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Abstract The potential link between dysbiosis, features of metabolic syndrome (MetS), inflammation, and sensation impairment has been recently recognized. However, in this context, there are few indications available regarding the effects of co‐supplementation with Bacillus indicus, Bacillus coagulans, and fructooligosaccharide (FOS) prebiotics on patients with MetS. Therefore, this study aimed to investigate the effects of synbiotic supplementation on glycemic indices, inflammatory biomarkers, and appetite among adults with MetS. This study is a randomized, double‐blind, placebo‐controlled clinical trial conducted in the Endocrine and Metabolism Research Center outpatient clinic in Isfahan, Iran. Fifty‐eight MetS patients were randomly assigned to receive either synbiotics (n = 29) or placebo (n = 29) supplementation twice per day for 8 weeks. Finally, 55 patients were recruited for analyses (28 in the intervention group and 27 in the placebo group). Random permuted blocks and a computer‐generated random number table were used for treatment allocation. No adverse effects were reported during the study. There were no significant differences in glycemic indices and inflammatory markers within‐ and between groups (all p > .05). However, a significant increase in the sensation of fullness was documented in the synbiotic group. In conclusion, the eight‐week treatment did not improve glycemic control and inflammatory markers. Nevertheless, it demonstrated potential efficacy in enhancing participants' appetite sensations, warranting further evaluation in longer intervention periods during future clinical trials.

Abstract Diabetes mellitus is causing serious health problems in the chronic period. Silibinin is a flavonoid obtained from the milk thistle (Silybum marianum), which is among the herbal ethnopharmacological administrations. In studies with silibinin, it has been reported that it increases the activity of pancreatic beta cells and insulin sensitivity and has a hyperglycemia‐reducing effect. However, behavioral parameters have not been evaluated together with insulin levels and liver function tests. Our aim in this study was to examine the effects of silibinin on insulin secretion, anxiety‐like behaviors, and learning in a streptozotocin (STZ)‐induced rat diabetes model. Wistar albino rats weighing 200–250 g were divided into 4 groups. Control: Saline solution, Diabetes: STZ 45 mg/kg, S 100: STZ 45 mg/kg + Silibinin 100 mg/kg, S 200: STZ 45 mg/kg + Silibinin 200 mg/kg. Administrations were continued for 21 days. On the 21st day, open field and elevated plus maze as unconditional anxiety tests; Barnes maze for learning and memory; and rotarod test for locomotor activity were conducted. Following behavioral tests, blood samples were taken under anesthesia. Blood glucose levels and ALT values were measured. Insulin levels were measured with an ELISA plate reader. Silibinin shortened the time to find the correct hole. Silibinin prevented the decrease in insulin due to STZ, exhibited a hyperglycemia‐reducing effect and decreased the elevation of ALT.

ABSTRACT Background Diabetes mellitus, notably type 2, is a rising global health challenge, prompting the need for effective management strategies. Common medications such as metformin, insulin, repaglinide and sitagliptin can induce side effects like gastrointestinal disturbances, hypoglycemia, weight gain and specific organ risks. Plant‐derived therapies like Karanjin from Pongamia pinnata present promising alternatives due to their historical use, holistic health benefits and potentially fewer adverse effects. This study employs in silico analysis to explore Karanjin's interactions with diabetes‐associated receptors, aiming to unveil its therapeutic potential while addressing the limitations and side effects associated with conventional medications. Methodology The research encompassed the selection of proteins from the Protein Data Bank (PDB), followed by structural refinement processes and optimization. Ligands such as Karanjin and standard drugs were retrieved from PubChem, followed by a comprehensive analysis of their ADMET profiling and pharmacokinetic properties. Protein–ligand interactions were evaluated through molecular docking using AutoDockTools 1.5.7, followed by the analysis of structural stability using coarse‐grained simulations with CABS Flex 2.0. Molecular dynamics simulations were performed using Desmond 7.2 and the OPLS4 force field to explore how Karanjin interacts with proteins over 100 nanoseconds, focusing on the dynamics and structural stability. Results Karanjin, a phytochemical from Pongamia pinnata, shows superior drug candidate potential compared to common medications, offering advantages in efficacy and reduced side effects. It adheres to drug‐likeness criteria and exhibits optimal ADMET properties, including moderate solubility, high gastrointestinal absorption and blood–brain barrier penetration. Molecular docking revealed Karanjin's highest binding energy against receptor 3L2M (Pig pancreatic alpha‐amylase) at −9.1 kcal/mol, indicating strong efficacy potential. Molecular dynamics simulations confirmed stable ligand–protein complexes with minor fluctuations in RMSD and RMSF, suggesting robust interactions with receptors 3L2M. Conclusion Karanjin demonstrates potential in pharmaceutical expansion for treating metabolic disorders such as diabetes, as supported by computational analysis. Prospects for Karanjin in pharmaceutical development include structural modifications for enhanced efficacy and safety. Nanoencapsulation may improve bioavailability and targeted delivery to pancreatic cells, while combination therapies could optimize treatment outcomes in diabetes management. Clinical trials and experimental studies are crucial to validate its potential as a novel therapeutic agent.

Abstract An 8‐year‐old male neutered Miniature Schnauzer was diagnosed with diabetes mellitus based on fasting hyperglycemia and glucosuria after a 2‐week history of polydipsia and periuria, in line with the Agreeing Language in Veterinary Endocrinology consensus definition. Treatment of insulin and dietary management was initiated. The insulin dose was gradually reduced and eventually discontinued over the next year based on spot blood glucose concentrations that revealed euglycemia or hypoglycemia. After discontinuation, the dog remained free of clinical signs for 1 year until it was again presented for polyuria/polydipsia with fasting hyperglycemia and glucosuria. Insulin therapy was resumed and continued for the remainder of the dog's life. Although diabetic remission often occurs in cats and humans, the presumed etiopathogenesis of pancreatic beta cell loss makes remission rare in dogs, except for cases occurring with diestrus or pregnancy. This case demonstrates that diabetic remission is possible in dogs, even in cases without an identifiable reversible trigger.

Abstract Polycystic ovary syndrome (PCOS) is associated with reproductive disorders and adverse cardiometabolic risk factors that can negatively impact the general health of women. Inulin‐type fructans (ITFs) are proposed to beneficially affect risk factors associated with metabolic disorders. Whether ITFs can help with the management of PCOS by modifying insulin resistance (IR) and androgen levels has not yet been explored. The aim of this study was to investigate the effects of ITFs with different degrees of polymerization on insulin resistance, blood lipids, anthropometric measures, and hormonal status in overweight and obese women with PCOS. In a randomized double‐blind placebo‐controlled trial, seventy‐five women with PCOS aged 18–40 years old were randomly assigned to receive 10 g/day of high‐performance inulin (HPI) or oligofructose‐enriched inulin (OEI) or maltodextrin for 12 weeks. Biochemical and clinical outcomes were measured at baseline and after the intervention. Participants in the HPI and OEI groups experienced improvements in waist circumference, total testosterone, free androgen index, sex hormone‐binding globulin, and triglycerides compared to the placebo group. Also, the number of women with irregular menses or oligomenorrhoea decreased significantly in both ITF groups. Participants in the HPI group reported lower body mass, fasting insulin, and HOMA‐IR, as well as a higher quantitative insulin sensitivity check index. ITF supplementation, especially with long‐chain ITFs, when given for 12 weeks may improve metabolic outcomes, androgen status and clinical manifestations in women with PCOS.

