ABSTRACT

Introduction Among the more pressing health concerns of modern life is the explosive rise in rates of obesity, diabetes, and the metabolic syndrome. There is a

Introduction ...................................................................................................... 97 Mechanisms of carnitine involvement in insulin resistance ...................... 98 Lipotoxicity ....................................................................................................... 99

DAGs and ceramides .................................................................................. 99 Impaired FAO ............................................................................................ 100

Mitochondrial overload theory .................................................................... 100 Energy balance ........................................................................................... 101 Mitochondrial load and glucose uptake ................................................ 102

Therapeutic role of carnitine ........................................................................ 103 Overview of carnitine supplementation studies .................................. 103

Mechanisms of carnitine’s effects in skeletal muscle ................................ 105 Increased FAO ............................................................................................ 105 Decreased FAO .......................................................................................... 106 Reduced mitochondrial load ................................................................... 106

Carnitine insufficiency as it relates to insulin resistance and type 2 diabetes ............................................................................................................ 109

Sequestration of carnitine in the acylcarnitine pool ..............................110 Urinary carnitine excretion .......................................................................111 Potential impairments in carnitine biosynthesis ...................................111 Intestinal carnitine absorption ................................................................. 112 Maternal health and nutrition ..................................................................113 Potential problems with carnitine deficiency .........................................114

Summary and prospective studies ...............................................................115 References .........................................................................................................115

strong need for detailed mechanistic investigation that will pave the way for development of new preventive and treatment strategies. These must be both cost-effective to administer and free of potentially deleterious side effects with long-term treatment. Carnitine supplementation therapy has shown promising results in a limited number of human and animal trials, but several questions remain to be answered both practically and mechanistically. We first describe the current rationale for involvement of carnitine in diabetes and metabolic syndrome. Next, we briefly summarize existing animal and human studies of carnitine supplementation. We discuss in more detail mechanistic insights that have been gained both from carnitine supplementation and from genetic or pharmacological manipulation of the carnitine shuttle. Finally, we consider whether there is evidence for carnitine insufficiency in obesity/metabolic syndrome or diabetes that justifies the therapeutic use of supplementary carnitine. Looking forward to the future, we must identify patient characteristics associated with beneficial therapeutic outcomes. Key areas of research to accomplish this goal are highlighted.