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NIDDK Grantee News

Aug 1, 2014

The HMG-CoA reductase inhibitors (statins) are widely prescribed for patients with hyperlipidemia and are generally well tolerated. Mild elevations in serum aminotransferases arise in up to 3% of treated patients, but clinically apparent drug-induced liver injury is rare. The aim of this study is to report the presenting features and outcomes of 22 patients with clinically apparent liver injury due to statins.

NIDDK Grantee News

Jul 3, 2014

The presence of HLA haplotype DR3–DQ2 or DR4–DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG).

NIDDK Grantee News

Jul 1, 2014

Microvillus inclusion disease (MVID) is a severe form of congenital diarrhea that arises from inactivating mutations in the gene encoding myosin Vb (MYO5B). We have examined the association of mutations in MYO5B and disruption of microvillar assembly and polarity in enterocytes. Stable MYO5B knockdown (MYO5B-KD) in CaCo2-BBE cells elicited loss of microvilli, alterations in junctional claudins, and disruption of apical and basolateral trafficking; however, no microvillus inclusions were observed in MYO5B-KD cells.

NIDDK Grantee News

Jul 1, 2014

miRNAs are important regulators of biological processes in many tissues, including the differentiation and function of brown and white adipocytes. The endoribonuclease dicer is a major component of the miRNA-processing pathway, and in adipose tissue, levels of dicer have been shown to decrease with age, increase with caloric restriction, and influence stress resistance.

NIDDK Grantee News

Jun 19, 2014

Therapeutic food interventions have reduced mortality in children with severe acute malnutrition (SAM), but incomplete restoration of healthy growth remains a major problem1, 2. The relationships between the type of nutritional intervention, the gut microbiota, and therapeutic responses are unclear. In the current study, bacterial species whose proportional representation define a healthy gut microbiota as it assembles during the first two postnatal years were identified by applying a machine-learning-based approach to 16S ribosomal RNA data sets generated from monthly faecal samples obtained from birth onwards in a cohort of children living in an urban slum of Dhaka, Bangladesh, who exhibited consistently healthy growth.

NIDDK Grantee News

Jun 19, 2014

Clec16a has been identified as a disease susceptibility gene for type 1 diabetes, multiple sclerosis, and adrenal dysfunction, but its function is unknown. Here we report that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1. Loss of Clec16a leads to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas-specific deletion of Clec16a have abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal β cell function.

NIDDK Grantee News

Jun 17, 2014

α-Intercalated cells (A-ICs) within the collecting duct of the kidney are critical for acid-base homeostasis. Here, we have shown that A-ICs also serve as both sentinels and effectors in the defense against urinary infections. In a murine urinary tract infection model, A-ICs bound uropathogenic E. coli and responded by acidifying the urine and secreting the bacteriostatic protein lipocalin 2 (LCN2; also known as NGAL). A-IC-dependent LCN2 secretion required TLR4, as mice expressing an LPS-insensitive form of TLR4 expressed reduced levels of LCN2.

NIDDK Grantee News

Jun 15, 2014

The safety and effectiveness of automated glycemic management have not been tested in multiday studies under unrestricted outpatient conditions.

NIDDK Grantee News

Jun 5, 2014

Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure and improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines.

NIDDK Grantee News

Jun 5, 2014

Beige fat, which expresses the thermogenic protein UCP1, provides a defense against cold and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in mice and humans, the events that lead from the sensing of cold to the development of beige fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit, consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13, and alternatively activated macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat.

NIDDK Grantee News

Jun 5, 2014

Subcutaneous white adipose tissue can be induced to undergo “browning” and acquire thermogenic capacity in response to physiological stimuli such as cold exposure or exercise. In this issue of Cell, Qiu et al. and Rao et al. demonstrate that pink-staining eosinophils and alternatively activated macrophages play key roles in an immune cascade mediating this metabolic switch.

NIDDK Grantee News

Jun 4, 2014

Emerging data support bariatric surgery as a therapeutic strategy for management of type 2 diabetes mellitus.

