The COronaVirus DISease 19 (COVID-19) is a pandemic infectious disease caused by the novel coronavirus Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). Older age and presence of ...comorbidities, including diabetes, were shown to be associated with a more severe course and a higher fatality rate. Studies from the most affected countries, including China, United States and Italy, seem to indicate that prevalence of diabetes among patients affected by COVID-19 is not higher than that observed in the general population, thus suggesting that diabetes is not a risk factor for SARS-CoV-2 infection. However, a large body of evidence demonstrate that diabetes is a risk factor for disease progression towards critical illness, development of acute respiratory distress syndrome, need for mechanical ventilation or admission to intensive care unit, and ultimately death. The mechanisms underlying the relationship between COVID-19 and diabetes remain to be elucidated. In particular, it is still unresolved whether is diabetes per se, especially if poorly controlled, or rather the various comorbidities/complications associated with it that predispose patients with COVID-19 to a worse prognosis. In fact, conditions that cluster with diabetes in the context of the metabolic syndrome, such as obesity and hypertension, or complicate chronic hyperglycemia, such as cardiovascular disease and chronic kidney disease, have also been associated with poor prognosis in these individuals and the available studies have not consistently shown that diabetes predict disease severity independently of them.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the ...death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients' cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The IGFBP3/TMEM219 pathway is thus shown to be a physiological regulator of beta cell homeostasis and is also demonstrated to be disrupted in T1D/T2D. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.
The incidence of acute pancreatitis (AP) in liver transplanted people is reported to be 1.5-8%. On the other hand, the evidence for a causal relationship between glucagon-like peptide 1 receptor ...agonists (GLP1RAs) and pancreatitis in people with type 2 diabetes is still weak. In addition, there are currently no data on a possible increased risk of AP in liver-transplanted individuals with diabetes treated with GLP1RAs. In a population of liver-transplanted individuals with diabetes receiving GLP1RA-based therapy, we reported an incidence of AP of 3.0% (two subjects). No cases were reported in liver-transplanted individuals with diabetes receiving SGLT2 inhibitors, insulin or metformin, neither in kidney or lung-transplanted patients treated with GLP1RAs. In both patients with AP, the only additional risk factor for its development was a history of re-transplantation (liver or combined kidney/liver). For this reason, we suggest particular caution when considering GLP1RAs-based therapies in liver transplanted patients with multiple risk factors for AP, such as a history of repeated and complex abdominal surgery.
Abstract
Context
Coronavirus disease 2019 (COVID-19) represents a global health emergency, and infected patients with chronic diseases often present with a severe impairment. Adrenal insufficiency ...(AI) is supposed to be associated with an increased infection risk, which could trigger an adrenal crisis.
Objective
Our primary aim was to evaluate the incidence of COVID-19 symptoms and complications in AI patients.
Design and Setting
We conducted a retrospective case-control study. All patients were on active follow-up and lived in Lombardy, Italy, one of the most affected areas.
Patients
We enrolled 279 patients with primary and secondary AI and 112 controls (patients with benign pituitary lesions without hormonal alterations). All AI patients had been previously trained to modify their replacement therapy on stress doses.
Intervention
By administering a standardized questionnaire by phone, we collected data on COVID-19 suggestive symptoms and consequences.
Results
In February through April 2020, the prevalence of symptomatic patients (complaining at least 1 symptom of viral infection) was similar between the 2 groups (24% in AI and 22.3% in controls, P = 0.79). Highly suggestive COVID-19 symptoms (at least 2 including fever and/or cough) also occurred equally in AI and controls (12.5% in both groups). No patient required hospitalization and no adrenal crisis was reported. Few nasopharyngeal swabs were performed (n = 12), as indicated by sanitary regulations, limiting conclusions on the exact infection rate (2 positive results in AI and none in controls, P = 0.52).
Conclusions
AI patients who are adequately treated and trained seem to display the same incidence of COVID-19-suggestive symptoms and disease severity as controls.
It is unclear whether insulin resistance (IR) contributes to excess mortality in patients with type 2 diabetes independent of diabetic kidney disease (DKD), which is strongly associated with IR and ...is a major risk factor for cardiovascular disease (CVD), the main cause of death in these individuals. We tested this hypothesis in patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events Italian Multicentre Study.
