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Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase.
Hunter RW, Hughey CC, Lantier L, Sundelin EI, Peggie M, Zeqiraj E, Sicheri F, Jessen N, Wasserman DH, Sakamoto K
(2018) Nat Med 24: 1395-1406
MeSH Terms: Adenosine Monophosphate, Aminoimidazole Carboxamide, Animals, Base Sequence, Chickens, Disease Models, Animal, Fructose-Bisphosphatase, Glucose, Glucose Intolerance, Homeostasis, Humans, Hypoglycemia, Liver, Metformin, Mice, Inbred C57BL, Mutation, Obesity, Prodrugs, Ribonucleotides
Show Abstract · Added March 26, 2019
Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet-fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.
1 Communities
1 Members
0 Resources
19 MeSH Terms
Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis.
Winnick JJ, Kraft G, Gregory JM, Edgerton DS, Williams P, Hajizadeh IA, Kamal MZ, Smith M, Farmer B, Scott M, Neal D, Donahue EP, Allen E, Cherrington AD
(2016) J Clin Invest 126: 2236-48
MeSH Terms: Animals, Blood Glucose, Brain, Diabetes Mellitus, Type 1, Disease Models, Animal, Dogs, Female, Fructose, Glucose, Glucose Clamp Technique, Humans, Hypoglycemia, Insulin, Lactic Acid, Lipid Metabolism, Liver, Liver Glycogen, Male, Signal Transduction
Show Abstract · Added May 29, 2016
Liver glycogen is important for the counterregulation of hypoglycemia and is reduced in individuals with type 1 diabetes (T1D). Here, we examined the effect of varying hepatic glycogen content on the counterregulatory response to low blood sugar in dogs. During the first 4 hours of each study, hepatic glycogen was increased by augmenting hepatic glucose uptake using hyperglycemia and a low-dose intraportal fructose infusion. After hepatic glycogen levels were increased, animals underwent a 2-hour control period with no fructose infusion followed by a 2-hour hyperinsulinemic/hypoglycemic clamp. Compared with control treatment, fructose infusion caused a large increase in liver glycogen that markedly elevated the response of epinephrine and glucagon to a given hypoglycemia and increased net hepatic glucose output (NHGO). Moreover, prior denervation of the liver abolished the improved counterregulatory responses that resulted from increased liver glycogen content. When hepatic glycogen content was lowered, glucagon and NHGO responses to insulin-induced hypoglycemia were reduced. We conclude that there is a liver-brain counterregulatory axis that is responsive to liver glycogen content. It remains to be determined whether the risk of iatrogenic hypoglycemia in T1D humans could be lessened by targeting metabolic pathway(s) associated with hepatic glycogen repletion.
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2 Members
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19 MeSH Terms
Electronic medical records and genomics (eMERGE) network exploration in cataract: several new potential susceptibility loci.
Ritchie MD, Verma SS, Hall MA, Goodloe RJ, Berg RL, Carrell DS, Carlson CS, Chen L, Crosslin DR, Denny JC, Jarvik G, Li R, Linneman JG, Pathak J, Peissig P, Rasmussen LV, Ramirez AH, Wang X, Wilke RA, Wolf WA, Torstenson ES, Turner SD, McCarty CA
(2014) Mol Vis 20: 1281-95
MeSH Terms: Age Factors, Aged, Aged, 80 and over, Algorithms, Cataract, Databases, Nucleic Acid, Electronic Health Records, Female, Fructose-Bisphosphate Aldolase, Genetic Markers, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Health Care Costs, Humans, MAP Kinase Kinase Kinase 1, MEF2 Transcription Factors, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, United States
Show Abstract · Added March 14, 2018
PURPOSE - Cataract is the leading cause of blindness in the world, and in the United States accounts for approximately 60% of Medicare costs related to vision. The purpose of this study was to identify genetic markers for age-related cataract through a genome-wide association study (GWAS).
METHODS - In the electronic medical records and genomics (eMERGE) network, we ran an electronic phenotyping algorithm on individuals in each of five sites with electronic medical records linked to DNA biobanks. We performed a GWAS using 530,101 SNPs from the Illumina 660W-Quad in a total of 7,397 individuals (5,503 cases and 1,894 controls). We also performed an age-at-diagnosis case-only analysis.
RESULTS - We identified several statistically significant associations with age-related cataract (45 SNPs) as well as age at diagnosis (44 SNPs). The 45 SNPs associated with cataract at p<1×10(-5) are in several interesting genes, including ALDOB, MAP3K1, and MEF2C. All have potential biologic relationships with cataracts.
CONCLUSIONS - This is the first genome-wide association study of age-related cataract, and several regions of interest have been identified. The eMERGE network has pioneered the exploration of genomic associations in biobanks linked to electronic health records, and this study is another example of the utility of such resources. Explorations of age-related cataract including validation and replication of the association results identified herein are needed in future studies.
