D-chiro-inositol glycan reduces food intake by regulating hypothalamic neuropeptide expression via AKT-FoxO1 pathway.

The regulation of food intake is important for body energy homeostasis. Hypothalamic insulin signaling decreases food intake by upregulating the expression of anorexigenic neuropeptides and downregulating the expression of orexigenic neuropeptides. INS-2, a Mn(2+) chelate of 4-O-(2-amino-2-deoxy-ß-D-galactopyranosyl)-3-O-methyl-D-chiro-inositol, acts as an insulin mimetic and sensitizer. We found that intracerebroventricular injection of INS-2 decreased body weight and food intake in mice. In hypothalamic neuronal cell lines, INS-2 downregulated the expression of neuropeptide Y (NPY), an orexigenic neuropeptide, but upregulated the expression of proopiomelanocortin (POMC), an anorexigenic neuropeptide, via modulation of the AKT-forkhead box-containing protein-O1 (FoxO1) pathway. Pretreatment of these cells with INS-2 enhanced the action of insulin on downstream signaling, leading to a further decrease in NPY expression and increase in POMC expression. These data indicate that INS-2 reduces food intake by regulating the expression of the hypothalamic neuropeptide genes through the AKT-FoxO1 pathway downstream of insulin.

Insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome.

Some actions of insulin are mediated by inositolphosphoglycan (IPG) mediators. Deficient release of a putative D-chiro-inositol-containing (DCI) IPG mediator may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Previously, we demonstrated that oral DCI supplementation improved ovulation and metabolic parameters in women with PCOS. However, whether oral DCI mediates an increase in the release of the DCI-IPG mediator and an improvement in insulin sensitivity in women with PCOS is unknown. We conducted a randomized controlled trial of DCI supplementation vs placebo in 11 women with PCOS who were assessed at 2 time points 6 weeks apart. Plasma DCI, DCI-IPG release during oral glucose tolerance test (AUC(DCI-IPG)), and insulin sensitivity (S(i)) by frequently sampled intravenous glucose tolerance test were assessed at baseline and end of study. The study was terminated early because of a sudden unavailability of the study drug. However, in all subjects without regard to treatment assignment, there was a positive correlation between the change in AUC(DCI-IPG)/AUC(insulin) ratio and the change in S(i) during the 6-week period (r = 0.69, P = .02), which remained significant after adjustment for body mass index (P = .022) and after further adjustment for body mass index and treatment allocation (P = .0261). This suggests that, in women with PCOS, increased glucose-stimulated DCI-IPG release is significantly correlated with improved insulin sensitivity. The significant relationship between DCI-IPG release and insulin sensitivity suggests that the DCI-IPG mediator may be a target for therapeutic interventions in PCOS.

Dietary administration of inositol and/or inositol-6-phosphate prevents chemically-induced rat hepatocarcinogenesis.

Chemoprevention is considered a rational strategy for dietary approaches to prevention of cancer. Multiple lines of evidence suggest that many of our dietary principles are able to intervene in the multistage carcinogenesis process and phytic acid (inositol hexaphosphate, IP6), a phytochemical present in a variety of plant species, has been shown to prevent various cancers, including those of the mammary gland, colon and liver. However, the mechanism of chemoprevention by IP6 has not been fully elucidated. In the present study, we examined the effects of inositol and/or IP6 supplementation on rat hepatocarcinogenesis initiated by diethylnitrosamine (DEN) and promoted by partial hepatectomy (PH). Supplementation with either inositol or IP6, or their combination, starting one week prior to administration of DEN, resulted in a significant decrease in both the area and the number of placental glutathione S-transferase positive (GST-P+) foci, a preneoplastic marker for DEN-initiated hepatocarcinogenesis. The administration of inositol and/or IP6 in drinking water caused marked enhancement in the glutathione S-transferase (GST) activity. In addition, the production of thiobarbituric acid reactive substances and the catalase activity were significantly reduced in rats supplemented with inositol and /or IP6. Based on these findings, it is likely that the chemopreventive effects of inositol and/or IP6 on rat hepatocarcinogenesis initiated by DEN and promoted by PH are associated with induction of GST activity and suppression of lipid peroxidation.

Buckwheat concentrate reduces serum glucose in streptozotocin-diabetic rats.

