Novel pharmacological interventions for diabetic kidney disease.

PURPOSE OF REVIEW: The purpose of this review is to summarize the latest evidence on the prevention and progression of diabetic kidney disease (DKD), as well as novel pharmacological interventions from preclinical and early clinical studies with promising findings in the reduction of this condition's burden. RECENT FINDINGS: We will cover the latest evidence on the reduction of proteinuria and kidney function decline in DKD achieved through established renin-angiotensin-aldosterone system (RAAS) system blockade and the more recent addition of SGLT2i, nonsteroidal mineralocorticoid receptor antagonists (MRAs) and GLP1-RA, that combined will most likely integrate the mainstay for current DKD treatment. We also highlight evidence from new mechanisms of action in DKD, including other haemodynamic anti-inflammatory and antifibrotic interventions, oxidative stress modulators and cell identity and epigenetic targets. SUMMARY: Renal specific outcome trials have become more popular and are increasing the available armamentarium to diminish the progression of renal decline in patients at greater risk of end-stage kidney disease (ESKD) such as diabetic individuals. A combined pharmaceutical approach based on available rigorous studies should include RAAS blockade, SGLT2 inhibitors, nonsteroidal MRA and expectedly GLP1-RA on a personalized based-intervention. New specific trials designed to address renal outcomes will be needed for innovative therapies to conclude on their potential benefits in DKD.

The Non-Coding RNA Journal Club: Highlights on Recent Papers-10.

We are delighted to share with you our seventh Journal Club and highlight some of the most interesting papers published recently [...].

ApoE and apoC-III-defined HDL subtypes: a descriptive study of their lecithin cholesterol acyl transferase and cholesteryl ester transfer protein content and activity.

BACKGROUND: The functionality of high-density lipoproteins (HDL) is a better cardiovascular risk predictor than HDL concentrations. One of the key elements of HDL functionality is its apolipoprotein composition. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are enzymes involved in HDL-mediated reverse cholesterol transport. This study assessed the concentration and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans. METHODS: Eighteen adults (ten women and eight men, mean age 55.6, BMI 26.9 Kg/m2, HbA1c 5.4%) were studied. HDL from each participant were isolated and divided into four subspecies containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E + C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E + C+). The concentration and enzymatic activity of LCAT and CETP were measured within each HDL subspecies using immunoenzymatic and fluorometric methods. Additionally, the size distribution of HDL in each apolipoprotein-defined fraction was determined using non-denaturing electrophoresis and anti-apoA-I western blotting. RESULTS: HDL without apoE or apoC-III was the predominant HDL subtype. The size distribution of HDL was very similar in all the four apolipoprotein-defined subtypes. LCAT was most abundant in E-C- HDL (3.58 mg/mL, 59.6% of plasma LCAT mass), while HDL with apoE or apoC-III had much less LCAT (19.8, 12.2 and 8.37% of plasma LCAT respectively for E + C-, E-C+ and E + C+). LCAT mass was lower in E + C- HDL relative to E-C- HDL, but LCAT activity was similar in both fractions, signaling a greater activity-to-mass ratio associated with the presence of apoE. Both CETP mass and CETP activity showed only slight variations across HDL subspecies. There was an inverse correlation between plasma LCAT activity and concentrations of both E-C+ pre-beta HDL (r = - 0.55, P = 0.017) and E-C- alpha 1 HDL (r = - 0.49, P = 0.041). Conversely, there was a direct correlation between plasma CETP activity and concentrations of E-C+ alpha 1 HDL (r = 0.52, P = 0.025). CONCLUSIONS: The presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol. These results favor an interpretation that LCAT and apoE interact to enhance anti-atherogenic pathways of HDL.

Plasma Levels of Myonectin But Not Myostatin or Fibroblast-Derived Growth Factor 21 Are Associated with Insulin Resistance in Adult Humans without Diabetes Mellitus.

BACKGROUND: Myokines are a group of protein mediators produced by skeletal muscle under stress or physical exertion. Even though their discovery and effects in cell culture and animal models of disease have elicited great enthusiasm, very little is known about their role in human metabolism. We assessed whether plasma concentrations of three known myokines [myonectin, myostatin, and fibroblast-derived growth factor 21 (FGF-21)] would be associated with direct and indirect indicators of insulin resistance (IR) in individuals who did not have a diagnosis of diabetes. METHODS: We studied 81 adults of both sexes comprising a wide range of body adiposity and insulin sensitivity. All participants underwent a thorough clinical assessment and a 5-point oral glucose tolerance test with calculation of multiple IR and insulin sensitivity indices. Twenty-one of them additionally underwent a hyperinsulinemic-euglycemic clamp with determination of steady-state whole-body insulin-stimulated glucose disposal ("M"). We compared plasma myokine concentrations across quartiles of IR indices and clinical IR surrogates, and explored the correlation of each myokine with the M-value. RESULTS: Plasma myonectin levels increased monotonically across quartiles of the incremental area under the insulin curve (higher values indicate more IR) (p-trend = 0.021) and decreased monotonically across quartiles of the insulin sensitivity index (ISI - higher values indicate less IR) (p-trend = 0.012). After multivariate adjustment for other relevant determinants of IR (body mass index, age, and sex), the negative association of myonectin with ISI persisted (standardized beta = -0.235, p = 0.023). Myostatin was not associated with any clinical IR indicator or direct IR index measure. In multivariate analyses, FGF-21 showed a trend toward a positive correlation with glucose disposal that did not reach statistical significance (standardized beta = 0.476, p = 0.091). CONCLUSION: The secretion of myonectin may constitute an attempt at a compensatory mechanism against IR in humans.

Antibodies against glutamic acid decarboxylase and indices of insulin resistance and insulin secretion in nondiabetic adults: a cross-sectional study.

BACKGROUND: Autoimmunity against insulin-producing beta cells from pancreatic islets is a common phenomenon in type 1 diabetes and latent autoimmune diabetes in adults. Some reports have also related beta-cell autoimmunity to insulin resistance (IR) in type 2 diabetes. However, the extent to which autoimmunity against components of beta cells is present and relates to IR and insulin secretion in nondiabetic adults is uncertain. AIM: To explore the association between antibodies against glutamic acid decarboxylase (GADA), a major antigen from beta cells, and indices of whole-body IR and beta-cell capacity/insulin secretion in adults who do not have diabetes. METHODS: We studied 81 adults of both sexes aged 30-70, without known diabetes or any autoimmune disease. Participants underwent an oral glucose tolerance test (OGTT) with determination of plasma glucose and insulin at 0, 30, 60, 90, and 120 minutes. From these results we calculated indices of insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] and incremental area under the insulin curve [iAUCins]) and insulin secretion (corrected insulin response at 30 minutes and HOMA beta-cell%). GADAs were measured in fasting plasma using immunoenzymatic methods. RESULTS: We found an overall prevalence of GADA positivity of 21.3%, without differences by sex and no correlation with age. GADA titers did not change monotonically across quartiles of any of the IR or insulin secretion indices studies. GADA did not correlate linearly with fasting IR expressed as HOMA-IR (Spearman's r=-0.18, p=0.10) or postabsorptive IR expressed as iAUCins (r=-0.15, p=0.18), but did show a trend toward a negative correlation with insulin secretory capacity expressed by the HOMA-beta cell% index (r=-0.20, p=0.07). Hemoglobin A1c, body mass index, and waist circumference were not associated with GADA titers. CONCLUSION: GADA positivity is frequent and likely related to impaired beta-cell function among adults without known diabetes.