Hepatosteatosis, which is frequently associated with development of metabolic syndrome and insulin resistance, manifests when triglyceride (TG) input in the liver is greater than TG output, resulting in the excess accumulation of TG. Dysregulation of lipogenesis therefore has the potential to increase lipid accumulation in the liver, leading to insulin resistance and type 2 diabetes. Recently, efforts have been made to examine the epigenetic regulation of metabolism by histone-modifying enzymes that alter chromatin accessibility for activation or repression of transcription. For regulation of lipogenic gene transcription, various known lipogenic transcription factors, such as USF1, ChREBP, and LXR, interact with and recruit specific histone modifiers, directing specificity toward lipogenesis. Alteration or impairment of the functions of these histone modifiers can lead to dysregulation of lipogenesis and thus hepatosteatosis leading to insulin resistance and type 2 diabetes.

In type 2 diabetes, β-cells endure various forms of cellular stress, including oxidative stress and endoplasmic reticulum stress, secondary to increased demand for insulin production and extracellular perturbations, including hyperglycemia. Chronic exposure to stress causes impaired insulin secretion, apoptosis, and loss of cell identity, and a combination of these processes leads to β-cell failure and severe hyperglycemia. Therefore, a better understanding of the molecular mechanisms underlying stress responses in β-cells promises to reveal new therapeutic opportunities for type 2 diabetes. In this perspective, we discuss posttranscriptional control of gene expression as a critical, but underappreciated, layer of regulation with broad importance during stress responses. Specifically, regulation of mRNA translation occurs pervasively during stress to activate gene expression programs; however, the convenience of RNA sequencing has caused translational regulation to be overlooked compared with transcriptional controls. We highlight the role of RNA binding proteins in shaping selective translational regulation during stress and the mechanisms underlying this level of regulation. A growing body of evidence indicates that RNA binding proteins control an array of processes in β-cells, including the synthesis and secretion of insulin. Therefore, systematic evaluations of translational regulation and the upstream factors shaping this level of regulation are critical areas of investigation to expand our understanding of β-cell failure in type 2 diabetes.

Errol B. Marliss
Feb 1, 2002; 51:S271-S283
Section 6: Pusatile and Phasic Insulin Release in Normal and Diabetic Men

3 December 2019

Franz M Matschinsky
Feb 1, 1996; 45:223-241
Banting Lecture 1995

J. Denis McGarry
Jan 1, 2002; 51:7-18
Banting Lecture 2001

JC Henquin
Nov 1, 2000; 49:1751-1760
Articles

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.

The American Dental Association, along with 75 organizations, is urging Congress to support legislation to regulate vaping devices and liquids in the same manner the Food and Drug Administration regulates cigarettes and other tobacco products.

Dentists can find regulations, recommendations and mandates regarding the practice of dentistry in their state during the COVID-19 pandemic on the ADA Center for Professional Success.

European policymakers are fixated on reform of the Dublin Regulation, the contentious rules that carve up responsibility for asylum claims between EU states. They see it not only as a long-term prophylactic against future fluctuations in irregular migration, but as a marker of the success or failure of solidarity in Europe overall. Yet rather than doggedly working to salvage Dublin, policymakers need to stop and consider why they regard it as so integral to European cooperation, as this commentary explores.

It’s the middle of an election year and, according to the Pew Research Center, the country hasn’t been this polarized since the Civil War. In such a climate, it would seem to be an oxymoron for a company to push for both financial growth and tighter regulations. Gregg Renfrew, CEO & Founder of Beautycounter, wouldn’t […]

Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster, coding for the α5, α3, and β4 nicotinic acetylcholine receptor (nAChR) subunits, to nicotine addiction. β4*nAChRs have been implicated in nicotine withdrawal, aversion, and reinforcement. Here we show that β4*nAChRs also are involved in non-nicotine-mediated responses that may predispose to addiction-related behaviors. β4 knock-out (KO) male mice show increased novelty-induced locomotor activity, lower baseline anxiety, and motivational deficits in operant conditioning for palatable food rewards and in reward-based Go/No-go tasks. To further explore reward deficits we used intracranial self-administration (ICSA) by directly injecting nicotine into the ventral tegmental area (VTA) in mice. We found that, at low nicotine doses, β4KO self-administer less than wild-type (WT) mice. Conversely, at high nicotine doses, this was reversed and β4KO self-administered more than WT mice, whereas β4-overexpressing mice avoided nicotine injections. Viral expression of β4 subunits in medial habenula (MHb), interpeduncular nucleus (IPN), and VTA of β4KO mice revealed dose- and region-dependent differences: β4*nAChRs in the VTA potentiated nicotine-mediated rewarding effects at all doses, whereas β4*nAChRs in the MHb-IPN pathway, limited VTA-ICSA at high nicotine doses. Together, our findings indicate that the lack of functional β4*nAChRs result in deficits in reward sensitivity including increased ICSA at high doses of nicotine that is restored by re-expression of β4*nAChRs in the MHb-IPN. These data indicate that β4 is a critical modulator of reward-related behaviors.

SIGNIFICANCE STATEMENT Human genetic studies have provided strong evidence for a relationship between variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and nicotine addiction. Yet, little is known about the role of β4 nicotinic acetylcholine receptor (nAChR) subunit encoded by this cluster. We investigated the implication of β4*nAChRs in anxiety-, food reward- and nicotine reward-related behaviors. Deletion of the β4 subunit gene resulted in an addiction-related phenotype characterized by low anxiety, high novelty-induced response, lack of sensitivity to palatable food rewards and increased intracranial nicotine self-administration at high doses. Lentiviral vector-induced re-expression of the β4 subunit into either the MHb or IPN restored a "stop" signal on nicotine self-administration. These results suggest that β4*nAChRs provide a promising novel drug target for smoking cessation.

Amid the Trump administration's push to slash federal red tape, educators, advocates, and parents tell the U.S. secretary of education they're worried about the effect that could have on historically overlooked groups of students.

Infant behavioral dysregulation is a common concern, involving irritability, excessive crying, and problems with feeding and sleep. Previous research into its behavioral outcomes has been limited by small cohorts and short follow-up, and findings have been contradictory.

Long-term follow-up of a large cohort showed that infant behavioral dysregulation was a risk factor for maternal-reported behavior concerns at 5 and 14 years, but was unrelated to young adult mental health outcomes. (Read the full article)

Several studies have been published evaluating the impact of 2011 Accreditation Council for Graduate Medical Education duty hour regulations. Although resident quality of life may be improved, it appears that resident education and patient care may be worse.

This is the first study to evaluate pediatric program director approval of 2011 Accreditation Council for Graduate Medical Education Common Program Requirements and the perceived impact of the regulations on patient care, resident education, and quality of life. (Read the full article)

Several studies suggest that excessive media use in early childhood predicts poorer developmental outcomes. It has not been studied whether infants with self-regulation problems, who may be at higher developmental risk, develop excessive media use habits.

This study shows that infants and toddlers with self-regulation difficulties (ie, problems with self-soothing, sleep, emotional regulation, and attention) view more media at 2 years of age, independent of other important confounders. (Read the full article)

Restrictive feeding by parents is associated with poorer eating self-regulation and increased child weight status. However, this association could be due to confounding home environmental or genetic factors that are challenging to control.

Differential maternal restrictive feeding is associated with differences in twins' caloric compensation and BMI z score. Controlling for the shared home environment and partially for genetics, these findings further support a true (ie, unconfounded) association between restriction and childhood obesity. (Read the full article)

Previous studies have examined state regulations for child care facilities and found substantial variation among states. None of these studies examined regulations related to healthy sleep practices, which is an important and often overlooked intervention target for obesity prevention.

We reviewed state regulations related to healthy sleep in child care and compared them to recent national recommendations put forth by the Institute of Medicine. We found that many states lacked regulations, highlighting an important and timely opportunity for improvement. (Read the full article)

Meropenem/vaborbactam resistance in Klebsiella pneumoniae is associated with loss of function mutations in the OmpK35 and OmpK36 porins. Here we identify two previously unknown loss of function mutations that confer cefuroxime resistance in K. pneumoniae. The proteins lost were NlpD and KvrA; the latter is a transcriptional repressor controlling capsule production. We demonstrate that KvrA loss reduces OmpK35 and OmpK36 porin production, which confers reduced susceptibility to meropenem/vaborbactam in a KPC-3 producing K. pneumoniae isolate.

