Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto-Kakizaki rats

Ana Francisca Soares; Jakob D. Nissen; Alba M. Garcia-Serrano; Sakura S. Nussbaum; Helle S. Waagepetersen; João M.N. Duarte

doi:10.1002/jnr.24437

Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto-Kakizaki rats

Ana Francisca Soares, Jakob D. Nissen, Alba M. Garcia-Serrano, Sakura S. Nussbaum, Helle S. Waagepetersen, João M.N. Duarte^*

^*Corresponding author for this work

7 Citations (Scopus)

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Abstract

Diabetes impacts the central nervous system predisposing to cognitive decline. While glucose is the main source of energy fueling the adult brain, brain glycogen is necessary for adequate neuronal function, synaptic plasticity and memory. In this study, we tested the hypothesis that brain glycogen metabolism is impaired in type 2 diabetes (T2D). ¹³ C magnetic resonance spectroscopy (MRS) during [1- ¹³ C]glucose i.v. infusion was employed to detect ¹³ C incorporation into whole-brain glycogen in male Goto-Kakizaki (GK) rats, a lean model of T2D, and control Wistar rats. Labeling from [1- ¹³ C]glucose into brain glycogen occurred at a rate of 0.25 ± 0.12 and 0.48 ± 0.22 µmol/g/h in GK and Wistar rats, respectively (p = 0.028), despite similar brain glycogen concentrations. In addition, the appearance of [1- ¹³ C]glucose in the brain was used to evaluate glucose transport and consumption. T2D caused a 31% reduction (p = 0.031) of the apparent maximum transport rate (T _max ) and a tendency for reduced cerebral metabolic rate of glucose (CMR _glc ; −29%, p = 0.062), indicating impaired glucose utilization in T2D. After MRS in vivo, gas chromatography-mass spectrometry was employed to measure regional ¹³ C fractional enrichment of glucose and glycogen in the cortex, hippocampus, striatum, and hypothalamus. The diabetes-induced reduction in glycogen labeling was most prominent in the hippocampus and hypothalamus, which are crucial for memory and energy homeostasis, respectively. These findings were further supported by changes in the phosphorylation rate of glycogen synthase, as analyzed by Western blotting. Altogether, the present results indicate that T2D is associated with impaired brain glycogen metabolism.

Original language	English
Journal	Journal of Neuroscience Research
Volume	97
Pages (from-to)	1004-1017
ISSN	0360-4012
DOIs	https://doi.org/10.1002/jnr.24437
Publication status	Published - Aug 2019

Keywords

brain metabolism
diabetes
glucose
glycogen
insulin resistance

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Soares_et_al-2019-Journal_of_Neuroscience_ResearchFinal published version, 1.26 MBLicence: CC BY

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title = "Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto-Kakizaki rats",

abstract = " Diabetes impacts the central nervous system predisposing to cognitive decline. While glucose is the main source of energy fueling the adult brain, brain glycogen is necessary for adequate neuronal function, synaptic plasticity and memory. In this study, we tested the hypothesis that brain glycogen metabolism is impaired in type 2 diabetes (T2D). 13 C magnetic resonance spectroscopy (MRS) during [1- 13 C]glucose i.v. infusion was employed to detect 13 C incorporation into whole-brain glycogen in male Goto-Kakizaki (GK) rats, a lean model of T2D, and control Wistar rats. Labeling from [1- 13 C]glucose into brain glycogen occurred at a rate of 0.25 ± 0.12 and 0.48 ± 0.22 µmol/g/h in GK and Wistar rats, respectively (p = 0.028), despite similar brain glycogen concentrations. In addition, the appearance of [1- 13 C]glucose in the brain was used to evaluate glucose transport and consumption. T2D caused a 31% reduction (p = 0.031) of the apparent maximum transport rate (T max ) and a tendency for reduced cerebral metabolic rate of glucose (CMR glc ; −29%, p = 0.062), indicating impaired glucose utilization in T2D. After MRS in vivo, gas chromatography-mass spectrometry was employed to measure regional 13 C fractional enrichment of glucose and glycogen in the cortex, hippocampus, striatum, and hypothalamus. The diabetes-induced reduction in glycogen labeling was most prominent in the hippocampus and hypothalamus, which are crucial for memory and energy homeostasis, respectively. These findings were further supported by changes in the phosphorylation rate of glycogen synthase, as analyzed by Western blotting. Altogether, the present results indicate that T2D is associated with impaired brain glycogen metabolism. ",

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author = "Soares, {Ana Francisca} and Nissen, {Jakob D.} and Garcia-Serrano, {Alba M.} and Nussbaum, {Sakura S.} and Waagepetersen, {Helle S.} and Duarte, {Jo{\~a}o M.N.}",

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T1 - Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto-Kakizaki rats

AU - Soares, Ana Francisca

AU - Nissen, Jakob D.

