Role of extracellular vesicles in insulin resistance: Signaling pathways, bioactive substances, miRNAs, and therapeutic potential.

Extracellular vesicles are small lipid bilayer particles that resemble the structure of cells and range in size from 30 to 1000 nm. They transport a variety of physiologically active molecules, such as proteins, lipids, and miRNAs. Insulin resistance (IR) is a pathological disease in which insulin-responsive organs or components become less sensitive to insulin's physiological effects, resulting in decreased glucose metabolism in target organs such as the liver, muscle, and adipose tissue. Extracellular vesicles have received a lot of attention as essential intercellular communication mediators in the setting of IR. This review looks at extracellular vesicles' role in IR from three angles: signaling pathways, bioactive compounds, and miRNAs. Relevant publications are gathered to investigate the induction, inhibition, and bidirectional regulation of extracellular vesicles in IR, as well as their role in insulin-related illnesses. Furthermore, considering the critical function of extracellular vesicles in regulating IR, the study analyzes the practicality of employing extracellular vesicles for medication delivery and the promise of combination therapy for IR.

The C5aR1 complement receptor: A novel immunomodulator of insulin action in skeletal muscle.

The complement system constitutes an integral component of the innate immune system and plays a critical role in adaptive immunity. Activation of this system engenders the production of complement peptide fragments, including C5a, which engage G-protein coupled receptors predominantly expressed in immune-associated cells, such as neutrophils, initiating pro-inflammatory responses. Intriguingly, our investigation has unveiled the presence of C5a receptor 1 (C5aR1) expression within skeletal muscle, a key metabolic tissue and primary target of insulin. Herein, we demonstrate that C5aR1 activation by C5a in differentiated human skeletal muscle cells elicits acute suppression of insulin signalling. This suppression manifests as impaired insulin-dependent association between IRS1 and the p85 subunit of PI3-kinase, a 50% reduction in Akt phosphorylation, and a 60% decline in insulin-stimulated glucose uptake. This impairment in insulin signalling is associated with a three-fold elevation in intramyocellular diacylglycerol (DAG) levels and a two-fold increase in cytosolic calcium content, which promote PKC-mediated IRS1 inhibition via enhanced phosphorylation at IRS1 Ser1101. Significantly, our findings demonstrate that structurally diverse C5aR1 antagonists, along with genetic deletion or stable silencing of C5aR1 by 80% using short-hairpin RNA, effectively attenuate repression of insulin signalling by C5a in LHCN-M2 human skeletal myotubes. These results underscore the potential of heightened C5aR1 activation, characteristic of obesity and chronic inflammatory conditions, to detrimentally impact insulin function within skeletal muscle cells. Additionally, the study suggests that agents targeting the C5a-C5aR axis, originally devised for mitigating complement-dependent inflammatory conditions, may offer therapeutic avenues to ameliorate immune-driven insulin resistance in key peripheral metabolic tissues, including skeletal muscle.

Insulin and aging - a disappointing relationship.

Experimental studies in animal models of aging such as nematodes, fruit flies or mice have observed that decreased levels of insulin or insulin signaling promotes longevity. In humans, hyperinsulinemia and concomitant insulin resistance are associated with an elevated risk of age-related diseases suggestive of a shortened healthspan. Age-related disorders include neurodegenerative diseases, hypertension, cardiovascular disease, and type 2 diabetes. High ambient insulin concentrations promote increased lipogenesis and fat storage, heightened protein synthesis and accumulation of non-functional polypeptides due to limited turnover capacity. Moreover, there is impaired autophagy activity, and less endothelial NO synthase activity. These changes are associated with mitochondrial dysfunction and oxidative stress. The cellular stress induced by anabolic activity of insulin initiates an adaptive response aiming at maintaining homeostasis, characterized by activation of the transcription factor Nrf2, of AMP activated kinase, and an unfolded protein response. This protective response is more potent in the long-lived human species than in short-lived models of aging research resulting in a stronger pro-aging impact of insulin in nematodes and fruit flies. In humans, resistance to insulin-induced cell stress decreases with age, because of an increase of insulin and insulin resistance levels but less Nrf2 activation. These detrimental changes might be contained by adopting a lifestyle that promotes low insulin/insulin resistance levels and enhances an adaptive response to cellular stress, as observed with dietary restriction or exercise.

