Pharmacokinetic similarity of switching SAR341402 insulin aspart biosimilar and NovoLog insulin aspart versus continuous use of NovoLog in adults with type 1 diabetes: The GEMELLI X trial.

AIM: To assess whether multiple switches between SAR341402 biosimilar insulin aspart (SAR-Asp) and the insulin aspart reference product (NovoLog; NN-Asp) leads to equivalent pharmacokinetic (PK) exposure compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D). MATERIALS AND METHODS: This multicentre, open-label, phase 3 study randomized (1:1) 210 subjects with T1D treated with once-daily insulin glargine U100 as basal insulin to four 4-week periods of alternating multiple daily injections of SAR-Asp and NN-Asp (NN-Asp for the first 4 weeks, SAR-Asp in the last 4 weeks; switching group) versus 16 weeks of continuous NN-Asp (non-switching group). At week 16, a single dose (0.15 U/kg) of SAR-Asp in the switching group (n = 95) or NN-Asp in the non-switching group (n = 105) was given in the morning before breakfast. Primary PK endpoints were area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax ) of SAR-Asp versus NN-Asp after the single dose at week 16. RESULTS: The extent of PK exposure was similar between the two treatments (SAR-Asp in the switching group and NN-Asp in the non-switching group) at week 16, with point estimates of treatment ratios close to 1. The 90% confidence intervals for AUC treatment ratios were contained within 0.8-1.25. For Cmax in the primary analysis set, the upper confidence limit was 1.32. This was because of the profiles of three participants with implausible high values. A prespecified sensitivity analysis excluding implausible values showed results contained within 0.8-1.25. CONCLUSIONS: PK exposure of SAR-Asp (switching group) and reference NN-Asp (non-switching group) were similar, supporting interchangeability between these two insulin aspart products.

Recent advances in oral insulin delivery technologies.

With the rise in diabetes mellitus cases worldwide, oral delivery of insulin is preferred over subcutaneous insulin administration due to its good patient compliance and non-invasiveness, simplicity, and versatility. However, oral insulin delivery is hampered by various gastrointestinal barriers that result in low drug bioavailability and insufficient therapeutic efficiency. Numerous strategies have been developed to overcome these barriers and increase the bioavailability of oral insulin. Yet, no commercial oral insulin product is available to address all clinical hurdles because of various substantial obstacles related to the structural organization and physiological function of the gastrointestinal tract. Herein, we discussed the significant physiological barriers (including chemical, enzymatic, and physical barriers) that hinder the transportation and absorption of orally delivered insulin. Then, we showcased recent significant and innovative advances in oral insulin delivery technologies. Finally, we concluded the review with remarks on future perspectives on oral insulin delivery technologies and potential challenges for forthcoming clinical translation of oral insulin delivery technologies.

Pharmacokinetics, pharmacodynamics, and safety of prandial oral insulin (N11005) in healthy subjects.

Aims: To verify whether the oral insulin N11005 is administered as a prandial insulin by assessing the pharmacokinetics (PK), pharmacodynamics (PD), and safety profiles of N11005 with a short-acting biosynthetic human insulin (Novolin R) as reference. Methods: This was a randomized, open-label, single-dose, crossover hyperinsulinemic-euglycemic clamp study in healthy Chinese male subjects. A total of 12 subjects were enrolled in the test (T) group (N11005, 300 IU, p.o.) and the reference (R) group (Novolin R, 0.1 IU/Kg, i.h.) with a washout period of 14 days. All subjects were administered on the same day of the clamp study. Glucose Infusion Rates (GIR), serum insulin, and C-peptide concentration were determined during every 8-hour clamp cycle. Trial registration: Clinicaltrials.gov identifier NCT04975022. Results: After administration, the ratios of mean serum C-peptide concentration to baseline concentration in both T and R groups were lower than 50%, which confirmed the stability of the clamp platform. T group (N11005) showed a more rapid onset of action (tGIR10%max≈11 min) and a comparable duration of action to the R group, which was basically in line with the characteristics of prandial insulins. No adverse events (AEs) occurred throughout the study, which demonstrated that N11005 and Novolin R are safe and well-tolerated. Conclusions: The PD profiles of the single-dose N11005 in the human body are similar to those of prandial insulins, with an excellent safety profile. Clinical trial registration: Clinicaltrials.gov, identifier NCT04975022.

