Type 2 Diabetes Mellitus Drugs Research Articles

Effects of lipid-lowering agents on plasma lipid profile and apolipoprotein B in patients with type 2 diabetes mellitus

Objectives: Type 2 Diabetes Mellitus (T2DM) accounts for about 90% of all cases of Diabetes Mellitus. Dyslipidaemia has been demonstrated to form a synergy with T2DM as risk factors for cardiovascular events. This study aimed to determine the plasma levels of Lipids and Apolipoprotein B-100 among Type 2 Diabetic patients, assess the effects of Lipid Lowering agents, and to study the relationship, if any, between these lipid parameters and glycemic control.Methods: One hundred and fifty participants consisting of fifty T2DM patients on a lipid-lowering agent, fifty newly diagnosed T2DM patients who are drug naïve (not on any anti-diabetic agent) and fifty apparently healthy non-diabetic controls were recruited for this study. Fasting blood samples were collected from all study participants for determination of Total Cholesterol (TC), LDL-C, Triglycerides(TG), High-Density Lipoprotein (HDL-C) and Apo B-100.
 Results: The results showed significant increases in plasma TC, LDL-C, TG and Apo B-100 with a remarkable reduction in plasma HDL-C level in the Type 2 Diabetic drug naïve group compared with the treatment and control groups. There was a significant positive correlation observed between serum Apo B-100 and level of glycaemia in the T2DM drug naïve group.Conclusion: This study further confirms the therapeutic benefits of lipid-lowering agents in reducing Apo B-100 among T2DM patients. Furthermore, maintaining good glycaemic control reduces the risk for the development of dyslipidaemia.
 Keywords: T2DM, Dyslipidaemia, Cardiovascular Diseases, Apolipoprotein B-100, Nigeria.

S1P Signaling Pathways in Pathogenesis of Type 2 Diabetes.

The pathogenesis of type 2 diabetes mellitus (T2DM) is very complicated. The currently well-accepted etiology is the “Ominous Octet” theory proposed by Professor Defronzo. Since presently used drugs for T2DM have limitations and harmful side effects, studies regarding alternative treatments are being conducted. Analyzing the pharmacological mechanism of biomolecules in view of pathogenesis is an effective way to assess new drugs. Sphingosine 1 phosphate (S1P), an endogenous lipid substance in the human body, has attracted increasing attention in the T2DM research field. This article reviews recent study updates of S1P, summarizing its effects on T2DM with respect to pathogenesis, promoting β cell proliferation and inhibiting apoptosis, reducing insulin resistance, protecting the liver and pancreas from lipotoxic damage, improving intestinal incretin effects, lowering basal glucagon levels, etc. With increasing research, S1P may help treat and prevent T2DM in the future.

Potential type 2 diabetes mellitus drug HMPA promotes short‐chain fatty acid production by improving carbon catabolite repression effect of gut microbiota

Gut microbiota plays an important role in type 2 diabetes mellitus (T2DM) progression. From our previous work N-(4-Hydroxyphenethyl)-3-mercapto-2-methylpropanamide (HMPA) is a potential T2DM drug. We evaluated the effect of HMPA on gut microbiota and studied the molecular mechanism underlying HMPA's regulation of gut microbiota. The pseudo germ-free (PGF) T2DM model and faecal microbiota transplantation method were used to study whether gut microbiota mediates the actions of HMPA. The composition of gut microbiota was detected by using 16S rRNA sequence. Short-chain fatty acids (SCFAs) content was detected by gas chromatography. The HMPA probe was synthesised for finding and identifying the target protein of HMPA. The effect of HMPA on the utilisation of carbon sources in Bifidobacterium was evaluated. HMPA has a slight effect on the PGF T2DM model. The gut microbiota changed by HMPA can also alleviate the symptoms of T2DM. HMPA can regulate gut microbiota structure, increase SCFAs production and reduce nitrate content in the intestinal tissues. The thickness of the mucus on colon tissues increases after HMPA treatment. The target protein of HMPA in gut microbiota is the nitrogen metabolism global transcriptional regulator (GlnR). HMPA promotes the utilisation of less preferred carbon source in the gut microbiota and increases the fermentation product of SCFAs. HMPA plays a hypoglycaemic role through the gut microbiota. HMPA improves the carbon catabolite repression effect of gut microbiota and increases SCFAs production by targeting GlnR. GlnR may be a target for gut microbiota regulation.

