Modulation Of Insulin Secretion Research Articles

Placental small extracellular vesicles from normal pregnancy and gestational diabetes increase insulin genetranscription and content in β cells.

Insulin secretion increases progressively during pregnancy to maintain normal maternal blood glucose levels. The placenta plays a crucial role in this process by releasing hormones and extracellular vesicles into the maternal circulation, which drive significant changes in pregnancy physiology. Placental extracellular vesicles, which are detectable in the plasma of pregnant women, have been shown to signal peripheral tissues and contribute to pregnancy-related conditions. While studies using murine models have demonstrated that extracellular vesicles can modulate insulin secretion in pancreatic islets, it remains unclear whether these effects translate to human biology. Understanding how placental signals enhance insulin synthesis and secretion from β cells could be pivotal in developing new therapies for diabetes. In our study, we isolated placental small extracellular vesicles from human placentae and utilised the human β cell line, EndoC-βH3, to investigate their effects on β-cell function in vitro. Our results indicate that human β cells internalise placental small extracellular vesicles, leading to enhanced insulin gene expression and increased insulin content within the β cells. Moreover, these vesicles upregulated the expression of Annexin A1, a protein known to increase insulin content. This upregulation of Annexin A1 holds promise as a potential mechanism by which placental small extracellular vesicles enhance insulin biosynthesis.

Bioprospection of rattlesnake venom peptide fractions with anti-adipose and anti-insulin resistance activity in vitro

Animal venoms are natural products that have served as a source of novel molecules that have inspired novel drugs for several diseases, including for metabolic diseases such as type-2 diabetes and obesity. From venoms, toxins such as exendin-4 (Heloderma suspectum) and crotamine (Crotalus durissus terrificus) have demonstrated their potential as treatments for obesity. Moreover, other toxins such as Phospholipases A2 and Disintegrins have shown their potential to modulate insulin secretion in vitro. This suggests an unexplored diversity of venom peptides with a potential anti-obesogenic in Mexican rattlesnake venoms. For that reason, this study explored the in vitro effect of Crotalus venom peptide-rich fractions on models for insulin resistance, adipocyte lipid accumulation, antioxidant activity, and inflammation process through nitric oxide production inhibition. Our results demonstrated that the peptide-rich fractions of C. aquilus, C. ravus, and C. scutulatus scutulatus were capable of reverting insulin resistance, enhancing glucose consumption to normal control; C. culminatus, C. molossus oaxacus, and C. polystictus diminished the lipid accumulation on adipocytes by 20%; C. aquilus, C. ravus, and C. s. salvini had the most significant cellular antioxidant activity, having nearly 80% of ROS inhibition. C. aquilus, C. pyrrhus, and C. s. salvini inhibited nitric oxide production by about 85%. We demonstrated the potential of these peptides from Crotalus venoms to develop novel drugs to treat type-2 diabetes and obesity. Moreover, we described for the first time that Crotalus venom peptide fractions have antioxidant and inflammatory properties in vitro models.

The GHSR1a antagonist LEAP2 regulates islet hormone release in a sex-specific manner.

LEAP2, a liver-derived antagonist for the ghrelin receptor, GHSR1a, counteracts effects of ghrelin on appetite and energy balance. Less is known about its impact on blood glucose-regulating hormones from pancreatic islets. Here we investigate whether acyl-ghrelin (AG) and LEAP2 regulate islet hormone release in a cell type- and sex-specific manner. Hormone content from secretion experiments with isolated islets from male and female mice was measured by radioimmunoassay and mRNA expression by qPCR. LEAP2 enhanced insulin secretion in islets from males (p<0.01) but not females (p<0.2), whilst AG-stimulated somatostatin release was significantly reversed by LEAP2 in males (p<0.001) but not females (p<0.2). Glucagon release was not significantly affected by AG and LEAP2. Ghsr1a, Ghrelin, Leap2, Mrap2, Mboat4 and Sstr3 islet mRNA expression did not differ between sexes. In control male islets maintained without 17-beta oestradiol (E2), AG exerted an insulinostatic effect (p<0.05), with a trend towards reversal by LEAP2 (p=0.06). Both were abolished by 72h E2 pre-treatment (10 nmol/l, p<0.2). AG-stimulated somatostatin release was inhibited by LEAP2 from control (p<0.001) but not E2-treated islets (p<0.2). LEAP2 and AG did not modulate insulin secretion from MIN6 beta cells and Mrap2 was downregulated (P<0.05) and Ghsr1a upregulated (P<0.0001) in islets from Sst-/- mice. Our findings show that AG and LEAP2 regulate insulin and somatostatin release in an opposing and sex-dependent manner, which in males can be modulated by E2. We suggest that regulation of SST release is a key starting point for understanding the role of GHSR1a in islet function and glucose metabolism.