NIDDK Grantee News

Jun 4, 2014

The SEARCH study demonstrated a significant increase in the incidence of type 1 diabetes (T1D) among non–Hispanic white (NHW) youth from 2002 through 2009 overall and in all but the youngest age group. Continued surveillance of T1D in youth in the United States to identify future trends in T1D incidence and to plan for health care delivery is warranted.

NIDDK Grantee News

May 28, 2014

Abdominal pain after cholecystectomy is common and may be attributed to sphincter of Oddi dysfunction. Management often involves endoscopic retrograde cholangiopancreatography (ERCP) with manometry and sphincterotomy.

NIDDK Grantee News

May 21, 2014

Lipolysis regulates energy homeostasis through the hydrolysis of intracellular triglycerides and the release of fatty acids for use as energy substrates or lipid mediators in cellular processes. Genes encoding proteins that regulate energy homeostasis through lipolysis are thus likely to play an important role in determining susceptibility to metabolic disorders.

NIDDK Grantee News

May 21, 2014

Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia1, 2. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown.

NIDDK Grantee News

May 7, 2014

Despite concern about an “epidemic,” there are limited data on trends in prevalence of either type 1 or type 2 diabetes across US race and ethnic groups.

NIDDK Grantee News

May 6, 2014

WNK1 [with no lysine (K)] is a serine-threonine kinase associated with a form of familial hypertension. WNK1 is at the top of a kinase cascade, leading to phosphorylation of several cotransporters, in particular those transporting sodium, potassium, and chloride (NKCC), sodium and chloride (NCC), and potassium and chloride (KCC). The responsiveness of NKCC, NCC, and KCC to changes in extracellular chloride parallels their phosphorylation state, provoking the proposal that these transporters are controlled by a chloride-sensitive protein kinase.

NIDDK Grantee News

May 6, 2014

Men with sickle cell disease (SCD) risk developing priapism. Recognizing that SCD is a disease of hypoxia, we investigated the effect of hypoxia on gene expression in corporal smooth muscle (CSM) cells. Rat CSM cells in vitro were treated with CoCl2 or low oxygen tension to mimic hypoxia. Hypoxic conditions increased expression of genes previously associated with priapism in animal models.

NIDDK Grantee News

May 4, 2014

Children with febrile urinary tract infection commonly have vesicoureteral reflux. Because trial results have been limited and inconsistent, the use of antimicrobial prophylaxis to prevent recurrences in children with reflux remains controversial.

NIDDK Grantee News

May 1, 2014

To evaluate feasibility, safety, and efficacy of overnight closed-loop insulin delivery in free-living youth with type 1 diabetes.

NIDDK Grantee News

May 1, 2014

To investigate the cell-intrinsic aging mechanisms that erode the function of somatic stem cells during aging, we have conducted a comprehensive integrated genomic analysis of young and aged cells. We profiled the transcriptome, DNA methylome, and histone modifications of young and old murine hematopoietic stem cells (HSCs).

NIDDK Grantee News

Apr 15, 2014

Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.

NIDDK Grantee News

Apr 1, 2014

The vagus nerve innervates visceral organs providing a link between key metabolic cues and the CNS. However, it is not clear whether vagal neurons can directly respond to changing lipid levels and whether altered “lipid sensing” by the vagus nerve regulates energy balance. In this study, we systematically profiled the expression of all known nuclear receptors in laser-captured nodose ganglion (NG) neurons. In particular, we found PPARγ expression was reduced by high-fat-diet feeding. Deletion of PPARγ in Phox2b neurons promoted HFD-induced thermogenesis that involved the reprograming of white adipocyte into a brown-like adipocyte cell fate.

NIDDK Grantee News

Mar 20, 2014

Nephrons, the functional units of the kidney, develop from progenitor cells (cap mesenchyme [CM]) surrounding the epithelial ureteric bud (UB) tips. Reciprocal signaling between UB and CM induces nephrogenesis and UB branching. Although low nephron number is implicated in hypertension and renal disease, the mechanisms that determine nephron number are obscure. To test the importance of nephron progenitor cell number, we genetically ablated 40% of these cells, asking whether this would limit kidney size and nephron number or whether compensatory mechanisms would allow the developing organ to recover.

NIDDK Grantee News

Feb 14, 2014

Risk of end-stage renal disease (ESRD) in kidney donors has been compared with risk faced by the general population, but the general population represents an unscreened, high-risk comparator. A comparison to similarly screened healthy nondonors would more properly estimate the sequelae of kidney donation.

