Sleep is required to consolidate odor memory and remodel olfactory synapses.

Animals with complex nervous systems demand sleep for memory consolidation and synaptic remodeling. Here, we show that, although the Caenorhabditis elegans nervous system has a limited number of neurons, sleep is necessary for both processes. In addition, it is unclear if, in any system, sleep collaborates with experience to alter synapses between specific neurons and whether this ultimately affects behavior. C. elegans neurons have defined connections and well-described contributions to behavior. We show that spaced odor-training and post-training sleep induce long-term memory. Memory consolidation, but not acquisition, requires a pair of interneurons, the AIYs, which play a role in odor-seeking behavior. In worms that consolidate memory, both sleep and odor conditioning are required to diminish inhibitory synaptic connections between the AWC chemosensory neurons and the AIYs. Thus, we demonstrate in a living organism that sleep is required for events immediately after training that drive memory consolidation and alter synaptic structures.

Production of polyhydroxyalkanoate (PHA) copolymer from food waste using mixed culture for carboxylate production and Pseudomonas putida for PHA synthesis.

Production of polyhydroxyalkanoates (PHAs) with high concentration of carboxylate, that was accumulated from solid state fermentation (SSF) of food waste (FW), was tested using Pseudomonas putida strain KT2440. Mixed-culture SSF of FW supplied in a high concentration of carboxylate, which caused a high PHA production of 0.56 g PHA/g CDM under nutrients control. Interestingly, this high PHA fraction in CDM was almost constant at 0.55 g PHA/g CDM even under high nutrients concentration (25 mM NH4+), probably due to high reducing power maintained by high carboxylate concentration. PHA characterization indicated that the dominant PHA building block produced was 3-hydroxybutyrate, followed by 3-hydroxy-2-methylvalerate and 3-hydroxyhenxanoate. Carboxylate profiles before and after PHA production suggested that acetate, butyrate, and propionate were the main precursors to PHA via several metabolic pathways. Our result support that mixed culture SSF of FW for high concentration carboxylate and P. putida for PHA production enables sustainable production of PHA in cost-effective manners.

ß-Sitosterol & quercetin enhances brain development in iodine deficient rat models.

BACKGROUND: Recently thyroid hormone studies on brain growth, development and activity are regaining popularity. Thyroid hormones have long been believed to play critical role in mammalian brain growth and maturation regulating facets of neuronal cell growth, proliferation and differentiation and further signaling and glial cell differentiation. Deficiency of these hormones in mother leads to mental retardation in the subsequent offspring's. METHODS: In this presented study, brain development of iodine deficient rat models created through deficiency in feeding, mating and further selection. Young adult female wistar rats were induced with iodine deficiency and then mated with healthy male rats. These pregnant hypothyroid induced females were treated with ß-sitosterol (150 mg/kg/day) and quercetin (150 mg/kg/day) alone and in combination for whole gestation period. Analysis were dealt with the genetic and histological studies of the pups brain. PCR based RNA analysis was also carried out. Histology was done using eosin and hematoxylin. RESULTS: Positive impacts of the ß-sitosterol and quercetin on the iodine deficient brain were observed upon histological and PCR analysis. Altogether, the analysis proves that combined doses of ß-sitosterol and quercetin for normal brain development in iodine deficient infants hence can be potentially applied as therapeutics in iodine deficiency circumstances.

ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells.

In the mammalian inner ear, bicellular and tricellular tight junctions (tTJs) seal the paracellular space between epithelial cells. Tricellulin and immunoglobulin-like (Ig-like) domain containing receptor 1 (ILDR1, also referred to as angulin-2) localize to tTJs of the sensory and non-sensory epithelia in the organ of Corti and vestibular end organs. Recessive mutations of TRIC (DFNB49) encoding tricellulin and ILDR1 (DFNB42) cause human nonsyndromic deafness. However, the pathophysiology of DFNB42 deafness remains unknown. ILDR1 was recently reported to be a lipoprotein receptor mediating the secretion of the fat-stimulated cholecystokinin (CCK) hormone in the small intestine, while ILDR1 in EpH4 mouse mammary epithelial cells in vitro was shown to recruit tricellulin to tTJs. Here we show that two different mouse Ildr1 mutant alleles have early-onset severe deafness associated with a rapid degeneration of cochlear hair cells (HCs) but have a normal endocochlear potential. ILDR1 is not required for recruitment of tricellulin to tTJs in the cochlea in vivo; however, tricellulin becomes mislocalized in the inner ear sensory epithelia of ILDR1 null mice after the first postnatal week. As revealed by freeze-fracture electron microscopy, ILDR1 contributes to the ultrastructure of inner ear tTJs. Taken together, our data provide insight into the pathophysiology of human DFNB42 deafness and demonstrate that ILDR1 is crucial for normal hearing by maintaining the structural and functional integrity of tTJs, which are critical for the survival of auditory neurosensory HCs.

