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Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca-Regulated Genes.
Stancill JS, Cartailler JP, Clayton HW, O'Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA
(2017) Diabetes 66: 2175-2187
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Calcium, Calcium Signaling, Cell Adhesion, Cell Cycle Proteins, Cell Lineage, Cell Polarity, Gene Expression, Gene Expression Regulation, Insulin-Secreting Cells, KATP Channels, Mice, Pancreatic Polypeptide-Secreting Cells, S100 Calcium Binding Protein A6, S100 Calcium-Binding Protein A4, S100 Proteins, Sulfonylurea Receptors
Show Abstract · Added June 2, 2017
We used mice lacking , a key component of the β-cell K-channel, to analyze the effects of a sustained elevation in the intracellular Ca concentration ([Ca]) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lacking into pancreatic polypeptide cells but not to α- or δ-cells. RNA-sequencing analysis of FACS-purified β-cells confirmed an increase in gene expression and revealed altered expression of more than 4,200 genes, many of which are involved in Ca signaling, the maintenance of β-cell identity, and cell adhesion. The expression of and , two highly upregulated genes, is closely correlated with membrane depolarization, suggesting their use as markers for an increase in [Ca] Moreover, a bioinformatics analysis predicts that many of the dysregulated genes are regulated by common transcription factors, one of which, , was confirmed to be directly controlled by Ca influx in β-cells. Interestingly, among the upregulated genes is , a putative marker of β-cell dedifferentiation, and other genes associated with β-cell failure. Taken together, our results suggest that chronically elevated β-cell [Ca] in islets contributes to the alteration of β-cell identity, islet cell numbers and morphology, and gene expression by disrupting a network of Ca-regulated genes.
© 2017 by the American Diabetes Association.
3 Communities
4 Members
0 Resources
18 MeSH Terms
Metabolic responses to exogenous ghrelin in obesity and early after Roux-en-Y gastric bypass in humans.
Tamboli RA, Antoun J, Sidani RM, Clements A, Harmata EE, Marks-Shulman P, Gaylinn BD, Williams B, Clements RH, Albaugh VL, Abumrad NN
(2017) Diabetes Obes Metab 19: 1267-1275
MeSH Terms: Acylation, Anti-Obesity Agents, Cohort Studies, Combined Modality Therapy, Cross-Over Studies, Energy Metabolism, Gastric Bypass, Ghrelin, Gluconeogenesis, Glucose Clamp Technique, Human Growth Hormone, Humans, Infusions, Intravenous, Insulin Resistance, Liver, Muscle, Skeletal, Obesity, Morbid, Pancreatic Polypeptide, Pancreatic Polypeptide-Secreting Cells, Pituitary Gland, Anterior, Postoperative Care, Preoperative Care, Protein Precursors, Single-Blind Method
Show Abstract · Added April 3, 2017
AIMS - Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB).
MATERIALS AND METHODS - We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg  min ) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp.
RESULTS - Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion.
CONCLUSIONS - These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB.
© 2017 John Wiley & Sons Ltd.
0 Communities
3 Members
0 Resources
24 MeSH Terms
Counterregulatory responses to hypoglycemia differ between glimepiride and glyburide in non diabetic individuals.
Joy NG, Tate DB, Davis SN
(2015) Metabolism 64: 729-37
MeSH Terms: Adult, Blood Glucose, C-Peptide, Female, Glucagon, Glucose Clamp Technique, Glyburide, Humans, Hypoglycemia, Hypoglycemic Agents, Insulin, Leptin, Male, Pancreatic Polypeptide, Single-Blind Method, Sulfonylurea Compounds
Show Abstract · Added July 30, 2015
OBJECTIVE - Reported rates of hypoglycemia in patients with type 2 diabetes mellitus are lower with glimepiride as compared to glyburide. The aim of this study was to determine whether physiologic differences in counterregulatory neuroendocrine and metabolic mechanisms during hypoglycemia provide a basis for the observed clinical differences between glimepiride and glyburide.
