Effects of hypoglycaemic agents on reducing surrogate metabolic parameters for the prevention of cardiovascular events and death in patients with type 2 diabetes: A systematic review and meta-analysis.

AIMS: To investigate the impact of glucose-lowering therapy-induced glycated haemoglobin (HbA1c) reduction on the risk of major clinical events according to body weight change and, as a secondary objective, to evaluate the impact of concomitant reductions in HbA1c and body weight on major clinical events. MATERIALS AND METHODS: We searched the MEDLINE and EMBASE databases up to June 30, 2022, for large-scale studies on glucose-lowering therapies in which more than 1000 patient-years of follow-up in each randomized group were completed. The primary outcome was all-cause mortality. The study was registered in PROSPERO (CRD42022355479). RESULTS: Thirty-four trials involving 227 220 patients with type 2 diabetes were meta-analysed using a random-effects model. Each 1% reduction in HbA1c was associated with a different risk of mortality depending on the ability of glucose-lowering therapies to induce body weight loss or gain. When glucose-lowering therapies were associated with weight gain, the risk of mortality increased by 8% (hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.00-1.16) for each 1% reduction in HbA1c. When glucose-lowering therapies were associated with weight loss, the risk of mortality was reduced by 22% (HR 0.78, 95% CI 0.72-0.85) for each 1% reduction in HbA1c. In addition, concomitant reductions in HbA1c and body weight were associated with a significantly lower risk of mortality and vascular events. CONCLUSIONS: In patients with type 2 diabetes, concomitant reductions in HbA1c and body weight might be more effective in preventing the risk of vascular events and mortality.

Safety and Efficacy of Sustained Automated Insulin Delivery Compared With Sensor and Pump Therapy in Adults With Type 1 Diabetes at High Risk for Hypoglycemia: A Randomized Controlled Trial.

OBJECTIVE: Assess the safety and efficacy of automated insulin delivery (AID) in adults with type 1 diabetes (T1D) at high risk for hypoglycemia. RESEARCH DESIGN AND METHODS: Participants were 72 adults with T1D who used an insulin pump with Clarke Hypoglycemia Perception Awareness scale score >3 and/or had severe hypoglycemia during the previous 6 months confirmed by time below range (TBR; defined as sensor glucose [SG] reading <70 mg/dL) of at least 5% during 2 weeks of blinded continuous glucose monitoring (CGM). Parallel-arm, randomized trial (2:1) of AID (Tandem t:slim ×2 with Control-IQ technology) versus CGM and pump therapy for 12 weeks. The primary outcome was TBR change from baseline. Secondary outcomes included time in target range (TIR; 70-180 mg/dL), time above range (TAR), mean SG reading, and time with glucose level <54 mg/dL. An optional 12-week extension with AID was offered to all participants. RESULTS: Compared with the sensor and pump (S&P), AID resulted in significant reduction of TBR by -3.7% (95% CI -4.8, -2.6), P < 0.001; an 8.6% increase in TIR (95% CI 5.2, 12.1), P < 0.001; and a -5.3% decrease in TAR (95% CI -87.7, -1.8), P = 0.004. Mean SG reading remained similar in the AID and S&P groups. During the 12-week extension, the effects of AID were sustained in the AID group and reproduced in the S&P group. Two severe hypoglycemic episodes occurred using AID. CONCLUSIONS: In adults with T1D at high risk for hypoglycemia, AID reduced the risk for hypoglycemia more than twofold, as quantified by TBR, while improving TIR and reducing hyperglycemia. Hence, AID is strongly recommended for this specific population.

Assessment of Meal Anticipation for Improving Fully Automated Insulin Delivery in Adults With Type 1 Diabetes.

OBJECTIVE: Meals are a consistent challenge to glycemic control in type 1 diabetes (T1D). Our objective was to assess the glycemic impact of meal anticipation within a fully automated insulin delivery (AID) system among adults with T1D. RESEARCH DESIGN AND METHODS: We report the results of a randomized crossover clinical trial comparing three modalities of AID systems: hybrid closed loop (HCL), full closed loop (FCL), and full closed loop with meal anticipation (FCL+). Modalities were tested during three supervised 24-h admissions, where breakfast, lunch, and dinner were consumed per participant's home schedule, at a fixed time, and with a 1.5-h delay, respectively. Primary outcome was the percent time in range 70-180 mg/dL (TIR) during the breakfast postprandial period for FCL+ versus FCL. RESULTS: Thirty-five adults with T1D (age 44.5 ± 15.4 years; HbA1c 6.7 ± 0.9%; n = 23 women and n = 12 men) were randomly assigned. TIR for the 5-h period after breakfast was 75 ± 23%, 58 ± 21%, and 63 ± 19% for HCL, FCL, and FCL+, respectively, with no significant difference between FCL+ and FCL. For the 2 h before dinner, time below range (TBR) was similar for FCL and FCL+. For the 5-h period after dinner, TIR was similar for FCL+ and FCL (71 ± 34% vs. 72 ± 29%; P = 1.0), whereas TBR was reduced in FCL+ (median 0% [0-0%] vs. 0% [0-0.8%]; P = 0.03). Overall, 24-h control for HCL, FCL, and FCL+ was 86 ± 10%, 77 ± 11%, and 77 ± 12%, respectively. CONCLUSIONS: Although postprandial control remained optimal with hybrid AID, both fully AID solutions offered overall TIR >70% with similar or lower exposure to hypoglycemia. Anticipation did not significantly improve postprandial control in AID systems but also did not increase hypoglycemic risk when meals were delayed.