The antihyperglycemic effects of chemically synthesized d-chiro-inositol (d-CI), a component of an insulin mediator, have been demonstrated in rats. Buckwheat contains relatively high levels of d-CI: thus, it has been proposed as a source of d-CI for reducing serum glucose concentrations in diabetics. The present study evaluates the effects of a buckwheat concentrate, containing d-CI, on hyperglycemia and glucose tolerance in streptozotocin (STZ) rats. In fed STZ rats, both doses of the buckwheat concentrate (containing 10 and 20 mg of d-CI/kg of body weight) were effective for lowering serum glucose concentrations by 12-19% at 90 and 120 min after administration. Findings from this study demonstrate that a buckwheat concentrate is an effective source of d-CI for lowering serum glucose concentrations in rats and therefore may be useful in the treatment of diabetes.

Effect of inositol-trisphosphate on fluid transport and protein extravasation in the obstructed small bowel.

BACKGROUND: Small-bowel obstruction is characterized by accumulation of fluid in the obstructed intestine. A pronounced inflammation in the obstructed gut wall has been shown to play an important role in the pathogenesis of the profuse fluid losses. alpha-Trinositol (D-myo-inositol-1,2,6-trisphosphate; PP56) has potent anti-inflammatory as well as antisecretory properties. The effects of alpha-Trinositol on inflammation and fluid losses in the obstructed small intestine are examined. METHODS: A total obstruction of the proximal part of the rat jejunum was induced during 18 h by thread ligation. A small segment of the obstructed intestine, with intact vascular and nervous supply, was placed in a chamber suspended from a force displacement transducer allowing for continuous registration of net fluid transport on a Grass polygraph. Three groups were included. One group (n = 12) received low-dose alpha-Trinositol (bolus: 2 mg kg(-1); IV infusion: 10 mg kg(-1) min(-1)), a second group (n = 10) received high-dose alpha-Trinositol (bolus: 12 mg kg(-1); IV infusion: 60 mg kg(-1) min(-1)), while a control group (n = 9) received corresponding volumes of isotonic saline (bolus: 0.5 ml; IV infusions 15 microl min(-1)). Quantitative measurement of extra-vasated Evans blue albumin in the obstructed jejunum was used as a marker of inflammation. RESULTS: High-dose alpha-Trinositol induced a significant (P < 0.001) inhibition of net fluid secretion, while low-dose alpha-Trinositol had no significant effect versus saline. In contrast, both doses of alpha-Trinositol induced significant inhibition of EB-albumin leakage (P < 0.05). CONCLUSION: High-dose alpha-Trinositol is a potent inhibitor of fluid secretion in obstructive ileus, most probably involving an anti-inflammatory mechanism.

Effects of chronic infusions of alpha-trinositol on regional and cardiac haemodynamics in conscious rats.

1. Male, Long Evans rats (350-450 g) were chronically instrumented for the measurement of renal, mesenteric and hindquarters haemodynamics, and were given three consecutive, 24 h infusions of vehicle (sterile saline at 0.3 ml h-1, n = 8) or alpha-trinositol (D-myo-inositol-1,2,6-triphosphate) at 5, 20 and 80 mg kg-1 h-1 (0.3 ml h-1; n = 9). During infusion of alpha-trinositol at 5 or 20 mg kg-1 h-1, cardiovascular changes were little different from those seen during saline infusion. However, during infusion of alpha-trinositol at 80 mg kg-1 h-1 there were increases in hindquarters vascular conductance, renal flow and vascular conductance, that were all significantly different from the changes seen in the saline group. Infusion of alpha-trinositol at the high dose in naive rats (n = 8) had even more marked vasodilator effects. 2. Two groups of rats (n = 8 in each), chronically instrumented for the measurement of cardiac haemodynamics, were given 48 h infusions of saline (0.3 ml h-1) or alpha-trinositol (2 mg kg-1 bolus, 80 mg kg-1 h-1 infusion at 0.3 ml h-1). During the infusion of saline, there were slight reductions in heart rate, cardiac index, peak aortic flow, dF/dtmax and central venous pressure. In the animals receiving alpha-trinositol, with the exception of central venous pressure, all the above variables, together with total peripheral conductance, increased. 3. These results, collectively, indicate that incremental infusions of alpha-trinositol do not reveal its full vasodilator potential, possibly due to concurrent activation of counter-regulatory vasoconstrictor mechanisms. However, infusion of alpha-trinositol at a high dose causes substantial increases in renal,mesenteric and hindquarters flows and vascular conductances, supported by significant increases in indices of cardiac inotropism. Such effects, in the absence of significant hypotension, tachycardia or signs of desensitization, give alpha-trinositol a unique cardiovascular profile.