RESEARCH DESIGN AND METHODS - Non-diabetic volunteers (age 38±2years, BMI 26±1kg/m(2)) were studied in a single-blind fashion during separate 2day randomized protocols consisting of 2h hyperinsulinemic (9pmol/kg/min) euglycemic (4.9±0.1mmol) and hypoglycemic (2.9±0.1mmol/L) clamps. Individuals received biologically equivalent doses of glimepiride (4mg) or glyburide (10mg) 1h prior to each glucose clamp (n=11) as well as a control group of placebo studies. Glucose kinetics were calculated using D-Glucose-6-6d2.
RESULTS - Insulin and C-peptide levels were increased (p<0.05) during euglycemia in both sulfonylurea groups as compared to placebo. However, despite equivalent hypoglycemia, insulin and C-peptide levels were higher (p<0.05) only after glyburide. Glucagon responses and endogenous glucose production (EGP) were decreased (p<0.05) during hypoglycemia following glyburide administration as compared to glimepiride. Glyburide reduced (p<0.05) norepinephrine responses during euglycemic clamps. In addition combined epinephrine and norepinephrine responses during hypoglycemia were reduced (p<0.05) following glyburide as compared to placebo. Leptin levels fell by a greater amount (p<0.05) during hypoglycemia with both sulfonylureas as compared to placebo.
CONCLUSIONS - In summary, glimepiride and glyburide can both similarly increase insulin and C-peptide levels during hyperinsulinemic euglycemia. However, during moderate hyperinsulinemic hypoglycemia (2.9mmol/L) glyburide resulted in increased C-peptide and insulin, but blunted glucagon, sympathetic nervous system and EGP responses. We conclude that glyburide can acutely reduce key neuroendocrine and metabolic counterregulatory defenses during hypoglycemia in healthy individuals.
Copyright © 2015. Published by Elsevier Inc.
0 Communities
0 Members
2 Resources
16 MeSH Terms
Position and length of fatty acids strongly affect receptor selectivity pattern of human pancreatic polypeptide analogues.
Mäde V, Bellmann-Sickert K, Kaiser A, Meiler J, Beck-Sickinger AG
(2014) ChemMedChem 9: 2463-74
MeSH Terms: Amino Acid Sequence, Animals, Anti-Obesity Agents, COS Cells, Chlorocebus aethiops, Fatty Acids, Half-Life, Humans, Kinetics, Ligands, Liver, Molecular Sequence Data, Pancreatic Polypeptide, Receptors, Neuropeptide Y
Show Abstract · Added January 24, 2015
Pancreatic polypeptide (PP) is a satiety-inducing gut hormone targeting predominantly the Y4 receptor within the neuropeptide Y multiligand/multireceptor family. Palmitoylated PP-based ligands have already been reported to exert prolonged satiety-inducing effects in animal models. Here, we suggest that other lipidation sites and different fatty acid chain lengths may affect receptor selectivity and metabolic stability. Activity tests revealed significantly enhanced potency of long fatty acid conjugates on all four Y receptors with a preference of position 22 over 30 at Y1 , Y2 and Y5 receptors. Improved Y receptor selectivity was observed for two short fatty acid analogues. Moreover, [K(30)(E-Prop)]hPP2-36 (15) displayed enhanced stability in blood plasma and liver homogenates. Thus, short chain lipidation of hPP at key residue 30 is a promising approach for anti-obesity therapy because of maintained selectivity and a sixfold increased plasma half-life.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
1 Communities
1 Members
0 Resources
14 MeSH Terms
Pancreatic polypeptide is recognized by two hydrophobic domains of the human Y4 receptor binding pocket.