Repurposing GLP-1 Receptor Agonists for Parkinson's Disease: Current Evidence and Future Opportunities.

The global burden of chronic disorders such as Parkinson's disease (PD) has rapidly increased over recent decades. Despite an increasing understanding of PD pathophysiology, there are no effective therapies capable of stopping or slowing the progression of this neurological condition. It has been suggested that type 2 diabetes mellitus (T2DM) may be a risk factor for PD and comorbid T2DM may worsen PD symptoms, as well as accelerate neurodegeneration. In fact, the similar pathological mechanisms shared by PD and T2DM have inspired several studies on the therapeutic potential of T2DM drugs against PD, among which glucagon-like peptide-1 receptor (GLP-1R) agonists are promising candidates. Here, we highlight the mechanisms linking T2DM and PD, as well as the links between insulin resistance (IR) and PD patients' risk of developing cognitive deficits. We also briefly review the effects of GLP-1R agonists on PD and discuss how the successful use of these substances in preclinical models of PD has paved the way for PD clinical trials. We further discuss how recent evidence on the beneficial effects of dulaglutide on cognitive function of T2DM patients may have important implications for PD drug repurposing.

Role of gut microbiome in regulating the effectiveness of metformin in reducing colorectal cancer in type 2 diabetes.

The prevalence of colorectal cancer (CRC) and type 2 diabetes mellitus (T2DM) is increasing globally. It is rarely noticed that the incidence of CRC is higher in patients with T2DM. What needs to be mentioned is that metformin, a commonly used clinical drug for T2DM, attracts scholars’ attention because of its benefits in lowering the risk of developing CRC. Hence, we try to find the common grounds of initiation of T2DM and CRC and the reason why metformin reduces the risk of CRC in patients with T2DM. We noticed consistent changes of gut microbiota, such as elevated Bacteroides, Prevotella and Bifidobacterium and depressed Firmicutes and Lactobacillus. Furthermore, many studies in recent years have proved that the efficacy of metformin, such as improving blood glucose, depends on the gut microbiota. Coincidentally, the progression of CRC is inseparable from the contributions of gut microbiota. Therefore, we first proposed the concept of the metformin-gut microbiota–CRC (in T2DM) axis to explain the effect of metformin in reducing CRC in patients with T2DM. In this review, we elaborated the new concept and its potential clinical application value.

Abstract PR16: All-cause and cause-specific mortality among Medicaid-insured women with preexisting type 2 diabetes diagnosed with breast cancer: A cancer registry-Medicaid linkage

Abstract Background: Previous studies have reported that women with type 2 diabetes mellitus (T2DM) diagnosed with breast cancer have greater overall morality compared to nondiabetic breast cancer patients, while limited knowledge exists on cause-specific mortality. Among the nonelderly U.S. population, Medicaid-insured individuals have higher breast cancer mortality and elevated risk of T2DM-related complications compared to other insurance types. However, the role of preexisting T2DM on mortality among Medicaid-insured women diagnosed with breast cancer remains unknown. We investigated the influence preexisting T2DM and antidiabetic drugs have on all-cause and cause-specific mortality among Medicaid-insured women diagnosed with breast cancer. Methods: Data for 9,221 women aged <64 years who were diagnosed with breast cancer and reported to the New York State (NYS) Cancer Registry from 2004-2016 were linked with Medicaid claims data. Preexisting T2DM was determined by three diagnosis claims for T2DM with at least one claim prior to breast cancer diagnosis and a prescription claim for an antidiabetic drug within three months following breast cancer diagnosis. Estimated menopausal status was determined by age (premenopausal age <50; postmenopausal age ≥50). Hazard ratios (HR) and 95% confidence intervals (95%CI) were calculated with Cox proportional hazards regression, adjusting for potential confounders. Results: Women with preexisting T2DM had greater all-cause (HR=1.42; 95%CI 1.22, 1.65), cancer-specific (HR=1.26; 95%CI 1.06, 1.50), and cardiovascular-specific (HR=2.45; 95%CI 1.54, 3.89) mortality hazard compared to nondiabetic women. In subgroup analyses, the association between T2DM and all-cause mortality was observed among non-Hispanic White (HR 1.80 95%CI 1.39, 2.32), postmenopausal (HR=1.49; 95%CI 1.24, 1.79) women, but not among other race/ethnicity groups or premenopausal women. Additionally, compared to women prescribed metformin, all-cause mortality hazard was elevated among women prescribed sulfonylurea (HR=1.44; 95%CI 1.07, 1.94) or insulin (HR=1.54; 95%CI 1.12, 2.11). Conclusion: Among Medicaid-insured women with breast cancer, those with preexisting T2DM have an increased mortality hazard, especially when prescribed sulfonylurea or insulin. Further research is warranted to determine the optimal course of treatment for women with preexisting T2DM diagnosed with breast cancer. Citation Format: Wayne R. Lawrence, Akiko S. Hosler, Margaret Gates Kuliszewski, Matthew C. Leinung, Wangjian Zhang, Francis P. Boscoe. All-cause and cause-specific mortality among Medicaid-insured women with preexisting type 2 diabetes diagnosed with breast cancer: A cancer registry-Medicaid linkage [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PR16.

