Insulin sensitivity and insulin secretion in adults with Friedreich's Ataxia: the role of skeletal muscle.

INTRODUCTION: Friedreich's Ataxia (FRDA) is a multi-system disorder caused by frataxin deficiency. FRDA-related diabetes mellitus (DM) is common. Frataxin supports skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity, a mediator of insulin sensitivity. Our objective was to test the association between skeletal muscle health and insulin sensitivity and secretion in adults with FRDA without DM. METHODS: Case-control study (NCT02920671). Glucose and insulin metabolism (stable-isotope oral glucose tolerance tests), body composition (dual-energy x-ray absorptiometry), physical activity (self-report), and skeletal muscle OXPHOS capacity (creatine chemical exchange saturation transfer MRI) were assessed. RESULTS: Participants included 11 individuals with FRDA (4 female), median age 27y (IQR 23, 39), BMI 26.9kg/m2 (24.1, 29.4), and 24 controls (11 female), 29y (26, 39), 24.4kg/m2 (21.8, 27.0). Fasting glucose was higher in FRDA (91 vs. 83mg/dL (5.0 vs. 4.6mmol/L), p<0.05). Individuals with FRDA had lower insulin sensitivity (WBISI 2.8 vs. 5.3, p<0.01), higher post-prandial insulin secretion (insulin secretory rate iAUC 30-180 minutes, 24,652 vs. 17,858, p<0.05), and more suppressed post-prandial endogenous glucose production (-0.9% vs. 26.9% of fasting EGP, p<0.05). In regression analyses, lower OXPHOS and inactivity explained some of the difference in insulin sensitivity. More visceral fat contributed to lower insulin sensitivity independent of FRDA. Insulin secretion accounting for sensitivity (disposition index) was not different. CONCLUSIONS: Lower mitochondrial OXPHOS capacity, inactivity, and visceral adiposity contribute to lower insulin sensitivity in FRDA. Higher insulin secretion appears compensatory, and when inadequate, could herald DM. Further studies are needed to determine if muscle- or adipose-focused interventions could delay FRDA-related DM.

Update on the transdifferentiation of pancreatic cells into functional beta cells for treating diabetes.

The increasing global prevalence and associated comorbidities need innovative approaches for type 2 diabetes mellitus (T2DM) prevention and treatment. Genetics contributes significantly to T2DM susceptibility, and genetic counseling is significant in detecting and informing people about the diabetic risk. T2DM is also intricately linked to overnutrition and obesity, and nutritional advising is beneficial to mitigate diabetic evolution. However, manipulating pancreatic cell plasticity and transdifferentiation could help beta cell regeneration and glucose homeostasis, effectively contributing to the antidiabetic fight. Targeted modulation of transcription factors is highlighted for their roles in various aspects of pancreatic cell differentiation and function, inducing non-beta cells' conversion into functional beta cells (responsive to glucose). In addition, pharmacological interventions targeting specific receptors and pathways might facilitate cell transdifferentiation aiming to maintain or increase beta cell mass and function. However, the mechanisms underlying cellular reprogramming are not yet well understood. The present review highlights the primary transcriptional factors in the endocrine pancreas, focusing on transdifferentiation as a primary mechanism. Therefore, islet cell reprogramming, converting one cell type to another and transforming non-beta cells into insulin-producing cells, depends, among others, on transcription factors. It is a promising fact that new transcription factors are discovered every day, and their actions on pancreatic islet cells are revealed. Exploring these pathways associated with pancreatic development and islet endocrine cell differentiation could unravel the molecular intricacies underlying transdifferentiation processes, exploring novel therapeutic strategies to treat diabetes. The medical use of this biotechnology is expected to be achievable within a short time.

Proteomic Analysis of a Rat Streptozotocin Model Shows Dysregulated Biological Pathways Implicated in Alzheimer's Disease.

