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Nuclear import of glucokinase in pancreatic beta-cells is mediated by a nuclear localization signal and modulated by SUMOylation.

Recent Publications of BIIC Members - Tue, 06/27/2017 - 10:41
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Nuclear import of glucokinase in pancreatic beta-cells is mediated by a nuclear localization signal and modulated by SUMOylation.

Mol Cell Endocrinol. 2017 Jun 22;:

Authors: Johansson BB, Fjeld K, Solheim MH, Shirakawa J, Zhang E, Keindl M, Hu J, Lindqvist A, Døskeland A, Mellgren G, Flatmark T, Njølstad PR, Kulkarni RN, Wierup N, Aukrust I, Bjørkhaug L

Abstract
The localization of glucokinase in pancreatic beta-cell nuclei is a controversial issue. Although previous reports suggest such a localization, the mechanism for its import has so far not been identified. Using immunofluorescence, subcellular fractionation and mass spectrometry, we here present evidence in support of glucokinase localization in beta-cell nuclei of human and mouse pancreatic sections, as well as in human and mouse isolated islets, and murine MIN6 cells. We have identified a conserved, seven-residue nuclear localization signal ((30)LKKVMRR(36)) in the human enzyme. Substituting the residues KK(31,32) and RR(35,36) with AA led to a loss of its nuclear localization in transfected cells. Furthermore, our data indicates that SUMOylation of glucokinase modulates its nuclear import, while high glucose concentrations do not significantly alter the enzyme nuclear/cytosolic ratio. Thus, for the first time, we provide data in support of a nuclear import of glucokinase mediated by a redundant mechanism, involving a nuclear localization signal, and which is modulated by its SUMOylation. These findings add new knowledge to the functional role of glucokinase in the pancreatic beta-cell.

PMID: 28648619 [PubMed - as supplied by publisher]

Interrelations between 3-hydroxypropionate and propionate metabolism in rat liver: Relevance to disorders of propionyl-CoA metabolism.

Recent Publications of BIIC Members - Sat, 06/24/2017 - 10:03
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Interrelations between 3-hydroxypropionate and propionate metabolism in rat liver: Relevance to disorders of propionyl-CoA metabolism.

Am J Physiol Endocrinol Metab. 2017 Jun 20;:ajpendo.00105.2017

Authors: Wilson KA, Han Y, Zhang M, Hess J, Chapman KA, Cline GW, Tochtrop GP, Brunengraber H, Zhang GF

Abstract
Propionate, 3-hydroxypropionate (3HP), methylcitrate, related compounds and ammonium accumulate in body fluids of patients with disorders of propionyl-CoA metabolism, such as propionic acidemia. Although liver transplantation alleviates hyperammonemia, high concentrations of propionate, 3HP and methylcitrate persist in body fluids. We hypothesized that conserved metabolic perturbations occurring in transplanted patients result from the simultaneous presence of propionate and 3HP in body fluids. We investigated the interrelations of propionate and 3HP metabolism in perfused livers from normal rats using metabolomic and stable isotopic technologies. In the presence of propionate, 3HP or both, we observed the following metabolic perturbations. First, the citric acid cycle (CAC) is overloaded, but does not provide sufficient reducing equivalents to the respiratory chain to maintain the homeostasis of adenine nucleotides. Second, there is major CoA trapping in the propionyl-CoA pathway, and a tripling of liver total CoA within 1 hr. Third, liver proteolysis is stimulated. Fourth, propionate inhibits the conversion of 3HP to acetyl-CoA and its oxidation in the CAC. Fifth, some propionate and some 3HP are converted to nephrotoxic maleate by different processes. Our data have implication for the clinical management of propionic acidemia. They also emphasize the perturbations of liver intermediary metabolism induced by supraphysiological i.e., mM concentrations of labeled propionate used to trace intermediary metabolism, in particular inhibition of CAC flux and major decreases in the [ATP]/[ADP] and [ATP]/[AMP] ratios.

PMID: 28634175 [PubMed - as supplied by publisher]

A Unified Pathophysiological Construct of Diabetes and its Complications.

Recent Publications of BIIC Members - Sat, 06/24/2017 - 10:03
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A Unified Pathophysiological Construct of Diabetes and its Complications.

