Alpha-Lipoic Acid Shows Promise to Improve Migraine in Patients with Insulin Resistance: A 6-Month Exploratory Study.

Alpha-lipoic acid (ALA) is known to lower insulin resistance (IR), which is common among migraineurs. To assess the effect of ALA on headache in migraineurs with IR, we performed an exploratory study on a cohort of patients with migraine, followed at our Headache Center. The 32 patients took ALA 400 mg b.i.d. for 6 months in addition to their on-going treatment. The percentage of patients with a reduction of at least 50% of the attacks was 0.53 (confidence interval [95% CI] 0.36-0.70) at 2 months, 0.56 (0.39-0.73) at 4 months, and 0.69 (0.53-0.85) at 6 months. The incidence rate ratio of attacks at 6 months versus baseline was 0.48 (0.43-0.53, P < .001), corresponding to a mean (95% CI) number of attacks of 5 (4-6) versus 11 (10-12). The number of days of treatment in the previous month was 7.7 (6.8-8.7) at baseline, 5.4 (4.6-6.2) at 2 months, 5.3 (4.5-6.1) at 4 months, and 4.3 (3.6-5.0) at 6 months. Baseline and 120-min glucose and insulin and quantitative insulin sensitivity check index (QUICKI) and the Stumvoll index did not change at 6 months versus baseline. This exploratory study shows that the administration of ALA may be associated with a reduction in the number of attacks and the days of treatment in migraineurs with IR. A randomized controlled trial is needed to test this possibility.

Taurine supplementation regulates Iκ-Bα protein expression in adipose tissue and serum IL-4 and TNF-α concentrations in MSG obesity.

PURPOSE: Obesity is usually associated with low-grade inflammation, which impairs insulin action. The amino acid, taurine (TAU), regulates glucose homeostasis and lipid metabolism and presents anti-inflammatory actions. Here, we evaluated whether inflammatory markers are altered in the serum and retroperitoneal adipose tissue of monosodium glutamate (MSG) obese rats, supplemented or not with TAU. METHODS: Male Wistar rats received subcutaneous injections of MSG (4 mg/kg body weight/day, MSG group) or hypertonic saline (CTL) during the first 5 days of life. From 21 to 120 days of age, half of each of the MSG and CTL groups received 2.5 % TAU in their drinking water (CTAU and MTAU). RESULTS: At 120 days of age, MSG rats were obese and hyperinsulinemic. TAU supplementation reduced fat deposition without affecting insulinemia in MTAU rats. MSG rats presented increased pIκ-Bα/Iκ-Bα protein expression in the retroperitoneal adipose tissue. TAU supplementation decreased the ratio of pIκ-Bα/Iκ-Bα protein, possibly contributing to the increased Iκ-Bα content in MTAU adipose tissue. Furthermore, MSG obesity or supplementation did not alter TNF-α, IL-1ß or IL-6 content in adipose tissue. In contrast, MSG rats presented lower serum TNF-α, IL-4 and IL-10 concentrations, and these alterations were prevented by TAU treatment. CONCLUSION: MSG obesity in rats was not associated with alterations in pro-inflammatory markers in retroperitoneal fat stores; however, reductions in the serum concentrations of anti-inflammatory cytokines and of TNF-α were observed. TAU treatment decreased adiposity, and this effect was associated with the normalization of circulating TNF-α and IL-4 concentrations in MTAU rats.

Metabolic Correction as a tool to improve diabetes type 2 management.