Alzheimer's Disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive impairment, affecting 35 million individuals worldwide. Intracerebroventricular (ICV) injection of low to moderate doses of streptozotocin (STZ) in adult male Wistar rats can reproduce classical physiopathological hallmarks of AD. This biological model is known as ICV-STZ. Most studies are focused on the description of behavioral and morphological aspects of the ICV-STZ model. However, knowledge regarding the molecular aspects of the ICV-STZ model is still incipient. Therefore, this work is a first attempt to provide a wide proteome description of the ICV-STZ model based on mass spectrometry (MS). To achieve that, samples from the pre-frontal cortex (PFC) and hippocampus (HPC) of the ICV-STZ model and control (wild-type) were used. Differential protein abundance, pathway, and network analysis were performed based on the protein identification and quantification of the samples. Our analysis revealed dysregulated biological pathways implicated in the early stages of late-onset Alzheimer's disease (LOAD), based on differentially abundant proteins (DAPs). Some of these DAPs had their mRNA expression further investigated through qRT-PCR. Our results shed light on the AD onset and demonstrate the ICV-STZ as a valid model for LOAD proteome description.

KSRP improves pancreatic beta cell function and survival.

Impaired insulin production and/or secretion by pancreatic beta cells can lead to high blood glucose levels and type 2 diabetes (T2D). Therefore, investigating new proteins involved in beta cell response to stress conditions could be useful in finding new targets for therapeutic approaches. KH-type splicing regulatory protein (KSRP) is a protein usually involved in gene expression due to its role in post-transcriptional regulation. Although there are studies describing the important role of KSRP in tissues closely related to glucose homeostasis, its effect on pancreatic beta cells has not been explored so far. Pancreatic islets from diet-induced obese mice (C57BL/6JUnib) were used to determine KSRP expression and we also performed in vitro experiments exposing INS-1E cells (pancreatic beta cell line) to different stressors (palmitate or cyclopiazonic acid-CPA) to induce cellular dysfunction. Here we show that KSRP expression is reduced in all the beta cell dysfunction models tested. In addition, when manipulated to knock down KSRP, beta cells exhibited increased death and impaired insulin secretion, whereas KSRP overexpression prevented cell death and increased insulin secretion. Taken together, our findings suggest that KSRP could be an important target to protect beta cells from impaired functioning and death.

Structural modifications of INGAP-PP present in HTD4010 peptide potentiate its effect on rat islet gene expression and insulin secretion.

Type 2 diabetes (T2D) is characterized by peripheral insulin resistance and altered insulin secretion due to a progressive loss of ß-cell mass and function. Today, most antidiabetic agents are designed to resolve impaired insulin secretion and/or insulin resistance, and only GLP-1-based formulations contribute to stopping the decline in ß-cell mass. HTD4010, a peptide carrying two modifications of the amino acid sequence of INGAP-PP (N-terminus acetylation and substitution of Asn13 by Ala) showed greater plasma stability and could be a good candidate for proposal as a drug that could improve ß cell mass and function lost in T2D. In the present study, we showed that HTD4010 included in the culture media of normal rat islets at a dose 100 times lower than that used for INGAP-PP was able to modulate, in the same way as the original peptide, both insulin secretion in response to glucose and the expression of key genes related to insular function, insulin and leptin intracellular pathways, neogenesis, apoptosis, and inflammatory response. Our results confirm the positive effect of HTD4010 on ß-cell function and gene expression of factors involved in the maintenance of ß-cell mass. Although new assays in animal models of prediabetes and T2D must be performed to be conclusive, our results are very encouraging, and they suggest that the use of HTD4010 at a dose 100 times lower than that of INGAP-PP could minimize its side effects in a future clinical trial.

Association between protein undernutrition and diabetes: Molecular implications in the reduction of insulin secretion.

Undernutrition is still a recurring nutritional problem in low and middle-income countries. It is directly associated with the social and economic sphere, but it can also negatively impact the health of the population. In this sense, it is believed that undernourished individuals may be more susceptible to the development of non-communicable diseases, such as diabetes mellitus, throughout life. This hypothesis was postulated and confirmed until today by several studies that demonstrate that experimental models submitted to protein undernutrition present alterations in glycemic homeostasis linked, in part, to the reduction of insulin secretion. Therefore, understanding the changes that lead to a reduction in the secretion of this hormone is essential to prevent the development of diabetes in undernourished individuals. This narrative review aims to describe the main molecular changes already characterized in pancreatic ß cells that will contribute to the reduction of insulin secretion in protein undernutrition. So, it will provide new perspectives and targets for postulation and action of therapeutic strategies to improve glycemic homeostasis during this nutritional deficiency.

Vertical sleeve gastrectomy improves glucose-insulin homeostasis by enhancing ß-cell function and survival via FGF15/19.

