Potential Role of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Cognitive Decline and Dementia in Diabetes Mellitus.

Dementia is a permanent illness characterized by mental instability, memory loss, and cognitive decline. Many studies have demonstrated an association between diabetes and cognitive dysfunction that proceeds in three steps, namely, diabetes-associated cognitive decrements, mild cognitive impairment (MCI; both non-amnesic MCI and amnesic MCI), and dementia [both vascular dementia and Alzheimer's disease (AD)]. Based on this association, this disease has been designated as type 3 diabetes mellitus. The underlying mechanisms comprise insulin resistance, inflammation, lipid abnormalities, oxidative stress, mitochondrial dysfunction, glycated end-products and autophagy. Moreover, insulin and insulin-like growth factor-1 (IGF-1) have been demonstrated to be involved. Insulin in the brain has a neuroprotective role that alters cognitive skills and alteration of insulin signaling determines beta-amyloid (Aß) accumulation, in turn promoting brain insulin resistance. In this complex mechanism, other triggers include hyperglycemia-induced overproduction of reactive oxygen species (ROS) and inflammatory cytokines, which result in neuroinflammation, suggesting that antidiabetic drugs may be potential treatments to protect against AD. Among these, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are the most attractive antidiabetic drugs due to their actions on synaptic plasticity, cognition and cell survival. The present review summarizes the significant data concerning the underlying pathophysiological and pharmacological mechanisms between diabetes and dementia.

Characteristics, Management, and Outcomes of Elderly Patients with Diabetes in a Covid-19 Unit: Lessons Learned from a Pilot Study.

Background and objectives: Diabetes may affect in-hospital mortality of patients with Coronavirus disease 2019 (COVID-19). We have retrospectively evaluated clinical characteristics, diabetes management, and outcomes in a sample of COVID-19 patients with diabetes admitted to our hospital. Materials and Methods: All patients admitted to the Infectious Diseases Unit from 28 March 2020, to 16 June 2020, were enrolled. Clinical information and biochemical parameters were collected at the time of admission. Patients were ranked according to diabetes and death. Results: Sixty-one patients with COVID-19 were analyzed. Most of them were from a long-term health care facility. Mean age was 77 ± 16 years, and 19 had type 2 diabetes (T2D). Eighteen patients died, including 8 with T2D and 10 without T2D (p = 0.15). Patients with diabetes were significantly older, had a higher prevalence of cardiovascular diseases, and a significantly lower lymphocyte count. No significant relationship was found between diabetes and in-hospital mortality (Odds Ratio OR 2.3; Confidence Interval CI 0.73-7.38, p = 0.15). Patients with diabetes were treated with insulin titration algorithm. Severe hypoglycemic events, ketoacidosis and hyperosmolar hyperglycemias did not occur during hospitalization. Mean pre-meal capillary blood glucose was 157 ± 45 mg/dL, and the coefficient of variation of glycaemia was 29%. Conclusions: Our study, albeit limited by the small number of subjects, did not describe any significant association between T2D diabetes and mortality. Clinical characteristics of patients, and acceptable glucose control prior and during hospitalization may have influenced the result. The use of an insulin titration algorithm should be pursued during hospitalization.

Effect of dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist on weight loss in subjects with obesity.

The occurrence of obesity is an increasing issue worldwide, especially in industrialized countries. Weight loss is important both to treat obesity and to prevent the development of complications. Currently, several drugs are used to treat obesity, but their efficacy is modest. Thus, new anti-obesity treatments are needed. Recently, there has been increased interest in the development of incretins that combine body-weight-lowering and glucose-lowering effects. Therefore, a new drug that simultaneously coactivates both the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R) has been developed. Tirzepatide, the first in this class, improves glycemic control by increasing insulin sensitivity and lipid metabolism as well as by reducing body weight. Combining the activation of the two receptors, greater improvement of ß-cell function offers more effective treatment of diabetes and obesity with fewer adverse effects than selective GLP-1R agonists. In the present review, we discuss the progress in the use of GIPR and GLP-1R coagonists and review literature from in vitro studies, animal studies, and human trials, highlighting the synergistic mechanisms of tirzepatide.

Short term effect of sacubitril/valsartan on comprehensive geriatric assessment in chronic heart failure: a real life analysis.