Structural basis of insulin fibrillation.

Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is prone to unfolding and forming cross-ß fibers. Fibrillation complicates insulin storage and therapeutic application. Molecular details of insulin fibrillation remain unclear, hindering efforts to prevent fibrillation process. Here, we characterized insulin fibrils using cryo-electron microscopy (cryo-EM), showing multiple forms that contain one or more of the protofilaments containing both the A and B chains of insulin linked by disulfide bonds. We solved the cryo-EM structure of one of the fibril forms composed of two protofilaments at 3.2-Å resolution, which reveals both the ß sheet conformation of the protofilament and the packing interaction between them that underlie the fibrillation. On the basis of this structure, we designed several insulin mutants that display reduced fibrillation while maintaining native IR signaling activity. These designed insulin analogs may be developed into more effective therapeutics for type 1 diabetes.

A Review on the Crosstalk between Insulin and Wnt/ß-Catenin Signalling for Bone Health.

A positive association between insulin resistance and osteoporosis has been widely established. However, crosstalk between the signalling molecules in insulin and Wingless (Wnt)/beta-(ß-)catenin transduction cascades orchestrating bone homeostasis remains not well understood. The current review aims to collate the existing evidence, reporting (a) the expression of insulin signalling molecules involved in bone-related disorders and (b) the expression of Wnt/ß-catenin signalling molecules involved in governing insulin homeostasis. The downstream effector molecule, glycogen synthase kinase-3 beta (GSK3ß), has been identified to be a point of convergence linking the two signal transduction networks. This review highlights that GSK3ß may be a drug target in the development of novel anabolic agents and the potential use of GSK3ß inhibitors to treat bone-related disorders.

Impact of food processing on postprandial glycaemic and appetite responses in healthy adults: a randomized, controlled trial.

Chickpeas are among the lowest glycaemic index carbohydrate foods eliciting protracted digestion and enhanced satiety responses. In vitro studies suggest that mechanical processing of chickpeas significantly increases starch digestion. However, there is little evidence regarding the impact of processing on postprandial glycaemic response in response to chickpea intake in vivo. Therefore, the aim of this study was to determine the effect of mechanical processing on postprandial interstitial glycaemic and satiety responses in humans. In a randomised crossover design, thirteen normoglycaemic adults attended 4 separate laboratory visits following an overnight fast. On each occasion, one of four test meals, matched for available carbohydrate content and consisting of different physical forms of chickpeas (whole, puree, and pasta) or control (mashed potato), was administered followed by a subsequent standardised lunch meal. Continuous glucose monitoring captured interstitial glucose responses, accompanied by periodic venous blood samples for retrospective analysis of C-peptide, glucagon like peptide-1 (GLP-1), ghrelin, leptin, resistin, and cortisol. Subjective appetite responses were measured by Visual Analogue Scale (VAS). Postprandial glycaemic responses were comparable between chickpea treatments albeit significantly lower than the control (p < 0.001). Similarly, all chickpea treatments elicited significantly lower C-peptide and GLP-1 responses compared to the control (p < 0.05), accompanied by enhanced subjective satiety responses (p < 0.05), whilst no significant differences in satiety hormones were detected among different intervention groups (p > 0.05). Chickpea consumption elicits low postprandial glycaemic responses and enhanced subjective satiety responses irrespective of processing methods.

Lifespan prolonging mechanisms and insulin upregulation without fat accumulation in long-lived reproductives of a higher termite.

