Chromosomal deletions involving several disease-associated genes exhibit diverse phenotypes. HNF1A is one of the causative genes of maturity-onset diabetes of the young. Furthermore, heterozygous variants in DHX37 and SETD1B, located near HNF1A, cause 46,XY disorders of sex development and syndromic neurodevelopmental disorders, respectively. This study describes a 12-yr-old boy with a 12q24.31-32 chromosomal deletion involving HNF1A, DHX37, and SETD1B. The boy was born small-for-gestational age, and experienced seizures, autism spectrum disorder, hearing loss, short stature, and intellectual disability. At five years of age, an 8.6-Mb chromosomal deletion at 12q24.31-32 was identified by array-based comparative genomic hybridization. At 12 yr of age, he developed islet autoantibody-negative diabetes. As the deletion region identified included HNF1A, this suggested that it is a cause of diabetes. Furthermore, SETD1B was considered to be a cause of intellectual disability and autism spectrum disorder. Owing to his intellectual disability, self-management of hypoglycemia was challenging; thus, nateglinide and insulin therapy were deemed effective for diabetes management rather than sulfonylurea drugs. Furthermore, DHX37 haploinsufficiency was considered a cause of hypogonadism. These findings emphasize the importance of diabetes management tailored to the characteristics of children with intellectual disabilities and the potential for hypogonadism due to DHX37 haploinsufficiency.

We report an asymmetric α-amination of aldehydes using a nonsilyl bicyclic secondary amine organocatalyst at 0.1 mol% in the presence of propanoic acid (100 mol%). Catalyst stability toward dibenzyl azodicarboxylate is investigated by 1H NMR spectroscopy under varying acid loadings. This method exhibits a broad substrate scope, affording products in up to 96% yield and 94% ee. This scalable methodology is applied to the concise asymmetric synthesis of solriamfetol and nateglinide.

