Recent Publications of BIIC Members

Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells.

Thu, 02/15/2018 - 09:27
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Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells.

J Cell Mol Med. 2018 Feb 12;:

Authors: Shin H, Han JH, Yoon J, Sim HJ, Park TJ, Yang S, Lee EK, Kulkarni RN, Egan JM, Kim W

Abstract
Cannabinoid 1 receptors (CB1Rs) are expressed in peripheral tissues, including islets of Langerhans, where their function(s) is under scrutiny. Using mouse β-cell lines, human islets and CB1R-null (CB1R-/- ) mice, we have now investigated the role of CB1Rs in modulating β-cell function and glucose responsiveness. Synthetic CB1R agonists diminished GLP-1-mediated cAMP accumulation and insulin secretion as well as glucose-stimulated insulin secretion in mouse β-cell lines and human islets. In addition, silencing CB1R in mouse β cells resulted in an increased expression of pro-insulin, glucokinase (GCK) and glucose transporter 2 (GLUT2), but this increase was lost in β cells lacking insulin receptor. Furthermore, CB1R-/- mice had increased pro-insulin, GCK and GLUT2 expression in β cells. Our results suggest that CB1R signalling in pancreatic islets may be harnessed to improve β-cell glucose responsiveness and preserve their function. Thus, our findings further support that blocking peripheral CB1Rs would be beneficial to β-cell function in type 2 diabetes.

PMID: 29431265 [PubMed - as supplied by publisher]

Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis.

Fri, 02/09/2018 - 05:43

Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis.

Cell Metab. 2018 Feb 06;27(2):339-350.e3

Authors: Ouyang X, Han SN, Zhang JY, Nemeth BT, Pacher P, Feng D, Bataller R, Cabezas J, Stärkel P, Caballeria J, Pongratz RL, Cai SY, Schnabl B, Hoque R, Chen Y, Yang WH, Martinez IG, Wang FS, Gao B, Torok NJ, Kibbey RG, Mehal WZ

Abstract
Sterile inflammation after tissue damage is a ubiquitous response, yet it has the highest amplitude in the liver. This has major clinical consequences, for alcoholic and non-alcoholic steatohepatitis (ASH and NASH) account for the majority of liver disease in industrialized countries and both lack therapy. Requirements for sustained sterile inflammation include increased oxidative stress and activation of the HIF-1α signaling pathway. We demonstrate the ability of digoxin, a cardiac glycoside, to protect from liver inflammation and damage in ASH and NASH. Digoxin was effective in maintaining cellular redox homeostasis and suppressing HIF-1α pathway activation. A proteomic screen revealed that digoxin binds pyruvate kinase M2 (PKM2), and independently of PKM2 kinase activity results in chromatin remodeling and downregulation of HIF-1α transactivation. These data identify PKM2 as a mediator and therapeutic target for regulating liver sterile inflammation, and demonstrate a novel role for digoxin that can effectively protect the liver from ASH and NASH.

PMID: 29414684 [PubMed - in process]

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]

Endoplasmic reticulum stress in beta cells and autoimmune diabetes.

Sat, 12/30/2017 - 09:49
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Endoplasmic reticulum stress in beta cells and autoimmune diabetes.

Curr Opin Immunol. 2016 Dec;43:60-66

Authors: Clark AL, Urano F

Abstract
Type 1 diabetes results from the autoimmune destruction of pancreatic β cells, leading to insulin deficiency and hyperglycemia. Although multiple attempts have been made to slow the autoimmune process using immunosuppressive or immunomodulatory agents, there are still no effective treatments that can delay or reverse the progression of type 1 diabetes in humans. Recent studies support endoplasmic reticulum (ER) as a novel target for preventing the initiation of the autoimmune reaction, propagation of inflammation, and β cell death in type 1 diabetes. This review highlights recent findings on ER stress in β cells and development of type 1 diabetes and introduces potential new treatments targeting the ER to combat this disorder.

PMID: 27718448 [PubMed - indexed for MEDLINE]

Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet-induced oxidative stress.

Tue, 12/26/2017 - 09:49
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Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet-induced oxidative stress.

