Oral Sulfonylurea Research Articles

Focusing on Rare Variants Related to Maturity‐Onset Diabetes of the Young in Children

Background: In this study, we analysed the clinical and genetic characteristics and follow‐up data of patients with maturity‐onset diabetes of the young (MODY).Methods: From January 2015 to December 2022, patients with persistent hyperglycaemia suspected of having monogenic diabetes or diabetes syndrome were recruited, and next‐generation sequencing (NGS) was performed at the Shanghai Children’s Medical Center. Patients’ clinical and laboratory findings were recorded preceding follow‐ups. Candidate variants were verified using Sanger sequencing. Variant pathogenicity was evaluated according to the American College of Medical Genetics and Genomics (ACMG) guidelines.Results: Genetic testing was performed in 175 children. MODY‐related pathogenic or likely pathogenic gene variants were identified in 30 patients from different families. Of these, 11 were diagnosed with GCK‐MODY (36.7%), six with INS‐MODY (20%), five with HNF1A‐MODY (16.7%), five with ABCC8‐MODY (16.7%), two with HNF1B‐MODY (6.7%) and one with HNF4A‐MODY (3.3%). There was one shift variant and seven splice‐site variants, and the rest were missense variants. We discovered six novel variants. Of the 30 patients, 63.3% had a family history of diabetes, 13.3% had diabetic ketoacidosis (DKA), and 16.7% had positive diabetes‐associated autoantibodies. The diabetes phenotype of patients with the INS variant was similar to that of patients with type 1 diabetes. All patients, including those having positive autoantibodies, required long‐term insulin therapy during follow‐ups. Four patients with the ABCC8 variant were unable to switch to oral sulfonylurea therapy and continued insulin therapy.Conclusion: Genetic testing is helpful for the precise diagnosis and treatment of patients with MODY, including those with DKA history and positive diabetes autoantibody. GCK‐MODY is the most common type of MODY, and patients with INS variant account for a relatively large proportion of MODY cases in our cohort.

Four Patients with Neonatal Diabetes Mellitus and their Outcomes: A Case Series

Background: Neonatal diabetes mellitus (NDM) is a severe type of glucose metabolism disorder that appears in the first months of life and mostly presents with symptoms such as dehydration, inability to gain weight, and in extreme cases, ketoacidosis and coma. Strong evidence shows the benefits of early molecular tests that investigate variability in kATP channels such as KCNJ11, ABCC8, INS gene mutations, and 6q24 abnormalities. In the presence of these genomics changes, switching from Insulin treatment toward high-dose oral sulfonylurea can enhance the course of treatment, prognosis, and quality of life. Case Report: In this study, we report four cases of neonatal diabetes with different symptoms who were referred to Shahid Sadoughi Medical Center in Yazd, Iran. Conclusion: The diagnosis and treatment of NDM is a good model for implementing patient-centered and personalized medicine. For all patients with diabetes diagnosed before the 6th month of their age (even the 12th month), genetic testing should be considered.

Clinical and functional characterization of a novel KCNJ11 (c.101G > A, p.R34H) mutation associated with maturity-onset diabetes mellitus of the young type 13.

This study aimed to describe the clinical features, diagnostic and therapeutic course of a patient with MODY13 caused by KCNJ11 (c.101G > A, p.R34H) and how it contributes to the pathogenesis of MODY13, and to explore new therapeutic targets. Whole-exome sequencing was used to screen prediagnosed individuals and family members with clinically suspected KCNJ11 mutations. Real-time fluorescence quantitative PCR, western blotting, thallium flux of potassium channels, glucose-stimulated insulin secretion (GSIS), and immunofluorescence assays were used to analyze the regulation of insulin secretion by the KCNJ11 mutant in MIN6 cells. Daily blood glucose levels were continuously monitored for 14 days in the proband using the ambulatory blood glucose meter (SIBIONICS). Mutation screening of the entire exon of the gene identified a heterozygous KCNJ11 (c.101G > A, p.R34H) mutation in the proband and his mother. Cell-based GSIS assays after transfection of MIN6 using wild-type and mutant plasmids revealed that this mutation impaired insulin secretory function. Furthermore, we found that this impaired secretory function is associated with reduced functional activity of the mutant KCNJ11 protein and reduced expression of the insulin secretion-associated exocytosis proteins STXBP1 and SNAP25. For the first time, we revealed the pathogenic mechanism of KCNJ11 (c.101G > A, p.R34H) associated with MODY13. This mutant can cause alterations in KATP channel activity, reduce sensitivity to glucose stimulation, and impair pancreatic β-cell secretory function by downregulating insulin secretion-associated exocytosis proteins. Therefore, oral sulfonylurea drugs can lower blood glucose levels through pro-insulinotropic effects and are more favorable for patients with this mutation.

