Recent Publications of BIIC Members

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NCBI: db=pubmed; Term=Gray JP OR Heart E OR Zarrouki B OR Corkey BE OR Bonner-Weir S OR Urano F OR Cline GW OR Sharp GW OR Holz GG OR Weir GC OR Kulkarni RN OR Tornheim K OR Kibbey RG OR Fonseca SG OR Straub SG OR Jetton TL OR Poitout V OR Prentki M
Updated: 6 hours 2 min ago

Nutrient regulation of pancreatic β-cell proliferation.

Wed, 10/11/2017 - 07:14

Nutrient regulation of pancreatic β-cell proliferation.

Biochimie. 2017 Oct 04;:

Authors: Moullé VS, Ghislain J, Poitout V

Abstract
Excess consumption of energy-dense foods combined with a sedentary lifestyle is driving an obesity epidemic. Although obesity is closely associated with insulin resistance, most individuals meet the insulin demand by increasing their functional β-cell mass. Those who eventually develop type 2 diabetes are distinguished by a failure in this compensatory process. Although a causal role of insulin resistance in compensatory β-cell responses has received considerable experimental support, precisely how the β cell senses changes in the metabolic environment is still unknown. As metabolism of glucose, lipids and amino acids is profoundly altered in obesity, it is not surprising that these nutrients are conspicuous among the factors proposed to contribute. In this review we summarise our understanding of the role of nutrients, in particular glucose, fatty acids and amino acids in β-cell compensation with a particular emphasis on their relation to insulin resistance-induced factors and their underlying mechanism of action. Finally, we describe the concept of epigenetic programming and review recent studies illustrating how the status of the β cell epigenome is a product of its nutrient environment, and how metabolic programming of the β cell contributes to diabetes risk.

PMID: 28987628 [PubMed - as supplied by publisher]

Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) β-cells using metformin-induced metabolic deceleration as a model.

Thu, 10/05/2017 - 03:10
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Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) β-cells using metformin-induced metabolic deceleration as a model.

J Biol Chem. 2017 Oct 02;:

Authors: Lamontagne J, Al-Mass A, Nolan CJ, Corkey BE, Madiraju SRM, Joly E, Prentki M

Abstract
Metabolic deceleration in pancreatic β-cells is associated with inhibition of glucose-induced insulin secretion (GIIS), but only in the presence of intermediate/sub-maximal glucose concentrations. Here, we used acute metformin treatment as a tool to induce metabolic deceleration in INS1 (832/13) β-cells, with the goal of identifying key pathways and metabolites involved in GIIS. Metabolites and pathways previously implicated as signals for GIIS were measured in the cells at 2-25 mM glucose, with or without 5 mM metformin. We defined three criteria to identify candidate signals: 1) glucose-responsiveness, 2) sensitivity to metformin-induced inhibition of the glucose effect at intermediate glucose concentrations, and 3) alleviation of metformin inhibition by elevated glucose concentrations. Despite the lack of recovery from metformin-induced impairment of mitochondrial energy metabolism (glucose oxidation, O2 consumption and ATP production), insulin secretion was almost completely restored at elevated glucose concentrations. Meeting the criteria for candidates involved in promoting GIIS were the following metabolic indicators and metabolites: cytosolic NAD(+)/NADH ratio (inferred from the dihydroxyacetone phosphate:glycerol-3-phosphate ratio), mitochondrial membrane potential, ADP, Ca(2+), 1-monoacylglycerol, diacylglycerol, malonyl-CoA, and HMG-CoA. On the contrary, most of the purine and nicotinamide nucleotides, acetoacetyl-CoA, H2O2, reduced glutathione and 2-monoacylglycerol were not glucose-responsive. Overall these results underscore the significance of mitochondrial energy metabolism-independent signals in GIIS regulation, in particular, the candidate lipid signaling molecules 1-monoacylglycerol, diacylglycerol and malonyl-CoA; the predominance of KATP/Ca(2+) signaling control by low ADP.Mg(2+) rather than by high ATP levels; and a role for a more oxidized state (NAD(+)/NADH) in the cytosol during GIIS that favors high glycolysis rates.

PMID: 28972173 [PubMed - as supplied by publisher]

Thymoquinone ameliorates diabetic phenotype in Diet-Induced Obesity mice via activation of SIRT-1-dependent pathways.