Abstract Background Mice lacking vitamin D receptor (VDR) exhibit a glycogen storage disorder, disrupting carbohydrate utilization in muscle. Here, we asked if the defective carbohydrate metabolism alters the fat utilization by the skeletal muscles of vdr−/− mice. Methods To check the effect of high‐fat‐containing diets on muscle mass and metabolism of vdr−/− mice, we subjected them to two different milk fat‐based diets (milk fat diet with 60% of energy from milk fat and milk‐based diet [MBD] with 37% of energy from milk fat) and lard‐based high‐fat diet (HFD) containing 60% of energy from lard fat. Skeletal muscles and pancreas from these mice were analysed using RNA sequencing, quantitative reverse transcription polymerase chain reaction and western blot to understand the changes in signalling and metabolic pathways. Microscopic analyses of cryosections stained with haematoxylin and eosin, BODIPY, succinate dehydrogenase and periodic acid–Schiff reagent were performed to understand changes in morphology and metabolism of muscle fibres and pancreatic islets. Results Transcriptomic analyses showed that the skeletal muscles of vdr−/− mice exhibit upregulation of the fatty acid oxidation pathways, suggesting a shift towards increased lipid utilization even in a carbohydrate‐enriched regular chow diet (chow). Two different milk fat‐enriched diets restored body weight (12.01 ± 0.33 g in chow vs. 17.99 ± 0.62 g in MBD) and muscle weights (38.58 ± 3.84 mg in chow vs. 110.72 ± 1.96 mg in MBD for gastrocnemius [GAS]) of vdr−/− mice. Muscle ATP levels (0.56 ± 0.18 μmol in chow vs. 1.48 ± 0.08 μmol in MBD) and protein synthesis (0.25 ± 0.04 A.U. in chow vs. 2.02 ± 0.06 A.U. in MBD) were upregulated by MBD. However, despite increasing muscle energy levels, HFD failed to restore the muscle mass and cross‐sectional area to that of wild‐type (WT) mice (104.95 ± 2.6 mg for WT mice on chow vs. 77.26 ± 1.7 mg for vdr−/− mice on HFD for GAS). Moreover, HFD disrupted glucose homeostasis in vdr−/− mice, while MBD restored it. We further analysed insulin response and pancreatic insulin levels of these mice to show that HFD led to reduced insulin levels in pancreatic beta cells of vdr−/− mice (mean intensity of 1.5 × 10−8 for WT mice on chow vs. 4.3 × 10−9 for vdr−/− mice on HFD). At the same time, MBD restored glucose‐stimulated pancreatic insulin response (mean intensity of 9.2 × 10−9). Conclusions Skeletal muscles of vdr−/− mice are predisposed to utilize fatty acids as their primary energy source to circumvent their defective carbohydrate utilization. Thus, HFDs could restore energy levels in the skeletal muscles of vdr−/− mice. This study reveals that when mice are subjected to a lard‐based HFD, VDR signalling is essential for maintaining insulin levels in pancreatic islets. Our data show a critical role of VDR in muscle metabolic flexibility and pancreatic insulin response.

Abstract Background Decreased insulin availability and high blood glucose levels, the hallmark features of poorly controlled diabetes, drive disease progression and are associated with decreased skeletal muscle mass. We have shown that mice with β‐cell dysfunction and normal insulin sensitivity have decreased skeletal muscle mass. This project asks how insulin deficiency impacts on the structure and function of the remaining skeletal muscle in these animals. Methods Skeletal muscle function was determined by measuring exercise capacity and specific muscle strength prior to and after insulin supplementation for 28 days in 12‐week‐old mice with conditional β‐cell deletion of the ATP binding cassette transporters ABCA1 and ABCG1 (β‐DKO mice). Abca1 and Abcg1 floxed (fl/fl) mice were used as controls. RNAseq was used to quantify changes in transcripts in soleus and extensor digitorum longus muscles. Skeletal muscle and mitochondrial morphology were assessed by transmission electron microscopy. Myofibrillar Ca2+ sensitivity and maximum isometric single muscle fibre force were assessed using MyoRobot biomechatronics technology. Results RNA transcripts were significantly altered in β‐DKO mice compared with fl/fl controls (32 in extensor digitorum longus and 412 in soleus). Exercise capacity and muscle strength were significantly decreased in β‐DKO mice compared with fl/fl controls (P = 0.012), and a loss of structural integrity was also observed in skeletal muscle from the β‐DKO mice. Supplementation of β‐DKO mice with insulin restored muscle integrity, strength and expression of 13 and 16 of the dysregulated transcripts in and extensor digitorum longus and soleus muscles, respectively. Conclusions Insulin insufficiency due to β‐cell dysfunction perturbs the structure and function of skeletal muscle. These adverse effects are rectified by insulin supplementation.

Abstract Diabetes mellitus (DM) is a common chronic disease affecting humans globally. It is characterized by abnormally elevated blood glucose levels due to the failure of insulin production or reduction of insulin sensitivity and functionality. Insulin and glucagon‐like peptide (GLP)‐1 replenishment or improvement of insulin resistance are the two major strategies to treat diabetes. Recently, optogenetics that uses genetically encoded light‐sensitive proteins to precisely control cell functions has been regarded as a novel therapeutic strategy for diabetes. Here, we summarize the latest development of optogenetics and its integration with synthetic biology approaches to produce light‐responsive cells for insulin/GLP‐1 production, amelioration of insulin resistance and neuromodulation of insulin secretion. In addition, we introduce the development of cell encapsulation and delivery methods and smart bioelectronic devices for the in vivo application of optogenetics‐based cell therapy in diabetes. The remaining challenges for optogenetics‐based cell therapy in the clinical translational study are also discussed.

Abstract Background Early identification and management of pediatric type 2 diabetes mellitus (T2DM) is crucial for improving long‐term outcomes. This study aimed to assess if the severity of T2DM at presentation, inferred by the location of treatment initiation (inpatient or outpatient), influences long‐term clinical outcomes. Methods A retrospective chart review was conducted on 116 pediatric T2DM patients. Data on treatment initiation location, initial and subsequent glycated hemoglobin (HbA1c) levels, prescribed insulin, and body mass index were collected from electronic medical records. Results Of the 116 patients, 69 were initially treated in an inpatient setting, and 47 received outpatient treatment. At treatment initiation, the inpatient group had significantly higher HbA1c levels compared to the outpatient group (p

ABSTRACT Aims The once‐weekly insulin icodec, a new basal insulin analog, may positively support a reduction in injection frequency and improve adherence to therapy in type 2 diabetes (T2D). This study aimed to evaluate the safety and efficacy of insulin icodec compared with those of once‐daily glargine U100. Methods A comprehensive literature search was conducted using PubMed/MEDLINE, Embase and the Cochrane Library from inception till September 2023. Data about clinical outcomes in both groups were extracted. Forest plots were generated using the random‐effects model by pooling odds ratios (ORs) and mean differences (MDs). Results Five randomised controlled trials and 2019 individuals with T2DM were included. In the pooled analysis, time in range was significantly higher (MD = 4.35; 95% CI: 1.65 to 7.05; p = 0.002) in the icodec group than in the once‐daily glargine group. The HbA1c levels were significantly reduced (MD = −0.13; 95% CI: −0.24 to −0.03; p = 0.02) in the weekly icodec group compared with those in the once‐daily glargine group. The weight gain was significantly less in the glargine group than in the weekly icodec group (MD = 0.41; 95% CI: 0.04 to 0.78; p = 0.03); however, in the subgroup analysis, this change became statistically insignificant in both insulin‐naïve and previously insulin‐treated individuals. The results were comparable across two groups for fasting plasma glucose levels, hypoglycaemia alert (Level 1), clinically significant (Level 2) or severe hypoglycaemia (Level 3), and adverse events. Conclusion Insulin icodec was associated with a reduction in glycated haemoglobin levels and higher time in range, with a similar safety profile as compared to insulin glargine U100. However, further evidence is still needed to reach a definitive conclusion.

Abstract Diabetes mellitus is one of the chronic metabolic diseases whose control remains a challenge. Its increased incidence was mainly attributed to increased environmental contamination. Therefore, this study aims to investigate the effect of feeding clover microgreen (CM) on a diabetes model with or without aflatoxin exposure. Rats were distributed into 8 groups. G1 was a control group. G2 was fed CM. G3 was administered aflatoxin orally. G4 was fed clover and administered aflatoxin. G5 was diabetic rats. G6 was diabetic rats fed CM. G7 was diabetic rats administered aflatoxin. G8 was diabetic rats administered aflatoxin and fed CM. Phytochemical analysis of the CM showed that gardenin was the most common compound. The administration of aflatoxin aggravated diabetes. The groups fed CM showed a decreased glucose concentration compared to the unfed groups. Liver and kidney function parameters were improved by CM. The histopathological alteration of the pancreas, liver, and kidneys was relieved in CM‐fed groups. The area % of insulin in islets of Langerhans was increased in CM‐fed groups. Feeding CM also enhanced the oxidative stress biomarkers. In conclusion, CM improved all evaluated parameters in diabetic rats either exposed to aflatoxin or not compared to the control.

