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Circulating proteins associated with transforming growth factor–β (TGF-β) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-β signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD. Predicting kidney disease progression: Patients with diabetes are at risk of kidney complications. Kobayashi et al. surveyed 25 circulating proteins in patient cohorts of both type 1 and type 2 diabetes and report that circulating neuroblastoma suppressor of tumorigenicity 1 (NBL1) protein is associated with 10-year risk for progression to end-stage kidney disease across multiple cohorts. This association was backed up by analysis of biopsied renal tissue. NBL1 may thus provide a noninvasive risk predictor for advanced diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease is the leading cause of end-stage kidney disease in high-income countries. The strict control of glycemic oscillations is the principal therapeutic target, but this could be hard to achieve in uremic patients due to their unpredictable insulin sensitivity. Currently, the evaluation of the glycemic profile relies on serum markers (glycated hemoglobin HbA1c, glycated albumin, and fructosamine), capillary glucose blood control (self-monitoring of blood glucose), and interstitial glucose control (continue glucose monitoring). We conducted a systematic review of published articles on continue glucose monitoring in hemodialysis patients with type 2 diabetes, which included 12 major articles. Four studies found significant fluctuations in glucose levels during hemodialysis sessions. All studies reported a higher mean amplitude of glucose variations on the hemodialysis day. Three studies agreed that continue glucose monitoring is better than glycated hemoglobin in detecting these abnormalities. Moreover, continue glucose monitoring was more accurate and perceived as easier to use by patients and their caregivers. In patients with type 2 diabetes on hemodialysis, glucose levels show different variation patterns than the patients on hemodialysis without diabetes. Considering manageability, accuracy, and cost-effectiveness, continue glucose monitoring could be the ideal diagnostic tool for the patient with diabetes on hemodialysis. [ABSTRACT FROM AUTHOR]

Objective: Poor outcomes have been reported in patients with type 2 diabetes and coronavirus disease 2019 (COVID-19); thus, it is mandatory to explore novel therapeutic approaches for this population.Research Design and Methods: In a multicenter, case-control, retrospective, observational study, sitagliptin, an oral and highly selective dipeptidyl peptidase 4 inhibitor, was added to standard of care (e.g., insulin administration) at the time of hospitalization in patients with type 2 diabetes who were hospitalized with COVID-19. Every center also recruited at a 1:1 ratio untreated control subjects matched for age and sex. All patients had pneumonia and exhibited oxygen saturation <95% when breathing ambient air or when receiving oxygen support. The primary end points were discharge from the hospital/death and improvement of clinical outcomes, defined as an increase in at least two points on a seven-category modified ordinal scale. Data were collected retrospectively from patients receiving sitagliptin from 1 March through 30 April 2020.Results: Of the 338 consecutive patients with type 2 diabetes and COVID-19 admitted in Northern Italy hospitals included in this study, 169 were on sitagliptin, while 169 were on standard of care. Treatment with sitagliptin at the time of hospitalization was associated with reduced mortality (18% vs. 37% of deceased patients; hazard ratio 0.44 [95% CI 0.29-0.66]; P = 0.0001), with an improvement in clinical outcomes (60% vs. 38% of improved patients; P = 0.0001) and with a greater number of hospital discharges (120 vs. 89 of discharged patients; P = 0.0008) compared with patients receiving standard of care, respectively.Conclusions: In this multicenter, case-control, retrospective, observational study of patients with type 2 diabetes admitted to the hospital for COVID-19, sitagliptin treatment at the time of hospitalization was associated with reduced mortality and improved clinical outcomes as compared with standard-of-care treatment. The effects of sitagliptin in patients with type 2 diabetes and COVID-19 should be confirmed in an ongoing randomized, placebo-controlled trial. [ABSTRACT FROM AUTHOR]

