abscisic-acid and Diabetes-Mellitus--Type-2

Abscisic acid (ABA) is a hormone with a very long evolutionary history, dating back to the earliest living organisms, of which modern (ABA-producing) cyanobacteria are likely the descendants, well before separation of the plant and animal kingdoms, with a conserved role as a signal regulating cell responses to environmental challenges. In mammals, nanomolar ABA controls the metabolic response to glucose availability by stimulating glucose uptake in skeletal muscle and adipose tissue with an insulin-independent mechanism and increasing energy expenditure in the brown and white adipose tissues. Activation by ABA of AMP-dependent kinase (AMPK), in contrast to the insulin-induced activation of AMPK-inhibiting Akt, is responsible for stimulation of GLUT4-mediated muscle glucose uptake, and for the browning effect on white adipocytes. Intake of micrograms per Kg body weight of ABA improves glucose tolerance in both normal and in borderline subjects and chronic intake of such a dose of ABA improves blood glucose, lipids and morphometric parameters (waist circumference and body mass index) in borderline subjects for prediabetes and the metabolic syndrome. This review summarizes the most recent results obtained in vivo with microgram amounts of ABA, the role of the receptor LANCL2 in the hormone's action and the significance of the endowment by mammals of two different hormones controlling the metabolic response to glucose availability. Finally, open issues in need of further investigation and perspectives for the clinical use of nutraceutical ABA are discussed.

Topics: Abscisic Acid; Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Humans; Inflammation; Insulin; Lipids; Membrane Proteins; Metabolic Syndrome; Phosphate-Binding Proteins; Prediabetic State; Pregnancy; Signal Transduction

Abscisic acid (ABA) is an important phytohormone that regulates plant growth, development, dormancy and stress responses. Recently, it was discovered that ABA is produced by a wide range of animals including sponges (Axinella polypoides), hydroids (Eudendrium racemosum), human parasites (Toxoplasma gondii), and by various mammalian tissues and cells (leukocytes, pancreatic cells, and mesenchymal stem cells). ABA is a universal signaling molecule that stimulates diverse functions in animals through a signaling pathway that is remarkably similar to that used by plants; this pathway involves the sequential binding of ABA to a membrane receptor and the activation of ADP-ribose cyclase, which results in the overproduction of the intracellular cyclic ADP-ribose and an increase in intracellular Ca²⁺ concentrations. ABA stimulates the stress response (heat and light) in animal cells, immune responses in leukocytes, insulin release from pancreatic β cells, and the expansion of mesenchymal and colon stem cells. ABA also inhibits the growth and induces the differentiation of cancer cells. Unlike some drugs that act as cell killers, ABA, when functioning as a growth regulator, does not have significant toxic side effects on animal cells. Research indicated that ABA is an endogenous immune regulator in animals and has potential medicinal applications for several human diseases. This article summarizes recent advances involving the discovery, signaling pathways and functions of ABA in animals.

Topics: Abscisic Acid; Animals; Atherosclerosis; Diabetes Mellitus, Type 2; Granulocytes; Humans; Inflammatory Bowel Diseases; Islets of Langerhans; Microglia; Monocytes; Neoplasms; Phytotherapy; Plant Growth Regulators; Signal Transduction; Stem Cells

Abscisic acid is a phytohormone found in fruits and vegetables and is endogenously produced in mammals. In humans and mice, lanthionine synthetase C-like 2 (LANCL2) has been characterized as the natural receptor for ABA. Herein, we characterize the efficacy of a fig fruit extract of ABA in promoting glycemic control. This ABA-enriched extract, at 0.125 µg ABA/kg body weight, improves glucose tolerance, insulin sensitivity and fasting blood glucose in diet-induced obesity (DIO) and db/db mouse models. In addition to decreasing systemic inflammation and providing glycemic control without increasing insulin, ABA extract modulates the metabolic activity of muscle. ABA increases expression of important glycogen synthase, glucose, fatty acid and mitochondrial metabolism genes and increases direct measures of fatty acid oxidation, glucose oxidation and metabolic flexibility in soleus muscle cells from ABA-treated mice with DIO. Glycolytic and mitochondrial ATP production were increased in ABA-treated human myotubes. Further, ABA synergized with insulin to dramatically increase the rate of glycogen synthesis. The loss of LANCL2 in skeletal muscle abrogated the effect of ABA extract in the DIO model and increased fasting blood glucose levels. This data further supports the clinical development of ABA in the treatment of pre-diabetes, type 2 diabetes and metabolic syndrome.

