Impaired insulin stimulation of muscular ATP production in patients with type 1 diabetes.

Abstract

OBJECTIVE:

in type 2 diabetic patients and their first-degree relatives, insulin resistance (IR) is associated with impairment of insulin-stimulated myocellular glucose-6-phosphate (g6p) and unidirectional flux through ATP synthase (fATP), suggesting the presence of inherited abnormal mitochondrial oxidative fitness. We hypothesized that patients with long-standing type 1 diabetes may also exhibit insulin resistance as well as lower fATP.

DESIGN:

this single-centre trial was registered at ClinicalTrials.gov (NCT00481598).

SUBJECTS:

we included eight nonobese type 1 diabetic patients (mean diabetes duration: 17 years) with near-target glycaemic control [haemoglobin A1c (HbA1c): 6.8 ± 0.4%] during treatment with continuous subcutaneous insulin infusion pumps and eight healthy volunteers (HbA1c: 5.4 ± 0.2%) of comparable age, body mass and level of physical activity.

OUTCOME MEASURES:

myocellular fATP, g6p and intramyocellular lipid content (IMCL) were measured with (1) H/(31) P magnetic resonance spectroscopy during fasting and hyperinsulinaemic-euglycaemic clamp tests.

RESULTS:

fasting fATP, g6p and IMCL did not differ between groups. During stimulation by insulin, type 1 diabetic patients exhibited approximately 50% (P < 0.001) lower whole-body glucose disposal along with approximately 42% (P = 0.003) lower intramyocellular g6p and approximately25% (P = 0.024) lower fATP. Insulin-stimulated fATP correlated positively with whole-body insulin sensitivity (R = 0.706, P = 0.002) and negatively with HbA1c (R = -0.675, P = 0.004).

CONCLUSIONS:

despite documented near-target glycaemic control for 1 year, nonobese patients with long-standing type 1 diabetes can exhibit insulin resistance. This associates with lower insulin-stimulated flux through muscular ATP synthase which could result from glucose toxicity.

• Authors: M Kacerovsky, A Brehm, M Chmelik, A I Schmid, J Szendroedi, G Kacerovsky-Bielesz, P Nowotny, A Lettner, M Wolzt, J G Jones, M Roden
• Journal: Journal of internal medicine (J Intern Med) Vol. 269 Issue 2 Pg. 189-99 (Feb 2011) ISSN: 1365-2796 [Electronic] England
• PMID: 21205021 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Insulin
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (biosynthesis)
• Adult
• Anthropometry (methods)
• Blood Glucose (metabolism)
• Diabetes Mellitus, Type 1 (drug therapy, metabolism, physiopathology)
• Fasting (physiology)
• Female
• Glucose Clamp Technique
• Humans
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Infusions, Subcutaneous
• Insulin (pharmacology, therapeutic use)
• Insulin Resistance (physiology)
• Magnetic Resonance Spectroscopy (methods)
• Male
• Middle Aged
• Muscle, Skeletal (drug effects, metabolism)
• Young Adult