Trends Endocrinol Metab. 2017 Jun 16;:

Authors: Schwartz SS, Epstein S, Corkey BE, Grant SFA, Gavin Iii JR, Aguilar RB, Herman ME

Abstract
Advances in understanding diabetes mellitus (DM) through basic and clinical research have helped clarify and reunify a disease state fragmented into numerous etiologies and subtypes. It is now understood that a common pathophysiology drives the diabetic state throughout its natural history and across its varied clinical presentations, a pathophysiology involving metabolic insults, oxidative damage, and vicious cycles that aggravate and intensify organ dysfunction and damage. This new understanding of the disease requires that we revisit existing diagnostics and treatment approaches, which were built upon outmoded assumptions. 'The Common Pathophysiologic Origins of Diabetes Mellitus and its Complications Construct' is presented as a more accurate, foundational, and translatable construct of DM that helps make sense of the hitherto ambiguous findings of long-term outcome studies.

PMID: 28629897 [PubMed - as supplied by publisher]

Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents.

Recent Publications of BIIC Members - Sat, 06/24/2017 - 10:03
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Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents.

Am J Physiol Endocrinol Metab. 2016 Aug 01;311(2):E461-70

Authors: Perry RJ, Cardone RL, Petersen MC, Zhang D, Fouqueray P, Hallakou-Bozec S, Bolze S, Shulman GI, Petersen KF, Kibbey RG

Abstract
Imeglimin is a promising new oral antihyperglycemic agent that has been studied in clinical trials as a possible monotherapy or add-on therapy to lower fasting plasma glucose and improve hemoglobin A1c (1-3, 9). Imeglimin was shown to improve both fasting and postprandial glycemia and to increase insulin secretion in response to glucose during a hyperglycemic clamp after 1-wk of treatment in type 2 diabetic patients. However, whether the β-cell stimulatory effect of imeglimin is solely or partially responsible for its effects on glycemia remains to be fully confirmed. Here, we show that imeglimin directly activates β-cell insulin secretion in awake rodents without affecting hepatic insulin sensitivity, body composition, or energy expenditure. These data identify a primary amplification rather than trigger the β-cell mechanism that explains the acute, antidiabetic activity of imeglimin.

PMID: 27406738 [PubMed - indexed for MEDLINE]

Prostaglandin E1 inhibits endocytosis in the β-cell endocytosis.

Recent Publications of BIIC Members - Mon, 06/12/2017 - 05:40
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Prostaglandin E1 inhibits endocytosis in the β-cell endocytosis.

J Endocrinol. 2016 Jun;229(3):287-94

Authors: Zhao Y, Fang Q, Straub SG, Lindau M, Sharp GW

Abstract
Prostaglandins inhibit insulin secretion in a manner similar to that of norepinephrine (NE) and somatostatin. As NE inhibits endocytosis as well as exocytosis, we have now examined the modulation of endocytosis by prostaglandin E1 (PGE1). Endocytosis following exocytosis was recorded by whole-cell patch clamp capacitance measurements in INS-832/13 cells. Prolonged depolarizing pulses producing a high level of Ca(2+) influx were used to stimulate maximal exocytosis and to deplete the readily releasable pool (RRP) of granules. This high Ca(2+) influx eliminates the inhibitory effect of PGE1 on exocytosis and allows specific characterization of the inhibitory effect of PGE1 on the subsequent compensatory endocytosis. After stimulating exocytosis, endocytosis was apparent under control conditions but was inhibited by PGE1 in a Pertussis toxin-sensitive (PTX)-insensitive manner. Dialyzing a synthetic peptide mimicking the C-terminus of the α-subunit of the heterotrimeric G-protein Gz into the cells blocked the inhibition of endocytosis by PGE1, whereas a control-randomized peptide was without effect. These results demonstrate that PGE1 inhibits endocytosis and Gz mediates the inhibition.

PMID: 27068696 [PubMed - indexed for MEDLINE]

Age-dependent insulin resistance in male mice with null deletion of the carcinoembryonic antigen-related cell adhesion molecule 2 gene.

Recent Publications of BIIC Members - Sat, 06/03/2017 - 00:16
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Age-dependent insulin resistance in male mice with null deletion of the carcinoembryonic antigen-related cell adhesion molecule 2 gene.

Diabetologia. 2017 May 31;:

Authors: Ghanem SS, Muturi HT, DeAngelis AM, Hu J, Kulkarni RN, Heinrich G, Najjar SM