For prehospital providers, there are several causes for the patient with altered mental status or being unconscious to include the mnemonic AEIOU TIPS for Alcohol and acidosis, Endocrine, Epilepsy, Electrolytes, Encephalopathy, Infection, Opiates, Overdose, Uremia, Underdose, Trauma (head injury and blood loss), Insulin, Poisoning, Psychosis, Stroke, Seizure, and Syncope. Hypoglycemia, or low blood glucose level, is one of the most common causes of altered mental status for patients with and without diabetes. Estimates are that 1 to 2 percent of prehospital encounters and 7% of refusals are for hypoglycemia.[1][2] Diabetes mellitus often referred to as "diabetes" or "sugar" by laypeople is the most common endocrine disorder where the body does not either produce enough insulin or has a resistance to the circulating insulin, and is characterized by high blood sugar levels over prolonged periods. The three main types of diabetes are type I (previously referred to as insulin-dependent diabetes mellitus (IDDM) or juvenile-onset), type II (formerly referred to as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset) and gestational.[3] Insulin is an anabolic hormone produced in the beta cells of the pancreatic islets. The primary function of insulin is to regulate the metabolism of carbohydrates, protein, and fat through the absorption of glucose sugar from the blood into the liver, fat, and skeletal muscle cells. These small glucose molecules are then converted into larger molecules and stored for later usage.  Type 1 Diabetes Mellitus (T1DM) [4] This condition is commonly referred to as insulin-dependent diabetes or previously as childhood/adolescent-onset diabetes. It accounts for approximately 5% to 10% of all cases of diabetes. It can be related to the autoimmune destruction of insulin-producing beta cells in the islets of the pancreas from different causes, including genetic susceptivity, viral illness, toxins or alcohol-induced pancreatitis, or some dietary factors.  The age group affected is usually children and adolescents, but adults can develop T1DM.  As the name "insulin-dependent" implies, it requires the administration of subcutaneous insulin via intermittent injections or pump infusion. Type 2 Diabetes Mellitus (T2DM) [4] [5] This variant is commonly referred to as non-insulin diabetes or previously as adult-onset diabetes.  It accounts for approximately 90% of all cases of diabetes.  It is related to the desensitization of insulin/insulin resistance (response to insulin becomes diminished) in various tissues. Initially, there is an increase in insulin production, but this decreases over time. T2DM most commonly presents in persons older than 45 years, but it increasingly occurs in children, adolescents, and younger adults due to rising levels of obesity, physical inactivity, and energy-dense diets. Gestational Diabetes Mellitus (GDM) Hyperglycemia first detected during pregnancy is classified as gestational diabetes mellitus (GDM). Although it can occur anytime during pregnancy, GDM generally affects pregnant women during the second and third trimesters. According to the American Diabetes Association (ADA), GDM complicates 7% of all pregnancies. Women with GDM and their offspring have an increased risk of developing type 2 diabetes mellitus in the future.  Types of Therapies [6] Therapy for hyperglycemia is dependant upon how much insulin the body is producing, or how well that insulin that is produced is working.  The majority of patients with T2DM will be on an oral type of medication.  Patients with T1DM will be on a combination of either long-acting insulin with short-acting as a sliding scale, intermediate-acting insulin with short-acting insulin as a sliding scale, combination premixed insulin, or be on an insulin pump. Hypoglycemia  One of the public health concerns for diabetes mellitus and unintended complications for the reduction in blood glucose levels is hypoglycemia.[1][7][8] Hypoglycemia, by definition, is a plasma glucose concentration below 70 mg/dL, with most patients not having signs or symptoms until the plasma glucose concentrations drop below 55 mg/dL.[9]  Low plasma glucose concentration that requires assistance from another individual qualifies as severe hypoglycemia, and by context, all EMS encounters fall into this category.[1][10]  There has been an increase in morbidity (poor quality of life, series falls or car accidents, dementia, and hospitalization) and mortality related to severe hypoglycemia.[1]  Based upon 2015 data from NEMSIS, prehospital activation for diabetes-related cases accounts for about 2.3% of all activations, with the primary EMS encounter being hypoglycemia.[11] Patients experiencing severe hypoglycemia or other diabetes-related concerns typically reach out for help by calling 911 who may dispatch a fire department or EMS agency depending on the jurisdiction. Care is then provided by the first on scene provider who may be an emergency medical technician (EMT) intermediate or advanced emergency medical technician (IEMT or AEMT) or paramedic. Treat and release versus transport of patients with hypoglycemia by EMS providers depends on the clinical guidelines or protocols from either the state or regional level by medical directors. It is important to understand that patients with severe hypoglycemia are at a higher risk of having complications related to the hypoglycemic state.  Villani et al. indicated that approximately 50% of patients with severe hypoglycemia required transport to the hospital, and of that group, 41.3% were admitted to the hospital.[12][13][14]  One of the first studies on the topic of treating and releasing hypoglycemic patients in the field was "Development and Evaluation of Criteria Allowing Paramedics to Treat and Release Patients Presenting with Hypoglycemia: A Retrospective Study" published in Prehospital and Disaster Medicine in 1991.   Their study design proposed five criteria that would allow for appropriate release that would not require additional treatment from prehospital providers to include: 1. The patient has a history of type 1 or type 2 diabetes. 2. Blood sugar prior to treatment is below 4.4 mmol/L or 80 mg/dL. 3. Blood sugar after treatment is equal to or greater than 4.4 mmol/L or 80 mg/dL. 4. The patient has a normal mental status within 10 minutes of treatment.  5. The patient does not have any other complicating factors that required ED evaluation to such alcohol, chest pain, dyspnea, injuries related to falls, and/or renal dialysis. A 2016 study by Rostykus et al. reviewed prehospital clinical guidelines for hypoglycemia in 185 EMS agencies in the United States.  It revealed that less than half allowed for non-transport of patients with hypoglycemia after the low plasma glucose level was corrected.[15] A study by Moffet et al. looked at hypoglycemic patients treated by EMS in Alameda County from 2013 to 2015 and found that the transport rate was 13.5%. The demographic trends for those non-transported patients were adult patients < 60 years of age, males, finger stick blood glucose levels > 60 mg/dl, and EMS arrival times between 1800 and 0600.[1]

No information is available on the use of nateglinide during breastfeeding. Nateglinide is a weak acid that is over 98% protein bound, so it is unlikely to pass into breastmilk in clinically important amounts. Monitor breastfed infants for signs of hypoglycemia such as jitteriness, excessive sleepiness, poor feeding, seizures cyanosis, apnea, or hypothermia. If there is concern, monitoring of the breastfed infant's blood glucose is advisable during maternal therapy with nateglinide.[1] However, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