Imeglimin: Current Development and Future Potential in Type 2 Diabetes.

Imeglimin is the first of the "glimins," a new class of drugs developed for the treatment of type 2 diabetes mellitus (T2DM). This review highlights its mechanism of action and its context in the field of T2DM treatment. Preclinical data in multiple rodent models have detailed significant effects on mitochondria, particularly improved mitochondrial bioenergetics. This includes changes favoring complex II and complex III metabolism, a mechanism potentially promoting increased fatty acid oxidation, leading to the decrease in hepatic lipid accumulation observed in these mice. Imeglimin was also shown to increase muscle glucose uptake and decrease hepatic glucose production, both in vitro and in vivo. Though studies have also shown imeglimin to significantly improve insulin secretion and decrease β-cell death, whether its physiologic effects are purely insulin dependent remains unclear. Early preclinical studies have shown evidence for improvements in cardiac and renal function in rats with metabolic syndrome, effects not conferred by most currently available T2DM drugs. Clinical studies of imeglimin in humans have shown increased insulin secretion, along with decreased fasting plasma glucose and glycated hemoglobin. Its observed efficacy was comparable to that of currently available agents metformin and sitagliptin and was increased when given in combination with either agent. When considered alongside its benign safety profile reported in patients with chronic kidney disease, imeglimin shows true promise to provide a novel mechanism for T2DM treatment, with potential application in a larger, more comprehensive patient population.

Quality-of-Life Comparison of Dapagliflozin Versus Dipeptidyl Peptidase4 Inhibitors in Patients with Type2 Diabetes Mellitus: A Randomized Controlled Trial (J-BOND Study).

IntroductionNo study has compared the effects of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP4is) on patients’ quality-of-life (QOL).MethodsWe enrolled 253 drug-naïve Japanese patients with type 2 diabetes mellitus (T2DM), randomly assigned them into a dapagliflozin (SGLT2i) group or DPP4i group in approximately 1:1 ratio, and monitored them for 24 weeks. The primary endpoint was the proportion of subjects indicating improvement in the “overall quality of life” domain of SHIELD-WQ-9 at week 24. Secondary endpoints included other domains of SHIELD-WQ-9, DTR-QOL, EQ-5D-5L, medication preference, medication adherence, diet therapy adherence, body weight, body mass index (BMI), abdominal circumference, HbA1c, and frequency of adverse events.ResultsThe proportion of subjects indicating improvement in the “overall quality of life” domain of SHIELD-WQ-9 at week 24 was higher in the dapagliflozin group (28.4%) than in the DPP4i group (18.6%) (p = 0.08). The proportion of subjects indicating improvement in the “physical health” domain of SHIELD-WQ-9 at week 24 was significantly higher in the dapagliflozin group (42.2%) than in the DPP4i group (23.7%) (p = 0.004). Total scores and domain 1 scores of DTR-QOL showed greater improvement in the dapagliflozin group (14.3 ± 15.6 and 15.5 ± 20.8, respectively) than in the DPP4i group (10.2 ± 15.6 and 10.3 ± 19.5, respectively) (both p = 0.05). EQ-5D-5L scores had significantly improved in the DPP4i group (0.023 ± 0.088) (p = 0.005); the intergroup difference was not significant (p = 0.14). Body weight (p < 0.001), BMI (p < 0.001), and abdominal circumference (p = 0.019) had significantly decreased in the dapagliflozin group compared with the corresponding values in the DPP4i group.ConclusionDapagliflozin showed a comparable or more favorable benefit on Japanese patients’ QOL compared with DPP4is. Dapagliflozin was well tolerated. It significantly reduced body weight, which was significantly correlated with improvement in the patients’ QOL. This study demonstrates that dapagliflozin can be used as a first-line drug for T2DM in Japan with a beneficial impact on patients’ QOL.Trial RegistrationUniversity Hospital Medical Information Network Clinical Trial Registry (UMIN000030514); Japan Registry of Clinical Trials (jRCTs051180165).Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-020-00941-8) contains supplementary material, which is available to authorized users.