Abstract
AIMS/HYPOTHESIS: Cc2 (-/-) mice lacking the gene encoding the carcinoembryonic-antigen-related cell adhesion molecule 2 (Cc2 [also known as Ceacam2]) exhibit hyperphagia that leads to obesity and insulin resistance. This starts at 2 months of age in female mice. Male mutants maintain normal body weight and insulin sensitivity until the last age previously examined (7-8 months), owing to increased sympathetic tone to white adipose tissue and energy expenditure. The current study investigates whether insulin resistance develops in mutant male mice at a later age and whether this is accompanied by changes in insulin homeostasis.
METHODS: Insulin response was assessed by insulin and glucose tolerance tests. Energy balance was analysed by indirect calorimetry.
RESULTS: Male Cc2 (-/-) mice developed overt metabolic abnormalities at about 9 months of age. These include elevated global fat mass, hyperinsulinaemia and insulin resistance (as determined by glucose and insulin intolerance, fed hyperglycaemia and decreased insulin signalling pathways). Pair-feeding experiments showed that insulin resistance resulted from hyperphagia. Indirect calorimetry demonstrated that older mutant male mice had compromised energy expenditure. Despite increased insulin secretion caused by Cc2 deletion, chronic hyperinsulinaemia did not develop in mutant male mice until about 9 months of age, at which point insulin clearance began to decline substantially. This was probably mediated by a marked decrease in hepatic CEACAM1 expression.
CONCLUSIONS/INTERPRETATION: The data demonstrate that at about 9 months of age, Cc2 (-/-) male mice develop a reduction in energy expenditure and energy imbalance which, combined with a progressive decrease in CEACAM1-dependent hepatic insulin clearance, causes chronic hyperinsulinaemia and sustained age-dependent insulin resistance. This represents a novel mechanistic underpinning of age-related impairment of hepatic insulin clearance.

PMID: 28567513 [PubMed - as supplied by publisher]

Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis.

Recent Publications of BIIC Members - Sat, 05/27/2017 - 22:26
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Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis.

EMBO Rep. 2017 May 24;:

Authors: Mahdaviani K, Benador IY, Su S, Gharakhanian RA, Stiles L, Trudeau KM, Cardamone M, Enríquez-Zarralanga V, Ritou E, Aprahamian T, Oliveira MF, Corkey BE, Perissi V, Liesa M, Shirihai OS

Abstract
BAT-controlled thermogenic activity is thought to be required for its capacity to prevent the development of insulin resistance. This hypothesis predicts that mediators of thermogenesis may help prevent diet-induced insulin resistance. We report that the mitochondrial fusion protein Mitofusin 2 (Mfn2) in BAT is essential for cold-stimulated thermogenesis, but promotes insulin resistance in obese mice. Mfn2 deletion in mice through Ucp1-cre (BAT-Mfn2-KO) causes BAT lipohypertrophy and cold intolerance. Surprisingly however, deletion of Mfn2 in mice fed a high fat diet (HFD) results in improved insulin sensitivity and resistance to obesity, while impaired cold-stimulated thermogenesis is maintained. Improvement in insulin sensitivity is associated with a gender-specific remodeling of BAT mitochondrial function. In females, BAT mitochondria increase their efficiency for ATP-synthesizing fat oxidation, whereas in BAT from males, complex I-driven respiration is decreased and glycolytic capacity is increased. Thus, BAT adaptation to obesity is regulated by Mfn2 and with BAT-Mfn2 absent, BAT contribution to prevention of insulin resistance is independent and inversely correlated to whole-body cold-stimulated thermogenesis.

PMID: 28539390 [PubMed - as supplied by publisher]

GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice.

Recent Publications of BIIC Members - Sun, 05/21/2017 - 19:40
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GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice.

Diabetologia. 2017 May 20;:

Authors: Kawamori D, Shirakawa J, Liew CW, Hu J, Morioka T, Duttaroy A, Burkey B, Kulkarni RN

Abstract
AIMS/HYPOTHESIS: We aimed to investigate potential interactions between insulin and glucagon-like peptide (GLP)-1 signalling pathways in the regulation of beta cell-cycle dynamics in vivo, in the context of the therapeutic potential of GLP-1 to modulate impaired beta cell function.
METHODS: Beta cell-specific insulin receptor knockout (βIRKO) mice, which exhibit beta cell dysfunction and an age-dependent decrease in beta cell mass, were treated with the dipeptidyl peptidase-4 inhibitor vildagliptin. Following this, glucose homeostasis and beta cell proliferation were evaluated and underlying molecular mechanisms were investigated.
RESULTS: The sustained elevation in circulating GLP-1 levels, caused by treatment of the knockout mice with vildagliptin for 6 weeks, significantly improved glucose tolerance secondary to enhanced insulin secretion and proliferation of beta cells. Treating βIRKO beta cell lines with the GLP-1 analogue, exendin-4, promoted Akt phosphorylation and protein expression of cyclins A, D1 and E two- to threefold, in addition to cyclin D2. Pancreases from the vildagliptin-treated βIRKO mice exhibited increased cyclin D1 expression, while cyclin D2 expression was impaired.
CONCLUSIONS/INTERPRETATION: Activation of GLP-1 signalling compensates for impaired growth factor (insulin) signalling and enhances expression of cyclins to promote beta cell proliferation. Together, these data indicate the potential of GLP-1-related therapies to enhance beta cell proliferation and promote beneficial outcomes in models with dysfunctional beta cells.

