The entero-insular axis: a journey in the physiopathology of diabetes

Glycemic homeostasis is an essential mechanism for the proper working of an organism. However, balance in blood lipid and protein levels also plays an important role. The discovery of the hormone insulin and the description of its function for glycemic control made fundamental scientific progress in this field. However, since then our view of the problem has been deeply influenced only in terms of glucose and insulin (in an insulin-centric and glucose-centric way). Based on recent scientific discoveries, a fine and sophisticated network of hormonal and metabolic interactions, involving almost every apparatus and tissue of the human body, has been theorized. Efficient metabolic homeostasis is founded on these intricate interactions. Although it is still not fully defined, this complex network can undergo alterations that lead to metabolic disorders such as diabetes mellitus (DM). The endocrine pancreas plays a crucial role in the metabolic balance of an organism, but insulin is just one of the elements involved and each single pancreatic islet hormone is worthy of our concern. Moreover, pancreatic hormones need to be considered in a general view, concerning both their systemic function as direct mediators and as hormones, which, in turn, are regulated by other hormones or other substances. This more complex scenario should be taken into account for a better understanding of the pathophysiology and the therapeutic algorithms of DM. As a consequence, improvements in modern medicine could help to contemplate this new perspective. This review is focused on some aspects of gut-pancreas interaction, aiming to integrate this synergy into a wider context involving other organs and tissues

Coffee Restores Expression of lncRNAs Involved in Steatosis and Fibrosis in a Mouse Model of NAFLD

Background and aim: Coffee intake exerts protective effects against non-alcoholic fatty liver disease (NAFLD), although without fully cleared mechanisms. In this study we aimed to assess whether coffee consumption may influence the expression of long non-coding RNAs (lncRNAs) in the liver. Methods: C57BL/6J mice were fed a 12-week standard diet (SD), high-fat diet (HFD) or HFD plus decaffeinated coffee solution (HFD + coffee). Expression of specific lncRNAs involved in NAFLD was analyzed by real-time PCR. For the most differentially expressed lncRNAs, the analysis was also extended to their mRNA targets. Results: Decaffeinated coffee intake reduced body weight gain, prevented NAFLD, lowered hyperglycemia and hypercholesterolemia. NAFLD was associated with lower hepatic expression of Gm16551, a lncRNA inhibiting de novo lipogenesis, and higher expression of H19, a lncRNA promoting fibrogenesis. Coffee intake restored Gm16551 to levels observed in lean mice and downregulated gene expression of its targets acetyl coenzyme A carboxylase 1 and stearoyl coenzyme A desaturase 1. Furthermore, coffee consumption markedly decreased hepatic expression of H19 and of its target gene collagen alpha-1(I) chain; consistently, in mice fed HFD + coffee liver expression of αSMA protein returned to levels of mice fed SD. Expression of lncRNA involved in circadian clock such as fatty liver-related lncRNA 1 (FLRL1) and fatty liver-related lncRNA 2 (FLRL2) were upregulated by HFD and were also modulated by coffee intake. Conclusion: Hepatoprotective effects of coffee may be depending on the modulation of lncRNAs involved in key pathways of NAFLD onset and progression

High glomerular filtration rate is associated with impaired arterial stiffness and subendocardial viability ratio in prediabetic subjects.

BACKGROUND AND AIMS High glomerular filtration rate (HGFR) is associated with cardiovascular damage in the setting of various conditions such as obesity and diabetes. Prediabetes was also associated with increased GFR, however, the association between prediabetes, HGFR and cardiovascular damage has not been investigated. In this study, we investigated the association between HGFR and early markers of cardiovascular disease in subjects with prediabetes. METHODS AND RESULTS Augmentation pressure (Aug), augmentation index (AIx), subendocardial viability ratio (SEVR), pulse wave velocity (PWV), intima-media thickness (IMT) and estimated GFR (eGFR) were evaluated in 230 subjects with prediabetes. The eGFR was assessed using the Chronic Kidney Disease Epidemiology Collaboration formula. HGFR was defined as an eGFR above the 75th percentile. Prediabetic subjects were divided into two groups according to presence/absence of HGFR: 61 subjects with HGFR and 169 subjects without HGFR. Subjects with HGFR showed higher Aug, AIx and lower SEVR compared with prediabetic subjects with lower eGFR (14.1 ± 7.2 vs 10.8 ± 6.2, 32.9 ± 12.7 vs 27.6 ± 11.7, 153.5 ± 27.8 vs 162 ± 30.2, p < 0.05). No differences were found in PWV and IMT values between the two groups. Then, we performed multiple regression analysis to test the relationship between Aug, SEVR and several cardiovascular risk factors. In multiple regression analysis Aug was associated with age, systolic blood pressure (BP), HOMA-IR and eGFR; the major determinants of SEVR were systolic BP, HOMA-IR and eGFR. CONCLUSION Subjects with prediabetes and HGFR exhibited an increased Aug, AIx and a reduced SEVR. These alterations are associated with eGFR, insulin resistance and systolic BP