JCI Insight. 2017 Dec 21;2(24):

Authors: Abebe T, Mahadevan J, Bogachus L, Hahn S, Black M, Oseid E, Urano F, Cirulli V, Robertson RP

Abstract
Many theories have been advanced to better understand why β cell function and structure relentlessly deteriorate during the course of type 2 diabetes (T2D). These theories include inflammation, apoptosis, replication, neogenesis, autophagy, differentiation, dedifferentiation, and decreased levels of insulin gene regulatory proteins. However, none of these have considered the possibility that endogenous self-repair of existing β cells may be an important factor. To examine this hypothesis, we conducted studies with female Zucker diabetic fatty rats fed a high-fat diet (HFD) for 1, 2, 4, 7, 9, 18, or 28 days, followed by a return to regular chow for 2-3 weeks. Repair was defined as reversal of elevated blood glucose and of inappropriately low blood insulin levels caused by a HFD, as well as reversal of structural damage visualized by imaging studies. We observed evidence of functional β cell damage after a 9-day exposure to a HFD and then repair after 2-3 weeks of being returned to normal chow (blood glucose [BG] = 348 ± 30 vs. 126 ± 3; mg/dl; days 9 vs. 23 day, P < 0.01). After 18- and 28-day exposure to a HFD, damage was more severe and repair was less evident. Insulin levels progressively diminished with 9-day exposure to a HFD; after returning to a regular diet, insulin levels rebounded toward, but did not reach, normal values. Increase in β cell mass was 4-fold after 9 days and 3-fold after 18 days, and there was no increase after 28 days of a HFD. Increases in β cell mass during a HFD were not different when comparing values before and after a return to regular diet within the 9-, 18-, or 28-day studies. No changes were observed in apoptosis or β cell replication. Formation of intracellular markers of oxidative stress, intranuclear translocation of Nrf2, and formation of intracellular antioxidant proteins indicated the participation of HFD/oxidative stress induction of the Nrf2/antioxidant pathway. Flow cytometry-based assessment of β cell volume, morphology, and insulin-specific immunoreactivity, as well as ultrastructural analysis by transmission electron microscopy, revealed that short-term exposure to a HFD produced significant changes in β cell morphology and function that are reversible after returning to regular chow. These results suggest that a possible mechanism mediating the ability of β cells to self-repair after a short-term exposure to a HFD is the activation of the Nrf2/antioxidant pathway.

PMID: 29263299 [PubMed - as supplied by publisher]

CMPF: A Biomarker for Type 2 Diabetes Mellitus Progression?

Fri, 12/22/2017 - 09:49
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CMPF: A Biomarker for Type 2 Diabetes Mellitus Progression?

Trends Endocrinol Metab. 2016 Jul;27(7):439-40

Authors: Koppe L, Poitout V

Abstract
The factors that precipitate the transition from insulin resistance to type 2 diabetes mellitus (T2DM) remain elusive. A recent study showed that circulating levels of the furan fatty acid (FA) metabolite 3-Carboxy-4-Methyl-5-Propyl-2-Furanopropanoic Acid (CMPF) increase in individuals who progress from prediabetes to T2DM. CMPF increases oxidative stress and impairs insulin granule maturation and secretion.

PMID: 27132217 [PubMed - indexed for MEDLINE]

Bisphosphonates prevent age-related weight loss in Japanese postmenopausal women.

Fri, 12/15/2017 - 09:49
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Bisphosphonates prevent age-related weight loss in Japanese postmenopausal women.

J Bone Miner Metab. 2017 Dec 13;:

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

Abstract
Decline of body weight with aging is a major risk factor for frailty, osteoporosis and fracture, suggesting that treatment for osteoporosis may affect body composition. Recently, we have shown that 5-year treatment with raloxifene prevented age-related weight loss, suggesting some other drugs for osteoporosis may also prevent a decrease in body weight with aging. The present study aimed to identify the relationship between bisphosphonate treatment and body composition markers. We measured bone mineral density (BMD), body composition, and bone remodeling markers in 551 Japanese postmenopausal women with bisphosphonate treatment, which included risedronate or alendronate treatment (BP-treatment group; N = 193) and without treatment by any osteoporosis drug (no-treatment group; N = 358) for 4-7 years (mean observation periods; 5.5 years) and analyzed the relationship of these with BMD, body mass index (BMI), body weight, and biochemical markers. The mean (SD) age of the participants was 68.6 (9.8) years in the BP-treatment group and 63.7 (10.6) years in the no-treatment group. Percent changes in body weight and BMI were significantly different between the BP-treatment and no-treatment groups (P < 0.01 and P < 0.01, respectively). In multiple linear regression analysis, bisphosphonate treatment was a significant independent determinant of percent changes in body weight and BMI (P < 0.01 and P = 0.01, respectively). Long-term use of bisphosphonates prevented reductions in BMI and body weight, usually observed in elderly women. Our results suggest that bisphosphonate treatment not only reduces the risk for incident osteoporotic fractures but also for frailty in the elderly.