Vertical sleeve gastrectomy (VSG) restores glucose homeostasis in obese mice and humans. In addition, the increased fibroblast growth factor (FGF)15/19 circulating level postsurgery has been implicated in this effect. However, the impact of FGF15/19 on pancreatic islets remains unclear. Using a diet-induced obese mice model, we demonstrate that VSG attenuates insulin hypersecretion in isolated pancreatic islets, likely due to morphological alterations in the endocrine pancreas such as reduction in islet, ß-cell, and α-cell mass. In addition, VSG relieves gene expression of endoplasmic reticulum (ER) stress and inflammation markers in islets from obese mice. Incubation of INS-1E ß-cells with serum from obese mice induced dysfunction and cell death, whereas these conditions were not induced with serum from obese mice submitted to VSG, implicating the involvement of a humoral factor. Indeed, VSG increased FGF15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E cells treated with the serum from these mice. Moreover, exposing INS-1E cells to an FGFR inhibitor abolished the effects of VSG serum on insulin secretion and cell death. Also, recombinant FGF19 prevents INS-1E cells from dysfunction and death induced by serum from obese mice. These findings indicate that the amelioration of glucose-insulin homeostasis promoted by VSG is mediated, at least in part, by FGF15/19. Therefore, approaches promoting FGF15/19 release or action may restore pancreatic islet function in obesity.NEW & NOTEWORTHY Vertical sleeve gastrectomy (VSG) decreases insulin secretion, endoplasmic reticulum (ER) stress, and inflammation in pancreatic islets from obese mice. In addition, VSG increased fibroblast growth factor (FGF)15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E ß-cells treated with the serum from these mice. Serum from operated mice protects INS-1E cells from dysfunction and apoptosis, which was mediated by FGF15/19.

Dietary Supplementation with Yerba Mate (Ilex paraguariensis) Infusion Increases IRS-1 and PI3K mRNA Levels and Enhances Insulin Sensitivity and Secretion in Rat Pancreatic Islets.

"Yerba mate" (YM), an aqueous extract of Ilex paraguariensis, has antioxidant, diuretic, cardio-protective and hypoglycaemic properties. Since its effect on the pancreatic islets remains unclear, we evaluated insulin sensitivity and glucose-stimulated insulin secretion (GSIS) in rats consuming YM or tap water (C) for 21 days. Glucose tolerance, glycemia, triglyceridemia, insulinemia, TBARS and FRAP serum levels were evaluated. GSIS and mRNA levels of insulin signaling pathway and inflammatory markers were measured in isolated pancreatic islets from both groups. In C rats, islets were incubated with YM extract or its phenolic components to measure GSIS. YM improved glucose tolerance, enhanced GSIS, increased FRAP plasma levels and islet mRNA levels of IRS-1 and PI3K (p110), and decreased TBARS plasma levels and islet gene expression of TNF-α and PAI-1. Islets from C rats incubated with 100 µg/mL dry YM extract, 1 µM chlorogenic acid, 0.1 and 1 µM rutin, 1 µM caffeic acid or 1 µM quercetin showed an increase in GSIS. Our results suggest that YM enhances glucose tolerance because of its positive effects on GSIS, oxidative stress rate and insulin sensitivity in rat islets, suggesting that long-term dietary supplementation with YM may improve glucose homeostasis in pre-diabetes or type 2 diabetes.

Effect of Fucoxanthin on Metabolic Syndrome, Insulin Sensitivity, and Insulin Secretion.

The aim of this study was to evaluate the effect of fucoxanthin on metabolic syndrome (MetS), insulin sensitivity, and insulin secretion. A randomized, double-blind, placebo-controlled clinical trial was conducted in 28 patients diagnosed with MetS. Patients were randomly assigned to receive 12 mg of fucoxanthin or placebo once a day for 12 weeks. Before and after the intervention, the components of MetS, insulin sensitivity (Matsuda index), first phase of insulin secretion (Stumvoll index), and total insulin secretion were evaluated during a 2-h oral glucose tolerance test. After fucoxanthin administration, significant differences were observed in body weight (BW) (80.6 ± 11.2 vs. 79.16 ± 12.3 kg, P < .01), body mass index (BMI) (31.1 ± 3.6 vs. 30.3 ± 3.7 kg/m2, P < .01), waist circumference (WC) (101.2 ± 9.1 vs. 98.9 ± 9.3 cm, P < .01), systolic blood pressure (SBP) (126.1 ± 10.3 vs. 120.8 ± 9.7 mmHg, P < .01), diastolic blood pressure (DBP) (81.5 ± 6.5 vs. 78.6 ± 6.3 mmHg, P < .01), triglycerides (TG) (2.2 ± 0.7 vs. 2.1 ± 0.7 mmol/L, P < .01), Stumvoll index (2403 ± 621 vs. 2907 ± 732, P < .05), and total insulin secretion (0.84 ± 0.31 vs. 1.02 ± 0.32, P < .05). In conclusion, fucoxanthin administration leads to a decrease in BW, BMI, WC, SBP, DBP, TG, as well as increase in the first phase of insulin secretion and total insulin secretion in patients with MetS. Clinical Trial Registration number: NCT03613740.