The Effect of BMI on Pharmacokinetic and Pharmacodynamic Parameters of Insulin Degludec: Results from an Euglycemic Glucose Clamp Study.

PURPOSE: This study evaluated the effect of body mass index (BMI) on pharmacokinetic (PK) and pharmacodynamic (PD) parameters of insulin degludec in healthy Chinese males, depending on an euglycemic glucose clamp study. METHODS: Sixty-five healthy male subjects were divided into four groups according to quartile of BMI value. Group A: BMI ≤ 20.7 kg/m2; group B: 20.7 < BMI ≤ 22.5 kg/m2; group C: 22.5 < BMI ≤ 23.6 kg/m2; group D: BMI > 23.6 kg/m2. Each volunteer received a single subcutaneous dose (0.4 U/kg) of insulin degludec and accepted a 24-h euglycemic glucose clamp study. The primary PK parameters were maximum observed drug concentration (Cmax) and the area under the curve (AUCINS) for the specified time intervals. The primary PD parameters were the time to the start of glucose infusion (Tonset), maximal glucose infusion rate (GIRmax) and area under the curve (AUCGIR) for the specified time intervals. The differences of these PK/PD parameters were compared among groups. RESULTS: Cmax and the AUC of insulin (0-6 h, 6-12 h and 0-24 h) were more than onefold higher in group A than those in groups B, C, D, and the concentration-time curve of group A was significantly shifted to the left compared with the other three groups. The GIRmax, total AUCGIR, and AUCGIR for each time interval were significantly higher in group A than those in other three groups. The proportion of AUCGIR in group A was the lowest proportion among four groups seen in the late stage. Multiple linear regression analysis showed that BMI was negatively correlated with AUCGIR,0-24 h. CONCLUSIONS: Insulin degludec in healthy Chinese male subjects with BMI ≤ 20.7 kg/m2 had a faster absorption, clearance, and a stronger glucose-lowering effect, but a steeper decrease of insulin action in the late stage after dosing.

The strawberry-derived permeation enhancer pelargonidin enables oral protein delivery.

Although patients generally prefer oral drug delivery to injections, low permeability of the gastrointestinal tract makes this method impossible for most biomacromolecules. One potential solution is codelivery of macromolecules, including therapeutic proteins or nucleic acids, with intestinal permeation enhancers; however, enhancer use has been limited clinically by modest efficacy and toxicity concerns surrounding long-term administration. Here, we hypothesized that plant-based foods, which are well tolerated by the gastrointestinal tract, may contain compounds that enable oral macromolecular absorption without causing adverse effects. Upon testing more than 100 fruits, vegetables, and herbs, we identified strawberry and its red pigment, pelargonidin, as potent, well-tolerated enhancers of intestinal permeability. In mice, an oral capsule formulation comprising pelargonidin and a 1 U/kg dose of insulin reduced blood glucose levels for over 4 h, with bioactivity exceeding 100% relative to subcutaneous injection. Effects were reversible within 2 h and associated with actin and tight junction rearrangement. Furthermore, daily dosing of mice with pelargonidin for 1 mo resulted in no detectable side effects, including weight loss, tissue damage, or inflammatory responses. These data suggest that pelargonidin is an exceptionally effective enhancer of oral protein uptake that may be safe for routine pharmaceutical use.

Effects of Unsuppressed Endogenous Insulin on Pharmacokinetics and/or Pharmacodynamics of Study Insulin in the Healthy: A Retrospective Study.

