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1.
Sci Adv ; 8(33): eabq2640, 2022 Aug 19.
Article in English | MEDLINE | ID: mdl-35977019

ABSTRACT

People who are blind do not have access to graphical data and imagery produced by science. This exclusion complicates learning and data sharing between sighted and blind persons. Because blind people use tactile senses to visualize data (and sighted people use eyesight), a single data format that can be easily visualized by both is needed. Here, we report that graphical data can be three-dimensionally printed into tactile graphics that glow with video-like resolution via the lithophane effect. Lithophane forms of gel electropherograms, micrographs, electronic and mass spectra, and textbook illustrations could be interpreted by touch or eyesight at ≥79% accuracy (n = 360). The lithophane data format enables universal visualization of data by people regardless of their level of eyesight.

2.
Sci Adv ; 7(22)2021 05.
Article in English | MEDLINE | ID: mdl-34049883

ABSTRACT

Handheld models help students visualize three-dimensional (3D) objects, especially students with blindness who use large 3D models to visualize imagery by hand. The mouth has finer tactile sensors than hand, which could improve visualization using microscopic models that are portable, inexpensive, and disposable. The mouth remains unused in tactile learning. Here, we created bite-size 3D models of protein molecules from "gummy bear" gelatin or nontoxic resin. Models were made as small as rice grain and could be coded with flavor and packaged like candy. Mouth, hands, and eyesight were tested at identifying specific structures. Students recognized structures by mouth at 85.59% accuracy, similar to recognition by eyesight using computer animation. Recall accuracy of structures was higher by mouth than hand for 40.91% of students, equal for 31.82%, and lower for 27.27%. The convenient use of entire packs of tiny, cheap, portable models can make 3D imagery more accessible to students.

3.
BMC Neurosci ; 18(1): 78, 2017 Dec 06.
Article in English | MEDLINE | ID: mdl-29207951

ABSTRACT

BACKGROUND: The formation of visuotopically-aligned projections in the brain is required for the generation of functional binocular circuits. The mechanisms which underlie this process are unknown. Ten-m3 is expressed in a broad high-ventral to low-dorsal gradient across the retina and in topographically-corresponding gradients in primary visual centres. Deletion of Ten-m3 causes profound disruption of binocular visual alignment and function. Surprisingly, one of the most apparent neuroanatomical changes-dramatic mismapping of ipsilateral, but not contralateral, retinal axons along the representation of the nasotemporal retinal axis-does not correlate well with Ten-m3's expression pattern, raising questions regarding mechanism. The aim of this study was to further our understanding of the molecular interactions which enable the formation of functional binocular visual circuits. METHODS: Anterograde tracing, gene expression studies and protein pull-down experiments were performed. Statistical significance was tested using a Kolmogorov-Smirnov test, pairwise-fixed random reallocation tests and univariate ANOVAs. RESULTS: We show that the ipsilateral retinal axons in Ten-m3 knockout mice are mismapped as a consequence of early axonal guidance defects. The aberrant invasion of the ventral-most region of the dorsal lateral geniculate nucleus by ipsilateral retinal axons in Ten-m3 knockouts suggested changes in the expression of other axonal guidance molecules, particularly members of the EphA-ephrinA family. We identified a consistent down-regulation of EphA7, but none of the other EphA-ephrinA genes tested, as well as an up-regulation of ipsilateral-determinants Zic2 and EphB1 in visual structures. We also found that Zic2 binds specifically to the intracellular domain of Ten-m3 in vitro. CONCLUSION: Our findings suggest that Zic2, EphB1 and EphA7 molecules may work as effectors of Ten-m3 signalling, acting together to enable the wiring of functional binocular visual circuits.