Mexican Plants Involved in Glucose Homeostasis and Body Weight Control: Systematic Review.

BACKGROUND: Obesity is defined as abnormal or excessive fat accumulation, provoking many different diseases, such as obesity and type 2 diabetes. Type 2 diabetes is a chronic-degenerative disease characterized by increased blood glucose levels. Obesity and type 2 diabetes are currently considered public health problems, and their prevalence has increased over the last few years. Because of the high cost involved in the treatment of both diseases, different alternatives have been sought. However, the general population uses medicinal plants, in the form of tea or infusions, to treat different diseases. Therefore, traditional medicine using medicinal plants has been investigated as a possible treatment for type 2 diabetes and body weight control. AIM OF THE STUDY: The purpose of this review is to find medicinal plants used in Mexico that could exert their beneficial effect by regulating insulin secretion and body weight control. MATERIAL AND METHOD: For the development of this review, Mexican plants used in traditional medicine to treat type 2 diabetes and body weight control were searched in PubMed, Google Scholar, and Scopus. The inclusion criteria include plants that presented a significant reduction in blood glucose levels and/or an increase in insulin secretion. RESULTS: We found 306 Mexican plants with hypoglycemic effects. However, plants that did not show evidence of an increase in insulin secretion were eliminated. Finally, only five plants were included in this review: Momordica charantia L. (melón amargo), Cucurbita ficifolia bouché (chilacayote), Coriandrum sativum L. (cilantro), Persea americana Mill. (aguacate) Bidens pilosa (amor seco), including 39 articles in total. Here, we summarized the plant extracts (aqueous and organic) that have previously been reported to present hypoglycemic effects, body weight control, increased secretion and sensitivity of insulin, improvement of pancreatic ß cells, and glucose tolerance. Additionally, these effects may be due to different bioactive compounds present in the plants' extracts. CONCLUSION: Both in vivo and in vitro studies are required to understand the mechanism of action of these plant extracts regarding insulin secretion to be used as a possible treatment for type 2 diabetes and body weight control in the future.

Δ9-Tetrahydrocannabinol Treatment Modifies Insulin Secretion in Pancreatic Islets from Prediabetic Mice Under Hypercaloric Diet.

Background: The endocannabinoid system over-activation is associated with type-2 diabetes mellitus onset, involving physiological, metabolic, and genetic alterations in pancreatic islets. The use of Δ9-Tetrahydrocannabinol (THC) as treatment is still controversial since its effects and mechanisms on insulin secretion are unclear. The aim of this study was to evaluate the effects of THC treatment in pancreatic islets from prediabetic mice. Methods: Prediabetes was induced in mice by hypercaloric diet, and then treated with THC for 3 weeks. Blood glucose and body weight were determined, after behavior tests. Histological changes were evaluated in whole pancreas; in isolated islets we analyzed the effect of THC exposure in glucose-stimulated insulin secretion (GSIS), gene expression, intracellular cyclic adenosine monophosphate (cAMP), and cytosolic calcium changes. Results: THC treatment in prediabetic mice enhanced anxiety and antidepressive behavior without changes in food ingestion, decreased oral-glucose tolerance test, plasma insulin and weight, with small alterations on pancreatic histology. In isolated islets from healthy mice THC increased GSIS, cAMP, and CB1 receptor (CB1r) expression, meanwhile calcium release was diminished. Small changes were observed in islets from prediabetic mice. Conclusions: THC treatment improves some clinical parameters in prediabetic mice, however, in isolated islets, modifies GSIS, intracellular calcium and gene expression, suggesting specific effects related to diabetes evolution.