PMID: 29236162 [PubMed - as supplied by publisher]

The role of the carboxyl ester lipase (CEL) gene in pancreatic disease.

Fri, 12/15/2017 - 09:49
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The role of the carboxyl ester lipase (CEL) gene in pancreatic disease.

Pancreatology. 2017 Dec 05;:

Authors: Johansson BB, Fjeld K, El Jellas K, Gravdal A, Dalva M, Tjora E, Ræder H, Kulkarni RN, Johansson S, Njølstad PR, Molven A

Abstract
The enzyme carboxyl ester lipase (CEL), also known as bile salt-dependent or -stimulated lipase (BSDL, BSSL), hydrolyzes dietary fat, cholesteryl esters and fat-soluble vitamins in the duodenum. CEL is mainly expressed in pancreatic acinar cells and lactating mammary glands. The human CEL gene resides on chromosome 9q34.3 and contains a variable number of tandem repeats (VNTR) region that encodes a mucin-like protein tail. Although the number of normal repeats does not appear to significantly influence the risk for pancreatic disease, single-base pair deletions in the first VNTR repeat cause a syndrome of endocrine and exocrine dysfunction denoted MODY8. Hallmarks are low fecal elastase levels and pancreatic lipomatosis manifesting before the age of twenty, followed by development of diabetes and pancreatic cysts later in life. The mutant protein forms intracellular and extracellular aggregates, suggesting that MODY8 is a protein misfolding disease. Recently, a recombined allele between CEL and its pseudogene CELP was discovered. This allele (CEL-HYB) encodes a chimeric protein with impaired secretion increasing five-fold the risk for chronic pancreatitis. The CEL gene has proven to be exceptionally polymorphic due to copy number variants of the CEL-CELP locus and alterations involving the VNTR. Genome-wide association studies or deep sequencing cannot easily pick up this wealth of genetic variation. CEL is therefore an attractive candidate gene for further exploration of links to pancreatic disease.

PMID: 29233499 [PubMed - as supplied by publisher]

GPR119 Agonist AS1269574 Activates TRPA1 Cation Channels to Stimulate GLP-1 Secretion.

Fri, 12/15/2017 - 09:49
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GPR119 Agonist AS1269574 Activates TRPA1 Cation Channels to Stimulate GLP-1 Secretion.

Mol Endocrinol. 2016 Jun;30(6):614-29

Authors: Chepurny OG, Holz GG, Roe MW, Leech CA

Abstract
GPR119 is a G protein-coupled receptor expressed on intestinal L cells that synthesize and secrete the blood glucose-lowering hormone glucagon-like peptide-1 (GLP-1). GPR119 agonists stimulate the release of GLP-1 from L cells, and for this reason there is interest in their potential use as a new treatment for type 2 diabetes mellitus. AS1269574 is one such GPR119 agonist, and it is the prototype of a series of 2,4,6 trisubstituted pyrimidines that exert positive glucoregulatory actions in mice. Here we report the unexpected finding that AS1269574 stimulates GLP-1 release from the STC-1 intestinal cell line by directly promoting Ca(2+) influx through transient receptor potential ankyrin 1 (TRPA1) cation channels. These GPR119-independent actions of AS1269574 are inhibited by TRPA1 channel blockers (AP-18, A967079, HC030031) and are not secondary to intracellular Ca(2+) release or cAMP production. Patch clamp studies reveal that AS1269574 activates an outwardly rectifying membrane current with properties expected of TRPA1 channels. However, the TRPA1 channel-mediated action of AS1269574 to increase intracellular free calcium concentration is not replicated by GPR119 agonists (AR231453, oleoylethanolamide) unrelated in structure to AS1269574. Using human embryonic kidney-293 cells expressing recombinant rat TRPA1 channels but not GPR119, direct TRPA1 channel activating properties of AS1269574 are validated. Because we find that AS1269574 also acts in a conventional GPR119-mediated manner to stimulate proglucagon gene promoter activity in the GLUTag intestinal L cell line, new findings reported here reveal the surprising capacity of AS1269574 to act as a dual agonist at two molecular targets (GPR119/TRPA1) important to the control of L-cell function and type 2 diabetes mellitus drug discovery research.

PMID: 27082897 [PubMed - indexed for MEDLINE]

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