V1bR enhances glucose-stimulated insulin secretion by paracrine production of glucagon which activates GLP-1 receptor

BackgroundArginine vasopressin (AVP) has been reported to regulate insulin secretion and glucose homeostasis in the body. Previous study has shown that AVP and its receptor V1bR modulate insulin secretion via the hypothalamic-pituitary-adrenal axis. AVP has also been shown to enhance insulin secretion in islets, but the exact mechanism remains unclear.ResultsIn our study, we unexpectedly discovered that AVP could only stimulates insulin secretion from islets, but not β cells, and AVP-induced insulin secretion could be blocked by V1bR selective antagonist. Single-cell transcriptome analysis identified that V1bR is only expressed by the α cells. Further studies indicated that activation of the V1bR stimulates the α cells to secrete glucagon, which then promotes glucose-dependent insulin secretion from β cells in a paracrine way by activating GLP-1R but not GCGR on these cells.ConclusionsOur study revealed a crosstalk between α and β cells initiated by AVP/V1bR and mediated by glucagon/GLP-1R, providing a mechanism to develop new glucose-controlling therapies targeting V1bR.

Tannins-enriched fraction of TeMac™ protects against aluminum chloride induced Alzheimer's disease-like pathology by modulating aberrant insulin resistance and alleviating oxidative stress in diabetic rats

Ethnopharmacological relevanceAlzheimer's disease is the most common neurodegenerative disease with therapeutic limitations. Insulin resistance plays a role in the progression of Alzheimer's disease. Therapies that modulate insulin secretion and signaling, as well as oxidative stress in the brain are now being investigated for their potential role in the prevention of Alzheimer's disease (AD). Terminalia macroptera (Combretaceae) is a plant that different parts have been used traditionally for the treatment of metabolic and neurological conditions. Previous study has indicated that the crude extract exhibit anti-diabetic property. In addition, the plant is a rich source of tannins, phenolic acids, flavonoids, triterpenes. However, there is no study on its protective effect against biochemical alterations of AD in diabetic rats. Aim of the studyThe present research study investigated the neuroprotective effects of TeMac™ on Alzheimer-like pathology induced by aluminum chloride (AlCl3) in diabetic rats. MethodsA phytochemical analysis of TeMac™ was carried out to quantify tannins. The potential effect of the tannins-enriched fraction (TEF) of TeMac™ to prevent the formation of senile plaques was conducted by its ability to inhibit the activities of β-secretase (EC 3.4.23.46), monoamine oxidase A (EC 1.4.3.4) and the fibrillation of Aβ. A diabetic model was induced from female Wistar rats by a single intraperitoneal injection of streptozotocin (STZ, 35 mg/kg BW). After that, the blood glucose level was measured to confirm the induction of diabetes. Three days after induction, animals received AlCl3 (75 mg/kg BW) alone (AD control) or concomitantly with 400 mg/kg BW of TEF of TeMac™ or 5 mg/kg BW Daonil by daily gavage for 42 days. At the end of the experiment, rats were sacrificed, blood and brains were collected. The levels of amyloid fibrils, glucose, albumin and the activities of DPP4, β-secretase and phosphatase, and markers of oxidative stress in the brain were assessed. ResultsTEF of TeMac™ displays a potential ability to inhibit the activities of β-secretase, monoamine oxidase, and Aβ fibrillation. Treatment with TEF of TeMac™ significantly inhibited DPP4 and BACE1 activities and reduced brain glucose and amyloid fibril levels, and improved cerebral albumin levels and modulated oxidative stress markers. ConclusionOur findings indicate that TEF of TeMac™ prevents Alzheimer's-type pathology linked to insulin resistance in rats. TEF of TeMac™ may be a potential drug candidate for the treatment of diabetes-associated cognitive impairment.

Decoding the nexus: branched-chain amino acids and their connection with sleep, circadian rhythms, and cardiometabolic health.