Kings and queens of eusocial termites can live for decades, while queens sustain a nearly maximal fertility. To investigate the molecular mechanisms underlying their long lifespan, we carried out transcriptomics, lipidomics and metabolomics in Macrotermes natalensis on sterile short-lived workers, long-lived kings and five stages spanning twenty years of adult queen maturation. Reproductives share gene expression differences from workers in agreement with a reduction of several aging-related processes, involving upregulation of DNA damage repair and mitochondrial functions. Anti-oxidant gene expression is downregulated, while peroxidability of membranes in queens decreases. Against expectations, we observed an upregulated gene expression in fat bodies of reproductives of several components of the IIS pathway, including an insulin-like peptide, Ilp9. This pattern does not lead to deleterious fat storage in physogastric queens, while simple sugars dominate in their hemolymph and large amounts of resources are allocated towards oogenesis. Our findings support the notion that all processes causing aging need to be addressed simultaneously in order to prevent it.

Capillary Endothelial Insulin Transport: The Rate-limiting Step for Insulin-stimulated Glucose Uptake.

The rate-limiting step for skeletal muscle glucose uptake is transport from microcirculation to muscle interstitium. Capillary endothelium poses a barrier that delays the onset of muscle insulin action. Defining physiological barriers that control insulin access to interstitial space is difficult because of technical challenges that confront study of microscopic events in an integrated physiological system. Two physiological variables determine muscle insulin access. These are the number of perfused capillaries and the permeability of capillary walls to insulin. Disease states associated with capillary rarefaction are closely linked to insulin resistance. Insulin permeability through highly resistant capillary walls of muscle poses a significant barrier to insulin access. Insulin may traverse the endothelium through narrow intercellular junctions or vesicular trafficking across the endothelial cell. Insulin is large compared with intercellular junctions, making this an unlikely route. Transport by endothelial vesicular trafficking is likely the primary route of transit. Studies in vivo show movement of insulin is not insulin receptor dependent. This aligns with single-cell transcriptomics that show the insulin receptor is not expressed in muscle capillaries. Work in cultured endothelial cell lines suggest that insulin receptor activation is necessary for endothelial insulin transit. Controversies remain in the understanding of transendothelial insulin transit to muscle. These controversies closely align with experimental approaches. Control of circulating insulin accessibility to skeletal muscle is an area that remains ripe for discovery. Factors that impede insulin access to muscle may contribute to disease and factors that accelerate access may be of therapeutic value for insulin resistance.

Polycystic ovarian syndrome: signs and feedback effects of hyperandrogenism and insulin resistance.

Polycystic ovary syndrome (PCOS) is a disease whose diagnosis is based on the detection of hyperandrogenism (HA) and ovulatory dysfunction. Women with PCOS frequently develop insulin resistance (IR), which generates a metabolic condition that involves a decrease in the action of insulin at the cellular level and is linked to compensatory hyperinsulinemia (HI). In PCOS, the ovary remains sensitive to the action of insulin. Additionally, it has been observed that the main effect of insulin in the ovary is the stimulation of androgen synthesis, resulting in HA, one of the fundamental characteristics of the PCOS. In this sense, the excess of androgens favors the development of IR, thus perpetuating the cycle of IR-HI-HA, and therefore PCOS. Moreover, mitochondrial dysfunction is present in PCOS patients and is a common feature in both IR and HA. This review places electron transfer as a key element in HA and IR development, with emphasis on the relationship between androgen biosynthesis and mitochondrial function. Indeed, metformin has been involved in repair mitochondrial dysfunction, decrease of oxidative stress, reduction of androgens levels and the enhancing of insulin sensitivity. Therefore, we propose that treatment with metformin could decrease HI and consequently HA, restoring, at least in part, the metabolic and hormonal disorders of PCOS.

Increased insulin signaling in the Anopheles stephensi fat body regulates metabolism and enhances the host response to both bacterial challenge and Plasmodium falciparum infection.

