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Several aspects need to be explored in drug therapy for diabetes patients. Some specific glucose-reducing medicines are present, while other medicines are associated with unintentional changes in hyperglycemia. Diabetes is a developing epidemic that has caused significant socioeconomic problems in several countries throughout the world. Despite scientific discoveries, greater healthcare services, and higher literacy rates, the disease continues to plague many industries, particularly developing countries. The current trends show an increase in premature mortality, which threatens world prosperity. Experimental and technical improvements have been made in sulphonylureas, alpha-glucosidase inhibitors, biguanides, and thiazolidinediones, all of which are beneficial in lowering glucose levels. The latest drug research techniques have led to the development of novel therapeutic groups such as amylin analogs, incretin mimetics, GIP analogs, active peroxisome proliferator receptors, and dipeptidyl peptidase-4 inhibitors as targets for future diabetes therapy medications. Furthermore, drug development and detection for diabetes treatment have been revolutionized by identifying and investigating bioactive compounds from herbs. This chapter discusses vital fields of clinical diabetology regarding opportunities for stem cells and nanotechnology as next-generation therapies, with an emphasis on evolving developments and reviews why plant-derived products are reliably common for treating and managing diabetes.

Natural products embedded crown ethers were prepared by utilizing bioactive natural products including chrysin, tetrahydroisoquinoline (THIQ), and biochanin-A. The prepared crown ether scaffolds were evaluated and compared with their natural product precursors for insulin secretory activity on isolated mice islets and for their fluorescent properties. All the crown adducts were found more active as compared to their natural product precursors. Bischrysin 32-crown-10 (6d), THIQ 15-Crown-5 (6a) and chrysin 16-crown-5 (6c) showed mild, moderate and strong insulin secretory activity, respectively when compared with the standard drug tolbutamide (TB). Particularly crown derivative 6c showed strong activity (31.10 ng/islet/h) that is almost two (02) fold higher than that of standard drug TB (16.82 ng/islet/h). To the best of our knowledge crown ethers based antidiabetic study is being reported for the first time in literature through this work. Furthermore, fluorescence study showed the significant increase in absorption and emission maximum (hypsochromic effect) in crown structures when compared with their natural product precursors. Present optimistic results obtained from this study may be a guided template for developing new effective insulin secretory agents.

Background Diabetes is now a global problem and millions of people are suffering all over the world. Reports exist for the allopathic use of turmeric, black pepper, and date palm as an antidiabetic and antioxidant agent. Aim The current study was designed to assess the antihyperglycemic, antioxidants and antihyperlipidemic consequences of black pepper (BP), turmeric (T), ajwa pulp (AP), and ajwa seeds (AS) in alloxan-induced diabetic rats. Methodology Diabetes was induced by a single intraperitoneal injection of alloxan (150 mg/kg b.w) in rats. They were randomly divided into 11 groups of 18 male and 18 female rats each. Group-1 normal control, group-2 diabetic control, group-3 was administered with glibenclamide (10 mg/kg), group-4 was administered with aqueous extract of BP (50 mg/kg), group-5, 6, 7 were administered with T, AP and AS (500 mg/kg) and group-8, 9, 10, 11 were administered with different combinations of aqueous extract (500 mg/kg) once in a day for eight weeks. The antihyperglycemic potential was determined through biochemical and histological investigations of the experimental animals at the end of the experiment. Results The results of the study revealed that treatments improved glucose (229.53 mg/dL), Ghb (7.68%), insulin (13.63 U/L), Tg (95.92 mg/dL), Tc (152.86 mg/dL), HDL (23.22 mg/dL), LDL (110.30 mg/dL), TAC (1.89 mmol/L) and TOS (20.05 μmol/L) in comparison to diabetic control rats after 8 weeks of study period. Histological and immunohistochemical investigation of tissues exhibited severe changes in the pancreas of diabetic rats and treatments modulate these changes; this improvement in cells may explain the antidiabetic effects. Conclusion It is concluded that aqueous extract of BP+AS; and BP+T+AP+AS could be promising nutraceutical therapy for diabetes management and its associated complications.

Background: A good number of medicinal and dietary plants are used for diabetes treatment in Burkina Faso. Aim of the Study: The present study aimed to investigate the antidiabetic activity of Guiera senegalensis galls extracts and its potential mechanisms in streptozotocin-induced diabetic rats. Methodology: The methanol extract was administered by gavage to healthy Wistar rats for the determination of toxicity, to normal and diabetic Wistar rats for the determination of glucose reduction level, lipid profile, insulin level and glycaemic parameters in serum. The histology and immunohistochemistry of the pancreas were also determined. Results: The acute toxicity results showed that the medium lethal dose (LD50) of the methanol galls extract of Guiera senegalensis is greater than 2000 mg/kg body weight in rats. Guiera senegalensis methanolic extract (250 mg/kg) and the tolbutamide (100 mg/kg) recorded a significantly (p < 0.05) lower level of triglyceride compared to the diabetic group. The methanol extract (250 and 500 mg/kg pc) significantly (p < 0.05) decreased the blood glucose level and increased the serum insulin level in diabetic rats. Interestingly, improved ß-cell function and antioxidant status were also observed in G. senegalensis-treated diabetic rats when compared to tolbutamide-treated diabetic rats. Conclusion: These data showed direct evidence that G. senegalensis has antidiabetic activity by decreasing blood glucose level, improving insulin secretion and β-cell functions and modulating antioxidant status.

