Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer

K. J. Mather, G. D. Hutchins, K. Perry, W. Territo, R. Chisholm, A. Acton, B. Glick-Wilson, R. V. Considine, S. Moberly, Timothy R DeGrado

Research output: Contribution to journalArticle

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Abstract

Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16- [18F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([11C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m‑2·min‑1) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM.

Original languageEnglish (US)
Pages (from-to)E452-E460
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume310
Issue number6
DOIs
StatePublished - 2016

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Type 2 Diabetes Mellitus
Fatty Acids
Insulin
Glucose Clamp Technique
Oxygen Consumption
Perfusion
F(18) 4-thiapalmitate
Nonesterified Fatty Acids
Positron-Emission Tomography
Myocardial Ischemia
Volunteers
Heart Diseases
Fasting
Heart Rate
Stroke
Oxygen
Blood Pressure

Keywords

  • Diabetes
  • Heart
  • Metabolic flexibility
  • Metabolism
  • Myocardial
  • Positron emission tomography

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Medicine(all)
  • Physiology (medical)

Cite this

Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer. / Mather, K. J.; Hutchins, G. D.; Perry, K.; Territo, W.; Chisholm, R.; Acton, A.; Glick-Wilson, B.; Considine, R. V.; Moberly, S.; DeGrado, Timothy R.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 310, No. 6, 2016, p. E452-E460.

Research output: Contribution to journalArticle

Mather, K. J. ; Hutchins, G. D. ; Perry, K. ; Territo, W. ; Chisholm, R. ; Acton, A. ; Glick-Wilson, B. ; Considine, R. V. ; Moberly, S. ; DeGrado, Timothy R. / Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer. In: American Journal of Physiology - Endocrinology and Metabolism. 2016 ; Vol. 310, No. 6. pp. E452-E460.
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AU - Perry, K.

AU - Territo, W.

AU - Chisholm, R.

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AB - Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16- [18F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([11C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m‑2·min‑1) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM.

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KW - Heart

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