Recent Publications of BIIC Members

Publisher Correction: Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA).

Sat, 02/03/2018 - 01:32
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Publisher Correction: Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA).

Nat Commun. 2018 Jan 31;9(1):498

Authors: Perry RJ, Peng L, Cline GW, Butrico GM, Wang Y, Zhang XM, Rothman DL, Petersen KF, Shulman GI

Abstract
The originally published version of this Article contained an error in Equation 30, which was inadvertently introduced during the production process. This has now been corrected in the PDF and HTML versions of the Article.

PMID: 29386503 [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.

Sat, 02/03/2018 - 01:32
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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 Dec;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 - indexed for MEDLINE]

Identification and determination of the inulin content in the roots of the Northeast Brazilian species Pombalia calceolaria L.

Tue, 01/30/2018 - 20:53
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Identification and determination of the inulin content in the roots of the Northeast Brazilian species Pombalia calceolaria L.

Carbohydr Polym. 2016 09 20;149:391-8

Authors: Pontes AG, Silva KL, Fonseca SG, Soares AA, Feitosa JP, Braz-Filho R, Romero NR, Bandeira MA

Abstract
A polysaccharide was extracted from the roots of Pombalia calceolaria, a plant used in folk medicine in Northeastern Brazil, by decoction followed by precipitation with methanol, yielding a concentration of 13.0% w/w, and purification with acetone. The molar mass peak was estimated to be 4.0×10(3)Da using gel permeation chromatography (GPC). Polarized light photomicrography of histological sections revealed the presence of inulin in the cortical parenchyma. The chemical composition of inulin was identified by 1D and 2D NMR and FT-IR spectroscopy and the findings were compared with the literature. This is the first time inulin has been identified on FT-IR and NMR for the species Pombalia calceolaria.

PMID: 27261763 [PubMed - indexed for MEDLINE]

Central Agonism of GPR120 Acutely Inhibits Food Intake and Food Reward and Chronically Suppresses Anxiety-Like Behavior in Mice.

Tue, 01/30/2018 - 20:53
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Central Agonism of GPR120 Acutely Inhibits Food Intake and Food Reward and Chronically Suppresses Anxiety-Like Behavior in Mice.

Int J Neuropsychopharmacol. 2016 Jul;19(7):

Authors: Auguste S, Fisette A, Fernandes MF, Hryhorczuk C, Poitout V, Alquier T, Fulton S

Abstract
BACKGROUND: GPR120 (FFAR4) is a G-protein coupled receptor implicated in the development of obesity and the antiinflammatory and insulin-sensitizing effects of omega-3 (ω-3) polyunsaturated fatty acids. Increasing central ω-3 polyunsaturated fatty acid levels has been shown to have both anorectic and anxiolytic actions. Despite the strong clinical interest in GPR120, its role in the brain is largely unknown, and thus we sought to determine the impact of central GPR120 pharmacological activation on energy balance, food reward, and anxiety-like behavior.
METHODS: Male C57Bl/6 mice with intracerebroventricular cannulae received a single injection (0.1 or 1 µM) or continuous 2-week infusion (1 µM/d; mini-pump) of a GPR120 agonist or vehicle. Free-feeding intake, operant lever-pressing for palatable food, energy expenditure (indirect calorimetry), and body weight were measured. GPR120 mRNA expression was measured in pertinent brain areas. Anxiety-like behavior was assessed in the elevated-plus maze and open field test.
RESULTS: GPR120 agonist injections substantially reduced chow intake during 4 hours postinjection, suppressed the rewarding effects of high-fat/-sugar food, and blunted approach-avoidance behavior in the open field. Conversely, prolonged central GPR120 agonist infusions reduced anxiety-like behavior in the elevated-plus maze and open field, yet failed to affect free-feeding intake, energy expenditure, and body weight on a high-fat diet.
CONCLUSION: Acute reductions in food intake and food reward suggest that GPR120 could mediate the effects of central ω-3 polyunsaturated fatty acids to inhibit appetite. The anxiolytic effect elicited by GPR120 agonist infusions favors the testing of compounds that can enter the brain to activate GPR120 for the mitigation of anxiety.

PMID: 26888796 [PubMed - indexed for MEDLINE]

Evaluation of PET Brain Radioligands for Imaging Pancreatic β-Cell Mass: Potential Utility of 11C-PHNO.

Sat, 01/27/2018 - 20:05
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Evaluation of PET Brain Radioligands for Imaging Pancreatic β-Cell Mass: Potential Utility of 11C-PHNO.