Pedragosa-Badia X, Sliwoski GR, Dong Nguyen E, Lindner D, Stichel J, Kaufmann KW, Meiler J, Beck-Sickinger AG
(2014) J Biol Chem 289: 5846-59
MeSH Terms: Animals, Binding Sites, COS Cells, Chlorocebus aethiops, Crystallography, X-Ray, HEK293 Cells, Humans, Hydrophobic and Hydrophilic Interactions, Pancreatic Polypeptide, Protein Structure, Quaternary, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Neuropeptide Y
Show Abstract · Added January 24, 2015
Structural characterization of the human Y4 receptor (hY4R) interaction with human pancreatic polypeptide (hPP) is crucial, not only for understanding its biological function but also for testing treatment strategies for obesity that target this interaction. Here, the interaction of receptor mutants with pancreatic polypeptide analogs was studied through double-cycle mutagenesis. To guide mutagenesis and interpret results, a three-dimensional comparative model of the hY4R-hPP complex was constructed based on all available class A G protein-coupled receptor crystal structures and refined using experimental data. Our study reveals that residues of the hPP and the hY4R form a complex network consisting of ionic interactions, hydrophobic interactions, and hydrogen binding. Residues Tyr(2.64), Asp(2.68), Asn(6.55), Asn(7.32), and Phe(7.35) of Y4R are found to be important in receptor activation by hPP. Specifically, Tyr(2.64) interacts with Tyr(27) of hPP through hydrophobic contacts. Asn(7.32) is affected by modifications on position Arg(33) of hPP, suggesting a hydrogen bond between these two residues. Likewise, we find that Phe(7.35) is affected by modifications of hPP at positions 33 and 36, indicating interactions between these three amino acids. Taken together, we demonstrate that the top of transmembrane helix 2 (TM2) and the top of transmembrane helices 6 and 7 (TM6-TM7) form the core of the peptide binding pocket. These findings will contribute to the rational design of ligands that bind the receptor more effectively to produce an enhanced agonistic or antagonistic effect.
1 Communities
1 Members
0 Resources
13 MeSH Terms
Ptf1a-mediated control of Dll1 reveals an alternative to the lateral inhibition mechanism.
Ahnfelt-Rønne J, Jørgensen MC, Klinck R, Jensen JN, Füchtbauer EM, Deering T, MacDonald RJ, Wright CV, Madsen OD, Serup P
(2012) Development 139: 33-45
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Bromodeoxyuridine, Calcium-Binding Proteins, Chromatin Immunoprecipitation, Galactosides, Gene Expression Regulation, Homeodomain Proteins, Immunohistochemistry, Indoles, Intercellular Signaling Peptides and Proteins, Mice, Mice, Transgenic, Nerve Tissue Proteins, Pancreas, Pancreatic Polypeptide-Secreting Cells, Stem Cells, Transcription Factor HES-1, Transcription Factors
Show Abstract · Added November 6, 2013
Neurog3-induced Dll1 expression in pancreatic endocrine progenitors ostensibly activates Hes1 expression via Notch and thereby represses Neurog3 and endocrine differentiation in neighboring cells by lateral inhibition. Here we show in mouse that Dll1 and Hes1 expression deviate during regionalization of early endoderm, and later during early pancreas morphogenesis. At that time, Ptf1a activates Dll1 in multipotent pancreatic progenitor cells (MPCs), and Hes1 expression becomes Dll1 dependent over a brief time window. Moreover, Dll1, Hes1 and Dll1/Hes1 mutant phenotypes diverge during organ regionalization, become congruent at early bud stages, and then diverge again at late bud stages. Persistent pancreatic hypoplasia in Dll1 mutants after eliminating Neurog3 expression and endocrine development, together with reduced proliferation of MPCs in both Dll1 and Hes1 mutants, reveals that the hypoplasia is caused by a growth defect rather than by progenitor depletion. Unexpectedly, we find that Hes1 is required to sustain Ptf1a expression, and in turn Dll1 expression in early MPCs. Our results show that Ptf1a-induced Dll1 expression stimulates MPC proliferation and pancreatic growth by maintaining Hes1 expression and Ptf1a protein levels.