Positive and negative gustatory inputs affect Drosophila lifespan partly in parallel to dFOXO signaling.

In Caenorhabditis elegans, a subset of gustatory neurons, as well as olfactory neurons, shortens lifespan, whereas a different subset of gustatory neurons lengthens it. Recently, the lifespan-shortening effect of olfactory neurons has been reported to be conserved in Drosophila. Here we show that the Drosophila gustatory system also affects lifespan in a bidirectional manner. We find that taste inputs shorten lifespan through inhibition of the insulin pathway effector dFOXO, whereas other taste inputs lengthen lifespan in parallel to this pathway. We also note that the gustatory influence on lifespan does not necessarily depend on food intake levels. Finally, we identify the nature of some of the taste inputs that could shorten versus lengthen lifespan. Together our data suggest that different gustatory cues can modulate the activities of distinct signaling pathways, including different insulin-like peptides, to promote physiological changes that ultimately affect lifespan.

Single-Stage Operation of Hybrid Dark-Photo Fermentation to Enhance Biohydrogen Production through Regulation of System Redox Condition: Evaluation with Real-Field Wastewater.

Harnessing hydrogen competently through wastewater treatment using a particular class of biocatalyst is indeed a challenging issue. Therefore, biohydrogen potential of real-field wastewater was evaluated by hybrid fermentative process in a single-stage process. The cumulative hydrogen production (CHP) was observed to be higher with distillery wastewater (271 mL) than with dairy wastewater (248 mL). Besides H2 production, the hybrid process was found to be effective in wastewater treatment. The chemical oxygen demand (COD) removal efficiency was found higher in distillery wastewater (56%) than in dairy wastewater (45%). Co-culturing photo-bacterial flora assisted in removal of volatile fatty acids (VFA) wherein 63% in distillery wastewater and 68% in case of dairy wastewater. Voltammograms illustrated dominant reduction current and low cathodic Tafel slopes supported H2 production. Overall, the augmented dark-photo fermentation system (ADPFS) showed better performance than the control dark fermentation system (DFS). This kind of holistic approach is explicitly viable for practical scale-up operation.

CD36-dependent signaling mediates fatty acid-induced gut release of secretin and cholecystokinin.

Genetic variants in the fatty acid (FA) translocase FAT/CD36 associate with abnormal postprandial lipids and influence risk for the metabolic syndrome. CD36 is abundant on apical enterocyte membranes in the proximal small intestine, where it facilitates FA uptake and FA-initiated signaling. We explored whether CD36 signaling influences FA-mediated secretion of cholecystokinin (CCK) and secretin, peptides released by enteroendocrine cells (EECs) in the duodenum/jejunum, which regulate events important for fat digestion and homeostasis. CD36 was immunodetected on apical membranes of secretin- and CCK-positive EECs and colocalized with cytosolic granules. Intragastric lipid administration to CD36 mice released less secretin (-60%) and CCK (-50%) compared with wild-type mice. Likewise, diminished secretin and CCK responses to FA were observed with CD36 intestinal segments in vitro, arguing against influence of alterations in fat absorption. Signaling mechanisms underlying peptide release were examined in STC-1 cells stably expressing human CD36 or a signaling-impaired mutant (CD36K/A). FA stimulation of cells expressing CD36 (vs. vector or CD36K/A) released more secretin (3.5- to 4-fold) and CCK (2- to 3-fold), generated more cAMP (2- to 2.5-fold), and enhanced protein kinase A activation. Protein kinase A inhibition (H-89) blunted secretin (80%) but not CCK release, which was reduced (50%) by blocking of calmodulin kinase II (KN-62). Coculture of STC-1 cells with Caco-2 cells stably expressing CD36 did not alter secretin or CCK release, consistent with a minimal effect of adjacent enterocytes. In summary, CD36 is a major mediator of FA-induced release of CCK and secretin. These peptides contribute to the role of CD36 in fat absorption and to its pleiotropic metabolic effects.

Recent advances in the regulation of pancreatic secretion.

