Reinforcing the Recommendations for Future Research

(Poly)phenols have anti-diabetic properties that are mediated through the regulation of the main biomarkers associated with type 2 diabetes mellitus (T2DM) (fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), insulin resistance (IR)), as well as the modulation of other metabolic, inflammatory and oxidative stress pathways. A wide range of human and pre-clinical studies supports these effects for different plant products containing mixed (poly)phenols (e.g., berries, cocoa, tea) and for some single compounds (e.g., resveratrol). We went through some of the latest human intervention trials and pre-clinical studies looking at (poly)phenols against T2DM to update the current evidence and to examine the progress in this field to achieve consistent proof of the anti-diabetic benefits of these compounds. Overall, the reported effects remain small and highly variable, and the accumulated data are still limited and contradictory, as shown by recent meta-analyses. We found newly published studies with better experimental strategies, but there were also examples of studies that still need to be improved. Herein, we highlight some of the main aspects that still need to be considered in future studies and reinforce the messages that need to be taken on board to achieve consistent evidence of the anti-diabetic effects of (poly)phenols.publishersversionpublishe

Peripheral Dopamine Directly Acts on Insulin-Sensitive Tissues to Regulate Insulin Signaling and Metabolic Function

Funding: This work was supported by a grant from GIFT (Grupo de Investigacao Fundamental e Translacional) from the Portuguese Society of Diabetes. G.T and B.F.M. were supported by PhD Grants from the Portuguese Foundation for Science and Technology, Reference PD/BD/127822/2016 and PD/BD/128336/2017, respectively. FOM is supported by the Portuguese Foundation for Science and Technology, contract CEECIND/04266/2017.Dopamine is a key regulator of glucose metabolism in the central nervous system. However, dopamine is also present in the periphery and may have direct effects on insulin-sensitive tissues. Dopamine receptor 2 (D2R) agonist bromocriptine is a FDA-approved drug for type 2 diabetes. Herein, we explored the role of peripheral dopamine and its receptors in regulating glucose uptake and metabolism on insulin-sensitive tissues. Peripheral dopamine effect in [3H]2-deoxyglucose uptake in insulin-sensitive tissues was tested in vivo in rats. Direct effects on [3H]2-deoxyglucose uptake, insulin receptor phosphorylation, and regulation of metabolic function were tested ex vivo in the liver, soleus muscle, and white and brown adipose tissues. Bromocriptine and the antagonists domperidone, D2R antagonist, and haloperidol, antagonist of both dopamine receptor 1 (D1R) and D2R, were used to disclose dopamine receptors’ involvement. Peripheral dopamine increases glucose uptake in vivo. Ex vivo, only dopamine increased glucose uptake in the soleus, while bromocriptine increased it in the liver; the effects were reverted by haloperidol and domperidone, respectively. In adipose tissue, domperidone reverted dopamine- and bromocriptine-mediated potentiation of insulin-induced glucose uptake, but in turn increased the insulin receptor, Akt, AMPK, HSL, ACC, and ACL, phosphorylation. In the soleus muscle, AMPK-phosphorylation increased with bromocriptine and dopamine whose effects were suppressed by domperidone and haloperidol. In conclusion, peripheral dopamine stimulates glucose uptake with its receptors being differentially involved in glucose uptake in insulin-sensitive tissues. Dopamine also has a role in lipid metabolism in white adipose tissue. Altogether, these results suggest that peripheral modulation of the dopaminergic system should be further evaluated as a putative therapeutic approach for metabolic disorders.publishersversionpublishe

CIRURGIA METABÓLICA EM DOENTES COM DIABETES TIPO 2. FICÇÃO OU OPÇÃO TERAPÊUTICA?

A diabetes tipo 2 tem uma elevada prevalência a nível mundial e está associada à inatividade física e ao excesso de peso. Em doentes obesos, a redução de peso através de cirurgia bariátrica tem-se revelado mais eficaz no controlo do metabolismo glicídico que abordagens conservadoras. Por outro lado, o reconhecimento do papel das hormonas digestivas no controlo glicémico e na homeostase energética conduziu a uma nova visão dos mecanismos subjacentes à cirurgia bariátrica que, no contexto da sua eficácia no controlo de comorbilidades, também tem sido apelidada de cirurgia metabólica. Após a cirurgia, observa-se um aumento pós-prandial das hormonas com efeitos anorético e incretina, bem como a supressão de hormonas orexigénicas. Estudos experimentais em modelos não-obesos de diabetes tipo 2 demonstraram efeitos pós-cirúrgicos semelhantes, aparentemente independentes da perda de peso. Pequenas séries iniciais, utilizando técnicas estandardizadas em doentes portadores de diabetes tipo 2 com um índice de massa corporal <35 kg/m2, demonstraram resultados favoráveis. Novas técnicas cirúrgicas derivadas da experimentação animal que incluem a transposição de um segmento ileal para o tubo digestivo próxima,l demonstraram resultados promissores em estudos que incluíam doentes diabéticos tipo 2 anteriormente considerados sem indicação cirúrgica. Sociedades científicas da área médica e da área cirúrgica têm vindo a modificar as suas orientações terapêuticas no sentido de considerar a opção cirúrgica num grupo cada vez mais alargado de doentes

