Effect of insulin deprivation on muscle mitochondrial ATP production and gene transcript levels in type 1 diabetic subjects.
OBJECTIVE
Muscle mitochondrial dysfunction occurs in many insulin-resistant states, such as type 2 diabetes, prompting a hypothesis that mitochondrial dysfunction may cause insulin resistance. We determined the impact of insulin deficiency on muscle mitochondrial ATP production by temporarily depriving type 1 diabetic patients of insulin treatment.


METHODS
We withdrew insulin for 8.6 +/- 0.6 h in nine C-peptide-negative type 1 diabetic subjects and measured muscle mitochondrial ATP production and gene transcript levels (gene array and real-time quantitative PCR) and compared with insulin-treated state. We also measured oxygen consumption (indirect calorimetry); plasma levels of glucagon, bicarbonate, and other substrates; and urinary nitrogen.


RESULTS
Withdrawal of insulin resulted in increased plasma glucose, branched chain amino acids, nonesterified fatty acids, beta-hydroxybutyrate, and urinary nitrogen but no change in bicarbonate. Insulin deprivation decreased muscle mitochondrial ATP production rate (MAPR) despite an increase in whole-body oxygen consumption and altered expression of many muscle mitochondrial gene transcripts. Transcript levels of genes involved in oxidative phosphorylation were decreased, whereas those involved in vascular endothelial growth factor (VEGF) signaling, inflammation, cytoskeleton signaling, and integrin signaling pathways were increased.


CONCLUSIONS
Insulin deficiency and associated metabolic changes reduce muscle MAPR and expression of oxidative phosphorylation genes in type 1 diabetes despite an increase in whole-body oxygen consumption. Increase in transcript levels of genes involved in VEGF, inflammation, cytoskeleton, and integrin signaling pathways suggest that vascular factors and cell proliferation that may interact with mitochondrial changes occurred.
Karakelides
Helen
H
Division of Endocrinology and Metabolism and Endocrine Research Unit, Mayo Clinic, 200 First St. SW, Joseph 5-194, Rochester, MN 55905, USA.
Asmann
Yan W
YW
Bigelow
Maureen L
ML
Short
Kevin R
KR
Dhatariya
Ketan
K
Coenen-Schimke
Jill
J
Kahl
Jane
J
Mukhopadhyay
Debabrata
D
Nair
K Sreekumaran
KS
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006801:Humans; D007328:Insulin / Q000172:deficiency*; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D016133:Polymerase Chain Reaction; D014158:Transcription, Genetic
D001786:Blood Glucose; D017931:DNA Primers; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D000255:Adenosine Triphosphate