AI4FoodDB: a database for personalized e-Health nutrition and lifestyle through wearable devices and artificial intelligence.

The increasing prevalence of diet-related diseases calls for an improvement in nutritional advice. Personalized nutrition aims to solve this problem by adapting dietary and lifestyle guidelines to the unique circumstances of each individual. With the latest advances in technology and data science, researchers can now automatically collect and analyze large amounts of data from a variety of sources, including wearable and smart devices. By combining these diverse data, more comprehensive insights of the human body and its diseases can be achieved. However, there are still major challenges to overcome, including the need for more robust data and standardization of methodologies for better subject monitoring and assessment. Here, we present the AI4Food database (AI4FoodDB), which gathers data from a nutritional weight loss intervention monitoring 100 overweight and obese participants during 1 month. Data acquisition involved manual traditional approaches, novel digital methods and the collection of biological samples, obtaining: (i) biological samples at the beginning and the end of the intervention, (ii) anthropometric measurements every 2 weeks, (iii) lifestyle and nutritional questionnaires at two different time points and (iv) continuous digital measurements for 2 weeks. To the best of our knowledge, AI4FoodDB is the first public database that centralizes food images, wearable sensors, validated questionnaires and biological samples from the same intervention. AI4FoodDB thus has immense potential for fostering the advancement of automatic and novel artificial intelligence techniques in the field of personalized care. Moreover, the collected information will yield valuable insights into the relationships between different variables and health outcomes, allowing researchers to generate and test new hypotheses, identify novel biomarkers and digital endpoints, and explore how different lifestyle, biological and digital factors impact health. The aim of this article is to describe the datasets included in AI4FoodDB and to outline the potential that they hold for precision health research. Database URL https://github.com/AI4Food/AI4FoodDB.

Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation.

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by hyperglucagonaemia and perturbed function of pancreatic glucagon-secreting alpha cells but the molecular mechanisms contributing to these phenotypes are poorly understood. Insulin-degrading enzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degrade glucagon as well as insulin, suggesting that IDE may play an important role in alpha cell function in vivo. METHODS: We have generated and characterised a novel mouse model with alpha cell-specific deletion of Ide, the A-IDE-KO mouse line. Glucose metabolism and glucagon secretion in vivo was characterised; isolated islets were tested for glucagon and insulin secretion; alpha cell mass, alpha cell proliferation and α-synuclein levels were determined in pancreas sections by immunostaining. RESULTS: Targeted deletion of Ide exclusively in alpha cells triggers hyperglucagonaemia and alpha cell hyperplasia, resulting in elevated constitutive glucagon secretion. The hyperglucagonaemia is attributable in part to dysregulation of glucagon secretion, specifically an impaired ability of IDE-deficient alpha cells to suppress glucagon release in the presence of high glucose or insulin. IDE deficiency also leads to α-synuclein aggregation in alpha cells, which may contribute to impaired glucagon secretion via cytoskeletal dysfunction. We showed further that IDE deficiency triggers impairments in cilia formation, inducing alpha cell hyperplasia and possibly also contributing to dysregulated glucagon secretion and hyperglucagonaemia. CONCLUSIONS/INTERPRETATION: We propose that loss of IDE function in alpha cells contributes to hyperglucagonaemia in type 2 diabetes.

Potential protective effect against SARS-CoV-2 infection by APOE rs7412 polymorphism.

The pandemic burden caused by the SARS-CoV-2 coronavirus constitutes a global public health emergency. Increasing understanding about predisposing factors to infection and severity is now a priority. Genetic, metabolic, and environmental factors can play a crucial role in the course and clinical outcome of COVID-19. We aimed to investigate the putative relationship between genetic factors associated to obesity, metabolism and lifestyle, and the presence and severity of SARS-CoV-2 infection. A total of 249 volunteers (178 women and 71 men, with mean and ± SD age of 49 ± 11 years) characterized for dietary, lifestyle habits and anthropometry, were studied for presence and severity of COVID-19 infection, and genotyped for 26 genetic variants related to obesity, lipid profile, inflammation, and biorhythm patterns. A statistically significant association was found concerning a protective effect of APOE rs7412 against SARS-CoV-2 infection (p = 0.039; OR 0.216; CI 0.084, 0.557) after correction for multiple comparisons. This protective effect was also ascribed to the APOɛ2 allele (p = 0.001; OR 0.207; CI 0.0796, 0.538). The genetic variant rs7412 resulting in ApoE2, genetic determinant of lipid and lipoprotein levels, could play a significant role protecting against SARS-CoV-2 infection.

Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme.

Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin levels for peripheral tissues. Emerging evidence, however, suggests that IDE has several other important physiological functions relevant to glucose and insulin homeostasis, including the regulation of insulin secretion from pancreatic ß-cells. Investigation of mice with tissue-specific genetic deletion of Ide in the liver and pancreatic ß-cells (L-IDE-KO and B-IDE-KO mice, respectively) has revealed additional roles for IDE in the regulation of hepatic insulin action and sensitivity. In this review, we discuss current knowledge about IDE's function as a regulator of insulin secretion and hepatic insulin sensitivity, both evaluating the classical view of IDE as an insulin protease and also exploring evidence for several non-proteolytic functions. Insulin proteostasis and insulin sensitivity have both been highlighted as targets controlling blood sugar levels in type 2 diabetes, so a clearer understanding the physiological functions of IDE in pancreas and liver could led to the development of novel therapeutics for the treatment of this disease.

Hepatic insulin-degrading enzyme regulates glucose and insulin homeostasis in diet-induced obese mice.

The insulin-degrading enzyme (IDE) is a metalloendopeptidase with a high affinity for insulin. Human genetic polymorphisms in Ide have been linked to increased risk for T2DM. In mice, hepatic Ide ablation causes glucose intolerance and insulin resistance when mice are fed a regular diet. OBJECTIVE: These studies were undertaken to further investigate its regulatory role in glucose homeostasis and insulin sensitivity in diet-induced obesity. METHODS: To this end, we have compared the metabolic effects of loss versus gain of IDE function in mice fed a high-fat diet (HFD). RESULTS: We demonstrate that loss of IDE function in liver (L-IDE-KO mouse) exacerbates hyperinsulinemia and insulin resistance without changes in insulin clearance but in parallel to an increase in pancreatic ß-cell function. Insulin resistance was associated with increased FoxO1 activation and a ~2-fold increase of GLUT2 protein levels in the liver of HFD-fed mice in response to an intraperitoneal injection of insulin. Conversely, gain of IDE function (adenoviral delivery) improves glucose tolerance and insulin sensitivity, in parallel to a reciprocal ~2-fold reduction in hepatic GLUT2 protein levels. Furthermore, in response to insulin, IDE co-immunoprecipitates with the insulin receptor in liver lysates of mice with adenoviral-mediated liver overexpression of IDE. CONCLUSIONS: We conclude that IDE regulates hepatic insulin action and whole-body glucose metabolism in diet-induced obesity via insulin receptor levels.

Pancreatic ß-cell-specific deletion of insulin-degrading enzyme leads to dysregulated insulin secretion and ß-cell functional immaturity.

Inhibition of insulin-degrading enzyme (IDE) has been proposed as a possible therapeutic target for type 2 diabetes treatment. However, many aspects of IDE's role in glucose homeostasis need to be clarified. In light of this, new preclinical models are required to elucidate the specific role of this protease in the main tissues related to insulin handling. To address this, here we generated a novel line of mice with selective deletion of the Ide gene within pancreatic beta-cells, B-IDE-KO mice, which have been characterized in terms of multiple metabolic end points, including blood glucose, plasma C-peptide, and intraperitoneal glucose tolerance tests. In addition, glucose-stimulated insulin secretion was quantified in isolated pancreatic islets and beta-cell differentiation markers and insulin secretion machinery were characterized by RT-PCR. Additionally, IDE was genetically and pharmacologically inhibited in INS-1E cells and rodent and human islets, and insulin secretion was assessed. Our results show that, in vivo, life-long deletion of IDE from beta-cells results in increased plasma C-peptide levels. Corroborating these findings, isolated islets from B-IDE-KO mice showed constitutive insulin secretion, a hallmark of beta-cell functional immaturity. Unexpectedly, we found 60% increase in Glut1 (a high-affinity/low-Km glucose transporter), suggesting increased glucose transport into the beta-cell at low glucose levels, which may be related to constitutive insulin secretion. In parallel, IDE inhibition in INS-1E and islet cells resulted in impaired insulin secretion after glucose challenge. We conclude that IDE is required for glucose-stimulated insulin secretion. When IDE is inhibited, insulin secretion machinery is perturbed, causing either inhibition of insulin release at high glucose concentrations or constitutive secretion.

Intestinal Fructose and Glucose Metabolism in Health and Disease.