The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and, either directly or indirectly, overall body health, encompassing metabolic and cardiovascular well-being. Given the heightened metabolic activity of the brain, there exists a considerable demand for nutrients in comparison to other organs. Among these, the branched-chain amino acids, comprising leucine, isoleucine, and valine, display distinctive significance, from their contribution to protein structure to their involvement in overall metabolism, especially in cerebral processes. Among the first amino acids that are released into circulation post-food intake, branched-chain amino acids assume a pivotal role in the regulation of protein synthesis, modulating insulin secretion and the amino acid sensing pathway of target of rapamycin. Branched-chain amino acids are key players in influencing the brain's uptake of monoamine precursors, competing for a shared transporter. Beyond their involvement in protein synthesis, these amino acids contribute to the metabolic cycles of γ-aminobutyric acid and glutamate, as well as energy metabolism. Notably, they impact GABAergic neurons and the excitation/inhibition balance. The rhythmicity of branched-chain amino acids in plasma concentrations, observed over a 24-hour cycle and conserved in rodent models, is under circadian clock control. The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood. Disturbed sleep, obesity, diabetes, and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics. The mechanisms driving these effects are currently the focal point of ongoing research efforts, since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies. In this context, the Drosophila model, though underutilized, holds promise in shedding new light on these mechanisms. Initial findings indicate its potential to introduce novel concepts, particularly in elucidating the intricate connections between the circadian clock, sleep/wake, and metabolism. Consequently, the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle. They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health, paving the way for potential therapeutic interventions.

A nutrient responsive lipase mediates gut-brain communication to regulate insulin secretion in Drosophila

Pancreatic β cells secrete insulin in response to glucose elevation to maintain glucose homeostasis. A complex network of inter-organ communication operates to modulate insulin secretion and regulate glucose levels after a meal. Lipids obtained from diet or generated intracellularly are known to amplify glucose-stimulated insulin secretion, however, the underlying mechanisms are not completely understood. Here, we show that a Drosophila secretory lipase, Vaha (CG8093), is synthesized in the midgut and moves to the brain where it concentrates in the insulin-producing cells in a process requiring Lipid Transfer Particle, a lipoprotein originating in the fat body. In response to dietary fat, Vaha stimulates insulin-like peptide release (ILP), and Vaha deficiency results in reduced circulatory ILP and diabetic features including hyperglycemia and hyperlipidemia. Our findings suggest Vaha functions as a diacylglycerol lipase physiologically, by being a molecular link between dietary fat and lipid amplified insulin secretion in a gut-brain axis.

Pharmacological and phytochemical insights on the pancreatic β-cell modulation by Angelica L. roots

Ethnopharmacological relevanceAngelica roots are a significant source of traditional medicines for various cultures around the northern hemisphere, from indigenous communities in North America to Japan. Among its many applications, the roots are used to treat type 2 diabetes mellitus; however, this application is not mentioned often. Ethnopharmacological studies have reported the use of A. japonica var. hirsutiflora, A. furcijuga, A. shikokiana, and A. keiskei to treat diabetes symptoms, and further reports have demonstrated the three angelica roots, i.e., A. japonica var. hirsutiflora, A. reflexa, and A. dahurica, exhibit insulin secretagogue activity. Aim of the studyThis study aimed to phytochemically characterize and compare angelica roots monographed in the European Pharmacopeia 11th, isolate major plant metabolites, and assess extracts and isolates' capability to modulate pancreatic β-cell function. Materials and methodsRoot extracts of Angelica archangelica, Angelica dahurica, Angelica biserrata, and Angelica sinensis were phytochemically profiled using liquid chromatography method coupled with mass spectrometry. Based on this analysis, simple and furanocoumarins were isolated using chromatography techniques. Extracts (1.6–50 μg/mL) and isolated compounds (5–40 μmol/L) were studied for their ability to modulate insulin secretion in the rat insulinoma INS-1 pancreatic β-cell model. Insulin was quantified by the homogeneous time-resolved fluorescence method. ResultsForty-one secondary metabolites, mostly coumarins, were identified in angelica root extracts. A. archangelica, A. dahurica, and A. biserrata root extracts at concentration of 12.5–50 μg/mL potentiated glucose-induced insulin secretion, which correlated with their high coumarin content. Subsequently, 23 coumarins were isolated from these roots and screened using the same protocol. Coumarins substituted with the isoprenyl group were found to be responsible for the extracts' insulinotropic effect. ConclusionsInsulinotropic effects of three pharmacopeial angelica roots were found, the metabolite profiles and pharmacological activities of the roots were correlated, and key structures responsible for the modulation of pancreatic β-cell function were identified. These findings may have implications for the traditional use of angelica roots in treating diabetes. Active plant metabolites may also become lead structures in the search for new antidiabetic treatments.