Thu, 09/28/2017 - 23:52
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Thymoquinone ameliorates diabetic phenotype in Diet-Induced Obesity mice via activation of SIRT-1-dependent pathways.

PLoS One. 2017;12(9):e0185374

Authors: Karandrea S, Yin H, Liang X, Slitt AL, Heart EA

Abstract
Thymoquinone, a natural occurring quinone and the main bioactive component of plant Nigella sativa, undergoes intracellular redox cycling and re-oxidizes NADH to NAD+. TQ administration (20 mg/kg/bw/day) to the Diet-Induced Obesity (DIO) mice reduced their diabetic phenotype by decreasing fasting blood glucose and fasting insulin levels, and improved glucose tolerance and insulin sensitivity as evaluated by oral glucose and insulin tolerance tests (OGTT and ITT). Furthermore, TQ decreased serum cholesterol levels and liver triglycerides, increased protein expression of phosphorylated Akt, decreased serum levels of inflammatory markers resistin and MCP-1, and decreased NADH/NAD+ ratio. These changes were paralleled by an increase in phosphorylated SIRT-1 and AMPKα in liver and phosphorylated SIRT-1 in skeletal muscle. TQ also increased insulin sensitivity in insulin-resistant HepG2 cells via a SIRT-1-dependent mechanism. These findings are consistent with the TQ-dependent re-oxidation of NADH to NAD+, which stimulates glucose and fatty acid oxidation and activation of SIRT-1-dependent pathways. Taken together, these results demonstrate that TQ ameliorates the diabetic phenotype in the DIO mouse model of type 2 diabetes.

PMID: 28950020 [PubMed - in process]

BDE-47 and BDE-85 stimulate insulin secretion in INS-1 832/13 pancreatic β-cells through the thyroid receptor and Akt.

Thu, 09/07/2017 - 11:09
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BDE-47 and BDE-85 stimulate insulin secretion in INS-1 832/13 pancreatic β-cells through the thyroid receptor and Akt.

Environ Toxicol Pharmacol. 2017 Sep 01;56:29-34

Authors: Karandrea S, Yin H, Liang X, Heart EA

Abstract
PBDEs (polybrominated diphenyl ethers) are environmental pollutants that have been linked to the development of type 2 diabetes, however, the precise mechanisms are not clear. Particularly, their direct effect on insulin secretion is unknown. In this study, we show that two PBDE congeners, BDE-47 and BDE-85, potentiate glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells. This effect of BDE-47 and BDE-85 on GSIS was dependent on thyroid receptor (TR). Both BDE-47 and BDE-85 (10μM) activated Akt during an acute exposure. The activation of Akt by BDE-47 and BDE-85 plays a role in their potentiation of GSIS, as pharmacological inhibition of PI3K, an upstream activator of Akt, significantly lowers GSIS compared to compounds alone. This study shows that BDE-47 and BDE-85 directly act on pancreatic β-cells to stimulate GSIS, and that this effect is mediated by the thyroid receptor (TR) and Akt activation.

PMID: 28869857 [PubMed - as supplied by publisher]

Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes.

Mon, 09/04/2017 - 08:49
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Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes.

J Biol Chem. 2017 Aug 31;:

Authors: Dirice E, Ng R, Martinez R, Hu J, Wagner FF, Holson EB, Wagner BK, Kulkarni RN

Abstract
Preservation of insulin-secreting β-cells is an important goal for therapies aimed at restoring normoglycemia in patients with diabetes. One approach, the inhibition of histone deacetylases (HDACs), has been reported to suppress pancreatic islet inflammation and β-cell apoptosis in vitro. In this report, we demonstrate the efficacy of HDAC inhibitors (HDACi) in vivo. We show that daily administration of BRD3308, an isoform-selective HDAC3 inhibitor, for 2 weeks to female nonobese diabetic (NOD) mice, beginning at 3 weeks of age, followed by twice-weekly injections until age 25 weeks, protects the animals from diabetes. The preservation of β-cells was due to a significant decrease in islet infiltration of mononuclear cells. Moreover, the BRD3308 treatment increased basal insulin secretion from islets cultured in vitro. All metabolic tissues tested in vehicle- or BRD3308-treated groups showed virtually no sign of immune cell infiltration, except minimal infiltration in white adipose tissue in animals treated with the highest BRD3308 dose (10 mg/kg), providing additional evidence of protection from immune attack in the treated groups. Furthermore, pancreata from animals treated with 10 mg/kg BRD3308 exhibited significantly decreased numbers of apoptotic β-cells compared with those treated with vehicle or low-dose BRD3308. Finally, animals treated with 1 or 10 mg/kg BRD3308 had enhanced β-cell proliferation. These in vivo results point to the potential use of selective HDAC3 inhibitors as a therapeutic approach to suppress pancreatic islet infiltration and prevent β-cell death with the long-term goal of limiting the progression of type 1 diabetes.

