Therapeutics For Diabetes Mellitus Research Articles

Pharmacoinformatics approach for type 2 diabetes mellitus therapeutics using phytocompounds from Costus genus: an in-silico investigation

Type 2 Diabetes Mellitus (T2DM), as a significant health concern globally, particularly in India, underscoring the vital need for effective therapeutics. Current drug therapies for T2DM may have limitations, leading researchers to explore natural products as alternatives. In this study. We have investigated the anti-diabetic compounds from the Costus genus, known as the insulin plant, which is abundant in southern India. The bioinformatics tools and software used for in-silico analysis to identify potential therapeutic compounds and hub genes associated with T2DM in the Indian population that could cut short the in-vitro and in-vivo experimental approaches in near future. The systematic review and combinatorial in-silico analysis revealed IGF2BP2, INS and TCF as the key targets that are associated with T2DM. The compounds stigmasterol, cycloartenol, and diosgenone were explored to be potent among all the 38 phytocompounds from genus Costus with binding energies −8.48, −10.07, and −10.31 kcal/mol against IGF2BP2, INS and TCF. The molecular dynamics (MD) simulation studies of these complexes demonstrated stable and consistent dynamic behavior, particularly in the INS-cycloartenol, IGF2BP2-stigmasterol and TCF7L2-diosgenone complexes. The identified compounds and associated targets represent potential candidates for T2DM therapeutics in the Indian population. The pharmacoinformatics approach presented in the study could streamline the drug discovery process by prioritizing compounds for further experimental validation. Communicated by Ramaswamy H. Sarma

Conjugation of insulin-mimetic [meso-tetrakis(4-sulfonatophenyl)porphyrinato]zinc(II) with chitosan in aqueous solution: kinetics, equilibrium and thermodynamics

Conjugation of insulin-mimetic [meso-tetrakis(4-sulfonatophenyl)porphyrinato]Zn(II), Zn(tpps), with chitosan was examined in aqueous solution at various contact time, Zn(tpps) concentrations and solution temperatures, respectively. The chitosan–Zn(tpps) conjugate was characterized by UV–Vis and Fourier transform infrared (FTIR) spectroscopic techniques. The electrostatic interaction between negatively charged sulfonate $$({\mathrm{SO}}_{3}^{-})$$ groups of Zn(tpps) and positively charged amino ( $${\mathrm{NH}}_{3}^{+}$$ ) groups of chitosan is responsible for the formation of chitosan–Zn(tpps) conjugate. Chitosan efficiently inhibits the demetallization and aggregation of Zn(tpps) in acidic aqueous solution. The conjugation kinetic data taken from various batch studies were examined by the pseudo-first-order, pseudo-second-order, Elovich kinetic, film diffusion and intra-particle diffusion models. The equilibrium conjugation isotherms were analyzed by Freundlich, Temkin and Langmuir isotherm models, respectively. The batch conjugation kinetic data were obeyed by the pseudo-second-order kinetic model rather than the pseudo-first-order and Elovich kinetic models. Equilibrium conjugation isotherms were explained well by the Langmuir isotherm model, and the highest extent of Zn(tpps) bound to chitosan was obtained to be 151.52 µmol/g at 45 °C. The activation energy (Ea: 10.21 kJ/mol), changes in Gibb’s free energy (∆G: –26.38 to –28.12 kJ/mol), enthalpy (∆H: 8.74 kJ/mol) and entropy (∆S: 115.94 J/mol K) suggest that the chitosan–Zn(tpps) conjugation is an endothermic spontaneous process. The in vitro release of Zn(tpps) from chitosan–Zn(tpps) conjugate was investigated in phosphate buffer solution (pH 7.4) at 37 °C. The kinetics of Zn(tpps) release followed the first-order kinetics with a rate constant 0.0025 h‒1. The chitosan–Zn(tpps) conjugate may be used as an oral therapeutics for diabetes mellitus.

Precision Medicine, Diabetes, and the U.S. Food and Drug Administration.

The U.S. Food and Drug Administration (FDA) has long sought to achieve the broader use of personalized medicine, which is better targeting of FDA-approved therapies through incorporating precise knowledge of a patient's underlying condition to therapies optimally chosen to match those needs. While some strides have been made in precision medicine-particularly in oncology and rare genetic diseases-most of the standard general medicine indications have yet to realize the benefits of precision-guided therapies. This includes those for diabetes mellitus (DM), both type 1 and type 2. Although the scientific and regulatory considerations needed to move to a more "precise" future of DM prevention and treatment differ between the two disease subsets, scientific advances in both must occur before the FDA can incorporate precision medicine into its oversight of DM drug development and approval. This article provides an overview of the regulatory expectations and challenges in realizing a future where the therapeutics for DM are informed by precise knowledge of a patient's genetics and specific phenotype.

Structure Activity Relationship Studies of Gymnemic Acid Analogues for Antidiabetic Activity Targeting PPARγ.

