Antidiabetic Potential of Purple and Red Rice (Oryza sativa L.) Bran Extracts.

Pigmented rice contains anthocyanins and proanthocyanidins that are concentrated in the bran layer. In this study, we determined the phenolic, flavonoid, anthocyanin, and proanthocyanidin content of five rice bran (1 brown, 2 red, and 2 purple) extracts. Each bran extract was evaluated for inhibitory effects on α-amylase and α-glucosidase activity, two key glucosidases required for starch digestion in humans. All purple and red bran extracts inhibited α-glucosidase activity, however only the red rice bran extracts inhibited α-amylase activity. Additionally, each bran extract was examined for their ability to stimulate glucose uptake in 3T3-L1 adipocytes, a key function in glucose homeostasis. Basal glucose uptake was increased between 2.3- and 2.7-fold by exposure to the red bran extracts, and between 1.9- and 3.1-fold by exposure to the purple bran extracts. In red rice bran, the highest enzyme inhibition and glucose uptake was observed with a proanthocyanidin-enriched fraction. Both IITA red bran and IAC purple bran increased expression of GLUT1 and GLUT4 mRNA, and genes encoding insulin-signaling pathway proteins.

Addition of a Gastrointestinal Microbiome Modulator to Metformin Improves Metformin Tolerance and Fasting Glucose Levels.

BACKGROUND: Adverse effects of metformin are primarily related to gastrointestinal (GI) intolerance that could limit titration to an efficacious dose or cause discontinuation of the medication. Because some metformin side effects may be attributable to shifts in the GI microbiome, we tested whether a GI microbiome modulator (GIMM) used in combination with metformin would ameliorate the GI symptoms. METHODS: A 2-period crossover study design was used with 2 treatment sequences, either placebo in period 1 followed by GIMM in period 2 or vice versa. Study periods lasted for 2 weeks, with a 2-week washout period between. During the first week, type 2 diabetes patients (T2D) who experienced metformin GI intolerance took 500 mg metformin along with their assigned NM504 (GIMM) or placebo treatment with breakfast and with dinner. In the second week, the 10 subjects took 500 mg metformin (t.i.d.), with GIMM or placebo consumed with the first and third daily metformin doses. Subjects were permitted to discontinue metformin dosing if it became intolerable. RESULTS: The combination of metformin and GIMM treatment produced a significantly better tolerance score to metformin than the placebo combination (6.78 ± 0.65 [mean ± SEM] versus 4.45 ± 0.69, P = .0006). Mean fasting glucose levels were significantly (P < .02) lower with the metformin-GIMM combination (121.3 ± 7.8 mg/dl) than with metformin-placebo (151.9 ± 7.8 mg/dl). CONCLUSION: Combining a GI microbiome modulator with metformin might allow the greater use of metformin in T2D patients and improve treatment of the disease.

Glyceollins, soy isoflavone phytoalexins, improve oral glucose disposal by stimulating glucose uptake.

Soy glyceollins, induced during stress, have been shown to inhibit cancer cell growth in vitro and in vivo. In the present study, we used prediabetic rats to examine the glyceollins effect on blood glucose. During an oral glucose tolerance test (OGTT), the blood glucose excursion was significantly decreased in the rats treated with oral administration of either 30 or 90 mg/kg glyceollins. Plasma analysis demonstrated that glyceollins are absorbed after oral administration, and duration of exposure extends from 20 min to at least 4 h postadministration. Exposure of 3T3-L1 adipocytes to glyceollins significantly increased both insulin-stimulated and basal glucose uptake. Basal glucose uptake was increased 1.5-fold by exposure to 5 µM glyceollin in a dose-response manner. Coincubation with insulin significantly stimulated maximal glucose uptake above basal uptake levels and tended to increase glucose uptake beyond the levels of either stimulus alone. On a molecular level, polymerase chain reaction showed significantly increased levels of glucose transporter GLUT4 mRNA in 3T3-L1 adipocytes, especially when the cells were exposed to 5 µM glyceollins for 3 h in vitro. It correlated with elevated protein levels of GLUT4 detected in the 5 µM glyceollin-treated cells. Thus, the simulative effect of the glyceollins on adipocyte glucose uptake was attributed to up-regulation of glucose transporters. These findings indicate potential benefits of the glyceollins as an intervention in prediabetic conditions as well as a treatment for type 1 and type 2 diabetes by increasing both the insulin-mediated and the basal, insulin-independent, glucose uptake by adipocytes.

Fat and water 1H MRI to investigate effects of leptin in obese mice.

Leptin is known to be associated with regulation of body weight and fat content. The effects of exogenous leptin on abdominal visceral (VS) and subcutaneous (SC) fat volume and hepatic fat-to-water ratio in leptin-deficient obese mice were investigated by (1)H magnetic resonance imaging (MRI). Chemical shift-selected fat and water (1)H MRI of control and leptin-treated mice were obtained 1 day before treatment and after 7 days of treatment (0.3 mg/kg/day). Hepatic fat-to-water ratio and VS fat volume decreased significantly with treatment, whereas SC fat volume did not change. Noninvasive measurement of fat and water content in different body regions using MRI should prove useful for evaluating new drugs for the treatment of obesity and other metabolic disorders.