030 - Venues for finals of UEFA 2015 club competitions chosen

If you own a quadcopter or are planning to buy one, you should be aware of FAA rules for flying outdoors. Here's everything you need to know about owning and flying a drone for fun.

Statistics from the Division of Professional Regulation, which licenses controlled substance prescribers, show a 12-percent drop in opioid prescriptions statewide compared to the first quarter of 2017. The number of Delaware patients being treated with opioid medications has also declined by 8 percent over the same time period, the division reports.

Regulations promulgated by the Secretary of State and slated to take effect Jan. 1 will require that new business entities formed in Delaware be screened against lists of persons and groups that have been prohibited from doing business in the United States.

Unearthing cartels by invoking applicant confidence: Lesser penalty regulations, 2009

The Delaware Office of Management and Budget will be holding three public hearings to gather public comment on regulations under Governor Markell’s Executive Order 36, a statewide review by all agencies to identify and remove regulatory hurdles.

OMB accepting public input on agency regulations through December 1.

The Office of Management and Budget (OMB) is currently accepting comments and will hold a series of public hearings on three OMB regulations in accordance with the regulatory review provisions of HB 147 of the 148th General Assembly. Comments will be accepted through November 1 for the following regulations: • 4102 Regulations for the Annual […]

The Department of Natural Resources and Environmental Control and the Department of Agriculture have proposed new regulations expanding the scope of legal possession of firearms within Delaware’s state parks, state wildlife areas and state forests.

DNREC and Department of Agriculture will conduct a joint public hearing Monday, March 12 on proposed regulations for possessing firearms in Delaware’s state parks and wildlife areas and state forests.

DOVER, Del. – The Delaware Department of Agriculture (DDA) Food Products Inspection was granted statutory authority on June 11, 2019 to enforce compliance with the Produce Safety Rule in the Food Safety Modernization Act (FSMA). The Food Safety Modernization Act is a proactive approach to prevent foodborne illnesses by strengthening the food supply. These regulations, […]

Agency: LEG Closing Date: 6/19/2020

The number of prescriptions for opioid medications in Delaware, as well as the total quantity of opioids dispensed, have dropped significantly in the 12 months since the Department of State enacted stricter prescribing regulations to help combat the opioid crisis statewide.

DEPARTMENT OF SAFETY AND HOMELAND SECURITY: Delaware Council on Police Training

DNREC reduces the striped bass fishing quota for commercial fishing and limits the number and size of fish that recreational anglers can keep.

Biocidal active substance could be used in public health areas

MEE Order 12 comes into force 1 January 2021

As our lives come to depend on internet and apps, it is time we try to introduce the concept of accountability.

U.S. Secretary of the Interior David Bernhardt has unveiled changes to the implementing regulations of the Endangered Species Act (ESA) that Interior says is “designed to increase transparency and effectiveness and bring the administration of the Act into the 21st century.”

This week energy developer BayWa r.e. published its Energy Report 2019, which surveyed 1,200 European corporations about their attitudes toward renewable energy.

U.S. Secretary of the Interior David Bernhardt has unveiled changes to the implementing regulations of the Endangered Species Act (ESA) that Interior says is “designed to increase transparency and effectiveness and bring the administration of the Act into the 21st century.”

This week energy developer BayWa r.e. published its Energy Report 2019, which surveyed 1,200 European corporations about their attitudes toward renewable energy.

This week energy developer BayWa r.e. published its Energy Report 2019, which surveyed 1,200 European corporations about their attitudes toward renewable energy.

European Union leaders backed the most-ambitious carbon emissions goals of any major economy, in a bid to crank up pressure on the U.S. and China ahead of climate talks in December.

U.S. electricity markets face years of higher prices as clean-air regulations shut more coal-fired power plants than earlier forecast, cutting supply and forcing producers to rely more on natural gas.

Earlier this month, when EPA proposed a new health-protective air quality standard for the pollutants that form “ozone,” some critics predictably pounced on it as another example of a long string of “job-killing EPA regulations.” Yet last week, we learned that the U.S. economy created about 320,000 new jobs in November, and average wages are starting to rise as the labor market tightens.