Epinephrine also acts on beta cells and insulin secretion.

In a recent review examining neurotransmitter modulation of insulin secretion, the significant impact of epinephrine was not addressed. Its primary action involves inhibiting insulin release via alpha-adrenergic receptors, thereby reducing the response to insulin secretion stimulators, through the activation of K+ channels and resulting in membrane hyperpolarization in beta cells.

Dietary Supplementation with Cholic Acid Reduces Insulin Secretion in Response to Intraperitoneal Glucose Administration in Rats.

The major characteristic of type 2 diabetes is insulin resistance, which is associated with plasma level of 12-hydroxylated bile acids (BAs) in humans. In this study, we investigated whether the rise of enterohepatic 12-hydroxylated BAs associates with glucose tolerance and/or insulin secretion using rats fed a diet supplemented with cholic acid (CA) at a level of 0.5 g/kg diet. Almost no increase was observed in plasma insulin in response to the intraperitoneal glucose administration in the CA-fed rats despite the significant increase of plasma insulin in control with the same treatment. In contrast, the changes in insulin secretion were observed in both groups and no difference was detected between the groups in the oral glucose tolerance test. Increases were observed in pancreatic expressions of Ins1 and Ins2 although the insulin protein content decreased in the pancreas without any sign in ectopic fat accumulation and histological damage in the CA-fed rats. Our results suggest that enterohepatic 12-hydroxylated BAs modulate insulin secretion in response to intraperitoneal glucose administration. The decrease in insulin store might be responsible for the reduction in the insulin secretion in the CA-fed rats.

KCNH6 is essential for insulin secretion by regulating intracellular ER Ca2+ store.

Appropriate Ca2+ concentration in the endoplasmic reticulum (ER), modulating cytosolic Ca2+ signal, serves significant roles in physiological function of pancreatic β cells. To maintaining ER homeostasis, Ca2+ movement across the ER membrane is always accompanied by a simultaneous K+ flux in the opposite direction. KCNH6 was proven to modulate insulin secretion by controlling plasma membrane action potential duration and intracellular Ca2+ influx. Meanwhile, the specific function of KCNH6 in pancreatic β-cells remains unclear. In this study, we found that KCNH6 exhibited mainly ER localization and Kcnh6 β-cell-specific knockout (βKO) mice suffered from abnormal glucose tolerance and impaired insulin secretion in adulthood. ER Ca2+ store was overloaded in islets of βKO mice, which contributed to ER stress and ER stress-induced apoptosis in β cells. Next, we verified that ethanol treatment induced increases in ER Ca2+ store and apoptosis in pancreatic β cells, whereas adenovirus-mediated KCNH6 overexpression in islets attenuated ethanol-induced ER stress and apoptosis. In addition, tail-vein injections of KCNH6 lentivirus rescued KCNH6 expression in βKO mice, restored ER Ca2+ overload and attenuated ER stress in β cells, which further confirms that KCNH6 protects islets from ER stress and apoptosis. These data suggest that KCNH6 on the ER membrane may help to stabilize intracellular ER Ca2+ stores and protect β cells from ER stress and apoptosis. In conclusion, our study reveals the protective potential of KCNH6-targeting drugs in ER stress-induced diabetes.

The NERP-4–SNAT2 axis regulates pancreatic β-cell maintenance and function

Insulin secretion from pancreatic β cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. The granin protein VGF has dual roles in β cells: regulating secretory granule formation and functioning as a multiple peptide precursor. A VGF-derived peptide, neuroendocrine regulatory peptide-4 (NERP-4), increases Ca2+ influx in the pancreata of transgenic mice expressing apoaequorin, a Ca2+-induced bioluminescent protein complex. NERP-4 enhances glucose-stimulated insulin secretion from isolated human and mouse islets and β-cell–derived MIN6-K8 cells. NERP-4 administration reverses the impairment of β-cell maintenance and function in db/db mice by enhancing mitochondrial function and reducing metabolic stress. NERP-4 acts on sodium-coupled neutral amino acid transporter 2 (SNAT2), thereby increasing glutamine, alanine, and proline uptake into β cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on β-cell maintenance. These findings demonstrate a novel autocrine mechanism of β-cell maintenance and function that is mediated by the peptide–amino acid transporter axis.