Formulation of Glibenclamide proniosomes for oral administration: Pharmaceutical and pharmacodynamics evaluation

Glibenclamide (GB), oral antidiabetic sulfonylurea, is used in the management of diabetes mellitus type II. It suffers from low bioavailability due to low water solubility. This work aimed to enhance the dissolution of GB by formulating the drug as a proniosomes which then improves the pharmacological effect. GB proniosomal formulations were prepared using a slurry method with sucrose as a carrier. The formulations were characterized by particle size, zeta potential, entrapment efficiency %, flow properties of the powder, and in vitro dissolution study. The pharmacological effect was also assessed by determining and measuring the fasting blood glucose level (BGL) before and after the treatment. Formulating GB proniosomes with the slurry method produces a free-flowing powder with a particle size range from 190.050 ± 43.204 to 1369.333 ± 150.407 nm and the zeta potential was above 20 mV (-24 to −58 mV), indicating good stability. The dissolution rate for all formulations was higher than that of the pure drug, indicating the efficiency of the proniosome in enhancing the drug solubility. A significant reduction in the fasting blood glucose level (73 %) was observed in animals treated with proniosomal formulation with no sign of liver damage. In contrast, the pharmacodynamics results show a significant reduction in fasting blood glucose level for animals treated with proniosomes compared to a 17.6 % reduction in BGL after treatment with pure drug. Moreover, the histopathological results showed no sign of liver damage that occurred with proniosomal treatment. GB proniosomal formulations is a promising drug delivery system with good therapeutic efficacy and stability.

SAT078 A Case Of MODY Due To A Rare Activating Variant In The ABCC8 Gene

Abstract Disclosure: J. Milosavljevic: None. J.M. Greally: None. S. Milman: None. Background: ATP-binding cassette transporter subfamily C member 8 (ABCC8) gene encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the beta cell ATP-sensitive K+ channel (KATP). Activating mutations in the ABCC8 cause both neonatal and maturity-onset diabetes of the young (MODY). The majority of patients (85%) with diabetes due to ABCC8 gene mutations could be successfully treated with oral sulfonylureas. A substitution c.2473C>T in the ABCC8 gene results in R825W change in the nucleotide-binding domain 1 of SUR1 and in activation of the KATP channel. We report a case of MODY with an activating mutation of ABCC8 gene (R825W). Clinical Case: A 23-year old woman with a history of ventricular septal defect was diagnosed with diabetes mellitus after she presented with a 2-month history of polyuria and polydipsia. At the time of diagnosis, random serum glucose level was 242 mg/dL, Hemoglobin A1c 7.6%, and BMI was 18 kg/m2. There was absence of acanthosis nigricans on exam or a family history of diabetes, although paternal medical history was unknown. A history of low birth weight was reported, but no developmental delays, neonatal diabetes or history of hypoglycemia. A history of seizure during childhood was also noted but was not associated with hypoglycemia. Additional work-up revealed absence of glutamic acid decarboxylase, islet cell, and insulin autoantibodies. C-peptide level was 2.0 ng/mL with blood glucose 113 mg/dL. The patient did not experience microvascular complications of diabetes. Genetic testing was negative for known mutations in HNF1A, HNF1B, HNF4A, GCK, and PPX1 genes. The patient was initially treated with metformin, but never achieved adequate glycemic control and experienced side effects. She was subsequently treated with sitagliptin and ertugliflozin, however, glycemic control remained inadequate (HbA1C 8.1%). At the age of 33 she was referred for clinical exome sequencing. This detected heterozygous ABCC8 variant c.2473 C>T; p.(R825W). Glucose control improved once therapy was switched to glipizide, resulting in the most recent HbA1C of 6.0%. Conclusion: Activating mutations of ABCC8 gene are infrequent genetic causes of diabetes in adults. Sequencing of the ABCC8 gene should be considered in select adult patients, as diagnosis can guide management decisions. Presentation: Saturday, June 17, 2023

