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Luiz F. Rezende - One of the best experts on this subject based on the ideXlab platform.

  • Acute Exercise Improves Insulin Clearance and Increases the Expression of Insulin-Degrading Enzyme in the Liver and Skeletal Muscle of Swiss Mice
    PLOS ONE, 2016
    Co-Authors: Mirian Ayumi Kurauti, Ricardo Freitas-dias, Sandra Mara Ferreira, Jean F. Vettorazzi, Tarlliza R. Nardelli, Hygor N. Araujo, Gustavo Jorge Dos Santos, Everardo M. Carneiro, Antonio Carlos Boschero, Luiz F. Rezende
    Abstract:

    The effects of exercise on Insulin Clearance and IDE expression are not yet fully elucidated. Here, we have explored the effect of acute exercise on Insulin Clearance and IDE expression in lean mice. Male Swiss mice were subjected to a single bout of exercise on a speed/angle controlled treadmill for 3-h at approximately 60–70% of maximum oxygen consumption. As expected, acute exercise reduced glycemia and Insulinemia, and increased Insulin tolerance. The activity of AMPK-ACC, but not of IR-Akt, pathway was increased in the liver and skeletal muscle of trained mice. In an apparent contrast to the reduced Insulinemia, glucose-stimulated Insulin secretion was increased in isolated islets of these mice. However, Insulin Clearance was increased after acute exercise and was accompanied by increased expression of the Insulin-degrading enzyme (IDE), in the liver and skeletal muscle. Finally, C2C12, but not HEPG2 cells, incubated at different concentrations of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) for 3-h, showed increased expression of IDE. In conclusion, acute exercise increases Insulin Clearance, probably due to an augmentation of IDE expression in the liver and skeletal muscle. The elevated IDE expression, in the skeletal muscle, seems to be mediated by activation of AMPK-ACC pathway, in response to exercise. We believe that the increase in the IDE expression, comprise a safety measure to maintain glycemia at or close to physiological levels, turning physical exercise more effective and safe.

  • acute exercise restores Insulin Clearance in diet induced obese mice
    Journal of Endocrinology, 2016
    Co-Authors: Mirian Ayumi Kurauti, André Otávio Peres Protzek, Gustavo J. Santos, Sandra Mara Ferreira, Tarlliza R. Nardelli, Luiz F. Rezende, Jose M Costajunior, Antonio Carlos Boschero
    Abstract:

    The aim of this study was to investigate the Insulin Clearance in diet-induced obese (DIO) mice submitted to acute endurance exercise (3h of treadmill exercise at 60-70% VO2max). Glucose-stimulated Insulin secretion in isolated islets; ipGTT; ipITT; ipPTT; in vivo Insulin Clearance; protein expression in liver, skeletal muscle, and adipose tissue (Insulin degrading enzyme (IDE), Insulin receptor subunitβ(IRβ), phospho-Akt (p-Akt) and phospho-AMPK (p-AMPK)), and the activity of IDE in the liver and skeletal muscle were accessed. In DIO mice, acute exercise reduced fasting glycemia and Insulinemia, improved glucose and Insulin tolerance, reduced hepatic glucose production, and increased p-Akt protein levels in liver and skeletal muscle and p-AMPK protein levels in skeletal muscle. In addition, Insulin secretion was reduced, whereas Insulin Clearance and the expression of IDE and IRβ were increased in liver and skeletal muscle. Finally, IDE activity was increased only in skeletal muscle. In conclusion, we propose that the increased Insulin Clearance and IDE expression and activity, primarily, in skeletal muscle, constitute an additional mechanism, whereby physical exercise reduces Insulinemia in DIO mice.

  • HyperInsulinemia caused by dexamethasone treatment is associated with reduced Insulin Clearance and lower hepatic activity of Insulin-degrading enzyme.
    The Journal of Steroid Biochemistry and Molecular Biology, 2015
    Co-Authors: André Otávio Peres Protzek, José M. Costa-júnior, Mirian Ayumi Kurauti, Sandra Mara Ferreira, Luiz F. Rezende, Everardo M. Carneiro, Ana Paula Gameiro Cappelli, Flavia M.m. Paula, Jane Cristina De Souza, Alex Rafacho
    Abstract:

    Abstract Objectives Glucocorticoid treatment induces Insulin resistance (IR), which is counteracted by a compensatory hyperInsulinemia, due to increased pancreatic β-cell function. There is evidence for also reduced hepatic Insulin Clearance, but whether this correlates with altered activity of Insulin-degrading enzyme (IDE) in the liver, is not fully understood. Here, we investigated whether hyperInsulinemia, in glucocorticoid-treated rodents, is associated with any alteration in the Insulin Clearance and activity of the IDE in the liver. Materials/methods Adult male Swiss mice and Wistar rats were treated with the synthetic glucocorticoid dexamethasone intraperitoneally [1 mg/kg body weight (b.w.)] for 5 consecutive days. Results Glucocorticoid treatment induced IR and hyperInsulinemia in both species, but was more impactful in rats that also displayed glucose intolerance and hyperglycemia. Insulin Clearance was reduced in glucocorticoid-treated rats and mice, as judged by the reduction of Insulin decay rate and increased Insulin area-under-the-curve (47% and 87%, respectively). These results were associated with reduced activity (35%) of hepatic IDE in rats and a tendency to reduction (p = 0.068) in mice, without alteration in hepatic IDE mRNA content, in both species. Conclusion In conclusion, the reduced Insulin Clearance in glucocorticoid-treated rodents was due to the reduction of hepatic IDE activity, at least in rats, which may contributes to the compensatory hyperInsulinemia. These findings corroborate the idea that short-term and/or partial inhibition of IDE activity in the liver could be beneficial for the glycemic control.