2 Communities
2 Members
5 Resources
19 MeSH Terms
Portal glucose infusion exerts an incretin effect associated with changes in pancreatic neural activity in conscious dogs.
Dunning BE, Moore MC, Ikeda T, Neal DW, Scott MF, Cherrington AD
(2002) Metabolism 51: 1324-30
MeSH Terms: Algorithms, Animals, Dogs, Female, Glucagon, Glucose, Hematocrit, Hormones, Hydrocortisone, Infusions, Intravenous, Insulin, Kinetics, Male, Norepinephrine, Pancreas, Pancreatic Polypeptide, Parasympathetic Nervous System, Portal Vein
Show Abstract · Added December 10, 2013
We sought to determine whether an incretin effect could be observed when glucose was infused via the hepatic portal (Po) vein versus a peripheral (Pe) vein. Identical hyperglycemia (155 +/- 7 and 154 +/- 8 mg/dL, respectively) was produced in 2 groups (n = 9 each) of conscious dogs by Po or Pe glucose infusion. During glucose infusion, arterial plasma insulin levels increased by 28 +/- 5 and 16 +/- 3 microU/mL in Po and Pe, respectively (P <.05 between groups). Pancreatic insulin output increased by 10.4 +/- 3.2 and 6.7 +/- 2.3 mU/min in Po and Pe, respectively (P =.12 between groups). Arterial plasma glucagon levels and pancreatic glucagon output were similarly suppressed by Po and Pe glucose infusion. Pancreatic polypeptide (PP) output and norepinephrine (NE) spillover were measured as indices of pancreatic parasympathetic and sympathetic neural activity, respectively. During Pe, pancreatic PP output decreased from basal (delta -4.8 +/- 2.5 ng/min, P <.05), with no significant change in NE spillover (delta +4.4 +/- 4.0 ng/min). The PP output:NE spillover ratio decreased by 65% (P <.05), suggesting a shift toward a dominance of sympathetic tone. During Po, there were no significant changes in PP output (delta -1.4 +/- 3.1 ng/min) or NE spillover (delta +1.6 +/- 1.2 ng/min), and consequently there was no significant change in the PP output:NE spillover ratio. Thus, activation of the Po glucose signal appears to inhibit the shift toward sympathetic dominance that would otherwise result, thereby causing an incretin effect.
Copyright 2002, Elsevier Science (USA). All rights reserved.
0 Communities
2 Members
0 Resources
18 MeSH Terms
Pancreatic response to mild non-insulin-induced hypoglycemia does not involve extrinsic neural input.
Sherck SM, Shiota M, Saccomando J, Cardin S, Allen EJ, Hastings JR, Neal DW, Williams PE, Cherrington AD
(2001) Diabetes 50: 2487-96
MeSH Terms: Animals, Blood Glucose, Denervation, Dogs, Female, Glucagon, Hypoglycemia, Insulin, Male, Nervous System, Norepinephrine, Pancreas, Pancreatic Polypeptide
Show Abstract · Added December 10, 2013
Mild non-insulin-induced hypoglycemia achieved by administration of a glycogen phosphorylase inhibitor results in increased glucagon and decreased insulin secretion in conscious dogs. Our aim was to determine whether the response of the endocrine pancreas to this mild hypoglycemia can occur in the absence of neural input to the pancreas. Seven dogs underwent surgical pancreatic denervation (PDN [study group]), and seven dogs underwent sham denervation (control [CON] group). Each study consisted of a 100-min equilibration period, a 40-min control period, and a 180-min test period. At the start of the test period, Bay R3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally. Arterial plasma glucose (mmol/l) fell to a similar minimum in CON (5.0 +/- 0.1) and PDN (4.9 +/- 0.3). Arterial plasma insulin also fell to similar minima in both groups (CON, 20 +/- 6 pmol/l; PDN, 14 +/- 5 pmol/l). Arterial plasma glucagon rose to a similar maximum in CON (73 +/- 8 ng/l) and PDN (72 +/- 9 ng/l). Insulin and glucagon secretion data support these plasma hormone results, and there were no significant differences in the responses in CON and PDN for any parameter. Pancreatic norepinephrine content in PDN was only 4% of that in CON, confirming successful sympathetic denervation. Pancreatic polypeptide levels tended to increase in CON and decrease in PDN in response to mild hypoglycemia, indicative of parasympathetic denervation. It thus can be concluded that the responses of alpha- and beta-cells to mild non-insulin-induced hypoglycemia can occur in the absence of extrinsic neural input.
