Markers of autophagy are adapted to hyperglycaemia in skeletal muscle in type 2 diabetes

Rikke Kruse; Birgitte F Vind; Stine Juhl Petersson; Jonas M. Kristensen; Kurt Højlund

doi:10.1007/s00125-015-3654-0

Markers of autophagy are adapted to hyperglycaemia in skeletal muscle in type 2 diabetes

Rikke Kruse
, Birgitte F Vind
, Stine Juhl Petersson
, Jonas M. Kristensen
, Kurt Højlund

Sygeplejerskeuddannelsen i Odense

Odense University Hospital
University of Southern Denmark

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

AIMS/HYPOTHESIS: Autophagy is a catabolic process that maintains cellular homeostasis by degradation of protein aggregates and selective removal of damaged organelles, e.g. mitochondria (mitophagy). Insulin resistance in skeletal muscle has been linked to mitochondrial dysfunction and altered protein metabolism. Here, we investigated whether abnormalities in autophagy are present in human muscle in obesity and type 2 diabetes.

METHODS: Using a case-control design, skeletal muscle biopsies obtained in the basal and insulin-stimulated states from patients with type 2 diabetes during both euglycaemia and hyperglycaemia, and from glucose-tolerant lean and obese individuals during euglycaemia, were used for analysis of mRNA levels, protein abundance and phosphorylation of autophagy-related proteins.

RESULTS: Muscle transcript levels of autophagy-related genes (ULK1, BECN1, PIK3C3, ATG5, ATG7, ATG12, GABARAPL1, MAP1LC3B, SQSTM1, TP53INP2 and FOXO3A [also known as FOXO3]), including some specific for mitophagy (BNIP3, BNIP3L and MUL1), and protein abundance of autophagy-related gene (ATG)7 and Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), as well as content and phosphorylation of forkhead box O3A (FOXO3A) were similar among the groups. Insulin reduced lipidation of microtubule-associated protein light chain 3 (LC3)B-I to LC3B-II, a marker of autophagosome formation, with no effect on p62/sequestosome 1 (SQSTM1) content in muscle of lean and obese individuals. In diabetic patients, insulin action on LC3B was absent and p62/SQSTM1 content increased when studied under euglycaemia, whereas the responses of LC3B and p62/SQSTM1 to insulin were normalised during hyperglycaemia.

CONCLUSIONS/INTERPRETATION: Our results demonstrate that the levels of autophagy-related genes and proteins in muscle are normal in obesity and type 2 diabetes. This suggests that muscle autophagy in type 2 diabetes has adapted to hyperglycaemia, which may contribute to preserve muscle mass.

Original language	English
Journal	Diabetologia
Volume	58
Issue number	9
Pages (from-to)	2087-95
Number of pages	9
ISSN	0012-186X
DOIs	https://doi.org/10.1007/s00125-015-3654-0
Publication status	Published - Sept 2015

Keywords

Apoptosis Regulatory Proteins
Autophagy
Biopsy
Case-Control Studies
Diabetes Mellitus, Type 2
Female
Forkhead Box Protein O3
Forkhead Transcription Factors
Glucose Clamp Technique
Glucose Tolerance Test
Homeostasis
Humans
Hyperglycemia
Insulin Resistance
Journal Article
Male
Microtubule-Associated Proteins
Middle Aged
Mitochondria
Muscle, Skeletal
Obesity
Phosphorylation
RNA, Messenger
Research Support, Non-U.S. Gov't
TOR Serine-Threonine Kinases