PMID: 28526921 [PubMed - as supplied by publisher]

Nuclear Export of FoxO1 Is Associated with ERK Signaling in β-Cells Lacking Insulin Receptors.

Recent Publications of BIIC Members - Sun, 05/21/2017 - 19:40
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Nuclear Export of FoxO1 Is Associated with ERK Signaling in β-Cells Lacking Insulin Receptors.

J Biol Chem. 2016 Oct 07;291(41):21485-21495

Authors: Mezza T, Shirakawa J, Martinez R, Hu J, Giaccari A, Kulkarni RN

Abstract
The insulin/insulin-like growth factor (IGF) signaling pathway plays a critical role in the regulation of islet cell biology. However, the signaling pathway(s) utilized by insulin to directly modulate β-cells is unclear. To interrogate whether insulin exerts endocrine effects in regulating proteins in the insulin/IGF-1 signaling cascade in vivo in physiological states via the insulin receptor, we designed two experimental approaches: 1) glucose gavage and 2) hyperinsulinemic intravenous infusion, for studies in either β-cell specific insulin receptor knock-out (βIRKO) or control mice. Immunostaining of sections of pancreas (collected immediately after glucose gavage or insulin infusion) from controls showed significant increases in pAKT+, p-p70S6K+, and pERK+ β-cells and a significant decrease in % nuclear FoxO1+ β-cells compared with corresponding vehicle-treated groups. In contrast, in βIRKOs, we observed no significant changes in pAKT+ or p-p70S6K+ β-cells in either experiment; however, pERK+ β-cells were significantly increased, and an attenuated decrease in % nuclear FoxO1+ β cells was evident in response to glucose gavage or insulin infusion. Treatment of control and βIRKO β-cell lines with glucose or insulin showed significantly decreased % nuclear FoxO1+ β-cells suggesting direct effects. Furthermore, blocking MAPK signaling had virtually no effect on FoxO1 nuclear export in controls, in contrast to attenuated export in βIRKO β-cells. These data suggest insulin acts on β-cells in an endocrine manner in the normal situation; and that in β-cells lacking insulin receptors, insulin and glucose minimally activate the Akt pathway, while ERK phosphorylation and FoxO1 nuclear export occur independently of insulin signaling.

PMID: 27535223 [PubMed - indexed for MEDLINE]

Heterogeneity of proliferative markers in pancreatic β-cells of patients with severe hypoglycemia following Roux-en-Y gastric bypass.

Recent Publications of BIIC Members - Thu, 05/18/2017 - 18:03
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Heterogeneity of proliferative markers in pancreatic β-cells of patients with severe hypoglycemia following Roux-en-Y gastric bypass.

Acta Diabetol. 2017 May 17;:

Authors: Patti ME, Goldfine AB, Hu J, Hoem D, Molven A, Goldsmith J, Schwesinger WH, La Rosa S, Folli F, Kulkarni RN

Abstract
AIMS: Severe postprandial hypoglycemia with neuroglycopenia is an increasingly recognized, debilitating complication of Roux-en-Y gastric bypass (RYGB) surgery. Increased secretion of insulin and incretin hormones is implicated in its pathogenesis. Histopathologic examination of pancreas has demonstrated increased islet size and/or nuclear diameter in post-RYGB patients who underwent pancreatectomy for severe refractory hypoglycemia with neuroglycopenia (RYGB + NG). We aimed to determine whether β-cell proliferation or apoptosis is altered in RYGB + NG.
METHODS: We performed an observational study to analyze markers of proliferation, apoptosis, cell cycle, and transcription factor expression in pancreatic tissue from affected RYGB + NG patients (n = 12), normoglycemic patients undergoing pancreatic surgery for benign lesions (controls, n = 6), and individuals with hypoglycemia due to insulinoma (n = 52).
RESULTS: Proliferative cell nuclear antigen (PCNA) expression was increased in insulin-positive cells in RYGB + NG patients (4.5-fold increase, p < 0.001 vs. controls) and correlated with β-cell mass. Ki-67 immunoreactivity was low in both RYGB + NG and controls, but did not differ between groups. Phospho-histone H3 levels did not differ between RYGB + NG and controls. PCNA and Ki-67 were both significantly lower in both controls and RYGB + NG than insulinomas. Markers of apoptosis and cell cycle (M30, p27, and p21) did not differ between groups. PDX1 and menin exhibited similar expression patterns, while FOXO1 appeared to be more cytosolic in RYGB + NG.
CONCLUSIONS: Markers of proliferation are heterogeneous in patients with severe post-RYGB hypoglycemia. Increased β-cell proliferation in some individuals may contribute to increased β-cell mass observed in severely affected patients.