Diabetes Mellitus type 2 (DM2) is a metabolic disease that develops by a decrease in sensitivity of insulin receptors as an effect of the disruption certain metabolic functions in the processing of glucose. DM2 patients have, uncontrolled glucose levels, and commonly have problems with obesity and cardiovascular disease. Patients are treated with standard diet, insulin, diabetic oral agents and antihypertensive drugs, but this approach does not completely stops tissue deterioration since it does not address the metabolic root of the disease. Metabolic correction is proposed as a suitable adjunct treatment to improve clinical outcomes. Metabolic correction is based on diet modification, proper hydration and scientific supplementation directed to improve cellular biochemistry and metabolic efficiency. In addition, other possible benefits may include reduction in medication use, disease complications and medical costs. To test the results of a metabolic correction program, 25 patients with DM2 participated in an education program about adequate food consumption that promoted control of blood glucose levels. Anthropometric measurements and blood tests were performed during a 13 week program based on a low carbohydrate diet, proper hydration and magnesium supplementation. The metabolic correction program implemented by a proprietary educational system resulted in significant reductions in glucose, triglycerides, cholesterol, weight and waist circumference. Improvements in these values could represent an important reduction of coronary heart disease risk factors as well as other chronic degenerative diseases. In addition there was medication dosage reduction in one or more medications in 21 of the 25 participating patients, which suggest that the program has the potential to improve health outcomes and reduce health care costs.

Hypocaloric diet associated with the consumption of jam enriched with microencapsulated fish oil decreases insulin resistance.

BACKGROUND: The metabolic syndrome is related to the increase in cardiovascular diseases. Polyunsaturated fatty acids from fish oil help in reducing cardiovascular risk factors and are natural bindings of PPAR2. OBJECTIVE: To evaluate the impact of hypocaloric diet associated with microencapsulated fish oil supplementation in women with metabolic syndrome. METHODS: We conducted a randomized, single-blind and placebo-controlled clinical trial with adult women who presented metabolic syndrome (n = 30) for 90 days. The volunteers were divided into two groups: placebo group (n = 15) and microencapsulated fish oil group (n = 15) (3 g/day of microencapsulated fish oil containing 0.41 g/day of eicosapentaenoic acid and decosahexaneoic acid). Anthropometric, body composition, clinical and laboratory parameters were assessed before and after the intervention. Paired t-test was used for comparisons within groups and Student's t-test for comparison between groups. We considered p < 0.05 as significant values. RESULTS: The comparison between groups revealed a significant reduction of blood glucose, insulinemia and the homeostasis model assessment in the microencapsulated fish oil group after 90 days, as opposed to the placebo group. We also observed reduction of the systolic arterial pressure in the microencapsulated fish oil group. CONCLUSION: A hypocaloric diet associated with the consumption of microencapsulated fish oil was effective in reducing blood glucose, insulinemia and insulin resistance in women with MS.

Antecedentes: El síndrome metabólico se relaciona con un incremento de las enfermedades cardiovasculares. Los ácidos grasos poliinsaturados del aceite de pescado ayudan a reducir los factores de riesgo cardiovascular y son ligandos naturales del PPAR2. Objetivo: Evaluar el impacto de la dieta hipocalórica asociada con suplementación de aceite de pescado microencapsulado en mujeres con síndrome metabólico. Métodos: Realizamos un ensayo clínico de distribución aleatoria, simple ciego y controlado con placebo en mujeres adultas con síndrome metabólico (n = 30) durante 90 días. Se dividió a las voluntarias en dos grupos: el grupo placebo (n = 15) y el grupo con aceite de pescado microencapsulado (n = 15) (3 g/día de aceite de pescado microencapsulado que contienen 0,41 g/día de ácido eicosapentaenoico y de ácido decosahexaneoico). Se evaluaron parámetros antropométricos, clínicos y de laboratorio y la composición corporal antes y después de la intervención. Se emplearon la prueba t pareada para las comparaciones dentro de los grupos y la prueba t de Student para la comparación entre grupos. Consideramos valores significativos de p < 0,05. Resultados: La comparación entre grupos reveló una reducción significativa de la glucosa sanguínea, la insulinemia y la evaluación del modelo homeostático en el grupo de aceite de pescado microencapsulado tras 90 días, en comparación con el grupo placebo. También observamos una reducción de la presión arterial sistólica en el grupo con aceite de pescado microencapsulado. Conclusión: La dieta hipocalórica asociada con el consumo de aceite de pescado microencapsulado fue eficaz en la reducción de la glucosa sanguínea, la insulinemia y la resistencia a la insulina en mujeres con SM.