Subject(s)
Membrane Proteins/metabolism , Nerve Tissue Proteins/metabolism , Visual Pathways/growth & development , Visual Pathways/metabolism , Animals , Axons/metabolism , Cell Enlargement , Functional Laterality , Gene Expression Regulation, Developmental , Geniculate Bodies/cytology , Geniculate Bodies/growth & development , Geniculate Bodies/metabolism , Intracellular Space/metabolism , Membrane Proteins/genetics , Mice, Knockout , Nerve Tissue Proteins/genetics , Receptor, EphA7/metabolism , Receptor, EphB1/metabolism , Retinal Ganglion Cells/cytology , Retinal Ganglion Cells/metabolism , Superior Colliculi/cytology , Superior Colliculi/growth & development , Superior Colliculi/metabolism , Transcription Factors/metabolism , Vision, Binocular/physiology , Visual Pathways/cytology
4.
PLoS One ; 11(8): e0161003, 2016.
Article in English | MEDLINE | ID: mdl-27536869

ABSTRACT

A dominant appetite for protein drives increased energy intake in humans when the proportion of protein in the diet is reduced down to approximately 10% of total energy. Compensatory feeding for protein is apparent over a 1­2 d period but the mechanisms driving this regulation are not fully understood. Fibroblast growth factor-21 (FGF-21) has been identified as a candidate protein signal as levels increase in the circulation when dietary protein is low. The aim of this randomised controlled trial was to assess whether changes in percent dietary protein over a 4 d ad libitum experimental period in lean, healthy participants influenced energy intake, metabolic health, circulating FGF-21 and appetite regulating hormones including ghrelin, glucagon like peptide-1 and cholecystokinin. Twenty-two lean, healthy participants were fed ad libitum diets containing 10, 15 and 25% protein, over three, 4 d controlled, in-house experimental periods. Reduced dietary protein intake from 25% to 10% over a period of 4 d was associated with 14% increased energy intake (p = 0.02) as previously reported, and a 6-fold increase in fasting circulating plasma FGF-21 levels (p<0.0001), a 1.5-fold increase in serum triglycerides (p<0.0001), and a 0.9-fold decrease in serum total cholesterol (p = 0.02). Serum HDL cholesterol was reduced with a reduction in dietary protein from 15% to 10% (p = 0.01) over 4 d but not from 25% to 10% (p = 0.1) and the change from baseline was not different between diets. Plasma fasting insulin levels following the 4 d study period were significantly lower following the 25% ad libitum study period compared to the 15% protein period (p = 0.014) but not the 10% protein period (p = 0.2). Variability in interstitial glucose during each study period increased with a decrease in dietary protein from 25% to 15% and 10% (p = 0.001 and p = 0.04, respectively). Ghrelin, glucagon-like peptide-1 and cholecystokinin were unchanged. Increases in energy intake, plasma FGF-21 and serum triglycerides were associated with reductions in percent dietary protein from 25% to 10% energy over a 4 d ad libitum in-house feeding period and may be important in regulation of dietary protein intake. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12616000144415.


Subject(s)
Dietary Proteins/pharmacology , Energy Intake/physiology , Fibroblast Growth Factors/blood , Triglycerides/blood , Adolescent , Adult , Blood Glucose/analysis , Cholecystokinin/blood , Dietary Proteins/administration & dosage , Female , Ghrelin/blood , Glucagon-Like Peptide 1/blood , Humans , Male , Middle Aged , Young Adult
5.
PLoS One ; 6(11): e27260, 2011.
Article in English | MEDLINE | ID: mdl-22076142

ABSTRACT

BACKGROUND: Maternal smoking leads to intrauterine undernutrition and is associated with low birthweight and higher risk of offspring obesity. Intrauterine smoke exposure (SE) may alter neuroendocrine mediators regulating energy homeostasis as chemicals in cigarette smoke can reach the fetus. Maternal high-fat diet (HFD) consumption causes fetal overnutrition; however, combined effects of HFD and SE are unknown. Thus we investigated the impact of combined maternal HFD and SE on adiposity and energy metabolism in offspring. METHOD: Female Balb/c mice had SE (2 cigarettes/day, 5 days/week) or were sham exposed for 5 weeks before mating. Half of each group was fed HFD (33% fat) versus chow as control. The same treatment continued throughout gestation and lactation. Female offspring were fed chow after weaning and sacrificed at 12 weeks. RESULTS: Birthweights were similar across maternal groups. Faster growth was evident in pups from SE and/or HFD dams before weaning. At 12 weeks, offspring from HFD-fed dams were significantly heavier than those from chow-fed dams (chow-sham 17.6±0.3 g; chow-SE 17.8±0.2 g; HFD-sham 18.7±0.3 g; HFD-SE 18.8±0.4 g, P<0.05 maternal diet effect); fat mass was significantly greater in offspring from chow+SE, HFD+SE and HFD+sham dams. Both maternal HFD and SE affected brain lactate transport. Glucose intolerance and impaired brain response to insulin were observed in SE offspring, and this was aggravated by maternal HFD consumption. CONCLUSION: While maternal HFD led to increased body weight in offspring, maternal SE independently programmed adverse health outcomes in offspring. A smoke free environment and healthy diet during pregnancy is desirable to optimize offspring health.


