age-related impairment in glucose homeostasis, inflammatory profile, and thermogenic regulation, as demonstrated by reduced expression of genes like glucose transporter (Glut-4), adiponectin (AdipoQ), and uncoupling protein 1 (Ucp-1). Importantly, gene expression of the batokines regulating sympathetic neurite outgrowth and vascularization, including bone morphogenic protein 8b (Bmp8b), fibroblast growth factor 21 (Fgf-21), neuregulin 4 (Nrg-4) were altered in BAT from db/db mice. Likewise, gene expression of meteorin-like (Metrnl), growth differentiation factor 15 (Gdt-15), and C-X-C motif chemokine-14 (Cxcl-14) regulating pro- and anti-inflammation were altered. This data provides some new insights into the pathophysiological mechanisms involved in BAT hypertrophy (or whitening) and the disturbances of batokines during the development and progression of T2D. However, these are only preliminary results as additional experiments are necessary to confirm these findings in other experimental models of T2D.

A brown fat-enriched adipokine Adissp controls adipose thermogenesis and glucose homeostasis.

The signaling mechanisms underlying adipose thermogenesis have not been fully elucidated. Particularly, the involvement of adipokines that are selectively expressed in brown adipose tissue (BAT) and beige adipocytes remains to be investigated. Here we show that a previously uncharacterized adipokine (UPF0687 protein / human C20orf27 homolog) we named as Adissp (Adipose-secreted signaling protein) is a key regulator for white adipose tissue (WAT) thermogenesis and glucose homeostasis. Adissp expression is adipose-specific and highly BAT-enriched, and its secretion is stimulated by β3-adrenergic activation. Gain-of-functional studies collectively showed that secreted Adissp promotes WAT thermogenesis, improves glucose homeostasis, and protects against obesity. Adipose-specific Adissp knockout mice are defective in WAT browning, and are susceptible to high fat diet-induced obesity and hyperglycemia. Mechanistically, Adissp binds to a putative receptor on adipocyte surface and activates protein kinase A independently of β-adrenergic signaling. These results establish BAT-enriched Adissp as a major upstream signaling component in thermogenesis and offer a potential avenue for the treatment of obesity and diabetes.

Longitudinal monitoring of pancreatic islet damage in streptozotocin-treated mice with optical coherence microscopy.

Pancreatic islets regulate glucose homeostasis in the body, and their dysfunction is closely related to diabetes. Islet transplantation into the anterior chamber of the eye (ACE) was recently developed for both in vivo islet study and diabetes treatment. Optical coherence microscopy (OCM) was previously used to monitor ACE transplanted islets in non-obese diabetic (NOD) mice for detecting autoimmune attack. In this study, OCM was applied to streptozotocin (STZ)-induced diabetic mouse models for the early detection of islet damage. A custom extended-focus OCM (xfOCM) was used to image islet grafts in the ACE longitudinally during STZ-induced beta cell destruction together with conventional bright-field (BF) imaging and invasive glucose level measurement. xfOCM detected local structural changes and vascular degradation during the islet damage which was confirmed by confocal imaging of extracted islet grafts. xfOCM detection of islet damage was more sensitive than BF imaging and glucose measurement. Longitudinal xfOCM images of islet grafts were quantitatively analyzed. All these results showed that xfOCM could be used as a non-invasive and sensitive monitoring method for the early detection of deficient islet grafts in the ACE with potential applications to human subjects.

Sphingosine kinase 2 regulates insulin receptor trafficking in hepatocytes.

