Insulin Regulation of Ketone Body Metabolism

Abstract

The overarching concern in the hormonal control of ketone body metabolism is the insulin level. In circumstances where insulin levels are relatively high, such as the fed state, both substrate (free fatty acid, [FFA]) availability and FFA oxidation are suppressed, directing FFA to storage and employing glucose to meet the energy needs of the body. In situations of relative insulin deficiency, such as starvation or type I diabetes, FFA oxidation is increased, driving the production of alternative energy‐producing substrates, ketone bodies, for use by the brain, as well as peripheral tissues. Insulin influences the activity of three key processes: FFA availability (lipolysis), ketone body production (ketogenesis), and disposal in peripheral tissues. All of these processes can be altered in pathophysiologic conditions such as type 1 and type 2 diabetes, obesity, starvation, and hyperthyroidism. The key control point is carnitine palmitoyltransferase‐I (CPT‐I), which mediates the passage of long chain fatty acyl coenzyme A (FA‐CoA) esters across the outer mitochondrial membrane, prior to oxidation or ketogenesis. Insulin regulates CPT‐I both at the level of gene transcription and by influencing the affinity for allosteric modulators. Regulation of hepatic CPT‐I expression or activity holds potential significance as an approach for controlling hyperglycemia and insulin resistance.

Links Between Metabolic and Structural Changes in the Brain of Cognitively Normal Older Adults: A 4-Year Longitudinal Follow-Up

“…Similar to other studies that reported a negative association between insulin resistance and CMR glc (Baker et al, 2011; Castellano et al, 2015a; Willette et al, 2015), we show here that a higher HOMA-IR correlated significantly with lower K glc and tended to correlate with lower plasma ketones ( p = 0.06). Insulin influences three aspects of ketone metabolism: free fatty acid availability from adipose tissue by lipolysis, ketogenesis in the liver and peripheral ketone clearance (Ciaraldi and Henry, 2004). Ketone transport into tissues is influenced by insulin (Balasse and Havel, 1971; Hall et al, 1984) and the inhibitory influence of insulin resistance on ketone body metabolism can be present at raised but still physiological insulin levels (Singh et al, 1993).…”

Differential insulin sensitivity of NMR-based metabolomic measures in a two-step hyperinsulinemic euglycemic clamp study

“…After an overnight fast, ketogenesis is activated in the liver to meet the energy demand of the body (in particular the brain) and ketone bodies such as three-hydroxybutyrate, acetate and acetoacetate are formed in this process (Barnett & Barnett, 2003 ). After the infusion of glucose and insulin during the clamp procedure, which is performed in the fasted state, the secretion of ketone bodies is acutely inhibited which explains their decreased concentrations (Ciaraldi, 2004 ).…”

The Metabolic Syndrome, a Human Disease

“…The main problem (excess of 2C supply with respect to energy needs) remains, and is simply 'exported' to peripheral tissues, often not fully designed to use them as main energy substrates. In addition, ketone bodies induce metabolic irritation, causing acidosis [601] and, eventually, serious bidirectional alterations in the control of insulin and glycaemia [602][603][604]. Dietary protein may in part limit these problems by providing hydrocarbon skeletons that partly compensate (see below) the problems elicited by lipid-laden ketogenic diets.…”