The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecular and cellular mechanisms of fructose and glucose transport and sensing in the intestine, the intracellular signaling effects of dietary sugar metabolism, and its impact on glucose homeostasis in health and disease. Finally, the peripheral and central effects of dietary sugars on the gut-brain axis will be reviewed.

Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice.

The role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood. OBJECTIVE: This study aimed to clarify whether IDE is a major mediator of insulin clearance, and to define its role in the etiology of hepatic insulin resistance. METHODS: We generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action. RESULTS: L-IDE-KO mice exhibited higher (~20%) fasting and non-fasting plasma glucose levels, glucose intolerance and insulin resistance. This phenotype was associated with ~30% lower plasma membrane insulin receptor levels in liver, as well as ~55% reduction in insulin-stimulated phosphorylation of the insulin receptor, and its downstream signaling molecules, AKT1 and AKT2 (reduced by ~40%). In addition, FoxO1 was aberrantly distributed in cellular nuclei, in parallel with up-regulation of the gluconeogenic genes Pck1 and G6pc. Surprisingly, L-IDE-KO mice showed similar plasma insulin levels and hepatic insulin clearance as control mice, despite reduced phosphorylation of the carcinoembryonic antigen-related cell adhesion molecule 1, which upon its insulin-stimulated phosphorylation, promotes receptor-mediated insulin uptake to be degraded. CONCLUSION: IDE is not a rate-limiting regulator of plasma insulin levels in vivo.

Insulin degrading enzyme is up-regulated in pancreatic ß cells by insulin treatment.

Insulin Degrading Enzyme (IDE) is an endopeptidase that degrades insulin and glucagon. Ide gene has been associated with type-2 diabetes mellitus (DM2). However, the physiological role(s) of IDE in glucose homeostasis and its potential therapeutic benefit remain not completely known. To contribute in the understanding of IDE's role in glucose metabolism, we analyzed IDE protein level in pancreatic islets from two hyperinsulinemic mouse models, db/db and high-fat diet (HFD) mice, as well as in human islets from DM2 patients treated with oral hypoglycemic agents (OHAs) or insulin. IDE protein level was detected by staining and by western-blot. INS1E cells, rat and human islets were treated with insulin and IDE protein level was studied. We have shown for the first time IDE staining in rodent and human tissue, using the proper negative control, IDE null mouse tissue. Our staining indicates that IDE is expressed in both beta- and alpha-cells, with higher expression in alpha-cells. Db/db and HFD mice islets showed increased IDE protein level. Interestingly, human islets from DM2 patients treated with OHAs showed decreased IDE protein level in beta-cells. Meanwhile, islets from insulin-treated DM2 patients showed augmented IDE protein level compared to OHAs patients, pointing to an upregulation of IDE protein level stimulated by insulin. These data correlate nicely with insulin-stimulated upregulation of IDE in cultured INS1E cells, as well as in rat and human islets. In conclusion, our study shows that IDE is expressed in pancreatic beta- and alpha-cells of both rodents and humans, having higher expression in alpha-cells. Furthermore, insulin stimulates IDE protein level in pancreatic beta-cells. These results may have implications in how DM2 patient's treatment affects their beta-cell function.

Protective effects of epoxypukalide on pancreatic ß-cells and glucose metabolism in STZ-induced diabetic mice.

Diabetes is a consequence of a decrease on functional ß-cell mass. We have recently demonstrated that epoxypukalide (Epoxy) is a natural compound with beneficial effects on primary cultures of rat islets. In this study, we extend our previous investigations to test the hypothesis that Epoxy protects ß-cells and improves glucose metabolism in STZ-induced diabetic mice. We used 3-months old male mice that were treated with Epoxy at 200 µg/kg body weight. Glucose intolerance was induced by multiple intraperitoneal low-doses of streptozotocin (STZ) on 5 consecutive days. Glucose homeostasis was evaluated measuring plasma insulin levels and glucose tolerance. Histomorphometry was used to quantify the number of pancreatic ß-cells per islet. ß-cell proliferation was assessed by BrdU incorporation, and apoptosis by TUNEL staining. Epoxy treatment significantly improved glucose tolerance and plasma insulin levels. These metabolic changes were associated with increased ß-cell numbers, as a result of a two-fold increase in ß-cell proliferation and a 50% decrease in ß-cell death. Our results demonstrate that Epoxy improves whole-body glucose homeostasis by preventing pancreatic ß-cell death due to STZ-induced toxicity in STZ-treated mice.