C-peptide, a marker of endogenous insulin, should be consistently inhibited during euglycemic clamping, while an elevated postdosing C-peptide (CPpostdosing ) is not an occasional phenomenon. This was a retrospective study that included 33 men who underwent a manual euglycemic clamp with a subcutaneous injection of insulin aspart (IAsp) aiming to describe the effects of insufficient suppression of endogenous insulin on estimates of the pharmacokinetics and pharmacodynamics of injected insulin. The time profiles of whole blood glucose, human insulin, glucose infusion rate (GIR), and C-peptide were recorded. The subjects were divided into 2 groups at a ratio of 2:1: group A ([CPpostdosing ]max >baseline CP [CPbaseline ]), group B ([CPpostdosing ]max ≤ CPbaseline ). The endogenous insulin was approximately equal to the measured value of human insulin or calculated from the C-peptide. The basal glucose, CPbaseline , basal human insulin, homeostatic model assessment of insulin resistance, IAsp dose, and demographic statistics were all comparable between the 2 groups except the "clamped" glucose. The average clamped glucose was 99.7% (group A) and 94.9% (group B) of baseline. After correction for clamped glucose, GIR area under the concentration-time curve from time 0 to 8 hours was higher in group A (P < .05) under comparable IAsp exposure. Endogenous insulin area under the concentration-time curve from time 0 to 8 hours calculated from C-peptide was different from that measured from human insulin in group A (P < .05), whereas no statistical difference between these measures was observed in group B. Hence, blood glucose should be controlled below the baseline to ensure the inhibition of endogenous insulin. Unsuppressed endogenous insulin may contribute to observed GIR, and the endogenous insulin-corrected pharmacokinetics estimated by C-peptide may be inaccurate with insufficient endogenous insulin suppression.

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.

Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-ß Peptides and Insulin.

BACKGROUND: Age is the most common risk factor for Alzheimer's disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-ß (Aß) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. OBJECTIVE: Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aß peptides and insulin in mice. METHODS: Upon systemic injection of 125I-Aß40, 125I-Aß42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. RESULTS: The brain influx of 125I-Aß40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aß42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aß40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aß and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. CONCLUSION: Aging differentially affects the plasma pharmacokinetics and brain influx of Aß isoforms and insulin in a manner that could potentially augment AD risk.

Design, fabrication, and characterisation of a silicon microneedle array for transdermal therapeutic delivery using a single step wet etch process.

The fabrication of silicon in-plane microneedle arrays from a simple single wet etch step is presented. The characteristic 54.7° sidewall etch angle obtained via KOH etching of (100) orientation silicon wafers has been used to create a novel microneedle design. The KOH simultaneously etches both the front and back sides of the wafer to produce V shaped grooves, that intersect to form a sharp pyramidal six-sided microneedle tip. This method allows fabrication of solid microneedles with different geometries to determine the optimal microneedle length and width for effective penetration and minimally invasive drug delivery. A modified grooved microneedle design can also be used to create a hollow microneedle, via bonding of two grooved microneedles together, creating an enclosed hollow channel. The microneedle arrays developed, effectively penetrate the skin without significant indentation, thereby enabling effective delivery of active ingredients via either a poke and patch application using solid microneedles or direct injection using hollow microneedles. This simple, scalable and cost effective method utilises KOH to etch the silicon wafer in-plane, allowing microneedles with variable length of several mm to be fabricated, as opposed to out-of-plane MNs, which are geometrically restricted to dimensions less than the thickness of the wafer. These microneedle arrays have been used to demonstrate effective delivery of insulin and hyaluronic acid into the skin.

Novel porous starch/alginate hydrogels for controlled insulin release with dual response to pH and amylase.

