Possible Links between Intestinal Permeablity and Food Processing: A Potential Therapeutic Niche for Glutamine

Increased intestinal permeability is a likely cause of various pathologies, such as allergies and metabolic or even cardiovascular disturbances. Intestinal permeability is found in many severe clinical situations and in common disorders such as irritable bowel syndrome. In these conditions, substances that are normally unable to cross the epithelial barrier gain access to the systemic circulation. To illustrate the potential harmfulness of leaky gut, we present an argument based on examples linked to protein or lipid glycation induced by modern food processing. Increased intestinal permeability should be largely improved by dietary addition of compounds, such as glutamine or curcumin, which both have the mechanistic potential to inhibit the inflammation and oxidative stress linked to tight junction opening. This brief review aims to increase physician awareness of this common, albeit largely unrecognized, pathology, which may be easily prevented or improved by means of simple nutritional changes

Apnéia obstrutiva do sono e resistência à insulina: qual o papel da microcirculação?

Obstructive sleep apnea is an increasingly recognized medical problem. The recent attention to its frequency in the general population and its important role in metabolic, vascular, and behavioral aspects have sharply increased the number and nature of investigations, thereby revealing new aspects that open new approaches in research. Whereas obstructive sleep apnea is a well-known phenomenon accompanying obesity and diabetes, new findings strongly suggest that this close relationship may also operate in the opposite direction. Indeed obstructive sleep apnea may be a primary feature inducing or aggravating a series of vascular and metabolic disturbances closely resembling the metabolic syndrome. This review will discuss established and potential mechanisms responsible for these changes. Obstructive sleep apnea indeed appears to gather all the elements necessary to induce insulin resistance, hypertension, and possibly heart failure. After careful analysis of these modifications and considering how they are intertwined, we propose that microcirculation could represent the common denominator mediating the progression of this pathology, as it is eventually the case in the metabolic syndrome and diabetes domain. This plausible hypothesis is discussed in detail and should be verified by appropriate preclinical and clinical protocols, which are now achievable by using noninvasive techniques in humans.A apnéia obstrutiva do sono é um problema médico cujo reconhecimento tem aumentado. As últimas pesquisas mostrando sua freqüência na população em geral e seu importante papel metabólico, vascular e comportamental aumentou o número e a natureza das investigações revelando, assim, novos aspectos que abrem caminhos para estudos. Embora a apnéia obstrutiva do sono seja um fenômeno bem conhecido acompanhando diabetes e obesidade, novas descobertas sugerem que esta relação causal pode também ser verdadeira no sentido inverso. Na realidade, a apnéia obstrutiva do sono pode ser o marco inicial ou primário que induz ou agrava uma série de distúrbios vasculares e metabólicos que se aproximam da síndrome metabólica. Esta revisão discutirá mecanismos estabelecidos e potenciais responsáveis por estas mudanças. A apnéia obstrutiva do sono parece realmente juntar todos os elementos necessários para induzir resistência à insulina, hipertensão e possivelmente insuficiência cardíaca. Após análise cuidadosa destas modificações, considerando que as mesmas são interligadas, propomos que a microcirculação, como ocorre nos casos de síndrome metabólica e diabetes, poderia representar o denominador comum que mediaria a progressão desta patologia. Esta hipótese é discutida em detalhe e deve ser verificada em estudos pré-clínicos e clínicos apropriados que são atualmente possíveis usando técnicas não-invasivas em humanos

Fructose and Cardiometabolic Disorders: The Controversy Will, and Must, Continue

The present review updates the current knowledge on the question of whether high fructose consumption is harmful or not and details new findings which further pushes this old debate. Due to large differences in its metabolic handling when compared to glucose, fructose was indeed suggested to be beneficial for the diet of diabetic patients. However its growing industrial use as a sweetener, especially in soft drinks, has focused attention on its potential harmfulness, possibly leading to dyslipidemia, obesity, insulin resistance/metabolic syndrome and even diabetes. Many new data have been generated over the last years, confirming the lipogenic effect of fructose as well as risks of vascular dysfunction and hypertension. Fructose exerts various direct effects in the liver, affecting both hepatocytes and Kupffer cells and resulting in non-alcoholic steatotic hepatitis, a well known precursor of the metabolic syndrome. Hepatic metabolic abnormalities underlie indirect peripheral metabolic and vascular disturbances, for which uric acid is possibly the culprit