In vertebrates and invertebrates, the insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) cascade is highly conserved and plays a vital role in many different physiological processes. Among the many tissues that respond to IIS in mosquitoes, the fat body has a central role in metabolism, lifespan, reproduction, and innate immunity. We previously demonstrated that fat body specific expression of active Akt, a key IIS signaling molecule, in adult Anopheles stephensi and Aedes aegypti activated the IIS cascade and extended lifespan. Additionally, we found that transgenic females produced more vitellogenin (Vg) protein than non-transgenic mosquitoes, although this did not translate into increased fecundity. These results prompted us to further examine how IIS impacts immunity, metabolism, growth and development of these transgenic mosquitoes. We observed significant changes in glycogen, trehalose, triglycerides, glucose, and protein in young (3-5 d) transgenic mosquitoes relative to non-transgenic sibling controls, while only triglycerides were significantly changed in older (18 d) transgenic mosquitoes. More importantly, we demonstrated that enhanced fat body IIS decreased both the prevalence and intensity of Plasmodium falciparum infection in transgenic An. stephensi. Additionally, challenging transgenic An. stephensi with Gram-positive and Gram-negative bacteria altered the expression of several antimicrobial peptides (AMPs) and two anti-Plasmodium genes, nitric oxide synthase (NOS) and thioester complement-like protein (TEP1), relative to non-transgenic controls. Increased IIS in the fat body of adult female An. stephensi had little to no impact on body size, growth or development of progeny from transgenic mosquitoes relative to non-transgenic controls. This study both confirms and expands our understanding of the critical roles insulin signaling plays in regulating the diverse functions of the mosquito fat body.

A comparison among three maximal mathematical models of the glucose-insulin system.

The most well-known and widely used mathematical representations of the physiology of a diabetic individual are the Sorensen and Hovorka models as well as the UVAPadova Simulator. While the Hovorka model and the UVAPadova Simulator only describe the glucose metabolism of a subject with type 1 diabetes, the Sorensen model was formulated to simulate the behaviour of both normal and diabetic individuals. The UVAPadova model is the most known model, accepted by the FDA, with a high level of complexity. The Hovorka model is the simplest of the three models, well documented and used primarily for the development of control algorithms. The Sorensen model is the most complete, even though some modifications were required both to the model equations (adding useful compartments for modelling subcutaneous insulin delivery) and to the parameter values. In the present work several simulated experiments, such as IVGTTs and OGTTs, were used as tools to compare the three formulations in order to establish to what extent increasing complexity translates into richer and more correct physiological behaviour. All the equations and parameters used for carrying out the simulations are provided.

Central 5-HTR2C in the Control of Metabolic Homeostasis.

The 5-hydroxytryptamine 2C receptor (5-HTR2C) is a class G protein-coupled receptor (GPCR) enriched in the hypothalamus and the brain stem, where it has been shown to regulate energy homeostasis, including feeding and glucose metabolism. Accordingly, 5-HTR2C has been the target of several anti-obesity drugs, though the associated side effects greatly curbed their clinical applications. Dissecting the specific neural circuits of 5-HTR2C-expressing neurons and the detailed molecular pathways of 5-HTR2C signaling in metabolic regulation will help to develop better therapeutic strategies towards metabolic disorders. In this review, we introduced the regulatory role of 5-HTR2C in feeding behavior and glucose metabolism, with particular focus on the molecular pathways, neural network, and its interaction with other metabolic hormones, such as leptin, ghrelin, insulin, and estrogens. Moreover, the latest progress in the clinical research on 5-HTR2C agonists was also discussed.

Increasing plasma glucose before the development of type 1 diabetes-the TRIGR study.