Microvascular disorders in obese Zucker rats are restored by a rice bran diet.

BACKGROUND AND AIM: Nutritional-based approaches aimed to prevent microvascular dysfunction associated to obesity present potential advantages over pharmacological strategies. Our aim was to test whether a rice bran enzymatic extract (RBEE)-supplemented diet could attenuate microvascular alterations in obese rats. METHODS AND RESULTS: Lean and obese Zucker rats were fed standard diet supplemented or not with 1% and 5% RBEE for 20 weeks. Functional studies were performed in small mesenteric arteries in isometric myograph. Immunoblotting and fluorescence studies were made in arterial homogenates and arterial sections, respectively. RBEE-supplementation restored microvascular function in obese rats through a marked increase in NO and endothelial-derived hyperpolarizing factor contribution by up-regulation of eNOS and calcium-activated potassium channels expression, respectively, in association to a substantial reduction of microvascular inflammation and superoxide anion formation. These data agrees with the beneficial actions of RBEE on dyslipidemia, hyperinsulinemia and hypertension in obesity. CONCLUSION: The multi-factorial properties of RBEE-diet, especially for restoring the function of small resistance arteries shows this dietary-based approach to be a promising candidate for prevention of microvascular alterations in obesity, which are crucial in cardiovascular events in obese subjects.

Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance in mice with established obesity.

Our group recently demonstrated that simultaneous administration of trehalose with a high-fat diet (HFD) suppresses adipocyte hypertrophy and mitigates insulin resistance in mice. For the present study, we hypothesized that similar effects of trehalose would be observed in mice with previously-established obesity. Obese mice were fed a HFD and drinking water containing 0.3 or 2.5% (weight/volume) trehalose or distilled water (DW) ad libitum for 8 wk. After 7 wk intake of a HFD and trehalose, fasting serum insulin levels and homeostasis model assessment-insulin resistance (HOMA-IR) in the 0.3% Tre/HFD group were significantly lower than those in the DW/HFD group (p<0.05). After 8 wk of treatment, mesenteric adipocytes in the 0.3% Tre/HFD group showed significantly less hypertrophy than those in the DW/HFD group. Mechanistic analysis indicated that levels of high molecular weight (HMW) adiponectin in the serum of the 0.3% Tre/HFD group were significantly higher than those in the DW/HFD group. The expression levels of insulin receptor substrate-1 (IRS-1) and insulin receptor substrate-2 (IRS-2) messenger RNA (mRNA) in muscle were also significantly increased by trehalose intake. Our data therefore suggest that administration of trehalose to obese mice mitigates insulin resistance by suppressing adipocyte hypertrophy and increasing serum HMW adiponectin, resulting in upregulation of IRS-1, and IRS-2 expression in muscle. These results further suggest that trehalose is a functional saccharide that may be used to prevent the progression of insulin resistance.

Modulation of Zn-induced hyperinsulinemia/insulin resistance in Wistar rat fed modified poultry egg(psi).