Case of neonatal diabetes mellitus due to KCNJ11 mutation: Therapeutic implications of a genetic diagnosis

Abstract BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare condition occurring in approximately 1 in 90,000 live births. CASE REPORT: We describe a 2.5-month-old infant with neonatal diabetes who presented with diabetic ketoacidosis due to a mutation affecting the KCNJ11 gene, which encodes the Kir6.2 subunit of the ATP-sensitive potassium channel in pancreatic beta cells. CONCLUSION: Availing a genetic diagnosis has crucial therapeutic implications in the initiation of oral sulfonylureas in KCNJ11 and ABCC8 mutations as against the continued use of subcutaneous insulin in some other causes of neonatal diabetes.

The Role of Platelets in Hypoglycemia-Induced Cardiovascular Disease: A Review of the Literature.

Cardiovascular diseases (CVDs) are the leading cause of death globally as well as the leading cause of mortality and morbidity in type 2 diabetes (T2D) patients. Results from large interventional studies have suggested hyperglycemia and poor glycemic control to be largely responsible for the development of CVDs. However, the association between hypoglycemia and cardiovascular events is also a key pathophysiological factor in the development of CVDs. Hypoglycemia is especially prevalent in T2D patients treated with oral sulfonylurea agents or exogenous insulin, increasing the susceptibility of this population to cardiovascular events. The adverse cardiovascular risk of hypoglycemia can persist even after the blood glucose levels have been normalized. Hypoglycemia may lead to vascular disease through mechanisms such as enhanced coagulation, oxidative stress, vascular inflammation, endothelial dysfunction, and platelet activation. In the following review, we summarize the evidence for the role of hypoglycemia in platelet activation and the subsequent effects this may have on the development of CVD. In addition, we review current evidence for the effectiveness of therapies in reducing the risk of CVDs.

Insulin Docking Within the Open Hemichannel of Connexin 43 May Reduce Risk of Amyotrophic Lateral Sclerosis.

Type 2 diabetes (T2D), characterized by hyperinsulinemia, protects motor neurons against amyotrophic lateral sclerosis (ALS). Type 1 diabetes and a total lack of insulin are associated with increased risk of ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open pore via which toxic substances from the astrocytes reach motor neurons. In the current study, we performed molecular docking of insulin with monomeric Cx31, monomeric Cx43, and hexameric Cx31 to assess whether insulin might affect the pore. Hexameric Cx31 and hexameric Cx43 are transmembrane hemichannels composed of 6 subunits; they bind together to form gap junction intercellular channels. We used the program AutoDock Vina Extended for the molecular docking study. Cx31 shares amino acid and structural similarity to Cx43, and insulin docks to the same position at the N-terminal domain of monomeric Cx31 and monomeric Cx43. Insulin docks within the open hemichannel of hexameric Cx31, potentially blocking it. Molecular dynamics simulation shows that the block is highly stable and may be responsible for the protective effect of T2D on ALS. Insulin, especially intranasal insulin, might be a treatment for ALS. An insulin secretogogue such as oral sulfonylurea or meglitinide might also be of value.

Clinical Characteristics and Gene Mutations of Two Families with MODY 3 in Inner Mongolia.

This study aimed to analyze the clinical characteristics and gene mutations of two families with maturity-onset diabetes of the young 3 (MODY 3) in Inner Mongolia. Fifty-three patients in Inner Mongolia suspected of having MODY 3 were enrolled in this study according to clinical manifestations. Blood samples were collected, and all exons of the HNF1α gene were analyzed; the second-generation DNA of the splicing regions of the gene was determined by direct sequencing. In Family 1, the proband, mother, and uncle all carried the missense heterozygous mutation on exon 2 of the HNF1α gene (c.512G>A, p.Arg171Gln), and both the proband and uncle had MODY 3. In Family 2, the proband, grandfather, father, uncle I, and uncle II all carried a missense mutation on exon 2 (c.391C>t, p.Arg131Trp), and all had MODY 3. The blood glucose control in these patients was stable while they were being treated with oral sulfonylurea hypoglycemic drugs alone or with insulin. Uncle II had serious macrovascular and microvascular complications. Maturity-onset diabetes of the young 3 gene mutations (c.512G>A, p.Arg171Gln) and (c.391C>T, p.Arg131Trp) may be the main pathogenic genes of the two families with MODY 3. The two gene mutations found in this study have not been reported previously in China.