0 Communities
1 Members
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22 MeSH Terms
Hepatic glucose uptake and disposition during short-term high-fat vs. high-fructose feeding.
Coate KC, Kraft G, Moore MC, Smith MS, Ramnanan C, Irimia JM, Roach PJ, Farmer B, Neal DW, Williams P, Cherrington AD
(2014) Am J Physiol Endocrinol Metab 307: E151-60
MeSH Terms: Animals, Blood Glucose, Diet, High-Fat, Dietary Carbohydrates, Dietary Fats, Dogs, Fructose, Glucokinase, Glucose, Glycerol, Lactic Acid, Liver, Male, Triglycerides
Show Abstract · Added June 2, 2014
In dogs consuming a high-fat and -fructose diet (52 and 17% of total energy, respectively) for 4 wk, hepatic glucose uptake (HGU) in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery is markedly blunted with reduction in glucokinase (GK) protein and glycogen synthase (GS) activity. The present study compared the impact of selective increases in dietary fat and fructose on liver glucose metabolism. Dogs consumed weight-maintaining chow (CTR) or hypercaloric high-fat (HFA) or high-fructose (HFR) diets diet for 4 wk before undergoing clamp studies with infusion of somatostatin and intraportal insulin (3-4 times basal) and glucagon (basal). The hepatic glucose load (HGL) was doubled during the clamp using peripheral vein (Pe) glucose infusion in the first 90 min (P1) and portal vein (4 mg·kg(-1)·min(-1)) plus Pe glucose infusion during the final 90 min (P2). During P2, HGU was 2.8 ± 0.2, 1.0 ± 0.2, and 0.8 ± 0.2 mg·kg(-1)·min(-1) in CTR, HFA, and HFR, respectively (P < 0.05 for HFA and HFR vs. CTR). Compared with CTR, hepatic GK protein and catalytic activity were reduced (P < 0.05) 35 and 56%, respectively, in HFA, and 53 and 74%, respectively, in HFR. Liver glycogen concentrations were 20 and 38% lower in HFA and HFR than CTR (P < 0.05). Hepatic Akt phosphorylation was decreased (P < 0.05) in HFA (21%) but not HFR. Thus, HFR impaired hepatic GK and glycogen more than HFA, whereas HFA reduced insulin signaling more than HFR. HFA and HFR effects were not additive, suggesting that they act via the same mechanism or their effects converge at a saturable step.
Copyright © 2014 the American Physiological Society.
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4 Members
2 Resources
14 MeSH Terms
Acute myopia and angle closure glaucoma from topiramate in a seven-year-old: a case report and review of the literature.
Rapoport Y, Benegas N, Kuchtey RW, Joos KM
(2014) BMC Pediatr 14: 96
MeSH Terms: Anticonvulsants, Child, Diagnosis, Differential, Female, Fructose, Glaucoma, Angle-Closure, Headache, Humans, Myopia, Seizures, Topiramate
Show Abstract · Added March 19, 2018
BACKGROUND - A case is reported of acute bilateral myopia and angle closure glaucoma in a 7-year-old patient from topiramate toxicity. This is the second known reported case of topiramate induced acute angle closure glaucoma and third known reported case of topiramate induced acute myopia in a pediatric patient.
CASE PRESENTATION - This case presents a 7-year-old who had recently begun topiramate therapy for seizures and headache. She developed painless blurred vision and acute bilateral myopia, which progressed to acute bilateral angle closure glaucoma. After a routine eye exam where myopia was diagnosed, the patient presented to the emergency room with symptoms of acute onset blurry vision, tearing, red eyes, swollen eyelids, and photophobia. The symptoms, myopia, and angle closure resolved with topical and oral intraocular pressure lowering medications, topical cyclopentolate, and discontinuation of topiramate.
CONCLUSION - Acute angle closure glaucoma is a well-known side effect of topiramate, but is rarely seen in children. It cautions providers to the potential ophthalmic side effects of commonly used medications in the pediatric population. It highlights the need to keep a broad differential in mind when encountering sudden onset blurry vision in the primary care clinic, the need for careful consideration of side effects when starting topiramate therapy in a child, and the need for parental counseling of side effects.
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1 Members
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11 MeSH Terms
Hepatic glucose metabolism in late pregnancy: normal versus high-fat and -fructose diet.
