Covid-19 and diabetes mellitus: unveiling the interaction of two pandemics

A novel RNA betacoronavirus causing coronavirus disease 2019 (Covid-19) has now been declared pandemic disease by WHO. Guo et al published the first report of biochemical features in patients with diabetes and the further risk that this disease can determine to the progression of Covid-19. Among different cytokines found significantly higher in patients with diabetes compared to those without, Interleukin-6 (IL-6), which is already increased in conditions of chronic inflammation, may play a more deleterious role in Covid-19 infection. Targeting the overexpression of Il-6 effects with a monoclonal antibody against IL-6 receptor or using Janus Kinase inhibitors may be particularly helpful for treatment of Covid-19 pneumonia in diabetes

Intestinal hormones, gut microbiota and nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and has a complex pathophysiology with multiple pathways of development and progression implicated. Intestinal hormones regulate multiple biological functions and may play a role in the pathogenesis of non alcoholic fatty liver disease (NAFLD) by affecting food intake, body weight and insulin resistance. Bacterial products can affect the secretion of these hormones and thus have an effect on metabolism. Gut microbiota are normally involved in the intestinal energy harvest and their role has been increasingly been implicated in the pathogenesis of obesity and NAFLD. The intestinal hormone pathways as well as in the intestinal microbiota populations are potential therapeutic targets in the management of NAFLD. We review the evidence on the associations of the intestinal hormones and gut microbiota in the development, progression and treatment of NAFLD

The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The 'two-hit' hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The "multiple hit" hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis

The complex combination of COVID-19 and diabetes: pleiotropic changes in glucose metabolism

Purpose: Angiotensin converting enzyme 2 (ACE2) is the door for SARS-CoV-2, expressed in critical metabolic tissues. So, it is rational that the new virus causes pleiotropic alterations in glucose metabolism, resulting in the complication of pre-existing diabetes’s pathophysiology or creating new disease mechanisms. However, it seems that less attention has been paid to this issue. This review aimed to highlight the importance of long-term consequences and pleiotropic alterations in glucose metabolism following COVID-19 and emphasize the need for basic and clinical research in metabolism and endocrinology. Results: SARS-CoV-2 shifts cellular metabolism from oxidative phosphorylation to glycolysis, which leads to a decrease in ATP generation. Together with metabolic imbalance, the impaired immune system elevates the susceptibility of patients with diabetes to this deadly virus. SARS-CoV-2-induced metabolic alterations in immune cells can result in hyper inflammation and a cytokine storm. Metabolic dysfunction may affect therapies against SARS-CoV-2 infection. The effective control of metabolic complications could prove useful therapeutic targets for combating COVID-19. It is also necessary to understand the long-term consequences that will affect patients with diabetes who survived COVID-19. Conclusions: Since the pathophysiology of COVID-19 is still mostly unknown, identifying the metabolic mechanisms contributing to its progression is essential to provide specific ways to prevent and improve this dangerous virus’s detrimental effects. The findings show that the new virus may induce new-onset diabetes with uncertain metabolic and clinical features, supporting a potential role of COVID-19 in the development of diabetes

Interleukin-18 mediates cardiac dysfunction induced by western diet independent of obesity and hyperglycemia in the mouse

Obesity and diabetes are independent risk factors for heart failure and are associated with the consumption of diet rich in saturated fat and sugar, Western diet (WD), known to induce cardiac dysfunction in the mouse through incompletely characterized inflammatory mechanisms. We hypothesized that the detrimental cardiac effects of WD are mediated by interleukin-18 (IL-18), pro-inflammatory cytokine linked to cardiac dysfunction. C57BL/6J wild-type male mice and IL-18 knockout male mice were fed high-saturated fat and high-sugar diet for 8 weeks. We measured food intake, body weight and fasting glycemia. We assessed left ventricular (LV) systolic and diastolic function by Doppler echocardiography and cardiac catheterization. In wild-type mice, WD induced a significant increase in isovolumetric relaxation time, myocardial performance index and left ventricular end-diastolic pressure, reflecting an impairment in diastolic function, paired with a mild reduction in LV ejection fraction. IL-18 KO mice had higher food intake and greater increase in body weight without significant differences in hyperglycemia. Despite displaying greater obesity, IL-18 knockout mice fed with WD for 8 weeks had preserved cardiac diastolic function and higher left ventricular ejection fraction. IL-18 mediates diet-induced cardiac dysfunction, independent of food intake and obesity, thus highlighting a disconnect between the metabolic and cardiac effects of IL-18

Zinc Transporter 8 Antibodies Complement GAD and IA-2 Antibodies in the Identification and Characterization of Adult-Onset Autoimmune Diabetes: Non Insulin Requiring Autoimmune Diabetes (NIRAD) 4