Subject(s)
Brain/drug effects , Glucose Intolerance/chemically induced , Insulin/metabolism , Maternal Nutritional Physiological Phenomena , Prenatal Exposure Delayed Effects/chemically induced , Smoking/adverse effects , Adiposity , Animals , Blotting, Western , Body Weight/drug effects , Brain/metabolism , Carnitine O-Palmitoyltransferase/genetics , Carnitine O-Palmitoyltransferase/metabolism , Diet, High-Fat , Female , Leptin/genetics , Leptin/metabolism , Lipase/genetics , Lipase/metabolism , Maternal Exposure , Mice , Mice, Inbred BALB C , Monocarboxylic Acid Transporters/genetics , Monocarboxylic Acid Transporters/metabolism , Muscle Proteins , Pregnancy , Pregnancy Complications/chemically induced , Pregnancy Complications/metabolism , Prenatal Exposure Delayed Effects/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Tumor Necrosis Factor-alpha
6.
PLoS One ; 6(10): e25929, 2011.
Article in English | MEDLINE | ID: mdl-22022472

ABSTRACT

A significant contributor to the rising rates of human obesity is an increase in energy intake. The 'protein leverage hypothesis' proposes that a dominant appetite for protein in conjunction with a decline in the ratio of protein to fat and carbohydrate in the diet drives excess energy intake and could therefore promote the development of obesity. Our aim was to test the 'protein leverage hypothesis' in lean humans by disguising the macronutrient composition of foods offered to subjects under ad libitum feeding conditions. Energy intakes and hunger ratings were measured for 22 lean subjects studied over three 4-day periods of in-house dietary manipulation. Subjects were restricted to fixed menus in random order comprising 28 foods designed to be similar in palatability, availability, variety and sensory quality and providing 10%, 15% or 25% energy as protein. Nutrient and energy intake was calculated as the product of the amount of each food eaten and its composition. Lowering the percent protein of the diet from 15% to 10% resulted in higher (+12±4.5%, p = 0.02) total energy intake, predominantly from savoury-flavoured foods available between meals. This increased energy intake was not sufficient to maintain protein intake constant, indicating that protein leverage is incomplete. Urinary urea on the 10% and 15% protein diets did not differ statistically, nor did they differ from habitual values prior to the study. In contrast, increasing protein from 15% to 25% did not alter energy intake. On the fourth day of the trial, however, there was a greater increase in the hunger score between 1-2 h after the 10% protein breakfast versus the 25% protein breakfast (1.6±0.4 vs 25%: 0.5±0.3, p = 0.005). In our study population a change in the nutritional environment that dilutes dietary protein with carbohydrate and fat promotes overconsumption, enhancing the risk for potential weight gain.


Subject(s)
Dietary Proteins/metabolism , Thinness/metabolism , Adolescent , Adult , Dietary Carbohydrates/metabolism , Dietary Fiber/metabolism , Energy Metabolism , Female , Humans , Hunger , Male , Middle Aged , Sodium Chloride/metabolism , Young Adult
7.
Cell Metab ; 9(5): 417-27, 2009 May.
Article in English | MEDLINE | ID: mdl-19416712