Coate KC, Smith MS, Shiota M, Irimia JM, Roach PJ, Farmer B, Williams PE, Moore MC
(2013) Diabetes 62: 753-61
MeSH Terms: Animals, Diabetes, Gestational, Diet, High-Fat, Disease Models, Animal, Dogs, Down-Regulation, Female, Fructose, Glucokinase, Glucose, Glucose Intolerance, Glycogen Phosphorylase, Liver Form, Glycogen Synthase, Hyperglycemia, Insulin Resistance, Liver, Liver Glycogen, Maternal Nutritional Physiological Phenomena, Postprandial Period, Pregnancy
Show Abstract · Added June 2, 2014
Net hepatic glucose uptake (NHGU) is an important contributor to postprandial glycemic control. We hypothesized that NHGU is reduced during normal pregnancy and in a pregnant diet-induced model of impaired glucose intolerance/gestational diabetes mellitus (IGT/GDM). Dogs (n = 7 per group) that were nonpregnant (N), normal pregnant (P), or pregnant with IGT/GDM (pregnant dogs fed a high-fat and -fructose diet [P-HFF]) underwent a hyperinsulinemic-hyperglycemic clamp with intraportal glucose infusion. Clamp period insulin, glucagon, and glucose concentrations and hepatic glucose loads did not differ among groups. The N dogs reached near-maximal NHGU rates within 30 min; mean ± SEM NHGU was 105 ± 9 µmol·100 g liver⁻¹·min⁻¹. The P and P-HFF dogs reached maximal NHGU in 90-120 min; their NHGU was blunted (68 ± 9 and 16 ± 17 µmol·100 g liver⁻¹·min⁻¹, respectively). Hepatic glycogen synthesis was reduced 20% in P versus N and 40% in P-HFF versus P dogs. This was associated with a reduction (>70%) in glycogen synthase activity in P-HFF versus P and increased glycogen phosphorylase (GP) activity in both P (1.7-fold greater than N) and P-HFF (1.8-fold greater than P) dogs. Thus, NHGU under conditions mimicking the postprandial state is delayed and suppressed in normal pregnancy, with concomitant reduction in glycogen storage. NHGU is further blunted in IGT/GDM. This likely contributes to postprandial hyperglycemia during pregnancy, with potential adverse outcomes for the fetus and mother.
0 Communities
2 Members
0 Resources
20 MeSH Terms
Portal vein glucose entry triggers a coordinated cellular response that potentiates hepatic glucose uptake and storage in normal but not high-fat/high-fructose-fed dogs.
Coate KC, Kraft G, Irimia JM, Smith MS, Farmer B, Neal DW, Roach PJ, Shiota M, Cherrington AD
(2013) Diabetes 62: 392-400
MeSH Terms: Animals, Diet, High-Fat, Dogs, Fructose, Glucokinase, Glucose, Glucose Intolerance, Glycogen Synthase, Hyperglycemia, Hyperinsulinism, Liver, Liver Glycogen, Male, Portal Vein, Signal Transduction
Show Abstract · Added December 5, 2013
The cellular events mediating the pleiotropic actions of portal vein glucose (PoG) delivery on hepatic glucose disposition have not been clearly defined. Likewise, the molecular defects associated with postprandial hyperglycemia and impaired hepatic glucose uptake (HGU) following consumption of a high-fat, high-fructose diet (HFFD) are unknown. Our goal was to identify hepatocellular changes elicited by hyperinsulinemia, hyperglycemia, and PoG signaling in normal chow-fed (CTR) and HFFD-fed dogs. In CTR dogs, we demonstrated that PoG infusion in the presence of hyperinsulinemia and hyperglycemia triggered an increase in the activity of hepatic glucokinase (GK) and glycogen synthase (GS), which occurred in association with further augmentation in HGU and glycogen synthesis (GSYN) in vivo. In contrast, 4 weeks of HFFD feeding markedly reduced GK protein content and impaired the activation of GS in association with diminished HGU and GSYN in vivo. Furthermore, the enzymatic changes associated with PoG sensing in chow-fed animals were abolished in HFFD-fed animals, consistent with loss of the stimulatory effects of PoG delivery. These data reveal new insight into the molecular physiology of the portal glucose signaling mechanism under normal conditions and to the pathophysiology of aberrant postprandial hepatic glucose disposition evident under a diet-induced glucose-intolerant condition.
1 Communities
3 Members
1 Resources
15 MeSH Terms
A chemically programmed antibody is a long-lasting and potent inhibitor of influenza neuraminidase.
Hayakawa M, Toda N, Carrillo N, Thornburg NJ, Crowe JE, Barbas CF
(2012) Chembiochem 13: 2191-5
MeSH Terms: Animals, Antibodies, Monoclonal, Antiviral Agents, Click Chemistry, Fructose-Bisphosphate Aldolase, Humans, Immunoconjugates, Influenza A virus, Influenza, Human, Mice, Models, Molecular, Neuraminidase, Orthomyxoviridae Infections, Zanamivir
Show Abstract · Added October 28, 2012
Programming an anti-flu strategy: A new and potent neuraminidase inhibitor that maintains long-term systemic exposure of an antibody and the therapeutic activity of the neuraminadase inhibitor zanamivir has been created. This strategy could provide a promising new class of influenza A drugs for therapy and prophylaxis, and validates enzyme inhibitors as programming agents in synthetic immunology.