Primary Effects on Skeletal Muscle

The present study was supported by the Portuguese Society of Diabetes. JS was supported by a PhD Grant from the Portuguese Foundation for Science and Technology, PD/BD/105890/2014.Epidemiological studies showed that chronic caffeine intake decreased the risk of type 2 diabetes. Previously, we described that chronic caffeine intake prevents and reverses insulin resistance induced by hypercaloric diets and aging, in rats. Caffeine has several cellular mechanisms of action, being the antagonism of adenosine receptors the only attained with human coffee consumption. Here, we investigated the subtypes of adenosine receptors involved on the effects of chronic caffeine intake on insulin sensitivity and the mechanisms and sex differences behind this effect. Experiments were performed in male and female Wistar rats fed either a chow or high-sucrose (HSu) diet (35% of sucrose in drinking water) during 28 days, to induce insulin resistance. In the last 15 days of diet the animals were submitted to DPCPX (A1 antagonist, 0.4 mg/kg), SCH58261 (A2A antagonist, 0.5 mg/kg), or MRS1754 (A2B antagonist, 9.5 μg/kg) administration. Insulin sensitivity, fasting glycaemia, blood pressure, catecholamines, and fat depots were assessed. Expression of A1, A2A, A2B adenosine receptors and protein involved in insulin signaling pathways were evaluated in the liver, skeletal muscle, and visceral adipose tissue. UCP1 expression was measured in adipose tissue. Paradoxically, SCH58261 and MRS1754 decreased insulin sensitivity in control animals, whereas they both improved insulin response in HSu diet animals. DPCPX did not alter significantly insulin sensitivity in control or HSu animals, but reversed the increase in total and visceral fat induced by the HSu diet. In skeletal muscle, A1, A2A, and A2B adenosine receptor expression were increased in HSu group, an effect that was restored by SCH58261 and MRS1754. In the liver, A1, A2A expression was increased in HSu group, while A2B expression was decreased, being this last effect reversed by administration of MRS1754. In adipose tissue, A1 and A2A block upregulated the expression of these receptors. A2 adenosine antagonists restored impaired insulin signaling in the skeletal muscle of HSu rats, but did not affect liver or adipose insulin signaling. Our results show that adenosine receptors exert opposite effects on insulin sensitivity, in control and insulin resistant states and strongly suggest that A2 adenosine receptors in the skeletal muscle are the majors responsible for whole-body insulin sensitivity.publishersversionpublishe

Circulating Dopamine Is Regulated by Dietary Glucose and Controls Glucagon-like 1 Peptide Action in White Adipose Tissue

Funding: This work was supported by a grant from GIFT (Grupo de Investigação Fundamental e Translational) from the Portugal Society of Diabetes and Portugal Foundation for Science and Technology (PEst UID/NEU/04539/2013 and UID/NEU/04539/2019: CNC.IBILI; PEst UIDB/04539/2020 and UIDP/04539/2020: CIBB). G.T. and D.R.S. were supported by Ph.D. Grants from the Portuguese Foundation for Science and Technology (PD/BD/127822/2016 and 2021.08160.BD respectively). J.F.S. is supported by a contract from the Portuguese Foundation for Science and Technology (CEEC IND/02428/2018).Dopamine directly acts in the liver and white adipose tissue (WAT) to regulate insulin signaling, glucose uptake, and catabolic activity. Given that dopamine is secreted by the gut and regulates insulin secretion in the pancreas, we aimed to determine its regulation by nutritional cues and its role in regulating glucagon-like peptide 1 (GLP-1) action in WAT. Solutions with different nutrients were administered to Wistar rats and postprandial dopamine levels showed elevations following a mixed meal and glucose intake. In high-fat diet-fed diabetic Goto-Kakizaki rats, sleeve gastrectomy upregulated dopaminergic machinery, showing the role of the gut in dopamine signaling in WAT. Bromocriptine treatment in the same model increased GLP-1R in WAT, showing the role of dopamine in regulating GLP-1R. By contrast, treatment with the GLP-1 receptor agonist Liraglutide had no impact on dopamine receptors. GLP-1 and dopamine crosstalk was shown in rat WAT explants, since dopamine upregulated GLP-1-induced AMPK activity in mesenteric WAT in the presence of the D2R and D3R inhibitor Domperidone. In human WAT, dopamine receptor 1 (D1DR) and GLP-1R expression were correlated. Our results point out a dietary and gut regulation of plasma dopamine, acting in the WAT to regulate GLP-1 action. Together with the known dopamine action in the pancreas, such results may identify new therapeutic opportunities to improve metabolic control in metabolic disorders.publishersversionpublishe

Nutritional Modulation of Dietary Sugars as a Strategy to Improve Insulin Resistance and Energy Balance in Diabetes

Lifestyle changes and less healthy behaviours include dietary changes toward increased consumption of Westernised diets and processed food [...