Vachellia farnesiana Pods or a Polyphenolic Extract Derived from Them Exert Immunomodulatory, Metabolic, Renoprotective, and Prebiotic Effects in Mice Fed a High-Fat Diet.

Obesity causes systemic inflammation, hepatic and renal damage, as well as gut microbiota dysbiosis. Alternative vegetable sources rich in polyphenols are known to prevent or delay the progression of metabolic abnormalities during obesity. Vachellia farnesiana (VF) is a potent source of polyphenols with antioxidant and anti-inflammatory activities with potential anti-obesity effects. We performed an in vivo preventive or an interventional experimental study in mice and in vitro experiments with different cell types. In the preventive study, male C57BL/6 mice were fed with a Control diet, a high-fat diet, or a high-fat diet containing either 0.1% methyl gallate, 10% powdered VFP, or 0.5%, 1%, or 2% of a polyphenolic extract (PE) derived from VFP (Vachellia farnesiana pods) for 14 weeks. In the intervention study, two groups of mice were fed for 14 weeks with a high-fat diet and then one switched to a high-fat diet with 10% powdered VFP for ten additional weeks. In the in vitro studies, we evaluated the effect of a VFPE (Vachellia farnesiana polyphenolic extract) on glucose-stimulated insulin secretion in INS-1E cells or of naringenin or methyl gallate on mitochondrial activity in primary hepatocytes and C2C12 myotubes. VFP or a VFPE increased whole-body energy expenditure and mitochondrial activity in skeletal muscle; prevented insulin resistance, hepatic steatosis, and kidney damage; exerted immunomodulatory effects; and reshaped fecal gut microbiota composition in mice fed a high-fat diet. VFPE decreased insulin secretion in INS-1E cells, and its isolated compounds naringenin and methyl gallate increased mitochondrial activity in primary hepatocytes and C2C12 myotubes. In conclusion VFP or a VFPE prevented systemic inflammation, insulin resistance, and hepatic and renal damage in mice fed a high-fat diet associated with increased energy expenditure, improved mitochondrial function, and reduction in insulin secretion.

Validity and reliability of simple surrogate indexes to evaluate beta-cell function and insulin sensitivity

BACKGROUND: Simple surrogate indexes (SSI) to assess beta-cell function, insulin sensitivity (IS) and insulin resistance (IR) are an easy and economic tool used in clinical practice to identify glucose metabolism disturbances. AIM: To evaluate the validity and reliability of SSI that estimate beta-cell function, IS and IR using as a reference the parameters obtained from the frequently sampled intravenous glucose tolerance test (FSIVGTT). MATERIAL AND METHODS: We included 62 subjects aged 20-45 years, with a normal body mass index and without diabetes or prediabetes. SSI were compared with the acute insulin response to glucose (AIRg), insulin sensitivity index (Si) and disposition index (DI) obtained from the FSIVGTT using the minimal model approach. Half of the participants (n = 31) were randomly selected for a second visit two weeks later to evaluate the reliability of all the variables. RESULTS: HOMA1-%B and HOMA2-%B had a significant correlation with AIRg (Spearman Rho (rs) = 0.33 and 0.37 respectively, p 0.50) with Si were fasting insulin, HOMA1-IR, HOMA2-IR, HOMA1-%S, HOMA2-%S, QUICKI, and the McAuley index. The parameters that showed good reliability with an intraclass correlation coefficient (ICC) > 0.75 were AIRg, HOMA1-%S, HOMA2-%S, and QUICKI. Conclusions: Our results suggest that most of the SSI are useful and reliable.