Disturbed insulin receptor (InsR) trafficking is associated with impaired insulin signaling and the development of diabetes. Sphingosine kinase (SphK), including SphK1 and SphK2, is a key enzyme of sphingolipid metabolism, which has been implicated in the regulation of membrane trafficking. More recently, we have reported that SphK2 is a key regulator of hepatic insulin signaling and glucose homeostasis. However, the role of SphK in InsR trafficking is still undefined. Huh7 cells were treated with specific SphK1 and SphK2 inhibitors or SphK1- and SphK2-specific small interfering RNA (siRNA) in the presence or absence of insulin. Flow cytometry and immunofluorescence assays were carried out to investigate the role of SphK in InsR trafficking. InsR endocytosis, recycling, and insulin signaling were analyzed. Inhibition of SphK2, but not SphK1, by either specific pharmaceutic inhibitors or siRNA, significantly suppressed InsR endocytosis and recycling following insulin stimulation. Consequently, the insulin-stimulated Akt activation was significantly attenuated by SphK2 inhibition in hepatocytes. Moreover, the effect of SphK2 on InsR trafficking was mediated via the clathrin-dependent mechanism. Thus, our results show that SphK2 is able to regulate InsR trafficking. These findings suggest that SphK2 may impinge on hepatic insulin signaling by regulating InsR trafficking, providing further mechanistic evidence that SphK2 could serve as a potential intervention target against insulin resistance and T2D (type 2 diabetes).

RF04 | PSUN297 Genetic Knockout of Intestinal Hexokinase Domain Containing Protein-1 Affects Enterocyte Glucose Transport in Mice Fed High Fat Diet

Abstract Hexokinase domain containing protein-1, or HKDC1, is a widely expressed novel hexokinase that is genetically associated with elevated 2-hour gestational blood glucose levels during an oral glucose tolerance test, suggesting a role for HKDC1 in postprandial glucose regulation during pregnancy. Our earlier studies utilizing transgenic mice containing whole-body HKDC1 knockdown, or mice in which hepatic HKDC1 was overexpressed or knocked out, indicated that HKDC1 is important for whole-body glucose homeostasis in aging and pregnancy, through modulation of glucose tolerance, peripheral tissue glucose utilization, and hepatic energy storage. However, our knowledge of the precise mechanisms by which HKDC1 regulates postprandial glucose homeostasis under normal and diabetic conditions is lacking. As the intestine is the main entry portal for dietary glucose, and since HKDC1 is highly expressed within the intestine, in this study we assessed and characterized the in vivo significance of intestine-specific HKDC1 in regulating glucose homeostasis under normal and obesogenic conditions. We developed an intestine-specific HKDC1 knockout mouse model, HKDC1Int-/-, utilizing Cre-mediated recombination of HKDC1 in which Cre was expressed under the control of the villin gene promoter, leading to genetic knockout of HKDC1 solely within the intestinal epithelium. Mice were maintained until 28 weeks of age on either a normal chow diet or a high fat diet to develop obesity, hyperglycemia, and insulin resistance. While no overt glycemic phenotype was observed, 28-week-old HKDC1Int-/- mice fed a high fat diet exhibited an increased glucose excursion following an oral glucose load compared to mice expressing intestinal HKDC1. This finding was not due to differences in insulin levels, whole-body insulin tolerance, or gluconeogenesis, nor was it a result of alterations in enterocyte glucose utilization or a reduction in peripheral skeletal muscle glucose uptake. Furthermore, the enhanced glucose excursion was related to transport of glucose through the intestinal epithelium, as mice administered an intraperitoneal glucose load did not exhibit alterations in post-load glycemic excursion. Assessment of intestinal glucose transporters in high fat diet-fed HKDC1Int-/- mice indicated an increased expression of GLUT2 in the enterocyte apical membrane in the fasting state. Taken together, our results indicate that intestine-specific HKDC1 contributes to postprandial glycemic regulation by modulating dietary glucose transport across the intestinal epithelium under conditions of enhanced metabolic stress, such as obesity, hyperglycemia, and diabetes. Presentation: Saturday, June 11, 2022 1:24 p.m. - 1:29 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

The Association of Peptide Hormones with Glycemia, Dyslipidemia, and Obesity in Lebanese Individuals.