ABSTRACT

Hepatic insulin resistance is the major contributor to fasting hyperglycemia in type 2 diabetes. Here we report that the endosomal adaptor protein APPL1 increases hepatic insulin sensitivity by potentiating insulin-mediated suppression of the gluconeogenic program. Insulin-stimulated activation of Akt and suppression of gluconeogenesis in hepatocytes are enhanced by APPL1 overexpression, but are attenuated by APPL1 knockdown. APPL1 interacts with Akt and blocks the association of Akt with its endogenous inhibitor tribble 3 (TRB3) through direct competition, thereby promoting Akt translocation to the plasma membrane and the endosomes for further activation. In db/db diabetic mice, the blockage of the augmented interaction between Akt and TRB3 by hepatic overexpression of APPL1 is accompanied by a marked attenuation of hyperglycemia and insulin resistance. These results suggest that the potentiating effects of APPL1 on insulin-stimulated suppression of hepatic glucose production are attributed to its ability in counteracting the inhibition of Akt activation by TRB3.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Carrier Proteins/metabolism , Diabetes Mellitus, Type 2/enzymology , Glucose/biosynthesis , Hepatocytes/enzymology , Insulin/metabolism , Nerve Tissue Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Animals , Binding, Competitive , Cell Cycle Proteins/metabolism , Cells, Cultured , Gene Knockdown Techniques , Gluconeogenesis , Glucose/metabolism , Mice , Mice, Inbred C57BL , Mice, Obese , RNA Interference , Rats , Signal Transduction
8.
Diabetes ; 57(10): 2603-12, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18519802

ABSTRACT

OBJECTIVE: Ingested glucose is detected by specialized sensors in the enteric/hepatoportal vein, which send neural signals to the brain, which in turn regulates key peripheral tissues. Hence, impairment in the control of enteric-neural glucose sensing could contribute to disordered glucose homeostasis. The aim of this study was to determine the cells in the brain targeted by the activation of the enteric glucose-sensing system. RESEARCH DESIGN AND METHODS: We selectively activated the axis in mice using a low-rate intragastric glucose infusion in wild-type and glucagon-like peptide-1 (GLP-1) receptor knockout mice, neuropeptide Y-and proopiomelanocortin-green fluorescent protein-expressing mice, and high-fat diet diabetic mice. We quantified the whole-body glucose utilization rate and the pattern of c-Fos positive in the brain. RESULTS: Enteric glucose increased muscle glycogen synthesis by 30% and regulates c-Fos expression in the brainstem and the hypothalamus. Moreover, the synthesis of muscle glycogen was diminished after central infusion of the GLP-1 receptor (GLP-1Rc) antagonist Exendin 9-39 and abolished in GLP-1Rc knockout mice. Gut-glucose-sensitive c-Fos-positive cells of the arcuate nucleus colocalized with neuropeptide Y-positive neurons but not with proopiomelanocortin-positive neurons. Furthermore, high-fat feeding prevented the enteric activation of c-Fos expression. CONCLUSIONS: We conclude that the gut-glucose sensor modulates peripheral glucose metabolism through a nutrient-sensitive mechanism, which requires brain GLP-1Rc signaling and is impaired during diabetes.


Subject(s)
Central Nervous System/drug effects , Glucose/pharmacology , Receptors, Glucagon/physiology , Animals , Blood Glucose/metabolism , Brain/drug effects , Brain/metabolism , Central Nervous System/metabolism , Central Nervous System/physiology , Glucagon-Like Peptide 1/blood , Glucagon-Like Peptide-1 Receptor , Glucose/administration & dosage , Glycogen/metabolism , Immunohistochemistry , Insulin/blood , Liver/drug effects , Liver/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Receptors, Glucagon/metabolism
9.
J Endocrinol ; 190(3): 651-8, 2006 Sep.
Article in English | MEDLINE | ID: mdl-17003266

ABSTRACT

Lipid accumulation in non-adipose tissues is strongly associated with the metabolic syndrome, possibly due to aberrant partitioning of intracellular fatty acids between storage and oxidation. In the present study, we administered the non-metabolizable fatty acid analog [9,10-(3)H]-(R)-2-bromopalmitate, and authentic (14)C-palmitate to conscious rats, in order to directly examine the initial intracellular fate of fatty acids in a range of insulin-sensitive tissues, including white and red muscles, liver, white adipose tissue, and heart. Rats were studied after administration of an oral glucose load to examine the effect of physiological elevation of glucose and insulin. The tracer results showed that glucose administration partitioned fatty acid toward storage in white muscle (storage:uptake ratios, vehicle vs glucose; 0.64 +/- 0.02 vs 0.92 +/- 0.09, P < 0.05), and in liver (0.66 +/- 0.07 vs 0.98 +/- 0.04, P < 0.05), but not in red muscle (1.18 +/- 0.07 vs 1.36 +/- 0.11, P = not significant). These results demonstrate the physiological relevance of the so-called 'reverse' Randle cycle, but surprisingly show that it may be more important in white rather than oxidative red muscle.


