Diabetes mellitus is a chronic disease, typified by hyperglycemia resulting from failures in complex multifactorial metabolic functions, that requires life-long medication. Prolonged uncontrolled hyperglycemia leads to micro- and macro-vascular complications. Although antidiabetic drugs are prescribed as the first-line treatment, many of them lose efficacy over time or have severe side effects. There is a lack of in-depth study on the patents filed concerning the use of natural compounds to manage diabetes. Thus, this patent analysis provides a comprehensive report on the antidiabetic therapeutic activity of 6 phytocompounds when taken alone or in combinations. Four patent databases were searched, and 17,649 patents filed between 2001 and 2021 were retrieved. Of these, 139 patents for antidiabetic therapeutic aids that included berberine, curcumin, gingerol, gymnemic acid, gymnemagenin and mangiferin were analyzed. The results showed that these compounds alone or in combinations, targeting acetyl-coenzyme A carboxylase 2, serine/threonine protein kinase, α-amylase, α-glucosidase, lipooxygenase, phosphorylase, peroxisome proliferator-activated receptor-γ (PPARγ), protein tyrosine phosphatase 1B, PPARγ co-activator-1α, phosphoinositide 3-kinase and protein phosphatase 1 regulatory subunit 3C, could regulate glucose metabolism which are validated by pharmacological rationale. Synergism, or combination therapy, including different phytocompounds and plant extracts, has been studied extensively and found effective, whereas the efficacy of commercial drugs in combination with phytocompounds has not been studied in detail. Curcumin, gymnemic acid and mangiferin were found to be effective against diabetes-related complications. Please cite this article as: DasNandy A, Virge R, Hegde HV, Chattopadhyay D. A review of patent literature on the regulation of glucose metabolism by six phytocompounds in the management of diabetes mellitus and its complications. J Integr Med. 2023; 21(3): 226-235.
Humans ; PPAR gamma/metabolism* ; Curcumin/therapeutic use* ; Phosphatidylinositol 3-Kinases ; Diabetes Mellitus/drug therapy* ; Hypoglycemic Agents/pharmacology* ; Hyperglycemia/drug therapy* ; Glucose

Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, which showed decent hypoglycemic and body weight lowering activity. However, the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins, we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual agonists. One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays. As expected, O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. Importantly, chronic administration of 1f potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism and adiposity in both db/db and diet induced obesity (DIO) mice models. These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.
Mice ; Animals ; Glucagon-Like Peptide 1/metabolism* ; Receptors, Glucagon/therapeutic use* ; Xenopus laevis/metabolism* ; Diabetes Mellitus, Type 2/drug therapy* ; Glycopeptides/therapeutic use* ; Obesity/drug therapy* ; Hypoglycemic Agents/pharmacology* ; Peptides/pharmacology*

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus (T2DM), dyslipidemia, central obesity and hypertension. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors were widely used to treat T2DM. These agents improve glycemic control, promote weight loss and improve lipid metabolism. Recent studies have demonstrated that the GLP-1 receptor (GLP-1R) is present and functional in human and rat hepatocytes. In this review, we present data from animal researches and human clinical studies that showed GLP-1 analogues and DPP-4 inhibitors can decrease hepatic triglyceride (TG) content and improve hepatic steatosis, although some effects could be a result of improvements in metabolic parameters. Multiple hepatocyte signal transduction pathways and mRNA from key enzymes in fatty acid metabolism appear to be activated by GLP-1 and its analogues. Thus, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies to treat patients with NAFLD.
Animals ; Clinical Trials as Topic ; Dipeptidyl-Peptidase IV Inhibitors ; pharmacology ; therapeutic use ; Glucagon-Like Peptide 1 ; agonists ; Humans ; Hypoglycemic Agents ; pharmacology ; therapeutic use ; Lipid Metabolism ; drug effects ; Non-alcoholic Fatty Liver Disease ; drug therapy ; metabolism ; Triglycerides ; metabolism