Sacubitril/Valsartan (Sac-Val) has improved clinical prognosis in patients affected by heart failure (HF) with reduced ejection fraction (HFrEF). Comorbidities have a crucial impact on clinical presentation and prognosis in HF patients. Cognitive impairment (CoI) and Depression are a very common comorbidity in patients with HF and is widely recognized as a specific determinant of chronic disability, and HF patients with poor physical functional performance in Short physical performance battery (SPPB) showed a worse prognosis. The aim of the present study was to evaluate the potential effects of Sac-Val on functional, humoral, and cognitive aspects, evaluated by performing comprehensive geriatric assessment (CGA), in a cohort of elderly HFrEF. We studied 61 patients (51 men and 10 women, mean age 76.4 ± 5.1 years) suffering from HFrEF. After 6 months follow-up, we observed a significant improvement in humoral and functional parameters of CGA, renal function, NTpro-BNP levels and echocardiographic parameters. In the whole population, multivariate analysis shows that changes of Cardiac Index, NT-proBNP and Respiratory rate contributed for 26.0%, 9.7% and 4.8% to GDS variability, respectively, and the whole model accounted for a 41.1% of GDS variation; moreover changes of Global longitudinal strain, estimated glomerular filtration rate, Cardiac Index and BMI contributed for 23.9%, 11.7%, 5.4% and 4.0% to SPPB variability, respectively, and the whole model accounted for a 45% of SPPB variation. This represents the first real-world study carried out in an elderly population suffering from chronic HFrEF with numerous comorbidities, in which treatment with Sac-Val for 6 months induced important improvements in clinical, humoral, hemodynamic, and functional outcomes, without adverse effects on cognitive performance.

Reactive hypoglycemia in binge eating disorder, food addiction, and the comorbid phenotype: unravelling the metabolic drive to disordered eating behaviours.

BACKGROUND: Impaired metabolic response such as blood glucose fast fluctuations may be hypothesized in binge eating disorder (BED) and food addiction (FA) by virtue of the repetitive consumption of highly processed food. Conversely, rapid changes in plasma glucose (i.e., hypoglycemia) may trigger craving for the same food products. The investigation of early glycemic disturbances in BED and FA could enhance the understanding of the metabolic mechanisms involved in the maintenance of the disorders. Present study investigated hypoglycemia events during a 5-h-long oral glucose tolerance test (OGTT) in people with BED, FA, and the comorbid phenotype. Further, the association between the severity of eating psychopathology and the variability in hypoglycaemia events was explored. METHODS: Two-hundred participants with high weight and no diabetes completed the extended OGTT and were screened for BED, FA, BED-FA, or no-BED/FA. The four groups were compared in hypoglycemia events, OGTT-derived measures, and eating psychopathology. The association between predictors (eating psychopathology), confounders (demographics, metabolic features), and the outcomes (hypoglycemia, early/late hypoglycemia, severe hypoglycemia, reactive hypoglycemia) was examined through logistic regression. RESULTS: Hypoglycemia in general, and reactive hypoglycemia were highly frequent (79% and 28% of the sample, respectively). Hypoglycemia events (< 70 mg/dL) were equally experienced among groups, whilst severe hypoglycemia (< 54 mg/dL) was more frequent in BED at the late stage of OGTT (5 h; χ2 = 1.120, p = .011). The FA and BED groups exhibited significantly higher number of reactive hypoglycemia (χ2 = 13.898, p = .003), in different times by diagnosis (FA: 210'-240'; BED: at the 270'). FA severity was the only predictor of early and reactive hypoglycemia. CONCLUSIONS: People with BED or FA are prone to experiencing reactive hypoglycemia; FA severity may predict early and symptomatic hypoglycemia events. This can further reinforce disordered eating behaviours by promoting addictive responses, both biologically and behaviourally. These results inform professionals dealing with eating disorders about the need to refer patients for metabolic evaluation. On the other hand, clinicians dealing with obesity should screen for and address BED and FA in patients seeking care for weight loss.

Impairment in blood glucose control may be attended in binge eating disorder (BED) and food addiction (FA), two distinct eating disorders which are characterized by the recurrent consumption of highly palatable food rich in high-glucose index carbohydrates. Conversely, rapid changes in blood glucose, such as hypoglycemia, may intensify craving for high-calorie products, thus reinforcing pathological eating behaviours. This study investigated the presence of hypoglycemia events in people suffering from BED, FA, both, or no eating disorder, and explored whether the severity of eating behaviours correlated with a higher probability of having hypoglycemia. Results showed that people with BED and FA experienced more episodes of symptomatic hypoglycemia than those with obesity but no eating disorder. The severity of binge eating was associated with more severe hypoglycemia events, indicated by lower plasma glucose values. Lastly, people with severe FA were more prone to experiencing early post-meal hypoglycemia accompanied by symptoms. These results inform professionals dealing with eating disorders about the need to refer patients for metabolic evaluation. On the other hand, clinicians dealing with obesity should screen for and address BED and FA in patients seeking care for weight loss.