NIDDK Grantee News

Jan 30, 2014

Reprogramming somatic cells to induced pluripotency by Yamanaka factors is usually slow and inefficient and is thought to be a stochastic process. We identified a privileged somatic cell state, from which acquisition of pluripotency could occur in a nonstochastic manner. Subsets of murine hematopoietic progenitors are privileged whose progeny cells predominantly adopt the pluripotent fate with activation of endogenous Oct4 locus after four to five divisions in reprogramming conditions.

NIDDK Grantee News

Jan 28, 2014

The purpose of this study was to determine the effect of tibial nerve stimulation (TNS) on the micturition reflex. Experiments were conducted in 24 rats under urethane anesthesia.

NIDDK Grantee News

Jan 16, 2014

Coevolution of beneficial microorganisms with the mammalian intestine fundamentally shapes mammalian physiology. Here, we report that the intestinal microbe Bacteroides fragilis modifies the homeostasis of host invariant natural killer T (iNKT) cells by supplementing the host’s endogenous lipid antigen milieu with unique inhibitory sphingolipids. The process occurs early in life and effectively impedes iNKT cell proliferation during neonatal development.

NIDDK Grantee News

Nov 21, 2013

In this study the authors compared responses of human CD4 T cells from recent onset type 1 diabetic (T1D) and control subjects to WE14 and to an enzymatically modified version of this peptide. This work suggests that ChgA is an important target antigen in human T1D subjects and that post–translational modification may play a role in its reactivity and relationship to disease.

NIDDK Grantee News

Sep 19, 2013

Mammals harbour a complex gut microbiome, comprising bacteria that confer immunological, metabolic and neurological benefits1. Despite advances in sequence-based microbial profiling and myriad studies defining microbiome composition during health and disease, little is known about the molecular processes used by symbiotic bacteria to stably colonize the gastrointestinal tract. We sought to define how mammals assemble and maintain the Bacteroides, one of the most numerically prominent genera of the human microbiome.

NIDDK Grantee News

Aug 28, 2013

In adults with chronic kidney disease (CKD), cigarette smoking is associated with an increased risk for CKD progression and transplant failure. In children, secondhand smoke (SHS) exposure has been associated with elevated blood pressure. There are no studies on the prevalence and effect of SHS exposure in CKD.

NIDDK Grantee News

Jul 23, 2013

Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1. This nonshivering thermogenesis is crucial for mammals as a defense against cold and obesity/diabetes.

NIDDK Grantee News

Jul 8, 2013

To better understand the difficulty of looking for a cure, or even effective treatment, one must understand the large and complex nature of the CFTR protein. It is made up of 1,480 amino acids strung together in five three-dimensional strands (called domains) that spin together and fold to act as building blocks for the CFTR protein.

NIDDK Grantee News

Jun 6, 2013

Shwachman-Diamond syndrome (SDS), a rare autosomal-recessive disorder characterized by exocrine pancreatic insufficiency and hematopoietic dysfunction, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene.

NIDDK Grantee News

May 8, 2013

Urinary tract infections (UTIs) are common in women, and recurrence is a major clinical problem. Most UTIs are caused by uropathogenic Escherichia coli (UPEC). UPEC are generally thought to migrate from the gut to the bladder to cause UTI. UPEC form specialized intracellular bacterial communities in the bladder urothelium as part of a pathogenic mechanism to establish a foothold during acute stages of infection. Evolutionarily, such a specific adaptation to the bladder environment would be predicted to result in decreased fitness in other habitats, such as the gut. To examine this prediction, we characterized 45 E. coli strains isolated from the feces and urine of four otherwise healthy women with recurrent UTI.

NIDDK Grantee News

May 1, 2013

[Albert Einstein College of Medicine] While the search continues for the Fountain of Youth, researchers may have found the body’s “fountain of aging”: the brain region known as the hypothalamus. For the first time, scientists at Albert Einstein College of Medicine of Yeshiva University report that the hypothalamus of mice controls aging throughout the body. Their discovery of a specific age-related signaling pathway opens up new strategies for combating diseases of old age and extending lifespan.