Cymbopogon citratus is a widely distributed perennial herb belonging to the Poaceae family and has been extensively consumed for its medicinal, cosmetic, and nutritional effects for centuries. A large number of reports have been published describing the pharmacological, biological, and therapeutic actions of this herb. In this review, we summarized the literatures on related studies (up to January, 2014) that highlighted the pharmacologic and biological effects of the major phytochemicals isolated from C. citratus extracts and its essential oil. The components of the essential oils found in C. citratus have a similar pharmacokinetic properties, including absorption, distribution, metabolism, and excretion. They are quickly absorbed following oral, pulmonary, and dermal administration. Based on the published reports, it can also be inferred that, after absorption from the small intestine, some phytochemicals in C. citratus can undergo oxidation, glucuronidation, sulfation, and/or O-methylation. Excretion is through urine, feces and/or expired volatiles. The biotransformation reactions of C. citratus bioactive constituents are essential for its relatively safe consumption and therapeutic applications. The data available so far warrant further studies evaluating C. citratus pharmacokinetics. Reliable pharmacokinetic data in humans would be critical for a better understanding of the the systemic handling of C. citratus.
Animals ; Anti-Infective Agents ; pharmacokinetics ; pharmacology ; therapeutic use ; Anti-Inflammatory Agents ; pharmacokinetics ; pharmacology ; therapeutic use ; Anti-Obesity Agents ; pharmacokinetics ; pharmacology ; therapeutic use ; Antineoplastic Agents ; pharmacokinetics ; pharmacology ; therapeutic use ; Antioxidants ; pharmacokinetics ; pharmacology ; therapeutic use ; Central Nervous System Agents ; pharmacokinetics ; pharmacology ; therapeutic use ; Cymbopogon ; Ethnopharmacology ; Hematologic Agents ; pharmacokinetics ; pharmacology ; therapeutic use ; Humans ; Hypoglycemic Agents ; pharmacokinetics ; pharmacology ; therapeutic use ; Male ; Mice ; Oils, Volatile ; pharmacokinetics ; pharmacology ; therapeutic use ; Plant Extracts ; pharmacokinetics ; pharmacology ; therapeutic use ; Plant Oils ; pharmacokinetics ; pharmacology ; therapeutic use ; Rats, Inbred F344 ; Urological Agents ; pharmacokinetics ; pharmacology ; therapeutic use

Seven terpenoids and three sterols were isolated from the methanol extracts of the aerial parts of Ricinus communis by chromatography methods and their structures were identified by spectra analysis as ficusic acid( 1), phytol(2), callyspinol(3) , lupeol(4), 30-norlupan-3beta-ol-20-one(5) , lup-20(29)-en-3beta,15alpha-diol(6) , acetylaleuritolic acid( 7), stigmast4-en-3-one(8) , stig-mast-4-en-6beta-ol-3-one(9) , and stigmast4-en-3,6-dione(10). Compounds 1-3 and 5-10 were obtained from this species for the first time and 5 and 6 showed significant inhibitive activity and good selectivity against 11beta-HSD of mouse and human in vitro. [Key words] Ricinus communis; terpenoids; sterols; 11beta-HSD
11-beta-Hydroxysteroid Dehydrogenase Type 1 ; antagonists & inhibitors ; 11-beta-Hydroxysteroid Dehydrogenase Type 2 ; antagonists & inhibitors ; Animals ; Diabetes Mellitus ; drug therapy ; enzymology ; Humans ; Hypoglycemic Agents ; pharmacology ; therapeutic use ; Inhibitory Concentration 50 ; Mice ; Ricinus ; chemistry ; Sterols ; pharmacology ; therapeutic use ; Terpenes ; pharmacology ; therapeutic use