Psychological care of patients during the pancreas transplantation process: issues and prospects.

Pancreas transplantation for patients with type 1 diabetes is a therapeutic option when other treatments are not effective and physical complications occur. Psychological burden is prominent in patients, and non-adherence to treatment is often one manifestation of such difficulties. Time projection is an important factor affected by chronic disease. The prospect of transplantation has the potential to repair this disruption. It could re-establish a continuity in the patient's self and history, by connecting the future to a life that was only about past and present. Taking care of oneself, adhering to treatment, being part of a long-term therapeutic project and going through transplantation are all processes that need a good ability to self-project in time. This is specifically a domain of psychotherapeutic interventions. In this article, the psychological implications of pancreas transplantation for patients and caregivers alike will be discussed, as well as the role of the psychiatrist in the transplantation process.

Accuracy of a Factory-Calibrated Continuous Glucose Monitor in Individuals With Diabetes on Hemodialysis.

OBJECTIVE: Continuous glucose monitoring (CGM) improves diabetes management, but its reliability in individuals on hemodialysis is poorly understood and potentially affected by interstitial and intravascular volume variations. RESEARCH DESIGN AND METHODS: We assessed the accuracy of a factory-calibrated CGM by using venous blood glucose measurements (vBGM) during hemodialysis sessions and self-monitoring blood glucose (SMBG) at home. RESULTS: Twenty participants completed the protocol. The mean absolute relative difference of the CGM was 13.8% and 14.4%, when calculated on SMBG (n = 684) and on vBGM (n = 624), and 98.7% and 100% of values in the Parkes error grid A/B zones, respectively. Throughout 181 days of CGM monitoring, the median time in range (70-180 mg/dL) was 38.5% (interquartile range 29.3-57.9), with 28.7% (7.8-40.6) of the time >250 mg/dL. CONCLUSIONS: The overall performance of a factory-calibrated CGM appears reasonably accurate and clinically relevant for use in practice by individuals on hemodialysis and health professionals to improve diabetes management.

The nuclear receptor REV-ERBα is implicated in the alteration of ß-cell autophagy and survival under diabetogenic conditions.

Pancreatic ß-cell failure in type 2 diabetes mellitus (T2DM) is associated with impaired regulation of autophagy which controls ß-cell development, function, and survival through clearance of misfolded proteins and damaged organelles. However, the mechanisms responsible for defective autophagy in T2DM ß-cells remain unknown. Since recent studies identified circadian clock transcriptional repressor REV-ERBα as a novel regulator of autophagy in cancer, in this study we set out to test whether REV-ERBα-mediated inhibition of autophagy contributes to the ß-cell failure in T2DM. Our study provides evidence that common diabetogenic stressors (e.g., glucotoxicity and cytokine-mediated inflammation) augment ß-cell REV-ERBα expression and impair ß-cell autophagy and survival. Notably, pharmacological activation of REV-ERBα was shown to phenocopy effects of diabetogenic stressors on the ß-cell through inhibition of autophagic flux, survival, and insulin secretion. In contrast, negative modulation of REV-ERBα was shown to provide partial protection from inflammation and glucotoxicity-induced ß-cell failure. Finally, using bioinformatic approaches, we provide further supporting evidence for augmented REV-ERBα activity in T2DM human islets associated with impaired transcriptional regulation of autophagy and protein degradation pathways. In conclusion, our study reveals a previously unexplored causative relationship between REV-ERBα expression, inhibition of autophagy, and ß-cell failure in T2DM.

The Plasmatic Aldosterone and C-Reactive Protein Levels, and the Severity of Covid-19: The Dyhor-19 Study.

BACKGROUND: The new coronavirus SARS-CoV-2, responsible for the Covid-19 pandemic, uses the angiotensin converting enzyme type 2 (ACE2), a physiological inhibitor of the renin angiotensin aldosterone system (RAAS), as a cellular receptor to infect cells. Since the RAAS can induce and modulate pro-inflammatory responses, it could play a key role in the pathophysiology of Covid-19. Thus, we aimed to determine the levels of plasma renin and aldosterone as indicators of RAAS activation in a series of consecutively admitted patients for Covid-19 in our clinic. METHODS: Plasma renin and aldosterone levels were measured, among the miscellaneous investigations needed for Covid-19 management, early after admission in our clinic. Disease severity was assessed using a seven-category ordinal scale. Primary outcome of interest was the severity of patients' clinical courses. RESULTS: Forty-four patients were included. At inclusion, 12 patients had mild clinical status, 25 moderate clinical status and 7 severe clinical status. In univariate analyses, aldosterone and C-reactive protein (CRP) levels at inclusion were significantly higher in patients with severe clinical course as compared to those with mild or moderate course (p < 0.01 and p = 0.03, respectively). In multivariate analyses, only aldosterone and CRP levels remained positively associated with severity. We also observed a positive significant correlation between aldosterone and CRP levels among patients with an aldosterone level greater than 102.5 pmol/L. CONCLUSIONS: Both plasmatic aldosterone and CRP levels at inclusion are associated with the clinical course of Covid-19. Our findings may open new perspectives in the understanding of the possible role of RAAS for Covid-19 outcome.