0 Communities
2 Members
0 Resources
13 MeSH Terms
Effect of hepatic denervation on the counterregulatory response to insulin-induced hypoglycemia in the dog.
Jackson PA, Cardin S, Coffey CS, Neal DW, Allen EJ, Penaloza AR, Snead WL, Cherrington AD
(2000) Am J Physiol Endocrinol Metab 279: E1249-57
MeSH Terms: 3-Hydroxybutyric Acid, Alanine, Animals, Blood Glucose, Cold Temperature, Consciousness, Dogs, Epinephrine, Fatty Acids, Nonesterified, Female, Glucagon, Glycerol, Heart Rate, Hydrocortisone, Hypoglycemia, Hypoglycemic Agents, Insulin, Lactic Acid, Liver, Male, Norepinephrine, Pancreatic Polypeptide, Parasympathectomy, Vagus Nerve
Show Abstract · Added December 10, 2013
Our aim was to determine whether complete hepatic denervation would affect the hormonal response to insulin-induced hypoglycemia in dogs. Two weeks before study, dogs underwent either hepatic denervation (DN) or sham denervation (CONT). In addition, all dogs had hollow steel coils placed around their vagus nerves. The CONT dogs were used for a single study in which their coils were perfused with 37 degrees C ethanol. The DN dogs were used for two studies in a random manner, one in which their coils were perfused with -20 degrees C ethanol (DN + COOL) and one in which they were perfused with 37 degrees C ethanol (DN). Insulin was infused to create hypoglycemia (51 +/- 3 mg/dl). In response to hypoglycemia in CONT, glucagon, cortisol, epinephrine, norepinephrine, pancreatic polypeptide, glycerol, and hepatic glucose production increased significantly. DN alone had no inhibitory effect on any hormonal or metabolic counterregulatory response to hypoglycemia. Likewise, DN in combination with vagal cooling also had no inhibitory effect on any counterregulatory response except to reduce the arterial plasma pancreatic polypeptide response. These data suggest that afferent signaling from the liver is not required for the normal counterregulatory response to insulin-induced hypoglycemia.
0 Communities
1 Members
0 Resources
24 MeSH Terms
Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages.
Herrera PL
(2000) Development 127: 2317-22
MeSH Terms: Animals, Cell Differentiation, Cell Lineage, Female, Gene Expression, Glucagon, Homeodomain Proteins, Humans, Insulin, Islets of Langerhans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Pancreatic Polypeptide, Stem Cells, Trans-Activators
Show Abstract · Added July 7, 2015
To analyze cell lineage in the pancreatic islets, we have irreversibly tagged all the progeny of cells through the activity of Cre recombinase. Adult glucagon alpha and insulin beta cells are shown to derive from cells that have never transcribed insulin or glucagon, respectively. Also, the beta-cell progenitors, but not alpha-cell progenitors, transcribe the pancreatic polypeptide (PP) gene. Finally, the homeodomain gene PDX1, which is expressed by adult beta-cells, is also expressed by alpha-cell progenitors. Thus the islet alpha- and beta-cell lineages appear to arise independently during ontogeny, probably from a common precursor.
0 Communities
0 Members
0 Resources
18 MeSH Terms