Aims: The possibility that verapamil has new beneficial effects in diabetic patients in terms of an improvement in glycometabolic control has been put forward recently in several studies. However, to date the issue is still under debate. We conducted the first systematic review examining the impact of verapamil-based treatment on glycometabolic outcomes, in type 2 diabetes (T2D) patients. Methods: We searched the PubMed, MEDLINE, Embase, Cochrane and ClinicalTrials.gov up to 9 October 2018, for all studies evaluating whether verapamil-based treatment is associated with changes in glycated haemoglobin (HbA1c), fasting plasma glucose levels, glucose and C-peptide areas from baseline in humans, without restrictions for study type. Results: Plasma glucose levels were lowered significantly by verapamil-based treatment in patients with T2D (mean change − 13 ± 5.29; P = 0.049); HbA1c values were instead not affected by the drug (mean change − 0.10 ± 0.12; P = 0.453). In five studies, groups exposed to verapamil achieved lower value of glycometabolic outcomes: comparison with values recorded in control groups showed a significant difference, in terms of both HbA1c and plasma glucose levels. Conclusions: Despite the fact that plasma glucose levels were lowered significantly by verapamil-based treatment in patients with T2D (the HbA1c values were not affected by the drug), the clinical significance of the glycometabolic response induced by verapamil-based treatment remains unclear due to the high variety of sample size and type of studies presently available. Further experimental and clinical trials are needed to clarify unambiguously the role of verapamil in metabolic control. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is the leading and possibly the most devastating complication of diabetes, with a prevalence ranging from 25 to 40 % in diabetic individuals, and as such represents an important challenge for public health worldwide. As a major cause of end-stage renal disease, diabetic nephropathy also accounts for a large proportion of deaths in diabetic individuals. To date, therapeutic options for overt diabetic nephropathy include medical interventions to reduce blood glucose levels and to control blood pressure and proteinuria. Recent evidence suggests a strong role for inflammation in the development and progression of diabetic nephropathy. Various immune cells, cytokines and chemokines have been implicated in the onset of diabetic nephropathy, while immune-related transcription factors and adhesion molecules have been correlated with the establishment of a renal proinflammatory microenvironment. Both inflammation and immune activation may promote severe distress in the kidney, with subsequent increased local fibrosis, ultimately leading to the development of end-stage renal disease. Stem cells are undifferentiated cells capable of regenerating virtually any organ or tissue and bearing important immunoregulatory and anti-inflammatory properties. Due to the aforementioned considerations, significant interest has been ignited with regard to the use of stem cells as novel therapeutics for diabetic nephropathy. Here, we will be examining in detail how anti-inflammatory properties of different populations of stem cells may offer novel therapy for the treatment of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Inflammation has a major role in diabetic kidney disease. We thus investigated the role of the IL-8-CXCR1/2 axis in favoring kidney damage in diabetes. Urinary IL-8 levels were measured in 1247 patients of the Joslin Kidney Study in type 2 diabetes (T2D). The expression of IL-8 and of its membrane receptors CXCR1/CXCR2 was quantified in kidney tissues in patients with T2D and in controls. The effect of CXCR1/2 blockade on diabetic kidney disease was evaluated in db/db mice. IL-8 urinary levels were increased in patients with T2D and diabetic kidney disease, with the highest urinary IL-8 levels found in the patients with the largest decline in glomerular filtration rate, with an increased albumin/creatine ratio and the worst renal outcome. Moreover, glomerular IL-8 renal expression was increased in patients with T2D, as compared to controls. High glucose elicits abundant IL-8 secretion in cultured human immortalized podocytes in vitro. Finally, in diabetic db/db mice and in podocytes in vitro , CXCR1/2 blockade mitigated albuminuria, reduced mesangial expansion, decreased podocyte apoptosis and reduced DNA damage. The IL-8- CXCR1/2 axis may have a role in diabetic kidney disease by inducing podocyte damage. Indeed, targeting the IL-8-CXCR1/2 axis may reduce the burden of diabetic kidney disease. • The IL-8-CXCR1/2 axis is overactive in diabetic kidney disease • High glucose stimulates IL-8 secretion in podocytes in vitro • IL-8-CXCR1/2 axis blockade improves renal function in diabetic db/db mice • CXCR1/2 blockade in type 2 diabetes patients may reduce the burden of diabetic kidney disease [ABSTRACT FROM AUTHOR]

The most effective and physiological way to treat hyperglycemia is to restore beta-cell function and to rescue production of endogenous insulin. Increasing evidence suggests that both type 1 and type 2 diabetes are characterized by a significant defect in beta-cell mass, leading to the manifestation of the disease. Novel alternative approaches are needed to spare and expand beta-cell mass in patients with diabetes. This review sets out to describe the latest findings on how to restore the beta-cell mass and function in both forms of diabetes to modulate their progression. [ABSTRACT FROM AUTHOR]

Dapagliflozin has been demonstrated to improve glycemic control, blood pressure, and body weight in type 2 diabetes mellitus (T2D); indeed, it can also reduce the risk of progression to renal failure, of hospitalization for heart failure and of cardiovascular death. We aim to investigate the acute effect of Dapagliflozin on kidney function in the common clinical practice in T2D. This is a study including 1402 patients with T2D recruited from 11 centers in Lombardia, Italy, who were evaluated at baseline and after 6 months of treatment with Dapagliflozin 10 mg per day. The primary outcome of the study was the change in HbA1c, while the secondary outcomes were modification of weight, BMI, systolic and diastolic pressure, creatinine, eGFR and albuminuria status. After 24 weeks of treatment with Dapagliflozin, a reduction in Hb1Ac was observed (−0.6 ± 1.8%) as well as in BMI (−1.5 ± 5.2 kg/m2). Statistically significant changes were also found for systolic and diastolic blood pressure, cholesterol and triglycerides. Interestingly, a statistically significant acute improvement of kidney function was evident. Our analyses confirm the beneficial effects of dapagliflozin after 6 months of therapy, with improvements of glycemic and lipid profiles, blood pressure, BMI. Finally, an acute positive effect on albuminuria and KIDGO classes was observed during a 6 months treatment with dapagliflozin in patients with T2D. [Display omitted] [ABSTRACT FROM AUTHOR]

Obesity is frequently a comorbidity of type 2 diabetes. Even modest weight loss can significantly improve glucose homeostasis and lessen cardiometabolic risk factors in patients with type 2 diabetes, but lifestyle‐based weight loss strategies are not long‐term effective. There is an increasing need to consider pharmacological approaches to assist weight loss in the so called diabesity syndrome. Aim of this review is to analyze the weight-loss effect of non-insulin glucose lowering drugs in patients with type 2 diabetes. A systematic analysis of the literature on the effect of non-insulin glucose lowering drugs on weight loss in patients with type 2 diabetes was performed. For each class of drugs, the following parameters were analyzed: kilograms lost on average, effect on body mass index and body composition. Our results suggested that anti-diabetic drugs can be stratified into 3 groups based on their efficacy in weight loss: metformin, acarbose, empagliflozin and exenatide resulted in a in a mild weight loss (less than 3.2% of initial weight); canagliflozin, ertugliflozin, dapagliflozin and dulaglutide induces a moderate weight loss (between 3.2% and 5%); liraglutide, semaglutide and tirzepatide resulted in a strong weight loss (greater than 5%). This study shows that new anti-diabetic drugs, particularly GLP1-RA and Tirzepatide, are the most effective in inducing weight loss in patients with type 2 diabetes. Interestingly, exenatide appears to be the only GLP1-RA that induces a mild weight loss. [Display omitted] [ABSTRACT FROM AUTHOR]