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Results: 1 to 8 of 8

Publication Record


Synaptotagmin 4 Regulates Pancreatic β Cell Maturation by Modulating the Ca Sensitivity of Insulin Secretion Vesicles.
Huang C, Walker EM, Dadi PK, Hu R, Xu Y, Zhang W, Sanavia T, Mun J, Liu J, Nair GG, Tan HYA, Wang S, Magnuson MA, Stoeckert CJ, Hebrok M, Gannon M, Han W, Stein R, Jacobson DA, Gu G
(2018) Dev Cell 45: 347-361.e5
MeSH Terms: Animals, Biological Transport, Calcium, Cell Differentiation, Female, Gene Expression Regulation, Glucose, Humans, Hypoglycemic Agents, Insulin, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Sweetening Agents, Synaptotagmins
Show Abstract · Added April 17, 2018
Islet β cells from newborn mammals exhibit high basal insulin secretion and poor glucose-stimulated insulin secretion (GSIS). Here we show that β cells of newborns secrete more insulin than adults in response to similar intracellular Ca concentrations, suggesting differences in the Ca sensitivity of insulin secretion. Synaptotagmin 4 (Syt4), a non-Ca binding paralog of the β cell Ca sensor Syt7, increased by ∼8-fold during β cell maturation. Syt4 ablation increased basal insulin secretion and compromised GSIS. Precocious Syt4 expression repressed basal insulin secretion but also impaired islet morphogenesis and GSIS. Syt4 was localized on insulin granules and Syt4 levels inversely related to the number of readily releasable vesicles. Thus, transcriptional regulation of Syt4 affects insulin secretion; Syt4 expression is regulated in part by Myt transcription factors, which repress Syt4 transcription. Finally, human SYT4 regulated GSIS in EndoC-βH1 cells, a human β cell line. These findings reveal the role that altered Ca sensing plays in regulating β cell maturation.
Copyright © 2018 Elsevier Inc. All rights reserved.
3 Communities
3 Members
0 Resources
17 MeSH Terms
Functional coding variation in the presynaptic dopamine transporter associated with neuropsychiatric disorders drives enhanced motivation and context-dependent impulsivity in mice.
Davis GL, Stewart A, Stanwood GD, Gowrishankar R, Hahn MK, Blakely RD
(2018) Behav Brain Res 337: 61-69
MeSH Terms: Animals, Choice Behavior, Disease Models, Animal, Dopamine Plasma Membrane Transport Proteins, Food Preferences, Impulsive Behavior, Male, Mental Disorders, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motivation, Mutation, Reinforcement (Psychology), Sucrose, Sweetening Agents, Valine
Show Abstract · Added October 4, 2017
Recent genetic analyses have provided evidence that clinical commonalities associated with different psychiatric diagnoses often have shared mechanistic underpinnings. The development of animal models expressing functional genetic variation attributed to multiple disorders offers a salient opportunity to capture molecular, circuit and behavioral alterations underlying this hypothesis. In keeping with studies suggesting dopaminergic contributions to attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BPD) and autism spectrum disorder (ASD), subjects with these diagnoses have been found to express a rare, functional coding substitution in the dopamine (DA) transporter (DAT), Ala559Val. We developed DAT Val559 knock-in mice as a construct valid model of dopaminergic alterations that drive multiple clinical phenotypes, and here evaluate the impact of lifelong expression of the variant on impulsivity and motivation utilizing the 5- choice serial reaction time task (5-CSRTT) and Go/NoGo as well as tests of time estimation (peak interval analysis), reward salience (sucrose preference), and motivation (progressive ratio test). Our findings indicate that the DAT Val559 variant induces impulsivity behaviors that are dependent upon the reward context, with increased impulsive action observed when mice are required to delay responding for a reward, whereas mice are able to withhold responding if there is a probability of reward for a correct rejection. Utilizing peak interval and progressive ratio tests, we provide evidence that impulsivity is likely driven by an enhanced motivational phenotype that also may drive faster task acquisition in operant tasks. These data provide critical validation that DAT, and more generally, DA signaling perturbations can drive impulsivity that can manifest in specific contexts and not others, and may rely on motivational alterations, which may also drive increased maladaptive reward seeking.
Copyright © 2017 Elsevier B.V. All rights reserved.
1 Communities
0 Members
0 Resources
17 MeSH Terms
Microtubules Negatively Regulate Insulin Secretion in Pancreatic β Cells.