Tolbutamide is an oral anti-diabetic agent for the treatment of type 2 diabetic patients. Its lower absorption results in its inferior therapeutic efficacy. Nano-carrier systems have the subject of...

Teucrium yemense, a medicinal plant commonly grown in Saudi Arabia and Yemen, is traditionally used to treat infections, kidney diseases, rheumatism, and diabetes. Extraction of the dried aerial parts of the plant with methanol, followed by further extraction with butanol and chromatography, gave twenty novel neoclerodanes. Their structures, relative configurations and some conformations were determined by MS and 1-D and 2-D NMR techniques. Most were fairly conventional but one contained an unusual stable orthoester, one had its (C-16)–(C-13)–(C-14)–(C-15) (tetrahydro)furan unit present as a succinic anhydride and one had a rearranged carbon skeleton resulting from ring-contraction to give a central octahydroindene bicyclic core, rather than the usual decalin. Mechanisms are proposed for the biosynthetic formation of the orthoester and for the ring-contraction. Four novel neoclerodanes increased the glucose-triggered release of insulin from isolated murine pancreatic islets by more than the standard drug tolbutamide, showing that they are potential leads for the development of new anti-diabetic drugs.

Teucrium yemense, a medicinal plant commonly grown in Saudi Arabia and Yemen, is traditionally used to treat infections, kidney diseases, rheumatism, and diabetes. Extraction of the dried aerial parts of the plant with methanol, followed by further extraction with butanol and chromatography, gave twenty novel neoclerodanes. Their structures, relative configurations and some conformations were determined by MS and 1-D and 2-D NMR techniques. Most were fairly conventional but one contained an unusual stable orthoester, one had its (C-16)-(C-13)-(C-14)-(C-15) (tetrahydro)furan unit present as a succinic anhydride and one had a rearranged carbon skeleton resulting from ring-contraction to give a central octahydroindene bicyclic core, rather than the usual decalin. Mechanisms are proposed for the biosynthetic formation of the orthoester and for the ring-contraction. Four novel neoclerodanes increased the glucose-triggered release of insulin from isolated murine pancreatic islets by more than the standard drug tolbutamide, showing that they are potential leads for the development of new anti-diabetic drugs.

In the present study, we have estimated the binding affinities of nine flavonoids with cAMP sensing protein kinase A (PKA) by molecular docking. Furthermore, their potential roles in stimulating insulin secretion in a PKA-dependent manner were evaluated in isolated islets using H-89, a PKA inhibitor. Among selected flavonoids, i.e. eriodictyol, kaempferol, hesperetin, naringin, apigenin, hesperidin, quercetin, naringenin and rutin, we found that eriodictyol, kaempferol, and naringenin speculated the best binding interactions with crucial residues in PKA binding pocket. Glucose-dependent insulin secretion was inhibited by eriodictyol, kaempferol and naringenin of 92%, 87%, and 89%, respectively in isolated islets co-incubated with H-89. In contrast, quercetin also got binding with PKA; however, showed no significant PKA-dependent insulinotropic activity in vitro. Rutin showed the least docking interactions with PKA, reflects well in vitro by exhibiting a PKA-independent mode of action. Naringin, hesperetin, hesperidin, and apigenin showed favourable docking affinities with PKA but not with the hot spot residues. Although naringin and hesperetin mimic well in vitro by showing PKA-independent mode of action, hesperidin and apigenin were still exhibited the PKA-dependent effect. The present work suggests that few of the selected flavonoids have strong potential to be used as alternative insulin secretagogues in diabetic treatment.

Tambulin, a flavonol isolated from Zanthoxylum armatum, showed potent insulin secretory activity in our preliminary anti-diabetic screening. Here, we explored the insulin secretory mechanism(s) of tambulin focusing in glucose-dependent, KATP ‒ and Ca2+‒channels dependent, and cAMP-PKA pathways. Mice islets and MIN6 cells were incubated with tambulin in the presence of pharmacological agonists/antagonists and the secreted insulin was measured using mouse insulin ELISA kit. The intracellular cAMP was measured by an acetylation cAMP ELISA kit. Tambulin (200 μM) showed potent insulin secretory activity only at stimulatory glucose (11–25 mM) concentrations; however, no change in insulin release was observed at basal glucose both in mice islets and MIN6 cells. Notably, in the presence of diazoxide, a KATP channel opener; the incomplete inhibition of tambulin-induced insulin secretion was observed whereas, complete inhibition was found using verapamil, an L-type Ca2+ channel blocker. Furthermore, the insulinotropic potential of tambulin was amplified in tolbutamide treated, and depolarized islets suggest tambulin’s target other than tolbutamide. Tambulin showed no additive effect in the IBMX-induced intracellular cAMP; whereas, exerted an additive effect in the IBMX-induced insulin secretion. Furthermore, tambulin-induced insulin secretion was dramatically inhibited by PKA inhibitor (H-89), while moderate inhibition was found by using PKC inhibitor (calphostin C). Molecular docking studies also showed the best binding affinities of tambulin with PKA suggest the PKA dependent signaling cascade is involved more in tambulin-induced insulin secretion. Based on these findings, it is concluded that tambulin stimulates insulin secretion in a Ca2+ channel-dependent but KATP channel-independent manner, most likely by activating the cAMP-PKA pathway.