Diabetes accounts for high mortality rate worldwide affecting million of lives annually. Global prevalence of diabetes and its rising frequency makes it a key area of research in drug discovery programs. The research article describes the development of quantitative structure activity relationship model against PPARγ, a promising drug target for diabetes. Multiple linear regression approach was adopted for statistical model development and the QSAR relationship suggested the regression coefficient (r2) of 0.84 and the cross validation coefficient (rCV2) of 0.77. Further, the study suggested that chemical descriptors viz., dipole moment, electron affinity, dielectric energy, secondary amine group count and LogP correlated well with the activity. The docking studies showed that most active gymnemic acid analogues viz., gymnemasin D and gymnemic acid VII possess higher binding affinity to PPARγ. QSAR and ADMET studies based other predicted active gymnemc acid analogues were gymnemic acid I, gymnemic acid II, gymnemic acid III, gymnemic acid VIII, gymnemic acid X, gymnemic acid XII, gymnemic acid XIV, gymnemic acid XVIII and gymnemoside W2. Predicted activity results of three query compounds were found comparable to experimental in vivo data. Oral bioavailability of these active analogues is still a limiting factor and therefore further lead optimization required. Also, such study would be of great help in active pharmacophore discovery and lead optimization, and offering new insights into therapeutics for diabetes mellitus.

Antidiabetic Effects of Omega-3 Polyunsaturated Fatty Acids: From Mechanism to Therapeutic Possibilities

Diabetes mellitus (DM) is chronic disease characterized by hyperglycemia and insulin resistance caused by dysfunction of pancreatic β cells. Over the past few decades, epidemiological studies have suggested that dietary long-chain polyunsaturated fatty acids such as docosahexaenoic acid and eicosapentaenoic acid decrease the risk of metabolic diseases including DM. The mechanisms underlying the therapeutic efficacy of dietary long-chain polyunsaturated fatty acids in treating DM have been partly revealed. In this review, the authors describe the antidiabetic effects of long-chain polyunsaturated fatty acids and also discuss their possibilities as therapeutics for DM in the light of recent findings.

Effect of two herbal polyphenol compounds on human amylin amyloid formation and destabilization

Human Islet amyloid polypeptide gathering in the β-cell of the pancreas has been implicated in the pathology of type 2 diabetes. Inhibition of the formation of amylin fibrils could be therapeutic aims for the treatment of type 2 diabetes mellitus. In this study, the fluorimetric assay was used to examine the role of two herbal polyphenol compounds including Rosmarinic acid and Curcumin on amyloid formation and destabilization of human amylin amyloid under near-physiological circumstances. The results showed that after 192 h incubation by shaker incubator at 37°C, Rosmarinic acid at 10 and 40 µM repressed amylin amyloid formation by 18.6 and 19.3% respectively (P<0.05), and the similar values of Curcumin inhibited the formation of β-sheet structure by 17.2 and 29.9%, respectively (P<0.05). The obtained data also confirmed that amyloidal sheet opening was induced by Rosmarinic acid and Curcumin significantly (P<0.05). It was concluded that islet amyloid cytotoxicity to β-cells may be reduced by these two herbal extracts and these compounds should be key molecules for the development of the therapeutics for diabetes mellitus. Key words: Amylin, diabetes, rosmarinic acid, curcumin, amyloid.

Therapeutic perspectives of adipocytokines

Various adipocyte-secreted factors have been described which profoundly affect insulin sensitivity and might potentially link obesity, insulin resistance and cardiovascular disease. Among those, adiponectin, visfatin and omentin appear as insulin-sensitising adipocytokines, whereas TNF-α, IL-6 and resistin induce insulin resistance. Moreover, leptin is a fat-derived key regulator of appetite and energy expenditure. Due to their profound effect on whole-body glucose and energy metabolism, adipocytokines have attracted interest as potential new therapeutics for diabetes mellitus and obesity. The current knowledge on function, regulation and therapeutic potential of various adipocytokines, as well as their clinical implications, are discussed in this review.

Anti-inflammatory and anti-nociceptive effects of the extract from Kalopanax pictus, Pueraria thunbergiana and Rhus verniciflua

The combined extracts obtained from three Chinese herb medicine, Kalopanax pictus, Pueraria thunbergiana and Rhus verniciflua, have been used as therapeutics for diabetes mellitus in Korea. In the present study, we have investigated their possible anti-inflammatory effects by comparing the potency of individual extracts with that of the combined extracts. An individual water extract prepared from Kalopanax pictus, Pueraria thunbergiana, and Rhus verniciflua was named K-1, P-1, and R-1, respectively. Simultaneously, we also prepared the combined extracts from above three plant materials by identical methods and named KPR-1. These four extracts were further fractionated into the EtOAc extracts, and these were designated as K-2, P-2, R-2, and KPR-2, respectively. These eight samples were subjected to the nitrite assays in LPS-induced macrophage 264.7 cells. KPR-2 exhibited the most pronounced effect on the inhibition of NO production among all the extracts. KPR-2 also significantly decreased PGE 2, and TNF-α release. In addition, KPR-2 showed in vivo anti-inflammatory activity against acute paw edema induced by carrageenan in rats. When analgesic activity was measured by the acetic acid-induced abdominal constriction and hot plate test, KPR-2 showed a dose-dependent inhibition in animal models. These results suggested that the mixture extract and successive fractionation could lead to the better use of anti-inflammatory medicinal crude drugs.