PURPOSE OF REVIEW: This review highlights recent progress made in the field of pancreatic secretion. RECENT FINDINGS: This review summarizes a number of recent studies demonstrating the intracellular pathways by which hormones and neural inputs regulate pancreatic exocrine and endocrine secretion. In particular, the effects of vasoactive intestinal peptide and secretin on intra-acinar cell adenosine 3',5'-cyclic monophosphate are explored. Considerable attention is paid to regulation of ß-cell function and includes studies detailing the mechanisms of regulation of insulin by somatostatin, serotonin, and melanocortins. These studies emphasize the critical role that hormonal, paracrine, and neural factors play in glucose homeostasis. SUMMARY: Exocrine and endocrine pancreatic secretions are regulated by hormonal and neural mechanisms, and understanding these pathways will enable the discovery and design of new and improved therapies for prevention and control of diabetes and perhaps exocrine insufficiency.

Modulation of pancreatic exocrine and endocrine secretion.

PURPOSE OF REVIEW: Recent advances in the regulation of pancreatic secretion by secretagogues, modulatory proteins and neural pathways are discussed. RECENT FINDINGS: Downstream events involved in secretagogue stimulation of pancreatic secretion have been elucidated through characterization of the Src kinase pathway. An additional mechanism regulating vagus nerve effects on the pancreas involves Group II and III metabotropic glutamate receptors that are located presynaptically on certain vagal pancreas-projecting neurons. Hypothalamic neurons perceive glucose and regulate insulin release by direct communication with islets, and activation of proopiomelanocortin neurons by leptin enhances insulin secretion and modulates glucose but not energy homeostasis. Ghrelin and somatostatin mediate glucose-stimulated insulin secretion by differential receptor signaling that is dependent on the amount of ghrelin and state of receptor heterodimerization. Endoplasmic reticulum (ER) stress and loss-of-function mutations of a key ER stress protein are associated with disruption of membrane translocation and reduction in insulin secretion. The importance of hormones, neuropeptides, amino acids, cytokines and regulatory proteins in pancreatic secretion and the pathophysiology of type 2 diabetes are also discussed. SUMMARY: The biomolecular pathways regulating pancreatic secretions are still not fully understood. New secretagogues and mechanisms continue to be identified and this information will aid in drug discovery and development of new and improved therapy for pancreatic disorders.

Gut mucosal cells transfer α-synuclein to the vagus nerve.

Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease (PD). While past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut to brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of the gut mucosa express α-synuclein. In this study, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from gut epithelial cells in organoids co-cultured with vagal nodose neurons that are otherwise devoid of α-synuclein expression. In intact mice that express pathological human α-synuclein, but no mouse α-synuclein, α-synuclein fibril templating activity emerges in α-synuclein seeded fibril aggregation assays in tissues from the gut, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfers to the vagus nerve and to the dorsal motor nucleus. Subdiaphragmatic vagotomy prior to the induction of α-synuclein expression in the gut epithelial cells effectively protects the hindbrain from the emergence of α-synuclein fibril templating activity. Overall, these findings highlight a novel potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.

Gut mucosal cells transfer α-synuclein to the vagus nerve.

Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease. Although past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut-to-brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of intestinal mucosa express α-synuclein. Here, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from epithelial cells in organoids to cocultured nodose neurons devoid of α-synuclein. In mice expressing human α-synuclein, but no mouse α-synuclein, α-synuclein fibril-templating activity emerged in α-synuclein-seeded fibril aggregation assays in intestine, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfered to the vagus nerve and dorsal motor nucleus. Subdiaphragmatic vagotomy prior to induction of α-synuclein expression in intestinal epithelial cells effectively protected the hindbrain from emergence of α-synuclein fibril-templating activity. Overall, these findings highlight a potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.

Specific sensory neurons and insulin-like peptides modulate food type-dependent oogenesis and fertilization in Caenorhabditis elegans.

An animal's responses to environmental cues are critical for its reproductive program. Thus, a mechanism that allows the animal to sense and adjust to its environment should make for a more efficient reproductive physiology. Here, we demonstrate that in Caenorhabditis elegans specific sensory neurons influence onset of oogenesis through insulin signaling in response to food-derived cues. The chemosensory neurons ASJ modulate oogenesis onset through the insulin-like peptide (ILP) INS-6. In contrast, other sensory neurons, the olfactory neurons AWA, regulate food type-dependent differences in C. elegans fertilization rates, but not onset of oogenesis. AWA modulates fertilization rates at least partly in parallel to insulin receptor signaling, since the insulin receptor DAF-2 regulates fertilization independently of food type, which requires ILPs other than INS-6. Together our findings suggest that optimal reproduction requires the integration of diverse food-derived inputs through multiple neuronal signals acting on the C. elegans germline.