  • reduced Insulin Clearance and lower Insulin degrading enzyme expression in the liver might contribute to the thrifty phenotype of protein restricted mice
    British Journal of Nutrition, 2014
    Co-Authors: Luiz F. Rezende, Antonio Carlos Boschero, Rafael Ludemann Camargo, Renato Chaves Souto Branco, Ana Paula Gameiro Cappelli, Everardo M. Carneiro
    Abstract:

    Nutrient restriction during the early stages of life usually leads to alterations in glucose homeostasis, mainly Insulin secretion and sensitivity, increasing the risk of metabolic disorders in adulthood. Despite growing evidence regarding the importance of Insulin Clearance during glucose homeostasis in health and disease, no information exists about this process in malnourished animals. Thus, in the present study, we aimed to determine the effect of a nutrient-restricted diet on Insulin Clearance using a model in which 30-d-old C57BL/6 mice were exposed to a protein-restricted diet for 14 weeks. After this period, we evaluated many metabolic variables and extracted pancreatic islet, liver, gastrocnemius muscle (GCK) and white adipose tissue samples from the control (normal-protein diet) and restricted (low-protein diet, LP) mice. Insulin concentrations were determined using RIA and protein expression and phosphorylation by Western blot analysis. The LP mice exhibited lower body weight, glycaemia, and Insulinaemia, increased glucose tolerance and altered Insulin dynamics after the glucose challenge. The improved glucose tolerance could partially be explained by an increase in Insulin sensitivity through the phosphorylation of the Insulin receptor/protein kinase B and AMP-activated protein kinase/acetyl-CoA carboxylase in the liver, whereas the changes in Insulin dynamics could be attributed to reduced Insulin secretion coupled with reduced Insulin Clearance and lower Insulin-degrading enzyme (IDE) expression in the liver and GCK. In summary, protein-restricted mice not only produce and secrete less Insulin, but also remove and degrade less Insulin. This phenomenon has the double benefit of sparing Insulin while prolonging and potentiating its effects, probably due to the lower expression of IDE in the liver, possibly with long-term consequences.

  • Cafeteria diet inhibits Insulin Clearance by reduced Insulin-degrading enzyme expression and mRNA splicing
    Journal of Endocrinology, 2013
    Co-Authors: P Brandimarti, José M. Costa-júnior, André Otávio Peres Protzek, Gustavo J. Santos, Sandra Mara Ferreira, Everardo M. Carneiro, Antonio Carlos Boschero, Luiz F. Rezende
    Abstract:

    Insulin Clearance plays a major role in glucose homeostasis and Insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in Insulin Clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, Insulin tolerance tests, Insulin dynamics, and Insulin Clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated Insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced Insulin resistance, glucose intolerance, and increased Insulin secretion and total Insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced Insulin Clearance and decay rate as well as reduced Insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing Insulin sensitivity, but it also reduces Insulin Clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

Antonio Carlos Boschero - One of the best experts on this subject based on the ideXlab platform.

  • combined oral contraceptive in female mice causes hyperInsulinemia due to β cell hypersecretion and reduction in Insulin Clearance
    The Journal of Steroid Biochemistry and Molecular Biology, 2019
    Co-Authors: Cremilda Amaral Roso De Oliveira, Jean F. Vettorazzi, Antonio Carlos Boschero, Thiago R Araujo, Gesily De Souza Aguiar, Joel Alves Da Silva, Israelle Netto Freitas, Kenia M Oliveira, Maria Lucia Bonfleur, Julia R Clarke
    Abstract:

    Abstract Oral contraception is the most commonly used interventional method in the world. However, several women employ the continuous use of these hormones to avoid pre- and menstruation discomforts. Some studies indicate that oral contraceptives are associated with disturbances in glycemia and the effects of the use of a continuous regime are poorly elucidated. Herein, we evaluated the effects of the continuous administration of a combined oral contraceptive (COC) composed by ethinyl estradiol (EE) and drospirenone (DRSP) on glucose homeostasis in female mice. Adult Swiss mice received 0.6 μg EE and 60 μg DRSP (COC group) or vehicle [control (CTL)] daily by gavage for 35 days. COC treatment had no effect on body weight or adiposity, but increased uterus weight and induced hepatomegaly. Importantly, COC females displayed normal glycemia and glucose tolerance, but hyperInsulinemia and lower plasma C-peptide/Insulin ratio, indicating reduced Insulin Clearance. Furthermore, COC mice displayed reduced protein content of the β subunit of the Insulin receptor (IRβ) in the liver. Additionally, pancreatic islets isolated from COC mice secreted more Insulin in response to increasing glucose concentrations. This effect was associated with the activity of steroid hormones, since INS-1E cells incubated with EE plus DRSP also secreted more Insulin. Therefore, we provide the first evidence that the continuous administration of EE and DRSP lead to hyperInsulinemia, due to enhancement of Insulin secretion and the reduction of Insulin degradation, which possibly lead to the down-regulation of hepatic IRβ. These findings suggest that the continuous administration of COC could cause Insulin resistance with the prolongation of treatment.

  • Acute Exercise Improves Insulin Clearance and Increases the Expression of Insulin-Degrading Enzyme in the Liver and Skeletal Muscle of Swiss Mice
    PLOS ONE, 2016
    Co-Authors: Mirian Ayumi Kurauti, Ricardo Freitas-dias, Sandra Mara Ferreira, Jean F. Vettorazzi, Tarlliza R. Nardelli, Hygor N. Araujo, Gustavo Jorge Dos Santos, Everardo M. Carneiro, Antonio Carlos Boschero, Luiz F. Rezende
    Abstract:

    The effects of exercise on Insulin Clearance and IDE expression are not yet fully elucidated. Here, we have explored the effect of acute exercise on Insulin Clearance and IDE expression in lean mice. Male Swiss mice were subjected to a single bout of exercise on a speed/angle controlled treadmill for 3-h at approximately 60–70% of maximum oxygen consumption. As expected, acute exercise reduced glycemia and Insulinemia, and increased Insulin tolerance. The activity of AMPK-ACC, but not of IR-Akt, pathway was increased in the liver and skeletal muscle of trained mice. In an apparent contrast to the reduced Insulinemia, glucose-stimulated Insulin secretion was increased in isolated islets of these mice. However, Insulin Clearance was increased after acute exercise and was accompanied by increased expression of the Insulin-degrading enzyme (IDE), in the liver and skeletal muscle. Finally, C2C12, but not HEPG2 cells, incubated at different concentrations of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) for 3-h, showed increased expression of IDE. In conclusion, acute exercise increases Insulin Clearance, probably due to an augmentation of IDE expression in the liver and skeletal muscle. The elevated IDE expression, in the skeletal muscle, seems to be mediated by activation of AMPK-ACC pathway, in response to exercise. We believe that the increase in the IDE expression, comprise a safety measure to maintain glycemia at or close to physiological levels, turning physical exercise more effective and safe.

  • acute exercise restores Insulin Clearance in diet induced obese mice
    Journal of Endocrinology, 2016
    Co-Authors: Mirian Ayumi Kurauti, André Otávio Peres Protzek, Gustavo J. Santos, Sandra Mara Ferreira, Tarlliza R. Nardelli, Luiz F. Rezende, Jose M Costajunior, Antonio Carlos Boschero
    Abstract:

    The aim of this study was to investigate the Insulin Clearance in diet-induced obese (DIO) mice submitted to acute endurance exercise (3h of treadmill exercise at 60-70% VO2max). Glucose-stimulated Insulin secretion in isolated islets; ipGTT; ipITT; ipPTT; in vivo Insulin Clearance; protein expression in liver, skeletal muscle, and adipose tissue (Insulin degrading enzyme (IDE), Insulin receptor subunitβ(IRβ), phospho-Akt (p-Akt) and phospho-AMPK (p-AMPK)), and the activity of IDE in the liver and skeletal muscle were accessed. In DIO mice, acute exercise reduced fasting glycemia and Insulinemia, improved glucose and Insulin tolerance, reduced hepatic glucose production, and increased p-Akt protein levels in liver and skeletal muscle and p-AMPK protein levels in skeletal muscle. In addition, Insulin secretion was reduced, whereas Insulin Clearance and the expression of IDE and IRβ were increased in liver and skeletal muscle. Finally, IDE activity was increased only in skeletal muscle. In conclusion, we propose that the increased Insulin Clearance and IDE expression and activity, primarily, in skeletal muscle, constitute an additional mechanism, whereby physical exercise reduces Insulinemia in DIO mice.