OBJECTIVE: The ß-cell stress hypothesis suggests that increased insulin demand contributes to the development of type 1 diabetes. In the TRIGR trial we set out to assess the profile of plasma glucose and HbA1c before the diagnosis of clinical diabetes compared to nondiabetic children. RESEARCH DESIGN AND METHODS: A cohort of children (N = 2159) with an affected first-degree relative and increased HLA risk were recruited 2002-2007 and followed until 2017. To study the relationship between plasma glucose/HbA1c and the development of autoantibodies or clinical disease Kaplan-Meir curves were developed. Mixed models were constructed for plasma glucose and HbA1c separately. RESULTS: A family history of type 2 diabetes was related to an increase in plasma glucose (p < 0.001). An increase in glucose from the previous sample predicted clinical diabetes (p < 0.001) but not autoantibodies. An increase of HbA1c of 20% or 30% from the previous sample predicted the development of any autoantibody (p < 0.003 resp <0.001) and the development of diabetes (p < 0.002 resp <0.001. Participants without autoantibodies had lower HbA1c (mean 5.18%, STD 0.24; mean 33.08 mmol/mol, STD 2.85) than those who progressed to clinical disease (5.31%, 0.42; 34.46 mmol/mol, 4.68; p < 0.001) but higher than those who developed any autoantibody (5.10%, 0.30; 32.21 mmol/mol, 3.49; p < 0.001), or multiple autoantibodies (5.11%, 0.35; 32.26 mmol/mol, 3.92; p < 0.003). CONCLUSIONS: A pronounced increase in plasma glucose and HbA1c precedes development of clinical diabetes, while the association between plasma glucose or HbA1c and development of autoantibodies is complex. Increased insulin demand may contribute to development of type 1 diabetes.

Insulin treatment to type 1 male diabetic rats protects fertility by avoiding testicular apoptosis and cell cycle arrest.

BACKGROUND: Uncontrolled type 1 diabetes mellitus (T1D) impairs reproductive potential of males. Insulin treatment restores metabolic parameters but it is unclear how it protects male reproductive health. Herein, we hypothesized that insulin treatment to T1D rats protects testicular physiology by mediating mechanisms associated with apoptosis and cell cycle. METHODS: Mature male Wistar rats (n = 24) were divided into 3 groups: control, T1D-induced (received 40 mg kg-1 streptozotocin) and insulin-treated T1D (Ins T1D; received 40 mg kg-1 streptozotocin and then treated 0.9 IU/100 gr of insulin for 56 days) (N = 8/group). Expression levels of intrinsic apoptosis pathways regulators (Bcl-2, Bax, Caspase-3 and p53) and core regulators of cell cycle machinery (Cyclin D1, Cdk-4 and p21) were determined in testicular tissue by immunohistochemistry (IHC) and RT-PCR techniques. The percentage of testicular apoptotic cells was evaluated by TUNEL staining. RESULTS: Our data shows that insulin treatment to T1D rats restored (P < 0.05) T1D-induced increased of caspase-3 and p53 expression in testis. Moreover, the testis of T1D rats treated with insulin exhibited increased expression of Cyclin D1 and cdk-4, and a reduced expression of p21 when compared with the expression in testis of T1D rats. Finally, insulin treatment could fairly control T1D-induced apoptosis. Accordingly, treatment of T1D rats with insulin led to a remarkable reduction (p < 0.05) in the percentage of apoptotic cells in the testis. CONCLUSIONS: Insulin treatment is able to restore the network expression of apoptosis and proliferation-related genes caused by T1D in the testis and via this mechanism, preserve the fertility of males.

TIMEOR: a web-based tool to uncover temporal regulatory mechanisms from multi-omics data.

Uncovering how transcription factors regulate their targets at DNA, RNA and protein levels over time is critical to define gene regulatory networks (GRNs) and assign mechanisms in normal and diseased states. RNA-seq is a standard method measuring gene regulation using an established set of analysis stages. However, none of the currently available pipeline methods for interpreting ordered genomic data (in time or space) use time-series models to assign cause and effect relationships within GRNs, are adaptive to diverse experimental designs, or enable user interpretation through a web-based platform. Furthermore, methods integrating ordered RNA-seq data with protein-DNA binding data to distinguish direct from indirect interactions are urgently needed. We present TIMEOR (Trajectory Inference and Mechanism Exploration with Omics data in R), the first web-based and adaptive time-series multi-omics pipeline method which infers the relationship between gene regulatory events across time. TIMEOR addresses the critical need for methods to determine causal regulatory mechanism networks by leveraging time-series RNA-seq, motif analysis, protein-DNA binding data, and protein-protein interaction networks. TIMEOR's user-catered approach helps non-coders generate new hypotheses and validate known mechanisms. We used TIMEOR to identify a novel link between insulin stimulation and the circadian rhythm cycle. TIMEOR is available at https://github.com/ashleymaeconard/TIMEOR.git and http://timeor.brown.edu.