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Regulation of hepatic glucose uptake and storage in vivo.
Moore MC, Coate KC, Winnick JJ, An Z, Cherrington AD
(2012) Adv Nutr 3: 286-94
MeSH Terms: AMP-Activated Protein Kinases, Animals, Biological Transport, Blood Glucose, Fructose, Glucose, Glycogen, Humans, Insulin, Liver, Models, Animal, Portal Vein, Postprandial Period
Show Abstract · Added December 5, 2013
In the postprandial state, the liver takes up and stores glucose to minimize the fluctuation of glycemia. Elevated insulin concentrations, an increase in the load of glucose reaching the liver, and the oral/enteral/portal vein route of glucose delivery (compared with the peripheral intravenous route) are factors that increase the rate of net hepatic glucose uptake (NHGU). The entry of glucose into the portal vein stimulates a portal glucose signal that not only enhances NHGU but concomitantly reduces muscle glucose uptake to ensure appropriate partitioning of a glucose load. This coordinated regulation of glucose uptake is likely neurally mediated, at least in part, because it is not observed after total hepatic denervation. Moreover, there is evidence that both the sympathetic and the nitrergic innervation of the liver exert a tonic repression of NHGU that is relieved under feeding conditions. Further, the energy sensor 5'AMP-activated protein kinase appears to be involved in regulation of NHGU and glycogen storage. Consumption of a high-fat and high-fructose diet impairs NHGU and glycogen storage in association with a reduction in glucokinase protein and activity. An understanding of the impact of nutrients themselves and the route of nutrient delivery on liver carbohydrate metabolism is fundamental to the development of therapies for impaired postprandial glucoregulation.
1 Communities
3 Members
1 Resources
13 MeSH Terms
A high-fat, high-fructose diet accelerates nutrient absorption and impairs net hepatic glucose uptake in response to a mixed meal in partially pancreatectomized dogs.
Coate KC, Kraft G, Lautz M, Smith M, Neal DW, Cherrington AD
(2011) J Nutr 141: 1643-51
MeSH Terms: Alanine, Animal Feed, Animals, Blood Glucose, Blood Proteins, Dietary Carbohydrates, Dietary Fats, Dogs, Fatty Acids, Nonesterified, Fructose, Glucose, Glycerol, Glycogen, Insulin, Lactic Acid, Lipids, Liver, Male, Pancreatectomy, Proteins
Show Abstract · Added December 5, 2013
The aim of this study was to elucidate the impact of a high-fat, high-fructose diet (HFFD; fat, 52%; fructose, 17%), in the presence of a partial (~65%) pancreatectomy (PPx), on the response of the liver and extrahepatic tissues to an orally administered, liquid mixed meal. Adult male dogs were fed either a nonpurified, canine control diet (CTR; fat, 26%; no fructose; n = 5) or a HFFD (n = 5) for 8 wk. Diets were provided in a quantity to maintain neutral or positive energy balance in CTR or HFFD, respectively. Dogs underwent a sham operation or PPx at wk 0, portal and hepatic vein catheterization at wk 6, and a mixed meal test at wk 8. Postprandial glucose concentrations were significantly greater in the HFFD group (14.5 ± 2.0 mmol/L) than in the CTR group (9.2 ± 0.5 mmol/L). Impaired glucose tolerance in HFFD was due in part to accelerated gastric emptying and glucose absorption, as indicated by a more rapid rise in arterial plasma acetaminophen and the rate of glucose output by the gut, respectively, in HFFD than in CTR. It was also attributable to lower net hepatic glucose uptake (NHGU) in the HFFD group (5.5 ± 3.9 μmol · kg(-1) · min(-1)) compared to the CTR group (26.6 ± 7.0 μmol · kg(-1) · min(-1)), resulting in lower hepatic glycogen synthesis (GSYN) in the HFFD group (10.8 ± 5.4 μmol · kg(-1) · min(-1)) than in the CTR group (30.4 ± 7.0 μmol · kg(-1) · min(-1)). HFFD also displayed aberrant suppression of lipolysis by insulin. In conclusion, HFFD feeding accelerates gastric emptying and diminishes NHGU and GSYN, thereby impairing glucose tolerance following a mixed meal challenge. These data reveal a constellation of deleterious metabolic consequences associated with consumption of a HFFD for 8 wk.
1 Communities
2 Members
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20 MeSH Terms