Excessive bioavailability of Zn causes Cu and Mg deficiencies resulting in hyperglycemia and hyperinsulinemia/insulin resistance. These defects may ameliorate if the ionic imbalance in them is corrected. In view of this, three groups of rats were included in this study. Initially, they were fed on semi-synthetic equicalories basal diet containing 20 mg Zn (control, group-I), on 40 mg Zn (group-II) and 80 mg Zn/kg diet (group-III) respectively for 3 months. Thereafter, half of the rats in group-II and III were shifted on Cu and Mg enriched modified poultry egg (ME(Psi)) mixed diets (groups-IIME and IIIME) while the remaining were continued to feed on their respective diets for another 3 months completing a total of 6 months. Hyperglycemia, hyperinsulinemia, hypercortisolemia, hyperzincemia, hypercupremia and hypermagnesaemia with corresponding increase of lipid droplets in the zona fasciculate of adrenal cortex and reduction in liver glycogen content in rats of groups-II and III were recorded. These changes were linked with a rise in Zn and fall in Cu and Mg in their liver. The addition of ME(Psi) in their diets led to fall of Zn and rise in liver Cu and Mg, and fall in serum Zn, Cu and Mg resulting in the improvement of glucose disposal, increase in insulin sensitivity, reduction in lipid droplets in zona fasciculate and increase in glycogen content in the liver approaching closer to the control group-I. The data suggest that these ME(Psi) can serve as non-pharmacological dietary supplement to prevent insulin resistance/hyperinsulinemia in populations who are at higher risk of diabetes mellitus either due to their genetic predisposition of excessive absorption and retention of Zn or due to higher Zn content in the food chain.

Oral supplementation of propionyl-l-carnitine reduces body weight and hyperinsulinaemia in obese Zucker rats.

Propionyl-L-carnitine (PLC) is an SCFA esterified to carnitine that plays an important role in fatty acid oxidation and energy expenditure, in addition to having a protective effect on the endothelium. In order to evaluate the effect of PLC on an animal model of obesity, insulin resistance and, consequently, endothelial dysfunction, lean and obese Zucker rats (OZR) received either vehicle- or PLC-supplemented drinking water (200 mg/kg per d) for 20 weeks. Body weight, food intake, systolic blood pressure and heart rate were controlled weekly and an oral glucose tolerance test was performed. Fasting glucose, TAG, cholesterol, HDL, NEFA, adiponectin and insulin were analysed in serum. Visceral adipose tissue and liver were weighed and liver TAG liver composition was evaluated. Endothelial and vascular functions were assessed in the aorta and small mesenteric arteries by response to acetylcholine, sodium nitroprusside and phenylephrine (Phe); NO participation was evaluated after incubation with the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and endothelial NOS protein expression by Western blotting. PLC decreased body-weight gain, food intake, adiposity, insulin serum concentration and TAG liver content and improved insulin resistance. Aortae from OZR receiving either vehicle or PLC exhibited a lower contractile response to Phe. PLC-treated OZR showed an enhanced release of endothelial NO upon the adrenergic stimulation. The protection of vascular function found after treatment with PLC in an animal model of insulin resistance supports the necessity of clinical trials showing the effect of L-carnitine supplements on metabolic disorders.

High isoflavone soy diet increases insulin secretion without decreasing insulin sensitivity in premenopausal nonhuman primates.

Consuming soy and soy isoflavones has been shown to cause modest improvements in plasma lipids, lipoproteins, and indices of insulin sensitivity in postmenopausal women. The effect of soy on such end points is attributed often to estrogen receptor agonism by isoflavones. Recent in vitro studies suggest that isoflavones, in combination with high estrogen concentrations (within the range seen circulating in premenopausal women), function as estrogen receptor antagonists that potentially may counteract the beneficial effects seen with soy consumption. We studied insulin sensitivity in 15 premenopausal nonhuman primates consuming either a high isoflavone soy diet or a soy-free casein/lactalbumin diet for 4 months. Insulin sensitivity was measured by intravenous glucose tolerance testing, hyperinsulinemic-euglycemic clamps, and insulin-stimulated insulin receptor and protein kinase B phosphorylation levels in muscle. In addition, plasma lipids, adiponectin, thyroid hormone, and body weights are reported. We show that high isoflavones do not adversely affect insulin sensitivity but do significantly alter insulin secretion to glucose stimulation. Small but significant increases in thyroxine and increased high-density lipoprotein cholesterol were observed as has been reported commonly with soy intake. These study results demonstrate that consumption of soy containing high isoflavone levels is not associated with changes in insulin sensitivity in the high estrogen milieu of the premenopausal female.