A prospective guide for clinical implementation of selected OGTT- derived surrogate indices for the evaluation of β- cell function and insulin sensitivity in patients with transfusion-dependent β- thalassaemia.

The gold standard for the measurement of insulin secretion is the hyperglycemic clamp and for insulin sensitivity the hyperinsulinemic euglycemic clamp, respectively. A number of surrogate indices, derived from plasma glucose and insulin levels at a fasting state or after oral glucose load, have been proposed to estimate β-cell response, and the ability of β-cells to compensate for changes of insulin sensitivity by modulating insulin secretion (disposition index). Starting from the current recommendations for the annual screening of glucose dysregulation in patients with transfusion dependent β-thalassemia (β-TDT), this article summarizes the most frequently used indirect indices of insulin secretion and resistance derived from the oral glucose tolerance test (OGTT) and discusses the strengths and weaknesses of selected indices and the basic concepts underlying each method for the appropriate evaluation of glucose regulation. Basal indices for β-cell function and insulin sensitivity, albeit simple and cheap, have limited usefulness due to a high coefficient variation and the lack of data about response to glucose load. Therefore, measurement of indices during an OGTT, despite being costly and time-consuming, is suggested since it can detect, even subtle, dynamic changes in insulin secretion and glucose handling. In patients with β-TDT, the indices derived from OGTT may offer an additional factor to evaluate the efficiency of iron chelation therapy and detect patients who may need intensification of iron chelation therapy and/or pharmacological intervention.

Calpain and Cardiometabolic Diseases

Calpain is defined as a member of the superfamily of cysteine proteases possessing the CysPC motif within the gene. Calpain-1 and -2, which are categorized as conventional isozymes, execute limited proteolysis in a calcium-dependent fashion. Accordingly, the calpain system participates in physiological and pathological phenomena, including cell migration, apoptosis, and synaptic plasticity. Recent investigations have unveiled the contributions of both conventional and unconventional calpains to the pathogenesis of cardiometabolic disorders. In the context of atherosclerosis, overactivation of conventional calpain attenuates the barrier function of vascular endothelial cells and decreases the immunosuppressive effects attributed to lymphatic endothelial cells. In addition, calpain-6 induces aberrant mRNA splicing in macrophages, conferring atheroprone properties. In terms of diabetes, polymorphisms of the calpain-10 gene can modify insulin secretion and glucose disposal. Moreover, conventional calpain reportedly participates in amino acid production from vascular endothelial cells to induce alteration of amino acid composition in the liver microenvironment, thereby facilitating steatohepatitis. Such multifaceted functionality of calpain underscores its potential as a promising candidate for pharmaceutical targets for the treatment of cardiometabolic diseases. Consequently, the present review highlights the pivotal role of calpains in the complications of cardiometabolic diseases and embarks upon a characterization of calpains as molecular targets.

Modulation of insulin secretion by RBFOX2-mediated alternative splicing

Insulin secretion is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Although the molecular components of insulin granule trafficking and secretion are well established, how they are regulated to rapidly fine-tune secretion in response to changing environmental conditions is not well characterized. Recent studies have determined that dysregulation of RNA-binding proteins (RBPs) and aberrant mRNA splicing occurs at the onset of diabetes. We demonstrate that the RBP, RBFOX2, is a critical regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis. Conditional mutation of Rbfox2 in the mouse pancreas results in decreased insulin secretion and impaired blood glucose homeostasis. Consistent with defects in secretion, we observe reduced insulin granule docking and corresponding splicing defects in the SNARE complex components. These findings identify an additional mechanism for modulating insulin secretion in both healthy and dysfunctional pancreatic β cells.