NIDDK Grantee News

Apr 25, 2013

[Harvard University] Researchers at the Harvard Stem Cell Institute (HSCI) have discovered a hormone that holds promise for a dramatically more effective treatment of type 2 diabetes, a metabolic illness afflicting an estimated 26 million Americans.

NIDDK Grantee News

Apr 4, 2013

[Mt. Sinai School of Medicine] The Connectivity Map database contains microarray signatures of gene expression derived from approximately 6000 experiments that examined the effects of approximately 1300 single drugs on several human cancer cell lines. We used these data to prioritize pairs of drugs expected to reverse the changes in gene expression observed in the kidneys of a mouse model of HIV-associated nephropathy (Tg26 mice).

NIDDK Grantee News

Mar 31, 2013

[Yale University School of Medicine] Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation.

NIDDK Grantee News

Mar 27, 2013

[Harvard University] Scientists at Harvard may have new hope for people struggling with obesity.

NIDDK Grantee News

Mar 13, 2013

[Indiana University School of Medicine] INDIANAPOLIS -- Scientists say that non-steroidal anti-inflammatory drugs may be a boon to doctors gathering stem cells for transplants to treat patients with blood or bone marrow cancers, including non-Hodgkin’s lymphoma and multiple myeloma. The compounds, known as NSAIDs and which include aspirin, ibuprofen and other painkillers, increased the number of stem and progenitor cells harvested from the blood in animal testing and a small human study, according to work published online Wednesday in the journal Nature by a research team led by Indiana University School of Medicine scientists.

NIDDK Grantee News

Mar 7, 2013

[Harvard Medical School] Helium ion scanning microscopy is a novel imaging technology with the potential to provide sub-nanometer resolution images of uncoated biological tissues. So far, however, it has been used mainly in materials science applications. Here, we took advantage of helium ion microscopy to explore the epithelium of the rat kidney with unsurpassed image quality and detail. In addition, we evaluated different tissue preparation methods for their ability to preserve tissue architecture.

NIDDK Grantee News

Feb 26, 2013

[Johns Hopkins University School of Med] Researchers at The Johns Hopkins University and Yale University have discovered that a specialized receptor, normally found in the nose, is also in blood vessels throughout the body, sensing small molecules created by microbes that line mammalian intestines, and responding to these molecules by increasing blood pressure. The finding suggests that gut bacteria are an integral part of the body’s complex system for maintaining a stable blood pressure.

NIDDK Grantee News

Feb 8, 2013

[Harvard] Bladder urothelium senses and communicates information about bladder fullness. However, the mechanoreceptors that respond to tissue stretch are poorly defined. Integrins are mechanotransducers in other tissues. Therefore, we eliminated β1-integrin selectively in urothelium of mice using Cre-LoxP targeted gene deletion.

NIDDK Grantee News

Jan 30, 2013

[Washington University in St. Louis] A study of young twins in Malawi, in sub-Saharan Africa, finds that bacteria living in the intestine are an underlying cause of a form of severe acute childhood malnutrition.

NIDDK Grantee News

Jan 17, 2013

[UCSF] The risk of kidney failure is greater for people with chronic kidney disease who also have atrial fibrillation, one of the most common forms of irregular heart rhythm in adults, according to a new study by researchers at UCSF and the Kaiser Permanente Northern California Division of Research.

NIDDK Grantee News

Jan 10, 2013

[University of Melbourne and Case Western Reserve University] Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R).

NIDDK Grantee News

Jan 7, 2013

[University of Pennsylvania] For fifty years, one of the few classes of therapeutics effective in reducing the overactive glucose production associated with diabetes has been the biguanides, which includes metformin, the most frequently prescribed drug for type 2 diabetes. The inability of insulin to keep liver glucose output in check is a major factor in the high blood sugar of type 2 diabetes and other diseases of insulin resistance.

NIDDK Grantee News

Nov 19, 2012

[Case Western Reserve University] The objective of our study was to determine the effects of 2 antihypertensive drug dose schedules (PM dose and add-on dose) on nocturnal blood pressure (BP) in comparison with usual therapy (AM dose) in blacks with hypertensive chronic kidney disease and controlled office BP.