Abstract Background Hypothyroidism in dogs is associated with obesity and altered lipid and carbohydrate metabolism. The adipokines, visfatin, and betatrophin, affect glucose tolerance. Betatrophin is involved in lipid regulation. Hypothesis Visfatin and betatrophin serum concentrations are altered in hypothyroid dogs. Animals Dogs with naturally occurring hypothyroidism (n = 25) and healthy dogs (n = 25). Methods Insulin, visfatin, and betatrophin serum concentrations were measured in all dogs and 19 of the hypothyroid dogs after 30 days of thyroxine treatment. Body condition score (BCS) was determined (1‐9 scale). Results Visfatin concentrations were lower in hypothyroid compared with healthy dogs (mean, 95% confidence interval [CI]; 2.0 ng/mL, 1.2‐3.3 vs 5.1 ng/mL, 3.3‐7.8; P = .004) and increased post‐treatment (3.1 ng/mL, 1.9‐4.9 vs 2.6 ng/mL, 1.6‐4.1; P = .05). Betatrophin concentrations were lower in lean to normal (body condition score [BCS], 3‐5) hypothyroid dogs compared to lean to normal healthy dogs (52 pg/mL, 9‐307 vs 597 pg/mL, 216‐1648; P = .03), but were not different between overweight (BCS, 6‐9) hypothyroid and healthy dogs (341 pg/L, 168‐695 vs 178 pg/mL, 77‐415; P = .26), and decreased post‐treatment in overweight dogs (206 pg/mL, 87‐488 vs 268 pg/mL, 112‐640; P = .004). Visfatin concentrations were higher in overweight compared with lean to normal dogs (4.7 ng/mL, 3.3‐6.6 vs 2.2 ng/mL, 1.2‐4.2; P = .04). Betatrophin concentrations were positively correlated with BCS (r = .47, P = .02) and insulin concentrations (r = .48, P = .03) in hypothyroid dogs and negatively correlated with BCS (r = −.47, P = .02) and thyroid stimulating hormone concentrations (r = −.56, P = .01) in healthy dogs. Conclusions and Clinical Importance Hypothyroidism in dogs is associated with alterations in visfatin and betatrophin concentrations that partially resolve with thyroxine treatment.

Abstract Background Lovebird (Agapornis personatus) is a monotypic species of bird of the lovebird genus in the parrot family Psittaculidae and order Psittaciformes. Objectives The present study was designed to investigate the histology and immunohistochemistry of the pancreas in the lovebird. Methods Totally, three adult birds were used. The pancreas was assessed using histological and immunofluorescent staining to detect insulin, glucagon, somatostatin, pancreatic polypeptide (PP) and neuropeptide Y (NY). Results The exocrine pancreas was composed of pyramidal acinar cells with zymogen granules at the apical cytoplasm. The endocrine pancreas was identified as large alpha, small beta and mixed islets of Langerhans. No intercalated duct was observed. Alpha cells with a density of 28.55% were the most numerous cell type, which were populated throughout the large islets, especially at the periphery. The beta cells with a density of 15.78% were accumulated mostly at the periphery of islets. The delta cells exhibited 17.81% intensity. Despite their lower density, the distribution of delta cells was like that of A cells throughout the islets. PP and NY cells were distinguished with densities of 14.69% and 20.63%, respectively. Conclusions Although the arrangement of acinar cells, ductal systems and endocrine islets reflects patterns observed in various avian species, the absence of intercalated duct, the presence of three types of Langerhans islets as alpha, beta and mixed islets and the high expression of NY in the islets were some unique features observed in the current study. These findings contribute to the broader understanding of avian pancreas histology.

Abstract Introduction Cigarette smoking increases both the risk for insulin resistance and amyloid‐β (Aβ) aggregation, and impaired brain insulin/insulin‐like growth factor 1 (IGF1) signaling might increase risk factors for Alzheimer's disease (AD). We aimed to investigate the association among cerebrospinal fluid (CSF) insulin sensitivity/IGF1, glucose/lactate, and Aβ42 and further explore whether insulin sensitivity contributed to the risk for AD in active smokers. Methods In this cross‐sectional study, levels of insulin, IGF1, and lactate/glucose of 75 active smokers and 78 nonsmokers in CSF were measured. Three polymorphisms regulating IGF1 were genotyped. Analysis of variance was used to compare differences of variables between groups. Partial correlation was performed to test the relationship between CSF biomarkers and smoking status. General linear models were applied to test the interaction of the effect of single nucleotide polymorphisms and cigarette smoking on CSF IGF1 levels. Results In the CSF from active smokers, IGF1 and lactate levels were significantly lower (p = .016 and p = .010, respectively), whereas Aβ42 (derived from our earlier research) and insulin levels were significantly higher (p

Abstract Objective Prader‐Willi syndrome (PWS) is the most frequently diagnosed genetic cause of early childhood obesity. Individuals with PWS typically progress through 7 different nutritional phases during their lifetime. The main objective of this study was to assess potential factors, particularly insulin, that may be responsible for the weight gains in sub‐phase 2a and their role in the subsequent increase in fat mass and obesity in sub‐phase 2b and insatiable appetite in phase 3. Methods Fasting plasma insulin levels were measured in children with PWS between the ages of 0–12 years and in age‐matched non‐PWS participants with early‐onset major (clinically severe) obesity (EMO) and in healthy‐weight sibling controls (SC). Results Participants with PWS in nutritional phases 1a and 1b had plasma insulin levels comparable to SC. However, the transition from phase 1b up to phase 3 in the PWS group was accompanied by significant increases in insulin, coinciding in weight gains, obesity, and hyperphagia. Only individuals with PWS in phase 3 had comparable insulin levels to the EMO group who were higher than the SC group at any age. Conclusions Elevated insulin signaling is a probable trigger for weight gain and onset of hyperphagia in children with Prader‐Willi syndrome. Regulating insulin levels early in childhood before the onset of the early weight gain may be key in modulating the onset and severity of obesity and hyperphagia in individuals with PWS, as well as in other young children with non‐PWS early‐onset obesity. Preventing or reversing elevated insulin levels in PWS with pharmacological agents and/or through diet restrictions such as a combined low carbohydrate, low glycemic‐load diet may be a viable therapeutic strategy in combating obesity in children with PWS and others with early childhood obesity.

Abstract Guanidinoacetic acid (GAA) is a nutrient that has been used in human nutrition since the early 1950s. Recommended for its role in creatine biosynthesis, GAA demonstrated beneficial energy‐boosting effects in various clinical conditions. Dietary GAA has also been suggested to trigger several creatine‐independent mechanisms. Besides acting as a direct precursor of high‐energy phosphagen creatine, dietary GAA is suggested to reduce blood glucose concentration by acting as an insulinotropic food compound, spare amino acid arginine for other metabolic purposes (including protein synthesis), modulate taste, and perhaps alter methylation and fat deposition in various organs including the liver. GAA as a food component can have several important metabolic roles beyond creatine biosynthesis; future studies are highly warranted to address GAA overall role in human nutrition.

Abstract Background Although diabetes is one of the most common side effects of clozapine, a medication for the treatment of schizophrenia, to the best of our knowledge no study exists on clozapine‐induced glucose intolerance or hypoglycemia in patients with schizophrenia. Case Presentation We report a case of schizophrenia with repeated reactive hypoglycemia due to abnormal glucose tolerance during clozapine treatment. During clozapine administration in patients with schizophrenia, it is necessary to monitor physical and psychiatric symptoms due to reactive hypoglycemia and hyperglycemia. If abnormal glucose tolerance is a concern, it should be promptly detected using blood or oral glucose tolerance tests. Conclusion Early intervention for impaired glucose tolerance may prevent clozapine discontinuation due to diabetes or hyperglycemia.

Abstract Background Euglycemic diabetic ketoacidosis (EDKA) carries serious risks for mortality and morbidity for both the mother and the baby, and it is essential to recognize it early and start immediate treatment. Case Presentation We present a case of EDKA in a 28‐week pregnant woman known to have type 1 diabetes. She was found to have severe acidosis with a blood sugar level of 10.6 mmol/L (190.8 mg/dL) and normal anion gap. She was found to have EDKA, which was confirmed later with a depressed venous pH and bicarbonate level and an increased serum ketone level. The patient's acidosis was not improving significantly with 0.05 units/kg/h of insulin infusion, so a full dose of 0.1 unit/kg/h of insulin infusion was started following a full diabetic ketoacidosis (DKA) protocol regardless of her blood sugar level. The patient showed gradual improvement and was discharged home after 4 days, with follow‐up with endocrinology and obstetrics. Conclusion In conclusion, EDKA is a critical complication of diabetes, especially in pregnant women. Therefore, it is crucial to treat it early and potentially consider following a full DKA protocol using 0.1 unit/kg/h insulin infusion instead of 0.05 unit/kg/h.