Neurohormonal regulation of pancreatic secretion.

PURPOSE OF REVIEW: Recent advances in the regulation of pancreatic secretion by neural and hormonal mechanisms are discussed in this review. RECENT FINDINGS: It has been shown that the multidrug-resistance protein MRP4 may play a role in the efflux of cAMP from exocrine cells and neurokinin receptors are important in substance P-mediated inhibition of ductal bicarbonate secretion. Leptin attenuates glucagon secretion by downregulating glucagon gene expression, whereas ghrelin upregulates glucagon release by elevating intracellular calcium and phosphorylation of extracellular signal-regulated kinase (ERK). Cytokine interleukin 6 is secreted from muscles during exercise and induces the release of GLP-1 that stimulates insulin secretion. Osteocalcin and 17ß-estradiol mediate their effects through G protein-coupled receptors, resulting in ERK phosphorylation and activation of protein kinase-dependent signaling pathways. Melatonin and ghrelin inhibit insulin secretion through inhibitory G proteins, whereas aldosterone may attenuate insulin secretion by increasing oxidative stress in islets cells. Finally, the pattern of innervation of human pancreatic islets has been examined and demonstrated to be very different from that in the mouse. SUMMARY: Many different receptors and signaling pathways govern the complex biology of pancreatic secretion. Elucidation of these cellular mechanisms will aid in drug discovery and treatment as well as prevention of pancreatic diseases.

Nitrite reduction using a membrane biofilm reactor (MBfR) in a hypoxic environment with dilute methane under low pressures.

Methane-based membrane biofilm reactors (MBfRs) can be an effective solution for nitrogen control in wastewater, but there is limited information on nitrite reduction for dilute wastewater (e.g., municipal wastewater) in hypoxic MBfRs. This study assessed the impacts of dilute (20 %), low-pressure methane (0.35-2.41 kPa) applied to MBfRs at hydraulic retention times (HRTs) of 2-12 h on nitrite removals, dissolved methane concentrations, and the resulting changes in the microbial community. High nitrite flux along with rapid and virtually complete (>99 %) nitrite removals were observed at methane pressures of 1.03-2.41 kPa at HRTs above 4 h, despite the use of diluted methane gas for the MBfR. The lowest methane pressure (0.35 kPa) was also able to achieve up to 98 % nitrite removals but required HRTs of up to 12 h. All scenarios had low dissolved methane concentrations (<10 mg/L), indicating that dilute methane at low supply pressures can effectively remove nitrite while meeting dissolved methane guidelines in treated effluent. Methylococcus genus was the key bacterium in MBfR biofilm grown at different HRTs and methane pressures, along with Methylocystis and other heterotrophic denitrifiers (Terrimonas and Hyphomicrobium). This study indicates that methane-based denitrification MBfRs can be a valuable tool to meet nitrogen limits for dilute wastewater coupled to partial nitrification, while limiting the release of methane to the environment.

Gut microbiota interactions with anti-diabetic medications and pathogenesis of type 2 diabetes mellitus.

Microorganisms including bacteria, viruses, protozoa, and fungi living in the gastrointestinal tract are collectively known as the gut microbiota. Dysbiosis is the imbalance in microbial composition on or inside the body relative to healthy state. Altered Firmicutes to Bacteroidetes ratio and decreased abundance of Akkermansia muciniphila are the predominant gut dysbiosis associated with the pathogenesis of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Pathophysiological mechanisms linking gut dysbiosis, and metabolic diseases and their complications include altered metabolism of short-chain fatty acids and bile acids, interaction with gut hormones, increased gut microbial metabolite trimethylamine-N-oxide, bacterial translocation/Leaky gut syndrome, and endotoxin production such as lipopolysaccharides. The association between the gut microbiota and glycemic agents, however, is much less understood and is the growing focus of research and conversation. Recent studies suggest that the gut microbiota and anti-diabetic medications are interdependent on each other, meaning that while anti-diabetic medications alter the gut microbiota, the gut microbiota also alters the efficacy of anti-diabetic medications. With increasing evidence regarding the significance of gut microbiota, it is imperative to review the role of gut microbiota in the pathogenesis of T2DM. This review also discusses the interaction between gut microbiota and the various medications used in the treatment of T2DM.

Real-time continuous glucose monitoring improves glycemic control and reduces hypoglycemia: Real-world data.