AU - Garcia-Serrano, Alba M.

AU - Nussbaum, Sakura S.

AU - Waagepetersen, Helle S.

AU - Duarte, João M.N.

PY - 2019/8

Y1 - 2019/8

N2 - Diabetes impacts the central nervous system predisposing to cognitive decline. While glucose is the main source of energy fueling the adult brain, brain glycogen is necessary for adequate neuronal function, synaptic plasticity and memory. In this study, we tested the hypothesis that brain glycogen metabolism is impaired in type 2 diabetes (T2D). 13 C magnetic resonance spectroscopy (MRS) during [1- 13 C]glucose i.v. infusion was employed to detect 13 C incorporation into whole-brain glycogen in male Goto-Kakizaki (GK) rats, a lean model of T2D, and control Wistar rats. Labeling from [1- 13 C]glucose into brain glycogen occurred at a rate of 0.25 ± 0.12 and 0.48 ± 0.22 µmol/g/h in GK and Wistar rats, respectively (p = 0.028), despite similar brain glycogen concentrations. In addition, the appearance of [1- 13 C]glucose in the brain was used to evaluate glucose transport and consumption. T2D caused a 31% reduction (p = 0.031) of the apparent maximum transport rate (T max ) and a tendency for reduced cerebral metabolic rate of glucose (CMR glc ; −29%, p = 0.062), indicating impaired glucose utilization in T2D. After MRS in vivo, gas chromatography-mass spectrometry was employed to measure regional 13 C fractional enrichment of glucose and glycogen in the cortex, hippocampus, striatum, and hypothalamus. The diabetes-induced reduction in glycogen labeling was most prominent in the hippocampus and hypothalamus, which are crucial for memory and energy homeostasis, respectively. These findings were further supported by changes in the phosphorylation rate of glycogen synthase, as analyzed by Western blotting. Altogether, the present results indicate that T2D is associated with impaired brain glycogen metabolism.

AB - Diabetes impacts the central nervous system predisposing to cognitive decline. While glucose is the main source of energy fueling the adult brain, brain glycogen is necessary for adequate neuronal function, synaptic plasticity and memory. In this study, we tested the hypothesis that brain glycogen metabolism is impaired in type 2 diabetes (T2D). 13 C magnetic resonance spectroscopy (MRS) during [1- 13 C]glucose i.v. infusion was employed to detect 13 C incorporation into whole-brain glycogen in male Goto-Kakizaki (GK) rats, a lean model of T2D, and control Wistar rats. Labeling from [1- 13 C]glucose into brain glycogen occurred at a rate of 0.25 ± 0.12 and 0.48 ± 0.22 µmol/g/h in GK and Wistar rats, respectively (p = 0.028), despite similar brain glycogen concentrations. In addition, the appearance of [1- 13 C]glucose in the brain was used to evaluate glucose transport and consumption. T2D caused a 31% reduction (p = 0.031) of the apparent maximum transport rate (T max ) and a tendency for reduced cerebral metabolic rate of glucose (CMR glc ; −29%, p = 0.062), indicating impaired glucose utilization in T2D. After MRS in vivo, gas chromatography-mass spectrometry was employed to measure regional 13 C fractional enrichment of glucose and glycogen in the cortex, hippocampus, striatum, and hypothalamus. The diabetes-induced reduction in glycogen labeling was most prominent in the hippocampus and hypothalamus, which are crucial for memory and energy homeostasis, respectively. These findings were further supported by changes in the phosphorylation rate of glycogen synthase, as analyzed by Western blotting. Altogether, the present results indicate that T2D is associated with impaired brain glycogen metabolism.

KW - brain metabolism

KW - diabetes

KW - glucose

KW - glycogen

KW - insulin resistance

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SP - 1004

EP - 1017

JO - Journal of Neuroscience Research

JF - Journal of Neuroscience Research

ER -

Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto-Kakizaki rats

Abstract

Keywords

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