144-OR: The Antirheumatic Drug Auranofin Improves the Metabolic Phenotype of Obesity

Obesity is associated with chronic low-grade inflammation, reflecting significant alterations in the composition of immune cell populations that reside in white adipose tissue (WAT). The ensuing pro-inflammatory environment likely impinges on the metabolic functions of adipocytes and may partially explain the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). We recently demonstrated ectopic expression of the microRNA miR-30a in the subcutaneous fat pad of diabetic mice coupled improved insulin sensitivity and increased energy expenditure with decreased ectopic fat deposition in the liver and reduced WAT inflammation. We subsequently pursued the notion that pharmacological inhibitors of inflammation that exhibit a gene expression profile similar to ectopic miR-30a expression in WAT should represent new drugs for insulin resistance and T2DM. To this end, we used the Broad Connectivity Map to analyze a library of small molecules that induce mRNA profiles similar to that of exogenous miR-30a expression in WAT. Through this process, we nominated the rheumatoid arthritis compound auranofin. Treatment of obese mice with auranofin improved insulin sensitivity and glucose tolerance. Auranofin treatment also normalized other obesity-associated abnormalities, including hepatic steatosis, serum insulin and leptin. Mechanistically, a combination of proteomics and immunophenotyping established auranofin likely exerts antidiabetic activities by opposing low-grade inflammation in WAT and ectopic liver fat accumulation. These studies reveal important metabolic properties of anti-inflammatory treatments that may be re-purposed as therapies for insulin resistance and T2DM. Disclosure A. Cox: None. P.M. Masschelin: None. N. Chernis: None. P. Saha: None. Z. Lian: None. J.B. Felix: None. K. Kim: None. H. Wu: None. S.M. Hartig: None. Funding American Diabetes Association (1-18-IBS-105 to S.M.H.); National Institutes of Health (R01DK114356)

Management of heart failure and type 2 diabetes mellitus: Maximizing complementary drug therapy.

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and occurs in ~25% of patients with heart failure (HF). Patients with co-morbid HF and T2DM are at elevated risk of adverse outcomes, making optimization of complementary drug therapies essential. While research is ongoing, recent advances in drug therapy, including the introduction of sacubitril/valsartan for HF with reduced ejection fraction and the finding of positive cardiovascular effects of glucose-lowering agents (particularly sodium-glucose co-transporter-2 [SGLT2] inhibitors) have the potential to transform pharmacologic management of co-morbid HF and T2DM. In this review, we provide a comprehensive overview of cardiovascular clinical trials of therapies for HF and diabetes mellitus to date and identify areas requiring further investigation. We also discuss the pathophysiologic overlap of the two diseases and explore the complementary therapeutic effects of HF and T2DM drugs, with a particular focus on sacubitril/valsartan and SGLT2 inhibitors.

Independent effects of 15 commonly prescribed drugs on all-cause mortality among US elderly patients with type 2 diabetes mellitus

ObjectiveMost patients with type 2 diabetes mellitus (T2DM) also have hypertension and hyperlipidemia. Consequently, they are taking medications for all three conditions concurrently and the effect of one drug could...

Docking-based virtual screening in search for natural PTP1B inhibitors in treating type-2 diabetes mellitus and obesity