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Cite this

@article{9047c7f2f1d649b498ad28857ef9400a,

title = "Markers of autophagy are adapted to hyperglycaemia in skeletal muscle in type 2 diabetes",

abstract = "AIMS/HYPOTHESIS: Autophagy is a catabolic process that maintains cellular homeostasis by degradation of protein aggregates and selective removal of damaged organelles, e.g. mitochondria (mitophagy). Insulin resistance in skeletal muscle has been linked to mitochondrial dysfunction and altered protein metabolism. Here, we investigated whether abnormalities in autophagy are present in human muscle in obesity and type 2 diabetes.METHODS: Using a case-control design, skeletal muscle biopsies obtained in the basal and insulin-stimulated states from patients with type 2 diabetes during both euglycaemia and hyperglycaemia, and from glucose-tolerant lean and obese individuals during euglycaemia, were used for analysis of mRNA levels, protein abundance and phosphorylation of autophagy-related proteins.RESULTS: Muscle transcript levels of autophagy-related genes (ULK1, BECN1, PIK3C3, ATG5, ATG7, ATG12, GABARAPL1, MAP1LC3B, SQSTM1, TP53INP2 and FOXO3A [also known as FOXO3]), including some specific for mitophagy (BNIP3, BNIP3L and MUL1), and protein abundance of autophagy-related gene (ATG)7 and Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), as well as content and phosphorylation of forkhead box O3A (FOXO3A) were similar among the groups. Insulin reduced lipidation of microtubule-associated protein light chain 3 (LC3)B-I to LC3B-II, a marker of autophagosome formation, with no effect on p62/sequestosome 1 (SQSTM1) content in muscle of lean and obese individuals. In diabetic patients, insulin action on LC3B was absent and p62/SQSTM1 content increased when studied under euglycaemia, whereas the responses of LC3B and p62/SQSTM1 to insulin were normalised during hyperglycaemia.CONCLUSIONS/INTERPRETATION: Our results demonstrate that the levels of autophagy-related genes and proteins in muscle are normal in obesity and type 2 diabetes. This suggests that muscle autophagy in type 2 diabetes has adapted to hyperglycaemia, which may contribute to preserve muscle mass.",

keywords = "Apoptosis Regulatory Proteins, Autophagy, Biopsy, Case-Control Studies, Diabetes Mellitus, Type 2, Female, Forkhead Box Protein O3, Forkhead Transcription Factors, Glucose Clamp Technique, Glucose Tolerance Test, Homeostasis, Humans, Hyperglycemia, Insulin Resistance, Journal Article, Male, Microtubule-Associated Proteins, Middle Aged, Mitochondria, Muscle, Skeletal, Obesity, Phosphorylation, RNA, Messenger, Research Support, Non-U.S. Gov't, TOR Serine-Threonine Kinases",

author = "Rikke Kruse and Vind, \{Birgitte F\} and Petersson, \{Stine Juhl\} and Kristensen, \{Jonas M.\} and Kurt H{\o}jlund",

year = "2015",

month = sep,

doi = "10.1007/s00125-015-3654-0",

language = "English",

volume = "58",

pages = "2087--95",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

number = "9",

}

TY - JOUR

T1 - Markers of autophagy are adapted to hyperglycaemia in skeletal muscle in type 2 diabetes

AU - Kruse, Rikke

AU - Vind, Birgitte F

AU - Petersson, Stine Juhl

AU - Kristensen, Jonas M.

AU - Højlund, Kurt

PY - 2015/9

Y1 - 2015/9

N2 - AIMS/HYPOTHESIS: Autophagy is a catabolic process that maintains cellular homeostasis by degradation of protein aggregates and selective removal of damaged organelles, e.g. mitochondria (mitophagy). Insulin resistance in skeletal muscle has been linked to mitochondrial dysfunction and altered protein metabolism. Here, we investigated whether abnormalities in autophagy are present in human muscle in obesity and type 2 diabetes.METHODS: Using a case-control design, skeletal muscle biopsies obtained in the basal and insulin-stimulated states from patients with type 2 diabetes during both euglycaemia and hyperglycaemia, and from glucose-tolerant lean and obese individuals during euglycaemia, were used for analysis of mRNA levels, protein abundance and phosphorylation of autophagy-related proteins.RESULTS: Muscle transcript levels of autophagy-related genes (ULK1, BECN1, PIK3C3, ATG5, ATG7, ATG12, GABARAPL1, MAP1LC3B, SQSTM1, TP53INP2 and FOXO3A [also known as FOXO3]), including some specific for mitophagy (BNIP3, BNIP3L and MUL1), and protein abundance of autophagy-related gene (ATG)7 and Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), as well as content and phosphorylation of forkhead box O3A (FOXO3A) were similar among the groups. Insulin reduced lipidation of microtubule-associated protein light chain 3 (LC3)B-I to LC3B-II, a marker of autophagosome formation, with no effect on p62/sequestosome 1 (SQSTM1) content in muscle of lean and obese individuals. In diabetic patients, insulin action on LC3B was absent and p62/SQSTM1 content increased when studied under euglycaemia, whereas the responses of LC3B and p62/SQSTM1 to insulin were normalised during hyperglycaemia.CONCLUSIONS/INTERPRETATION: Our results demonstrate that the levels of autophagy-related genes and proteins in muscle are normal in obesity and type 2 diabetes. This suggests that muscle autophagy in type 2 diabetes has adapted to hyperglycaemia, which may contribute to preserve muscle mass.

