Estimation of scleral mechanical properties from air-puff optical coherence tomography

We introduce a method to estimate the biomechanical properties of the porcine sclera in intact eye globes ex vivo, using optical coherence tomography that is coupled with an air-puff excitation source, and inverse optimization techniques based on finite element modeling. Air-puff induced tissue deformation was determined at seven different locations on the ocular globe, and the maximum apex deformation, the deformation velocity, and the arc-length during deformation were quantified. In the sclera, the experimental maximum deformation amplitude and the corresponding arc length were dependent on the location of air-puff excitation. The normalized temporal deformation profile of the sclera was distinct from that in the cornea, but similar in all tested scleral locations, suggesting that this profile is independent of variations in scleral thickness. Inverse optimization techniques showed that the estimated scleral elastic modulus ranged from 1.84 ± 0.30 MPa (equatorial inferior) to 6.04 ± 2.11 MPa (equatorial temporal). The use of scleral air-puff imaging holds promise for non-invasively investigating the structural changes in the sclera associated with myopia and glaucoma, and for monitoring potential modulation of scleral stiffness in disease or treatment.     

SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function

OBJECTIVE

Inhibition of the Na⁺-glucose cotransporter type 2 (SGLT2) is currently being pursued as an insulin-independent treatment for diabetes; however, the behavioral and metabolic consequences of SGLT2 deletion are unknown. Here, we used a SGLT2 knockout mouse to investigate the effect of increased renal glucose excretion on glucose homeostasis, insulin sensitivity, and pancreatic β-cell function.

RESEARCH DESIGN AND METHODS

SGLT2 knockout mice were fed regular chow or a high-fat diet (HFD) for 4 weeks, or backcrossed onto the db/db background. The analysis used metabolic cages, glucose tolerance tests, euglycemic and hyperglycemic clamps, as well as isolated islet and perifusion studies.

RESULTS

SGLT2 deletion resulted in a threefold increase in urine output and a 500-fold increase in glucosuria, as well as compensatory increases in feeding, drinking, and activity. SGLT2 knockout mice were protected from HFD-induced hyperglycemia and glucose intolerance and had reduced plasma insulin concentrations compared with controls. On the db/db background, SGLT2 deletion prevented fasting hyperglycemia, and plasma insulin levels were also dramatically improved. Strikingly, prevention of hyperglycemia by SGLT2 knockout in db/db mice preserved pancreatic β-cell function in vivo, which was associated with a 60% increase in β-cell mass and reduced incidence of β-cell death.

CONCLUSIONS

Prevention of renal glucose reabsorption by SGLT2 deletion reduced HFD- and obesity-associated hyperglycemia, improved glucose intolerance, and increased glucose-stimulated insulin secretion in vivo. Taken together, these data support SGLT2 inhibition as a viable insulin-independent treatment of type 2 diabetes.Treatments of type 2 diabetes must balance the prevention of microvascular complications with the minimization of clinically significant hypoglycemia. The difficulty in safely achieving these goals, combined with epidemic increases in diabetes worldwide, has spurred the search for novel therapeutic strategies. Among these, inhibition of the Na⁺-glucose cotransporter type 2 (SGLT2) has emerged as a promising therapy (1,2). SGLT2 is a member of the SLC5 gene family and transports glucose across cells using the Na⁺ gradient established by Na⁺-K⁺-ATPases (3). SGLT2 is a low-affinity, high-capacity transporter expressed predominantly in the early proximal tubule of the kidney and accounts for about 90% of renal glucose reabsorption (4–6). Given that the kidney filters approximately 180 g of glucose daily, SGLT2 inhibition may not just reduce hyperglycemia but may also promote negative energy balance and weight loss.Type 2 diabetes is characterized by fasting hyperglycemia as a result of insulin resistance, but is often preceded by hyperinsulinemia and normal blood glucose levels, a state that is maintained by compensatory insulin secretion by the pancreatic β-cell (7). The ability of the β-cell to counteract an increased glucose load is short-lived, however, and eventually pancreatic islets fail, giving rise to hyperglycemia. Rodent and human studies have both shown that glucose toxicity is implicated in β-cell failure by increasing the rate of β-cell death by the induction of proapoptotic genes (8–10). Inhibition of SGLT2 therefore has the potential to not only acutely lower hyperglycemia but to also improve glucose homeostasis by reducing glucose toxicity and preventing islet failure.Despite recent interest in SGLT2 as a potential target for diabetes treatment, relatively few long-term models of SGLT2 deficiency have been characterized. Previously, nonselective inhibition of both SGLT1 and SGLT2 for 4 weeks in partially pancreatomized diabetic rats by injection of phlorizin led to increases in insulin sensitivity and insulin secretion (11,12). More recently, improvements in glucose homeostasis were demonstrated in diabetic rodent models after treatment with SGLT2-specific inhibitors for periods of 2 to 9 weeks (13–16). As many as seven different SGLT2 inhibitors designed for use in humans have been characterized in cell culture and animal studies, and many of these have moved on to clinical trials (2,17–22). Here, we describe the first in vivo characterization of glucose homeostasis in a SGLT2 knockout mouse model. We investigated the behavioral and metabolic consequences of SGLT2 deletion, and furthermore, we determined the effect of renal glucose excretion on glucose homeostasis, insulin sensitivity, and β-cell function in the context of both high-fat feeding and genetically determined obesity (db/db) and diabetes.     