Abstract The recent success of disease‐modifying anti‐amyloid monoclonal antibodies in slowing Alzheimer's disease (AD) symptoms has been an exciting step forward for the field. Despite successfully clearing amyloid from the brain, however, only modest symptomatic improvement has been demonstrated, and treatment‐related side effects such as amyloid‐related imaging abnormalities (ARIA) limit use for some. These limitations suggest that fully efficacious AD treatment may require combination therapy regimens, as are used in other complex disorders such as cancer and HIV. One reasonable strategy may be to use agents that address the biological changes that predict future amyloid accumulation, or accompany amyloid accumulation in preclinical disease states. Immunometabolic pathways, including the insulin signaling pathway, are dysregulated at the earliest stages of AD, concomitant with amyloid accumulation. It is plausible that agents that target these pathways may work synergistically with anti‐amyloid therapies to halt AD progression. Insulin signaling is integrally involved in innate and adaptive immune systems, with pleiotropic effects that moderate pro‐ and anti‐inflammatory responses. Metabolic modulators that enhance insulin sensitivity and function, such as GLP‐1 receptor agonists, SGLT2 inhibitors, and insulin itself have been shown to improve immune function and reduce chronic inflammation. Additional effects of insulin and metabolic modulators demonstrated in preclinical and clinical studies of AD include increased clearance of amyloid‐β, slowed tau progression, improved vascular function and lipid metabolism, reduced synaptotoxicity, and improved cognitive and functional outcomes. A large number of compounds that treat metabolic disorders have been extensively characterized with respect to mechanism of action and safety, and thus are readily available to be repurposed for combination therapy protocols. Determining the most successful combination regimens of these agents together with disease‐modifying therapies, and the appropriate timing of treatment, are promising next steps in the quest to treat and prevent AD.

Abstract The carotid body chemoreceptors (CBC) play an important role in the adaptive counter‐regulatory response to hypoglycaemia by evoking the CBC‐mediated sympathetic neuronal system to restore normoglycaemia. Ex vivo studies have shown varied responses of insulin‐induced hypoglycaemia on CBC function, and several in vivo studies have indirectly established the role of CBCs in restoring normoglycaemia in both animals and humans. However, a direct effect of insulin and/or insulin‐induced hypoglycaemia on CBC activity is not established in animal models. Therefore, the aim of this study was to evaluate in vivo effects of insulin and insulin‐induced hypoglycaemia on CBC activity and cardiorespiration in a preclinical large animal model. The carotid sinus nerve (CSN) activity and cardiorespiratory responses to sodium cyanide (NaCN; 25 µg/kg) were compared before (euglycaemic) and after (hypoglycaemic) intracarotid administration of insulin (12.5–100 µU/dogs) in beagle dogs. Insulin administration increased CSN activity and minute ventilation (V̇E) with significant (P

ABSTRACT This study investigated whether longer‐acting basal analogs (insulin degludec and insulin glargine U300) could reduce visit‐to‐visit hemoglobin A1c (HbA1c) variability in patients with type 1 diabetes. Ninety adults with type 1 diabetes for whom the basal insulin was switched to a longer‐acting insulin analog were analyzed retrospectively. The coefficient of variation of HbA1c levels (CV‐HbA1c) during the year before and after the switch was compared. The CV‐HbA1c after the switch was not significantly different from that before the switch (4.39 ± 2.24% vs 4.25 ± 2.07%; P = 0.506). The linear regression model revealed that CV‐HbA1c before the switch was independently associated with the change of CV‐HbA1c (regression coefficient per standard deviation = −0.568, P 0.05). In conclusion, CV‐HbA1c remained unchanged after the switch on average, but CV‐HbA1c before the switch was associated with the decrease of CV‐HbA1c in individuals with type 1 diabetes.

ABSTRACT Aims/Introduction Insulin stimulates translocation of glucose transporter 4 (GLUT4) from the perinuclear location to the plasma membrane. In the unstimulated state, intracellular vesicles containing GLUT4 are sequestered into specialized storage vesicles that have come to be known as the insulin‐responsive compartment (IRC). The IRC is a functional compartment in the perinuclear region that is a target of the insulin signaling cascade, although its precise nature is unclear. Here, we report a novel molecular mechanism facilitating formation of the IRC. Materials and Methods We determined synaptosomal‐associated protein of 29 kDa (SNAP29) by mass spectrometry to be an EH domain‐containing protein 1 (EHD1)‐binding protein. Then, its expression was confirmed by western blotting. Subcellular localization of SNAP29 was determined by immunofluorescent microscopy. Interactions between SNAP29 and syntaxins were determined by immunoprecipitation. We measured glucose uptake and GLUT4 translocation in 3T3‐L1 adipocyte expressing SNAP29 or silencing SNAP29. Results We found SNAP29 to be localized in the perinuclear region and to show partial co‐localization with GLUT4 under basal conditions. We also found that SNAP29 binds to syntaxin6, a Qc‐SNARE, in adipocytes. In SNAP29‐expressing cells, vesicles containing GLUT4 were observed to aggregate around the perinuclear region. In contrast, when SNAP29 was silenced, perinuclear GLUT4 vesicles were dispersed throughout the cytosol. Insulin‐stimulated glucose uptake was inhibited in both SNAP29‐expressing and SNAP29‐silenced cells. Conclusions These data suggest that SNAP29 sequesters and anchors GLUT4‐containing vesicles in the perinuclear region, and might have a role in the biogenesis of the perinuclear IRC.

Background There is limited evidence on the potential negative metabolic health impacts of prolonged and uninterrupted sedentary bouts in structurally disadvantaged youth. This study investigated associations between sedentary bout variables and metabolic health markers in the Hispanic Community Health Study/SOL Youth (Study of Latino Youth). Methods and Results SOL Youth was a population‐based cohort of 1466 youth (age range, 8–16 years; 48.5% female); 957 youth were included in the analytic sample based on complete data. Accelerometers measured moderate‐to‐vigorous physical activity (MVPA), total sedentary time, and sedentary bout patterns (daily time spent in sedentary bouts ≥30 minutes, median sedentary bout duration, and number of daily breaks from sedentary time). Clinical measures included body mass index, waist circumference, fasting glucose, glycated hemoglobin, fasting insulin, and the homeostasis model assessment of insulin resistance. After adjusting for sociodemographics, total sedentary time, and MVPA, longer median bout durations and fewer sedentary breaks were associated with a greater body mass index percentile (bbouts=0.09 and bbreaks=−0.18), waist circumference (bbouts=0.12 and bbreaks=−0.20), and fasting insulin (bbouts=0.09 and bbreaks=−0.21). Fewer breaks were also associated with a greater homeostasis model assessment of insulin resistance (b=−0.21). More time in bouts lasting ≥30 minutes was associated with a greater fasting glucose (b=0.18) and glycated hemoglobin (b=0.19). Conclusions Greater accumulation of sedentary time in prolonged and uninterrupted bouts had adverse associations with adiposity and glycemic control over and above total sedentary time and MVPA. Findings suggest interventions in Hispanic/Latino youth targeting both ends of the activity spectrum (more MVPA and less prolonged/uninterrupted sedentary patterns) may provide greater health benefits than those targeting only MVPA.

ABSTRACT Aims/Introduction The optimal therapy for latent autoimmune diabetes in adults (LADA) remains undefined. Increasing evidence has shown that sitagliptin and insulin treatment can benefit patients with LADA, but the efficacy still lacks systematic evaluation. We carried out this systematic review and meta‐analysis to summarize the current data on the efficacy and safety of sitagliptin combined with insulin on LADA, providing a reliable reference for the effective therapeutic treatment of LADA patients. Materials and Methods We retrieved the literature in PubMed, Cochrane Library, Embase, Web of Science and CNKI from inception to August 2021. Randomized controlled trials comparing the effects of sitagliptin plus insulin with insulin alone in LADA patients were identified. The outcome measures included parameters of glycemic control, β‐cell function, body mass index and adverse events. The Review Manager 5.2 and Stata 14.0 were utilized for data analysis. Results Eight randomized controlled trials involving 295 participants were identified. Sitagliptin and insulin treatment lowered hemoglobin A1c (weighted mean difference −0.36, 95% confidence interval −0.61 to −0.10, I2 = 91.6%), increased fasting C‐peptide (weighted mean difference 0.08, 95% confidence interval −0.02 to 0.17, I2 = 88.8%) and had fewer adverse events compared with insulin alone. The inter‐study heterogeneity, potential publication bias and other factors might interpret asymmetrical presentation of funnel plots. There was no significant association between sitagliptin plus insulin treatment and levels of hemoglobin A1c or fasting C‐peptide, regardless of the duration of intervention and sample size. Conclusions Sitagliptin combined with insulin can achieve better glycemic control and improve islet β‐cell function with lower incidence of hypoglycemia compared with insulin alone, which provides an effective and tolerated therapeutic regimen for LADA patients. However, further well‐designed and rigorous randomized controlled trials are required to validate this benefit due to the limited methodology quality of included trials.

