Paraphrasing the Swiss physician and father of toxicology Paracelsus (1493–1541) on chemical agents used as therapeutics, "the dose makes the poison," it is now realized that this aptly applies to the calorigenic nutrients. The case here is the pancreatic islet β-cell presented with excessive levels of nutrients such as glucose, lipids, and amino acids. The short-term effects these nutrients exert on the β-cell are enhanced insulin biosynthesis and secretion and changes in glucose sensitivity. However, chronic fuel surfeit triggers additional compensatory and adaptive mechanisms by β-cells to cope with the increased insulin demand or to protect itself. When these mechanisms fail, toxicity due to the nutrient surplus ensues, leading to β-cell dysfunction, dedifferentiation, and apoptosis. The terms glucotoxicity, lipotoxicity, and glucolipotoxicity have been widely used, but there is some confusion as to what they mean precisely and which is most appropriate for a given situation. Here we address the gluco-, lipo-, and glucolipo-toxicities in β-cells by assessing the evidence both for and against each of them. We also discuss potential mechanisms and defend the view that many of the identified "toxic" effects of nutrient excess, which may also include amino acids, are in fact beneficial adaptive processes. In addition, candidate fuel-excess detoxification pathways are evaluated. Finally, we propose that a more general term should be used for the in vivo situation of overweight-associated type 2 diabetes reflecting both the adaptive and toxic processes to mixed calorigenic nutrients excess: "nutrient-induced metabolic stress" or, in brief, "nutri-stress."

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.

Hepatic steatosis, the excess storage of intrahepatic lipids, is a rampant clinical problem associated with the obesity epidemic. Hepatic steatosis is linked to increased risk for insulin resistance, type 2 diabetes, and cardiovascular and advanced liver disease. Accumulating evidence shows that physical activity, exercise, and aerobic capacity have profound effects on regulating intrahepatic lipids and mediating susceptibility for hepatic steatosis. Moreover, exercise can effectively reduce hepatic steatosis independent of changes in body mass. In this perspective, we highlight 1) the relationship between obesity and metabolic pathways putatively driving hepatic steatosis compared with changes induced by exercise; 2) the impact of physical activity, exercise, and aerobic capacity compared with caloric restriction on regulating intrahepatic lipids and steatosis risk; 3) the effects of exercise training (modalities, volume, intensity) for treatment of hepatic steatosis, and 4) evidence for a sustained protection against steatosis induced by exercise. Overall, evidence clearly indicates that exercise powerfully regulates intrahepatic storage of fat and risk for steatosis.

Ole Schmitz
Dec 1, 2004; 53:S233-S238
Section V: The Incretin Pathway

Maria Sörhede Winzell
Dec 1, 2004; 53:S215-S219
Section V: The Incretin Pathway

Lena Eliasson
May 1, 2020; 69:804-812
Small Noncoding RNAs in Diabetes

Jens Juul Holst
Dec 1, 2004; 53:S197-S204
Section V: The Incretin Pathway

Marc Y. Donath
Dec 1, 2005; 54:S108-S113
Section III: Inflammation and beta-Cell Death

Miriam Cnop
Dec 1, 2005; 54:S97-S107
Section III: Inflammation and beta-Cell Death

Ralph A. DeFronzo
Apr 1, 2009; 58:773-795
Banting Lecture

Gunnar Stenström
Dec 1, 2005; 54:S68-S72
Section II: Type 1-Related Forms of Diabetes

4 February 2020

1 October 2008 , Number 11

Nuclear, biological or chemical weapons and acts of terror may make the headlines, but it is conventional arms that take the lives in large numbers; maybe around a thousand a day. This month, a United Nations committee will try to find a way to limit the arms trade with a new treaty. For those facing the barrel of a gun, it cannot come a moment too soon.

Invitation Only Research Event

Med Treatments India offers one stop solution for medical healthcare services and most affordable treatments facility with best hospitals & alternative treatments in India.

Dr shailesh kumar garge is an Vascular specialist and surgeons in Hyderabad with high success rate. Experienced endovascular and micro vascular specialist in gachibowli, hitech city | vascular surgeon in

Emerging film-makers will have the opportunity to produce a short film based on the theme ‘My Windrush Story – What Windrush Means to Me’ as part of the Windrush Caribbean Film Festival (WCFF), which will be held later this year as part of Black...