  • reduced Insulin Clearance and lower Insulin degrading enzyme expression in the liver might contribute to the thrifty phenotype of protein restricted mice
    British Journal of Nutrition, 2014
    Co-Authors: Luiz F. Rezende, Antonio Carlos Boschero, Rafael Ludemann Camargo, Renato Chaves Souto Branco, Ana Paula Gameiro Cappelli, Everardo M. Carneiro
    Abstract:

    Nutrient restriction during the early stages of life usually leads to alterations in glucose homeostasis, mainly Insulin secretion and sensitivity, increasing the risk of metabolic disorders in adulthood. Despite growing evidence regarding the importance of Insulin Clearance during glucose homeostasis in health and disease, no information exists about this process in malnourished animals. Thus, in the present study, we aimed to determine the effect of a nutrient-restricted diet on Insulin Clearance using a model in which 30-d-old C57BL/6 mice were exposed to a protein-restricted diet for 14 weeks. After this period, we evaluated many metabolic variables and extracted pancreatic islet, liver, gastrocnemius muscle (GCK) and white adipose tissue samples from the control (normal-protein diet) and restricted (low-protein diet, LP) mice. Insulin concentrations were determined using RIA and protein expression and phosphorylation by Western blot analysis. The LP mice exhibited lower body weight, glycaemia, and Insulinaemia, increased glucose tolerance and altered Insulin dynamics after the glucose challenge. The improved glucose tolerance could partially be explained by an increase in Insulin sensitivity through the phosphorylation of the Insulin receptor/protein kinase B and AMP-activated protein kinase/acetyl-CoA carboxylase in the liver, whereas the changes in Insulin dynamics could be attributed to reduced Insulin secretion coupled with reduced Insulin Clearance and lower Insulin-degrading enzyme (IDE) expression in the liver and GCK. In summary, protein-restricted mice not only produce and secrete less Insulin, but also remove and degrade less Insulin. This phenomenon has the double benefit of sparing Insulin while prolonging and potentiating its effects, probably due to the lower expression of IDE in the liver, possibly with long-term consequences.

  • Cafeteria diet inhibits Insulin Clearance by reduced Insulin-degrading enzyme expression and mRNA splicing
    Journal of Endocrinology, 2013
    Co-Authors: P Brandimarti, José M. Costa-júnior, André Otávio Peres Protzek, Gustavo J. Santos, Sandra Mara Ferreira, Everardo M. Carneiro, Antonio Carlos Boschero, Luiz F. Rezende
    Abstract:

    Insulin Clearance plays a major role in glucose homeostasis and Insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in Insulin Clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, Insulin tolerance tests, Insulin dynamics, and Insulin Clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated Insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced Insulin resistance, glucose intolerance, and increased Insulin secretion and total Insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced Insulin Clearance and decay rate as well as reduced Insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing Insulin sensitivity, but it also reduces Insulin Clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

Everardo M. Carneiro - One of the best experts on this subject based on the ideXlab platform.

  • Acute Exercise Improves Insulin Clearance and Increases the Expression of Insulin-Degrading Enzyme in the Liver and Skeletal Muscle of Swiss Mice
    PLOS ONE, 2016
    Co-Authors: Mirian Ayumi Kurauti, Ricardo Freitas-dias, Sandra Mara Ferreira, Jean F. Vettorazzi, Tarlliza R. Nardelli, Hygor N. Araujo, Gustavo Jorge Dos Santos, Everardo M. Carneiro, Antonio Carlos Boschero, Luiz F. Rezende
    Abstract:

    The effects of exercise on Insulin Clearance and IDE expression are not yet fully elucidated. Here, we have explored the effect of acute exercise on Insulin Clearance and IDE expression in lean mice. Male Swiss mice were subjected to a single bout of exercise on a speed/angle controlled treadmill for 3-h at approximately 60–70% of maximum oxygen consumption. As expected, acute exercise reduced glycemia and Insulinemia, and increased Insulin tolerance. The activity of AMPK-ACC, but not of IR-Akt, pathway was increased in the liver and skeletal muscle of trained mice. In an apparent contrast to the reduced Insulinemia, glucose-stimulated Insulin secretion was increased in isolated islets of these mice. However, Insulin Clearance was increased after acute exercise and was accompanied by increased expression of the Insulin-degrading enzyme (IDE), in the liver and skeletal muscle. Finally, C2C12, but not HEPG2 cells, incubated at different concentrations of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) for 3-h, showed increased expression of IDE. In conclusion, acute exercise increases Insulin Clearance, probably due to an augmentation of IDE expression in the liver and skeletal muscle. The elevated IDE expression, in the skeletal muscle, seems to be mediated by activation of AMPK-ACC pathway, in response to exercise. We believe that the increase in the IDE expression, comprise a safety measure to maintain glycemia at or close to physiological levels, turning physical exercise more effective and safe.

  • HyperInsulinemia caused by dexamethasone treatment is associated with reduced Insulin Clearance and lower hepatic activity of Insulin-degrading enzyme.
    The Journal of Steroid Biochemistry and Molecular Biology, 2015
    Co-Authors: André Otávio Peres Protzek, José M. Costa-júnior, Mirian Ayumi Kurauti, Sandra Mara Ferreira, Luiz F. Rezende, Everardo M. Carneiro, Ana Paula Gameiro Cappelli, Flavia M.m. Paula, Jane Cristina De Souza, Alex Rafacho
    Abstract:

    Abstract Objectives Glucocorticoid treatment induces Insulin resistance (IR), which is counteracted by a compensatory hyperInsulinemia, due to increased pancreatic β-cell function. There is evidence for also reduced hepatic Insulin Clearance, but whether this correlates with altered activity of Insulin-degrading enzyme (IDE) in the liver, is not fully understood. Here, we investigated whether hyperInsulinemia, in glucocorticoid-treated rodents, is associated with any alteration in the Insulin Clearance and activity of the IDE in the liver. Materials/methods Adult male Swiss mice and Wistar rats were treated with the synthetic glucocorticoid dexamethasone intraperitoneally [1 mg/kg body weight (b.w.)] for 5 consecutive days. Results Glucocorticoid treatment induced IR and hyperInsulinemia in both species, but was more impactful in rats that also displayed glucose intolerance and hyperglycemia. Insulin Clearance was reduced in glucocorticoid-treated rats and mice, as judged by the reduction of Insulin decay rate and increased Insulin area-under-the-curve (47% and 87%, respectively). These results were associated with reduced activity (35%) of hepatic IDE in rats and a tendency to reduction (p = 0.068) in mice, without alteration in hepatic IDE mRNA content, in both species. Conclusion In conclusion, the reduced Insulin Clearance in glucocorticoid-treated rodents was due to the reduction of hepatic IDE activity, at least in rats, which may contributes to the compensatory hyperInsulinemia. These findings corroborate the idea that short-term and/or partial inhibition of IDE activity in the liver could be beneficial for the glycemic control.

  • reduced Insulin Clearance and lower Insulin degrading enzyme expression in the liver might contribute to the thrifty phenotype of protein restricted mice
    British Journal of Nutrition, 2014
    Co-Authors: Luiz F. Rezende, Antonio Carlos Boschero, Rafael Ludemann Camargo, Renato Chaves Souto Branco, Ana Paula Gameiro Cappelli, Everardo M. Carneiro
    Abstract:

    Nutrient restriction during the early stages of life usually leads to alterations in glucose homeostasis, mainly Insulin secretion and sensitivity, increasing the risk of metabolic disorders in adulthood. Despite growing evidence regarding the importance of Insulin Clearance during glucose homeostasis in health and disease, no information exists about this process in malnourished animals. Thus, in the present study, we aimed to determine the effect of a nutrient-restricted diet on Insulin Clearance using a model in which 30-d-old C57BL/6 mice were exposed to a protein-restricted diet for 14 weeks. After this period, we evaluated many metabolic variables and extracted pancreatic islet, liver, gastrocnemius muscle (GCK) and white adipose tissue samples from the control (normal-protein diet) and restricted (low-protein diet, LP) mice. Insulin concentrations were determined using RIA and protein expression and phosphorylation by Western blot analysis. The LP mice exhibited lower body weight, glycaemia, and Insulinaemia, increased glucose tolerance and altered Insulin dynamics after the glucose challenge. The improved glucose tolerance could partially be explained by an increase in Insulin sensitivity through the phosphorylation of the Insulin receptor/protein kinase B and AMP-activated protein kinase/acetyl-CoA carboxylase in the liver, whereas the changes in Insulin dynamics could be attributed to reduced Insulin secretion coupled with reduced Insulin Clearance and lower Insulin-degrading enzyme (IDE) expression in the liver and GCK. In summary, protein-restricted mice not only produce and secrete less Insulin, but also remove and degrade less Insulin. This phenomenon has the double benefit of sparing Insulin while prolonging and potentiating its effects, probably due to the lower expression of IDE in the liver, possibly with long-term consequences.

  • Cafeteria diet inhibits Insulin Clearance by reduced Insulin-degrading enzyme expression and mRNA splicing
    Journal of Endocrinology, 2013
    Co-Authors: P Brandimarti, José M. Costa-júnior, André Otávio Peres Protzek, Gustavo J. Santos, Sandra Mara Ferreira, Everardo M. Carneiro, Antonio Carlos Boschero, Luiz F. Rezende
    Abstract:

    Insulin Clearance plays a major role in glucose homeostasis and Insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in Insulin Clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, Insulin tolerance tests, Insulin dynamics, and Insulin Clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated Insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced Insulin resistance, glucose intolerance, and increased Insulin secretion and total Insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced Insulin Clearance and decay rate as well as reduced Insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing Insulin sensitivity, but it also reduces Insulin Clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

  • ciliary neurotrophic factor cntf protects non obese swiss mice against type 2 diabetes by increasing beta cell mass and reducing Insulin Clearance
    Diabetologia, 2012
    Co-Authors: Luiz F. Rezende, Gustavo J. Santos, Everardo M. Carneiro, Junia Carolina Santossilva, Antonio Carlos Boschero
    Abstract:

    Aims/hypothesis Ciliary neurotrophic factor (CNTF) improves metabolic variables of obese animals with characteristics of type 2 diabetes, mainly by reducing Insulin resistance. We evaluated whether CNTF was able to improve other metabolic variables in mouse models of type 2 diabetes, such as beta cell mass and Insulin Clearance, and whether CNTF has any effect on non-obese mice with characteristics of type 2 diabetes.

