Is shortening of telomeres the missing link between aging and the Type 2 Diabetes epidemic?

The world is facing an impending epidemic of diabetes [1]. Diabetes occurs in two forms - Type 1 and Type 2. These are separate entities, although they share an elevation of fasting plasma glucose (≥7.0 mM or 126 mg/dl) as the only required diagnostic criterion. The diabetes epidemic can be attributed to Type 2 Diabetes. Historically, Type 2 Diabetes has been a disease of the aged population. Recently, a drift in the incidence is observed, with younger individuals developing Type 2 Diabetes

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems. Here, we have investigated the bioenergetic profile in myogenic cells from MDC1A and LS patients. We found dysregulated expression of genes related to energy production, apoptosis and proteasome in myoblasts and myotubes. Moreover, impaired mitochondrial function and a compensatory upregulation of glycolysis were observed when monitored in real-time. Also, alterations in cell cycle populations in myoblasts and enhanced caspase-3 activity in myotubes were observed. Thus, we have for the first time demonstrated an impairment of the bioenergetic status in human MDC1A and LS muscle cells, which could contribute to cell cycle disturbance and increased apoptosis. Our findings suggest that skeletal muscle metabolism might be a promising pharmacological target in order to improve muscle function, energy efficiency and tissue maintenance of MDC1A and LS patients

Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production

© 2018 The Author(s). Published by Elsevier Inc.Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their β cells (Fh1βKO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in α cells from hyperglycemic Fh1βKO and β-V59M gain-of-function KATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1βKO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.Peer reviewe

Influence of social networks in healthcare on preparation for selection procedures of health professions education:a Dutch interview study

OBJECTIVES: Health professions education (HPE) students are often not representative of the populations they will serve. The underrepresentation of non-traditional students is problematic because diversity is essential for promoting excellence in health education and care. This study aimed to understand the perceptions of traditional and non-traditional students regarding facilitators and barriers in preparing for HPE selection procedures, and to determine the role of social networks in their decision-making and preparations to apply. METHODS: A qualitative study was conducted with 26 Dutch youth who were interested in university-level HPE programmes. Semistructured interviews and sociograms were analysed using thematic analysis, adopting a constructivist approach. RESULTS: Twenty-six high school students participated, with traditional and non-traditional backgrounds, with and without social networks in healthcare and higher education. Two themes were constructed. First, four high-impact facilitators helped to overcome barriers to apply and in preparation for selection: access to a social network connection working or studying in healthcare, to correct information, to healthcare experience and to a social network connection in higher education. Lack of information was the main barrier while access to social network connections in healthcare was the main facilitator to overcome this barrier. However, this access was unevenly distributed. Second, access alone is not enough: the need for agency to make use of available facilitators is also essential. CONCLUSIONS: The themes are discussed using intersectionality. Traditional students with access to facilitators develop their self-efficacy and agency within social structures that privilege them, whereas non-traditional students must develop those skills without such structures. Our findings provide recommendations for the ways in which universities can remove barriers that cause unequal opportunities to prepare for the selection of HPE programmes. Along with equitable admissions, these recommendations can help to achieve a more representative student population and subsequently a better quality of health education and care

Regulated Exocytosis of GABA-containing Synaptic-like Microvesicles in Pancreatic β-cells

We have explored whether γ-aminobutyric acid (GABA) is released by regulated exocytosis of GABA-containing synaptic-like microvesicles (SLMVs) in insulin-releasing rat pancreatic β-cells. To this end, β-cells were engineered to express GABAA-receptor Cl−-channels at high density using adenoviral infection. Electron microscopy indicated that the average diameter of the SLMVs is 90 nm, that every β-cell contains ∼3,500 such vesicles, and that insulin-containing large dense core vesicles exclude GABA. Quantal release of GABA, seen as rapidly activating and deactivating Cl−-currents, was observed during membrane depolarizations from −70 mV to voltages beyond −40 mV or when Ca2+ was dialysed into the cell interior. Depolarization-evoked GABA release was suppressed when Ca2+ entry was inhibited using Cd2+. Analysis of the kinetics of GABA release revealed that GABA-containing vesicles can be divided into a readily releasable pool and a reserve pool. Simultaneous measurements of GABA release and cell capacitance indicated that exocytosis of SLMVs contributes ∼1% of the capacitance signal. Mathematical analysis of the release events suggests that every SLMV contains 0.36 amol of GABA. We conclude that there are two parallel pathways of exocytosis in pancreatic β-cells and that release of GABA may accordingly be temporally and spatially separated from insulin secretion. This provides a basis for paracrine GABAergic signaling within the islet