Subject(s)
Fatty Acids/metabolism , Glucose/administration & dosage , Insulin Resistance , Muscle Fibers, Fast-Twitch/metabolism , Adipose Tissue/metabolism , Administration, Oral , Animals , Blood Glucose/analysis , Carbon Isotopes , Fatty Acids, Nonesterified/blood , Glucose Tolerance Test , Glycerol/blood , Insulin/metabolism , Lipid Metabolism , Liver/metabolism , Male , Metabolic Clearance Rate , Myocardium/metabolism , Oxidation-Reduction , Palmitates/administration & dosage , Palmitates/metabolism , Rats , Rats, Sprague-Dawley
10.
Diabetes ; 55(10): 2797-804, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17003345

ABSTRACT

AMP-activated protein kinase (AMPK) has been implicated in the insulin-sensitizing actions of thiazolidinediones (TZDs), but it is not known whether TZD treatment can enhance tissue glucose uptake in response to AMPK activation. The present study investigated the influence of the TZD rosiglitazone on glucose turnover induced by intravenous infusion of the AMPK activator 5-aminoimidazole 4-carboxamide riboside (AICAR) under euglycemic and iso-insulinemic conditions in insulin-resistant high-fat-fed rats. We found that rosiglitazone treatment significantly enhanced AICAR-stimulated whole-body glucose disposal by 27% in high-fat-fed rats, and a 44% greater glucose infusion rate (both P < 0.01 vs. vehicle control rats) was required to maintain euglycemia. Along with this, both AICAR-stimulated glucose uptake and glucose incorporation into glycogen in muscle and adipose tissue were enhanced (P < 0.05). The enhanced glucose uptake and glycogen synthesis in muscle were associated with increased activity of total AMPK and the AMPKalpha2 subunit. In comparison, these effects were not apparent in rats fed standard rodent diet. Thus, our findings suggest that in addition to ameliorating insulin resistance, TZDs may enhance AMPK-stimulated glucose clearance into peripheral tissues in insulin-resistant states.


Subject(s)
Adipose Tissue/metabolism , Dietary Fats/administration & dosage , Glucose/metabolism , Multienzyme Complexes/metabolism , Muscles/metabolism , Protein Serine-Threonine Kinases/metabolism , Thiazolidinediones/pharmacology , AMP-Activated Protein Kinases , Acetyl-CoA Carboxylase/metabolism , Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/pharmacology , Animals , Blood Glucose/metabolism , Lipid Metabolism/drug effects , Male , Rats , Rats, Sprague-Dawley , Ribonucleotides/pharmacology , Rosiglitazone
11.
Diabetes ; 55(5): 1484-90, 2006 May.
Article in English | MEDLINE | ID: mdl-16644709

