Recent Publications of BIIC Members

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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]

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

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.

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.

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.

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.

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.

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?

Sat, 05/06/2017 - 09:56
Related Articles

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]

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