This observational, prospective, cohort study enrolled 15,773 patients with type 2 diabetes attending 19 Italian Diabetes Clinics in 2006-2008. Insulin sensitivity was assessed as estimated glucose disposal rate (eGDR), which was validated against the euglycaemic-hyperinsulinemic clamp technique. Vital status on October 31, 2015, was retrieved for 15,656 patients (99.3%). Participants were stratified by eGDR tertiles from T1 (≥ 5.35 mg/kg/min) to T3 (≤ 4.14 mg/kg/min, highest IR).
CVD risk profile was worse in T2 and T3 vs T1. eGDR tertiles were independently associated with micro- and macroalbuminuria and the albuminuric DKD phenotypes (albuminuria with preserved or reduced estimated glomerular filtration rate eGFR) as well as with eGFR categories or the nonalbuminuric DKD phenotype. Over a 7.4-year follow-up, unadjusted death rates and mortality risks increased progressively across eGDR tertiles, but remained significantly elevated after adjustment only in T3 vs T1 (age- and gender- adjusted death rate, 22.35 vs 16.74 per 1000 person-years, p < 0.0001, and hazard ratio HR adjusted for multiple confounders including DKD, 1.140 95% confidence interval CI, 1.049-1.238, p = 0.002). However, eGDR was independently associated with mortality in participants with no DKD (adjusted HR, 1.214 95% CI, 1.072-1.375, p = 0.002) and in those with nonalbuminuric DKD (1.276 1.034-1.575, p = 0.023), but not in those with the albuminuric DKD phenotypes. Moreover, the association was stronger in males and in younger individuals and was observed in those without but not with prior CVD, though interaction was significant only for age.
The proxy of insulin sensitivity eGDR predicts all-cause mortality in type 2 diabetes, independent of confounders including DKD. However, the impact of IR in individuals with albuminuric DKD may be mediated by its relationship with albuminuria.
ClinicalTrials.gov , NCT00715481, retrospectively registered 15 July 2008.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVEIn type 2 diabetes, prevalence of nonalbuminuric renal impairment is increasing worldwide, though its clinical significance remains unclear. This large-cohort study aimed at evaluating the ...association of this phenotype with cardiovascular risk factors and other complications.
METHODSType 2 diabetic patients from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study (n = 15 773), visiting consecutively 19 hospital-based Diabetes Clinics in years 2007–2008, were examined. Serum creatinine was assessed by the Jaffe method; albuminuria was measured by immunonephelometry or immunoturbidimetry.
RESULTSOf patients with renal impairment, as identified by an estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m, 56.6% were normoalbuminuric, 30.8% were microalbuminuric, and 12.6% were macroalbuminuric. Percentages were similar when GFR was estimated using the more accurate Chronic Kidney Disease Epidemiology Collaboration equation instead of the simplified Modification of Diet in Renal Disease formula, and were independent of age, thus indicating that the increasing prevalence of this phenotype does not reflects misclassification of elderly patients. Nonalbuminuric renal impairment was not associated with HbA1c and correlated less strongly with retinopathy and hypertension than albuminuria, either alone or associated with reduced eGFR. It was associated with a higher prevalence of cardiovascular disease (CVD) than albuminuria alone, but lower than albuminuric renal impairment. Female sex correlated with nonalbuminuric renal impairment and male sex with the albuminuric forms.
CONCLUSIONSThese data show that type 2 diabetic patients with nonalbuminuric renal impairment exhibit distinct clinical features, suggesting predominance of macroangiopathy as underlying renal pathology, and that this phenotype is associated with significant CVD burden.
One of the most common complications of cirrhosis is diabetes, which prevalence is strictly related to severity of hepatopathy. Actually, there are no data on the persistence of post-transplant ...glucose abnormalities and on a potential impact of diabetes on development of fibrosis in the transplanted liver. To this aim, we evaluated liver fibrosis in cirrhotic subjects before and after being transplanted.
The study included 111 individuals who had liver transplantation. The assessment was performed before and two years after surgery to investigate a potential impact of the persistence of diabetes on developing
fibrosis in the transplanted liver. The degree of fibrosis was assessed using the Fibrosis Index Based on 4 Factors (FIB-4) and the Aspartate to Platelet Ratio Index (APRI).