ANTECEDENTES: Los índices simples subrogados (ISS) que evalúan la función de célula beta, sensibilidad a la insulina (SI) y resistencia a la insulina (RI) son herramientas sencillas y económicas que se usan en la práctica clínica para identificar alteraciones del metabolismo de la glucosa. OBJETIVO: Evaluar la validez y confiabilidad de ISS para estimar la función de célula beta, SI y RI usando como referencia los parámetros de la prueba de tolerancia a la glucosa intravenosa con muestreo frecuente (FSIVGTT). MATERIAL Y MÉTODOS: Se incluyeron 62 sujetos de 20-45 años, con índice de masa corporal normal y sin diabetes mellitus o prediabetes. Los ISS se compararon con la respuesta aguda de la insulina a la glucosa (AIRg), índice de sensibilidad a la insulina (Si) e índice de disposición (DI) obtenidos de la FSIVGTT en base al modelo mínimo. La mitad de los participantes (n = 31) se seleccionaron aleatoriamente para acudir dos semanas después y evaluar la confiabilidad de todas las variables. RESULTADOS: HOMA1-%B y HOMA2-%B presentaron una correlación significativa con AIRg (Rho de Spearman (rs) = 0,33 and 0,37, respectivamente, p 0,50) con Si fueron insulina en ayuno, HOMA1-IR, HOMA2-IR, HOMA1-%S, HOMA2-%S, QUICKI y el índice de McAuley. Los parámetros que tuvieron buena confiabilidad (coeficiente de correlación intraclase > 0,75) fueron AIRg, HOMA1-%S, HOMA2-%S y QUICKI. Conclusiones: La mayoría de los ISS son instrumentos útiles y confiables.

Ellagic Acid Effect on the Components of Metabolic Syndrome, Insulin Sensitivity and Insulin Secretion: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors, usually with a common pathophysiological origin in insulin resistance and abdominal obesity. Considering the reported effects of ellagic acid (EA) on insulin resistance and abdominal obesity, the aim of this study was to evaluate the effect of EA on the components of MetS, insulin sensitivity and insulin secretion by conducting a randomized, double-blind, placebo-controlled, clinical trial with 32 volunteers diagnosed with MetS. Sixteen patients were randomly allocated, received 500 mg of EA orally twice a day for 12 weeks, and the other 16 received a placebo. Clinical and laboratory determinations were obtained at baseline and at the end of the study. After EA administration, patients reduced their waist circumference (females: 102.2 ± 4.2 to 99.5 ± 3.2 cm (p < 0.05); males: 99.8 ± 6.7 to 96.0 ± 4.7 cm (p < 0.01)), systolic blood pressure (118.1 ± 10.1 to 113.7 ± 7.8 mmHg (p < 0.01)), diastolic blood pressure (118.1 ± 10.1 to 113.7 ± 7.8 mmHg (p < 0.01)), triglycerides (2.8 ± 1.1 to 2.1 ± 0.7 mmol/L (p < 0.01)), fasting plasma glucose (6.5 ± 0.5 to 5.7 ± 0.6 mmol/L (p < 0.01)), fasting plasma insulin (p < 0.01), and insulin secretion (p < 0.05), with an increase of insulin sensitivity (p < 0.01). In male patients, high-density lipoprotein cholesterol increased (p < 0.05). In conclusion, EA improved the components of MetS, reduced hyperinsulinemia, and improved insulin sensitivity.

Dietary Protein Modulates the Efficacy of Taurine Supplementation on Adaptive Islet Function and Morphology in Obesity.

Adaptation of islet ß-cell mass and function under limiting or excess nutrient availability is critical for maintenance of glucose homeostasis. Taurine regulates islet function of obese mice in normal and low dietary protein conditions, but whether this involves remodeling of the endocrine pancreas architecture is not well understood. Here, we carried functional and morphometric evaluation of the endocrine pancreas of normal and protein-restricted mice fed a high-fat diet (HFD) and investigated the role of taurine supplementation. Weaned mice were placed in a normal (C) or a low-protein diet (R) for 6 weeks, followed by HFD for 8 weeks (CH and RH). Half of HFD groups received 5% taurine supplementation since weaning (CHT and RHT) until the end of the experiment. Isolated islets from both CH and RH groups showed increased insulin release in association with increased pancreas weight and independently of changes in islet or ß-cell area. In normal protein CHT mice, taurine supplementation prevented obesity-induced insulin hypersecretion and promoted increased islet and ß-cell areas in association with increased protein expression of the proliferation marker, PCNA. On a low-protein background, taurine effects on islet function and morphology were blunted, but it prevented obesity-induced DNA fragmentation. In summary, taurine regulates islet function and morphology to improve the adaptive response to diet-induced obesity, but these effects are dependent on adequate dietary protein levels.

The Taurine-Conjugated Bile Acid (TUDCA) Normalizes Insulin Secretion in Pancreatic ß-Cells Exposed to Fatty Acids: The Role of Mitochondrial Metabolism.