Zhu X, Hu R, Brissova M, Stein RW, Powers AC, Gu G, Kaverina I
(2015) Dev Cell 34: 656-68
MeSH Terms: Animals, Cells, Cultured, Cytoplasmic Granules, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Female, Glucose, Insulin, Insulin Secretion, Insulin-Secreting Cells, Mice, Microtubules, Sweetening Agents
Show Abstract · Added October 15, 2015
For glucose-stimulated insulin secretion (GSIS), insulin granules have to be localized close to the plasma membrane. The role of microtubule-dependent transport in granule positioning and GSIS has been debated. Here, we report that microtubules, counterintuitively, restrict granule availability for secretion. In β cells, microtubules originate at the Golgi and form a dense non-radial meshwork. Non-directional transport along these microtubules limits granule dwelling at the cell periphery, restricting granule availability for secretion. High glucose destabilizes microtubules, decreasing their density; such local microtubule depolymerization is necessary for GSIS, likely because granule withdrawal from the cell periphery becomes inefficient. Consistently, microtubule depolymerization by nocodazole blocks granule withdrawal, increases their concentration at exocytic sites, and dramatically enhances GSIS in vitro and in mice. Furthermore, glucose-driven MT destabilization is balanced by new microtubule formation, which likely prevents over-secretion. Importantly, microtubule density is greater in dysfunctional β cells of diabetic mice.
Copyright © 2015 Elsevier Inc. All rights reserved.
1 Communities
2 Members
0 Resources
13 MeSH Terms
Glucose suppression of glucagon secretion: metabolic and calcium responses from alpha-cells in intact mouse pancreatic islets.
Le Marchand SJ, Piston DW
(2010) J Biol Chem 285: 14389-98
MeSH Terms: Animals, Bacterial Proteins, Calcium, Cells, Cultured, Fluorescent Antibody Technique, Glucagon, Glucagon-Secreting Cells, Glucokinase, Glucose, Hypoglycemic Agents, Insulin, Islets of Langerhans, Luminescent Proteins, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, NADP, Sweetening Agents
Show Abstract · Added December 6, 2012
Glucagon is released from alpha-cells present in intact pancreatic islets at glucose concentrations below 4 mm, whereas higher glucose levels inhibit its secretion. The mechanisms underlying the suppression of alpha-cell secretory activity are poorly understood, but two general types of models have been proposed as follows: direct inhibition by glucose or paracrine inhibition from non-alpha-cells within the islet of Langerhans. To identify alpha-cells for analysis, we utilized transgenic mice expressing fluorescent proteins targeted specifically to these cells. Measurements of glucagon secretion from pure populations of flow-sorted alpha-cells show that contrary to its effect on intact islets, glucose does stimulate glucagon secretion from isolated alpha-cells. This observation argues against a direct inhibition of glucagon secretion by glucose and supports the paracrine inhibition model. Imaging of cellular metabolism by two-photon excitation of NAD(P)H autofluorescence indicates that glucose is metabolized in alpha-cells and that glucokinase is the likely rate-limiting step in this process. Imaging calcium dynamics of alpha-cells in intact islets reveals that inhibiting concentrations of glucose increase the intracellular calcium concentration and the frequency of alpha-cell calcium oscillations. Application of candidate paracrine inhibitors leads to reduced glucagon secretion but did not decrease the alpha-cell calcium activity. Taken together, the data suggest that suppression occurs downstream from alpha-cell calcium signaling, presumably at the level of vesicle trafficking or exocytotic machinery.
1 Communities
1 Members
0 Resources
19 MeSH Terms
General and persistent effects of high-intensity sweeteners on body weight gain and caloric compensation in rats.
Swithers SE, Baker CR, Davidson TL
(2009) Behav Neurosci 123: 772-80
MeSH Terms: Analysis of Variance, Animals, Body Weight, Diet, Energy Intake, Fabaceae, Feeding Behavior, Female, Glucose, Male, Random Allocation, Rats, Rats, Sprague-Dawley, Saccharin, Sweetening Agents, Thiazines, Time Factors, Weight Gain, Yogurt
Show Abstract · Added April 17, 2012
In an earlier work (S. E. Swithers & T. L. Davidson, 2008), rats provided with a fixed amount of a yogurt diet mixed with saccharin gained more weight and showed impaired caloric compensation relative to rats given the same amount of yogurt mixed with glucose. The present 4 experiments examined the generality of these findings and demonstrated that increased body weight gain was also demonstrated when animals consumed a yogurt diet sweetened with an alternative high-intensity sweetener (acesulfame potassium; AceK) as well as in animals given a saccharin-sweetened base diet (refried beans) that was calorically similar but nutritionally distinct from low-fat yogurt. These studies also extended earlier findings by showing that body weight differences persist after saccharin-sweetened diets are discontinued and following a shift to a diet sweetened with glucose. In addition, rats first exposed to a diet sweetened with glucose still gain additional weight when subsequently exposed to a saccharin-sweetened diet. The results of these experiments add support to the hypothesis that exposure to weak or nonpredictive relationships between sweet tastes and caloric consequences may lead to positive energy balance.