Topics: Abscisic Acid; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Ficus; Glucose; Humans; Inflammation; Insulin; Insulin Resistance; Membrane Proteins; Mice; Mice, Inbred NOD; Mitochondria; Muscle Cells; Muscle, Skeletal; Obesity; Phosphate-Binding Proteins; Plant Extracts

The plant hormone abscisic acid (ABA) is present and active in humans, regulating glucose homeostasis. In normal glucose tolerant (NGT) human subjects, plasma ABA (ABAp) increases 5-fold after an oral glucose load. The aim of this study was to assess the effect of an oral glucose load on ABAp in type 2 diabetes (T2D) subjects. We chose two sub-groups of patients who underwent an oral glucose load for diagnostic purposes: i) 9 treatment-naive T2D subjects, and ii) 9 pregnant women with gestational diabetes (GDM), who underwent the glucose load before and 8-12 weeks after childbirth. Each group was compared with matched NGT controls. The increase of ABAp in response to glucose was found to be abrogated in T2D patients compared to NGT controls. A similar result was observed in the women with GDM compared to pregnant NGT controls; 8-12 weeks after childbirth, however, fasting ABAp and ABAp response to glucose were restored to normal in the GDM subjects, along with glucose tolerance. We also retrospectively compared fasting ABAp before and after bilio-pancreatic diversion (BPD) in obese, but not diabetic subjects, and in obese T2D patients, in which BPD resulted in the resolution of diabetes. Compared to pre-BPD values, basal ABAp significantly increased 1 month after BPD in T2D as well as in NGT subjects, in parallel with a reduction of fasting plasma glucose. These results indicate an impaired hyperglycemia-induced ABAp increase in T2D and in GDM and suggest a beneficial effect of elevated ABAp on glycemic control.

Topics: Abscisic Acid; Adult; Aged; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetes, Gestational; Fasting; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Middle Aged; Pregnancy; Young Adult

Phyto-remedies for diabetic control are popular among patients with Type II Diabetes mellitus (DM), in addition to other diabetic control measures. A number of plant species are known to possess diabetic control properties. Costus pictus D. Don is popularly known as "Insulin Plant" in Southern India whose leaves have been reported to increase insulin pools in blood plasma. Next Generation Sequencing is employed as a powerful tool for identifying molecular signatures in the transcriptome related to physiological functions of plant tissues. We sequenced the leaf transcriptome of C. pictus using Illumina reversible dye terminator sequencing technology and used combination of bioinformatics tools for identifying transcripts related to anti-diabetic properties of C. pictus.. A total of 55,006 transcripts were identified, of which 69.15% transcripts could be annotated. We identified transcripts related to pathways of bixin biosynthesis and geraniol and geranial biosynthesis as major transcripts from the class of isoprenoid secondary metabolites and validated the presence of putative norbixin methyltransferase, a precursor of Bixin. The transcripts encoding these terpenoids are known to be Peroxisome Proliferator-Activated Receptor (PPAR) agonists and anti-glycation agents. Sequential extraction and High Performance Liquid Chromatography (HPLC) confirmed the presence of bixin in C. pictus methanolic extracts. Another significant transcript identified in relation to anti-diabetic, anti-obesity and immuno-modulation is of Abscisic Acid biosynthetic pathway. We also report many other transcripts for the biosynthesis of antitumor, anti-oxidant and antimicrobial metabolites of C. pictus leaves.. Solid molecular signatures (transcripts related to bixin, abscisic acid, and geranial and geraniol biosynthesis) for the anti-diabetic properties of C. pictus leaves and vital clues related to the other phytochemical functions like antitumor, anti-oxidant, immuno-modulatory, anti-microbial and anti-malarial properties through the secondary metabolite pathway annotations are reported. The data provided will be of immense help to researchers working in the treatment of DM using herbal therapies.