Potent oxindole based human beta3 adrenergic receptor agonists.

The synthesis and biological evaluation of a series of oxindole beta(3) adrenergic receptor agonists is described. A modulation of rat atrial tachycardia was observed with substitution at the 3-position of the oxindole moiety.

Potent peptide agonists for human melanocortin 3 and 4 receptors derived from enzymatic cleavages of human beta-MSH(5-22) by dipeptidyl peptidase I and dipeptidyl peptidase IV.

Human beta-MSH(1-22) was first isolated from human pituitary as a 22-amino acid (aa) peptide derived from a precursor protein, pro-opiomelanocortin (POMC). However, Bertagna et al. demonstrated that a shorter human beta-MSH(5-22), (DEGPYRMEHFRWGSPPKD), is a true endogenous peptide produced in human hypothalamus. In this report, we demonstrated that in vitro enzymatic cleavage of native human beta-MSH(5-22) with two ubiquitous dipeptidyl peptidases (DPP), DPP-I and DPP-IV, generated two potent MC3/4R peptide analogues, beta-MSH(7-22) (GPYRMEHFRWGSPPKD) and beta-MSH(9-22) (YRMEHFRWGSPPKD). In fact, the MC4R binding affinity and functional potency of beta-MSH(7-22) (Ki=4.6 nM, EC50=0.6 nM) and beta-MSH(9-22) (Ki=5.7 nM, EC50=0.6 nM) are almost an order of magnitude greater than those of their parent peptide, beta-MSH(5-22) (MC4R, Ki=23 nM, EC50= 3nM). Furthermore, the DPP-I/DPP-IV cleaved peptide, beta-MSH(9-22), when administered intracerebroventricularly (ICV) at a dose of 3 nmol/rat, potently induced an acute negative energy balance in a diet-induced obese rat model, while its parent molecule, beta-MSH(5-22), administered at the same dose did not have any effect. These data suggest that DPP-I and DPP-IV may play a role in converting the endogenous beta-MSH(5-22) to more potent peptides that regulate energy homeostasis in the hypothalamus.

Synthesis and biological evaluation of an orally active ghrelin agonist that stimulates food consumption and adiposity in rats.

2-(2-Amino-2-methyl-propionylamino)-5-phenyl-pentanoic acid [1-[1-(4-methoxy-phenyl)-1-methyl-2-oxo-2-pyrrolidin-1-yl-ethyl]-1H-imidazol-4-yl]-amide (LY444711, 6) is an orally active ghrelin agonist that binds with high affinity to and is a potent activator of the growth hormone secretagogue receptor 1a (GHS-R1a) receptor. In rat models of feeding behavior and pharmacology, 6 creates a positive energy balance and induces adiposity by stimulating food consumption and sparing fat utilization. As an orally active ghrelin agonist, 6 represents a new pharmacological tool to investigate the orexigenic role of ghrelin in regulating energy homeostasis.

The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis.

The gastrointestinal peptide hormone ghrelin stimulates appetite in rodents and humans via hypothalamic actions. We discovered expression of ghrelin in a previously uncharacterized group of neurons adjacent to the third ventricle between the dorsal, ventral, paraventricular, and arcuate hypothalamic nuclei. These neurons send efferents onto key hypothalamic circuits, including those producing neuropeptide Y (NPY), Agouti-related protein (AGRP), proopiomelanocortin (POMC) products, and corticotropin-releasing hormone (CRH). Within the hypothalamus, ghrelin bound mostly on presynaptic terminals of NPY neurons. Using electrophysiological recordings, we found that ghrelin stimulated the activity of arcuate NPY neurons and mimicked the effect of NPY in the paraventricular nucleus of the hypothalamus (PVH). We propose that at these sites, release of ghrelin may stimulate the release of orexigenic peptides and neurotransmitters, thus representing a novel regulatory circuit controlling energy homeostasis.

GH-releasing peptide-2 increases fat mass in mice lacking NPY: indication for a crucial mediating role of hypothalamic agouti-related protein.

Ghrelin, an endogenous GH secretagogue, is capable of stimulating adiposity in rodents. Because such adiposity was thought to be mediated by hypothalamic NPY neurons, we investigated by which mechanism a synthetic ghrelin receptor agonist, GHRP-2, would generate a positive energy balance in NPY-deficient [Npy(-/-) mice] and wild-type controls. A dose-dependent increase in body weight and food intake was observed during daily sc injections with GHRP-2. Pre- and posttreatment analysis of body composition indicated increased fat mass and bone mass but not lean mass. Respiratory quotient was increased in GHRP-2-treated mice, indicating preservation of fat. Hypothalamic mRNA levels of agouti- related protein (AGRP), an orexigenic melanocortin receptor antagonist, increased after GHRP-2 treatment. Competitive blockade of AGRP action by melanocortin-receptor agonist MT-II prevented GHRP-induced weight gain in Npy(-/-) mice. In conclusion, chronic peripheral treatment with a ghrelin receptor agonist induced a positive energy balance leading to fat gain in the absence of NPY. These effects could be mediated in part by AGRP. To date, there are few therapeutics that can produce a positive energy balance. Ghrelin receptor agonists offer a treatment option for syndromes like anorexia nervosa, cancer cachexia, or AIDS wasting.