Bile acid tauroursodeoxycholic (TUDCA), formed from the association of ursodeoxycholic acid (UDCA) with taurine, has already been shown to increase mitochondrial biogenesis and cell survival, in addition to reduce reticulum stress markers in different cell types. However, its mechanism of action upon insulin secretion control in obesity is still unknown. In this sense, we seek to clarify whether taurine, associated with bile acid, could improve the function of the pancreatic ß-cells exposed to fatty acids through the regulation of mitochondrial metabolism. To test this idea, insulin-producing cells (INS1-E) were exposed to a fatty acid mix containing 500 µM of each palmitate and oleate for 48 hours treated or not with 300 µM of TUDCA. After that, glucose-stimulated insulin secretion and markers of mitochondrial metabolism were evaluated. Our results showed that the fatty acid mix was efficient in inducing hyperfunction of INS1-E cells as observed by the increase in insulin secretion, protein expression of citrate synthase, and mitochondrial density, without altering cell viability. The treatment with TUDCA normalized insulin secretion, reducing the protein expression of citrate synthase, mitochondrial mass, and the mitochondrial membrane potential. This effect was associated with a decrease in the generation of mitochondrial superoxide and c-Jun N-terminal kinase (JNK) protein content. The findings are also consistent with the hypothesis that TUDCA normalizes insulin secretion by improving mitochondrial metabolism and redox balance. Thus, it highlights likely mechanisms of the action of this bile acid on the glycemic homeostasis reestablishment in obesity.

Participation of Magnesium in the Secretion and Signaling Pathways of Insulin: an Updated Review.

Several studies have demonstrated the participation of various minerals in mechanisms involving insulin. Magnesium, in particular, plays an important role in the secretion and action of this hormone. Therefore, this review aimed to examine the latest insights into the biochemical and molecular aspects of the participation of magnesium in insulin sensitivity. Magnesium plays a vital role in the activity of intracellular proteins involved in insulin secretion in ß-pancreatic cells, such as glucokinase, ATPase, and protein kinase C. In addition, evidence suggests that this mineral participates directly in insulin sensitivity and signaling in peripheral tissues, acting in the phosphorylation of the receptor tyrosine kinase and the insulin receptor substrates 1, insulin receptor substrates 2, phosphatidylinositol 3-kinase, and protein kinase B, and indirectly by reducing oxidative stress and chronic low-grade inflammation, which also lead to insulin resistance. Thus, magnesium deficiency is associated with glucose intolerance, while magnesium supplementation stimulates insulin secretion in pancreatic cells and improves insulin sensitivity in peripheral tissues. However, studies must consider assess short- and long-term nutritional status of mineral before performing intervention, the relevance of the balance of other nutrients that influence hormone secretion and sensibility, and health status of the assessed population.

HDL as Bidirectional Lipid Vectors: Time for New Paradigms.

The anti-atherogenic properties of high-density lipoproteins (HDL) have been explained mainly by reverse cholesterol transport (RCT) from peripheral tissues to the liver. The RCT seems to agree with most of the negative epidemiological correlations between HDL cholesterol levels and coronary artery disease. However, therapies designed to increase HDL cholesterol failed to reduce cardiovascular risk, despite their capacity to improve cholesterol efflux, the first stage of RCT. Therefore, the cardioprotective role of HDL may not be explained by RCT, and it is time for new paradigms about the physiological function of these lipoproteins. It should be considered that the main HDL apolipoprotein, apo AI, has been highly conserved throughout evolution. Consequently, these lipoproteins play an essential physiological role beyond their capacity to protect against atherosclerosis. We propose HDL as bidirectional lipid vectors carrying lipids from and to tissues according to their local context. Lipid influx mediated by HDL appears to be particularly important for tissue repair right on site where the damage occurs, including arteries during the first stages of atherosclerosis. In contrast, the HDL-lipid efflux is relevant for secretory cells where the fusion of intracellular vesicles drastically enlarges the cytoplasmic membrane with the potential consequence of impairment of cell function. In such circumstances, HDL could deliver some functional lipids and pick up not only cholesterol but an integral part of the membrane in excess, restoring the viability of the secretory cells. This hypothesis is congruent with the beneficial effects of HDL against atherosclerosis as well as with their capacity to induce insulin secretion and merits experimental exploration.