PMID: 28512677 [PubMed - as supplied by publisher]

Evaluation of pancreatic VMAT2 binding with active and inactive enantiomers of (18)F-FP-DTBZ in baboons.

Recent Publications of BIIC Members - Thu, 05/18/2017 - 18:03
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Evaluation of pancreatic VMAT2 binding with active and inactive enantiomers of (18)F-FP-DTBZ in baboons.

Nucl Med Biol. 2016 Dec;43(12):743-751

Authors: Naganawa M, Lin SF, Lim K, Labaree D, Ropchan J, Harris P, Huang Y, Ichise M, Carson RE, Cline GW

Abstract
INTRODUCTION: (18)F-Fluoropropyl-(+)-dihydrotetrabenazine ((18)F-FP-(+)-DTBZ) is a vesicular monoamine transporter type 2 (VMAT2) radiotracer for positron emission tomography (PET) imaging to quantify human β-cell mass. Renal cortex and spleen have been suggested as reference regions, however, little is known about (18)F-FP-(+)-DTBZ binding in these regions including the fraction of radiometabolite. We compared the kinetics of (18)F-FP-(+)-DTBZ and its inactive enantiomer (18)F-FP-(-)-DTBZ in baboons, estimated the non-displaceable binding (VND) of the tracers, and used ex vivo studies to measure radiometabolite fractions.
METHODS: PET scans were conducted for up to 4h with (+) and (-) enantiomers. Displacement experiments using unlabeled (+) and (-) enantiomers of FP-DTBZ and fluvoxamine (to evaluate sigma-1 receptor binding) were performed. SUV curves were used to calculate displacement values in the pancreas, renal cortex, and spleen. Distribution volumes (VT) were computed, and three approaches for calculation of VND were compared: (1) (18)F-FP-(+)-DTBZ reference VT, (2) (18)F-FP-(-)-DTBZ pancreatic VT, and (3) a scaled (18)F-FP-(+)-DTBZ reference VT values. Ex vivo study was conducted to measure radiometabolite fraction in homogenized tissue samples from baboons at 90min post-injection.
RESULTS: Spleen uptake was lowest for both tracers. Highest uptake was in the pancreas with (18)F-FP-(+)-DTBZ and renal cortex with (18)F-FP-(-)-DTBZ. Substantial displacement effect was observed only with unlabeled FP-(+)-DTBZ in the (18)F-FP-(+)-DTBZ studies. Radiometabolite fraction was higher in the renal cortex than the spleen. Approaches (1) and (3) with spleen to estimate VND provided lowest inter-subject variability of BPND.
CONCLUSIONS: VT differences among organs and between enantiomers indicated that scaling of reference region values is needed for quantification of VMAT2 binding in the pancreas with (18)F-FP-(+)-DTBZ. Since the kidney PET signal has greater partial volume averaging and more radiometabolites, the spleen was considered a more practical candidate for use as a scaled-reference region in the quantification of (18)F-FP-(+)-DTBZ in the pancreas.

PMID: 27673755 [PubMed - indexed for MEDLINE]

Temporal Characterization of β-cell Adaptive and Maladaptive Mechanisms During Chronic High Fat Feeding in C57BL/6NTac Mice.

Recent Publications of BIIC Members - Fri, 05/12/2017 - 13:33
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Temporal Characterization of β-cell Adaptive and Maladaptive Mechanisms During Chronic High Fat Feeding in C57BL/6NTac Mice.

J Biol Chem. 2017 May 09;:

Authors: Gupta D, Jetton TL, LaRock K, Monga N, Satish B, Lausier J, Peshavaria M, Leahy JL