ABSTRACT

Nondigestible fermentable dietary fibers such as oligofructose (OFS) exert an antidiabetic effect and increase the secretion of glucagon-like peptide 1 (GLP-1). To determine the importance of GLP-1 receptor-dependent mechanisms for the actions of OFS, we studied high-fat-fed diabetic mice treated with OFS for 4 weeks in the presence or absence of the GLP-1 receptor antagonist exendin 9-39 (Ex-9). OFS improved glucose tolerance, fasting blood glucose, glucose-stimulated insulin secretion, and insulin-sensitive hepatic glucose production and reduced body weight gain. Ex-9 totally prevented the beneficial effects of OFS. Furthermore, GLP-1 receptor knockout mice (GLP-1R(-/-)) were completely insensitive to the antidiabetic actions of OFS. At the molecular level, the effects of OFS on endogenous glucose production correlated with changes of hepatic IRS (insulin receptor substrate)-2 and Akt phosphorylation in an Ex-9-dependent manner. As inflammation is associated with diabetes and obesity, we quantified nuclear factor-kappaB and inhibitor of kappaB kinase beta in the liver. The activity of both intracellular inflammatory effectors was reduced by OFS but, importantly, this effect could not be reverted by Ex-9. In summary, our data show that the antidiabetic actions of OFS require a functional GLP-1 receptor. These findings highlight the therapeutic potential of enhancing endogenous GLP-1 secretion for the treatment of type 2 diabetes.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Experimental/physiopathology , Oligosaccharides/therapeutic use , Receptors, Glucagon/physiology , Adipose Tissue/anatomy & histology , Animals , Blood Glucose/drug effects , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/genetics , Epididymis , Fasting , Glucagon-Like Peptide-1 Receptor , Glucose Tolerance Test , Insulin/analysis , Insulin/blood , Islets of Langerhans/chemistry , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Proglucagon/genetics , RNA, Messenger/genetics , Receptors, Glucagon/deficiency , Receptors, Glucagon/genetics
12.
Endocrinology ; 147(5): 2432-41, 2006 May.
Article in English | MEDLINE | ID: mdl-16455782

ABSTRACT

The AMP-activated kinase (AMPK) is a serine threonine kinase that functions as a fuel sensor to regulate energy balance at both cellular and whole-body levels. Here we studied how hepatic AMPKalpha2 isoform affects hepatic glucose production and peripheral glucose uptake in vivo. We generated mice deleted for the AMPKalpha2 gene specifically in the liver (liveralpha2KO). Liveralpha2KO mice were glucose intolerant and hyperglycemic in the fasted state. Hyperglycemia was associated with a 50% higher endogenous glucose production than in controls as assessed in vivo. We then investigated whether this increased glucose production was sensitive to insulin. Insulin, when infused at a rate inducing physiological hyperinsulinemia, totally inhibited endogenous glucose production in liveralpha2KO mice, showing that they had normal insulin sensitivity. This was confirmed in vivo by normal insulin-induced phosphorylation of Akt and transcriptional regulation of the phosphoenolpyruvate carboxykinase, glucose-6 phosphatase, and pyruvate kinase in liver during the fasted/fed transition. Leptin and adiponectin regulate hepatic glucose production, so we then infused these adipokines into liveralpha2KO mice. Neither of these adipokines regulated hepatic glucose production in mice lacking hepatic AMPKalpha2, whereas both did so in control mice. In conclusion, we show that the hepatic AMPKalpha2 isoform is essential for suppressing hepatic glucose production and maintaining fasting blood glucose levels in the physiological range. We also demonstrate that regulation of hepatic glucose production by leptin and adiponectin, but not insulin, requires hepatic AMPKalpha2 activity.


Subject(s)
Adiponectin/chemistry , Glucose/metabolism , Insulin/metabolism , Leptin/chemistry , Liver/metabolism , Multienzyme Complexes/physiology , Protein Serine-Threonine Kinases/physiology , AMP-Activated Protein Kinases , Adiponectin/metabolism , Animals , Blood Glucose/metabolism , Blotting, Western , Catalysis , Disease Models, Animal , Gene Deletion , Gene Expression Regulation , Glucose Tolerance Test , Glucose-6-Phosphatase/metabolism , Hyperglycemia/metabolism , Insect Hormones/metabolism , Leptin/metabolism , Male , Mice , Mice, Knockout , Mice, Transgenic , Models, Genetic , Models, Statistical , Multienzyme Complexes/metabolism , Oligopeptides/metabolism , Phosphoenolpyruvate Carboxykinase (ATP)/metabolism , Phosphorylation , Protein Isoforms , Protein Serine-Threonine Kinases/metabolism , Pyrrolidonecarboxylic Acid/analogs & derivatives , Pyrrolidonecarboxylic Acid/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transcription, Genetic , Transcriptional Activation
13.
J Clin Invest ; 115(12): 3554-63, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16322793

ABSTRACT

Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.