Concurrent Use of Oral Anticoagulants and Sulfonylureas in Individuals With Type 2 Diabetes and Risk of Hypoglycemia: A UK Population-Based Cohort Study.

ObjectiveTo investigate the association of concurrent use of oral anticoagulants (OACs) and sulfonylureas and the risk of hypoglycemia in individuals with type 2 diabetes mellitus (T2DM).Research Design and MethodsA retrospective cohort study was conducted between 2001 and 2017 using electronic primary healthcare data from the IQVIA Medical Research Data (IMRD) that incorporates data supplied by The Health Improvement Network (THIN), a propriety database of Cegedim SA. Individuals with T2DM who received OAC prescription and sulfonylureas were included. We compared the risk of hypoglycemia with sulfonylureas and OACs using propensity score matching and Cox regression.Results109,040 individuals using warfarin and sulfonylureas and 77,296 using direct oral anticoagulants (DOACs) and sulfonylureas were identified and included. There were 285 hypoglycemia events in the warfarin with sulfonylureas group (incidence rate = 17.8 per 1,000 person-years), while in the sulfonylureas only, 304 hypoglycemia events were observed (incidence rate = 14.4 per 1,000 person-years). There were 14 hypoglycemic events in the DOACs with sulfonylureas group (incidence rates = 14.8 per 1,000 person-years), while in the sulfonylureas alone group, 60 hypoglycemia events were observed (incidence rate =23.7 per 1,000 person-years). Concurrent use of warfarin and sulfonylureas was associated with increased risk of hypoglycemia compared with sulfonylureas alone (HR 1.38; 95% CI 1.10–1.75). However, we found no evidence of an association between concurrent use of DOACs and sulfonylureas and risk of hypoglycemia (HR 0.54; 95% CI, 0.27–1.10) when compared with sulfonylureas only.ConclusionsWe provide real-world evidence of possible drug-drug interactions between warfarin and sulfonylureas. The decision to prescribe warfarin with coexistent sulfonylureas to individuals with T2DM should be carefully evaluated in the context of other risk factors of hypoglycemia, and availability of alternative medications.

NARRATIVE REVIEW: COST-EFFECTIVENESS ANALYSIS OF THE USE OF ORAL ANTIDIABETIC DRUGS BIGUANIDE AND SULFONYLUREA GROUP IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Diabetes Mellitus requires long-term management at a considerable cost. Therefore, a cost-Effectiveness analysis was used to assess several health interventions. Biguanide and Sulfonylurea provided the best results at the cheapest cost in this study. This study aims to gain a supporting theoretical foundation regarding the cost-effectiveness of using oral antidiabetic drugs biguanide and sulfonylureas in patients with type 2 diabetes mellitus. The method used in this study is a Narrative Review using literature that discusses the cost-effectiveness of oral antidiabetic drugs biguanide and sulfonylureas in patients with type 2 diabetes mellitus. Based on the results of this study, the age range of the occurrence of Type 2 Diabetes Mellitus is 45-65 years, with more percentage of male patients than women and a common complication is hypertension. In this study, the use of the biguanide drug (Metformin) was shown to provide a significant reduction in blood sugar levels at a reasonably low cost. The ICER results showed that combination drugs increased additional costs, but their use was more effective in healing and improving patients' quality of life. In conclusion to this study, the use of biguanide and sulfonylurea groups proved cost-effective compared to other antidiabetic drugs.

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

Design and Evaluation of Gastro-retentive Drug Delivery System for Glimepiride using Design of Experiment