Abstract
The onset of type 2 diabetes is characterized by transition from successful to failed insulin secretory compensation to obesity-related insulin resistance and dysmetabolism. Energy-rich diets in rodents are commonly-studied models of compensatory increases in both insulin secretion and β-cell mass. However, the mechanisms of these adaptive responses are incompletely understood, and it is also unclear why these responses eventually fail. We measured the temporal trends of glucose homeostasis, insulin secretion, β-cell morphometry, and islet gene expression in C57BL/6NTac mice fed a 60% high fat (HFD) or control diet for up to 16 weeks. A two-fold increased hyperinsulinemia was maintained for the first 4 weeks of HFD, and then further increased through 16 weeks. β-cell mass increased progressively starting at 4 weeks, principally through nonproliferative growth. Insulin sensitivity was not significantly perturbed until 11 weeks of HFD. Over the first 8 weeks, we observed two distinct waves of increased expression of β-cell functional and prodifferentiation genes. This was followed by activation of the uncoupled protein response at 8 weeks and overt β-cell endoplasmic reticulum (ER) stress at 12-16 weeks. In summary, β-cell adaptation to HFD in C57BL/6NTac mice entails early insulin hypersecretion and a robust growth phase along with hyperexpression of related genes that begins well before the onset of observed insulin resistance. However continued HFD exposure results in cessation of the gene hyperexpression and in β-cell functional failure and ER stress. These data point to a complex but not sustainable integration of β-cell adaptive responses to nutrient overabundance, obesity development, and insulin resistance.

PMID: 28487366 [PubMed - as supplied by publisher]

Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy Onset Diabetes, Congenital Sensorineural Deafness and Congenital Cataracts.

Recent Publications of BIIC Members - Sat, 05/06/2017 - 09:56
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Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy Onset Diabetes, Congenital Sensorineural Deafness and Congenital Cataracts.

Diabetes. 2017 May 03;:

Authors: De Franco E, Flanagan SE, Yagi T, Abreu D, Mahadevan J, Johnson MB, Jones G, Acosta F, Mulaudzi M, Lek N, Oh V, Petz O, Caswell R, Ellard S, Urano F, Hattersley AT

Abstract
Neonatal diabetes is frequently part of a complex syndrome with extra-pancreatic features: 18 genes causing syndromic neonatal diabetes have been identified to date. There remain patients with neonatal diabetes who have novel genetic syndromes.We performed exome sequencing in a patient and his unrelated, unaffected parents to identify the genetic aetiology of a syndrome characterized by neonatal diabetes, sensorineural deafness and congenital cataracts. Further testing was performed in 311 patients with diabetes diagnosed before 1 year of age in whom all known genetic causes had been excluded.We identified 5 patients, including the initial case, with 3 heterozygous missense mutations in WFS1 (4/5 confirmed de novo). They had diabetes diagnosed before 12 months (2 before 6 months) (5/5), sensorineural deafness diagnosed soon after birth (5/5), congenital cataracts (4/5) and hypotonia (4/5). In vitro studies showed that these WFS1 mutations are functionally different from known recessive Wolfram syndrome-causing mutations, as they tend to aggregate and induce robust endoplasmic reticulum stress.Our results establish specific dominant WFS1 mutations as a cause of a novel syndrome including neonatal/infancy onset diabetes, congenital cataracts, and sensorineural deafness. This syndrome has a discrete pathophysiology and differs genetically and clinically from recessive Wolfram syndrome.

PMID: 28468959 [PubMed - as supplied by publisher]

FGF-dependent metabolic control of vascular development.

Recent Publications of BIIC Members - Sat, 05/06/2017 - 09:56
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FGF-dependent metabolic control of vascular development.

Nature. 2017 May 03;:

Authors: Yu P, Wilhelm K, Dubrac A, Tung JK, Alves TC, Fang JS, Xie Y, Zhu J, Chen Z, De Smet F, Zhang J, Jin SW, Sun L, Sun H, Kibbey RG, Hirschi KK, Hay N, Carmeliet P, Chittenden TW, Eichmann A, Potente M, Simons M

Abstract
Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are important to these processes. Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism, little is understood about the role of fibroblast growth factors (FGFs) in this context. Here we identify FGF receptor (FGFR) signalling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signalling inputs results in decreased glycolysis, leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specific Hk2 knockouts phenocopy blood and/or lymphatic vascular defects seen in Fgfr1/Fgfr3 double mutant mice, while HK2 overexpression partly rescues the defects caused by suppression of FGF signalling. Thus, FGF-dependent regulation of endothelial glycolysis is a pivotal process in developmental and adult vascular growth and development.

PMID: 28467822 [PubMed - as supplied by publisher]

Hyperinsulinemia: a Cause of Obesity?

Recent Publications of BIIC Members - Sat, 05/06/2017 - 09:56
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Hyperinsulinemia: a Cause of Obesity?