FRI623 Beta Cell Primary Cilia Mediate Somatostatin Responsiveness Via SSTR3

Abstract Disclosure: S.E. Adamson: None. A. Li: None. J. Hughes: None. Somatostatin is an important modulator of beta cell function, but communication between beta and delta cells is not well-understood. Primary cilia are membrane organelles that act as signaling hubs due to their enrichment in certain G-protein coupled receptors and other signaling proteins. We show that somatostatin modulates insulin secretion via somatostatin receptor 3 (SSTR3) located on beta cell primary cilia in mouse islets. SSTR3 and the presence of primary cilia are required for normal beta cell response to somatostatin. Somatostatin signaling leads to beta cell calcium changes, which we characterize here using a beta cell specific genetically-encoded GCaMP6f calcium reporter. Our findings show that ciliary SSTR3 mediates delta to beta cell paracrine crosstalk. Presentation: Friday, June 16, 2023

SAT074 Induction Of Insulin Hypersecretion Uncovers Distinctions Between Adaptive And Maladaptive Endoplasmic Reticulum Stress Response In Beta Cells

Abstract Disclosure: G. Roy: None. K. Rodrigues dos Santos: None. M.B. Kwakye: None. Z. Tan: None. T.S. Johnson: None. M.A. Kalwat: None. Pancreatic islet β-cells release insulin to maintain glucose homeostasis. β-cells must translate, package, and secrete large amounts of insulin. During this process the unfolded protein response of the endoplasmic reticulum (UPRER) is induced to maintain these functions. However, stimuli that force β-cell to secrete insulin at enhanced rates and for prolonged durations risk inducing the terminal UPRER and eventual apoptosis. In a chemical screen for insulin secretion modulators, we discovered SW016789 which caused hypersecretion of insulin and led to a transient induction of the UPRER, but not apoptosis. In contrast, SERCA2 ER Ca2+ pump inhibitor thapsigargin induces the terminal UPRER. We hypothesized that SW016789 can be used as a tool compound to discover genes involved in β-cell adaptation to hypersecretion-induced stress. We performed time course transcriptomics in MIN6 β-cells exposed to SW016789 (5 µM) or thapsigargin (100 nM) from 0-24 h. Unbiased analyses using a Dirichlet process Gaussian process (DPGP) method revealed clusters of genes temporally co-regulated and the genes within these clusters were distinct between SW016789 and thapsigargin treatments. In particular, after 6 h of SW016789-induced hypersecretion we found a highly induced cluster of genes (SW cluster 3) enriched in adaptive UPRER factors (e.g. Manf). Conversely, most of the thapsigargin-induced genes clustered at 24 h and were enriched for terminal UPRER factors (e.g. Txnip). Pathway analysis of SW cluster 3 indicated that genes involved in in regulation of mRNA methylation and ER-associated degradation were also induced by SW016789 sooner and with greater amplitude than by thapsigargin, suggesting distinct differences in the handling of protein translation and degradation. From the SW cluster 3 genes we selected proteins known to be ER-associated or secreted and generated stable transgenic or CRISPR knockout MIN6 β-cell lines for each. Our data suggest altered expression of these factors may impair glucose-stimulated insulin secretion responses and alter cell viability in presence or absence of ER stressors including cytokines, thapsigargin, and tunicamycin. In conclusion, we have successfully shown that pharmacological induction of insulin hypersecretion can induce a distinct transcriptional outcome from that of canonically-induced UPRER and that we can take advantage of this property to discover new β-cell regulatory pathways and targets. We envision this dataset as a resource for the secretory biology and islet biology communities. Presentation: Saturday, June 17, 2023

Supplementary Effects of Allium hookeri Extract on Glucose Tolerance in Prediabetic Subjects and C57BL/KsJ-db/db Mice.