Whether supplementation of curcuminoids decreases serum adipocyte-fatty acid binding protein (A-FABP) level and whether this decrease benefits glucose control is unclear. One-hundred participants (n=50 administered curcuminoids, n=50 administered placebo) from our previous report on the effect of curcuminoids on type 2 diabetes in a 3-month intervention were assessed for levels of serum A-FABP, oxidative stress, and inflammatory biomarkers. Curcuminoids supplementation led to significant decreases in serum A-FABP, C-reactive protein (CRP), tumor necrosis factor-α, and interleukin-6 levels. Curcuminoids supplementation also significantly increased serum superoxide dismutase (SOD) activity. The change in serum A-FABP levels showed positive correlations with changes in levels of glucose, free fatty acids (FFAs), and CRP in subjects supplemented with curcuminoids. Further stepwise regression analysis showed that A-FABP was an independent predictor for levels of FFAs, SOD, and CRP. These results suggest that curcuminoids may exert anti-diabetic effects, at least in part, by reductions in serum A-FABP level. A-FABP reduction is associated with improved metabolic parameters in human type 2 diabetes.
Biomarkers ; blood ; Blood Glucose ; analysis ; Curcumin ; administration & dosage ; pharmacology ; therapeutic use ; Diabetes Mellitus, Type 2 ; blood ; complications ; drug therapy ; immunology ; Fatty Acid-Binding Proteins ; blood ; Humans ; Hypoglycemic Agents ; administration & dosage ; pharmacology ; therapeutic use ; Obesity ; blood ; complications ; drug therapy ; immunology ; Oxidative Stress ; drug effects ; immunology ; Treatment Outcome

AIM: To evaluate the effect of Cocus nucifera L. flowers in reducing the major multiple symptoms of letrozole-induced polycystic ovarian disease (PCOD) in female rats. METHOD: Female, virgin Wistar rats were treated with letrozole (1 mg/kg body wt) to induce PCOD, and after 21 days of induction rats were administered orally with 100 and 200 mg·kg(-1) of Cocus nucifera flower aqueous extract, respectively. Estrus cycle and blood sugar were monitored once a week throughout the study. After scarification, various biochemical parameters, such as antioxidant status (superoxide dismutase (SOD) and glutathione reductase (GSH)) of the uterus homogenate, lipid profile (total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides (TG)) of the serum were determined. Weights of the uterus and ovaries were separately monitored. The characteristics of changes in the ovary were evaluated by histopathological studies. RESULTS: GC-MS analysis of the aqueous extract showed the presence of volatile and pharmacologically active phytoconstituents. C. nucifera flower extract-treated groups showed estrus cyclicity and increased uterus weight which indicates the estrogenic effect. The improved blood sugar level, ideal lipid profile, good antioxidant status, and histopathology results revealed the recovery from poly cystic ovaries. CONCLUSION The results indicate that C. nucifera flower is a potential medicine for the treatment of PCOD and this study supports the traditional uses of C. nucifera flower.
Animals ; Antioxidants ; metabolism ; Blood Glucose ; metabolism ; Cocos ; chemistry ; Estrus ; drug effects ; Female ; Flowers ; chemistry ; Gas Chromatography-Mass Spectrometry ; Hypoglycemic Agents ; pharmacology ; therapeutic use ; Letrozole ; Lipids ; blood ; Nitriles ; Oils, Volatile ; analysis ; pharmacology ; therapeutic use ; Ovary ; drug effects ; pathology ; Phytoestrogens ; pharmacology ; therapeutic use ; Phytotherapy ; Plant Extracts ; chemistry ; pharmacology ; therapeutic use ; Polycystic Ovary Syndrome ; blood ; chemically induced ; drug therapy ; pathology ; Rats, Wistar ; Triazoles ; Uterus ; drug effects

AIM: The hypoglycemic and hypolipidemic effects of the methanol extract of Brassica oleracea var. capitata (MEB) was evaluated in alloxan-induced diabetic rabbits. METHOD: The study was conducted on twenty-eight healthy white rabbits of either sex. All animals were equally divided into four groups. After confirmation of hyperglycemia, the animals of the treated and standard groups were administered MEB (500 mg·kg(-1)) and glibenclamide (10 mg·kg(-1)), respectively for 15 and 30 days. The animals of the normal and diabetic controls received normal saline 1 mL/day equivalent to the volume of doses given to the test and standard animals. Biochemical tests were performed at the end of dosing, i.e. the 16(th) and 31(st) days. RESULTS: The MEB revealed a decrease of 106.6 mg·dL(-1) in fasting blood glucose as compared to diabetic control, which was almost comparable to glibenclamide; both of these changes were highly significant. The decrease in total cholesterol and low density lipoprotein was 94.3 and 96.5 mg·dL(-1), respectively, whereas the high-density lipoprotein was increased by 26.7 mg·dL(-1), as compared to diabetic control. All of the changes in lipid profile were statistically significant. CONCLUSION These results suggest the potential of MEB as a hypoglycemic and hypolipidemic agent.
Animals ; Blood Glucose ; metabolism ; Brassica ; Cholesterol ; blood ; Diabetes Mellitus, Experimental ; blood ; drug therapy ; Female ; Hypoglycemic Agents ; pharmacology ; therapeutic use ; Hypolipidemic Agents ; pharmacology ; therapeutic use ; Lipoproteins ; blood ; Male ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Rabbits ; Triglycerides ; blood