COVID-19 and diabetes-Two giants colliding: From pathophysiology to management.

Since December 2019, a new coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread around the world, causing the coronavirus 2019 (COVID-19) pandemic. From the beginning, SARS-CoV-2 has put a strain on the health system. In fact, many patients have had severe forms of the disease with the need for hospitalization due to respiratory failure. To contain the pandemic, the most widely used approach has been lockdowns. Social restrictions have been reduced thanks to the development of vaccines and targeted therapies. However, fatal events still occur among people at high risk of serious infection, such as patients with concomitant diabetes. Different mechanisms have been proposed to explain the poor prognosis of patients with diabetes and COVID-19, but the specific cause is unclear. It is now known that insulin resistance, inflammation, and cytokine storm are involved. Moreover, SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptors to enter cells. This receptor is expressed on pancreatic beta cells and, during infection, it appears that receptor involvement may induce hyperglycemia in patients with or without diabetes. In this study, we discuss the mechanisms underlying the poor prognosis in people with COVID-19 and diabetes and what may improve the outcome in these patients.

Up-Date on Diabetic Nephropathy.

Diabetes is one of the leading causes of kidney disease. Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide, and it is linked to an increase in cardiovascular (CV) risk. Diabetic nephropathy (DN) increases morbidity and mortality among people living with diabetes. Risk factors for DN are chronic hyperglycemia and high blood pressure; the renin-angiotensin-aldosterone system blockade improves glomerular function and CV risk in these patients. Recently, new antidiabetic drugs, including sodium-glucose transport protein 2 inhibitors and glucagon-like peptide-1 agonists, have demonstrated additional contribution in delaying the progression of kidney disease and enhancing CV outcomes. The therapeutic goal is regression of albuminuria, but an atypical form of non-proteinuric diabetic nephropathy (NP-DN) is also described. In this review, we provide a state-of-the-art evaluation of current treatment strategies and promising emerging treatments.

Endothelial Dysfunction in COVID-19: Potential Mechanisms and Possible Therapeutic Options.

SARS-CoV-2, a novel coronavirus found in Wuhan (China) at the end of 2019, is the etiological agent of the current pandemic that is a heterogeneous disease, named coronavirus disease 2019 (COVID-19). SARS-CoV-2 affects primarily the lungs, but it can induce multi-organ involvement such as acute myocardial injury, myocarditis, thromboembolic eventsandrenal failure. Hypertension, chronic kidney disease, diabetes mellitus and obesity increase the risk of severe complications of COVID-19. There is no certain explanation for this systemic COVID-19 involvement, but it could be related to endothelial dysfunction, due to direct (endothelial cells are infected by the virus) and indirect damage (systemic inflammation) factors. Angiotensin-converting enzyme 2 (ACE2), expressed in human endothelium, has a fundamental role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In fact, ACE2 is used as a receptor by SARS-CoV-2, leading to the downregulation of these receptors on endothelial cells; once inside, this virus reduces the integrity of endothelial tissue, with exposure of prothrombotic molecules, platelet adhesion, activation of coagulation cascades and, consequently, vascular damage. Systemic microangiopathy and thromboembolism can lead to multi-organ failure with an elevated risk of death. Considering the crucial role of the immunological response and endothelial damage in developing the severe form of COVID-19, in this review, we will attempt to clarify the underlying pathophysiological mechanisms.

Effects of sacubitril/valsartan on both metabolic parameters and insulin resistance in prediabetic non-obese patients with heart failure and reduced ejection fraction.