Abstract The amino acid‐stimulated Rag GTPase pathway is one of the main pathways that regulate mechanistic target of rapamycin complex 1 (mTORC1) activation and function, but little is known about the effects of growth factors on Rag GTPase‐mediated mTORC1 activation. Here, a highly conserved insulin‐responsive phosphorylation site on folliculin (FLCN), Ser62, that is phosphorylates by AKT1 is identified and characterized. mTORC2‐AKT1 is localized on lysosomes, and RagD‐specific recruitment of mTORC2‐AKT1 on lysosomes is identified as an essential step in insulin‐AKT1‐mediated FLCN phosphorylation. Additionally, FLCN phosphorylation inhibits the activity of RagC GTPase and is essential for insulin‐induced mTORC1 activation. Functionally, phosphorylated FLCN promotes cell viability and induces autophagy, and also regulates in vivo tumor growth in an mTORC1‐dependent manner. Its expression is also positively correlated with mTORC1 activity in colon cancer, clear cell renal cell carcinoma, and chordoma. These results indicate that FLCN is an important intermediate for cross‐talk between the amino acid and growth factor pathways. Further, FLCN phosphorylation may be a promising therapeutic target for diseases characterized by mTORC1 dysregulation.

Abstract Glucose homeostasis is closely regulated to maintain energy requirements of vital organs and skeletal muscle plays a crucial role in this process. Mustn1 is expressed during embryonic and postnatal skeletal muscle development and its function has been implicated in myogenic differentiation and myofusion. Whether Mustn1 plays a role in glucose homeostasis in anyway remains largely unknown. As such, we deleted Mustn1 in skeletal muscle using a conditional knockout (KO) mouse approach. KO mice did not reveal any specific gross phenotypic alterations in skeletal muscle. However, intraperitoneal glucose tolerance testing (IPGTT) revealed that 2‐month‐old male KO mice had significantly lower glycemia than their littermate wild type (WT) controls. These findings coincided with mRNA changes in genes known to be involved in glucose metabolism, tolerance, and insulin sensitivity; 2‐month‐old male KO mice had significantly higher expression of GLUT1 and GLUT10 transporters, MUP‐1 while OSTN expression was lower. These differences in glycemia and gene expression were statistically insignificant after 4 months. Identical experiments in female KO and WT control mice did not indicate any differences at any age. Our results suggest a link between Mustn1 expression and glucose homeostasis during a restricted period of skeletal muscle development/maturation. While this is an observational study, Mustn1's relationship to glucose homeostasis appears to be more complex with a possible connection to other key proteins such as GLUTs, MUP‐1, and OSTN. Additionally, our data indicate temporal and sex differences. Lastly, our findings strengthen the notion that Mustn1 plays a role in the metabolic capacity of skeletal muscle.

Abstract Mounting evidence links Type 1 diabetes (T1D) with cognitive dysfunction, psychiatric disorders, and synaptic alterations; however, the underlying mechanism remains unclear. Numerous synaptic proteins and synaptic adhesion molecules (SAMs) that orchestrate synaptic formation, restructuring, and elimination are essential for proper brain function. Currently, it is unclear whether the pathogenesis of T1D is related to the expression of synaptic proteins and SAMs. Here, we investigated whether T1D mice exhibited altered synaptic protein and SAM expression in the hippocampus and cortex. We discovered that T1D mice exhibited partially decreased levels of excitatory and inhibitory synapse proteins and SAMs, such as neurexins, neuroligins, and synaptic cell adhesion molecules. We also found that compared to control mice, T1D mice showed a marginal decrease in body weight and a significant increase in plasma glycoalbumin levels (a hyperglycemia marker). These results provide novel molecular‐level insights into synaptic dysfunction in mice with T1D.

Abstract Aims/Introduction To evaluate the relationship between early insulin initiation within a year after type 2 diabetes mellitus diagnosis and the risk of diabetic complications. Materials and methods We carried out a cohort study using the Korean National Health Insurance Service database. The study participants were newly diagnosed with type 2 diabetes mellitus between 2009 and 2013. After applying propensity score matching (1:1) to the cohort of patients who received two or more oral antidiabetic drugs (OADs) or insulin as the first prescription within 1 year after type 2 diabetes mellitus diagnosis, we computed hazard ratios (HRs) and 95% confidence intervals (CIs) using a Cox proportional hazards regression to compare the risk of diabetes‐related microvascular and macrovascular complications and all‐cause mortality in insulin versus OAD initiators. Results Within the cohort, 52,188 and 1,804 patients received OAD and insulin, respectively. After matching, each group contained 534 patients. Compared with the OAD group, the risk of overall microvascular complications was significantly higher for insulin (HR 1.48, 95% CI 1.28–1.71). No increased risks of overall macrovascular complications (HR 0.90, 95% CI 0.62–1.30) and all‐cause mortality were observed (HR 1.06, 95% CI 0.67–1.68). Conclusions In the present study, early insulin treatment was not associated with the risk of macrovascular complications and all‐cause mortality compared with OAD treatment; however, the risk of microvascular complications was higher in the insulin group.

Abstract Alkali burns are potentially blinding corneal injuries. Due to the lack of available effective therapies, the prognosis is poor. Thus, effective treatment methods for corneal alkali burns are urgently needed. Codelivery nanoparticles (NPs) with characteristics such as high bioavailability and few side effects have been considered effective therapeutic agents for ocular diseases. In this study, we designed a new combination therapy using liposomes and trimethyl chitosan (TMC) for the codelivery of insulin (INS) and vascular endothelial growth factor small interfering RNA (siVEGF) to treat alkali‐burned corneas. We describe the preparation and characterization of siVEGF‐TMC‐INS‐liposome (siVEGF‐TIL), drug release characteristics, intraocular tracing, pharmacodynamics, and biosafety. We found that siVEGF‐TIL could inhibit oxidative stress, inflammation, and the expression of VEGF in vitro and effectively maintained corneal transparency, accelerated epithelialization, and inhibited corneal neovascularization (CNV) in vivo. Morever, we found that the therapeutic mechanism of siVEGF‐TIL is possibly relevant to the inhibition of the ferroptosis signaling pathway by metabolomic analysis. In general, siVEGF‐TIL NPs could be a safe and effective therapy for corneal alkali burn.

Abstract Low concentrations of natriuretic peptides (NPs) have been associated with greater risk for Type 2 diabetes (T2D). African American individuals (AA) have lower NP levels and are disproportionately burdened by T2D. The purpose of this study was to test the hypothesis that higher post‐challenge insulin in AA adults is associated with lower plasma N‐terminal pro‐atrial natriuretic peptide (NT‐proANP). A secondary purpose was to explore associations between NT‐proANP and adipose depots. Participants were 112 AA and European American (EA) adult men and women. Measures of insulin were obtained from an oral glucose tolerance test and hyperinsulinemic‐euglycemic glucose clamp. Total and regional adipose depots were measured from DXA and MRI. Multiple linear regression analysis was used to assess associations of NT‐proANP with measures of insulin and adipose depots. Lower NT‐proANP concentrations in AA participants was not independent of 30‐min insulin area under the curve (AUC). NT‐proANP was inversely associated with 30‐min insulin AUC in AA participants, and with fasting insulin and HOMA‐IR in EA participants. Thigh subcutaneous adipose tissue and perimuscular adipose tissue were positively associated with NT‐proANP in EA participants. Higher post‐challenge insulin may contribute to lower ANP concentrations in AA adults.