The anti-diabetic activity of extracts, fractions and compounds of Moringa oleifera have been reported; however, several constituents from this well known medicinal plant are not yet screened for bio-perspecting role for diabetes. Current studies demonstrated the anti-diabetic properties of five chemical constituents of the plant viz, 4-hydroxyphenylacetonitrite (1), fluoropyrazine (3), methyl-4-hydroxybenzoate (4), vanillin (5), and 4-α-L-rhamnopyranosyloxybenzyl isothiocyanate (6) along with one related compound 3,4-dihydroxy benzonitrile (2) for the first time in vitro and in vivo. Furthermore, the mechanism of action of compounds was predicted by utilizing molecular docking with protein kinase A (PKA) and exchange protein activated by cAMP (Epac2A). The structure of compounds was elucidated by UV, IR, MS, and 1H NMR. The compounds 1, 3–5 induced significant insulin secretion at stimulatory (16.7 mM) glucose, but not at basal (3 mM) glucose concentration, and compound 3 seems to be the most active. Compounds 1, 3–5 showed dose-dependent insulin secretory activity with optimum response at 200 μM. In silico studies revealed that compound 3 has a noticeable electrostatic and hydrophobic interaction with protein kinase A (PKA). In vitro studies also showed that there was significant reduction of compounds 1–3 mediated insulin secretion in the presence of PKA inhibitor suggesting that there is a possible role of PKA signaling pathway on insulin secretion. Upon oral administration of 1, 3–5 to diabetic rats, compounds 1 and 3 significantly reduced blood glucose level in diabetic rats in a dose- and time-dependent manner. The oral glucose tolerance test in diabetic rats showed that compound 3 significantly enhanced plasma insulin and improved beta-cell function. In cytotoxicity assay, compounds 1, 3–5 did not show any toxic effect upto 200 μM. The insulin releasing characteristic of different constituents from M. oleifera conceivably correlate the lowering of blood glucose in in vivo diabetic rats by triggering glucose-induced insulin secretion from pancreatic islets possibly by PKA-mediated insulin secretory pathway.

Eriodictyol, a flavonoid isolated from Lyonia ovalifolia, was found to be the most potent insulin secretagogue in our preliminary studies. Here, we explored mechanism(s) of insulin secretory activity of eriodictyol in vitro and in vivo. Mice islets and MIN6 cells were incubated in basal and stimulatory glucose containing eriodictyol with or without agonist/antagonist. Secreted insulin and cAMP contents were measured using ELISA kits. K+- and Ca2+-channels currents were recorded with patch-clamp technique. Oral glucose tolerance test and plasma insulin was evaluated in non-diabetic and diabetic rats. Eriodictyol stimulated insulin secretion from mice islets and MIN6 cells only at stimulatory glucose concentrations with maximum effect at 200μM. Eriodictyol showed no pronounced effect on inward rectifying K+ and Ca2+ currents. Furthermore, in KCl depolarized islets, in the presence of diazoxide, insulin secretory ability of eriodictyol was enhanced. IBMX, a phosphodiesterase inhibitor, significantly (P

Several reports indicate anti-hyperglycemic effects of Syzygium aromaticum. In the present study, we report for the first time that clove extract (SAM) and its compound nigricin (NGC) decreases free fatty acid-mediated insulin resistance in mouse myoblasts. In addition, NGC was able to diminish insulin resistance in a diabetic mouse model. We observed that SAM and its compound NGC exhibited significant antioxidant activity in murine skeletal muscle cells. They also modulated stress signaling by reducing p38 MAP kinase phosphorylation. NGC and SAM treatments enhanced proximal insulin signaling by decreasing serine phosphorylation of insulin receptor substrate-1 (IRS-1) and increasing its tyrosine phosphorylation. SAM and NGC treatments also modified distal insulin signaling by enhancing protein kinase B (PKB) and glycogen synthase kinase-3-beta (GSK-3 beta) phosphorylation in muscle cells. Glucose uptake was enhanced in muscle cells after treatment with SAM and NGC. We observed increased glucose tolerance, glucose-stimulated insulin secretion, decreased insulin resistance, and increased beta cell function in diabetic mice treated with NGC. The results of our study demonstrate that clove extract and its active agent NGC can be potential therapeutic agents for alleviating insulin resistance.

Tambulin, a flavonol isolated from Zanthoxylum armatum, showed potent insulin secretory activity in our preliminary anti-diabetic screening. Here, we explored the insulin secretory mechanism(s) of tambulin focusing in glucose-dependent, K