Richard N. Bergman - One of the best experts on this subject based on the ideXlab platform.

  • response to comment on piccinini and bergman the measurement of Insulin Clearance diabetes care 2020 43 2296 2302
    Diabetes Care, 2021
    Co-Authors: Richard N. Bergman, Francesca Piccinini
    Abstract:

    We thank Dr. Gastadelli and colleagues for their interest in our review article (1) and their comments (2) on the limitations of different approaches to assessing Insulin Clearance in humans and putative limitations of the hypothesis (3) that lower Insulin Clearance might cause type 2 diabetes (T2D). In fact, many of their comments relate to a series of articles from our group, and in addition to the article they refer to (1), several others (4–6) are also relevant to their comments. Concerning the Polidori/Bergman model (4), they are correct that the approach used by Polidori et al. (4) assumes either linear or saturable hepatic Insulin extraction and chooses the model that best fits the data. We believe these are reasonable assumptions and that there is little support for the claim by Gastadelli et al. (2) that a saturable model of hepatic Insulin extraction is not justified based on experimental data. The articles they cite claiming that hepatic Insulin extraction does not reach saturability until Insulin concentrations are in the 300–500 mU/L range are based on comparisons between groups of …

  • The Measurement of Insulin Clearance
    American Diabetes Association, 2020
    Co-Authors: Francesca Piccinini, Richard N. Bergman
    Abstract:

    Insulin Clearance has recently been highlighted as a fundamental aspect of glucose metabolism, as it has been hypothesized that its impairment could be related to an increased risk of developing type 2 diabetes. This review focuses on methods used to calculate Insulin Clearance: from the early surrogate indices employing C-peptide to Insulin molar ratio, to direct measurement methods used in animal models, to modeling-based techniques to estimate the <i>components </i>of Insulin Clearance (hepatic versus extra-hepatic). The methods are explored and interpreted by critically highlighting advantages and limitations.

  • hypothesis role of reduced hepatic Insulin Clearance in the pathogenesis of type 2 diabetes
    Diabetes, 2019
    Co-Authors: Richard N. Bergman, Morvarid Kabir, Cathryn M Kolka, Francesca Piccinini, Marilyn Ader
    Abstract:

    There is wide variance among individuals in the fraction of Insulin cleared by the liver (20% to 80%). Hepatic Insulin Clearance is 67% lower in African Americans than European Americans. Clearance is also lower in African American children 7-13 years of age. Lower hepatic Insulin Clearance will result in peripheral hyperInsulinemia: this exacerbates Insulin resistance, which stresses the β-cells, possibly resulting in their ultimate failure and onset of type 2 diabetes. We hypothesize that lower Insulin Clearance can be a primary cause of type 2 diabetes in at-risk individuals.

  • 1330 p ethnic differences in Insulin Clearance relationship with admixture scores diet and physical activity
    Diabetes, 2019
    Co-Authors: Francesca Piccinini, Barbara A Gower, Jose R Fernandez, Richard N. Bergman
    Abstract:

    Recent studies showed that hepatic Insulin Clearance is lower in African Americans (AA) than European Americans (EA). The aim of this work is to elucidate the possible genetic/epigenetic versus lifestyle causes. The frequently-sampled intravenous glucose tolerance test (FSIGT) was performed in 142 children [38 AA, 69 EA, 28 HA (Hispanic Americans), both sexes, age 7-13 years, mean BMI = 19 kg/m 2 , basal plasma glucose = 99 mg/dL, Insulin = 78 pmol/L, C-peptide = 511 pmol/L]. Mathematical modeling provided hepatic (FE L ) and extra-hepatic (CL P ) Insulin Clearance values. Two-way analysis of covariance was done (groups: sex and ethnicity, covariates: age, Tanner stage and body fat from DXA). Data are mean (standard error). FE L was lower in AA than EA (18% (2%) vs. 31% (3%), p=0.001), but no difference was observed in HA. CL P was not different among ethnicities. Partial correlation was calculated between FE L , CL P and 1) diet composition (energy intake, % of calories from carbohydrate, fat, protein), 2) physical activity (PA: light, moderate, hard, very hard), 3) admixture scores (African, European, Amerindian). FE L was positively correlated with the European admixture score (r=0.3, p L was negatively associated with moderate PA in all the subjects (r=-0.2, p=0.01), and with hard PA in EA (r=-0.4, p P was positively correlated with moderate PA in AA (r=0.4, p=0.02). Concerning diet, FE L was only correlated with % of calories from fat in EA (r=0.3, p=0.01). Because of its negative association with the African admixture, but positive with the European one, the lower hepatic Insulin Clearance might be genetic in origin, possibly resulting in hyperInsulinemia and diabetes risk. Our data also suggest that detrimental effects of lower Insulin Clearance might be mitigated by lifestyle changes such as exercise: moderate PA in AA could lead to a normalization of Insulinemia by increasing extra-hepatic Insulin Clearance. Disclosure F. Piccinini: None. B. Gower: None. J.R. Fernandez: None. R.N. Bergman: Consultant; Self; Zafgen, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK067426); Nutrition Obesity Research Center (DK56336); National Institutes of Health (M01RR00032)

