The interferon landscape along the respiratory tract impacts the severity of COVID-19.

Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains debated. We scrutinized the production of IFNs along the respiratory tract of COVID-19 patients and found that high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity. Production of specific IFN-III, but not IFN-I, members denotes patients with a mild pathology and efficiently drives the transcription of genes that protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, compared to subjects with other infectious or noninfectious lung pathologies, IFNs are overrepresented in the lower airways of patients with severe COVID-19 that exhibit gene pathways associated with increased apoptosis and decreased proliferation. Our data demonstrate a dynamic production of IFNs in SARS-CoV-2-infected patients and show IFNs play opposing roles at distinct anatomical sites.

Vaccination against influenza viruses reduces infection, not hospitalization or death, from respiratory COVID-19: A systematic review and meta-analysis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and has brought a huge burden in terms of human lives. Strict social distance and influenza vaccination have been recommended to avoid co-infections between influenza viruses and SARS-CoV-2. Scattered reports suggested a protective effect of influenza vaccine on COVID-19 development and severity. We analyzed 51 studies on the capacity of influenza vaccination to affect infection with SARS-CoV-2, hospitalization, admission to Intensive Care Units (ICU), and mortality. All subjects taken into consideration did not receive any anti-SARS-CoV-2 vaccine, although their status with respect to previous infections with SARS-CoV-2 is not known. Comparison between vaccinated and not-vaccinated subjects for each of the four endpoints was expressed as odds ratio (OR), with 95% confidence intervals (CIs); all analyses were performed by DerSimonian and Laird model, and Hartung-Knapp model when studies were less than 10. In a total of 61 029 936 subjects from 33 studies, influenza vaccination reduced frequency of SARS-CoV-2 infection [OR plus 95% CI = 0.70 (0.65-0.77)]. The effect was significant in all studies together, in health care workers and in the general population; distance from influenza vaccination and the type of vaccine were also of importance. In 98 174 subjects from 11 studies, frequency of ICU admission was reduced with influenza vaccination [OR (95% CI) = 0.71 (0.54-0.94)]; the effect was significant in all studies together, in pregnant women and in hospitalized subjects. In contrast, in 4 737 328 subjects from 14 studies hospitalization was not modified [OR (95% CI) = 1.05 (0.82-1.35)], and in 4 139 660 subjects from 19 studies, mortality was not modified [OR (95% CI) = 0.76 (0.26-2.20)]. Our study emphasizes the importance of influenza vaccination in the protection against SARS-CoV-2 infection.

Metabolic disorders affecting the liver and heart: Therapeutic efficacy of miRNA-based therapies?

Liver and heart disease are major causes of death worldwide. It is known that metabolic alteration causing type 2 diabetes (T2D) and Nonalcoholic fatty liver (NAFLD) coupled with a derangement in lipid homeostasis, may exacerbate hepatic and cardiovascular diseases. Some pharmacological treatments can mitigate organ dysfunctions but the important side effects limit their efficacy leading often to deterioration of the tissues. It needs to develop new personalized treatment approaches and recent progresses of engineered RNA molecules are becoming increasingly viable as alternative treatments. This review outlines the current use of antisense oligonucleotides (ASOs), RNA interference (RNAi) and RNA genome editing as treatment for rare metabolic disorders. However, the potential for small non-coding RNAs to serve as therapeutic agents for liver and heart diseases is yet to be fully explored. Although miRNAs are recognized as biomarkers for many diseases, they are also capable of serving as drugs for medical intervention; several clinical trials are testing miRNAs as therapeutics for type 2 diabetes, nonalcoholic fatty liver as well as cardiac diseases. Recent advances in RNA-based therapeutics may potentially facilitate a novel application of miRNAs as agents and as druggable targets. In this work, we sought to summarize the advancement and advantages of miRNA selective therapy when compared to conventional drugs. In particular, we sought to emphasise druggable miRNAs, over ASOs or other RNA therapeutics or conventional drugs. Finally, we sought to address research questions related to efficacy, side-effects, and range of use of RNA therapeutics. Additionally, we covered hurdles and examined recent advances in the use of miRNA-based RNA therapy in metabolic disorders such as diabetes, liver, and heart diseases.