Relationship between ethanol intake and insulin sensitivity metabolism in men with no comorbidities: a systematic review / Relación entre la ingesta de etanol y el metabolismo de la sensibilidad a la insulina en hombres sin comorbilidades: una revisión sistemática

SUMMARY: The association of alcohol consumption with type 2 diabetes has been explained by increased insulin sensitivity, anti-inflammatory effects, or effects of adiponectin. The aim was to launch a consistent relation between alcohol intake and insulin sensitivity. Several databases (MEDLINE, EMBASE, Scopus and Web of Science) were searched from 1990 to April 2020 for studies in English, using MeSH terms and text words involving to alcohol consumption and insulin sensitivity. Protocol registered on PROSPERO CRD42020205107. A total of seven original articles were analyzed, where four collected data through cross-sectional study, two papers with randomized crossover design, and one used a non-randomized study. The protective effect of moderate alcohol consumption on type 2 diabetes has been described, where an improvement on insulin levels has been shown in adults between 26.5-57 years old. Our research shows that alcohol effects on blood insulin levels could vary depending of the type of alcoholic drink ingested; and that alcohol intake increased leptin and adiponectin levels, suggesting that alcohol consumption may increase glucose catabolism promoting insulin sensitivity via leptin and adiponectin. However, original studies should consider time of exposure, age, dosage, ethnicity, and alcohol type in order to conclude right affirmations.

RESUMEN: La asociación del consumo de alcohol con la diabetes tipo 2 se ha explicado por una mayor sensibilidad a la insulina, efectos antiinflamatorios o efectos de la adiponectina. El objetivo fue establecer una relación coherente entre la ingesta de alcohol y la sensibilidad a la insulina. Se realizaron búsquedas en varias bases de datos (MEDLINE, EMBASE, Scopus y Web of Science) desde 1990 hasta abril de 2020 en busca de estudios en inglés, utilizando términos MeSH y palabras de textos relacionadas con el consumo de alcohol y la sensibilidad a la insulina. Protocolo registrado en PROSPERO CRD42020205107. Se analizaron un total de siete artículos originales, donde cuatro recopilaron datos a través de un estudio transversal, dos artículos con diseño cruzado aleatorizado y uno utilizó un estudio no aleatorizado. Se ha descrito el efecto protector del consumo moderado de alcohol sobre la diabetes tipo 2, donde se ha demostrado una mejora de los niveles de insulina en adultos entre 26,5 y 57 años. Nuestra investigación muestra que los efectos del alcohol sobre los niveles de insulina en sangre pueden variar según el tipo de bebida alcohólica ingerida; y que la ingesta de alcohol aumenta los niveles de leptina y adiponectina, lo que sugiere que el consumo de alcohol puede aumentar el catabolismo de la glucosa promoviendo la sensibilidad a la insulina a través de la leptina y la adiponectina. Sin embargo, los estudios originales deben considerar el tiempo de exposición, la edad, la dosis, el origen étnico y el tipo de alcohol para concluir afirmaciones correctas.

Lower beta cell yield from donor pancreases after controlled circulatory death prevented by shortening acirculatory warm ischemia time and by using IGL-1 cold preservation solution.