Allium hookeri (AH) has been used as a nutritional and medicinal food in Asia for many years. Our previous studies have described its anti-diabetic, anti-obesity, and anti-inflammatory activities in animal models and prediabetes. This study investigated whether AH could improve glycemia by modulating insulin secretion in prediabetic subjects through an in-depth study. Eighty prediabetic subjects (100 ≤ fasting plasma glucose < 140 mg/dL) were randomly assigned to a placebo (n = 40) group or an ethanol AH extract (500 mg/day, n = 40) group for 12 weeks. Dietary intake and physical activity, blood glucose (an oral glucose tolerance test for 120 min), insulin (insulin response to oral glucose for 120 min), area under the curve (AUC) of glucose or insulin after oral glucose intake, insulin sensitivity markers, C-peptide, adiponectin, glycated hemoglobin A1c (HbA1c) levels, hematological tests (WBC, RBC, hemoglobin, hematocrit, and platelet count), blood biochemical parameters (ALP, AST, total bilirubin, total protein, albumin, gamma-GT, BUN, creatinine, LD, CK, and hs-CRP), and urine parameters (specific gravity and pH) were examined at both baseline and 12 weeks after supplementation with placebo or AH capsules. Fifty-eight participants (placebo group: 20 men and 10 women; AH group: 13 men and 15 women) completed the study. AH supplementation moderately reduced postprandial blood glucose at 60 min (-6.14 mg/dL, p = 0.061), postprandial insulin levels at 90 min (-16.69 µU/mL, p = 0.017), the glucose AUC at 90 min (-412.52 mg*min/dL, p = 0.021), as well as the insulin AUC at 90 min (-978.77 µU*min/mL, p = 0.021) and 120 min (-1426.41 µU*min/mL, p = 0.015) when compared with the placebo group. However, there were no effects of AH on dietary intake and physical activity; HOMA index; HbAlc; C-peptide; or adiponectin, hematological-, blood biochemical-, and urinary markers. To confirm the effects of AH extract on blood glucose insulin sensitivity, C57BL/6J or C57BL/KsJ-db/db mice were used (n = 8/group). Body weight, fasting plasma glucose level, lipid profiles, liver and renal function, pancreatic histology, and insulin immunoreactivity were assessed. In the diabetic db/db mice, hyperglycemia, which was accompanied by an increase in insulin secretion in diabetic mice, was significantly reduced by AH treatment, resulting in the alleviation of β-cell overcompensation and insulin resistance. We confirmed that AH supplementation can effectively control blood glucose and insulin levels by improving insulin sensitivity and may be a potential agent for glycemic control in subjects with prediabetes and type 2 diabetes mellitus.

Beta cell primary cilia mediate somatostatin responsiveness via SSTR3

ABSTRACT Somatostatin is a paracrine modulator of insulin secretion and beta cell function with pleotropic effects on glucose homeostasis. The mechanism of somatostatin-mediated communication between delta and beta cells is not well-understood, which we address in this study via the ciliary somatostatin receptor 3 (SSTR3). Primary cilia are membrane organelles that act as signaling hubs in islets by virtue of their subcellular location and enrichment in signaling proteins such as G-protein coupled receptors (GPCRs). We show that SSTR3, a ciliary GPCR, mediates somatostatin suppression of insulin secretion in mouse islets. Quantitative analysis of calcium flux using a mouse model of genetically encoded beta cell-specific GCaMP6f calcium reporter shows that somatostatin signaling alters beta cell calcium flux after physiologic glucose stimulation, an effect that depends on endogenous SSTR3 expression and the presence of intact primary cilia on beta cells. Comparative in vitro studies using SSTR isoform antagonists demonstrate a role for SSTR3 in mediating somatostatin regulation of insulin secretion in mouse islets. Our findings support a model in which ciliary SSTR3 mediates a distinct pathway of delta-to-beta cell regulatory crosstalk and may serve as a target for paracrine modulation.

PAQR9 regulates glucose homeostasis in diabetic mice and modulates insulin secretion in β cells in vitro under stress conditions

Progesterone and adipoQ receptor 9 (PAQR9) is an endoplasmic reticulum (ER)-localized membrane protein that is involved in protein quality control of ER by interacting with BAG6. One of the physiological functions of PAQR9 is regulation of fasting-induced ketogenesis and fatty acid oxidation in the liver via modulating protein degradation of PPARα. However, it is currently unknown whether or not PAQR9 impacts glucose homeostasis. We addressed this question using a Paqr9-deleted mouse model in which type 1 diabetes was induced by streptozotocin injection and type 2 diabetes was induced by high-fat diet (HFD) with streptozotocin injection. Paqr9 deletion improved hyperglycemia and glucose tolerance in both of the diabetic mouse models. In the pancreatic islets, Paqr9 deletion reduced apoptosis of β cells in type 2 diabetic mice. Paqr9 deletion also reduced HFD-induced hepatic steatosis and adiposity of white adipose tissue. In Min6 cells, overexpression of DUF3538 domain of BAG6 to block the interaction of PAQR9 with BAG6 was able to enhance glucose-stimulated insulin secretion upon treatment with inflammatory factors or thapsigargin, an ER stress inducer. Thapsigargin-induced ER stress markers were also reduced by overexpression of DUF3538 domain. Collectively, these results indicate that PAQR9 has a modulatory role in glucose homeostasis, associated with regulation on insulin secretion of β cells in vitro under stress conditions.