An important principle in the development of oral insulin is to protect insulin from the harsh conditions of the stomach and release it in a controlled manner in the intestine. In the present study, novel insulin-loaded porous starch-alginate hydrogel systems (In-S-Alg) including In-MS-Alg (prepared with porous maize starch), In-WS-Alg (porous waxy maize starch), and In-RS-Alg (porous rice starch) were successfully developed. As a representative, In-MS-Alg was further coated with gelatinized-retrograded high amylose maize starch (HA) films with different thicknesses to prepare In-MS-HA/Alg hydrogel beads for improving the functionality of controlled release of insulin under the action of α-amylase. The In-S-Alg and In-MS-HA/Alg hydrogel beads were evaluated in terms of structural and morphological properties, encapsulation effect on insulin as well as its release behavior. The results show that insulin was distributed in the pores and cavities of porous starch granules. In In-MS-HA/Alg hydrogel beads, insulin was increasingly blocked inside porous starch with the increased thickness of the HA film. Encapsulation efficiency of insulin in all In-S-Alg and In-MS-HA/Alg hydrogel beads was >80%. Amazingly, both the hydrogel beads successfully achieved the goal of triggered release upon pH changes and α-amylase addition. Most of the insulin (about 90%) was retained in the simulated gastric fluid; while the release rate of insulin in the simulated intestinal fluid increased gradually, and was further accelerated in the presence of α-amylase. Furthermore, for the In-MS-HA/Alg hydrogel beads, the insulin release rate can be gradually reduced by increasing the thickness of the HA film, which provided the possibility to match the rate of increase of the blood glucose level after the intake of food with different glycemic indices. Therefore, the novel hydrogel prepared in this study may be a promising and safe delivery carrier for oral insulin.

Ultra-Fast Insulin-Pramlintide Co-Formulation for Improved Glucose Management in Diabetic Rats.

Dual-hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion. Here, amphiphilic acrylamide copolymers are used to create a stable co-formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra-rapid action. The co-formulation is stable for over 16 h under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 h. The faster pharmacokinetics of monomeric insulin in this co-formulation result in increased insulin-pramlintide overlap of 75 ± 6% compared to only 47 ± 7% for separate injections. The co-formulation results in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats, the co-formulation reduces deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co-formulation will be well preserved in future translation to humans. Together these results suggest that the co-formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.

Effects of apolipoprotein E isoform, sex, and diet on insulin BBB pharmacokinetics in mice.

Age, apolipoprotein E (apoE) isoform, sex, and diet can independently affect the risk for the development of Alzheimer's disease (AD). Additionally, synergy between some of these risk factors have been observed. However, the relation between the latter three risk factors has not been investigated. Central nervous system (CNS) insulin resistance is commonly involved in each of these risk factors. CNS insulin is primarily derived from the periphery in which insulin must be transported across the blood-brain barrier (BBB). Additionally, insulin can bind the brain endothelial cell to affect intracellular signaling. Therefore, we hypothesized CNS access to insulin could be affected by the combination of apoE isoform, sex, and diet. We analyzed insulin BBB pharmacokinetics in aged apoE targeted replacement (E3 and E4) male and female mice on a low-fat and high-fat diet. There were differences within males and females due to apoE genotype and diet in insulin interactions at the BBB. These sex-, diet-, and apoE isoform-dependent differences could contribute to the cognitive changes observed due to altered CNS insulin signaling.

Replacing insulin with immunotherapy: Time for a paradigm change in Type 1 diabetes.

For almost a hundred years, the management of Type 1 diabetes has not advanced beyond insulin replacement. However, insulin does not provide satisfactory glycaemic control in the majority of individuals and there remains a major unmet need for novel treatments for Type 1 diabetes. Immunomodulation to preserve beta-cell function offers the prospect of making treatment with insulin easier and/or preventing the need for insulin, particularly when it comes to novel low-risk immunotherapies. Led by the concept that the best insulin-producing cell is a patient's own beta-cell, the Type 1 diabetes scientific community has a challenging task ahead-to fundamentally change the management of this devastating disease by using low-risk immunotherapy to preserve endogenous beta-cell function and make metabolic control substantially easier. In that way, insulin and/or beta-cell replacement (stem cell or transplantation) should in the future be considered rescue therapies reserved for delayed presentations.

Insulin Transdermal Delivery System for Diabetes Treatment Using a Biocompatible Ionic Liquid-Based Microemulsion.