Subject(s)
Brain/metabolism , Glucagon-Like Peptide 1/physiology , Glycogen/metabolism , Insulin Resistance , Insulin/metabolism , Muscles/metabolism , Adipose Tissue/metabolism , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Blood Glucose/metabolism , Dose-Response Relationship, Drug , Glucose/metabolism , Glucose Clamp Technique , Glucose Tolerance Test , Glycogen/chemistry , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Hyperglycemia/metabolism , Hyperglycemia/pathology , Hyperinsulinism , Insulin Secretion , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Proteins/metabolism , Osmosis , Peptide Fragments/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , RNA, Messenger/metabolism , Receptor, Insulin/genetics , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transcription Factors/metabolism
14.
Diabetes ; 53(7): 1649-54, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15220186

ABSTRACT

Insulin-stimulated glucose uptake is increased in white but not red muscle of insulin-resistant high-fat-fed (HF) rats after administration of the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). To investigate whether a lesser AICAR effect on glucose uptake in red muscle was offset by a greater effect on fatty acid (FA) uptake, we examined acute effects of AICAR on muscle glucose and FA fluxes in HF rats. HF rats received AICAR (250 mg/kg) subcutaneously. At 30 min, a mixture of either (3)H-(R)-2-bromopalmitate/(14)C-palmitate or (3)H-2-deoxyglucose/(14)C-glucose was administered intravenously to assess muscle FA and glucose uptake. AICAR decreased plasma levels of glucose (approximately 25%), insulin (approximately 60%), and FAs (approximately 30%) at various times over the next 46 min (P < 0.05 vs. controls). In white muscle, AICAR increased both FA (2.4-fold) and glucose uptake (4.9-fold), associated with increased glycogen synthesis (6-fold). These effects were not observed in red muscle. We conclude that both glucose and FA fluxes are enhanced by AICAR more in white versus red muscle, consistent with the relative degree of activation of AMPK. Therefore, a lesser effect of AICAR to alleviate muscle insulin resistance in red versus white muscle is not explained by a relatively greater effect on FA uptake in the red muscle.


Subject(s)
Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/pharmacology , Fatty Acids/metabolism , Glucose/metabolism , Multienzyme Complexes/metabolism , Muscle, Skeletal/metabolism , Protein Serine-Threonine Kinases/metabolism , Ribonucleotides/pharmacology , AMP-Activated Protein Kinases , Animals , Dietary Fats/administration & dosage , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Insulin Resistance , Male , Rats , Rats, Wistar
15.
Am J Physiol Endocrinol Metab ; 284(3): E531-40, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12556350

ABSTRACT

Peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma agonists lower lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPARalpha/gamma agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPARalpha agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPARgamma agonist rosiglitazone only slightly lessened liver triglyceride without affecting visceral adiposity. Compared with rosiglitazone or Wy-14643, ragaglitazar showed a much greater effect (79%, P < 0.05) to enhance insulin's suppression of hepatic glucose output. Whereas all three PPAR agonists lowered plasma triglyceride levels and lessened muscle long-chain acyl-CoAs, ragaglitazar and rosiglitazone had greater insulin-sensitizing action in muscle than Wy-14643, associated with a threefold increase in plasma adiponectin levels. There was a significant correlation of lipid content and insulin action in liver and particularly muscle with adiponectin levels (P < 0.01). We conclude that the PPARalpha/gamma agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPARgamma ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPARalpha activation, but without hepatomegaly.


Subject(s)
Dietary Fats/administration & dosage , Fatty Liver/drug therapy , Fatty Liver/physiopathology , Insulin Resistance , Oxazines/therapeutic use , Phenylpropionates/therapeutic use , Receptors, Cytoplasmic and Nuclear/agonists , Thiazolidinediones , Transcription Factors/agonists , Animals , Dietary Fats/adverse effects , Fatty Liver/etiology , Glucose/metabolism , Glucose Clamp Technique , Insulin/metabolism , Lipid Metabolism , Liver/metabolism , Male , Muscle, Skeletal/metabolism , Pyrimidines/therapeutic use , Rats , Rats, Wistar , Rosiglitazone , Thiazoles/therapeutic use
16.
Endocrinology ; 143(12): 4527-35, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12446579