2009 APA, all rights reserved
0 Communities
1 Members
0 Resources
19 MeSH Terms
Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community.
Dhingra R, Sullivan L, Jacques PF, Wang TJ, Fox CS, Meigs JB, D'Agostino RB, Gaziano JM, Vasan RS
(2007) Circulation 116: 480-8
MeSH Terms: Aged, Caffeine, Carbonated Beverages, Cholesterol, LDL, Cohort Studies, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Diet, Energy Intake, Feeding Behavior, Female, Follow-Up Studies, Glucose Intolerance, Humans, Hypertension, Hypertriglyceridemia, Incidence, Life Style, Male, Metabolic Syndrome, Middle Aged, Motor Activity, Obesity, Prospective Studies, Risk Factors, Smoking, Sucrose, Surveys and Questionnaires, Sweetening Agents, United States
Show Abstract · Added April 15, 2014
BACKGROUND - Consumption of soft drinks has been linked to obesity in children and adolescents, but it is unclear whether it increases metabolic risk in middle-aged individuals.
METHODS AND RESULTS - We related the incidence of metabolic syndrome and its components to soft drink consumption in participants in the Framingham Heart Study (6039 person-observations, 3470 in women; mean age 52.9 years) who were free of baseline metabolic syndrome. Metabolic syndrome was defined as the presence of > or = 3 of the following: waist circumference > or = 35 inches (women) or > or = 40 inches (men); fasting blood glucose > or = 100 mg/dL; serum triglycerides > or = 150 mg/dL; blood pressure > or = 135/85 mm Hg; and high-density lipoprotein cholesterol < 40 mg/dL (men) or < 50 mg/dL (women). Multivariable models included adjustments for age, sex, physical activity, smoking, dietary intake of saturated fat, trans fat, fiber, magnesium, total calories, and glycemic index. Cross-sectionally, individuals consuming > or = 1 soft drink per day had a higher prevalence of metabolic syndrome (odds ratio [OR], 1.48; 95% CI, 1.30 to 1.69) than those consuming < 1 drink per day. On follow-up (mean of 4 years), new-onset metabolic syndrome developed in 717 of 4033 participants (17.8%) consuming < 1 drink/day and in 433 of 2006 persons (21.6%) [corrected] consuming > or = 1 soft drink/day [corrected] Consumption of > or = 1 soft drink per day was associated with increased odds of developing metabolic syndrome (OR, 1.44; 95% CI, 1.20 to 1.74), obesity (OR, 1.31; 95% CI, 1.02 to 1.68), increased waist circumference (OR, 1.30; 95% CI, 1.09 to 1.56), impaired fasting glucose (OR, 1.25; 95% CI, 1.05 to 1.48), higher blood pressure (OR, 1.18; 95% CI, 0.96 to 1.44), hypertriglyceridemia (OR, 1.25; 95% CI, 1.04 to 1.51), and low high-density lipoprotein cholesterol (OR, 1.32; 95% CI 1.06 to 1.64).
CONCLUSIONS - In middle-aged adults, soft drink consumption is associated with a higher prevalence and incidence of multiple metabolic risk factors.
0 Communities
1 Members
0 Resources
30 MeSH Terms
Effect of sweeteners on energy uptake and its utilization by rats.
Gawecki J, Buchowski M, Kurhańska A, Urbanowicz M
(1978) Acta Physiol Pol 29: 481-7
MeSH Terms: Animals, Body Weight, Energy Metabolism, Female, Glucose, Glycine, Rats, Saccharin, Sweetening Agents
Show Abstract · Added July 31, 2015
The effect administration of saccharose, glucose and glycine in solutions of equivalent relative sweetness on the uptake and utilization of energy and on blood glucose level was studied in growing female Wistar rats. It was shown that the amount of saccharose and the remaining sweeteners added to drinks has an effect on the regulation of energy uptake from the food and on metabolic processes connected with the energy utilization.
0 Communities
1 Members
0 Resources
9 MeSH Terms
[Replacement of saccharose with other sweetening agents and their effect on experimental caries in rats].
Kurhańska A, Buchowski M, Gawecki J
(1979) Czas Stomatol 32: 143-8
MeSH Terms: Animals, Cariogenic Agents, Dental Caries, Glucose, Glycine, Rats, Sorbitol, Sucrose, Sweetening Agents
Added July 31, 2015
0 Communities
1 Members
0 Resources
9 MeSH Terms