Curr Obes Rep. 2017 May 02;:

Authors: Erion KA, Corkey BE

Abstract
PURPOSE OF REVIEW: This perspective is motivated by the need to question dogma that does not work: that the problem is insulin resistance (IR). We highlight the need to investigate potential environmental obesogens and toxins.
RECENT FINDINGS: The prequel to severe metabolic disease includes three interacting components that are abnormal: (a) IR, (b) elevated lipids and (c) elevated basal insulin (HI). HI is more common than IR and is a significant independent predictor of diabetes. We hypothesize that (1) the initiating defect is HI that increases nutrient consumption and hyperlipidemia (HL); (2) the cause of HI may include food additives, environmental obesogens or toxins that have entered our food supply since 1980; and (3) HI is sustained by HL derived from increased adipose mass and leads to IR. We suggest that HI and HL are early indicators of metabolic dysfunction and treating and reversing these abnormalities may prevent the development of more serious metabolic disease.

PMID: 28466412 [PubMed - as supplied by publisher]

Analysis of the risk factors for severity in post endoscopic retrograde cholangiopancreatography pancreatitis: The indication of prophylactic treatments.

Recent Publications of BIIC Members - Sat, 05/06/2017 - 09:56
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Analysis of the risk factors for severity in post endoscopic retrograde cholangiopancreatography pancreatitis: The indication of prophylactic treatments.

World J Gastrointest Endosc. 2017 Apr 16;9(4):189-195

Authors: Matsubara H, Urano F, Kinoshita Y, Okamura S, Kawashima H, Goto H, Hirooka Y

Abstract
AIM: To determine the risk factors of severe post endoscopic retrograde cholangiopancreatography pancreatitis (sPEP) and clarify the indication of prophylactic treatments.
METHODS: At our hospital, endoscopic retrograde cholangiopancreatography (ERCP) was performed on 1507 patients from May 2012 to December 2015. Of these patients, we enrolled all 121 patients that were diagnosed with post endoscopic retrograde PEP. Fourteen of 121 patients diagnosed as sPEP were analyzed.
RESULTS: Forty-one patients had contrast media remaining in the pancreatic duct after completion of ERCP. Seventy-one patients had abdominal pain within three hours after ERCP. These were significant differences for sPEP (P < 0.05). The median of Body mass index, the median time for ERCP, the median serum amylase level of the next day, past histories including drinking and smoking, past history of pancreatitis, sphincter of Oddi dysfunction, whether emergency or not, expertise of ERCP procedure, diverticulum nearby Vater papilla, whether there was sphincterotomy or papillary balloon dilation, pancreatic duct cannulation, use of intra-ductal ultrasonography enforcement, and transpapillary biopsies had no significant differences with sPEP.
CONCLUSION: Contrast media remaining in the pancreatic duct and the appearance of abdominal pain within three hours after ERCP were risk factors of sPEP.

PMID: 28465786 [PubMed - in process]

Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram and Thiamine-responsive megaloblastic anaemia.

Recent Publications of BIIC Members - Mon, 04/24/2017 - 02:37
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Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram and Thiamine-responsive megaloblastic anaemia.

Hum Mutat. 2017 Apr 21;:

Authors: Astuti D, Sabir A, Fulton P, Zatyka M, Williams D, Hardy C, Milan G, Favaretto F, Yu-Wai-Man P, Rohayem J, de Heredia ML, Hershey T, Tranebjaerg L, Chen JH, Chaussenot A, Nunes V, Marshall B, McAfferty S, Tillmann V, Maffei P, Paquis-Flucklinger V, Geberhiwot T, Mlynarski W, Parkinson K, Picard V, Bueno GE, Dias R, Arnold A, Richens C, Paisey R, Urano F, Semple R, Sinnott R, Barrett TG

Abstract
We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström and Thiamine-responsive megaloblastic anaemia syndromes respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype phenotype relations for the WFS1 gene. The presence of bi-allelic loss of function variants predicted Wolfram syndrome defined by insulin dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75-83%) and specificity of 92% (83-97%). The presence of minor loss of function variants in WFS1 predicted isolated diabetes, isolated deafness or isolated congenital cataracts without development of the full syndrome (sensitivity 100% (93-100%), specificity 78% (73-82%). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as Next Generation Sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org. This article is protected by copyright. All rights reserved.

PMID: 28432734 [PubMed - as supplied by publisher]

β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance.

Recent Publications of BIIC Members - Sat, 04/08/2017 - 16:57
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β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance.