Accurate identification of ligand binding modes on human serum albumin (HSA) is important for understanding drug-protein interactions that influence pharmacokinetics, including site-specific competition and protein-binding displacement. However, because HSA is a large, multisite binding protein that permits diverse binding configurations, conventional molecular docking often struggles to distinguish crystal-like poses from nonspecific surface-binding poses using static scoring functions alone. Here, we developed a machine-learning framework for HSA binding-pose identification that incorporates dynamic stability information derived from short molecular dynamics (MD) simulations. Time-dependent interaction patterns observed during MD trajectories, including contact persistence, distance fluctuations, and interaction energy-related descriptors, were quantified as interpretable features and integrated with docking scores. Using Leave-One-PDB-Out cross-validation on 31 HSA-ligand crystal structures, models incorporating MD-derived features significantly outperformed the docking score-only model under both pose-level (root-mean-square deviation [RMSD] ≤ 2.5 Å) and site-level (RMSD ≤ 5.0 Å) criteria (Holm-corrected p < 0.001). External validation using a temporally independent nateglinide-HSA complex further supported the utility of the framework for discriminating plausible binding modes within the HSA setting. Notably, informative dynamic features were obtained from 5 ns MD simulations, indicating that early-stage dynamic behavior is sufficient to improve pose discrimination. These findings show that short MD simulations can provide practically useful and interpretable features for machine-learning-based binding-pose identification on HSA. While broader validation will be required to establish applicability beyond HSA, the proposed framework offers a practical strategy for improving binding-mode analysis in pharmacokinetically relevant HSA studies.

Nateglinide (Nat) is an oral antidiabetic agent of the meglitinide class that has been reported to exert protective effects beyond glycemic control, particularly against oxidative stress and inflammation. Since oxidative stress and inflammation play a key role in the pathogenesis of acute kidney injury (AKI), especially following ischemia/reperfusion (I/R), this study aimed to evaluate the potential renoprotective effects of Nat in a rat model of I/R-induced AKI. Forty male Sprague Dawley rats were randomly divided into four groups (n = 10): Control, I/R, I/R + Nat (50 mg/kg), and I/R + Nat (100 mg/kg). Bilateral renal ischemia was induced by clamping renal arteries for 45 min, followed by 24 h of reperfusion. Nat was administered orally 1 h before ischemia. Renal levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and thiobarbituric acid reactive substances (TBARSs) were assessed. Serum blood urea nitrogen (BUN), creatinine, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were also measured, and histopathological analyses were performed. Nat significantly increased renal antioxidant parameters and reduced TBARS levels. Moreover, Nat markedly decreased serum BUN, creatinine, TNF-α, and IL-1β levels compared with the I/R group (p < 0.05). Histopathology confirmed attenuated renal damage in Nat-treated groups (p < 0.0001). These results indicate that Nat confers significant renoprotection against renal I/R injury via suppression of oxidative stress and inflammation.

Type 2 diabetes (T2D) is a complex metabolic disorder characterized by impaired glucose homeostasis resulting from dysfunctional pancreatic β-cells. Understanding the fundamental mechanisms governing β-cell dysfunction can pave the way for novel therapeutic interventions. In this study, comprehensive context-specific genome-scale metabolic models for healthy and T2D pancreatic β-cells were reconstructed using high-throughput transcriptomics data. These models underscore substantial shifts in metabolic flux profile within pancreatic β-cells of diabetic patients compared to their healthy counterparts. Disruptions in glucose metabolism and compromised insulin biosynthesis were identified in β-cells, highlighting critical factors contributing to the onset of T2D. Further, a correlation was observed between reduced metabolic activity in amino sugar, amino acid, and peptide metabolism and diminished insulin production. Moreover, reduced ubiquinone synthesis and enhanced fatty acid oxidation in T2D patients were found to play a critical role in impaired β-cell function. These findings provide novel insights into the metabolic dysregulation underlying T2D pathogenesis. Furthermore, metabolically impacted reactions were leveraged to identify biomarker genes associated with β-cell failure. Drug repurposing analysis using the identified genes revealed 23 potential targets, seven of which have already been linked to the treatment of T2D. The most commonly used antidiabetic drugs, such as metformin, glyburide, nateglinide, and insulin, overlapped with our identified drug candidates, supporting the reliability of our predictions. Additionally, 341 FDA-approved drug candidates were identified that may serve as potential therapeutics targeting T2D biomarker genes. These results pave the way for developing targeted therapeutic interventions to restore healthy β-cell function and improve glucose homeostasis in T2D patients.