Correction: La Sala et al. New Fast Acting Glucagon for Recovery from Hypoglycemia, a Life-Threatening Situation: Nasal Powder and Injected Stable Solutions. Int. J. Mol. Sci. 2021, 22, 10643.

The authors would like to make corrections to the reference citations in the original article [...].

Role of obesity and hypertension in the incidence of atrial fibrillation, ischaemic heart disease and heart failure in patients with diabetes.

In a cohort study performed using primary care databases in a General Practitioners Network, Groenewegen et al. report a clear association between diabetes and incidence of the major chronic progressive heart diseases, notably heart failure (Groenewegen et al. in Cardiovasc Diabetol 20:123, 2021). However, no mention is made of body mass index and hypertension in the methods or in the results. Obesity is linked to hypertension and hypertension is a major risk factor for all cardiovascular diseases, and prospective studies have shown that obesity and hypertension contribute significantly to atrial fibrillation in persons with diabetes. The data would be improved by assessing the role of obesity and of hypertension in the incidence of heart diseases in these patients. This would also lead to a better and personalized treatment of patients with diabetes, for instance through weight loss and intensification of treatment of hypertension, to modify the incidence of atrial fibrillation, ischaemic heart disease and heart failure.

High plasma renin activity associates with obesity-related diabetes and arterial hypertension, and predicts persistent hypertension after bariatric surgery.

BACKGROUND: Information about the renin-angiotensin-aldosterone system (RAAS) in obese individuals before and after bariatric surgery is scarce. Aim of this study was to analyze the RAAS in severely obese subjects, in relation to anthropometric and metabolic variables, with special reference to glucose tolerance. METHODS: 239 subjects were evaluated at baseline, and 181 one year after bariatric surgery [laparoscopic gastric banding (LAGB)]. RESULTS: At baseline, renin (plasma renin activity, PRA) was increased from normal to glucose tolerance and more in diabetes, also correlating with ferritin. After LAGB, the decrease of PRA and aldosterone was significant in hypertensive, but not in normotensive subjects, and correlatied with decrease of ferritin. PRA and glucose levels were predictive of persistent hypertension 1 year after LAGB. CONCLUSIONS: These data support the role of RAAS in the pathophysiology of glucose homeostasis, and in the regulation of blood pressure in obesity. Ferritin, as a proxy of subclinical inflammation, could be another factor contributing to the cross-talk between RAAS and glucose metabolism.

New Fast Acting Glucagon for Recovery from Hypoglycemia, a Life-Threatening Situation: Nasal Powder and Injected Stable Solutions.

The goal of diabetes care is to achieve and maintain good glycemic control over time, so as to prevent or delay the development of micro- and macrovascular complications in type 1 (T1D) and type 2 diabetes (T2D). However, numerous barriers hinder the achievement of this goal, first of all the frequent episodes of hypoglycemia typical in patients treated with insulin as T1D patients, or sulphonylureas as T2D patients. The prevention strategy and treatment of hypoglycemia are important for the well-being of patients with diabetes. Hypoglycemia is strongly associated with an increased risk of cardiovascular disease in diabetic patients, due probably to the release of inflammatory markers and prothrombotic effects triggered by hypoglycemia. Treatment of hypoglycemia is traditionally based on administration of carbohydrates or of glucagon via intramuscular (IM) or subcutaneous injection (SC). The injection of traditional glucagon is cumbersome, such that glucagon is an under-utilized drug. In 1983, it was shown for the first time that intranasal (IN) glucagon increases blood glucose levels in healthy volunteers, and in 1989-1992 that IN glucagon is similar to IM glucagon in resolving hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. IN glucagon was developed in 2010 and continued in 2015; in 2019 IN glucagon obtained approval in the US, Canada, and Europe for severe hypoglycemia in children and adults. In the 2010s, two ready-to-use injectable formulations, a stable non-aqueous glucagon solution and the glucagon analog dasiglucagon, were developed, showing an efficacy similar to traditional glucagon, and approved in the US in 2020 and in 2021, respectively, for severe hypoglycemia in adults and in children. Fast-acting glucagon (nasal administration and injected solutions) appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both adults and children. It is anticipated that the availability of fast-acting glucagon will expand the use of glucagon, improve overall metabolic control, and prevent hypoglycemia-related complications, in particular cardiovascular complications and cognitive impairment.