Metformin disrupts insulin secretion, causes proapoptotic and oxidative effects in rat pancreatic beta-cells in vitro.

Metformin is the first-line drug to treat type 2 diabetes mellitus. Its mechanism of action is still debatable, and recent studies report that metformin attenuates oxidative stress. This study evaluated the in vitro antioxidant effects of a broad range of metformin concentrations on insulin-producing cells. The cell cycle, metabolism, glucose-stimulated insulin secretion, and cell death were evaluated to determine the biguanide effects on beta-cell function and survival. Antioxidant potential was based on reactive oxygen species (ROS), reduced glutathione (GSH), oxidative stress biomarker levels, and antioxidant enzyme and transcriptional factor Nrf2 activities. The results demonstrate that metformin disrupted GSIS in a concentration-dependent manner, lowered insulin content, and attenuated beta-cell metabolism. At high concentrations, metformin induced cell death and cell cycle arrest as well as increased ROS generation, consequently reducing GSH content. Although carbonylated protein content was elevated, indicating oxidative stress, the antioxidant enzyme and Nrf2 activities were not altered. In conclusion, our results show that metformin disrupts pancreatic beta-cell functionality but does not exert a putative antioxidant effect. It is important to note that the drug could potentially affect beta-cells, especially at high circulating levels.

Fisiopatología y alteraciones clínicas de la diabetes mellitus tipo 2: revisión de literatura / Physiopathology and clinical alterations of diabetes mellitus 2: literature review

Resumen La diabetes mellitus tipo 2 constituye una condición clínica debilitante, degenerativa y multifacética de alta prevalencia a nivel mundial. Dada la complejidad de su fisiopatología y las variadas opciones terapéuticas que existen esta enfermedad presenta un desafío para el médico general, se hace imperativo describir comprensiblemente esta patología para mejorar la resolutividad de ésta en atención primaria. Tras una búsqueda bibliográfica exhaustiva de 103 estudios publicados hasta el año 2010, se identificaron los aspectos más importantes tanto de la fisiología, fisiopatología, complicaciones y terapéuticas de esta patología. La resistencia a la insulina (RI) es una condición metabólica central en la etiopatogenia de esta patología donde se logra reconocer de manera clásica tanto la pérdida de la acción periférica de la insulina por parte de los diferentes tejidos, así como defectos en la secreción de insulina conllevando estados de hiperglucemia constantes asociados tanto a complicaciones agudas como crónicas caracterizadas por provocar disfunción y fallo en diferentes órganos. Es de conocimiento general que parte importante de los resultados en el manejo de esta patología se logran con cambios en el estilo de vida que van desde modificaciones en la dieta a cambios en el patrón de actividad física con pérdida de peso corporal. No obstante, existe a su vez una amplia gama de terapias farmacológicas orientadas a controlar estados hiperglucémicos ante la falla de la terapia no farmacológica. Dentro de este mismo contexto varias son las dianas y objetivos terapéuticos en el tratamiento del diabético tipo 2, sin embargo, todas confluyen en el control metabólico de los estados de hiperglucemia y la prevención de sus complicaciones.

Abstract Type 2 diabetes mellitus is a debilitating, degenerative and multifaceted clinical condition with a high prevalence worldwide. Given the complexity of its pathophysiology and the various therapeutic options that exist, this disease presents a challenge for the general practitioner, it is imperative to understand this pathology to improve its resolution in primary care. After an exhaustive bibliographic search of 103 studies published up to 2010, the most important aspects of both the physiology, pathophysiology, complications, and therapeutics of this pathology were identified. Insulin resistance (IR) is a central metabolic condition in the etiopathogenesis of this pathology. Classically it is possible to recognize both the loss of the peripheral action of insulin by the different tissues as well as defects in the secretion of insulin that leads to constant hyperglycemic states associated with both acute and chronic complications characterized by causing dysfunction and failure in different organs. It is generally known that an important part of the results in the management of this pathology are achieved with changes in lifestyle that range from modifications in diet to changes in the pattern of physical activity with loss of body weight. However, there also is a wide range of pharmacological therapies aimed at controlling hyperglycemic states in the event of the failure of non-pharmacological therapy. Within this same context, there are several therapeutic targets and objectives in the treatment of type 2 diabetics, however, they all converge in the metabolic control of hyperglycemic states and the prevention of their complications