Abstract Alterations in perioperative metabolic function, particularly hyperglycemia, are associated with increased post‐operative complications, even in patients without preexisting metabolic abnormalities. Anesthetic medications and the neuroendocrine stress response to surgery may both contribute to altered energy metabolism through impaired glucose and insulin homeostasis but the discrete pathways involved are unclear. Prior human studies, though informative, have been limited by analytic sensitivity or technique, preventing resolution of underlying mechanisms. We hypothesized that general anesthesia with a volatile agent would suppress basal insulin secretion without altering hepatic insulin extraction, and that surgical stress would promote hyperglycemia through gluconeogenesis, lipid oxidation, and insulin resistance. In order to address these hypotheses, we conducted an observational study of subjects undergoing multi‐level lumbar surgery with an inhaled anesthetic agent. We measured circulating glucose, insulin, c‐peptide, and cortisol frequently throughout the perioperative period and analyzed the circulating metabolome in a subset of these samples. We found volatile anesthetic agents suppress basal insulin secretion and uncouple glucose‐stimulated insulin secretion. Following surgical stimulus, this inhibition disappeared and there was gluconeogenesis with selective amino acid metabolism. No robust evidence of lipid metabolism or insulin resistance was observed. These results show that volatile anesthetic agents suppress basal insulin secretion, which results in reduced glucose metabolism. The neuroendocrine stress response to surgery ameliorates the inhibitory effect of the volatile agent on insulin secretion and glucose metabolism, promoting catabolic gluconeogenesis. A better understanding of the complex metabolic interaction between anesthetic medications and surgical stress is needed to inform design of clinical pathways aimed at improving perioperative metabolic function.

Abstract Insulin release is tightly controlled by glucose‐stimulated calcium (GSCa) through hitherto equivocal pathways. This study investigates TRPC3, a non‐selective cation channel, as a critical regulator of insulin secretion and glucose control. TRPC3's involvement in glucose‐stimulated insulin secretion (GSIS) is studied in human and animal islets. TRPC3‐dependent in vivo insulin secretion is investigated using pharmacological tools and Trpc3−/− mice. TRPC3's involvement in islet glucose uptake and GSCa is explored using fluorescent glucose analogue 2‐[N‐(7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl) amino]‐2‐deoxy‐D‐glucose and calcium imaging. TRPC3 modulation by a small‐molecule activator, GSK1702934A, is evaluated in type 2 diabetic mice. TRPC3 is functionally expressed in human and mouse islet beta cells. TRPC3‐controlled insulin secretion is KATP‐independent and primarily mediated by diacylglycerol channel regulation of the cytosolic calcium oscillations following glucose stimulation. Conversely, glucose uptake in islets is independent of TRPC3. TRPC3 pharmacologic inhibition and knockout in mice lead to defective insulin secretion and glucose intolerance. Subsequently, TRPC3 activation through targeted small‐molecule enhances insulin secretion and alleviates diabetes hallmarks in animals. This study imputes a function for TRPC3 at the onset of GSIS. These insights strengthen one's knowledge of insulin secretion physiology and set forth the TRPC3 channel as an appealing candidate for drug development in the treatment of diabetes.

Abstract Introduction The incretin hormone glucagon‐like peptide‐1 (GLP‐1) slows gastric emptying, increases satiety and enhances insulin secretion. GLP‐1 receptor agonists, such as liraglutide, are used therapeutically in humans to improve glycaemic control and delay the onset of type 2 diabetes mellitus (T2DM). In UCD‐T2DM rats, a model of polygenic obesity and insulin resistance, we have previously reported that daily liraglutide administration delayed diabetes onset by >4 months. Growth hormone (GH) may exert anti‐diabetic effects, including increasing β‐cell mass and insulin secretion, while disrupting GH signalling in mice reduces both the size and number of pancreatic islets. We therefore hypothesized that GH supplementation would augment liraglutide's anti‐diabetic effects. Methods Male UCD‐T2DM rats were treated daily with GH (0.3 mg/kg) and/or liraglutide (0.2 mg/kg) from 2 months of age. Control (vehicle) and food‐restricted (with food intake matched to liraglutide‐treated rats) groups were also studied. The effects of treatment on diabetes onset and weight gain were assessed, as well as measures of glucose tolerance, lipids and islet morphology. Results Liraglutide treatment significantly reduced food intake and body weight and improved glucose tolerance and insulin sensitivity, relative to controls. After 4.5 months, none of the liraglutide‐treated rats had developed T2DM (overall p = .019). Liraglutide‐treated rats also displayed lower fasting triglyceride (TG) concentrations and lower hepatic TG content, compared to control rats. Islet morphology was improved in liraglutide‐treated rats, with significantly increased pancreatic insulin content (p

Abstract Sarcopenia, or the age‐related loss of skeletal muscle mass and function, is an increasingly prevalent condition that contributes to reduced quality of life, morbidity, and mortality in older adults. Older adults display blunted anabolic responses to otherwise anabolic stimuli—a phenomenon that has been termed anabolic resistance (AR)—which is likely a casual factor in sarcopenia development. AR is multifaceted, but historically much of the mechanistic focus has been on signalling impairments, and less focus has been placed on the role of the vasculature in postprandial protein kinetics. The vascular endothelium plays an indispensable role in regulating vascular tone and blood flow, and age‐related impairments in vascular health may impede nutrient‐stimulated vasodilation and subsequently the ability to deliver nutrients (e.g. amino acids) to skeletal muscle. Although the majority of data has been obtained studying younger adults, the relatively limited data on the effect of blood flow on protein kinetics in older adults suggest that vasodilatory function, especially of the microvasculature, strongly influences the muscle protein synthetic response to amino acid feedings. In this narrative review, we examine evidence of AR in older adults following amino acid and mixed meal consumption, examine the evidence linking vascular dysfunction and insulin resistance to age‐related AR, review the influence of nitric oxide and endothelin‐1 on age‐related vascular dysfunction as it relates to AR, briefly review the potential causal role of arterial stiffness in promoting skeletal muscle microvascular dysfunction and AR, and provide a brief overview and future considerations for research examining age‐related AR.

ABSTRACT Aims/Introduction Identifying diabetes‐susceptible genetic variants will help to provide personalized therapy for the management of type 2 diabetes. Previous studies have reported a genetic risk score (GRS), computed by the sum of nuclear DNA (nDNA) risk alleles, that may predict the future requirement for insulin therapy. Although mitochondrial dysfunction has a close association with insulin resistance (IR), there are few studies investigating whether genetic variants of mitochondrial DNA (mtDNA) will affect the clinical characteristics of type 2 diabetes. Materials and Methods Mitochondrial haplogroups were determined using mtDNA whole genome next generation sequencing and 13 single nucleotide polymorphisms (SNPs) in nDNA susceptibility loci of 13 genes in 604 Taiwanese subjects with type 2 diabetes. A GRS of nDNA was computed by summation of the number of risk alleles. The correlation between the mtDNA haplogroup and the clinical characteristics of type 2 diabetes was assessed by logistic regression analysis. The results were compared with the GRS subgroups for the risk of insulin requirement. Results Mitochondrial haplogroups modulate the clinical characteristics of type 2 diabetes, in which patients harboring haplogroup D4, compared with those harboring non‐D4 haplotypes, were less prone to require insulin treatment, after adjusting for age, gender, and diabetes duration. However, there was no association between insulin requirement and GRS calculated from nuclear genetic variants. Conclusions Mitochondrial haplogroups, but not nuclear genetic variants, have a better association with the insulin requirement. The results highlight the role of mitochondria in the management of common metabolic diseases.

Abstract Aims/Introduction We estimated the hazards of cardiovascular diseases (CVDs) and early all‐cause mortality in Korean adults according to the presence of recently diagnosed type 2 diabetes (type 2 diabetes for

Abstract Diabetes is a group of metabolic diseases characterized by hyperglycemia. Insulin resistance (IR) and insufficient insulin secretion are important pathophysiological basis and significant characteristics of diabetes. At present, animal is still the main model for investigation of Antidiabetic activity of bioactive substances, however, in vivo models always has the problems of long experimental cycle, complicated experiment, and high cost. Compared with the animal models, cell culture could avoid some impossible or difficult to eliminate under natural conditions, and observe the experimental results more simply, economically, quickly, and objectively. In this case, the establishment of in vitro diabetic cell model has gradually developed. Recently, cell models are more widely used in high‐throughput screening, metabolism analysis, molecular pharmacology investigation, pharmacodynamics evaluation of natural product, cell function, interaction between receptors and cytokines, and so on. These guidelines will point out and discuss to help researchers to choose cell model that are truly reliable and can be successfully applied for their intended investigation of antidiabetic activity.