Since injection administration for diabetes is invasive, it is important to develop an effective transdermal method for insulin. However, transdermal delivery remains challenging owing to the strong barrier function of the stratum corneum (SC) of the skin. Here, we developed ionic liquid (IL)-in-oil microemulsion formulations (MEFs) for transdermal insulin delivery using choline-fatty acids ([Chl][FAs])-comprising three different FAs (C18:0, C18:1, and C18:2)-as biocompatible surface-active ILs (SAILs). The MEFs were successfully developed using [Chl][FAs] as surfactants, sorbitan monolaurate (Span-20) as a cosurfactant, choline propionate IL as an internal polar phase, and isopropyl myristate as a continuous oil phase. Ternary phase behavior, dynamic light scattering, and transmission electron microscopy studies revealed that MEFs were thermodynamically stable with nanoparticle size. The MEFs significantly enhanced the transdermal permeation of insulin via the intercellular route by compromising the tight lamellar structure of SC lipids through a fluidity-enhancing mechanism. In vivo transdermal administration of low insulin doses (50 IU/kg) to diabetic mice showed that MEFs reduced blood glucose levels (BGLs) significantly compared with a commercial surfactant-based formulation by increasing the bioavailability of insulin in the systemic circulation and sustained the insulin level for a much longer period (half-life > 24 h) than subcutaneous injection (half-life 1.32 h). When [Chl][C18:2] SAIL-based MEF was transdermally administered, it reduced the BGL by 56% of its initial value. The MEFs were biocompatible and nontoxic (cell viability > 90%). They remained stable at room temperature for 3 months and their biological activity was retained for 4 months at 4 °C. We believe SAIL-based MEFs will alter current approaches to insulin therapy and may be a potential transdermal nanocarrier for protein and peptide delivery.

100 years of insulin: celebrating the past, present and future of diabetes therapy.

The year 2021 marks the centennial of Banting and Best's landmark description of the discovery of insulin. This discovery and insulin's rapid clinical deployment effectively transformed type 1 diabetes from a fatal diagnosis into a medically manageable chronic condition. In this Review, we describe key accomplishments leading to and building on this momentous occasion in medical history, including advancements in our understanding of the role of insulin in diabetes pathophysiology, the molecular characterization of insulin and the clinical use of insulin. Achievements are also viewed through the lens of patients impacted by insulin therapy and the evolution of insulin pharmacokinetics and delivery over the past 100 years. Finally, we reflect on the future of insulin therapy and diabetes treatment, as well as challenges to be addressed moving forward, so that the full potential of this transformative discovery may be realized.

100 years of physiology, discrimination and wonder.

There has been 100 years of research detailing the role of insulin in glucose, protein and free fatty acid metabolism. We explore the learnings though evolution and changes in management with an understanding of how it has impacted the care of people with diabetes. The discrimination endured is described and recent advances to empower and counter this are highlighted.

Characterization and optimization of de-esterified Tragacanth-chitosan nanocomposite as a potential carrier for oral delivery of insulin: In vitro and ex vivo studies.

Oral administration of insulin is one of the most challenging topics within this area, because insulin is degraded in stomach before it enters the bloodstream. In this study, for the first time, a nano-carrier for controlled and targeted oral delivery of insulin was developed using de-esterified Tragacanth and chitosan. The fabricated nanoparticles were synthesized using coacervation technique and their properties were optimized using response surface methodology. The effect of experimental variables on the particle size and loading efficiency was examined. In addition, the interactions between components were analyzed using Fourier transform infrared. The thermal stability of nanoparticles was studied by thermal gravimetric analysis. The insulin loading efficiency was measured and in vitro release profile and ex vivo insulin permeability was determined. Optimized nanoparticles showed spherical shape with a size less than 200 nm and zeta potential of +17 mV. Owing to their nanoscale dimensions and mucoadhesiveness, nanoparticles were synthesized using medium molecular weight of Chitosan. The insulin loading efficacy for the system was 6.4%, released under simulated gastrointestinal conditions in a pH-dependent manner. Based on all of the obtained results, it can be concluded that these nanoparticles can potentially be utilized as a carrier for the oral insulin delivery.