AIM: To study the effect of real time continuous glucose monitor (RT-CGM) use on glycemic parameters in patients with diabetes mellitus (DM) in real world practice. METHODS: We retrospectively studied 91 adult subjects with DM who had been using Dexcom™ RT-CGM. Two consecutive hemoglobin A1c (HbA1c), both prior to and after at least 3 months of RT-CGM initiation, were collected. A total of 31 subjects completed a 5-14 day user blinded CGM using a Freestyle Libre™ prior to RT-CGM initiation. The first two week period following at least 3 months use of RT-CGM was analyzed for CGM metrics. RESULTS: A total of 51.6 % of subjects had T1DM, 34.1 % used continuous subcutaneous insulin infusion (CSII), and 62.6 % had DM for > 10 years. Both HbA1c obtained following RT-CGM initiation decreased significantly compared to baseline (8.11 + 1.47% vs 7.69 + 1.25 %; P = 0.002 & 8.16 + 1.51 % vs 7.62 + 1.06 %; P = 0.001). Subjects with baseline HbA1c > 7.0 % showed even more robust reduction in both HbA1c after RT-CGM initiation (8.74 + 1.24 % vs 7.99 + 1.22 %; P = 0.000 & 8.74 + 1.32 % vs 7.85 + 1.07 %; P = 0.001). On comparison of CGM metrics, there was a significant reduction in time spent in hypoglycemia (sugars < 70 mg/dl) including severe hypoglycemia (sugars < 54 mg/dl) after initiation of the RT-CGM (9.16 + 8.68 % vs 1.29 + 2.21 %; P = <0.001 & 4.58 + 5.43 % vs 0.28 + 0.58 %; P = <0.001). CoV of glucose was also decreased significantly (39.61 + 9.36 % vs 31.06 + 6.74 %; P = <0.001) with RT- CGM use. CONCLUSION: RT-CGM use for at least 3 months in patients with DM results in meaningful HbA1c reductions with stable glycemic control without increasing the risk of hypoglycemia.

Ildr1 gene deletion protects against diet-induced obesity and hyperglycemia.

OBJECTIVE: Immunoglobulin-like Domain-Containing Receptor 1 (ILDR1) is expressed on nutrient sensing cholecystokinin-positive enteroendocrine cells of the gastrointestinal tract and it has the unique ability to induce fat-mediated CCK secretion. However, the role of ILDR1 in CCK-mediated regulation of satiety is unknown. In this study, we examined the effects of ILDR1 on food intake and metabolic activity using mice with genetically-deleted Ildr1. METHODS: The expression of ILDR1 in murine tissues and the measurement of adipocyte cell size were evaluated by light and fluorescence confocal microscopy. The effects of Ildr1 deletion on mouse metabolism were quantitated using CLAMS chambers and by targeted metabolomics assays of multiple tissues. Hormone levels were measured by ELISA. The effects of Ildr1 gene deletion on glucose and insulin levels were determined using in vivo oral glucose tolerance, meal tolerance, and insulin tolerance tests, as well as ex vivo islet perifusion. RESULTS: ILDR1 is expressed in a wide range of tissues. Analysis of metabolic data revealed that although Ildr1-/- mice consumed more food than wild-type littermates, they gained less weight on a high fat diet and exhibited increased metabolic activity. Adipocytes in Ildr1-/- mice were significantly smaller than in wild-type mice fed either low or high fat diets. ILDR1 was expressed in both alpha and beta cells of pancreatic islets. Based on oral glucose and mixed meal tolerance tests, Ildr1-/- mice were more effective at lowering post-prandial glucose levels, had improved insulin sensitivity, and glucose-regulated insulin secretion was enhanced in mice lacking ILDR1. CONCLUSION: Ildr1 loss significantly modified metabolic activity in these mutant mice. While Ildr1 gene deletion increased high fat food intake, it reduced weight gain and improved glucose tolerance. These findings indicate that ILDR1 modulates metabolic responses to feeding in mice.

Amino acids stimulate cholecystokinin release through the Ca2+-sensing receptor.