AIM: To identify the glucose lowering ability and chronic treatment effects of a novel coumarin-glucagon-like peptide-1 (GLP-1) conjugate HJ07. METHOD: A receptor activation experiment was performed in HEK 293 cells and the glucose lowering ability was evaluated with hypoglycemic duration and glucose stabilizing tests. Chronic treatment was performed by daily injection of exendin-4, saline, and HJ07. Body weight and HbA1c were measured every week, and an intraperitoneal glucose tolerance test was performed before treatment and after treatment. RESULTS: HJ07 showed well-preserved receptor activation efficacy. The hypoglycemic duration test showed that HJ07 possessed a long-acting, glucose-lowering effect and the glucose stabilizing test showed that the antihyperglycemic activity of HJ07 was still evident at a predetermined time (12 h) prior to the glucose challenge (0 h). The long time glucose-lowering effect of HJ07 was better than native GLP-1 and exendin-4. Furthermore, once daily injection of HJ07 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance. CONCLUSION The biological activity results of HJ07 suggest that HJ07 is a potential long-acting agent for the treatment of type 2 diabetes.
Animals ; Blood Glucose ; metabolism ; Coumarins ; pharmacology ; Diabetes Mellitus ; blood ; drug therapy ; Diabetes Mellitus, Type 2 ; drug therapy ; Exenatide ; Glucagon-Like Peptide 1 ; analogs & derivatives ; pharmacology ; therapeutic use ; Glucagon-Like Peptide-1 Receptor ; Glucose Tolerance Test ; Glycated Hemoglobin A ; metabolism ; HEK293 Cells ; Humans ; Hypoglycemic Agents ; pharmacology ; therapeutic use ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Peptides ; pharmacology ; Receptors, Glucagon ; metabolism ; Venoms ; pharmacology

AIM: To evaluate the effect of an active fraction from Leptadenia reticulata leaves on serum glucose and lipid profile in normal and diabetic rats. METHOD: Diabetes was induced by streptozotocin in Wistar rats. Petroleum ether, ethyl acetate, and ethanol extracts of Leptadenia reticulata leaves were administered orally at a dose of 200 mg·kg(-1), p.o. Metformin was used as standard anti diabetic drug (50 mg·kg(-1), p.o). The extract showing higher antidiabetic activity was subjected to column chromatography and led to the isolation of an active fraction, which was given trivial name Lr-1. Lr-1 (100 mg·kg(-1), p.o.) was studied for its hypoglycemic and hypolipidemic potential. RESULTS: The ethanol extract was found to lower the FBG level significantly (P < 0.05) in diabetic rats. Lr-1 caused a significant (P < 0.05) reduction in FBG level, and additionally it caused reduction in cholesterol, triglyceride levels, and an improvement in the HDL level in diabetic rats. CONCLUSION Reduction in the FBG, cholesterol, triglyceride levels, and an improvement in the HDL by Lr-1 indicates that Lr-1 has antidiabetic activity, along with cardioprotective potential, and provides a scientific rationale for the use as an antidiabetic agent.
Animals ; Apocynaceae ; Blood Glucose ; metabolism ; Cholesterol ; blood ; Cholesterol, HDL ; blood ; Diabetes Mellitus, Experimental ; blood ; drug therapy ; Hypoglycemic Agents ; pharmacology ; therapeutic use ; Lipids ; blood ; Male ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Plant Leaves ; Rats, Wistar ; Triglycerides ; blood