Research Event

Event participants

Dr Fatima Denton, Director, Special Initiatives Division, UN Economic Commission for Africa
Dr Chukwumerije Okereke, Associate Professor, University of Reading
Douglas Brew, Director External Affairs, Communications and Sustainable Living for Africa, Unilever
Chair: Bob Dewar, Associate Fellow, Africa Programme, Chatham House

23 February 2017

Although most renewable energy policy frameworks treat biomass as carbon-neutral at the point of combustion, biomass emits more carbon per unit of energy than most fossil fuels. 

IT IS said that every cloud has a silver lining, and that could still hold true, even in the midst of a terrifying global pandemic. Despite COVID-19, the cycle of life continues, and out of it has sprung forth an inspiring poetry competition,...

Industries across the world face uncertainty, as no one entity can absolutely declare when or if economies will revert to normal in the wake of COVID-19. The local entertainment industry suffers the same uncertainty – and to address it, the Jamaica...

This is one of the very most exciting internet sites I have actually ever observed. It is very exciting considering that of its one-of-a-kind subject matter and also amazing short articles.

Public reaction to the initial threat of the coronavirus (COVID-19) was predictably mixed. While international news of the contagion across continents helped people to appreciate that this was not restricted to a particular region, not many people...

The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates β-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in β-cells in response to glucose in a carbohydrate-response element–binding protein (ChREBP)–dependent manner. In addition, chromatin immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand.

Human but not mouse islets transplanted into immunodeficient NSG mice effectively accumulate lipid droplets (LDs). Because chronic lipid exposure is associated with islet β-cell dysfunction, we investigated LD accumulation in the intact human and mouse pancreas over a range of ages and states of diabetes. Very few LDs were found in normal human juvenile pancreatic acinar and islet cells, with numbers subsequently increasing throughout adulthood. While accumulation appeared evenly distributed in postjuvenile acinar and islet cells in donors without diabetes, LDs were enriched in islet α- and β-cells from donors with type 2 diabetes (T2D). LDs were also found in the islet β-like cells produced from human embryonic cell–derived β-cell clusters. In contrast, LD accumulation was nearly undetectable in the adult rodent pancreas, even in hyperglycemic and hyperlipidemic models or 1.5-year-old mice. Taken together, there appear to be significant differences in pancreas islet cell lipid handling between species, and the human juvenile and adult cell populations. Moreover, our results suggest that LD enrichment could be impactful to T2D islet cell function.

The host environment is a crucial factor for considering the transplant of stem cell–derived immature pancreatic cells in patients with type 1 diabetes. Here, we investigated the effect of insulin (INS)-deficient diabetes on the fate of immature pancreatic endocrine cell grafts and the underlying mechanisms. Human induced pluripotent stem cell–derived pancreatic endocrine progenitor cells (EPCs), which contained a high proportion of chromogranin A⁺ NK6 homeobox 1⁺ cells and very few INS⁺ cells, were used. When the EPCs were implanted under the kidney capsule in immunodeficient mice, INS-deficient diabetes accelerated increase in plasma human C-peptide, a marker of graft-derived INS secretion. The acceleration was suppressed by INS infusion but not affected by partial attenuation of hyperglycemia by dapagliflozin, an INS-independent glucose-lowering agent. Immunohistochemical analyses indicated that the grafts from diabetic mice contained more endocrine cells including proliferative INS-producing cells compared with that from nondiabetic mice, despite no difference in whole graft mass between the two groups. These data suggest that INS-deficient diabetes upregulates the INS-secreting capacity of EPC grafts by increasing the number of endocrine cells including INS-producing cells without changing the graft mass. These findings provide useful insights into postoperative diabetic care for cell therapy using stem cell–derived pancreatic cells.

Henry "Hank" Aaron was born in Alabama three years after Willie Mays, 85 years ago Tuesday. Now, all this time later, Aaron is as much the conscience and the soul of baseball as any man alive. But we don't just celebrate a great baseball life today. We celebrate a great American life.

To those of a certain age, Frank Robinson was the definition of greatness, leadership and toughness. Well into his 70's and 80's, he carried himself with the confidence and unmistakable gait of a great athlete.

Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell–specific reduction of HMG-CoA reductase (Hmgcr^m–/m–), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcr^m–/m– mice than in control Hmgcr^fl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcr^m–/m– and Hmgcr^fl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell–specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell–specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.