Beneficial effects of Zingiber officinale Roscoe on fructose induced hyperlipidemia and hyperinsulinemia in rats.

Fructose supplementation produced cardinal features of Syndrome-X including significant elevations in seum cholesterol, triglyceride, glucose and insulin and also in body weight. While treatment with methanolic extract of dried rhizomes of Zingiber officinale produced a significant reduction in fructose induced elevation in lipid levels, bodyweight, hyperglycemia and hyperinsulinemia, treatment with ethyl acetate extract of Z officinale did not poduce any significant change in either of the last two parameters. However, it produced a significant reduction in elevated lipid levels and body weight The concentration of 6-gingerol was found to be higher in methanolic extract and less in ethyl acetate extract. The results suggest that the methanolic extract of Z officinale produces better effects as compared to ethyl acetate extract in fructose induced hyperlipidemia associated with insulin resistance. The extent of activity appears to be dependent on the concentration of 6-gingerol present in the extracts.

Effect of Suaeda fruticosa aqueous extract in the hypercholesterolaemic and insulin-resistant sand rat.

To study the effect of Suaeda fruticosa in lipid and carbohydrate metabolism in the hypercholesterolaemic and insulin resistant sand rat, 25 rats were subjected to a high cholesterol diet for 90 days. On the 45th day the animals were divided into two groups: control and treated. Aqueous extract prepared in infusion at 10 per cent was administered orally at 1.5 ml per 100 g of body weight per day. On the 90th day, the control group developed a severe hyperlipidaemia, impaired glucose tolerance test and insulin resistance. Treatment by Suaeda fruticosa extract showed hypoglycaemic (41 per cent) and antihyperglycaemic (53 per cent) effects. Furthermore, the plant led to a decrease in plasma levels of insulin (31 per cent), total cholesterol (50 per cent), LDL cholesterol (55 per cent), VLDL cholesterol (49 per cent), oxidized LDL (40 per cent), lecithin cholesterol acyl transferase (44 per cent), triglycerides (57 per cent) and free fatty acids (36 per cent). We concluded that Suaeda fruticosa aqueous extract contains at least two compounds responsible for hypoglycaemic and hypolipidaemic activities.

Effects of Olea europea var. oleaster leaves in hypercholesterolemic insulin-resistant sand rats.

Sand rats fed a hypercaloric diet manifest obesity and diabetes. We have used this model to develop hypercholesterolaemia and describe the beneficial action of Olea europea var. oleaster leaves. Twenty-eight sand rats submitted to a high cholesterol diet for four months were assigned to control and treated groups. Plant decoction at 10 per cent was given orally for two months. Results showed that the control group exhibited hyperglycaemia, glucose intolerance, hypercholesterolaemia and moderate hyperinsulinaemia. Light microscopic study showed thickening of capillary walls in skin, pancreas and kidney. The treatment produced hypoglycaemic (43 per cent, p < 0.001), antihyperglycaemic (48 per cent, p < 0.001) and hypoinsulinaemic (39 per cent, p < 0.01) activities. In addition, the plant presented a hypocholesterolaemic effect (47 per cent, p < 0.001) accompanied by lowering of oxidized LDL (30 per cent, p < 0.01). Accordingly, capillary wall thickening was reduced in skin and pancreas and completely prevented in kidney. The data demonstrate that oleaster leaves possess at least two active compounds to treat hypercholesterolaemia and diabetes.

Islet amyloid polypeptide in Psammomys obesus (sand rat): effects of nutritionally induced diabetes and recovery on low-energy diet or vanadyl sulfate treatment.