Introduction: Growing incidence of type-2 diabetes mellitus (T2DM), together with obesity, shows the complexity and progressive nature of these metabolic disorders and alarms the necessity to explore new and alternative therapeutic pathways and drugs. Diabetes has also been proven to be a key cause of premature aging through different mechanisms. Understanding these mechanisms could lead us to manage diabetes more efficiently, thus curtailing its age-related complications. Insulin and leptin resistance are the most common pathophysiological link between T2DM and obesity. Protein tyrosine phosphatase 1B (PTP1B) is thought to interfere with glucose homeostasis and satiety through down-regulation of insulin and leptin signaling pathways. Thus, drugs that are potent to impede this enzyme should be effective in treating T2DM and obesity.&#x0D; Method: In line with that, our current study involved screening of potent PTP1B inhibitors from the Natural Product Discovery System (NADI) database using in silico virtual screening and in vitro PTP1B inhibition study. The compounds that showed promising interaction with PTP1B catalytic site were traced down to their plant of origin. Further, the extracts of the plants were tested in vitro for PTP1B inhibition activity.&#x0D; Results: Our results showed promising PTP1B inhibition activity of Pandanus amaryllifolius, Vitex negundo and Piper nigrum with 94.38%, 89.03% and 81.39% inhibition, respectively.&#x0D; Conclusion: Therefore, the compounds of these plants might be an attractive option to develop drugs for T2DM and obesity.

Impact of FDA-Required Cardiovascular Outcome Trials on Type 2 Diabetes Clinical Study Initiation From 2008 to 2017

Background:Since 2008, the US Food and Drug Administration (FDA) has required that drug manufacturers conduct postmarket cardiovascular outcomes trials (CVOTs) for approved type 2 diabetes mellitus (T2DM) drugs. The utility and impact of these studies in determining atherosclerotic cardiovascular risk was reviewed during an FDA Advisory Committee Meeting held on October 24, 2018. Drug manufacturers and patient advocates at this meeting contended that the FDA-required CVOT studies discouraged private sector investment into developing novel T2DM drugs. Here, we explore these contentions by reviewing private sector investment in T2DM drug development from 2000 through 2008, followed by a deductive analysis of how associated events—including the implementation of the CVOT requirement—may have precipitated any observed changes.Methods:We collected and analyzed industry-sponsored interventional trials for T2DM initiated between January 1, 2000, and December 31, 2017, and compared observed trends with those seen across all trials, specific diseases, and against patent filings of novel antidiabetic agents.Results:The analysis shows a marked decline in initiated T2DM clinical trials from 2008 through 2017. Possible influencing factors, including the 2008 financial crisis and a slow in the discovery of novel antidiabetic agents may have contributed, but could not fully account for this decline in T2DM studies.Conclusions:These observations are consistent with the statements made by industry representatives and patient advocates at the 2018 Advisory Committee meeting. As the FDA reconsiders postmarket requirements for T2DM products, these observations underscore the importance of considering more efficient postmarket study structures to assess cardiovascular safety beyond mandatory CVOTs.

Overview of Type 2 Diabetes Drugs on the Market

Type 2 Diabetes Mellitus (T2DM) is a systemic metabolic disorder with complex pathogenesis. In recent years, a variety of new T2DM drugs have emerged, such as sodium-dependent glucose transporters 2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. As traditional medicines, insulin also has developed kinds of formulations such as quick-acting or premixed insulin. In addition, new treatment schedules combining multiple drugs are also fully explored. The efficacy, the administration, the mechanism, the safety and the price of these drugs are all different, providing patients with multiple options. This paper reviews the main types of type 2 diabetes drugs on the market and describes the mechanism of action. The representative type 2 diabetes treatment drugs are listed, and the advantages and disadvantages of these representative drugs are preliminarily evaluated. This information is reviewed to help doctors with clinical medication.

Mechanism study on the abnormal accumulation and deposition of islet amyloid polypeptide by cold-spray ionization mass spectrometry.

The abnormal accumulation and deposition of islet amyloid polypeptide (IAPP) are important causes of type-2 diabetes mellitus (T2DM). The common anti-amyloid strategy employs inhibitors to prevent the formation of oligomers and the cytotoxicity caused by them, thus reducing the production of amyloid fibres. Therefore, the real characterization of the oligomers formed at the early stage of aggregation is crucial to understanding the structure of IAPP and the drug development of T2DM. For the first time, in this study, native cold-spray ionization mass spectrometry (CSI-MS) technology was employed to characterize the oligomers. It was found that CSI was more suitable for the determination of these unstable species compared to traditional ESI-MS. The ionic strengths, organic solvent and pH all had effects on the characterization of oligomers and the stability of protein conformation. The MS/MS experiments showed that odd-charge dimer ions were mainly composed of two monomer products. Moreover, a CSI-MS method for the rapid screening of IAPP-inhibitors was established and two of the most potential inhibitors (rutin and quercitrin) were screened from a series of flavonoids. Then, the structure-activity relationship and the mechanism between flavonoids and IAPP were studied. The results showed that 3-OH and sugar chains play a vital role and hydrogen bonds are the main binding force. We further confirmed that rutin and quercitrin could effectively inhibit the fibre formation of IAPP by fluorescence and TEM experiments. This study provides a new insight for analyzing the structure of IAPP and screening potential drugs for T2DM.