It took only two words for Alex Bregman to send 9-year-old Jax Nystrom into a frenzy, but this kind of reaction -- young people freaking out at the slightest bit of attention from him -- has become commonplace for the Astros' All-Star third baseman.

  WASHINGTON (AP) — More than 40 public companies are pledging to return money to the government’s small business coronavirus fund now that Treasury Secretary Steven Mnuchin is threatening criminal prosecutions for...

BOGOTA, Colombia (AP) — A Colombian advertising company is pitching a novel, if morbid, solution to shortages of hospital beds and coffins during the coronavirus pandemic: combine them. ABC Displays has created a cardboard bed with metal...

The UK’s austerity programme has disproportionately affected children and people with disabilities, says David Taylor-Robinson, a senior clinical lecturer in public health at the University of Liverpool. He joins us to discuss why the evidence shows the vulnerable are hit hardest by the cuts to public services, despite the UN conventions on...

One hundred years ago, Pennsylvanian surgeon Evan Kane penned a brief letter to JAMA in which he declared himself a rigorous proponent of the “benefic [sic] effects of the phonograph within the operating room.” Now David Bosenquet, a surgeon from University Hospital of Wales in Cardiff has written a Christmas editorial about the evidence for the...

Waiting times in theatre can be a source of friction – but is the delay due to mandatory anaesthetic faff around time (MAFAT), or AWOL surgeons? Elizabeth Travis, and orthopaedic house officer in New Zealand and colleagues, have been trying to create and evidence base to argue the toss, and she joins me now to discuss her study, Operating...

BMJ Voices is a collection of readers’ experiences of working in the NHS. For this, The BMJ is seeking short audio submissions from UK listeners. These submissions will be published on thebmj.com. Patrick Keating, a GP from Enfield, is concerned that small practices are under pressure to increase list size, but aren't able to muster resources to...

The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) has been examining the treatment of acute GI bleeds in England's NHS. Two of the authors, Martin Sinclair, consultant surgeon, and Simon McPherson, consultant vascular radiologist, join us to talk about their findings. Read the full...

Hepatic encephalopathy constitutes a spectrum of neuropsychiatric abnormalities, beginning with subtle psychomotor changes and progressing to confusion with asterixis, somnolence, and then coma, arising in patients with impaired liver function. In this podcast, Tim Cross, a consultant hepatologist from the Royal Liverpool University Hospital,...

The current orthodoxy is that home is the best and preferred place of death for most people, but in this podcast, Kristian Pollock a sociologist from Nottingham University questions these assumptions and calls for greater attention to improving the experience of dying in hospital and elsewhere. Read the full...

PTSD may develop after exposure to exceptionally threatening or horrifying events. About 3% of the adult population has PTSD at any one time, and more than 50% in survivors of rape. In this podcast Jonathan Bisson, professor of psychiatry at the School of Medicine in Cardiff joins us to talk about the evidence for diagnosis and treatment, and...

Larger portions of food increase consumption. Theresa Marteau, director of the Behaviour and Health Research Unit at the University of Cambridge, joins us to discuss how government action to tackle portion size and packaging could help reset our appetites and make us thinner. Read the full analysis: http://www.bmj.com/content/351/bmj.h5863

James Barrett, president of the British Association of Gender Identity Specialists, and Nina, a trans woman, join us to discuss how difficult it can be for trans people to access gender clinics, and what barriers are faced by the community after their transition has been completed. Read James Barrett's personal...

Medical error is not included on death certificates or in rankings of cause of death. Martin Makary, professor of surgery at Johns Hopkins University School of Medicine, joins us to explain why we don't measure medical error, and why it is so important that we start. Read the full analysis: http://www.bmj.com/content/353/bmj.i2139

Global evidence indicates that mandated treatment of drug dependence conflicts with drug users’ human rights and is not effective in treating addiction. Karsten Lunze, associate professor at the Boston University School of Medicine, joins us to describe the evidence, and why he is convinced seemingly counter intuitive hard reduction...

2.46 million people in England have osteoarthritis of the hip, and many of those go on to eventually have a hip replacement - which is now widely considered one of the most commonly performed and successful operations in the world. Jessamy Bagenal, clinical fellow with The BMJ, talks to Nick Aresti, a specialist registrar in trauma and...