Short-Term Treatment with Metformin Improves the Cardiovascular Risk Profile in First-Degree Relatives of Subjects with Type 2 Diabetes Mellitus who have a Metabolic Syndrome and Normal Glucose Tolerance without Changes in C-Reactive Protein or Fibrinogen

OBJECTIVE: To study if metformin, when administered to first-degree relatives of type 2 diabetes mellitus subjects who have metabolic syndrome and normal glucose tolerance, could improve the cardiovascular risk profile and reduce the levels of both C-reactive protein and fibrinogen. INTRODUCTION: Metabolic syndrome is associated with higher cardiovascular morbidity and mortality. Metformin has vasculo-protective effects even in normoglycemic subjects, and C-reactive protein and fibrinogen are considered markers of endothelial injury and inflammation. METHODS: Thirty-one non-diabetic first-degree relatives of type 2 diabetes mellitus subjects with metabolic syndrome were randomized (1:1) and double-blinded for placement in the placebo and metformin groups (850mg bid/±90days); 16 subjects were administered metformin (mean age 40.0 [33.5-50] years; 13 females) and 15 subjects were in the placebo group (mean age 37.0 [32-42] years; 9 females). Blood samples were collected at baseline and at the end of treatment for biochemical analyses, including an assessment of C-reactive protein and fibrinogen levels. RESULTS: Metformin improved the lipid profile and decreased fasting plasma glucose, systolic blood pressure, weight and body mass index without changing body composition. For those in the placebo we identified no changes in fibrinogen (282.2 [220.4-323.7] mg/L vs. 286.7 [249.6-295.1] mg/L; NS) or in C-reactive protein levels (0.68 [0.3-1.2] vs. 0.64 [0.3-1.0] mg/L; NS). The same was also observed for the levels of fibrinogen (303.9 [217.6-347.6] mg/L vs. 290.9 [251.5-301.9] mg/L; NS) and C-reactive proteins (0.78 [0.3-1.1] vs. 0.80 [0.4-0.9] mg/L; NS) in the metformin group. CONCLUSIONS: Metformin treatment in first-degree relatives of type 2 diabetes mellitus sufferers who have metabolic syndrome and normal glucose tolerance improved the cardiovascular risk profile without changing the levels of C-reactive protein and fibrinogen

The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease

Antioxidant plants and diabetes mellitus

The incidence of diabetes mellitus (DM) is increasing rapidly and it is expected to increase by 2030. Other than currently available therapeutic options, there are a lot of herbal medicines, which have been recommended for its treatment. Herbal medicines have long been used for the treatment of DM because of the advantage usually having no or less side-effects. Most of these plants have antioxidant activities and hence, prevent or treat hard curable diseases, other than having the property of combating the toxicity of toxic or other drugs. In this review other than presenting new findings of DM, the plants, which are used and have been evaluated scientifically for the treatment of DM are introduced

1,1-Dimethyl­biguanidium(2+) dinitrate

In the crystal structure of the title compound, C4H13N5 2+·2NO3 −, the main inter­molecular inter­actions are the N—H⋯O hydrogen bonds between the cationic amino groups and the O atoms of the nitrate ions. All amino H atoms and nitrate O atoms are involved in the three-dimensional hydrogen-bond network. There are two graph-set motifs R 2 2(8), which include the amino groups connected to the N atoms in the biguanide 3-, 4- and 5-positions, and the O atoms of a nitrate ion. They are extended along the a axis. An O atom of the second nitrate ion is involved in a graph-set motif C(4) that is a part of a helix-like N—H⋯O⋯H—N—H⋯O⋯ chain oriented along the b axis. There are also two weak C—H⋯O inter­actions in the crystal structure

Metformin improves skin capillary reactivity in normoglycaemic subjects with the metabolic syndrome