Glimepiride, oral sulfonyl urea, BCS class-II drug is used to treat diabetes (type-II). Due to its low solubility, it is an ideal candidate for solubility enhancement, leading to better bioavailability and subsequent dose. In the present study, the solid dispersion technique was used to improve the solubility using solvent evaporation method. The solid dispersions were prepared using affnisol 912 as a solubility enhancer. The prepared solid dispersions were evaluated for solubility in 0.1N HCl pH 1.2 and phosphate buffer pH 7.8 medium. The solubility of glimepiride in optimized solid dispersion (SD1) formulation was 682.44 µg/mL compared to 6.88 µg/mL for pure drug in pH 7.8 medium. The solid dispersion (SD1) was further formulated into the tablets. The gastro-retentive and mucoadhesive properties were contributed to the tablets by HPMC K4M and Carbopol 940, respectively. Factorial design (Central composite design) was used to optimize the gastro-retentive tablets. The tablet formulations showed good mucoadhesive properties and drug release up to 12 hours in pH 1.2 with 0.5% SLS medium. The optimized formulation (F2) showed cumulative drug release up to 97.20 ± 0.99% in 12 hours. The drug release kinetics also showed that the drug is release by dissolution and diffusion from the drug matrix. The gastro-retention studies in rabbits also showed the tablets remain within the GIT up to 12 hours as confirmed by x-ray images.

Diagnosi precoce di diabete neonatale permanente conseguente a mutazione del gene KCNJ11

Neonatal diabetes mellitus (NDM) is a rare condition characterized by onset of persistent hyperglycaemia with-in the first six months of life. Heterozygous mutations in KCNJ11 gene account for about half of the cases of per-manent form of NDM and are associated with a wide range of neurocognitive disabilities. In suspected NDM, immediate molecular genetic testing is recommended because most of the cases due to mutations in KCNJ11 gene are responsive to oral sulfonylurea (SU) therapy with excellent glycaemic control at long term follow up. The present report describes a case of early detection of permanent NDM, due to KCNJ11 gene mutation, which has been successfully treated with SU oral therapy.

A Case of Transient Neonatal Diabetes Mellitus Attributable to a Nonspecific Mutation in the ABCC8 Gene

Neonatal diabetes mellitus (NDM) is defined as hyperglycemia that persists for more than 2 weeks and requires insulin therapy. NDM principally occurs before 6 months of age. Transient NDM (TNDM) is a clinical form of NDM that persists for a median of 12 weeks and resolves completely by 18 months. However, it may relapse as type 2 DM during early adulthood. The major causes of TNDM are mutations in chromosome 6q24 or the KCNJ11 or ABCC8 genes; the latter encode the two subunits of the pancreatic adenosine triphosphate (ATP)-sensitive potassium channel (KATP-channel). This condition responds well to oral sulfonylurea therapy. Herein, we report a neonate who was small for gestational age and exhibited TNDM symptoms. Genetic analysis revealed a nonspecific mutation in ABCC8; he was successfully treated with oral sulfonylurea.

Molecular Genetics, Clinical Characteristics, and Treatment Outcomes of KATP-Channel Neonatal Diabetes Mellitus in Vietnam National Children’s Hospital

BackgroundNeonatal diabetes mellitus (NDM) is defined as insulin-requiring persistent hyperglycemia occurring within the first 6 months of life, which can result from mutations in at least 25 different genes. Activating heterozygous mutations in genes encoding either of the subunits of the ATP-sensitive K+ channel (KATP channel; KCNJ11 or ABCC8) of the pancreatic beta cell are the most common cause of permanent NDM and the second most common cause of transient NDM. Patients with NDM caused by KATP channel mutations are sensitive to sulfonylurea (SU) treatment; therefore, their clinical management can be improved by replacing insulin with oral agents.Patients and MethodsSeventy patients were diagnosed with NDM between May 2008 and May 2021 at Vietnam National Children’s Hospital, and molecular genetic testing for all genes known to cause NDM was performed at the Exeter Genomic Laboratory, UK. Patients with ABCC8 or KCNJ11 mutations were transferred from insulin to oral SU. Clinical characteristics, molecular genetics, and annual data relating to glycemic control, SU dose, severe hypoglycemia, and side effects were collected. The main outcomes of interest were SU dose, SU failure (defined as permanent reintroduction of daily insulin), and glycemic control (HbA1c).ResultsFifty-four of 70 patients (77%) with NDM harbored a genetic mutation and of these; 27 (50%) had activating heterozygous mutations in ABCC8 or KCNJ11. A total of 21 pathogenic mutations were identified in the 27 patients, including 13 mutations in ABCC8 and 8 mutations in KCNJ11. Overall, 51% had low birth weight (below 3rd percentile), 23 (85%) were diagnosed before 3 months of age, and 23 (85%) presented with diabetic ketoacidosis. At diagnosis, clinical and biochemical findings (mean ± SD) were pH 7.16 ± 0.16; , 7.9 ± 7.4 mmol/L; BE, −17.9 ± 9.1 mmol/L; HbA1C, 7.98% ± 2.93%; blood glucose, 36.2 ± 12.3 mmol/L; and C-peptide median, 0.09 (range, 0–1.61 nmol/l). Twenty-six patients were successfully transferred from insulin to SU therapy. In the remaining case, remission of diabetes occurred prior to transfer. Glycemic control on SU treatment was better than on insulin treatment: HbA1c and blood glucose level decreased from 7.58% ± 4.63% and 19.04 ± 14.09 mmol/L when treated with insulin to 5.8 ± 0.94% and 6.87 ± 3.46 mmol/L when treated with SU, respectively.ConclusionsThis is the first case series of NDM patients with ABCC8/KCNJ11 mutations reported in Vietnam. SU is safe in the short term for these patients and more effective than insulin therapy, consistent with all studies to date. This is relevant for populations where access to and cost of insulin are problematic, reinforcing the importance of genetic testing for NDM.