Abstract A 38‐year‐old lady, recently recovered from SARS‐CoV‐2 infection and taking grape seed extract, suffered multiple episodes of severe postprandial hyperinsulinemic hypoglycemia. A careful evaluation ruled out the common etiologies of hypoglycemia and identified grape seed extract consumption as a possible cause. She recovered after stopping the nutritional supplements. In her, hypoglycemia could have resulted from transient beta cell dysfunction associated with SARS‐CoV‐2 infection or proanthocyanidins in the grape seed extract.

Abstract Introduction Gestational diabetes mellitus (GDM) is a metabolic disease that affects mother and foetus during pregnancy, causing acute and chronic adverse effects. Irisin is proposed as a novel marker to predict GDM. The aim of this study was to assess the role of irisin peptide serum levels in gestational diabetes and compare with healthy pregnant women. Methods This case–control study was conducted on women at 24 to 34 weeks of gestation in Ghaem Hospital affiliated with Mashhad University of Medical Sciences between May 2016 and June 2019. In two study groups, GDM and non‐GDM women, an association between maternal serum irisin levels and clinical and biochemical parameters were evaluated. Maternal serum irisin levels were measured by an enzyme immunoassay method. Body mass index, serum levels of glucose, oral glucose tolerance test (OGTT), insulin, haemoglobin A1C, homeostatic model assessment of insulin resistance (HOMA IR) and irisin were evaluated. Results Totally, 56 participants (30 non‐GDM women and 26 women with GDM) were enrolled. Not statistically significant was observed in serum irisin levels between GDM and non‐GDM women. (p = .814) Irisin levels were not significantly associated with maternal age, systolic and diastolic blood pressure, the number of pregnancies, gestational age, fasting blood sugar, insulin, HOMA IR, one‐hour and two‐hour serum glucose and body mass index. Conclusions There is no significant difference between GDM and non‐GDM groups in the case of irisin value and later, no association of irisin with metabolic and anthropometric parameters. These findings need to be assessed in future experiments.

Abstract Introduction Factitious hypoglycaemia is defined as the surreptitious use of insulin or oral hypoglycaemic agents to deliberately induce self‐harm. It represents a challenging diagnosis and misdiagnosis is associated with significant morbidity and mortality. The aim of this study was to assess the prevalence and the associated factors of factitious hypoglycaemia in non‐diabetic patients. Methods This was a single‐centre, retrospective study including 70 non‐diabetic patients who were admitted for the investigation of hypoglycaemia. All patients fulfilled the Whipple triad. Epidemiological parameters, medical history, clinical and paraclinical data and the aetiology of hypoglycaemia were collected from medical records. Results The diagnosis of factitious hypoglycaemia was held in 11 patients (9 women and 2 men) corresponding to a prevalence of 16%. It was secondary to intentional insulin use in six patients and the ingestion of glibenclamide in five patients. The median age of the patients was 28 years (interquartile range: 21–43). Two patients with factitious hypoglycaemia had a personal history of psychiatric disorders. The other causes of hypoglycaemia were adrenal insufficiency (34%), prediabetes (24%), insulinoma (6%), iatrogenic hypoglycaemia (10%), criminal hypoglycaemia (1%) and alcohol intoxication (2%). Age ≤ 35 years (Odds Ratio = 5.6, p = .017), family history of diabetes mellitus (Odds Ratio = 1.29, p = .015), attention disorders during hypoglycaemia (Odds Ratio = 12.5, p = .017) and fasting glucose level

Advancement in all disciplines (art, science, education, and engineering) requires a careful balance of disruption and advancement of classical techniques. Often technologies are created with a limited understanding of fundamental principles and are prematurely abandoned. Over time, knowledge improves, new opportunities are identified, and technology is reassessed in a different light leading to a renaissance. Recovery of biological products is currently experiencing such a renaissance. Crystallization is one example of an elegant and ancient technology that has been applied in many fields and was employed to purify insulins from naturally occurring sources. Crystallization can also be utilized to determine protein structures. However, a multitude of parameters can impact protein crystallization and the "hit rate" for identifying protein crystals is relatively low, so much so that the development of a crystallization process is often viewed as a combination of art and science even today. Supplying the worldwide requirement for insulin (and associated variants) requires significant advances in process intensification to support scale of production and to minimize the overall cost to enable broader access. Expanding beyond insulin, the increasing complexity and diversity of biologics agents challenge the current purification methodologies. To harness the full potential of biologics, there is a need to fully explore a broader range of purification technologies, including nonchromatographic approaches. This impetus requires one to challenge and revisit the classical techniques including crystallization, chromatography, and filtration from a different vantage point and with a new set of tools, including molecular modeling. Fortunately, computational biophysics tools now exist to provide insights into mechanisms of protein/ligand interactions and molecular assembly processes (including crystallization) that can be used to support de novo process development. For example, specific regions or motifs of insulins and ligands can be identified and used as targets to support crystallization or purification development. Although the modeling tools have been developed and validated for insulin systems, the same tools can be applied to more complex modalities and to other areas including formulation, where the issue of aggregation and concentration-dependent oligomerization could be mechanistically modeled. This paper will illustrate a case study juxtaposing historical approaches to insulin downstream processes to a recent production process highlighting the application and evolution of technologies. Insulin production from Escherichia coli via inclusion bodies is an elegant example since it incorporates virtually all the unit operations associated with protein production-recovery of cells, lysis, solubilization, refolding, purification, and crystallization. The case study will include an example of an innovative application of existing membrane technology to combine three-unit operations into one, significantly reducing solids handling and buffer consumption. Ironically, a new separations technology was developed over the course of the case study that could further simplify and intensify the downstream process, emphasizing and highlighting the ever-accelerating pace of innovation in downstream processing. Molecular biophysics modeling was also employed to enhance the mechanistic understanding of the crystallization and purification processes., (© 2023 Wiley Periodicals LLC.)

Background and Purpose: Maintaining mitochondrial quality is attracting attention as a new strategy to treat diabetes and diabetic complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin-related protein (Drp) 1 and filamin, mediates chronic heart failure and cilnidipine, initially developed as an L/N-type Ca 2+ channel blocker, improves heart failure by inhibiting Drp1-filamin protein complex. We investigated whether cilnidipine improves hyperglycaemia of various diabetic mice models., Experimental Approach: Retrospective analysis focusing on haemoglobin A1c (HbA1c) was performed in hypertensive and hyperglycaemic patients taking cilnidipine and amlodipine. After developing diabetic mice by streptozotocin (STZ) treatment, an osmotic pump including drug was implanted intraperitoneally, followed by weekly measurements of blood glucose levels. Mitochondrial morphology was analysed by electron microscopy. A Ca 2+ channel-insensitive cilnidipine derivative (1,4-dihydropyridine [DHP]) was synthesized and its pharmacological effect was evaluated using obese (ob/ob) mice fed with high-fat diet (HFD)., Key Results: In patients, cilnidipine was superior to amlodipine in HbA1c lowering effect. Cilnidipine treatment improved systemic hyperglycaemia and mitochondrial morphological abnormalities in STZ-exposed mice, without lowering blood pressure. Cilnidipine failed to improve hyperglycaemia of ob/ob mice, with suppressing insulin secretion. 1,4-DHP improved hyperglycaemia and mitochondria abnormality in ob/ob mice fed HFD. 1,4-DHP and cilnidipine improved basal oxygen consumption rate of HepG2 cells cultured under 25 mM glucose., Conclusion and Implications: Inhibition of Drp1-filamin protein complex formation becomes a new strategy for type 2 diabetes treatment., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Abstract Background This meta‐analysis of randomized controlled trials (RCTs) compared long‐term adverse clinical outcomes of percutaneous coronary intervention (PCI) in insulin‐treated diabetes mellitus (ITDM) and non‐ITDM patients. Methods This is a meta‐analysis study. The PubMed and Embase databases were searched for articles on long‐term adverse clinical outcomes of PCI in ITDM and non‐ITDM patients. The risk ratios (RR) and 95% confidence intervals (CI) were calculated. Results A total of 11 related RCTs involving 8853 DM patients were included. Compared with non‐ITDM patients, ITDM patients had significantly higher all‐cause mortality (ACM) (RR = 1.52, 95% CI: 1.25–1.85, pheterogeneity = .689, I2 = 0%), major adverse cardiac and cerebrovascular events (MACCE) (RR = 1.35, 95% CI: 1.18–1.55, pheterogeneity = .57, I2 = 0%), myocardial infarction (MI) (RR = 1.41, 95% CI: 1.16–1.72, pheterogeneity = .962, I2 = 0%), and stent thrombosis (ST) (RR = 1.75, 95% CI: 1.23–2.48, pheterogeneity = .159, I2 = 32.4%). No significant difference was found in the target lesion revascularization (TLR) and target vessel revascularization (TVR) between the ITDM and non‐ITDM groups. Conclusions The results showed that ITDM patients had significantly higher ACM, MACCE, MI, and ST, compared with non‐ITDM patients.