Atorvastatin but not pravastatin impairs mitochondrial function in human pancreatic islets and rat β-cells. Direct effect of oxidative stress

Statins are a class of drugs widely prescribed as frontline therapy for lowering plasma LDL-cholesterol in cardiovascular risk prevention. Several clinical reports have recently suggested an increased risk of type 2 diabetes associated with chronic use of these drugs. The pathophysiology of this effect remains to be fully elucidated but impaired β-cell function constitutes a potential mechanism. The aim of this study was to explore the effect of a chronic treatment with lipophilic and hydrophilic statins on β-cell function, using human pancreatic islets and rat insulin-secreting INS-1 cells; we particularly focused on the role of mitochondria and oxidative stress. The present study demonstrates, for the first time, that atorvastatin (lipophilic) but not pravastatin (hydrophilic) affected insulin release and mitochondrial metabolism due to the suppression of antioxidant defense system and induction of ROS production in pancreatic β-cell models. Mevalonate addition and treatment with a specific antioxidant (N-AcetylCysteine) effectively reversed the observed defects. These data demonstrate that mitochondrial oxidative stress is a key element in the pathogenesis of statin-related diabetes and may have clinical relevance to design strategies for prevention or reduction of statin induced β-cell dysfunction and diabetes in patients treated with lipophilic statins

Metformin: When Should We Fear Lactic Acidosis?

Metformin, a molecule belonging to the biguanide family, represents one of the most commonly prescribed medications for the treatment of diabetes mellitus in the world. Over the sixty years during which it has been used, many benefits have been described, which are not limited to the treatment of diabetes mellitus. However, since metformin is similar to other members of the same drug family, there is still much concern regarding the risk of lactic acidosis. This article aims to highlight the correlation between the use of metformin and the onset of renal damage or lactic acidosis. Metformin-associated lactic acidosis exists; however, it is rare. The appropriate use of the drug, under safe conditions, induces benefits without risks

Clinical and Molecular Biomarkers for Diagnosis and Staging of NAFLD

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic pathology in industrialized countries, affecting about 25% of the general population. NAFLD is a benign condition, however, it could evolve toward more serious diseases, including non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and finally, hepatocellular carcinoma (HCC). Liver biopsy is still the gold standard for NAFLD diagnosis. Due to the risks associated with liver biopsy and the impossibility to apply it on a large scale, it is now necessary to identify non-invasive biomarkers, which may reliably identify patients at higher risk of progression. Therefore, several lines of research have tried to address this issue by identifying novel biomarkers using omics approaches, including lipidomics, metabolomics and RNA molecules’ profiling. Thus, in this review, we firstly report the conventional biomarkers used in clinical practice for NAFL and NASH diagnosis as well as fibrosis staging, and secondly, we pay attention to novel biomarkers discovered through omics approaches with a particular focus on RNA biomarkers (microRNAs, long-noncoding RNAs), showing promising diagnostic performance for NAFL/NASH diagnosis and fibrosis staging

Direct and Indirect Effects of SARS-CoV-2 Pandemic in Subjects with Familial Hypercholesterolemia: A Single Lipid-Center Real-World Evaluation

We evaluated the impact of direct and indirect effects of SARS-CoV-2 infection in subjects with familial hypercholesterolemia (FH). In this observational, retrospective study, 260 FH subjects participated in a telephone survey concerning lipid profile values, lipidologist and cardiologist consultations and vascular imaging evaluation during the 12 months before and after the Italian lockdown. The direct effect was defined as SARS-CoV-2 infection; the indirect effect was defined as the difference in one of the parameters evaluated by the telephone survey before and after lockdown. Among FH subjects, the percentage of the lipid profile evaluation was lower after lockdown than before lockdown (56.5% vs. 100.0%, p &lt; 0.01), HDL-C was significantly reduced (47.78 ± 10.12 vs. 53.2 ± 10.38 mg/dL, p &lt; 0.05) and a significant increase in non-HDL-C was found (117.24 ± 18.83 vs. 133.09 ± 19.01 mg/dL, p &lt; 0.05). The proportions of lipidologist and/or cardiologist consultations and/or vascular imaging were lower after lockdown than before lockdown (for lipidologist consultation 33.5% vs. 100.0%, p &lt; 0.001; for cardiologist consultation 22.3% vs. 60.8%, p &lt; 0.01; for vascular imaging 19.6% vs. 100.0%, p &lt; 0.001); the main cause of missed lipid profile analysis and/or healthcare consultation was the fear of SARS-CoV-2 contagion. The percentage of FH subjects affected by SARS-CoV-2 was 7.3%. In conclusion, a lower percentage of FH subjects underwent a lipid profile analysis, lipidologist and cardiologist consultations and vascular imaging evaluation after SARS-CoV-2 Italian lockdown