We investigated the possible relationship between islet amyloid polypeptide (IAPP) and the hyperinsulinemia and/or hyperglycemia that is seen in the desert-adapted gerbil Psammomys obesus, when the animal is transferred from a low-energy (LE) diet to a high-energy (HE) diet. The effects of vanadyl sulfate and transition from a HE to a LE diet on the diabetic state of the Psammomys were also studied. Psammomys maintained on a LE diet, showing normoinsulinemia and normoglycemia (group A), were used as controls. IAPP and insulin immunoreactivity in the islets of Langerhans was studied using the peroxidase-antiperoxidase technique and plasma levels of the two hormones were determined by radioimmunoassays. The islet immunoreactivity of both IAPP and insulin was significantly weaker in the hyperinsulinemic and hyperglycemic Psammomys (group C) compared to group A. Transfer to a LE diet resulted in complete recovery of the IAPP- and insulin-staining pattern to that seen in group A [group A--Rec (nutrition)]. The plasma IAPP levels of the group C animals were not significantly higher than in group A, while after vanadyl sulfate treatment the IAPP levels and IAPP/insulin ratios remained significantly higher [group A--Rec (vanadyl)]. At the same time the circulating levels of glucose and insulin were restored to normal. Conclusively, islet IAPP and insulin immunoreactivity disappeared and reappeared in parallel in Psammomys transferred to a HE diet and back to a LE diet. Furthermore, vanadyl sulfate treatment of the hyperinsulinemic and hyperglycemic animals normalized circulating glucose and insulin levels, but not IAPP levels, possibly due to a negative feedback effect of IAPP on insulin release.

L-glutamine supplementation of a high fat diet reduces body weight and attenuates hyperglycemia and hyperinsulinemia in C57BL/6J mice.

C57BL/6J (B/6J) mice are genetically predisposed to become overweight and develop hyperglycemia if raised on a high fat diet. The purpose of the present study was to explore the effect of dietary supplementation of L-glutamine (Gln), an inhibitor of fatty acid oxidation, on the development of hyperglycemia and excessive weight gain. Groups of 10 age- and weight-matched male B/6J mice were raised on one of four diets: 1) a low fat, low sucrose (LL), studied separately, 2) a high fat, low sucrose (HL) diet alone, 3) high fat, low sucrose supplemented with L-glutamine (HL+Gln) and 4) high fat, low sucrose supplemented with L-alanine (HL+Ala). Energy intake, body weight, plasma glucose and insulin concentrations were monitored over time. We found no difference in energy intake per unit body weight between any groups after the first 2 wk of feeding. However, the mean +/- SEM for body weight (27.1 +/- 0.6 g) of the LL group measured at 16 wk was lower (P < 0.05) than that of the HL group at 37.9 +/- 1.9 g. Also, after 5.5 mo, the mean +/- SEM for plasma glucose and insulin concentrations in the LL group of mice were 6.9 +/- 0.4 mmol/l and 146 +/- 30 pmol/l, which were lower (P < 0.05) than those in the HL group at 10.1 +/- 0.9 mmol/l and 438 +/- 84 pmol/l, respectively. Although both amino acids caused a 10% reduction (P < 0.05) in body weight compared with HL feeding at wk 16, only Gln supplementation resulted in persistent reductions in both plasma glucose and insulin concentrations over 5.5 mo. In another experiment, when Gln was added to the high fat (HL) diet of heavy hyperglycemic animals for 2 mo, body weight gain, hyperglycemia and hyperinsulinemia were attenuated. In conclusion, supplementing glutamine to a high fat diet reduces body weight and attenuated hyperglycemia and hyperinsulinemia in B/6J mice.

Effects of hyperinsulinism and of diabetes on proteoglycans of the intervertebral disc in weanling sand rats.

Weanling sand rats (Psammomys obesus) develop hyperinsulinemia or diabetes or both, if fed a standard laboratory diet without a supplement of fiber rich salt bush. The annuli fibrosi of hyperinsulinemic or diabetic animals, which are still hyperinsulinemic, show a slight but statistically significant increase in chondroitin sulfate and a lesser, statistically nonsignificant increase in keratan sulfate. Possible causes of these changes are discussed and the likelihood of a role of hyperinsulinism in their production is pointed out.