Background: The effects of sacubitril/valsartan (sac/val) on metabolic parameters and insulin resistance (IR) in non-obese/prediabetic patients have not been previously described. Aim: To evaluate the effects of sac/val on glycemic and metabolic parameters, Homeostatic Model Assessment of IR (HOMA-IR), and echocardiographic parameters in prediabetic patients with heart failure with reduced ejection fraction (HFrEF). Methods: Fifty-nine patients with HFrEF (EF < 35%) but without obesity and/or type 2 diabetes mellitus have been enrolled. All the patients at baseline and week 24 underwent complete anthropometrical evaluation and were subjected to an echocardiogram test. IR has been assessed by HOMA-IR. Results: After 24-week of treatment with sac/val, a significant reduction in fasting plasma glucose (109 ± 9 vs 103 ± 8 mg/dl, p < 0.0001), fasting plasma insulin (16 ± 4 vs 10 ± 4 UI/L), and hemoglobin A1c (HbA1c) value (6% ± 0.5% vs 5.3% ± 0.3%, p < 0.0001) was observed. Similarly, we observed a significant improvement in IR (HOMA-IR, 4.4 ± 0.9 vs 2.5 ± 0.6, p < 0.0001). The echocardiogram evaluation showed a significant reduction of the left ventricular end-diastolic volume (168 ± 24 vs 158 ± 22 ml, p < 0.05), a significant reduction of the left ventricular end-systolic volume (111 ± 26 vs 98 ± 22 ml, p < 0.005), and a significant reduction of E/e' ratio. Sac/val use was also associated with an average 5.1% increase in ejection fraction. Conclusions: Our data seem to indicate that sal/val enhances metabolic control and improves insulin resistance also in prediabetic non-obese patients with HFrEF.

A case report of pneumomediastinum in a COVID-19 patient treated with high-flow nasal cannula and review of the literature: Is this a "spontaneous" complication?

Oxygen support with high-flow nasal cannula (HFNC) is gentler than mechanical ventilation and may provide significant benefits, but more studies are needed to investigate the efficacy and safety of different respiratory supports in patients with COVID-19 pneumonia.

Role of a Dual Glucose-Dependent Insulinotropic Peptide (GIP)/Glucagon-like Peptide-1 Receptor Agonist (Twincretin) in Glycemic Control: From Pathophysiology to Treatment.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two gut hormones, defined incretins, responsible for the amplification of insulin secretion after oral glucose intake. Unlike GLP-1, GIP has little acute effect on insulin secretion and no effect on food intake; instead it seems that the GIP may be an obesity-promoting hormone. In patients with type2 diabetes mellitus (T2DM) some studies found a downregulation of GIP receptors on pancreatic ß cells caused by hyperglycemic state, but the glucagonotropic effect persisted. Agonists of the receptor for the GLP-1 have proven successful for the treatment of diabetes, since they reduce the risk for cardiovascular and renal events, but the possible application of GIP as therapy for T2DM is discussed. Moreover, the latest evidence showed a synergetic effect when GIP was combined with GLP-1 in monomolecular co-agonists. In fact, compared with the separate infusion of each hormone, the combination increased both insulin response and glucagonostatic response. In accordance with theseconsiderations, a dual GIP/GLP-1receptor agonist, i.e., Tirzepatide, known as a "twincretin" had been developed. In the pre-clinical trials, as well as Phase 1-3 clinical trials, Tirzepatideshowedpotent glucose lowering and weight loss effects within an acceptable safety.

Sodium-Glucose Co-transporter-2 Inhibitors and Nephroprotection in Diabetic Patients: More Than a Challenge.

Diabetic nephropathy is the most common cause of end-stage renal disease worldwide. Control of blood glucose and blood pressure (BP) reduces the risk of developing this complication, but once diabetic nephropathy is established, it is then only possible to slow its progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a novel class of oral hypoglycemic agents that increase urinary glucose excretion by suppressing glucose reabsorption at the renal proximal tubule. SGLT2is lower glycated hemoglobin (HbA1c) without increasing the risk of hypoglycemia, induce weight loss and improve various metabolic parameters including BP, lipid profile, albuminuria and uric acid. Several clinical trials have shown that SGLT2is (empagliflozin, dapagliflozin canagliflozin, and ertugliflozin) improve cardiovascular and renal outcomes and mortality in patients with type 2 diabetes. Effects of SGLT2is on the kidney can be explained by multiple pathways. SGLT2is may improve renal oxygenation and intra-renal inflammation thereby slowing the progression of kidney function decline. Additionally, SGLT2is are associated with a reduction in glomerular hyperfiltration, an effect which is mediated by the increase in natriuresis, the re-activation of tubule-glomerular feedback and independent of glycemic control. In this review, we will focus on renal results of major cardiovascular and renal outcome trials and we will describe direct and indirect mechanisms through which SGLT2is confer renal protection.

Histopathology and immunophenotyping of late onset cutaneous manifestations of COVID-19 in elderly patients: Three case reports.