J Nucl Med. 2018 Jan 25;:

Authors: Bini J, Naganawa M, Nabulsi NB, Huang YH, Ropchan J, Lim K, Najafzadeh S, Herold KC, Cline GW, Carson RE

Abstract
Type 1 diabetes mellitus (T1DM) is characterized by a loss of beta cells in the islets of Langerhans of the pancreas and subsequent deficient insulin secretion in response to hyperglycemia. Development of an in vivo test to measure β-cell mass (BCM) would greatly enhance the ability to track diabetes therapies. β-cells and neurological tissues have common cellular receptors and transporters, therefore, we screened brain radioligands for their ability to identify β-cells. Methods: We examined a β-cell gene atlas for endocrine pancreas receptor targets and cross-referenced these targets with brain radioligands that were available at our institution. Twelve healthy control (HC) subjects and two T1DM subjects underwent dynamic positron emission tomography/computed tomography (PET/CT) scans with six tracers. Results: The D2/D3-receptor agonist radioligand 11C-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO) was the only radioligand to demonstrate sustained uptake in the pancreas with high contrast versus abdominal organs such as the kidneys, liver, and spleen, based on the first 30 min of data. Mean standardized uptake value (SUV) from 20-30 minutes demonstrated high uptake of 11C-(+)-PHNO in HCs (SUV:13.8) with a 71% reduction in a T1DM subject with undetectable levels of C-peptide (SUV:4.0) and a 20% reduction in a T1DM subject with fasting C-peptide level of 0.38 ng/mL (SUV:11.0). SUV in abdominal organs outside the pancreas did not show measureable differences between the control and T1DM subjects, suggesting that the changes in SUV of 11C-(+)-PHNO may be specific to changes in the pancreas between HCs and T1DM subjects. Using D3- and D2-antagonists, in non-human primates (NHP), specific pancreatic binding (SUVR-1) of 11C-PHNO was reduced by 57% and 38%, respectively. Conclusion:11C-(+)-PHNO is a potential marker of BCM with 2:1 binding of D3-receptors over D2-receptors. Further in vitro and in vivo studies to establish D2/D3-receptor specificity to β-cells is warranted to characterize 11C-(+)-PHNO as a candidate for clinical measurement of BCM in HC and diabetic subjects.

PMID: 29371405 [PubMed - as supplied by publisher]

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

Thu, 01/18/2018 - 14:29
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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 Aug;54(8):737-747

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 - indexed for MEDLINE]

Clinical efficacy of fecal occult blood test and colonoscopy for dasatinib-induced hemorrhagic colitis in CML patients.

Thu, 01/18/2018 - 14:29
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Clinical efficacy of fecal occult blood test and colonoscopy for dasatinib-induced hemorrhagic colitis in CML patients.

Blood. 2017 01 05;129(1):126-128

Authors: Nishiwaki S, Maeda M, Yamada M, Okuno S, Harada Y, Suzuki K, Kurahashi S, Urano F, Okamura S, Sugiura I

PMID: 27864292 [PubMed - indexed for MEDLINE]

Adaptive preconditioning in neurological diseases - therapeutic insights from proteostatic perturbations.

Thu, 01/18/2018 - 14:29
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Adaptive preconditioning in neurological diseases - therapeutic insights from proteostatic perturbations.

Brain Res. 2016 Oct 01;1648(Pt B):603-616

Authors: Mollereau B, Rzechorzek NM, Roussel BD, Sedru M, Van den Brink DM, Bailly-Maitre B, Palladino F, Medinas DB, Domingos PM, Hunot S, Chandran S, Birman S, Baron T, Vivien D, Duarte CB, Ryoo HD, Steller H, Urano F, Chevet E, Kroemer G, Ciechanover A, Calabrese EJ, Kaufman RJ, Hetz C

Abstract
In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.

PMID: 26923166 [PubMed - indexed for MEDLINE]

A Vitamin B12 Conjugate of Exendin-4 Improves Glucose Tolerance Without Associated Nausea or Hypophagia in Rodents.

Mon, 01/15/2018 - 14:26
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A Vitamin B12 Conjugate of Exendin-4 Improves Glucose Tolerance Without Associated Nausea or Hypophagia in Rodents.

Diabetes Obes Metab. 2018 Jan 12;:

Authors: Mietlicki-Baase EG, Liberini CG, Workinger JL, Bonaccorso RL, Borner T, Reiner DJ, Koch-Laskowski K, McGrath LE, Lhamo R, Stein LM, De Jonghe BC, Holz GG, Roth CL, Doyle RP, Hayes MR

Abstract
AIMS: While pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed a conjugate of vitamin B12 bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability and retention of GLP-1R agonism. Here, we evaluate whether the conjugate (B12-Ex4) can improve glucose tolerance without producing anorexia and malaise.
MATERIALS AND METHODS: We evaluated the effects of systemic B12-Ex4 and unconjugated Ex4 on food intake and body weight change, oral glucose tolerance, and nausea/malaise in male rats, and on intraperitoneal glucose tolerance in mice. To evaluate whether differences in the profile of effects of B12-Ex4 versus unconjugated Ex4 are due to altered CNS penetrance, rats received systemic injections of fluorescein-Ex4 (Flex), Cy5-B12 or Cy5-B12-Ex4 and brain penetrance was evaluated using confocal microscopy. Uptake of systemically administered Cy5-B12-Ex4 in insulin-containing pancreatic beta cells was also examined.
RESULTS: B12-Ex4 conjugate improves glucose tolerance, but does not elicit the malaise and anorexia produced by unconjugated Ex4. While Flex robustly penetrates into the brain (dorsal vagal complex, paraventricular hypothalamus), Cy5-B12 and Cy5-B12-Ex4 fluorescence were not observed centrally, supporting a lack of CNS penetrance in line with observed reduction in CNS-associated Ex4 side effects. Cy5-B12-Ex4 colocalizes with insulin in the pancreas, suggesting direct pancreatic action as a potential mechanism underlying the hypoglycemic effects of B12-Ex4.
CONCLUSIONS: These novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.