Correction to: Characterization of immortalized human islet stromal cells reveals a MSC-like profile with pancreatic features.

An amendment to this paper has been published and can be accessed via the original article.

Characterization of immortalized human islet stromal cells reveals a MSC-like profile with pancreatic features.

BACKGROUND: Mesenchymal stromal cells (MSCs) represent an interesting tool to improve pancreatic islet transplantation. They have immunomodulatory properties and secrete supportive proteins. However, the functional properties of MSCs vary according to many factors such as donor characteristics, tissue origin, or isolation methods. To counteract this heterogeneity, we aimed to immortalize and characterize adherent cells derived from human pancreatic islets (hISCs), using phenotypic, transcriptomic, and functional analysis. METHODS: Adherent cells derived from human islets in culture were infected with a hTERT retrovirus vector and then characterized by microarray hybridization, flow cytometry analysis, and immunofluorescence assays. Osteogenic, adipogenic, and chondrogenic differentiation as well as PBMC proliferation suppression assays were used to compare the functional abilities of hISCs and MSCs. Extracellular matrix (ECM) gene expression profile analysis was performed using the SAM (Significance Analysis of Microarrays) software, and protein expression was confirmed by western blotting. RESULTS: hISCs kept an unlimited proliferative potential. They exhibited several properties of MSCs such as CD73, CD90, and CD105 expression and differentiation capacity. From a functional point of view, hISCs inhibited the proliferation of activated peripheral blood mononuclear cells. The transcriptomic profile of hISCs highly clusterized with bone marrow (BM)-MSCs and revealed a differential enrichment of genes involved in the organization of the ECM. Indeed, the expression and secretion profiles of ECM proteins including collagens I, IV, and VI, fibronectin, and laminins, known to be expressed in abundance around and within the islets, were different between hISCs and BM-MSCs. CONCLUSION: We generated a new human cell line from pancreatic islets, with MSCs properties and retaining some pancreatic specificities related to the production of ECM proteins. hISCs appear as a very promising tool in islet transplantation by their availability (as a source of inexhaustible source of cells) and ability to secrete a supportive "pancreatic" microenvironment.

The Second Phase of Insulin Secretion in Nondiabetic Islet-Grafted Recipients Is Altered and Can Predict Graft Outcome.

Context: Islet transplantation (IT) can treat patients with severely unstable type 1 diabetes. Prehepatic kinetics of insulin secretion (ISec) in two phases can be calculated by C-peptide levels during meal tests. We proposed to describe the ISec profile after a mixed-meal tolerance test (MMTT) in IT recipients and to determine whether the calculated ISec indexes can predict graft outcome. Methods: We analyzed 34 MMTT among 11 patients who underwent IT between 2011 and 2016 and compared them with healthy controls and patients with type 2 diabetes (T2D). ISec indexes and insulin sensitivity were calculated from models of Van Cauter, Breda, and Mari after MMTT. Graft success was defined by total insulin independence without any criteria for diabetes. Results: In patients with successful IT, the first- and second-phase ISec indexes were lower than those of controls (P < 0.001) and did not differ from those of the T2D group. Nevertheless, insulin sensitivity of IT recipients was similar to that of the control group and higher than that of the T2D group. The index of the second phase of ISec ɸS was correlated with total infused islet equivalents (IEQs), was a good predictor of diabetes (re)occurrence, and allowed us to calculate 9500 IEQ/kg as the minimum needed to reach insulin independence. Conclusion: We showed that indexes from the first and second phases of ISec are altered in insulin-independent IT recipients. Higher sensitivity distinguishes them from patients with T2D. Even in insulin-independent patients, IT remains a marginal mass model. Moreover, ɸS can estimate transplanted islet mass and predict IT recipient outcomes.

Comparison of HbA1c detection in whole blood and dried blood spots using an automated ion-exchange HPLC system.

AIM: Hemoglobin A1c (HbA1c) is a widely recognized analyte for diagnosing and monitoring diabetes. Dried blood spot (DBS) constitutes a useful alternative to blood collection by venipuncture. Analytical and clinical validation of DBS use is, however, necessary before implementation. Results/methodology: HbA1c levels from whole blood or DBS from a cohort patients with diabetes were compared. DBS specimens were stable at ambient temperature. HbA1c detection on DBS was accurate, robust, and the correlation and agreement with whole blood values was excellent. CONCLUSION: This study provides for the first time a complete method comparison and validation under the ISO15189 guideline using an automated HPLC system. This approach constitutes, therefore, a useful tool for diagnosing diabetes.