Abstract D-pinitol is one of the major inositol found in plants and studies suggest its potential hypoglycemic and hypolipidemic actions in diabetic rodents. Here, we investigated the actions of D-pinitol on adiposity, and in lipid and glycemic homeostasis in monosodium glutamate (MSG)-obese mice. Swiss mice received daily subcutaneous injections of MSG [(4g/kg of body weight (BW)] or saline [1.25g/kg BW; control (CTL)] during their first five days of life. From 90-120 day-old, half of the MSG and CTL groups received 50 mg D-pinitol/kg BW/day (MPIN and CPIN groups) or vehicle (saline; MSG and CTL groups) by gavage. MSG mice displayed higher abdominal adiposity and hepatic triglycerides (TG) deposition, and increased hepatic expression of lipogenic genes (SREBP-1c, ACC-1 and FASN), but downregulation in AMPKα mRNA. MSG mice also exhibited hyperinsulinemia, islet hypersecretion and hypertrophy, glucose intolerance and insulin resistance. D-pinitol did not change adiposity, glucose intolerance, insulin resistance, but increased hepatic triglycerides (TG) content in MPIN mice, which was associated with increases in gene expressions of SREBP-1c and FASN, but reduction in AMPKα. Furthermore, D-pinitol enhanced insulin secretion in MPIN and CPIN groups. Therefore, D-pinitol enhanced glucose-induced insulin secretion, which may account to enhances hepatic lipogenesis and TG deposition in MPIN mice.

As vias da fosfatidilinositol-3-cinase e da proteína cinase ativada por mitógeno medeiam crescimento, proliferação, sobrevivência e morte das células β. Investigamos se a restrição proteica durante a prenhez altera a morfometria da ilhota ou a expressão e a fosforilação de diversas proteínas envolvidas nas vias da fosfatidilinositol-3-cinase e da proteína cinase ativada por mitógeno. Como controles, ratas adultas não prenhes e prenhes foram alimentadas com uma dieta norpoproteica (17%). As ratas não prenhes e prenhes dos grupos experimentais foram alimentadas com dieta hipoproteica (6%) por 15 dias. A dieta hipoproteica durante a prenhez aumentou as concentrações séricas de prolactina, reduziu as concentrações séricas de corticosterona e a expressão da proteína cinase B/AKT1 (AKT1) e da proteína p70 ribossomal S6 cinase (p70S6K), bem como a área das ilhotas, mas não alterou o conteúdo de insulina nas ilhotas pancreáticas. A prenhez aumentou a expressão da proteína homóloga ao colágeno com domínio SH2 (SHC) e a proteína cinase regulada por sinal extracelular 1/2 (ERK1/2), independente da dieta consumida. A fosforilação da ERK1/2 (pERK1/2) foi similar em ilhotas de ratas prenhes e não prenhes alimentadas com dieta hipoproteica, e foi maior em ilhotas de ratas prenhes do que não prenhes alimentadas com dieta normoproteica. Portanto, um curto período de dieta hipoproteica durante a prenhez foi suficiente para reduzir o conteúdo de proteínas da via da fosfatidilinositol-3-cinase e afetar a morfometria da ilhota.

The phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways mediate β cell growth, proliferation, survival and death. We investigated whether protein restriction during pregnancy alters islet morphometry or the expression and phosphorylation of several proteins involved in the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. As controls, adult pregnant and non-pregnant rats were fed a normal-protein diet (17%). Pregnant and non-pregnant rats in the experimental groups were fed a low-protein diet (6%) for 15 days. Low protein diet during pregnancy increased serum prolactin level, reduced serum corticosterone concentration and the expression of both protein kinase B/AKT1 (AKT1) and p70 ribosomal protein S6 kinase (p70S6K), as well as the islets area, but did not alter the insulin content of pancreatic islets. Pregnancy increased the expression of the Src homology/collagen (SHC) protein and the extracellular signal-regulated kinases 1/2 (ERK1/2) independent of diet. ERK1/2 phosphorylation (pERK1/2) was similar in islets from pregnant and non-pregnant rats fed a low-protein diet, and was higher in islets from pregnant rats than in islets from non-pregnant rats fed a normal-protein diet. Thus, a short-term, low-protein diet during pregnancy was sufficient to reduce the levels of proteins in the phosphatidylinositol 3-kinase pathway and affect islet morphometry.