The Route from the Folded to the Amyloid State: Exploring the Potential Energy Surface of a Drug-Like Miniprotein.

The amyloid formation of the folded segment of a variant of Exenatide (a marketed drug for type‐2 diabetes mellitus) was studied by electronic circular dichroism (ECD) and NMR spectroscopy. We found that the optimum temperature for E5 protein amyloidosis coincides with body temperature and requires well below physiological salt concentration. Decomposition of the ECD spectra and its barycentric representation on the folded‐unfolded‐amyloid potential energy surface allowed us to monitor the full range of molecular transformation of amyloidogenesis. We identified points of no return (e.g.; T=37 °C, pH 4.1, c E5=250 μm, c NaCl=50 mm, t>4–6 h) that will inevitably gravitate into the amyloid state. The strong B‐type far ultraviolet (FUV)‐ECD spectra and an unexpectedly strong near ultraviolet (NUV)‐ECD signal (Θ ≈275–285 nm) indicate that the amyloid phase of E5 is built from monomers of quasi‐elongated backbone structure (φ≈−145°, ψ≈+145°) with strong interstrand Tyr↔Trp interaction. Misfolded intermediates and the buildup of “toxic” early‐stage oligomers leading to self‐association were identified and monitored as a function of time. Results indicate that the amyloid transition is triggered by subtle misfolding of the α‐helix, exposing aromatic and hydrophobic side chains that may provide the first centers for an intermolecular reorganization. These initial clusters provide the spatial closeness and sufficient time for a transition to the β‐structured amyloid nucleus, thus the process follows a nucleated growth mechanism.

A Review of Type 2 Diabetes Mellitus Predisposing Genes.

Scientists are considering the possibility of treating diabetes mellitus (DM) using a personalized approach in which various forms of the diseases will be treated based on the causal gene and its pathogenesis. To this end, scientists have identified mutations in certain genes as probable causes of Type 2 diabetes mellitus (T2DM) with diverse mechanisms. This review was aimed at articulating already identified T2DM genes with their mechanisms of action and phenotypic presentations for the awareness of all stakeholders. The Google search engine was used to retrieve relevant information on the subject from reliable academic databases such as PubMed, Medline, and Google Scholar, among others. At least seventy (70) genes are currently being suspected in the biogenesis of T2DM. However, mutations in, or variants of KCNJ11, PPARG, HNF1B and WFS1 genes, are the most suspected and reported in the pathogenesis of the disease. Mutations in these genes can cause disruption of insulin biosynthesis through the destruction of pancreatic beta cells, change of beta cell morphology, destruction of insulin receptors, among others. These cellular events may lead to insulin resistance and hyperglycemia and, along with environmental triggers such as obesity and overweight, culminate in T2DM. It was observed that each identified gene has its distinct mechanism by which it interacts with other genes and environmental factors to cause T2DM. Healthcare providers are advised to formulate T2DM drugs or treatment by targeting the causal genes along with their mechanisms.

LUTI: a double-function inhibitor isolated from naked flax seeds.

Acute glucose fluctuation during the postprandial period causes a risk for type 2 diabetes mellitus (T2DM). α-Glucosidase inhibitors have been approved as therapeutic agents for diabetes. In the present study, a protein with α-glucosidase inhibitory activity from Flax (Linum usitatissimum) seeds was isolated using a one-step purification with Q-Sepharose4B column, followed by Sephacryl S-200 size-exclusion chromatography. It was identified as a trypsin inhibitor, named L. usitatissimum trypsin inhibitor (LUTI). The half maximal inhibitory concentration (IC50) of LUTI was 113.92μM for α-glucosidase and 6.17μM for trypsin. Lineweaver-Burk kinetic experiment showed that the protein exhibited two distinct inhibitory modes, a competitive inhibitor type for α-glucosidase and a non-competitive type for trypsin. The interaction between LUTI and α-glucosidase was detected through gel filtration chromatography and dynamic light scattering. Increased glucose consumption and lactic acid production were also observed following LUTI treatment in Caco-2 and HepG2 cells. LUTI inhibits not only the activity of trypsin but also the activity of α-glucosidase. It is expected that LUTI will become an oral hypoglycemic polypeptide drug for T2DM.