Inequality of opportunity in selection procedures limits diversity in higher education:An intersectional study of Dutch selective higher education programs

Selection for higher education (HE) programs may hinder equal opportunities for applicants and thereby reduce student diversity and representativeness. However, variables which could play a role in inequality of opportunity are often studied separately from each other. Therefore, this retrospective cohort study conducts an innovative intersectional analysis of the inequality of opportunity in admissions to selective HE programs. Using a combination of multivariable logistic regression analyses and descriptive statistics, we aimed to investigate 1) the representativeness of student populations of selective HE programs, as compared to both the applicant pool and the demographics of the age cohort; 2) the demographic background variables which are associated with an applicant’s odds of admission; and 3) the intersectional acceptance rates of applicants with all, some or none of the background characteristics positively associated with odds of admission. The study focused on all selective HE programs (n = 96) in The Netherlands in 2019 and 2020, using Studielink applicant data (N = 85,839) and Statistics Netherlands microdata of ten background characteristics. The results show that student diversity in selective HE programs is limited, partly due to the widespread inequality of opportunity in the selection procedures, and partly due to self-selection. Out of all ten variables, migration background was most often (negatively) associated with the odds of receiving an offer of admission. The intersectional analyses provide detailed insight into how (dis)advantage has different effects for different groups. We therefore recommend the implementation of equitable admissions procedures which take intersectionality into account.</p

Diversity in the pathway from medical student to specialist in the Netherlands:a retrospective cohort study

Background: Medical specialist workforces are not representative of the society they serve, partially due to loss of diversity in the path from student to specialist. We investigated which demographic characteristics of bachelor students of medicine (BSM) are associated with becoming a physician and (particular type of) medical specialist; and whether this suggests ‘cloning’ (reproduction of sameness) of the existing workforce. Methods: We used a retrospective cohort design, based on Statistics Netherlands data of all first-year BSM in 2002–2004 in The Netherlands (N = 4503). We used logistic regression to analyze the impact of sex, migration background, urbanity of residence, parental income and assets categories, and having healthcare professional parents, on being registered as physician or medical specialist in 2021. We compared our results to the national pool of physicians (N = 76,845) and medical specialists (N = 49,956) to identify cloning patterns based on Essed's cultural cloning theory. Findings: Female students had higher odds of becoming a physician (OR 1.87 [1.53–2.28], p &lt; 0.001). Physicians with a migration background other than Turkish, Moroccan, Surinamese, Dutch Caribbean or Indonesian (TMSDI) had lower odds of becoming a specialist (OR 0.55 [0.43–0.71], p &lt; 0.001). This was not significant for TMSDI physicians (OR 0.74 [0.54–1.03], p = 0.073). We found a cloning pattern with regard to sex and migration background. Nationwide, physicians with a Turkish or Moroccan migration background, and female physicians with other migration backgrounds, are least likely to be a medical specialist. Interpretation: In light of equity in healthcare systems, we recommend that every recruitment body increases the representativeness of their particular specialist workforce. Funding: ODISSEI.</p

Genomic editing of metformin efficacy-associated genetic variants in SLC47A1 does not alter SLC47A1 expression

Several pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The genome-edited cells were evaluated for SLC47A1 expression and splicing. None of the common variants including rs2289669 showed significant association with metformin response. Genomic editing of either rs2289669 or rs8065082 did not alter SLC47A1 expression or splicing. Experimental and in silico analyses show that the rs2289669-containing haploblock does not appear to carry genetic variants that could explain its previously reported association with metformin efficacy.Peer reviewe