The effect of insulin on post-exercise hypoglycemia in adults with type 2 diabetes participating in outpatient exercise-based cardiac rehabilitation.

Few studies have reported on self-monitored blood glucose changes following acute exercise, particularly in patients with type 2 diabetes prescribed oral sulfonylureas and insulin medication. This study sought to determine the magnitude of post-exercise blood glucose changes and incidence of hypoglycemia (blood glucose < 4.0mmol/L) in relation to medication regimen. A retrospective chart review was conducted in adults with type 2 diabetes attending a 6-month rehabilitation program. Demographics, medications, exercise prescription and patient-reported pre/post-BG values were collected at program initiation. It was hypothesized that patients with type 2 diabetes will experience a post-exercise capillary blood glucose reduction (ΔcapBG), and that incidents of hypoglycemia (< 4.0mmol/L) will be strongly associated with insulin or oral secretagogue class of medication. A chart review was conducted (n = 52, 46.2% males, mean age: 62.7 ± 8.3years, A1c: 7.7 ± 1.6%, body mass index, BMI: 34.4 ± 7.8kg/m2) in patients with type 2 diabetes (9.0 ± 7.7years since diagnosis). A greater reduction in BG was related to a greater pre-exercise BG (beta [95% CI]: -0.46 [-0.54, -0.37] mmol, p < 0.0001), independent of BMI and exercise duration. Post-exercise hypoglycemia (< 4.0mmol) was associated with prescribed insulin use (vs. non-users: 14.5% vs. 3.0%, p < 0.05). Among insulin users, pre-mixed insulin had the highest incidence of hypoglycemia (vs. non-users: 50% vs. 3%, p < 0.0001) and insulin (bolus and basal; vs. non-users: 11.1% vs. 3%, p = 0.04). These findings may suggest a low post-exercise hypoglycemia occurrence in patients with type 2 diabetes, except when taking insulin. Self-management strategies should be considered, especially for patients on insulin medications.

Development of Glimepiride Loaded Sustained Release Microparticles Using Tubular Microreactor

Background: Glimepiride is a third-generation, oral anti-diabetic sulfonylurea drug, generally recommended for the treatment of type–II diabetes. A biocompatible polymer, Eudragit RS 100 is widely used for the preparation of targeted and time-controlled release of drugs. Glimepiride is encapsulated using Eudragit RS 100 for sustained release delivery. Objective: To develop sustained release microparticles of Glimepiride using microreactor technology to reduce the dosing frequency. Method: Microreactor precipitation method was used to develop sustained release microparticles of Glimepiride. Plackett-Burman design was employed for the optimization of all the parameters including the inner diameter of silicon tubing, the flow rate of solvent as well as antisolvent, length of tubing and concentration of polymer, etc. Microparticles prepared were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, Scanning electron microscopy and in vitro drug release as well as release kinetics study. Results: Placket Burman design was found to be effective for comparing more than two parameters at a time and showed the effect of parameters on design. The parameters A, B, C, D, E and J synergistically affected the encapsulation efficiency. FE-SEM demonstrated the smooth and spherical nature of particles. Fourier transformed infrared spectroscopy showed the absence of chemical interaction between polymer and drug; X-ray diffraction results showed the decrease in crystallinity of pure drug when it was transformed into encapsulated drug-loaded microparticles. The sustained drug release was observed for 12 h. Conclusion: Prepared Glimepiride loaded sustained release microparticles followed the first-order release kinetics. The developed formulation could reduce dose frequency and improve patient compliance.