Cholecystokinin (CCK) is produced by discrete endocrine cells in the proximal small intestine and is released following the ingestion of food. CCK is the primary hormone responsible for gallbladder contraction and has potent effects on pancreatic secretion, gastric emptying, and satiety. In addition to fats, digested proteins and aromatic amino acids are major stimulants of CCK release. However, the cellular mechanism by which amino acids affect CCK secretion is unknown. The Ca(2+)-sensing receptor (CaSR) that was originally identified on parathyroid cells is not only sensitive to extracellular Ca(2+) but is activated by extracellular aromatic amino acids. It has been postulated that this receptor may be involved in gastrointestinal hormone secretion. Using transgenic mice expressing a CCK promoter driven/enhanced green fluorescent protein (GFP) transgene, we have been able to identify and purify viable intestinal CCK cells. Intestinal mucosal CCK cells were enriched >200-fold by fluorescence-activated cell sorting. These cells were then used for real-time PCR identification of CaSR. Immunohistochemical staining with an antibody specific for CaSR confirmed colocalization of CaSR to CCK cells. In isolated CCK cells loaded with a Ca(2+)-sensitive dye, the amino acids phenylalanine and tryptophan, but not nonaromatic amino acids, caused an increase in intracellular Ca(2+) ([Ca(2+)](i)). The increase in [Ca(2+)](i) was blocked by the CaSR inhibitor Calhex 231. Phenylalanine and tryptophan stimulated CCK release from intestinal CCK cells, and this stimulation was also blocked by CaSR inhibition. Electrophysiological recordings from isolated CCK-GFP cells revealed these cells to possess a predominant outwardly rectifying potassium current. Administration of phenylalanine inhibited basal K(+) channel activity and caused CCK cell depolarization, consistent with changes necessary for hormone secretion. These findings indicate that amino acids have a direct effect on CCK cells to stimulate CCK release by activating CaSR and suggest that CaSR is the physiological mechanism through which amino acids regulate CCK secretion.

Recent advances in pancreatic endocrine and exocrine secretion.

PURPOSE OF REVIEW: This review presents recent advancements in the mechanisms by which integrated signaling mechanisms elicit and regulate pancreatic endocrine and exocrine secretion. RECENT FINDINGS: Cholecystokinin (CCK) can stimulate exocrine secretion by acting directly on neurons located in the dorsal motor of the vagus or indirectly by acting on pancreatic stellate cells. The importance of small GTPases such as RhoA and Rac1 in CCK-induced pancreatic secretion is also described. Ghrelin attenuates insulin secretion through the AMP-activated protein kinase-uncoupling protein 2 pathway. An exciting new report describes that leptin can influence insulin release by osteoclastin, a hormone produced by osteoblasts. This finding adds a new layer of complexity in the regulation of insulin secretion with implications for glucose and energy homeostasis. In addition, leptin also mediates insulin secretion through the sympathetic system and via pro-opiomelanocortin neurons, which could serve as the cross-road for leptin and melanocortin signaling pathways. Recent reports on the action of numerous other regulators such as atrial natriuretic peptide, neurotensin, and orexin B are also discussed. SUMMARY: The pancreas is an extremely complex gland. Elucidation of the secretory and regulatory pathways that control pancreatic secretion will aid in the development of treatment for diseases such as pancreatitis, diabetes, and obesity.

Effect of serum zinc and copper levels on insulin secretion, insulin resistance and pancreatic ß cell dysfunction in US adults: Findings from the National Health and Nutrition Examination Survey (NHANES) 2011-2012.

AIM: To compare zinc (Zn) and copper (Cu) levels in US adults with normoglycemia, prediabetes and diabetes, and study the association of serum Zn and Cu levels with pancreatic ß cell insulin secretion, pancreatic dysfunction and insulin resistance in US adults with normoglycemia and prediabetes. METHOD: Homeostatic Model Assessment (HOMA2) calculator was used to compute estimates of steady state ß cell insulin secretion (HOMA2-B), peripheral insulin sensitivity (HOMA2-S), insulin resistance (HOMA-IR), and disposition index (HOMA-DI) in 804 adult individuals from the National Health and Nutrition Examination Survey (NHANES 2011-2012). RESULTS: There was no significant difference between serum Zn and Cu levels among subjects with normoglycemia, prediabetes, and diabetes. After adjusting for multiple possible confounders, higher serum Zn concentrations were associated with lower ß cell insulin secretion (HOMA2-B; p = 0.01) and lower insulin resistance (HOMA-IR; p = 0.04) in the prediabetic subjects. In normoglycemic group, higher serum Zn levels were associated with improved pancreatic function (HOMA-DI; P = 0.02). On the other hand, higher serum Cu levels were associated with increased ß cell insulin secretion (HOMA2-B, P = 0.03) only in the subjects with prediabetes. CONCLUSION: These findings support the need for further studies to investigate the role of trace elements in diabetes pathogenesis.