Abstract Postbiotics are microbial‐derived components or metabolites that can influence host immunity and metabolism. Some postbiotics can improve blood glucose control and lower inflammation during bacterial or nutritional stress. Bacterial cell wall‐derived muramyl dipeptide (MDP) is a potent insulin‐sensitizing postbiotic that engages NOD2, RIPK2, and requires interferon regulatory factor 4 (IRF4) to lower inflammation and improve blood glucose. However, the sex‐dependent effects of this postbiotic and the cell type required for IRF4 to cause inflammatory versus glycemic responses to MDP were unknown. Here, we measured how MDP injection altered glucose tolerance and adipose tissue inflammation during low‐level endotoxemia and high fat diet (HFD)‐induced obesity in male and female adipocyte‐specific IRF4 knockout mice (AdipoIRF4fl/fl) compared to WTfl/fl mice. Adipocyte IRF4 was required for the blood glucose‐lowering effects of MDP during endotoxemia and HFD‐induced obesity in male mice. However, MDP did not alter blood glucose in female WTfl/fl and AdipoIRF4fl/f mice during endotoxemia. Unexpectedly, female HFD‐fed AdipoIRF4fl/f mice had lower blood glucose after MDP treatment compared to WTfl/fl mice. MDP lowered inflammatory gene expression in adipose tissue of HFD‐fed WTfl/fl and AdipoIRF4fl/fl mice of both sexes. Therefore, MDP‐mediated lowering of adipose inflammation does not require adipocyte IRF4 and was independent of sex. Together, these data show that injection of MDP, an insulin‐sensitizing postbiotic, lowers adipose tissue inflammation in male and female mice, but lower adipose inflammation is not always associated with improved blood glucose. The blood glucose‐lowering effect of the postbiotic MDP and dependence on adipocyte IRF4 is sex‐dependent.

Abstract Abnormal postprandial suppression of glucagon in Type 2 diabetes (T2DM) has been attributed to impaired insulin secretion. Prior work suggests that insulin and glucagon show an inverse coordinated relationship. However, dysregulation of α‐cell function in prediabetes occurs early and independently of changes in β‐cells, which suggests insulin having a less significant role on glucagon control. We therefore, sought to examine whether hepatic vein hormone concentrations provide evidence to further support the modulation of glucagon secretion by insulin. As part of a series of experiments to measure the effect of diabetes‐associated genetic variation in TCF7L2 on islet cell function, hepatic vein insulin and glucagon concentrations were measured at 2‐minute intervals during fasting and a hyperglycemic clamp. The experiment was performed on 29 nondiabetic subjects (age = 46 ± 2 years, BMI 28 ± 1 Kg/m2) and enabled post‐hoc analysis, using Cross‐Correlation and Cross‐Approximate Entropy (Cross‐ApEn) to evaluate the interaction of insulin and glucose. Mean insulin concentrations rose from fasting (33 ± 4 vs. 146 ± 12 pmol/L, p

Objectives To investigate the proportion of insulin‐dependent diabetes mellitus (IDDM) patients among diabetic patients undergoing total joint arthroplasty (TJA) and whether insulin dependence is associated with postoperative complications. Methods A systematic literature search was performed in EMBASE, PubMed, Ovid, Medline, the Cochrane Library, Web of Science, the China Science and Technology Journal Database, and China National Knowledge Infrastructure from the inception dates to 10 September 2019. Observational studies reporting adverse events with IDDM following TJA were included. Primary outcomes were cardiovascular complications, pulmonary complications, kidney complications, wound complications, infection, and other complications within 30 days of surgery. Secondary outcomes were the proportion of IDDM patients among diabetic patients undergoing TJA and its time trend. Results A total of 19 studies involving 85,689 participants were included. Among patients undergoing TJA, 26% of diabetic patients had IDDM. Compared with non‐insulin‐dependent diabetes (NIDDM), the incidences of cardiac arrest (risk ratio [RR], 2.346; 95% confidence interval [CI], 1.553 to 3.546), renal failure (relative risk [RR], 2.758; 95% CI, 1.830 to 4.156), deep incisional surgical site infection (RR, 1.968; 95% CI, 1.107 to 3.533), wound dehiscence (RR, 2.209; 95% CI, 1.830 to 4.156), and death (RR, 2.292; 95% CI, 1.568 to 3.349) were all significantly increased in IDDM. A significant time trend was witnessed for the prevalence of IDDM (P = 0.014). There was no statistical significance for organ/space surgical site infection, thrombotic events (deep venous thrombosis/ pulmonary embolism), and revision rates. Conclusion Insulin‐dependent diabetes is an independent high‐risk factor for increased adverse outcomes relative to NIDDM, suggesting that hierarchical and optimal blood glucose management may contribute to reducing the adverse complications after surgery for these patients. In addition, because the risk of sepsis, deep wound infection, organ/space surgical site infection, urinary tract infection, renal insufficiency, and renal failure significantly increase after TJA in IDDM patients, more active postoperative antimicrobial prophylaxis may be needed on the premise of protecting renal function.

Abstract Background Many diabetic dogs and cats require small doses of insulin that must be administered accurately. Objectives To compare the accuracy and precision of insulin syringes and pen‐injectors. Animals None. Methods To determine how accurately and precisely insulin doses are delivered, 0.5, 1, 2, 4, 8, and 16 U doses were dispensed 25 times from 5 SoloSTARs, 5 FlexPens, 5 KwikPens, 5 JuniorSTARs, 5 VetPens 0.5‐8 U, 5 VetPens 1‐16 U, and by 5 veterinarians using 30 U/0.3 mL and 40 U/mL insulin syringes. Each dose was weighed, using a precision balance, and the intended and delivered doses were compared. Results All pen‐injectors delivered less insulin than the intended dose, underdosage being inversely proportional to insulin dose. The differences between the intended and the delivered dose were not significant using JuniorSTAR and VetPen 0.5‐8 U at insulin doses of 0.5, 1, 2, and 4 U, using the 30 U/0.3 mL insulin syringe at the 4 U dose and using the 40 U/mL insulin syringe at the 4, 8, and 16 U doses. With all the devices, precision increased with increasing doses of insulin. The coefficient of variation was

Abstract Background The FreeStyle Libre (Abbott Laboratories) is a flash glucose monitoring system (FGMS) that measures interstitial glucose concentration (IG). The system is factory‐calibrated, easy to use, inexpensive, and could be useful for monitoring diabetic cats. Objectives To evaluate the analytical and clinical accuracy of the FGMS in cats and establish the lag‐time between IG and blood glucose concentration (BG). Animals Twenty client‐owned diabetic cats and 7 purpose‐bred healthy cats. Methods Prospective study. Blood glucose concentration was measured using a portable glucose meter validated for use in cats that served as a reference method for IG, as measured by FGMS. In diabetic cats, data were collected for sensor wearing time with different methods of application and accuracy across glycemic ranges. Accuracy was determined by fulfillment of ISO15197:2013 criteria. In healthy cats, lag‐time between IG and BG was established after IV administration of exogenous glucose. Results Good agreement between IG and BG was obtained (r = .93). Analytical accuracy was not achieved, whereas clinical accuracy was demonstrated with 100% of the results in zones A + B of the Parkes consensus error grid analysis. In the immediate 30 minutes after an IV bolus of glucose, when BG was increasing rapidly (approximately 2%/min), IG increased slowly, resulting in a difference of as much as 579 mg/dL, and no positive correlation between BG and IG was found. Conclusions and Clinical Importance The FGMS did not fulfill ISO requirements but is sufficiently accurate for glucose monitoring in cats, while considering the lag between IG and BG during periods of rapid changes in BG.