Genetic Reduction of Glucose Metabolism Preserves Functional ß-Cell Mass in KATP-Induced Neonatal Diabetes.

ß-Cell failure and loss of ß-cell mass are key events in diabetes progression. Although insulin hypersecretion in early stages has been implicated in ß-cell exhaustion/failure, loss of ß-cell mass still occurs in KATP gain-of-function (GOF) mouse models of human neonatal diabetes in the absence of insulin secretion. Thus, we hypothesize that hyperglycemia-induced increased ß-cell metabolism is responsible for ß-cell failure and that reducing glucose metabolism will prevent loss of ß-cell mass. To test this, KATP-GOF mice were crossed with mice carrying ß-cell-specific glucokinase haploinsufficiency (GCK+/-), to genetically reduce glucose metabolism. As expected, both KATP-GOF and KATP-GOF/GCK+/- mice showed lack of glucose-stimulated insulin secretion. However, KATP-GOF/GCK+/- mice demonstrated markedly reduced blood glucose, delayed diabetes progression, and improved glucose tolerance compared with KATP-GOF mice. In addition, decreased plasma insulin and content, increased proinsulin, and augmented plasma glucagon observed in KATP-GOF mice were normalized to control levels in KATP-GOF/GCK+/- mice. Strikingly, KATP-GOF/GCK+/- mice demonstrated preserved ß-cell mass and identity compared with the marked decrease in ß-cell identity and increased dedifferentiation observed in KATP-GOF mice. Moreover KATP-GOF/GCK+/- mice demonstrated restoration of body weight and liver and brown/white adipose tissue mass and function and normalization of physical activity and metabolic efficiency compared with KATP-GOF mice. These results demonstrate that decreasing ß-cell glucose signaling can prevent glucotoxicity-induced loss of insulin content and ß-cell failure independently of compensatory insulin hypersecretion and ß-cell exhaustion.

Stranger Months: How SARS-CoV-2, Fear of Contagion, and Lockdown Measures Impacted Attendance and Clinical Activity During February and March 2020 at an Urban Emergency Department in Milan.

OBJECTIVES: An unprecedented wave of patients with acute respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) hit emergency departments (EDs) in Lombardy, starting in the second half of February 2020. This study describes the direct and indirect impacts of the SARS-CoV-2 outbreak on an urban major-hospital ED. METHODS: Data regarding all patients diagnosed with COVID-19 presenting from February 1 to March 31, 2020, were prospectively collected, while data regarding non-COVID patients presenting within the same period in 2019 were retrospectively retrieved. RESULTS: ED attendance dropped by 37% in 2020. Two-thirds of this reduction occurred early after the identification of the first autochthonous COVID-19 case in Lombardy, before lockdown measures were enforced. Hospital admissions of non-COVID patients fell by 26%. During the peak of COVID-19 attendance, the ED faced an extraordinary increase in: patients needing oxygen (+239%) or noninvasive ventilation (+725%), transfers to the intensive care unit (+57%), and in-hospital mortality (+309%), compared with the same period in 2019. CONCLUSIONS: The COVID-19 outbreak determined an unprecedented upsurge in respiratory failure cases and mortality. Fear of contagion triggered a spontaneous, marked reduction of ED attendance, and, presumably, some as yet unknown quantity of missed or delayed diagnoses for conditions other than COVID-19.

High-fat-diet-induced remission of diabetes in a subset of KATP -GOF insulin-secretory-deficient mice.

AIMS: To examine the effects of a high-fat-diet (HFD) on monogenic neonatal diabetes, without the confounding effects of compensatory hyperinsulinaemia. METHODS: Mice expressing KATP channel gain-of-function (KATP -GOF) mutations, which models human neonatal diabetes, were fed an HFD. RESULTS: Surprisingly, KATP -GOF mice exhibited resistance to HFD-induced obesity, accompanied by markedly divergent blood glucose control, with some KATP -GOF mice showing persistent diabetes (KATP -GOF-non-remitter [NR] mice) and others showing remission of diabetes (KATP -GOF-remitter [R] mice). Compared with the severely diabetic and insulin-resistant KATP -GOF-NR mice, HFD-fed KATP -GOF-R mice had lower blood glucose, improved insulin sensitivity, and increased circulating plasma insulin and glucagon-like peptide-1 concentrations. Strikingly, while HFD-fed KATP -GOF-NR mice showed increased food intake and decreased physical activity, reduced whole body fat mass and increased plasma lipids, KATP -GOF-R mice showed similar features to those of control littermates. Importantly, KATP -GOF-R mice had restored insulin content and ß-cell mass compared with the marked loss observed in both HFD-fed KATP -GOF-NR and chow-fed KATP -GOF mice. CONCLUSION: Together, our results suggest that restriction of dietary carbohydrates and caloric replacement by fat can induce metabolic changes that are beneficial in reducing glucotoxicity and secondary consequences of diabetes in a mouse model of insulin-secretory deficiency.

N-cadherin Regulation of Bone Growth and Homeostasis Is Osteolineage Stage-Specific.

N-cadherin inhibits osteogenic cell differentiation and canonical Wnt/ß-catenin signaling in vitro. However, in vivo both conditional Cdh2 ablation and overexpression in osteoblasts lead to low bone mass. We tested the hypothesis that N-cadherin has different effects on osteolineage cells depending upon their differentiation stage. Embryonic conditional osteolineage Cdh2 deletion in mice results in defective growth, low bone mass, and reduced osteoprogenitor number. These abnormalities are prevented by delaying Cdh2 ablation until 1 month of age, thus targeting only committed and mature osteoblasts, suggesting they are the consequence of N-cadherin deficiency in osteoprogenitors. Indeed, diaphyseal trabecularization actually increases when Cdh2 is ablated postnatally. The sclerostin-insensitive Lrp5A214V mutant, associated with high bone mass, does not rescue the growth defect, but it overrides the low bone mass of embryonically Cdh2-deleted mice, suggesting N-cadherin interacts with Wnt signaling to control bone mass. Finally, bone accrual and ß-catenin accumulation after administration of an anti-Dkk1 antibody are enhanced in N-cadherin-deficient mice. Thus, although lack of N-cadherin in embryonic and perinatal age is detrimental to bone growth and bone accrual, in adult mice loss of N-cadherin in osteolineage cells favors bone formation. Hence, N-cadherin inhibition may widen the therapeutic window of osteoanabolic agents. © 2017 American Society for Bone and Mineral Research.