  • dissection of hepatic versus extra hepatic Insulin Clearance ethnic differences in childhood
    Diabetes Obesity and Metabolism, 2018
    Co-Authors: Francesca Piccinini, David Polidori, Barbara A Gower, Jose R Fernandez, Richard N. Bergman
    Abstract:

    AIMS Adult African American (AA) women have one third of the hepatic Insulin Clearance of European American (EA) women. This lower hepatic (but not extra-hepatic) Insulin Clearance in AA individuals is associated with higher plasma Insulin concentrations. This study aims to understand whether impairment of hepatic Insulin Clearance is seen in AA individuals since childhood, possibly suggesting that genetic/epigenetic factors, rather than lifestyle only, contribute to this. MATERIALS AND METHODS A total of 203 children (105 male and 98 female (55 AA, 88 EA and 60 Hispanic American [HA]; ages, 7-13 years; mean BMI, 19 kg/m2 )) underwent the frequently applied intravenous glucose tolerance test (FSIGT) at the University of Alabama at Birmingham, General Clinical Research Center and Department of Nutrition Sciences. Glucose, Insulin and C-peptide levels were measured and hepatic and extra-hepatic Insulin Clearances were calculated using mathematical modelling. RESULTS Fractional hepatic Insulin extraction (FEL ) was lower in AA than in EA children (mean (SD), 19% (20%) vs 33% (20%); P = 0.0007). Adjusting for age, Tanner stage and body fat, FEL was lower in AA than in EA children (P = 0.0012), and there was a slight sex-related difference (FEL, 24% (10%) vs 29% (10%) in boys vs girls; P = 0.04). Extra-hepatic Insulin Clearance did not differ with ethnicity (27 (12), 21 (12) and 24 (28) mL/kg/min for AA, HA and EA children, respectively; P > 0.05). CONCLUSIONS At a young age, FEL is lower in AAs than in EAs, which does not rule out genetic/epigenetic factors. These differences are related to hyperInsulinaemia and, over time, could possibly contribute to metabolic disorders in AA individuals.

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  • defining the relative role of Insulin Clearance in early dysglycemia in relation to Insulin sensitivity and Insulin secretion the microbiome and Insulin longitudinal evaluation study miles
    Metabolites, 2021
    Co-Authors: Alexis C Wood, Yiider Ida Chen, Jerome I Rotter, Elizabeth T Jensen, Gautam Ramesh, Alain G Bertoni, Stephen S Rich, Mark O Goodarzi
    Abstract:

    Insulin resistance and insufficient Insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced Insulin Clearance has been suggested, but few studies have investigated the contribution of Insulin Clearance while simultaneously examining decreased Insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in a cohort of 353 non-Hispanic White and African American individuals recruited in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Participants underwent oral glucose tolerance tests from which Insulin sensitivity, Insulin secretion, Insulin Clearance, and disposition index were calculated. Regression models examined the individual and joint contributions of these traits to early dysglycemia (prediabetes or newly diagnosed diabetes). In separate models, reduced Insulin sensitivity, reduced disposition index, and reduced Insulin Clearance were associated with dysglycemia. In a joint model, only Insulin resistance and reduced Insulin secretion were associated with dysglycemia. Models with Insulin sensitivity, disposition index, or three Insulin traits had the highest discriminative value for dysglycemia (area under the receiver operating characteristics curve of 0.82 to 0.89). These results suggest that in the race groups studied, Insulin resistance and compromised Insulin secretion are the main independent underlying defects leading to early dysglycemia.

  • 1085 p defining the role of Insulin Clearance in dysglycemia the microbiome and Insulin longitudinal evaluation study miles
    Diabetes, 2021
    Co-Authors: Alexis C Wood, Yiider Ida Chen, Jerome I Rotter, Elizabeth T Jensen, Gautam Ramesh, Zorayr Arzumanyan, Kelvin Lam, Alain G Bertoni, Mark O Goodarzi
    Abstract:

    Insulin resistance and insufficient Insulin secretion lead to type 2 diabetes. A role of reduced Insulin Clearance has been suggested, but few studies have investigated the contribution of Insulin Clearance while simultaneously examining Insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in 224 non-Hispanic White and 129 African Americans individuals from MILES (mean age 59, 62% female). Participants underwent oral glucose tolerance tests from which Insulin sensitivity, Insulin secretion, Insulin Clearance, and disposition index were calculated. Logistic regression models (controlling for age, sex, race, and BMI) examined the individual contributions of these traits separately, as well as the joint contribution of Insulin sensitivity, Clearance, and secretion, to early dysglycemia (prediabetes plus newly diagnosed diabetes; 46% of cohort). Models used standardized predictors such that odds ratios (OR) represent the change in odds of dysglycemia per standard deviation change. Model performance was assessed via Akaike’s Information Criterion (AIC) and area under the receiver operator characteristic curves (AUROC). In separate models, dysglycemia was associated with Insulin sensitivity (OR 0.2; 0.14-0.30; P Disclosure A. Wood: None. E. T. Jensen: None. G. Ramesh: None. Z. Arzumanyan: None. K. Lam: None. A. Bertoni: None. J. I. Rotter: None. Y. Chen: None. M. O. Goodarzi: None. Funding National Institutes of Health (R01DK109588)