BACKGROUND: Several cutaneous manifestations such as urticarial rash, erythematous patches and chilblain-like lesions have been described in young adults with coronavirus disease 2019 (COVID-19) and are present in up to 20% patients, but few reports exist describing histopathological and immunophenotypic characteristics of dermatological lesions in older patients. Our aim was to characterize skin lesions in elderly patients during late stages of COVID-19 from clinical, histological and immunophenotypic perspectives. CASE SUMMARY: Three patients, admitted for COVID-19, and who developed cutaneous manifestations underwent skin biopsies. Immunophenotypic analysis for CD20, CD3, CD4 and CD8 was performed on skin biopsies to assess immune cell infiltrates. CD1a was used as a marker of Langerhans cells, and CD31 as a marker of endothelial cells. In the three study patients, cutaneous manifestations were evident in the late-stage of COVID-19 (mean time from the first positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) swab to rash onset was 35 d). Skin biopsies showed a similar pattern of T lymphocyte infiltration in all patients. Indeed, a chronic dermatitis with perivascular lymphocytic infiltrate was observed with predominance of CD3+ T-cell (CD3+). CONCLUSION: Our study confirms previous reports. Histological and immunophenotypic patterns in our patients confirm results described in the two previous reported experiences. This pattern is similar to what is found in some lympho-proliferative disorders. Therefore, since these findings are non-specific, SARS-CoV-2 infection should be suspected.

Late-onset myocardial infarction and autoimmune haemolytic anaemia in a COVID-19 patient without respiratory symptoms, concomitant with a paradoxical increase in inflammatory markers: a case report.

BACKGROUND: In December 2019, a new coronavirus (named severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) spread from China, causing a pandemic in a very short time. The main clinical presentation of SARS-CoV-2 infection (COVID-19, coronavirus disease-2019) is pneumonia, but several cardiovascular complications may also occur (e.g., acute coronary syndromes, pulmonary embolism, stroke, arrhythmias, heart failure and cardiogenic shock). Direct or indirect mechanisms induced by SARS-CoV-2 could be implicated in the pathogenesis of these events. CASE PRESENTATION: We report herein the third case of COVID-19 autoimmune haemolytic anaemia (AIHA) reported so far, which occurredwithout any other possible explanations in a Caucasian patient. The patient also suffered from ST-elevation myocardial injury. CONCLUSIONS: Both complications occurred quite late after COVID-19 diagnosis and were probably precipitated by systemic inflammation, as indicated by a significant delayed increase in inflammatory markers, including interleukin-6 (IL-6).

Oxygen therapy via high flow nasal cannula in severe respiratory failure caused by Sars-Cov-2 infection: a real-life observational study.

The worldwide spread of coronavirus disease 2019 (COVID-19), caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization (WHO) in March 2020. According to clinical studies carried out in China and Italy, most patients experience mild or moderate symptoms; about a fifth of subjects develop a severe and critical disease, and may suffer from interstitial pneumonia, possibly associated with acute respiratory distress syndrome (ARDS) and death.In patients who develop respiratory failure, timely conventional oxygen therapy through nasal catheter plays a crucial role, but it can be used only in mild forms. Continuous positive airway pressure (CPAP) support or non-invasive mechanical ventilation (NIV) are uncomfortable, and require significant man-machine cooperation. Herein we describe our experience of five patients with COVID-19, who were treated with high-flow nasal cannula (HFNC) after failure of CPAP or NIV, and discuss the role of HFNC in COVID-19 patients. Our findings suggest that HFNC can be used successfully in selected patients with COVID-19-related ARDS.The reviews of this paper are available via the supplemental material section.

Clinical characteristics and predictors of mortality associated with COVID-19 in elderly patients from a long-term care facility.

Since December 2019, coronavirus disease 2019 (COVID-19) pandemic has spread from China all over the world and many COVID-19 outbreaks have been reported in long-term care facilities (LCTF). However, data on clinical characteristics and prognostic factors in such settings are scarce. We conducted a retrospective, observational cohort study to assess clinical characteristics and baseline predictors of mortality of COVID-19 patients hospitalized after an outbreak of SARS-CoV-2 infection in a LTCF. A total of 50 patients were included. Mean age was 80 years (SD, 12 years), and 24/50 (57.1%) patients were males. The overall in-hospital mortality rate was 32%. At Cox regression analysis, significant predictors of in-hospital mortality were: hypernatremia (HR 9.12), lymphocyte count < 1000 cells/µL (HR 7.45), cardiovascular diseases other than hypertension (HR 6.41), and higher levels of serum interleukin-6 (IL-6, pg/mL) (HR 1.005). Our study shows a high in-hospital mortality rate in a cohort of elderly patients with COVID-19 and hypernatremia, lymphopenia, CVD other than hypertension, and higher IL-6 serum levels were identified as independent predictors of in-hospital mortality. Given the small population size as major limitation of our study, further investigations are necessary to better understand and confirm our findings in elderly patients.