At pre-transplant evaluation, 63 out of 111 (56.8%) subjects were diabetic. Diabetic subjects had higher FIB-4 (Geometric mean, 95% confidence interval: 9.74, 8.32-11.41
5.93, 4.71-7.46,
<0.001) and APRI (2.04, 1.69-2.47
1.18, 0.90-1.55,
<0.001) compared to non-diabetic subjects. Two years after transplantation, 39 out of 111 (35.1%) subjects remained with diabetes and continued to show significantly higher FIB-4 (3.14, 2.57-3.82
1.87, 1.55-2.27,
<0.001) and APRI (0.52, 0.39-0.69
0.26, 0.21-0.32,
<0.001) compared to subjects without diabetes.
Thus, persistence of diabetes after surgery is a possible risk factor for an evolution to fibrosis in the transplanted liver, potentially leading to worsened long-term outcomes in this population.
Foot ulcers and/or infections are common long-term complications of diabetes and are associated with increased mortality, especially from cardiovascular disease, though only a few studies have ...investigated the independent contribution of these events to risk of death. This study aimed at assessing the association of history of diabetic foot with all-cause mortality in individuals with type 2 diabetes, independent of cardiovascular risk factors, other complications, and comorbidities.
This prospective cohort study enrolled 15,773 Caucasian patients in 19 Italian centers in the years 2006-2008. Prior lower extremity, coronary, and cerebrovascular events and major comorbidities were ascertained by medical records, diabetic retinopathy by fundoscopy, diabetic kidney disease by albuminuria and estimated glomerular filtration rate, cardiovascular risk factors by standard methods. All-cause mortality was retrieved for 15,656 patients on 31 October 2015.
At baseline, 892 patients (5.7%) had a history of diabetic foot, including ulcer/gangrene and/or amputation (n = 565; 3.58%), with (n = 126; 0.80%) or without (n = 439; 2.78%) lower limb revascularization, and revascularization alone (n = 330; 2.09%). History of diabetic foot was associated with all-cause death over a 7.42-year follow-up (adjusted hazard ratio, 1.502 95% confidence interval, 1.346-1.676, p < 0.0001), independent of confounders, among which age, male sex, smoking, hemoglobin A
, current treatments, other complications, comorbidities and, inversely, physical activity level and total and HDL cholesterol were correlated independently with mortality. Both ulcer/gangrene and amputation alone were independently associated with death, with a higher strength of association for amputation than for ulcer/gangrene (1.874 1.144-3.070, p = 0.013 vs. 1.567 1.353-1.814, p < 0.0001). Both ulcer/gangrene/amputation and lower limb revascularization alone were independently associated with death; mortality risk was much higher for ulcer/gangrene/amputation than for revascularization (1.641 1.420-1.895, p < 0.0001 vs. 1.229 1.024-1.475, p = 0.018) and further increased only slightly for combined ulcer/gangrene/amputation and revascularization (1.733 1.368-2.196, p < 0.0001).
In patients with type 2 diabetes, an history of diabetic foot event, including ulcer/gangrene, amputation, and lower limb revascularization, was associated with a ~ 50% increased risk of subsequent death, independent of cardiovascular risk factors, other complications and severe comorbidities, which were also significantly associated with mortality. The association with mortality was greatest for amputation, whereas that for revascularization alone was relatively modest.
ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study aimed to investigate the prevalence and determinants of glucose metabolism abnormalities and their impact on long-term clinical outcomes in kidney transplant recipients (KTxps). A ...retrospective analysis of 832 KTxps (2004-2020) was performed. Patients were assessed at 1 (T1), 6 (T6), and 12 (T12) months post-transplantation and clinically followed for an average of 103 ± 60 months. At T6, 484 patients underwent an oral glucose tolerance test for the diagnosis of alterations in glucose metabolism (AMG+) or post-transplant diabetes mellitus (PTDM+). The prevalence of pre-transplant diabetes was 6.2%, with 22.4% of PTDM+ within the 1st year. Patients with AMG were older and exhibited altered lipid profiles, higher body mass index, and increased inflammatory indices. Age at transplantation, lipid profile, and inflammatory status were significant determinants of PTDM. Graft loss was unaffected by glucose metabolism alterations. Survival analysis demonstrated significantly worse long-term survival for KTxps with diabetes (pre- and PTDM+,
= 0.04). In a comparison of the ND and PTDM+ groups, no significant differences in death with a functioning graft were found. The AMG+ group exhibited worse survival (
< 0.001) than AMG-, even after excluding patients with diabetes mellitus. Future randomized controlled trials are necessary to delve deeper into this subject, specifically examining the effects of new antidiabetic treatments.
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