Fat Metabolism and Diabetes: 2003 American Diabetes Association Postgraduate Course

• ADA, American Diabetes Association
• AMPK, AMP-activated protein kinase
• CCK, cholecystokinin
• CNS, central nervous system
• CRP, C-reactive protein
• DAG, diacylglycerol
• DPP, dipeptidyl peptidase
• FA, fatty acid
• FFA, free FA
• G3P, glycerol-3-phophate
• G6Pase, glucose-6 phosphatase
• GIP, glucose-dependent insulinotropic peptide
• GLP, glucagon-like peptide
• HGP, hepatic glucose production
• IGT, impaired glucose tolerance
• IL, interleukin
• IRS, insulin receptor substrate
• PAI, plasminogen activator inhibitor
• PEP, phosphoenol pyruvate
• PKC, protein kinase C
• PPAR, peroxisome proliferator-activated receptor
• SC, subcutaneous
• TNF, tumor necrosis factor
• TZD, thiazolidinedione
• WAT, white adipose tissue

At the American Diabetes Association Postgraduate Course in New York, New York, on 10 January 2003, David E. Kelley (Pittsburgh, PA) discussed the relationship between fat metabolism and diabetes. Over the past few decades, he noted, the prevalence of obesity has doubled in adults and has quadrupled in teenagers, with more than half of U.S. adults now being overweight or obese. This is a manifestation of a much more longstanding trend. Data from military recruitment records, for example, show that the average weight, adjusted for height, has been increasing over the past 150 years. Sixty-one percent of the prevalence of diabetes can be attributed to obesity. There is a strong correlation between BMI and body fat. One of the correlates of insulin resistance is the blood fatty acid (FA) level. In 1963, Randle (1) initially suggested that FAs compete with glucose for metabolism. Kelley showed that, in a euglycemic clamp, when comparing subjects with and without lipid infusion, the former have marked resistance to muscle glucose uptake, with increased glycolysis and decreased glycogen formation—“precisely the profile we get in type 2 diabetes.”

FA levels are strong predictors of muscle insulin resistance (2). Muscle fat content is increased in obesity and more so in type 2 diabetes. Electron microscopy shows decreased mitochondrial size in muscle from individuals with type 2 diabetes. Fats may not directly mediate insulin resistance, Kelly noted, but FA-derived muscle diacylglycerol (DAG) and fatty acyl CoA lead to increased intramuscular ceramide, which may directly affect muscle glucose uptake and metabolism. FA oxidation is greater and storage is lower in lean than in obese persons, but Kelley described an “inefficient use of fat” in persons with obesity: the normal insulin-induced increase in FA storage is attenuated and fails to improve with weight loss (3). He noted that while muscle …