ABSTRACT

Thiazolidinediones lower lipids, but it is unclear whether this is essential for their insulin-sensitizing action. We investigated relationships between lipid-lowering and insulin-sensitizing actions of a thiazolidinedione. Normal rats were pretreated with or without Pioglitazone (Pio, 3 mg/kg.d) for 2 wk. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp with elevation of free fatty acids (FFA) by Intralipid/heparin infusion over 6 h. In untreated rats insulin sensitivity decreased by 46% over 3-6 h of elevated FFA, whereas it remained normal but with a 50% increase in FFA clearance in Pio-treated rats. After matching plasma FFA, insulin sensitivity was still partially (30%) protected in Pio-treated rats, substantially by maintaining insulin suppressibility of hepatic glucose output. This was associated with lower hepatic long-chain acyl-coenzyme A. Plasma adiponectin was increased 2-fold in Pio-treated rats and was negatively correlated with hepatic glucose output (r2 = 0.70, P < 0.001) and liver long-chain acyl-coenzyme A (r2 = 0.39, P < 0.005). Pio-induced muscle insulin sensitization was largely diminished after matching plasma FFA elevation, but insulin-stimulated protein kinase B phosphorylation was protected. We conclude that thiazolidinediones can protect against lipid-induced insulin resistance with a significant component (mainly liver) of the protective effect not requiring lipid lowering. This may be related to chronic elevation of adiponectin by thiazolidinediones.


Subject(s)
Fatty Acids, Nonesterified/blood , Hypoglycemic Agents/pharmacology , Insulin Resistance , Intercellular Signaling Peptides and Proteins , Liver/physiology , Protein Serine-Threonine Kinases , Thiazoles/pharmacology , Thiazolidinediones , Acyl Coenzyme A/analysis , Adiponectin , Animals , Blood Glucose/metabolism , Fat Emulsions, Intravenous/administration & dosage , Glucose/metabolism , Glucose Clamp Technique , Heparin/administration & dosage , Hyperinsulinism , Insulin/pharmacology , Liver/drug effects , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Phosphorylation , Pioglitazone , Proteins/analysis , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Rats , Rats, Wistar
17.
Diabetes ; 51(10): 2886-94, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12351423

ABSTRACT

Exercise improves insulin sensitivity. As AMP-activated protein kinase (AMPK) plays an important role in muscle metabolism during exercise, we investigated the effects of the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) on insulin action in insulin-resistant high-fat-fed (HF) rats. Rats received a subcutaneous injection of 250 mg/kg AICAR (HF-AIC) or saline (HF-Con). The next day, euglycemic-hyperinsulinemic clamp studies were performed. Glucose infusion rate during the clamp was enhanced (50%) in HF-AIC compared with HF-Con rats. Insulin-stimulated glucose uptake was improved in white but not in red quadriceps, whereas glycogen synthesis was improved in both red and white quadriceps of HF-AIC rats. HF-AIC rats also showed increased insulin suppressibility of hepatic glucose output (HGO). AICAR-induced responses in both liver and muscle were accompanied by reduced malonyl-CoA content. Clamp HGO correlated closely with hepatic triglyceride content (r = 0.67, P < 0.01). Thus, a single dose of AICAR leads to an apparent enhancement in whole-body, muscle, and liver insulin action in HF rats that extends beyond the expected time of AMPK activation. Whether altered tissue lipid metabolism mediates AICAR effects on insulin action remains to be determined. Follow-up studies suggest that at least some of the post-AICAR insulin-enhancing effects also occur in normal rats. Independent of this, the results suggest that pharmacological activation of AMPK may have potential in treating insulin-resistant states and type 2 diabetes.


Subject(s)
Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/pharmacology , Hypoglycemic Agents/pharmacology , Insulin Resistance/physiology , Insulin/metabolism , Liver/metabolism , Muscle, Skeletal/metabolism , Ribonucleotides/pharmacology , Animals , Blood Glucose/metabolism , Body Weight , Dietary Fats/pharmacology , Glucose Clamp Technique , Male , Rats , Rats, Wistar
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