Impact of FDA-Required Cardiovascular Outcome Trials on Type 2 Diabetes Clinical Study Initiation From 2008 to 2017.

Since 2008, the US Food and Drug Administration (FDA) has required that drug manufacturers conduct postmarket cardiovascular outcomes trials (CVOTs) for approved type 2 diabetes mellitus (T2DM) drugs. The utility and impact of these studies in determining atherosclerotic cardiovascular risk was reviewed during an FDA Advisory Committee Meeting held on October 24, 2018. Drug manufacturers and patient advocates at this meeting contended that the FDA-required CVOT studies discouraged private sector investment into developing novel T2DM drugs. Here, we explore these contentions by reviewing private sector investment in T2DM drug development from 2000 through 2008, followed by a deductive analysis of how associated events-including the implementation of the CVOT requirement-may have precipitated any observed changes. We collected and analyzed industry-sponsored interventional trials for T2DM initiated between January 1, 2000, and December 31, 2017, and compared observed trends with those seen across all trials, specific diseases, and against patent filings of novel antidiabetic agents. The analysis shows a marked decline in initiated T2DM clinical trials from 2008 through 2017. Possible influencing factors, including the 2008 financial crisis and a slow in the discovery of novel antidiabetic agents may have contributed, but could not fully account for this decline in T2DM studies. These observations are consistent with the statements made by industry representatives and patient advocates at the 2018 Advisory Committee meeting. As the FDA reconsiders postmarket requirements for T2DM products, these observations underscore the importance of considering more efficient postmarket study structures to assess cardiovascular safety beyond mandatory CVOTs.

SAT-141 Effect of Vildagliptin versus Glibenclamide on Glycemic Variability and Endothelial Function in Individuals with Type 2 Diabetes and Hypertension: A Randomized Controlled Trial

Introduction: Glycemic variability has been considered as an important factor in the development of cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM). High glycemic variability causes endothelial dysfunction and increased oxidative stress. Among the drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitors improve endothelial function and decrease glycemic variability. Objectives: To investigate the effects of vildagliptin, a DPP-4 inhibitor, compared with glibenclamide on the glycemic variability and endothelial function of patients with T2DM and hypertension (HT). Methods: Prospective, randomized, open, drug-controlled study. Fifty patients older than 35 years with T2DM and HT without CVD were randomized to receive vildagliptin (n=25) or glibenclamide (n=25), in addition to metformin in both groups. Laboratory tests and analysis of endothelial function were performed before and 12 weeks after treatment. Endothelial function, defined by the reactive hyperemia index (RHI), was analyzed by peripheral artery tonometry (endo-PAT2000). The glycemic variability was evaluated by capillary glycemia with intermittent monitoring device, 6 measures/day, for 3 days, before and after 12 weeks of treatment. The calculation of the standard deviation (SD) of the means of glycemia was used to evaluate the glycemic variability. Results: Glycemic variability decreased in the vildagliptin group, defined by median of SD: before 35.2 mg/dL (13.9 - 59.7) vs 30.7 mg/dL (16.1 - 64.3) after treatment (p=0.037) and did not change with glibenclamide, 37.6 (16.0 - 54.9) vs 37.5 mg/dL (16.5 - 80.03) (p=NS). Glycated hemoglobin was similar in both groups at baseline and decreased after 12 weeks, not significantly (8.3% ± 1.0 vs 8.0% ± 1.34, p=0.18 for vildagliptin, 7.9% ± 0.9 vs 7.5% ± 1.4, p=0.17 for glibenclamide). The fasting glycemia decreased in the vildagliptin (166 ± 38.7 mg/dL vs 147.5 ± 42.6 mg/dL, p=0.01) and glibenclamide groups (164 ± 43.5 mg/dL vs. 139 ± 54 mg/dL, p=0.01), with no difference between them. There were no changes in the RHI before and after treatment in both groups (2.34 ± 0.58 vs 2.24 ± 0.60, for vildagliptin, p=NS; 2.36 ± 0.51 vs 2.33 ± 0.49, p=NS for glibenclamide) and there was no difference between groups. There was no correlation between glycemic variability and RHI. Conclusions: Vildagliptin reduces glycemic variability, but has no action on endothelial function, evaluated by endo-PAT2000.