The Role of TCF7L2 in Type 2 Diabetes.

TCF7L2 is the most potent locus for type 2 diabetes (T2D) risk and the first locus to have been robustly reported by genomic linkage studies. TCF7L2 is a transcription factor that forms a basic part of the Wnt signaling pathway. This gene has highly conserved sequence regions that correspond to functional domains. The association of TCF7L2 with T2D is one of the most powerful genetically discovered in studies of complex diseases, as it has been consistently replicated in multiple populations with diverse genetic origins. The mechanisms over which TCF7L2 exerts its effect on T2D are still not well understood. In this article, we describe the main molecular mechanisms of how TCF7L2 is related to T2D. TCF7L2 variants associated with T2D risk exert an influence on the initial therapeutic success of the hypoglycemic oral agent sulfonylurea. Thus, it is important to know whether there are other TCF7L2 variants associated with T2D that can influence treatment with oral hypoglycemic agents. Resequencing of the TCF7L2 gene in diverse ethnic groups is required to reveal common and rare variations and their role in different pathologies and in adverse reactions to drugs. Identification of TCF7L2-susceptibility disease variants will permit, at a given moment, offering of therapies to patients according to their genotype.

Role of Octreotide in Sulfonylurea-Induced Hypoglycemia

Introduction: The most common adverse effect associated with sulfonylurea ingestion is hypoglycemia. Sulfonylureas have very narrow therapeutic indices with a prolonged half-life in End-Stage renal Disease (ESRD). As per literature review, insulin and oral sulfonylureas are responsible for 13.9% and 10.7% of emergency hospitalizations respectively. It is, however, not surprising that intentional or unintentional overdose with these agents can lead to prolonged hypoglycemia which can prove to be fatal. Case Report:76-year-old female presented to the Emergency Department (ED) with complaints of generalized weakness since the past three days. Her past medical history was significant for ESRD, Hypertension and Non-Insulin Dependent Diabetes Mellitus type II (home regimen of glipizide 10 mg daily). On physical exam, she was tachypneic and appeared lethargic. Her neurological exam was intact, and she was oriented to time, place and person. Her labs were significant for BUN of 77 mg/dL (5–20 mg/dL), Creatinine of 9.94 mg/dL (<1.3mg/dL) and blood glucose of 89 mg/dL (70-140mg/dL). Liver and thyroid function tests were normal. Computed Tomography scan of the head was unremarkable. In the ED, she received 5 mg of glipizide after which she became more confused and lethargic. Her blood glucose level was 21mg/dL thus she received seven pushes of intravenous (IV) dextrose (25g each), two doses of intramuscular glucagon (1mg each) and was started on a continuous infusion of dextrose (D10) at 75cc/hour. Her blood glucose levels continued to remain low with a repeat value of 34 mg/dL and her mental status continued to worsen. Labs checked at that time were significant for a C-Peptide level of 22.13ng/ml (1.00–4.00ng/ml) and an insulin level of 43.7uU/ml (<20uU/ml) suggesting it to be sulfonylurea toxicity. Sulfonylurea level could not be checked due to laboratory limitations. She was started on subcutaneous octreotide 30 mcgs every 6 hours as per endocrinology recommendations. Her blood glucose started to improve, and her mental status returned to baseline. Per oral food intake was resumed, she remained euglycemic and octreotide was discontinued. Conclusion: Octreotide is a synthetic octapeptide analogue of somatostatin which can effectively suppress insulin secretion. Glucose, on the other hand, would stimulate insulin release and cause rebound hypoglycemia. Boyle et al, showed that octreotide was superior to diazoxide and glucose in preventing sulfonylurea-induced hypoglycemia. Therefore, we as clinicians should be able to quickly recognize sulfonylurea toxicity as the cause of hypoglycemia and attempt to administer octreotide as soon as possible. This in turn would help decrease length of hospital stay and avoid the detrimental effects of hypoglycemia like seizures, coma and death especially in older individuals.