Peptide-hormones, including pancreatic peptide-YY(PYY), glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), insulin, and leptin function as satiety signals, while ghrelin promotes hunger. These hormones are also involved in glucose homeostasis and body-weight regulation. The aim of this cross-sectional analysis was to examine the association of these peptide-hormones with obesity-markers, insulin-resistance, and dyslipidemia (total-cholesterol (TC), low-density-lipoprotein-cholesterol (LDL-C), high-density-lipoprotein-cholesterol (HDL-C), triglyceride (TG)). Sixteen-obese (OB) adults and 21 normal-weight (NW) age-and gender-matched counterparts were recruited. OB-participants showed significantly higher levels of leptin, insulin, Homeostatic-Model Assessment of Insulin Resistance (HOMA-IR), and TG. NW participants had significantly higher levels of ghrelin. GLP-1 was positively correlated with insulin, HOMA-IR, and obesity-markers except percent body fat. Leptin was positively correlated with all markers (except glucose and dyslipidemia). PYY was positively correlated with BMI, insulin and HOMA-IR. Ghrelin was inversely correlated with all of the markers except glucose, TC, and LDL-C. In the regression analysis model, leptin was positively associated with obesity markers and insulin resistance. Our results indicate a significant difference in peptide hormones among OB and NW Lebanese individuals. Since there is controversial evidence regarding body-weight and peptide-hormones in the literature, this study highlights a step forward towards finding ethnic based strategies to treat obesity and its consequences.

Quantification of changes in human islet G protein-coupled receptor mRNA expression in obesity.

G protein-coupled receptors (GPCRs) play crucial roles in regulating islet function, with Gαs- and Gαq-coupled receptors being linked to the stimulation of insulin secretion. We have quantified the mRNA expression of 384 non-olfactory GPCRs in islets isolated from lean and obese organ donors to determine alterations in islet GPCR mRNA expression in obesity. RT-qPCR was used to quantify GPCR mRNAs relative to five reference genes (ACTB, GAPDH, PPIA, TBP, and TFRC) in human islets isolated from lean (BMI=22.6± 0.5) and obese (BMI=32.0± 0.8) donors. Overall, 197 and 256 GPCR mRNAs were detected above trace level in islets from lean and obese donors, respectively, with 191 GPCR mRNAs being common to the lean and obese groups. 40.9% (n= 157) and 27.1% (n= 104) of the mRNAs were expressed at trace level whilst 7.8% and 6.3% were absent in islets from lean and obese donors, respectively. Hundred and seventeen GPCR mRNAs were upregulated at least twofold in islets from obese donors, and there was >twofold downregulation of 21 GPCR mRNAs. Of particular interest, several receptors signalling via Gαs or Gαq showed significant mRNA upregulation in islets from obese donors (fold increase: PTH2R: 54.0 ± 14.6; MC2R: 34.3 ± 11.5; RXFP1: 8.5± 2.1; HTR2B: 6.0 ± 2.0; GPR110: 3.9± 1.2; PROKR2: 3.9± 0.7). Under conditions of obesity, human islets showed significant alterations in mRNAs encoding numerous GPCRs. The increased expression of Gαs- and Gαq-coupled receptors that have not previously been investigated in β-cells opens up possibilities of novel therapeutic candidates that may lead to the potentiation of insulin secretion and/or β-cell mass to regulate glucose homeostasis.