Organs from donors after controlled circulatory death (DCD III) exhibit a higher risk for graft dysfunction due to an initial period of warm ischemia. This procurement condition can also affect the yield of beta cells in islet isolates from donor pancreases, and hence their use for transplantation. The present study uses data collected and generated by our Beta Cell Bank to compare the number of beta cells in isolates from DCD III (n = 141) with that from donors after brain death (DBD, n = 609), before and after culture, and examines the influence of donor and procurement variables. Beta cell number per DCD III-organ was significantly lower (58 x 106 versus 84 x 106 beta cells per DBD-organ; p < 0.001) but their purity (24% insulin positive cells) and insulin content (17 µg / 106 beta cells in DCD III-organs versus 19 µg / 106 beta cells in DBD-organs) were similar. Beta cell number correlated negatively with duration of acirculatory warm ischemia time above 10 min; for shorter acirculatory warm ischemia time, DCD III-organs did not exhibit a lower beta cell yield (74 x 106 beta cells). Use of Institut Georges Lopez-1 cold preservation solution instead of University of Wisconsin solution or histidine-tryptophan-ketoglutarate also protected against the loss in beta cell yield from DCD III-organs (86 x 106 for IGL-1 versus 54 x 106 and 65 x 106 beta cells respectively, p = 0.042). Multivariate analysis indicates that both limitation of acirculatory warm ischemia time and use of IGL-1 prevent the reduced beta cell yield in islet cell isolates from DCD III-organs.

Comparison betweeen dapagliflozin add-on therapy and insulin dose escalation in patients with uncontrolled type 2 diabetes treated with insulin: DVI study.

AIM: To assess the efficacy and tolerability of adjunct therapy with a sodium-glucose cotransporter-2 inhibitor, dapagliflozin, compared with insulin escalation for patients with uncontrolled type 2 diabetes on current insulin therapy. METHODS: A 12-month retrospective case-control study of patients with glycated hemoglobin (HbA1c) > 7% on insulin therapy. The study group received add-on therapy with dapagliflozin (10 mg once daily); the control group received titrated increases of their existing insulin dose by a mean of 21.6% from baseline. The primary endpoint was the change in HbA1c after 12 months. Secondary outcomes included changes in fasting plasma glucose, postprandial 2-h glucose levels, insulin requirements, and body weight. RESULTS: After 12 months, the reduction in HbA1c was significantly greater in the dapagliflozin group than in the control group (from 8.9 ±â€¯1.2% to 8.0 ±â€¯1.0% vs 9.1 ±â€¯1.2% to 8.7 ±â€¯1.5%, respectively). Results for fasting plasma glucose and postprandial 2-h glucose were similar. Dapagliflozin therapy decreased systolic blood pressure (-4.7 mmHg) and body weight (-1.4 kg) significantly, whereas body weight increased by 0.6 kg in the control group. The dapagliflozin group showed significantly fewer hypoglycemic events than the control group (18.5% vs 32.6%, respectively). Daily insulin dose increased by 5.4 ±â€¯6.1 U (21.6%) in the control group but decreased by 1.9 ±â€¯5.3 U (-4.5%) in the dapagliflozin group (p < 0.001). CONCLUSION: As an adjunct to insulin therapy, dapagliflozin therapy significantly improved glycemic control, with the clinical advantages of weight loss, insulin sparing, and less hypoglycemia.

Insulin action in the brain regulates both central and peripheral functions.

The brain has been traditionally thought to be insensitive to insulin, primarily because insulin does not stimulate glucose uptake/metabolism in the brain (as it does in classic insulin-sensitive tissues such as muscle, liver, and fat). However, over the past 20 years, research in this field has identified unique actions of insulin in the brain. There is accumulating evidence that insulin crosses into the brain and regulates central nervous system functions such as feeding, depression, and cognitive behavior. In addition, insulin acts in the brain to regulate systemic functions such as hepatic glucose production, lipolysis, lipogenesis, reproductive competence, and the sympathoadrenal response to hypoglycemia. Decrements in brain insulin action (or brain insulin resistance) can be observed in obesity, type 2 diabetes (T2DM), aging, and Alzheimer's disease (AD), indicating a possible link between metabolic and cognitive health. Here, we describe recent findings on the pleiotropic actions of insulin in the brain and highlight the precise sites, specific neuronal population, and roles for supportive astrocytic cells through which insulin acts in the brain. In addition, we also discuss how boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Overall, this perspective article serves to highlight some of these key scientific findings, identify unresolved issues, and indicate future directions of research in this field that would serve to improve the lives of people with metabolic and cognitive dysfunctions.