Topics: Abscisic Acid; Acyclic Monoterpenes; Base Sequence; Carotenoids; Chromatography, High Pressure Liquid; Computational Biology; Costus; Diabetes Mellitus, Type 2; Genes, Plant; High-Throughput Nucleotide Sequencing; Humans; Hypoglycemic Agents; Methyltransferases; Molecular Sequence Annotation; Molecular Sequence Data; Monoterpenes; Phytotherapy; Plant Extracts; Plant Leaves; Sequence Analysis, DNA; Terpenes; Transcriptome

The rates of type 2 diabetes (T2D) are rising to epidemic proportions in the US and worldwide. While current T2D medications are efficacious, significant side effects have limited their use and availability. Our laboratory has discovered that abscisic acid (ABA) exerts anti-diabetic effects, in part, by activating peroxisome proliferator-activated receptor γ (PPAR γ). However, since ABA does not bind to the ligand-binding domain (LBD) of PPAR γ, the mechanism of activation of PPAR γ by ABA remains unknown. Lanthionine synthetase component C-like protein 2 (LANCL2) was predicted to be a novel target for the binding and signaling of ABA in human granulocytes and rat insulinoma cells. The goal of this study was to determine whether LANCL2 is a molecular target of ABA and other PPAR γ agonists. To this end we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of LANCL1 as a template. Our molecular docking studies predicted that ABA and other PPAR γ agonists (e.g., rosiglitazone and pioglitazone) share a binding site on the surface of LANCL2. The identification of a binding site for PPAR γ agonists will facilitate the high-throughput virtual screening of large compound libraries and may shed new light on alternative mechanisms of PPAR γ activation.

Topics: Abscisic Acid; Amino Acid Sequence; Binding Sites; Conserved Sequence; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Ligands; Membrane Proteins; Models, Molecular; Molecular Sequence Data; Nuclear Proteins; Phosphate-Binding Proteins; PPAR gamma; Protein Structure, Tertiary; Receptors, G-Protein-Coupled; Sequence Alignment; Structure-Activity Relationship

Despite their efficacy in improving insulin sensitivity, thiazolidinediones (TZDs) are associated with a number of side effects (i.e. weight gain, hepatotoxicity, congestive heart failure) that have limited their use by millions of diabetic patients. We have investigated whether abscisic acid (ABA), a naturally occurring phytochemical with structural similarities to TZDs, could be used as an alternative to TZDs to improve glucose homeostasis.. We first examined whether ABA, similar to TZDs, activates PPARgamma in vitro. We next determined the lowest effective dose of dietary ABA (100 mg/kg) and assessed its effect on glucose tolerance, obesity-related inflammation, and mRNA expression of PPARgamma and its responsive genes in white adipose tissue (WAT) of db/db mice fed high-fat diets.. We found that ABA induced transactivation of PPARgamma in 3T3-L1 pre-adipocytes in vitro. Dietary ABA-supplementation for 36 days decreased fasting blood glucose concentrations, ameliorated glucose tolerance, and increased mRNA expression of PPARgamma and its responsive genes (i.e., adiponectin, aP2, and CD36) in WAT. We also found that adipocyte hypertrophy, tumor necrosis factor-alpha (TNF-alpha) expression, and macrophage infiltration in WAT were significantly attenuated in ABA-fed mice.. These findings suggest that ABA could be used as a nutritional intervention against type II diabetes and obesity-related inflammation.

Topics: Abscisic Acid; Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Glucose Tolerance Test; Humans; Inflammation; Male; Mice; Mice, Inbred Strains; Obesity; PPAR gamma; RNA, Messenger; Thiazolidinediones