Deletion of IG20 (also known as MADD), which can encode multiple isoforms, causes diabetes in mice by impairing glucose-stimulated insulin secretion. To evaluate the role of IG20 in mediating the therapeutic potential of glinide-class insulin secretagogues, we tested their effects in Ig20/Madd-knockout (KMA1ko) mice. Glucose tolerance tests revealed that repaglinide, mitiglinide, and nateglinide failed to lower blood glucose levels or enhance insulin secretion in KMA1ko mice, suggesting that IG20 deficiency significantly diminishes the therapeutic efficacy of glinides. The functional relevance of at least 6 IG20 isoforms remains to be defined. Interestingly, among the six IG20 splicing isoforms re-expressed in IG20-deficient Min6 cells, only KIAA0358 was capable of restoring glucose-stimulated insulin secretion. Notably, KIAA0358 re-expression also rescued repaglinide-induced insulin secretion in vivo. Further transmission electron microscopy and total internal reflection fluorescence microscopy analyses showed that KIAA0358 significantly promoted insulin granule transport and docking impaired by IG20 knockout. Furthermore, guanine nucleotide exchange assay and GST pull-down demonstrated that KIAA0358 functions as a Rab GEF to convert Rab3A and Rab27A from the GDP-bound to the active GTP-bound state, thereby restoring their interactions with the downstream effector proteins Rim2α and Slac-2a that were impaired by IG20 deficiency. Therefore, by regulating the activation states of Rab3A and Rab27A, KIAA0358 mediated the transport and docking of insulin granules to the plasma membrane. This study also highlights that the genes encoding non-drug target proteins can influence drug efficacy and provides a novel conceptual foundation for precision medicine strategies aimed at reducing drug resistance and enhancing the clinical efficacy of glinides.

In the booming era of nanomedicines, Caco-2 intestinal permeability experimental models allow characterizing intestinal permeabilities of nanopharmaceuticals and are conducted in the presence of cell culture media (CCM) and stabilizers. Methods for simultaneous quantification of furosemide (FRS) and nateglinide (NTG) in Caco-2 experiments are lacking. We developed and validated a novel, simple, and practical reversed-phase high-performance liquid chromatography (RP-HPLC) method with UV detection to simultaneously quantify FRS and NTG in the presence of CCM and stabilizers (Povidone K-25, Pluronic F-38) for Caco-2 intestinal permeability experiments exploring nanoformulations. FRS and NTG nanosuspensions were prepared using high-speed ultrasonic homogenization top-down technique. Caco-2 cell culture studies were conducted. ICH Q2(R1) guideline requirements (i.e., selectivity, specificity, accuracy, precision, robustness, stability) were met. System suitability and linearity (FRS: 5.12-40.00 μg/mL; NTG: 7.31-50.00 μg/mL), with high determination coefficients (>0.999), and short retention times (FRS: 3.3 min; NTG: 5.3 min) were achieved. NTG and FRS in Caco-2 samples were successfully simultaneously quantified, proving usefulness for nanodrug research applications. Varying stabilizers impact intestinal permeability. This work simulates pragmatic conditions, as cardiovascular patients are co-administered these drugs, paving the pathway to using our novel method for a wide range of "bench-to-bedside" nanomedicine research designs to tackle the challenges of polypharmacy in this complex population.

Nateglinide is a short-acting insulin secretagogue clinically used for the treatment of type 2 diabetes mellitus. Nateglinide exhibits a high plasma protein binding rate of approximately 98%, primarily binding to subdomain IIIA of human serum albumin (HSA). Here, we determined the crystal structure of the HSA-nateglinide complex at 2.80 Å resolution, revealing dual binding modes of nateglinide within the same binding site. To evaluate the stability of these alternative binding modes, molecular dynamics simulations were conducted, and binding free energies were calculated using the molecular mechanics Poisson-Boltzmann surface area method. The calculated binding free energy values were consistent with experimentally determined data. Our results highlight the structural adaptability of HSA and emphasize the possibility of alternative ligand binding modes existing within a single binding site, as well as the importance of identifying and characterizing these modes to enhance our understanding of drug-plasma protein interactions.