AB - AIMS/HYPOTHESIS: Autophagy is a catabolic process that maintains cellular homeostasis by degradation of protein aggregates and selective removal of damaged organelles, e.g. mitochondria (mitophagy). Insulin resistance in skeletal muscle has been linked to mitochondrial dysfunction and altered protein metabolism. Here, we investigated whether abnormalities in autophagy are present in human muscle in obesity and type 2 diabetes.METHODS: Using a case-control design, skeletal muscle biopsies obtained in the basal and insulin-stimulated states from patients with type 2 diabetes during both euglycaemia and hyperglycaemia, and from glucose-tolerant lean and obese individuals during euglycaemia, were used for analysis of mRNA levels, protein abundance and phosphorylation of autophagy-related proteins.RESULTS: Muscle transcript levels of autophagy-related genes (ULK1, BECN1, PIK3C3, ATG5, ATG7, ATG12, GABARAPL1, MAP1LC3B, SQSTM1, TP53INP2 and FOXO3A [also known as FOXO3]), including some specific for mitophagy (BNIP3, BNIP3L and MUL1), and protein abundance of autophagy-related gene (ATG)7 and Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), as well as content and phosphorylation of forkhead box O3A (FOXO3A) were similar among the groups. Insulin reduced lipidation of microtubule-associated protein light chain 3 (LC3)B-I to LC3B-II, a marker of autophagosome formation, with no effect on p62/sequestosome 1 (SQSTM1) content in muscle of lean and obese individuals. In diabetic patients, insulin action on LC3B was absent and p62/SQSTM1 content increased when studied under euglycaemia, whereas the responses of LC3B and p62/SQSTM1 to insulin were normalised during hyperglycaemia.CONCLUSIONS/INTERPRETATION: Our results demonstrate that the levels of autophagy-related genes and proteins in muscle are normal in obesity and type 2 diabetes. This suggests that muscle autophagy in type 2 diabetes has adapted to hyperglycaemia, which may contribute to preserve muscle mass.

KW - Apoptosis Regulatory Proteins

KW - Autophagy

KW - Biopsy

KW - Case-Control Studies

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Forkhead Box Protein O3

KW - Forkhead Transcription Factors

KW - Glucose Clamp Technique

KW - Glucose Tolerance Test

KW - Homeostasis

KW - Humans

KW - Hyperglycemia

KW - Insulin Resistance

KW - Journal Article

KW - Male

KW - Microtubule-Associated Proteins

KW - Middle Aged

KW - Mitochondria

KW - Muscle, Skeletal

KW - Obesity

KW - Phosphorylation

KW - RNA, Messenger

KW - Research Support, Non-U.S. Gov't

KW - TOR Serine-Threonine Kinases

U2 - 10.1007/s00125-015-3654-0

DO - 10.1007/s00125-015-3654-0

M3 - Journal article

C2 - 26048236

SN - 0012-186X

VL - 58

SP - 2087

EP - 2095

JO - Diabetologia

JF - Diabetologia

IS - 9

ER -

Markers of autophagy are adapted to hyperglycaemia in skeletal muscle in type 2 diabetes

Abstract

Keywords

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