Prevention of Diabetes and Cardiovascular Disease in Obesity.

Obesity is one of the major risk factors for the development of both impaired glucose tolerance (IGT, or prediabetes) and type 2 diabetes (T2D), and its prevalence worldwide drives toward an increased rate of cardiovascular morbidity and mortality. Given the estimations of the World Health Organization (WHO) and the recommendation of the Diabetes Prevention Program (DPP), where IGT and diabetes are considered as risk factors for the development of cardiovascular complications and obesity, the development of diabetes should be treated because of its potential reversibility. In this view, several interventions such as diet, lifestyle changes, and pharmacological treatment are effective, including bariatric metabolic surgery (BMS), which is the most incisive way to efficiently lower body weight. In this review, we sought to summarize some of the major aspects linked to diabetes prevention in overweight/obesity, focusing on the use of surgery; we also attempted to elucidate molecular pathways involved in a variety of obesity-induced processes able to favor the progression of chronic diseases, such as diabetes and its complications.

Does microRNA Perturbation Control the Mechanisms Linking Obesity and Diabetes? Implications for Cardiovascular Risk.

Metabolic disorders such as obesity and type 2 diabetes (T2D) are considered the major risk factors for the development of cardiovascular diseases (CVD). Although the pathological mechanisms underlying the mutual development of obesity and T2D are difficult to define, a better understanding of the molecular aspects is of utmost importance to identify novel therapeutic targets. Recently, a class of non-coding RNAs, called microRNAs (miRNAs), are emerging as key modulators of metabolic abnormalities. There is increasing evidence supporting the role of intra- and extracellular miRNAs as determinants of the crosstalk between adipose tissues, liver, skeletal muscle and other organs, triggering the paracrine communication among different tissues. miRNAs may be considered as risk factors for CVD due to their correlation with cardiovascular events, and in particular, may be related to the most prominent risk factors. In this review, we describe the associations observed between miRNAs expression levels and the most common cardiovascular risk factors. Furthermore, we sought to depict the molecular aspect of the interplay between obesity and diabetes, investigating the role of microRNAs in the interorgan crosstalk. Finally, we discussed the fascinating hypothesis of the loss of protective factors, such as antioxidant defense systems regulated by such miRNAs.

Long-term mortality in obese subjects undergoing malabsorptive surgery (biliopancreatic diversion and biliointestinal bypass) versus medical treatment.

BACKGROUND AND AIM: Aim of this study was to analyze long-term mortality in obese patients receiving malabsorptive bariatric surgery (BS)[biliopancreatic diversion (BPD) and biliointestinal bypass (BIBP)] in comparison to medical treatment of obesity. PATIENTS AND METHODS: Medical records of 1877 obese patients [body mass index (BMI) > 35 kg/m2, aged 18-65 years, undergoing BS (n = 472, 111 with diabetes) or non-surgical medical treatment (n = 1405, 385 with diabetes), during the period 1999-2008 (visit 1)] were collected; non-surgical patients were matched for age, sex, BMI, and blood pressure, and life status and causes of death were ascertained through December 2016. Survival was compared across surgery patients and non-surgical patients using Kaplan-Meier plots and Cox regression analyses. RESULTS: Observation period was 12.1 ± 3.41 years (mean ± SD). Compared to non-surgical patients, BS patients had reduced all-cause mortality (34/472 (7.2%) vs 181/1,405 (12.9%) patients, χ2 = 11.25, p = 0.001; HR = 0.64, 95% C.I. 0.43-0.93, p = 0.019). Cardiovascular and cancer causes of death were significantly less frequent in surgery vs no-surgery (HR = 0.26, 95% C.I. 0.09-0.72, p = 0.003; HR = 0.21, 95% C.I. 0.09-0.45, p < 0.001, respectively). CONCLUSION: Patients who have undergone BPD and BIBP have lower long-term all-cause, cardiovascular-caused and cancer-caused mortality compared to non-surgical medical weight-loss treatment patients. Malabsorptive bariatric surgery significantly reduces long-term mortality in severely obese patients.