PMID: 28860191 [PubMed - as supplied by publisher]

Intermittent Fasting Preserves Beta-Cell Mass in Obesity-induced Diabetes via the Autophagy-Lysosome Pathway.

Fri, 09/01/2017 - 06:52
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Intermittent Fasting Preserves Beta-Cell Mass in Obesity-induced Diabetes via the Autophagy-Lysosome Pathway.

Autophagy. 2017 Aug 30;:0

Authors: Liu H, Javaheri A, Godar RJ, Murphy J, Ma X, Rohatgi N, Mahadevan J, Hyrc K, Saftig P, Marshall C, McDaniel ML, Remedi MS, Razani B, Urano F, Diwan A

Abstract
Obesity-induced diabetes is characterized by hyperglycemia, insulin resistance, and progressive beta cell failure. In islets of mice with obesity-induced diabetes, we observe increased beta cell death and impaired autophagic flux. We hypothesized that intermittent fasting, a clinically sustainable therapeutic strategy, stimulates autophagic flux to ameliorate obesity-induced diabetes. Our data show that despite continued high-fat intake, intermittent fasting restores autophagic flux in islets and improves glucose tolerance by enhancing glucose-stimulated insulin secretion, beta cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration. In contrast, intermittent fasting does not rescue beta-cell death or induce NEUROG3 expression in obese mice with lysosomal dysfunction secondary to deficiency of the lysosomal membrane protein, LAMP2 or haplo-insufficiency of BECN1/Beclin-1, a protein critical for autophagosome formation. Moreover, intermittent fasting is sufficient to provoke beta cell death in non-obese lamp2 null mice, attesting to a critical role for lysosome function in beta cell homeostasis under fasting conditions. Beta cells in intermittently-fasted LAMP2- or BECN1-deficient mice exhibit markers of autophagic failure with accumulation of damaged mitochondria and upregulation of oxidative stress. Thus, intermittent fasting preserves organelle quality via the autophagy-lysosome pathway to enhance beta cell survival and stimulates markers of regeneration in obesity-induced diabetes.

PMID: 28853981 [PubMed - as supplied by publisher]

Glycerol-3-phosphate phosphatase/PGP: Role in intermediate metabolism and target for cardiometabolic diseases.

Sat, 08/26/2017 - 03:04
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Glycerol-3-phosphate phosphatase/PGP: Role in intermediate metabolism and target for cardiometabolic diseases.

Biochimie. 2017 Aug 04;:

Authors: Possik E, Madiraju SRM, Prentki M

Abstract
Metabolic diseases, including obesity, type 2 diabetes, and metabolic syndrome arise because of disturbances in glucose and fat metabolism, which impact associated physiological events such as insulin secretion and action, fat storage and oxidation. Even though, decades of research has contributed to our current understanding of the components involved in glucose and fat metabolism and their regulation, that led to the development of many therapeutics, there are still many unanswered questions. Glycerol-3-phosphate (Gro3P), which is formed during glycolysis, is at the intersection of glucose and fat metabolism, and the availability of this metabolite can regulate energy and intermediary metabolism in mammalian cells. During the course of evolution, mammalian cells are assumed to have lost the capacity to directly hydrolyze Gro3P to glycerol, until the recent discovery from our laboratory showing that a previously known mammalian enzyme, phosphoglycolate phosphatase (PGP), can function as Gro3P phosphatase (G3PP) and regulate this metabolite levels. Emerging evidence indicates that G3PP/PGP is an evolutionarily conserved "multi-tasking" enzyme that belongs to the superfamily of haloacid dehalogenase-like phosphatase enzymes, and is capable of hydrolyzing Gro3P, an abundant physiologically relevant substrate, as well as other metabolites including 2-phosphoglycolate, 4-phospherythronate and 2-phospholactate, which are present in much smaller amounts in cells, under normal conditions. G3PP, by regulating Gro3P levels, plays a critical role in intermediary metabolism, including glycolysis, glucose oxidation, cellular redox and ATP production, gluconeogenesis, esterification of fatty acids towards glycerolipid synthesis and fatty acid oxidation. Because of G3PP's ability to regulate energy and intermediary metabolism as well as physiological functions such as insulin secretion, hepatic glucose production, and fat synthesis, storage and oxidation, the pathophysiological role of this enzyme in metabolic diseases needs to be precisely defined. In this review, we summarize the present knowledge on the structure, function and regulation of G3PP/PGP, and we discuss its potential therapeutic role for cardiometabolic diseases.

PMID: 28826615 [PubMed - as supplied by publisher]

Low serum osteocalcin concentration is associated with incident type 2 diabetes mellitus in Japanese women.

Thu, 08/03/2017 - 10:39
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Low serum osteocalcin concentration is associated with incident type 2 diabetes mellitus in Japanese women.

J Bone Miner Metab. 2017 Aug 01;:

Authors: Urano T, Shiraki M, Kuroda T, Tanaka S, Urano F, Uenishi K, Inoue S

Abstract
Increasing evidence suggests that osteocalcin is involved in the regulation of glucose homeostasis. However, the relationship between serum osteocalcin levels and risk of incident type 2 diabetes mellitus is not clear. The objective of this study is to investigate whether serum osteocalcin levels are associated with the risk of incident type 2 diabetes mellitus. This study included 1691 Japanese postmenopausal women, 61 incident diabetes cases, and 1630 non-diabetic control subjects in the observation period. Baseline concentrations of intact osteocalcin, HbA1c, bone-specific alkaline phosphatase, adiponectin, leptin, urinary N-telopeptides were assessed. Serum osteocalcin levels were significantly correlated with HbA1c levels among 1691 Japanese postmenopausal women (R = -0.12, P < 0.0001). In receiver operating characteristic curve analysis, the optimal cut-off levels for serum osteocalcin to predict the development of type 2 diabetes mellitus was 6.1 ng/mL. The group with baseline osteocalcin levels <6.1 ng/mL showed a significantly higher risk for developing diabetes than the group with baseline osteocalcin levels >6.1 ng/mL (log-rank test, P  <  0.0001) during the mean observation period (7.6 ± 6.1 years; mean ± SD). In multiple Cox proportional hazard analysis, osteocalcin levels were significantly associated with development of type 2 diabetes mellitus during the observation period. Our results indicate that a decrease in serum osteocalcin levels is associated with future development of type 2 diabetes mellitus independent of conventional risk factors in Japanese postmenopausal women.

PMID: 28766135 [PubMed - as supplied by publisher]

Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death.

Sat, 07/22/2017 - 03:58
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Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death.

Sci Rep. 2017 Jul 17;7(1):5611

Authors: Clark AL, Kanekura K, Lavagnino Z, Spears LD, Abreu D, Mahadevan J, Yagi T, Semenkovich CF, Piston DW, Urano F

Abstract
Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.

PMID: 28717166 [PubMed - in process]

A case of a patient with granulocyte-colony stimulating factor-producing pancreatic cancer who responded to nab-paclitaxel plus gemcitabine.

Sun, 07/09/2017 - 19:30
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A case of a patient with granulocyte-colony stimulating factor-producing pancreatic cancer who responded to nab-paclitaxel plus gemcitabine.

