BMAL1 Regulates Glucokinase Expression Through E-Box Elements In Vitro.

The organization of a circadian system includes an endogenous pacemaker system, input pathways for environmental synchronizing (entraining) stimuli, and output pathways through which the clock regulates physiological and behavioral processes, for example, the glucose-sensing mechanism in the liver. The liver is the central regulator of metabolism and one of our peripherals clocks. In mammals, central to this pacemaker are the transcription factors Circadian Locomotor Output Cycles Kaput (CLOCK) and BMAL1 (Brain and Muscle ARNT-Like 1).

Portal milieu and the interplay of multiple antidiabetic effects after gastric bypass surgery.

Diabetes is a worldwide health problem. Roux-en-Y gastric bypass (RYGB) leads to rapid resolution of type 2 diabetes (T2D). Decreased hepatic insulin resistance is key, but underlying mechanisms are poorly understood.

Effect of Portal Glucose Sensing on Systemic Glucose Levels in SD and ZDF Rats.

Background: The global epidemic of Type-2-Diabetes (T2D) highlights the need for novel therapeutic targets and agents. Roux-en-Y-Gastric-Bypass (RYGB) is the most effective treatment. Studies investigating the mechanisms of RYGB suggest a role for post-operative changes in portal glucose levels.

Foregut exclusion disrupts intestinal glucose sensing and alters portal nutrient and hormonal milieu.

The antidiabetes effects of Roux-en-Y gastric bypass (RYGB) are well-known, but the underlying mechanisms remain unclear. Isolating the proximal small intestine, and in particular its luminal glucose sensors, from the nutrient stream has been proposed as a critical change, but the pathways involved are unclear. In a rodent model, we tested the effects of isolating and then stimulating a segment of proximal intestine using glucose analogs to examine their impact on glucose absorption (Gabsorp) and hormone secretion after a glucose bolus into the distal jejunum.

Insulin cessation and diabetes remission after bariatric surgery in adults with insulin-treated type 2 diabetes.

Objective: The impact of bariatric surgeries on insulin-treated type 2 diabetes (I-T2D) in the general population is largely undocumented. We assessed changes in insulin treatment after bariatric surgery in a large cohort of I-T2D patients, comparing Roux-en-Y gastric bypass surgery (RYGB) with laparoscopic adjustable gastric banding (LAGB), controlling for differences in weight loss between procedures.

Research Design And Methods: Of 113,638 adult surgical patients in the Bariatric Outcomes Longitudinal Database (BOLD), 10% had I-T2D.

Intestinal sweet-sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery.

Studies suggest that improvements in type 2 diabetes (T2D) post- Roux-en-Y gastric bypass (RYGB) surgery are attributable to decreased intestinal glucose absorption capacity mediated by exclusion of sweet taste-sensing pathways in isolated proximal bowel. We probed these pathways in rat models that had undergone RYGB with catheter placement in the biliopancreatic (BP) limb to permit post-RYGB exposure of isolated bowel to sweet taste stimulants. Lean Sprague Dawley (n = 13) and obese Zucker diabetic fatty rats (n = 15) underwent RYGB with BP catheter placement.

Role of growth factors in control of pancreatic beta cell mass: focus on betatrophin.

Purpose Of Review: Betatrophin is a newly described hormone, which potently stimulates beta cell replication in mice. This discovery has engendered great hope that it could prove clinically important in the treatment of type 1 and type 2 diabetes.

Recent Findings: Betatrophin, a 198-amino acid protein secreted by liver and adipose tissue, stimulates growth of pancreatic beta cell mass in insulin-resistant mice.

Disrupted circadian rhythmicity of the intestinal glucose transporter SGLT1 in Zucker diabetic fatty rats.

Background: Intestinal absorptive capacity shows a circadian rhythm synchronized with eating patterns. Disrupting these coordinated rhythms, e.g.

Reconciliation of sequence data and updated annotation of the genome of Agrobacterium tumefaciens C58, and distribution of a linear chromosome in the genus Agrobacterium.

Two groups independently sequenced the Agrobacterium tumefaciens C58 genome in 2001. We report here consolidation of these sequences, updated annotation, and additional analysis of the evolutionary history of the linear chromosome, which is apparently limited to the biovar I group of Agrobacterium.

Comparison of intact Arabidopsis thaliana leaf transcript profiles during treatment with inhibitors of mitochondrial electron transport and TCA cycle.

Plant mitochondria signal to the nucleus leading to altered transcription of nuclear genes by a process called mitochondrial retrograde regulation (MRR). MRR is implicated in metabolic homeostasis and responses to stress conditions. Mitochondrial reactive oxygen species (mtROS) are a MRR signaling component, but whether all MRR requires ROS is not established.

PER1 modulates SGLT1 transcription in vitro independent of E-box status.

Background And Aims: The intestine demonstrates profound circadian rhythmicity in glucose absorption in rodents, mediated entirely by rhythmicity in the transcription, translation, and function of the sodium glucose co-transporter SGLT1 (Slc5a1). Clock genes are rhythmic in the intestine and have been implicated in the regulation of rhythmicity of other intestinal genes; however, their role in the regulation of SGLT1 is unknown. We investigated the effects of one clock gene, PER1, on SGLT1 transcription in vitro.

Upregulation of proapoptotic microRNA mir-125a after massive small bowel resection in rats.

Objective: Short bowel syndrome remains a condition of high morbidity and mortality, and current therapeutic options carry significant side effects. To identify new treatments we focused on postresection changes in microRNAs--short noncoding RNAs, which suppress target genes--and suggest a previously undiscovered role for microRNA-125a (mir-125a) in intestinal adaptation.