O ciclo glicose-ácido graxo explica a preferência do tecido muscular pelos ácidos graxos durante atividade moderada de longa duração. Em contraste, durante o exercício de alta intensidade, há aumento na disponibilidade e na taxa de oxidação de glicose. A produção de espécies reativas de oxigênio (EROs) durante a atividade muscular sugere que o balanço redox intracelular é importante na regulação do metabolismo de lipídios/carboidratos. As EROs diminuem a atividade do ciclo de Krebs e aumentam a atividade da proteína desacopladora mitocondrial. O efeito oposto é esperado durante a atividade moderada. Assim, as questões levantadas nesta revisão são: Por que o músculo esquelético utiliza preferencialmente os lipídios no estado basal e de atividade moderada? Por que o ciclo glicose-ácido graxo falha em exercer seus efeitos durante o exercício intenso? Como o músculo esquelético regula o metabolismo de lipídios e carboidratos em regime envolvendo o ciclo contração-relaxamento.

The glucose-fatty acid cycle explains the preference for fatty acid during moderate and long duration physical exercise. In contrast, there is a high glucose availability and oxidation rate in response to intense physical exercise. The reactive oxygen species (ROS) production during physical exercise suggests that the redox balance is important to regulate of lipids/carbohydrate metabolism. ROS reduces the activity of the Krebs cycle, and increases the activity of mitochondrial uncoupling proteins. The opposite effects happen during moderate physical activity. Thus, some issues is highlighted in the present review: Why does skeletal muscle prefer lipids in the basal and during moderate physical activity? Why does glucose-fatty acid fail to carry out their effects during intense physical exercise? How skeletal muscles regulate the lipids and carbohydrate metabolism during the contraction-relaxation cycle?

Chronic administration of glucocorticoids induces insulin resistance that is compensated by an increase in p-cell function and mass. Since insulin signaling is involved in the control of p-cell function and mass, we investigated the content of insulin pathway proteins in pancreatic islets. Rats were made insulin resistant by daily administration of dexamethasone (1mg/kg, b.w., i.p.) for 5 consecutive days (DEX), whilst control rats received saline (CTL). Circulating insulin and insulin released from isolated islets were measured by radioimmunoassay whereas the content of proteins was analyzed by Western blotting. DEX rats were hyperinsulinemic and exhibited augmented insulin secretion in response to glucose (P < 0.01). The IRa-subunit, IRS-1, Shc, AKT, p-p70S6K, ERK1/2, p-ERK1/2, and glucocorticoid receptor protein levels were similar between DEX and CTL islets. However, the IRp-subunit, p-IRp-subunit, IRS-2, PI3-K, p-AKT and p70S6K protein contents were increased in DEX islets (P < 0.05). We conclude that IRS-2 may have a major role, among the immediate substrates of the insulin receptor, to link activated receptors to downstream signaling components related to islet function and growth in this insulin-resistant rat model.

During pregnancy and the perinatal period of life, prolactin (PRL) and other lactogenic substances induce adaptation and maturation of the stimulus-secretion coupling system in pancreatic β-cells. Since the SNARE molecules, SNAP-25, syntaxin 1, VAMP-2, and synaptotagmins participate in insulin secretion, we investigated whether the improved secretory response to glucose during these periods involves alteration in the expression of these proteins. mRNA was extracted from neonatal rat islets cultured for 5 days in the presence of PRL and from pregnant rats (17th-18th days of pregnancy) and reverse transcribed. The expression of genes was analyzed by semi-quantitative RT-PCR assay. The expression of proteins was analyzed by Western blotting and confocal microscopy. Transcription and expression of all SNARE genes and proteins were increased in islets from pregnant and PRL-treated neonatal rats when compared with controls. The only exception was VAMP-2 production in islets from pregnant rats. Increased mRNA and protein expression of synaptotagmin IV, but not the isoform I, also was observed in islets from pregnant and PRL-treated rats. This effect was not inhibited by wortmannin or PD098059, inhibitors of the PI3-kinase and MAPK pathways, respectively. As revealed by confocal laser microscopy, both syntaxin 1A and synaptotagmin IV were immunolocated in islet cells, including the insulin-containing cells. These results indicate that PRL modulates the final steps of insulin secretion by increasing the expression of proteins involved in membrane fusion.