Nihon Shokakibyo Gakkai Zasshi. 2017;114(7):1277-1284

Authors: Kataoka K, Achiwa K, Minami Y, Fujita M, Naitoh T, Yamada M, Yamamoto H, Matsubara H, Urano F

Abstract
A 67-year-old male patient presented with an irregular mass involving the pancreatic body and tail with multiple liver/lymph node metastases. A biopsy indicated the presence of a poorly differentiated adenocarcinoma. Fever and increased white blood cell count, C-reactive protein levels, and granulocyte-colony stimulating factor (G-CSF) levels led to the diagnose of G-CSF-producing pancreatic cancer. The patient did not respond to FOLFIRINOX therapy (leucovorin, fluorouracil, irinotecan, and oxaliplatin), but nab-paclitaxel plus gemcitabine treatment was effective, resulting in tumor shrinkage and reduced G-CSF levels. After the fifth course of this therapy, exacerbation was noted, and the patient died of primary cancer 6 months after initiating the therapy. Here we report the case of this patient with G-CSF-producing pancreatic cancer who responded to chemotherapy.

PMID: 28679984 [PubMed - in process]

Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages.

Fri, 06/30/2017 - 12:16
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Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages.

Cell Rep. 2017 Jun 27;19(13):2743-2755

Authors: Araldi E, Fernández-Fuertes M, Canfrán-Duque A, Tang W, Cline GW, Madrigal-Matute J, Pober JS, Lasunción MA, Wu D, Fernández-Hernando C, Suárez Y

Abstract
Macrophages perform critical functions in both innate immunity and cholesterol metabolism. Here, we report that activation of Toll-like receptor 4 (TLR4) in macrophages causes lanosterol, the first sterol intermediate in the cholesterol biosynthetic pathway, to accumulate. This effect is due to type I interferon (IFN)-dependent histone deacetylase 1 (HDAC1) transcriptional repression of lanosterol-14α-demethylase, the gene product of Cyp51A1. Lanosterol accumulation in macrophages, because of either treatment with ketoconazole or induced conditional disruption of Cyp51A1 in mouse macrophages in vitro, decreases IFNβ-mediated signal transducer and activator of transcription (STAT)1-STAT2 activation and IFNβ-stimulated gene expression. These effects translate into increased survival to endotoxemic shock by reducing cytokine secretion. In addition, lanosterol accumulation increases membrane fluidity and ROS production, thus potentiating phagocytosis and the ability to kill bacteria. This improves resistance of mice to Listeria monocytogenes infection by increasing bacterial clearance in the spleen and liver. Overall, our data indicate that lanosterol is an endogenous selective regulator of macrophage immunity.

PMID: 28658622 [PubMed - in process]

Mammalian ECD protein is a novel negative regulator of the PERK arm of unfolded protein response.

Fri, 06/30/2017 - 12:16
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Mammalian ECD protein is a novel negative regulator of the PERK arm of unfolded protein response.

Mol Cell Biol. 2017 Jun 26;:

Authors: Olou AA, Sarkar A, Bele A, Gurumurthy CB, Mir RA, Ammons SA, Mirza S, Saleem I, Urano F, Band H, Band V

Abstract
The mammalian Ecdysoneless (ECD) is a highly-conserved ortholog of the Drosophila Ecd gene product whose mutations impair the synthesis of Ecdysone and produce cell-autonomous survival defects but mechanisms by which ECD functions are largely unknown. Here, we present evidence that ECD regulates endoplasmic reticulum (ER) stress response. ER stress induction led to a reduced ECD protein but this effect was not seen in PERK KO or phospho-deficient eIF2α MEFs; moreover, ECD mRNA levels were increased, suggesting impaired ECD translation as the mechanism for reduced protein levels. ECD co-localizes and co-immunoprecipitates with PERK and GRP78. ECD depletion increased the levels of p-PERK, p-eIF2α, and these effects were enhanced upon ER stress induction. Reciprocally, overexpression of ECD led to a marked decrease in p-PERK, p-eIF2α and ATF4 levels, but a robust increase in GRP78 protein levels. However, GRP78 mRNA levels were unchanged, suggesting a post-transcriptional event. Knockdown of GRP78 reversed the attenuating effect of ECD over-expression on PERK signaling. Significantly, overexpression of ECD provided a survival advantage to cells upon ER stress induction. Taken together, we demonstrate that ECD promotes survival upon ER stress by increasing GRP78 protein levels to enhance the adaptive folding protein in the ER to attenuate PERK signaling.

PMID: 28652267 [PubMed - as supplied by publisher]

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

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.

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.

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.

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.

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.

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.

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.

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]

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