The last decade has taught us that the fat cell also plays a pivotal role in the pathogenesis of type 2 diabetes. Collectively, the fat cell and his three friends—the muscle, liver, and β-cell—comprise the harmonious quartet, or perhaps more appropriately, the dysharmonious quartet, since together they sing a very bad tune for the diabetic patient. Considerable evidence implicates deranged adipocyte metabolism and altered fat topography in the pathogenesis of glucose intolerance in type 2 diabetes (17
) Fat cells are resistant to insulin's antilipolytic effect, leading to day-long elevation in the plasma FFA concentration (26
) Chronically increased plasma FFA levels stimulate gluconeogenesis (180
), induce hepatic/muscle insulin resistance (142
), and impair insulin secretion (24
). These FFA-induced disturbances are referred to as lipotoxicity. 3
) Dysfunctional fat cells produce excessive amounts of insulin resistance–inducing, inflammatory, and atherosclerotic-provoking adipocytokines and fail to secrete normal amounts of insulin-sensitizing adipocytokines such as adiponectin (175
) Enlarged fat cells are insulin resistant and have diminished capacity to store fat (187
). When adipocyte storage capacity is exceeded, lipid “overflows” into muscle, liver, and β-cells, causing muscle/hepatic insulin resistance and impaired insulin secretion (rev. in (175
). Lipid can also overflow into arterial vascular smooth cells, leading to the acceleration of atherosclerosis.
C-palmitate in combination with the insulin clamp technique, Groop et al. (26
) demonstrated that the antilipolytic effect of insulin was markedly impaired in lean type 2 diabetic subjects, as well as in obese nondiabetic subjects (140
). In both type 2 diabetic (supplemental Fig. A5) and obese nondiabetic subjects, the ability of insulin to suppress the plasma FFA concentration and inhibit FFA turnover is significantly impaired compared with lean normal glucose tolerant control subjects at all plasma insulin concentrations spanning the physiological and pharmacological range.
Many investigators, including Boden, Shulman, and ourselves (181
), have shown that a physiological elevation in the plasma FFA concentration stimulates HGP and impairs insulin-stimulated glucose uptake in liver (190
) and muscle (151
). As discussed earlier, we and others (24
) have also shown that elevated plasma FFA levels inhibit insulin secretion.
Many years ago, Professor Philip Randle (195
) described his now famous cycle of substrate competition, whereby elevated FFA oxidation in muscle reciprocally impaired glucose oxidation. Although there clearly is substrate competition between FFA and glucose with respect to oxidative metabolism (196
), FFAs have been shown to have independent effects to inhibit glycogen synthase (198
) and both glucose transport and glucose phosphorylation (192
More recently, we have examined the effect of a 4-h lipid versus saline infusion on the insulin signal transduction system in healthy lean normal glucose tolerant subjects (201
). Lipid was infused at three rates (30, 60, and 90 ml/h) to cause a physiological and pharmacological elevation in the plasma FFA concentration. During the saline control study, insulin increased whole-body glucose metabolism from 2.7 to 10.8 mg · kg−1
. Lipid infusion caused a dose-response decline in insulin-stimulated whole-body glucose disposal (by 22, 30, and 34%, respectively), which primarily reflects muscle. Compared with the saline control study, lipid infusion caused a dose-response inhibition of muscle insulin receptor tyrosine phosphorylation, IRS-1 tyrosine phosphorylation, PI 3-kinase activity, and Akt serine phosphorylation ().
FIG. 11. Effect of lipid infusion to cause a physiological-pharmacological elevation in plasma FFA concentration on insulin signal transduction in healthy nondiabetic subjects (201). PY, phosphorylation.
After fatty acids enter the cell, they can be converted to triglycerides, which are inert, or to toxic lipid metabolites such as fatty acyl CoAs, diacylglycerol, and ceramide. Using magnetic resonance spectroscopy, we quantitated intramyocellular triglyceride content in healthy normal glucose tolerant and type 2 diabetic subjects and demonstrated that muscle lipid content was significantly increased in the diabetic group (R.A.D., unpublished data). Similar results have been reported by Petersen et al. (202
). Fatty acyl CoAs, which are known to inhibit insulin signaling (203
), were also significantly increased in muscle in diabetic subjects (205
). Diabetic subjects were treated with pioglitazone, which increases the expression of peroxisome proliferator–activated γ coactivator 1 (PGC-1) (207
). PGC-1 is the master regulator of mitochondrial biogenesis and augments the expression of multiple genes involved in mitochondrial oxidative phosphorylation (208
). Pioglitazone reduced the intramyocellular lipid and fatty acyl CoA concentrations, and the decrement in muscle fatty acyl CoA content was closely related to the improvement in insulin-stimulated muscle glucose disposal (205
). When we reduced the intramyocellular fatty acyl CoA content with acipimox, a potent inhibitor of lipolysis, a similar improvement in insulin-mediated glucose disposal was noted (206
). Increased intramyocellular levels of diacylglycerol (194
) and ceramides (212
) have also been demonstrated in type 2 diabetic and obese nondiabetic subjects and shown to be related to the insulin resistance and impaired insulin signaling in muscle. Most recently, we demonstrated that a 48-h lipid infusion, designed to increase the plasma FFA concentration ~1.5- to 2.0-fold, inhibited the expression of PGC1α, PGC1β, PDHA1, and multiple mitochondrial genes involved in oxidative phosphorylation in muscle (214
), thus mimicking the pattern of gene expression observed in type 2 diabetic subjects and in the normal glucose tolerant, insulin-resistant offspring of two type 2 diabetic parents (215
). Most recently, we examined the effect of palmitoyl carnitine on ATP synthesis in mitochondria isolated from muscle of normal glucose tolerant subjects (217
). Low concentrations of palmitoyl carnitine (1–4 μmol/l) augmented ATP synthesis. However, palmitoyl carnitine concentrations >4 μmol/l were associated with marked inhibition of ATP synthesis and a decrease in the inner mitochondrial membrane potential, which provides the electromotive driving force for electron transport. Collectively, these findings provide strong support for lipotoxicity and adipocyte insulin resistance in the pathogenesis of type 2 diabetes.