OBJECTIVE: Zinc transporter 8 (ZnT8) is an islet beta-cell secretory granule membrane protein recently identified as an autoantibody antigen in type 1 diabetes. The aim of this study was to determine the prevalence and role of antibodies to ZnT8 (ZnT8As) in adult-onset diabetes. RESEARCH DESIGN AND METHODS: ZnT8As were measured by a radioimmunoprecipitation assay using recombinant ZnT8 COOH-terminal or NH(2)-terminal proteins in 193 patients with adult-onset autoimmune diabetes having antibodies to either GAD (GADAs) or IA-2 (IA-2As) and in 1,056 antibody-negative patients with type 2 diabetes from the Non Insulin Requiring Autoimmune Diabetes (NIRAD) study. RESULTS: ZnT8As-COOH were detected in 18.6% patients with autoimmune diabetes and 1.4% with type 2 diabetes. ZnT8As-NH(2) were rare. ZnT8As were associated with younger age and a high GADA titer. The use of GADAs, IA-2As, and ZnT8As in combination allowed a stratification of clinical phenotype, with younger age of onset of diabetes and characteristics of more severe insulin deficiency (higher fasting glucose and A1C, lower BMI, total cholesterol, and triglycerides) in patients with all three markers, with progressive attenuation in patients with two, one, and no antibodies (all P(trend) < 0.001). Autoantibody titers, association with high-risk HLA genotypes, and prevalence of thyroid peroxidase antibodies followed the same trend (all P < 0.001). CONCLUSIONS: ZnT8As are detectable in a proportion of patients with adult-onset autoimmune diabetes and seem to be a valuable marker to differentiate clinical phenotypes

Use of DPP4 inhibitors in Italy does not correlate with diabetes prevalence among COVID-19 deaths

In a nationwide study of 3,818 charts from patients with fatal COVID-19, we found that geographical differences in Dipeptidyl peptidase 4 (DPP4) inhibitors use did not correlate with diabetes prevalence among COVID-19 deaths, thus not supporting the hypothesis of a clinically relevant involvement of DPP4 in COVID-19 development and progression

GADA titer-related risk for organ-specific autoimmunity in LADA subjects subdivided according to gender (NIRAD study 6).

CONTEXT: Latent autoimmune diabetes in adults (LADA) includes a heterogeneous population wherein, based on glutamic acid decarboxylase antibody (GADA) titer, different subgroups of subjects can be identified. OBJECTIVE: The aim of the present study was to evaluate GADA titer-related risk for β-cell and other organ-specific autoimmunity in LADA subjects. METHODS: Adult-onset autoimmune diabetes subjects (n=236) and type 2 diabetes (T2DM) subjects (n=450) were characterized for protein tyrosine phosphatase (IA-2IC and IA-2(256-760)), zinc transporter 8 (ZnT8), thyroid peroxidase, (TPO), steroid 21-hydroxylase (21-OH), tissue transglutaminase (tTG), and antiparietal cell (APC) antibodies. RESULTS: High GADA titer compared to low GADA titer showed a significantly higher prevalence of IA-2IC, IA-2(256-760), ZnT8, TPO, and APC antibodies (P≤0.04 for all comparison). 21-OH antibodies were detected in 3.4% of high GADA titer. A significant decreasing trend was observed from high GADA to low GADA and to T2DM subjects for IA-2(256-760), ZnT8, TPO, tTG, and APC antibodies (P for trend≤0.001). TPO was the only antibody showing a different prevalence between gender; low GADA titer and T2DM female patients had a higher frequency of TPO antibody compared to males (P=0.0004 and P=0.0006, respectively), where the presence of high GADA titer conferred an odds ratio of 8.6 for TPO compared to low GADA titer. After subdividing high and low GADA titer subjects according to the number of antibodies, we observed that 73.3% of high GADA titer subjects were positive for at least one or more antibodies, compared to 38.3% of low GADA titer (P<0.0001). CONCLUSIONS: In LADA subjects, high GADA titer was associated with a profile of more severe autoimmunity and, in male gender, specifically predisposed to thyroid autoimmunity. A regular screening for other antibodies is recommended in LADA patients according to GADA titer and gender

Gender differences in liver disease and the drug-dose gender gap

Although gender-based medicine is a relatively recent concept, it is now emerging as an important field of research, supported by the finding that many diseases manifest differently in men and women and therefore, might require a different treatment. Sex-related differences regarding the epidemiology, progression and treatment strategies of certain liver diseases have long been known, but most of the epidemiological and clinical trials still report results only about one sex, with consequent different rate of response and adverse reactions to treatment between men and women in clinical practice. This review reports the data found in the literature concerning the gender-related differences for the most representative hepatic diseases