Effects of finerenone in people with chronic kidney disease and type 2 diabetes are independent of HbA1c at baseline,HbA1c variability,diabetes duration and insulin use at baseline

Aim

To evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, diabetes duration and baseline insulin use on cardiorenal outcomes and diabetes progression.

Materials and Methods

Composite efficacy outcomes included cardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure), kidney (kidney failure, sustained ≥ 57% estimated glomerular filtration rate decline or renal death) and diabetes progression (new insulin initiation, increase in antidiabetic medication, 1.0% increase in HbA1c from baseline, new diabetic ketoacidosis diagnosis or uncontrolled diabetes).

Results

In 13 026 participants, risk reductions in the cardiovascular and kidney composite outcomes with finerenone versus placebo were consistent across HbA1c quartiles (P interaction .52 and .09, respectively), HbA1c variability (P interaction .48 and .10), diabetes duration (P interaction .12 and .75) and insulin use (P interaction .16 and .52). HbA1c variability in the first year of treatment was associated with a higher risk of cardiovascular and kidney events (hazard ratio [HR] 1.20; 95% confidence interval [CI] 1.07-1.35; P = .0016 and HR 1.36; 95% CI 1.21-1.52; P < .0001, respectively). There was no effect on diabetes progression with finerenone or placebo (HR 1.00; 95% CI 0.95-1.04). Finerenone was well-tolerated across subgroups; discontinuation and hospitalization because of hyperkalaemia were low.

Conclusions

Finerenone efficacy was not modified by baseline HbA1c, HbA1c variability, diabetes duration or baseline insulin use. Greater HbA1c variability appeared to be associated with an increased risk of cardiorenal outcomes.     

Reisen mit Immunsuppression

The rapidly increasing number of patients with immunosuppression is followed by their expectation to lead—as much as possible—a “normal” life, including long-distance travel. The advice and preventive measures for diseases associated with travelling depend overall on the mode of the patient’s immunosuppression. This report explains the individual preventive possibilities, limits and risks for travellers with asplenia, common variable immunodeficiency, chronic inflammatory bowel and rheumatic diseases, HIV, as well as for patients having undergone solid organ or bone marrow transplantation or chemotherapy.     

Calcium-phosphate metabolism parameters and erythrocyte Ca2+ concentration in autosomal dominant polycystic kidney disease patients with normal renal function

Introduction

The aim of this study was to assess calcium-phosphate metabolism of autosomal dominant polycystic kidney disease (ADPKD) patients with a special consideration to the following serum parameters: calcium (Ca²⁺), inorganic phosphate (Pi), parathyroid hormone (PTH) and intracellular erythrocyte calcium ([Ca²⁺]_i) concentrations.

Material and methods

The study included 49 adult ADPKD patients (19 males, 30 females) aged 36 ±11 years with normal renal function and no diagnosis of diabetes as well as 50 healthy controls (22 males, 28 females) matched for age and gender. Serum concentrations of sodium (Na⁺), potassium (K⁺) and magnesium (Mg²⁺) ions and Pi were determined with an indirect ion-selective method, while Ca2+ concentration was measured with a direct ion-selective method. The PTH was detected using a radioimmunometric method. [Ca²⁺]_i concentration was determined with the Ca²⁺ sensitive fluorescent dye Fura-2 method.

Results

In the ADPKD group, when compared to controls, the following concentrations were significantly higher: serum Ca²⁺ (1.18 ±0.06 mmol/l vs. 1.15 ±0.06 mmol/l, p = 0.0085), [Ca²⁺]_i (146.9 ±110.0 nmol/l vs. 96.5 ±52.7 nmol/l, p = 0.0075), serum Na+ (139.4 ±2.7 mmol/l vs. 138.5 ±2.1 mmol/l, p = 0.060, borderline significance), and PTH (15.5 ±6.8 pg/ml vs. 13.6 ±5.3 pg/ml, p = 0.066, borderline significance), while serum Mg²⁺ was significantly lower (0.81 ±0.09 mmol/l vs. 0.85 ±0.05 mmol/l, p = 0.021). In the ADPKD group we observed significant negative correlations of PTH with Ca²⁺ serum concentrations (Rs = –0.32, p = 0.025) and with estimated glomerular filtration rate (Rs = –0.31, p = 0.033).

Conclusions

The erythrocyte Ca²⁺ concentration is elevated in ADPKD patients with normal renal function. It may result from a dysfunction of mutated polycystins which can affect various aspects of electrolyte metabolism.