  • classification of type 2 diabetes genetic variants and a novel genetic risk score association with Insulin Clearance
    The Journal of Clinical Endocrinology and Metabolism, 2020
    Co-Authors: Mark O Goodarzi, Jinrui Cui, Xiuqing Guo, Yiider Ida Chen, Kent D Taylor, Thomas A Buchanan, Nicholette D Palmer, Leslie J Raffel, Lynne E Wagenknecht, Willa A Hsueh
    Abstract:

    Context Genome-wide association studies have identified more than 450 single nucleotide polymorphisms (SNPs) for type 2 diabetes (T2D). Objective To facilitate use of these SNPs in future genetic risk score (GRS)-based analyses, we aimed to classify the SNPs based on physiology. We also sought to validate GRS associations with Insulin-related traits in deeply phenotyped Mexican Americans. Design, setting, and participants A total of 457 T2D SNPs from the literature were assigned physiologic function based on association studies and cluster analyses. All SNPs (All-GRS), beta-cell (BC-GRS), Insulin resistance (IR-GRS), lipodystrophy (Lipo-GRS), and body mass index plus lipids (B + L-GRS) were evaluated for association with diabetes and indices of Insulin secretion (from oral glucose tolerance test), Insulin sensitivity and Insulin Clearance (from euglycemic clamp), and adiposity and lipid markers in 1587 Mexican Americans. Results Of the 457 SNPs, 52 were classified as BC, 30 as IR, 12 as Lipo, 12 as B + L, whereas physiologic function of 351 was undefined. All-GRS was strongly associated with T2D. Among nondiabetic Mexican Americans, BC-GRS was associated with reduced Insulinogenic index, IR-GRS was associated with reduced Insulin sensitivity, and Lipo-GRS was associated with reduced adiposity. B + L-GRS was associated with increased Insulin Clearance. The latter did not replicate in an independent cohort wherein Insulin Clearance was assessed by a different method. Conclusions Supporting their utility, BC-GRS, IR-GRS, and Lipo-GRS, based on SNPs discovered largely in Europeans, exhibited expected associations in Mexican Americans. The novel association of B + L-GRS with Insulin Clearance suggests that impaired ability to reduce Insulin Clearance in compensation for IR may play a role in the pathogenesis of T2D. Whether this applies to other ethnic groups remains to be determined.

  • Insulin Clearance is associated with hepatic lipase activity and lipid and adiposity traits in mexican americans
    PLOS ONE, 2016
    Co-Authors: Artak Labadzhyan, Miklos Peterfy, Jinrui Cui, Xiuqing Guo, Yiider Ida Chen, Willa A Hsueh, Jerome I Rotter, Mark O Goodarzi
    Abstract:

    Reduction in Insulin Clearance plays an important role in the compensatory response to Insulin resistance. Given the importance of this trait to the pathogenesis of diabetes, a deeper understanding of its regulation is warranted. Our goal was to identify metabolic and cardiovascular traits that are independently associated with metabolic Clearance rate of Insulin (MCRI). We conducted a cross-sectional analysis of metabolic and cardiovascular traits in 765 participants from the Mexican-American Coronary Artery Disease (MACAD) project who had undergone blood sampling, oral glucose tolerance test, euglycemic-hyperInsulinemic clamp, dual-energy X-ray absorptiometry, and carotid ultrasound. We assessed correlations of MCRI with traits from seven domains, including anthropometry, biomarkers, cardiovascular, glucose homeostasis, lipase activity, lipid profile, and liver function tests. We found inverse independent correlations between MCRI and hepatic lipase (P = 0.0004), Insulin secretion (P = 0.0002), alanine aminotransferase (P = 0.0045), total fat mass (P = 0.014), and diabetes (P = 0.03). MCRI and apolipoprotein A-I exhibited a positive independent correlation (P = 0.035). These results generate a hypothesis that lipid and adiposity associated traits related to liver function may play a role in Insulin Clearance.

  • systematic evaluation of validated type 2 diabetes and glycaemic trait loci for association with Insulin Clearance
    Diabetologia, 2013
    Co-Authors: Mark O Goodarzi, Jinrui Cui, Xiuqing Guo, Michelle Jones, Talin Haritunians, Anny H Xiang, Yd Ida Chen, Kent D Taylor, Thomas A Buchanan, Willa A Hsueh
    Abstract:

    Aims/hypothesis Insulin Clearance is a highly heritable trait, for which few quantitative trait loci have been discovered. We sought to determine whether validated type 2 diabetes and/or glycaemic trait loci are associated with Insulin Clearance.