Therapeutic Use of Intranasal Glucagon: Resolution of Hypoglycemia.

Episodes of hypoglycemia are frequent in patients with diabetes treated with insulin or sulphonylureas. Hypoglycemia can lead to severe acute complications, and, as such, both prevention and treatment of hypoglycemia are important for the well-being of patients with diabetes. The experience of hypoglycemia also leads to fear of hypoglycemia, that in turn can limit optimal glycemic control in patients, especially with type 1 diabetes. Treatment of hypoglycemia is still based on administration of carbohydrates (oral or parenteral according to the level of consciousness) or of glucagon (intramuscular or subcutaneous injection). In 1983, it was shown for the first time that intranasal (IN) glucagon drops (with sodium glycocholate as a promoter) increase blood glucose levels in healthy volunteers. During the following decade, several authors showed the efficacy of IN glucagon (drops, powders, and sprays) to resolve hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. Only in 2010, based on evaluation of patients' beliefs and patients' expectations, a canadian pharmaceutical company (Locemia Solutions, Montreal, Canada) reinitiated efforts to develop glucagon for IN administration. The project has been continued by Eli Lilly, that is seeking to obtain registration in order to make IN glucagon available to insulin users (children and adolescents) worldwide. IN glucagon is as effective as injectable glucagon, and devoid of most of the technical difficulties associated with administration of injectable glucagon. IN glucagon appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both children and adults.

A 23-year study of mortality and development of co-morbidities in patients with obesity undergoing bariatric surgery (laparoscopic gastric banding) in comparison with medical treatment of obesity.

BACKGROUND AND AIM: Several studies have shown that bariatric surgery reduces long term mortality compared to medical weight loss therapy. In a previous study we have demonstrated that gastric banding (LAGB) is associated with reduced mortality in patients with and without diabetes, and with reduced incidence of obesity co-morbidities (cardiovascular disease, diabetes, and cancer) at a 17 year follow-up. The aim of this study was to verify at a longer time interval (23 years) mortality and incidence of co-morbidities in patients undergoing LAGB or medical weight loss therapy. PATIENTS AND METHODS: As reported in the previous shorter-time study, medical records of obese patients [body mass index (BMI) > 35 kg/m2 undergoing LAGB (n = 385; 52 with diabetes) or medical treatment (controls, n = 681; 127 with diabetes), during the period 1995-2001 (visit 1)] were collected. Patients were matched for age, sex, BMI, and blood pressure. Identification codes of patients were entered in the Italian National Health System Lumbardy database, that contains life status, causes of death, as well as exemptions, prescriptions, and hospital admissions (proxies of diseases) from visit 1 to June 2018. Survival was compared across LAGB patients and matched controls using Kaplan-Meier plots adjusted Cox regression analyses. RESULTS: Final observation period was 19.5 ± 1.87 years (13.4-23.5). Compared to controls, LAGB was associated with reduced mortality [HR = 0.52, 95% CI 0.33-0.80, p = 0.003], significant in patients with diabetes [HR = 0.46, 95% CI 0.22-0.94, p = 0.034], borderline significant in patients without diabetes [HR = 0.61, 95% CI = 0.35-1.05, p = 0.076]. LAGB was associated with lower incidence of diabetes (15 vs 75 cases, p = 0.001), of CV diseases (61 vs 226 cases, p = 0.009), of cancer (10 vs 35, p = 0.01), and of renal diseases (0 vs 35, p = 0.001), and of hospital admissions (92 vs 377, p = 0.001). CONCLUSION: The preventive effect of LAGB on mortality is maintained up to 23 years, even with a decreased efficacy compared with the shorter-time study, while the preventive effect of LAGB on co-morbidities and on hospital admissions increases with time.

Intranasal glucagon for hypoglycaemia in diabetic patients. An old dream is becoming reality?