Various types of drugs can affect serum urate levels as side effects. Although these drugs are used to treat different diseases, they might share a structural component that acts on a common target to affect urate levels. Human urate transporter 1 (URAT1) plays an essential role in urate reabsorption at the renal proximal tubule and thus might be a common target for drugs that can affect serum urate levels. Our aim was to elucidate the structural requirements for a compound to show activity toward URAT1 and to identify clinically used drugs that can affect URAT1 activity. Our search was based on structural similarities in the compounds. [[14]C]Urate uptake by URAT1-expressing human embryonic kidney 293 (HEK-hURAT1) cells in the presence of an analog of a small molecule with known URAT1 activity suggested that structural moieties of salicylic acid can increase URAT1 cis-inhibitory activity. Therefore, we searched a database for drugs with substructures similar to salicylic acid. We were able to predict some types of loop diuretics, statins, and angiotensin receptor blockers as drug candidates that might affect URAT1. In addition, we found that glinides inhibit urate uptake by HEK-hURAT1 cells. Three glinides (nateglinide, mitiglinide, and repaglinide) all inhibited urate uptake by HEK-hURAT1 cells concentration-dependently (IC50: nateglinide, 39 μM; mitiglinide, 63 μM; repaglinide, 3.9 μM). Furthermore, glinides also showed trans-inhibition activity in URAT1-expressing Xenopus oocytes pretreated with the glinides. These findings suggest that glinides sharing a salicylic acid-like substructure might affect serum urate level by acting on URAT1. SIGNIFICANCE STATEMENT: Some types of loop diuretics, statins, angiotensin receptor blockers, and glinides were predicted to affect URAT1, based on their chemical structural similarity to salicylic acid, the structure of which allows it to interact with URAT1. Glinides in particular showed cis- and trans-inhibitory activity toward URAT1.

The hypoglycemic effects of nateglinide (NTG) were examined in rats with acute peripheral inflammation (API) induced by carrageenan treatment, and the mechanisms accounting for altered hypoglycemic effects were investigated. NTG was administered through the femoral vein in control and API rats, and its plasma concentration profile was characterized. The time courses of the changes in plasma glucose and insulin levels were also examined. Although the plasma concentration profile of NTG in API rats was marginally distinguishable from that in control rats, the hypoglycemic effect of NTG was more persistent in API rats than in control rats. In addition, NTG elevated the plasma level of insulin more intensely in API rats than in control rats. Then, the islets of Langerhans were procured by perfusing the pancreas with collagenase solution in control and API rats, and the pancreatic mRNA expression of preproinsulin (Ins1), as well as that of sulfonylurea receptor ABCC8 (Abcc8), were examined. As a result, the expression of preproinsulin and ABCC8 mRNA increased in API rats. These findings suggest that the hypoglycemic effect of NTG was potentiated in API rats due to increased insulin secretion in the pancreas, which was caused by enhanced preproinsulin synthesis and expression of the sulfonylurea receptor.

Nateglinide belongs to the meglitinide class of insulin secretagogues. It is used as an oral hypoglycemic agent for the treatment of type 2 diabetes mellitus. Nateglinide is an amino acid derivative of D-phenylalanine that binds to the ATP-sensitive potassium channels in pancreatic beta cells and stimulates the secretion of insulin. In this chapter, various aspects of Nateglinide are discussed. This includes methods used for its synthesis, physicochemical properties, and different techniques employed to determine its structure, such as elemental analysis, IR, UV, ([1]H and [13]C) NMR, MS, and XRD. Additionally, the chapter covers a literature review of various methods of analysis of Nateglinide, such as X-ray powder diffraction pattern analysis, differential scanning calorimetry, spectrophotometric, chromatographic, capillary electrophoresis and immunoassay methods. Moreover, the pharmacology of the title drug including pharmacokinetics, pharmacodynamics, mechanism of action, drug-drug and drug-food interactions are also reviewed.

In this study, a sensitive and selective spectrofluorimetric method was developed for the determination of the antidiabetic drug nateglinide based on its reaction with the xanthene dye acid red 87 (AR87). A fluorescence quenching process was observed for the AR87 at 545 nm upon the addition of nateglinide, which was exploited for the quantitative analysis. The reaction mechanism was investigated using quantum mechanical calculations suggesting a transfer between the electron-rich AR87 and the electron-deficient nateglinide. Additionally, the stoichiometry of the interaction was determined through Job's method revealing a 1:1 nateglinide-AR87 complex formation. The experimental parameters were optimized using a Box-Behnken design of experiments, including pH, reagent concentration, and buffer volume. The optimized method was validated according to ICH guidelines, demonstrating excellent linearity in the range of 0.1-3.0 μg/mL, with a detection limit of 0.0320 μg/mL and a quantitation limit of 0.0961 μg/mL. Furthermore, the greenness and blueness of the method were assessed using the AGREE and BAGI indices, indicating an environmentally friendly procedure. The developed method was successfully applied for the determination of nateglinide in pharmaceutical dosage forms and spiked human plasma samples posing a promising analytical tool for clinical and quality control applications.