WSTĘP. Insulinooporność i rodzinne występowanie cukrzycy niezależnie wiążą się z dysfunkcją śródbłonka. Stres oksydacyjny odgrywa kluczową rolę w patofizjologii uszkodzenia naczyń krwionośnych. Metformina, oprócz obniżania stężenia glukozy, działa ochronnie na naczynia. Celem niniejszej pracy by&#179;o zbadanie, czy metformina korzystnie wpływa na krążenie w odżywczych naczyniach włosowatych skóry oraz czy zmniejsza stres oksydacyjny u osób wysokiego ryzyka wystąpienia cukrzycy typu 2 i chorób sercowo-naczyniowych. METODY. Badaniem objęto 30 pacjentów z prawidłowym stężeniem glukozy i zespołem metabolicznym (MS), którzy mieli krewnych chorych na cukrzycę typu 2. średni wiek wynosił 39,1 &#177; 8,4 roku, a wskaźnik masy ciała (BMI) 35,8 &#177; 4,8 kg/m2 (średnia &#177; odchylenie standardowe). Pacjentów losowo podzielono na 2 grupy za pomocą metody podwójnie &#156;lepej próby w stosunku 1:1 - 14 osób otrzymywało placebo, a 16 metforminę (1700 mg/d.). Wyjściowo i po zakończeniu badania pobrano krew do analizy biochemicznej oraz mocz w celu określenia stężenia 8-epi-prostaglandyny F2&#945; (8-epi-PGF2&#945;). Krążenie w naczyniach włosowatych oceniano za pomocą wideokapilaroskopii obrąbka naskórkowego, podczas której analizowano średnicę pętli naczyń włosowatych doprowadzających (AF), odprowadzających (EF) i wierzchołkowych (AP), funkcjonalną gęstość naczyń włosowatych (FCD), prędkość przepływu czerwonych ciałek krwi w spoczynku (RBCV) oraz po 1 minucie od okluzji naczyń tętniczych (RBCVmax), a także czas potrzebny do jej osiągnięcia (TRBCVmax). WNIOSKI. Metformina poprawiła reaktywność naczyń włosowatych skóry u osób z prawidłową glikemią i zespołem metabolicznym, niezależnie od zmian stężenia 8-epi-PGF2&#945;.AIMS. Insulin resistance and a parental history of diabetes mellitus are independently associated with endothelial dysfunction. Oxidative stress has a pivotal role in the pathophysiology of vascular injury. Metformin, in addition to its glucose-lowering properties, has vasculoprotective effects. We investigated whether metformin has beneficial effects on the nutritive skin capillary circulation and deceases oxidative stress in a group at high risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease. METHODS. Thirty normoglycaemic subjects with the metabolic syndrome (MS), who had first-degree relatives with T2DM, participated. The mean age was 39.1 &#177; 8.4 years and body mass index (BMI) 35.7 &#177; &#177; 4.8 kg/m2 (mean &#177; SD). Subjects were randomized 1:1 to receive placebo (n = 14) or metformin (n = 16; 1700 mg/day) in a double-blind study. At baseline and post treatment, blood and urine samples were collected for biochemical and 8-epi-prostaglandin F2&#945; (8-epi-PGF2&#945;) analysis, respectively. Microcirculation was assessed by nailfold videocapillaroscopy, analysing afferent (AF), efferent (EF) and apical (AP) diameters of capillary loops, functional capillary density (FCD), red blood cell velocity at rest (RBCV), after 1 min arterial occlusion (RBCVmax) and time (TRBCVmax) taken to reach it. RESULTS. Groups did not differ significantly in anthropometric, clinical, laboratory or microvascular measurements at baseline. In the metformin group, weight, BMI, systolic blood pressure and fasting plasma glucose fell, and lipid profile and microcirculatory parameters FCD, AF, EF, AP, RBCVmax and TRBCVmax improved (all p < 0.01). No relationship between clinico-laboratory parameters and microvascular reactivity was observed, except for changes in total and lowdensity lipoprotein-cholesterol and RBCVmax. 8-epi-PGF2&#945; did not change significantly in either group. CONCLUSIONS. Metformin improved skin capillary reactivity in normoglycaemic MS subjects independently of significant changes in 8-epi-PGF2&#945; levels