1 h Postload Glycemia Is Associated with Low Endogenous Secretory Receptor for Advanced Glycation End Product Levels and Early Markers of Cardiovascular Disease

We investigated the correlation of the soluble receptor for advanced glycation end products (sRAGE) and endogenous secretory RAGE (esRAGE) with markers of cardiovascular disease in subjects with normal glucose tolerance (NGT) and 1 h postload glucose &ge;155 mg/dL after an oral glucose tolerance test. We stratified 282 subjects without a previous diagnosis of diabetes into three groups: 123 controls (NGT and 1 h postload glycemia &lt;155 mg/dL), 84 NGT and 1 h postload glycemia &ge;155 mg/dL (NGT 1 h high), and 75 subjects with impaired fasting glucose and/or impaired glucose tolerance (IFG/IGT). NGT 1 h high subjects exhibited lower esRAGE (0.36 &plusmn; 0.18 vs. 0.4 5 &plusmn; 0.2, p &lt; 0.05) and higher S100A12 levels than controls (5684 (3193.2&ndash;8295.6) vs. 3960.1 (2101.8&ndash;7419), p &lt; 0.05). Furthermore, they showed an increased pulse wave velocity (PWV) and intima&ndash;media thickness (IMT). No differences were found between the NGT 1 h high group and the IFG/IGT group regarding cardiometabolic profiles. After multiple regression analyses, esRAGE was associated with glycated hemoglobin (HbA1c) and high-sensitivity C-reactive protein (hs-CRP). Age, HbA1c, and esRAGE were the determinants of IMT, whereas S100A12 and systolic pressure were the determinants of PWV. The NGT 1 h high group exhibited low esRAGE levels and an altered cardiometabolic profile. HbA1c, S100A12, and hs-CRP were associated with these alterations. In conclusion, subjects with NGT are not a homogeneous population, and they present different cardiovascular and glycometabolic risks

Chronic Exposure to Palmitate Impairs Insulin Signaling in an Intestinal L-cell Line: A Possible Shift from GLP-1 to Glucagon Production

Obesity and type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and impaired glucagon-like peptide-1 (GLP-1) secretion/function. Lipotoxicity, a chronic elevation of free fatty acids in the blood, could affect insulin-signaling in many peripheral tissues. To date, the effects of lipotoxicity on the insulin receptor and insulin resistance in the intestinal L-cells need to be elucidated. Moreover, recent observations indicate that L-cells may be able to process not only GLP-1 but also glucagon from proglucagon. The aim of this study was to investigate the effects of chronic palmitate exposure on insulin pathways, GLP-1 secretion and glucagon synthesis in the GLUTag L-cell line. Cells were cultured in the presence/absence of palmitate (0.5 mM) for 24 h to mimic lipotoxicity. Palmitate treatment affected insulin-stimulated GLP-1 secretion, insulin receptor phosphorylation and IRS-1-AKT pathway signaling. In our model lipotoxicity induced extracellular signal-regulated kinase (ERK 44/42) activation both in insulin stimulated and basal conditions and also up-regulated paired box 6 (PAX6) and proglucagon expression (Gcg). Interestingly, palmitate treatment caused an increased glucagon secretion through the up-regulation of prohormone convertase 2. These results indicate that a state of insulin resistance could be responsible for secretory alterations in L-cells through the impairment of insulin-signaling pathways. Our data support the hypothesis that lipotoxicity might contribute to L-cell deregulation

Glucagon as a Therapeutic Approach to Severe Hypoglycemia: After 100 Years, Is It Still the Antidote of Insulin?

Hypoglycemia represents a dark and tormented side of diabetes mellitus therapy. Patients treated with insulin or drug inducing hypoglycemia, consider hypoglycemia as a harmful element, which leads to their resistance and lack of acceptance of the pathology and relative therapies. Severe hypoglycemia, in itself, is a risk for patients and relatives. The possibility to have novel strategies and scientific knowledge concerning hypoglycemia could represent an enormous benefit. Novel available glucagon formulations, even now, allow clinicians to deal with hypoglycemia differently with respect to past years. Novel scientific evidence leads to advances concerning physiopathological mechanisms that regulated glycemic homeostasis. In this review, we will try to show some of the important aspects of this field