Methods: Rats underwent either 80% massive small bowel resection or transection and were harvested after 48 hours.

Circadian clock genes and implications for intestinal nutrient uptake.

There has recently been increasing interest in the phenomenon of circadian rhythmicity. We have used circadian rhythms as a means to understanding the regulation of glucose absorption in the intestine. We and others have previously demonstrated rhythmicity in intestinal glucose uptake, mediated by rhythmicity in the expression of the sodium glucose cotransporter 1.

Boosting native promoter activities with non-adjacent response-element multimers.

Effective gene therapy requires regulated gene expression and vector safety. We developed a strategy to exponentially increase native promoter activity while retaining inherent regulation by inserting multi-copy response elements (REs) into non-adjacent locations. For the hepatocyte nuclear factor (HNF) 4α-dependent Hnf1a (MODY3) gene, HNF4α stimulation increased from 5- to 90-fold by inserting 3 additional HNF4α REs (H4REs).

MicroRNA mir-16 is anti-proliferative in enterocytes and exhibits diurnal rhythmicity in intestinal crypts.

Background And Aims: The intestine exhibits profound diurnal rhythms in function and morphology, in part due to changes in enterocyte proliferation. The regulatory mechanisms behind these rhythms remain largely unknown. We hypothesized that microRNAs are involved in mediating these rhythms, and studied the role of microRNAs specifically in modulating intestinal proliferation.

Rapid upregulation of sodium-glucose transporter SGLT1 in response to intestinal sweet taste stimulation.

Objective: We set out to examine the short-term regulation of the intestinal sodium/glucose cotransporter SGLT1 by its substrate glucose and sweet taste analogs.

Summary Background Data: Intestinal SGLT1 is a putative target for antidiabetic therapy; however, its physiological regulation is incompletely understood, limiting its application as a pharmacological target. While it is clearly regulated by dietary composition over a period of days, its short-term regulation by nutrients is unknown.

Restricted feeding phase shifts clock gene and sodium glucose cotransporter 1 (SGLT1) expression in rats.

The intestine exhibits striking diurnal rhythmicity in glucose uptake, mediated by the sodium glucose cotransporter (SGLT1); however, regulatory pathways for these rhythms remain incompletely characterized. We hypothesized that SGLT1 rhythmicity is linked to the circadian clock. To investigate this, we examined rhythmicity of Sglt1 and individual clock genes in rats that consumed food ad libitum (AL).

Circadian variation in intestinal dihydropyrimidine dehydrogenase (DPD) expression: a potential mechanism for benefits of 5FU chrono-chemotherapy.

Background: 5-fluorouracil (5FU) is associated with significant GI side-effects. Randomized trials have shown a 50% reduction in severe diarrhea with chrono-chemotherapy versus conventional regimens at similar doses. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in 5FU breakdown.

Novel P2 promoter-derived HNF4alpha isoforms with different N-terminus generated by alternate exon insertion.

Hepatocyte nuclear factor 4alpha (HNF4alpha) is a critical transcription factor for pancreas and liver development and functions in islet beta cells to maintain glucose homeostasis. Mutations in the human HNF4A gene lead to maturity onset diabetes of the young (MODY1) and polymorphisms are associated with increased risk for type 2 diabetes mellitus (T2DM). Expression of six HNF4alpha variants, three each from two developmentally regulated promoters, has been firmly established.

Diurnal expression of the rat intestinal sodium-glucose cotransporter 1 (SGLT1) is independent of local luminal factors.

Background: The intestinal sodium-glucose cotransporter 1 (SGLT1) is responsible for all secondary active transport of dietary glucose, and it presents a potential therapeutic target for obesity and diabetes. SGLT1 expression varies with a profound diurnal rhythm, matching expression to nutrient intake. The mechanisms entraining this rhythm remain unknown.

Diurnal rhythmicity in the transcription of jejunal drug transporters.

Intestinal drug efflux proteins play a major role in the pharmacokinetics of many drugs. We assessed diurnal rhythmicity in the expression of ten major drug transporters. We acquired male Sprague-Dawley rats and harvested jejunal mucosa at 3-h intervals across a 24-h period.

Defining the transcriptional regulation of the intestinal sodium-glucose cotransporter using RNA-interference mediated gene silencing.

Background: The sodium glucose cotransporter (SGLT1) is responsible for all active intestinal glucose uptake. Hepatocyte nuclear factors 1 alpha and beta (HNF 1 alpha and HNF 1 beta) activate the SGLT1 promoter, whereas GATA-binding protein 5 (GATA-5) and caudal-type homeobox protein 2 (CDX2) regulate transcription of other intestinal genes. We investigated SGLT1 regulation by these transcription factors using promoter studies and RNA interference.

Expression of HNF4alpha variants in pancreatic islets and Ins-1 beta cells.

Background: Hepatocyte nuclear factor (HNF4alpha) is a nuclear receptor essential for endodermal differentiation and cell functions in the adult pancreas, liver, and other tissues. Mutations in the HNF4A gene cause MODY1. Up to nine protein variants arise from two developmentally regulated promoters.

Diurnal rhythmicity in glucose uptake is mediated by temporal periodicity in the expression of the sodium-glucose cotransporter (SGLT1).

Background: Intestinal transport exhibits distinct diurnal rhythmicity. Understanding the mechanisms behind this may reveal new therapeutic strategies to modulate intestinal function in disease states such as diabetes and obesity, as well as short bowel syndrome. Although diurnal rhythms have been amply documented for several intestinal transporters, the complexity of transepithelial transport has precluded definitive attribution of rhythmicity in glucose uptake to a single transporter.