In 1983 it was shown that glucagon administered intranasally (IN) was absorbed through the nasal mucosa and increased blood glucose in healthy subjects. Shortly thereafter, it was shown that IN glucagon counteracts with hypoglycaemia in insulin-treated diabetic patients. In spite of this evidence, IN glucagon was not developed by any pharmaceutical company before 2010, when renewed interest led to intensive evaluation of a possible remedy for hypoglycaemia in insulin-treated diabetic adults and children. IN glucagon is now being developed as a needle-free device that delivers glucagon powder for treatment of severe hypoglycaemia; the ease of using this device stands in stark contrast to the difficulties encountered in use of the current intramuscular glucagon emergency kits. Studies have demonstrated the efficacy, safety and ease-of-use of this IN glucagon preparation, and suggest IN glucagon as a promising alternative to injectable glucagon for treating severe hypoglycaemia in children and adults who use insulin. This would meet the unmet medical need for an easily administered glucagon preparation.

Long-term mortality and incidence of cardiovascular diseases and type 2 diabetes in diabetic and nondiabetic obese patients undergoing gastric banding: a controlled study.

BACKGROUND AND AIM: Aim of this retrospective study was to compare long-term mortality and incidence of new diseases [diabetes and cardiovascular (CV) disease] in morbidly obese diabetic and nondiabetic patients, undergoing gastric banding (LAGB) in comparison to medical treatment. PATIENTS AND METHODS: Medical records of obese patients [body mass index (BMI) > 35 kg/m(2) undergoing LAGB (n = 385; 52 with diabetes) or medical treatment (controls, n = 681; 127 with diabetes), during the period 1995-2001 (visit 1)] were collected. Patients were matched for age, sex, BMI, and blood pressure. Identification codes of patients were entered in the Italian National Health System Lumbardy database, that contains life status, causes of death, as well as exemptions, drug prescriptions, and hospital admissions (proxies of diseases) from visit 1 to September 2012. Survival was compared across LAGB patients and matched controls using Kaplan-Meier plots adjusted Cox regression analyses. RESULTS: Observation period was 13.9 ± 1.87 (mean ± SD). Mortality rate was 2.6, 6.6, and 10.1 % in controls at 5, 10, and 15 years, respectively; mortality rate was 0.8, 2.5, and 3.1 % in LAGB patients at 5, 10, and 15 years, respectively. Compared to controls, surgery was associated with reduced mortality [HR 0.35, 95 % CI 0.19-0.65, p < 0.001 at univariate analysis, HR 0.41, 95 % CI 0.21-0.76, p < 0.005 at adjusted analysis], similar in diabetic [HR 0.34, 95 % CI 0.13-0.87, p = 0.025] and nondiabetic [HR 0.42, 95 % CI 0.19-0.97, p = 0.041] patients. Surgery was also associated with lower incidence of diabetes (15 vs 48 cases, p = 0.035) and CV diseases (52 vs 124 cases, p = 0.048), and of hospital admissions (88 vs 197, p = 0.04). CONCLUSION: Up to 17 years, gastric banding is associated with reduced mortality in diabetic and nondiabetic patients, and with reduced incidence of diabetes and cardiovascular diseases.

Alanine transferase levels (ALT) and triglyceride-glucose index are risk factors for type 2 diabetes mellitus in obese patients.

AIMS: The role of liver steatosis and increased liver enzymes (ALT) in increasing incident type 2 diabetes mellitus (T2DM) is debated, because of their differential effects on different ethnicities and populations. The aim of this study was to evaluate the role of elevated ALT in the development of T2DM in non-diabetic obese subjects receiving routine medical treatment. METHODS: A total of 1005 subjects [296 men and 709 women, aged 45.7 ± 13.12 years, body mass index (BMI) 39.5 ± 4.86 kg/m2] were followed for a mean period of 14.3 ± 4.44 years. Subjects were evaluated for several metabolic variables, including the triglyceride-glucose index and the presence of metabolic syndrome (IDF 2005 definition), and were subdivided into ALT quartiles. RESULTS: T2DM developed in 136 subjects, and the difference was significant between the first and the fourth ALT quartile (p = 0.048). Both at univariate analysis and at stepwise regression, ALT quartiles were associated with incident T2DM. Traditional risk factors for T2DM coexisted, with a somehow greater predictive value, such as triglyceride-glucose index, age, arterial hypertension, LDL-cholesterol, and metabolic syndrome. CONCLUSIONS: These data suggest an association between elevated ALT levels and the risk of incident T2DM in obesity.