PMID: 29327400 [PubMed - as supplied by publisher]

Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation.

Fri, 01/12/2018 - 11:56
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Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation.

Cell. 2017 Dec 29;:

Authors: Perry RJ, Wang Y, Cline GW, Rabin-Court A, Song JD, Dufour S, Zhang XM, Petersen KF, Shulman GI

Abstract
The transition from the fed to the fasted state necessitates a shift from carbohydrate to fat metabolism that is thought to be mostly orchestrated by reductions in plasma insulin concentrations. Here, we show in awake rats that insulinopenia per se does not cause this transition but that both hypoleptinemia and insulinopenia are necessary. Furthermore, we show that hypoleptinemia mediates a glucose-fatty acid cycle through activation of the hypothalamic-pituitary-adrenal axis, resulting in increased white adipose tissue (WAT) lipolysis rates and increased hepatic acetyl-coenzyme A (CoA) content, which are essential to maintain gluconeogenesis during starvation. We also show that in prolonged starvation, substrate limitation due to reduced rates of glucose-alanine cycling lowers rates of hepatic mitochondrial anaplerosis, oxidation, and gluconeogenesis. Taken together, these data identify a leptin-mediated glucose-fatty acid cycle that integrates responses of the muscle, WAT, and liver to promote a shift from carbohydrate to fat oxidation and maintain glucose homeostasis during starvation.

PMID: 29307489 [PubMed - as supplied by publisher]

Response to Comment on Schwartz et al. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell-Centric Classification Schema. Diabetes Care 2016;39:179-186.

Tue, 01/09/2018 - 10:48
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Response to Comment on Schwartz et al. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell-Centric Classification Schema. Diabetes Care 2016;39:179-186.

Diabetes Care. 2016 08;39(8):e129-30

Authors: Schwartz SS, Epstein S, Corkey BE, Grant SF, Gavin JR, Aguilar RB

PMID: 27457644 [PubMed - indexed for MEDLINE]

Skeletal muscle insulin resistance is induced by 4-hydroxy-2-hexenal, a by-product of n-3 fatty acid peroxidation.

Sat, 01/06/2018 - 09:49
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Skeletal muscle insulin resistance is induced by 4-hydroxy-2-hexenal, a by-product of n-3 fatty acid peroxidation.

Diabetologia. 2018 Jan 03;:

Authors: Soulage CO, Sardón Puig L, Soulère L, Zarrouki B, Guichardant M, Lagarde M, Pillon NJ

Abstract
AIMS/HYPOTHESIS: Oxidative stress is involved in the pathophysiology of insulin resistance and its progression towards type 2 diabetes. The peroxidation of n-3 polyunsaturated fatty acids produces 4-hydroxy-2-hexenal (4-HHE), a lipid aldehyde with potent electrophilic properties able to interfere with many pathophysiological processes. The aim of the present study was to investigate the role of 4-HHE in the development of insulin resistance.
METHODS: 4-HHE concentration was measured in plasma from humans and rats by GC-MS. Insulin resistance was estimated in healthy rats after administration of 4-HHE using hyperinsulinaemic-euglycaemic clamps. In muscle cells, glucose uptake was measured using 2-deoxy-D-glucose and signalling pathways were investigated by western blotting. Intracellular glutathione was measured using a fluorimetric assay kit and boosted using 1,2-dithiole-3-thione (D3T).
RESULTS: Circulating levels of 4-HHE in type 2 diabetic humans and a rat model of diabetes (obese Zucker diabetic fatty rats), were twice those in their non-diabetic counterparts (33 vs 14 nmol/l, p < 0.001), and positively correlated with blood glucose levels. During hyperinsulinaemic-euglycaemic clamps in rats, acute intravenous injection of 4-HHE significantly altered whole-body insulin sensitivity and decreased glucose infusion rate (24.2 vs 9.9 mg kg-1 min-1, p < 0.001). In vitro, 4-HHE impaired insulin-stimulated glucose uptake and signalling (protein kinase B/Akt and IRS1) in L6 muscle cells. Insulin-induced glucose uptake was reduced from 186 to 141.9 pmol mg-1 min-1 (p < 0.05). 4-HHE induced carbonylation of cell proteins and reduced glutathione concentration from 6.3 to 4.5 nmol/mg protein. Increasing intracellular glutathione pools using D3T prevented 4-HHE-induced carbonyl stress and insulin resistance.
CONCLUSIONS/INTERPRETATION: 4-HHE is produced in type 2 diabetic humans and Zucker diabetic fatty rats and blunts insulin action in skeletal muscle. 4-HHE therefore plays a causal role in the pathophysiology of type 2 diabetes and might constitute a potential therapeutic target to taper oxidative stress-induced insulin resistance.

PMID: 29299636 [PubMed - as supplied by publisher]

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