Cell Metab. 2017 Apr 04;25(4):898-910.e5

Authors: Aguayo-Mazzucato C, van Haaren M, Mruk M, Lee TB, Crawford C, Hollister-Lock J, Sullivan BA, Johnson JW, Ebrahimi A, Dreyfuss JM, Van Deursen J, Weir GC, Bonner-Weir S

Abstract
We hypothesized that the known heterogeneity of pancreatic β cells was due to subpopulations of β cells at different stages of their life cycle with different functional capacities and that further changes occur with metabolic stress and aging. We identified new markers of aging in β cells, including IGF1R. In β cells IGF1R expression correlated with age, dysfunction, and expression of known age markers p16(ink4a), p53BP1, and senescence-associated β-galactosidase. The new markers showed striking heterogeneity both within and between islets in both mouse and human pancreas. Acute induction of insulin resistance with an insulin receptor antagonist or chronic ER stress resulted in increased expression of aging markers, providing insight into how metabolic stress might accelerate dysfunction and decline of β cells. These novel findings about β cell and islet heterogeneity, and how they change with age, open up an entirely new set of questions about the pathogenesis of type 2 diabetes.

PMID: 28380379 [PubMed - in process]

Exploring inter-organ crosstalk to uncover mechanisms that regulate β-cell function and mass.

Recent Publications of BIIC Members - Sat, 03/18/2017 - 03:55
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Exploring inter-organ crosstalk to uncover mechanisms that regulate β-cell function and mass.

Eur J Clin Nutr. 2017 Mar 15;:

Authors: Shirakawa J, De Jesus DF, Kulkarni RN

Abstract
Impaired β-cell function and insufficient β-cell mass compensation are twin pathogenic features that underlie type 2 diabetes (T2D). Current therapeutic strategies continue to evolve to improve treatment outcomes in different ethnic populations and include approaches to counter insulin resistance and improve β-cell function. Although the effects of insulin secretion on metabolic organs such as liver, skeletal muscle and adipose is directly relevant for improving glucose uptake and reduce hyperglycemia, the ability of pancreatic β-cells to crosstalk with multiple non-metabolic tissues is providing novel insights into potential opportunities for improving β-cell function and/or mass that could have beneficial effects in patients with diabetes. For example, the role of the gastrointestinal system in the regulation of β-cell biology is well recognized and has been exploited clinically to develop incretin-related antidiabetic agents. The microbiome and the immune system are emerging as important players in regulating β-cell function and mass. The rich innervation of islet cells indicates it is a prime organ for regulation by the nervous system. In this review, we discuss the potential implications of signals from these organ systems as well as those from bone, placenta, kidney, thyroid, endothelial cells, reproductive organs and adrenal and pituitary glands that can directly impact β-cell biology. An added layer of complexity is the limited data regarding the relative relevance of one or more of these systems in different ethnic populations. It is evident that better understanding of this paradigm would provide clues to enhance β-cell function and/or mass in vivo in the long-term goal of treating or curing patients with diabetes.European Journal of Clinical Nutrition advance online publication, 15 March 2017; doi:10.1038/ejcn.2017.13.

PMID: 28294170 [PubMed - as supplied by publisher]

Insulin Signaling Regulates the FoxM1/PLK1/CENP-A Pathway to Promote Adaptive Pancreatic β Cell Proliferation.

Recent Publications of BIIC Members - Wed, 03/15/2017 - 01:58
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Insulin Signaling Regulates the FoxM1/PLK1/CENP-A Pathway to Promote Adaptive Pancreatic β Cell Proliferation.

Cell Metab. 2017 Feb 26;:

Authors: Shirakawa J, Fernandez M, Takatani T, El Ouaamari A, Jungtrakoon P, Okawa ER, Zhang W, Yi P, Doria A, Kulkarni RN

Abstract
Investigation of cell-cycle kinetics in mammalian pancreatic β cells has mostly focused on transition from the quiescent (G0) to G1 phase. Here, we report that centromere protein A (CENP-A), which is required for chromosome segregation during the M-phase, is necessary for adaptive β cell proliferation. Receptor-mediated insulin signaling promotes DNA-binding activity of FoxM1 to regulate expression of CENP-A and polo-like kinase-1 (PLK1) by modulating cyclin-dependent kinase-1/2. CENP-A deposition at the centromere is augmented by PLK1 to promote mitosis, while knocking down CENP-A limits β cell proliferation and survival. CENP-A deficiency in β cells leads to impaired adaptive proliferation in response to pregnancy, acute and chronic insulin resistance, and aging in mice. Insulin-stimulated CENP-A/PLK1 protein expression is blunted in islets from patients with type 2 diabetes. These data implicate the insulin-FoxM1/PLK1/CENP-A pathway-regulated mitotic cell-cycle progression as an essential component in the β cell adaptation to delay and/or prevent progression to diabetes.

PMID: 28286049 [PubMed - as supplied by publisher]

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