Clinical significance of apelin in the treatment of type 2 diabetic peripheral neuropathy.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes. As apelin is an adipocytokine closely associated with diabetes, this study explored the clinical significance of serum apelin levels in patients with type 2 DPN before and after treatment. METHODS: In total, 44 patients with T2DM without DPN (non-DPN group), 41 patients with DPN who received antihyperglycemic treatment (DPN-A group), 44 patients with DPN who received antihyperglycemic treatment combined with nutritional neurotherapy (DPN-B group), and 40 healthy control individuals (NC group) were selected continuously enrolled in the present study. Enzyme-linked immunosorbent assays (ELISA) were performed to determine serum levels of apelin and tumor necrosis factor-α (TNF-α). Related apelin, fasting blood glucose (FBG), glycosylated hemoglobin A1c, TNF-α, body mass index, fasting C peptide, and nerve conduction velocity (NCV) were recorded in each group before and after treatment. RESULTS: Serum levels of apelin and TNF-α were higher in patients with diabetes than those in the NC group, as well as in the DPN group as compared to the non-DPN group; furthermore, some NCV values were significantly reduced in the DPN group. After treatment, the serum levels of apelin, TNF-α, and FBG reduced in patients with diabetes; moreover, apelin levels were found significantly lower in the DPN-B group as compared to the DPN-A group, while some NCV values significantly increased in the DPN-B group. Apelin was negatively correlated with part of NCV values and positively correlated with TNF-α and FBG (P < .01). CONCLUSION: Our results show that the increase in serum apelin levels is an important clinical reference index for DPN, while a decrease indicates that the DPN treatment is effective.

The brain as an insulin-sensitive metabolic organ.

BACKGROUND: The brain was once thought of as an insulin-insensitive organ. We now know that the insulin receptor is present throughout the brain and serves important functions in whole-body metabolism and brain function. Brain insulin signaling is involved not only in brain homeostatic processes but also neuropathological processes such as cognitive decline and Alzheimer's disease. SCOPE OF REVIEW: In this review, we provide an overview of insulin signaling within the brain and the metabolic impact of brain insulin resistance and discuss Alzheimer's disease, one of the neurologic diseases most closely associated with brain insulin resistance. MAJOR CONCLUSIONS: While brain insulin signaling plays only a small role in central nervous system glucose regulation, it has a significant impact on the brain's metabolic health. Normal insulin signaling is important for mitochondrial functioning and normal food intake. Brain insulin resistance contributes to obesity and may also play an important role in neurodegeneration.

The effect of hypergravity in intestinal permeability of nanoformulations and molecules.

The oral administration of drugs remains a challenge due to rapid enzymatic degradation and minimal absorption in the gastrointestinal tract. Mechanical forces, namely hypergravity, can interfere with cellular integrity and drug absorption, and there is no study describing its influence in the intestinal permeability. In this work, it was studied the effect of hypergravity on intestinal Caco-2 cells and its influence in the intestinal permeability of different nanoformulations and molecules. It was shown that the cellular metabolic activity and integrity were maintained after exposure to different gravity-levels (g-levels). Expression of important drug transporters and tight junctions' proteins was evaluated and, most proteins demonstrated a switch of behavior in their expression. Furthermore, paracellular transport of FITC-Dextran showed to significantly increase with hypergravity, which agrees with the decrease of transepithelial electrical resistance and the increase of claudin-2 at higher g-levels. The diffusion of camptothecin released from polymeric micelles revealed a significant decrease, which agrees with the increased expression of the P-gp observed with the increase in g-levels, responsible for pumping this drug out. The neonatal Fc receptor-mediated transport of albumin-functionalized nanoparticles loaded with insulin showed no significant changes when increasing the g-levels. Thus, this study supports the effect of hypergravity on intestinal permeability is dependent on the molecule studied and the mechanism by which it is absorbed in the intestine.