ROCK1 regulates insulin secretion from β-cells

ObjectiveThe endocrine pancreatic β-cells play a pivotal role in maintaining whole-body glucose homeostasis and its dysregulation is a consistent feature in all forms of diabetes. However, knowledge of intracellular regulators that modulate β-cell function remains incomplete. We investigated the physiological role of ROCK1 in the regulation of insulin secretion and glucose homeostasis. MethodsMice lacking ROCK1 in pancreatic β-cells (RIP-Cre; ROCK1loxP/loxP, β-ROCK1−/−) were studied. Glucose and insulin tolerance tests as well as glucose-stimulated insulin secretion (GSIS) were measured. An insulin secretion response to a direct glucose or pyruvate or pyruvate kinase (PK) activator stimulation in isolated islets from β-ROCK1−/− mice or β-cell lines with knockdown of ROCK1 was also evaluated. A proximity ligation assay was performed to determine the physical interactions between PK and ROCK1. ResultsMice with a deficiency of ROCK1 in pancreatic β-cells exhibited significantly increased blood glucose levels and reduced serum insulin without changes in body weight. Interestingly, β-ROCK1−/− mice displayed a progressive impairment of glucose tolerance while maintaining insulin sensitivity mostly due to impaired GSIS. Consistently, GSIS markedly decreased in ROCK1-deficient islets and ROCK1 knockdown INS-1 cells. Concurrently, ROCK1 blockade led to a significant decrease in intracellular calcium and ATP levels and oxygen consumption rates in isolated islets and INS-1 cells. Treatment of ROCK1-deficient islets or ROCK1 knockdown β-cells either with pyruvate or a PK activator rescued the impaired GSIS. Mechanistically, we observed that glucose stimulation in β-cells greatly enhanced ROCK1 binding to PK. ConclusionsOur findings demonstrate that β-cell ROCK1 is essential for glucose-stimulated insulin secretion and for glucose homeostasis and that ROCK1 acts as an upstream regulator of glycolytic pyruvate kinase signaling.

Brain insulin resistance and cognitive function: influence of exercise.

Exercise has systemic health benefits in people, in part, through improving whole body insulin sensitivity. The brain is an insulin-sensitive organ that is often underdiscussed relative to skeletal muscle, liver, and adipose tissue. Although brain insulin action may have only subtle impacts on peripheral regulation of systemic glucose homeostasis, it is important for weight regulation as well as mental health. In fact, brain insulin signaling is also involved in processes that support healthy cognition. Furthermore, brain insulin resistance has been associated with age-related declines in memory and executive function as well as Alzheimer's disease pathology. Herein, we provide an overview of brain insulin sensitivity in relation to cognitive function from animal and human studies, with particular emphasis placed on the impact exercise may have on brain insulin sensitivity. Mechanisms discussed include mitochondrial function, brain growth factors, and neurogenesis, which collectively help combat obesity-related metabolic disease and Alzheimer's dementia.

Endothelial SIRT-1 has a critical role in the maintenance of capillarization in brown adipose tissue

Brown adipose tissue (BAT) has critical roles in thermogenesis and systemic metabolism. Capillary rarefaction was reported to develop in BAT with dietary obesity, and previous studies showed that suppression of vascular endothelial growth factor A (VEGF-A) reduced capillary density in BAT, promoting the functional decline of this organ. Capillarization is regulated through the balance between angiogenesis and vasculogenesis on the one hand and apoptosis of endothelial cells (ECs) on the other; however, the role of EC apoptosis in BAT remained to be explored. In studies testing the role of boysenberry polyphenols (BoyP) in BAT, we found that BoyP decreased EC apoptosis, enhanced capillarization in BAT, and ameliorated dietary BAT dysfunction, which was associated with the upregulation of nicotinamide adenine dinucleotide-dependent protein deacetylase sirtuin 1 (SIRT-1) in ECs. Our studies suggest that EC SIRT-1 would be one of the potential targets of BoyP that contributes to BAT capillarization and function.

Anti-Inflammatory Effects of GLP-1R Activation in the Retina.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone, mainly produced by enteroendocrine L cells, which participates in the regulation of glucose homeostasis, and in reduction in body weight by promoting satiety. Actions of GLP-1 are mediated by activation of its receptor GLP-1R, which is widely expressed in several tissues including the retina. The effects of GLP-1R activation are useful in the management of type 2 diabetes mellitus (T2DM). In addition, the activation of GLP-1R has anti-inflammatory effects in several organs, suggesting that it may be also useful in the treatment of inflammatory diseases. Inflammation is a common element in the pathogenesis of several ocular diseases, and the protective effects of treatment with GLP-1 emerged also in retinal diseases. In this review we highlight the anti-inflammatory effects of GLP-1R activation in the retina. Firstly, we summarized the pathogenic role of inflammation in ocular diseases. Then, we described the pleiotropic effects of GLP-1R activation on the cellular components of the retina which are mainly involved in the pathogenesis of inflammatory retinal diseases: the retinal ganglion cells, retinal pigment epithelial cells and endothelial cells.