We investigated whether decreased responsiveness of the heart to physiological increases in fatty acid availability results in lipid accumulation and lipotoxic heart disease. Lean and obese Zucker rats were either fed ad libitum or fasted overnight. Fasting increased plasma nonesterified fatty acid levels in both lean and obese rats, although levels were greatest in obese rats regardless of nutritional status. Despite increased fatty acid availability, the mRNA transcript levels of peroxisome proliferator-activated receptor (PPAR)-␣-regulated genes were similar in fed lean and fed obese rat hearts. Fasting increased expression of all PPAR-␣-regulated genes in lean Zucker rat hearts, whereas, in obese Zucker rat hearts, muscle carnitine palmitoyltransferase and medium-chain acyl-CoA dehydrogenase were unaltered with fasting. Rates of oleate oxidation were similar for hearts from fed rats. However, fasting increased rates of oleate oxidation only in hearts from lean rats. Dramatic lipid deposition occurred within cardiomyocytes of obese, but not lean, Zucker rats upon fasting. Cardiac output was significantly depressed in hearts isolated from obese rats compared with lean rats, regardless of nutritional status. Fasting increased cardiac output in hearts of lean rats only. Thus, the heart's inability to increase fatty acid oxidation in proportion to increased fatty acid availability is associated with lipid accumulation and contractile dysfunction of the obese Zucker rat.

Insulin resistance occurs in a variety of conditions, including diabetes, obesity and essential hypertension, but its underlying molecular mechanisms are unclear. In type 2 (non-insulin-dependent) diabetes mellitus, it is insulin-resistance in skeletal muscle, the chief site of insulin-mediated glucose disposal in humans, that predominantly accounts for the low rates of glucose clearance from the blood, and hence for impaired glucose tolerance. Human type 2 diabetes is characterized by a decrease in non-oxidative glucose storage (muscle glycogen synthesis), and by the deposition of amyloid in the islets of Langerhans. Amylin is a 37-amino-acid peptide which is a major component of islet amyloid and has structural similarity to human calcitonin gene-related peptide-2 (CGRP-2; ref. 8). CGRP is a neuropeptide which may be involved in motor activity in skeletal muscle. We now report that human pancreatic amylin and rat CGRP-1 are potent inhibitors of both basal and insulin-stimulated rates of glycogen synthesis in stripped rat soleus muscle in vitro. These results may provide a basis for a new understanding of the molecular mechanisms that cause insulin resistance in skeletal muscle.

Diabetes-associated peptide has recently been isolated and characterized from the amyloid of the islets of Langerhans in type 2 (non-insulin-dependent) diabetics, and immunoreactivity with antibodies to the peptide has been demonstrated in islet B cells of both normal and type 2 diabetic subjects. In view of the evidence presented in this paper that this 37-amino acid peptide may be a hormone present in normal individuals, we now propose the name "amylin" to replace "diabetes-associated peptide." Because increased amylin, deposited as amyloid within the islets of Langerhans, is characteristic of type 2 diabetes, the study below was performed to examine the possible effects of amylin on peripheral glucose metabolism. Whole amylin was synthesized by using solidphase techniques, with formation of the disulffide linkage by oxidation in dilute aqueous solution and recovery of the peptide by Iyophilization. The effects of amylin on glucose metabolism were studied in two preparations in vitro, isolated rat soleus muscle strips and isolated rat adipocytes. In skeletal muscle exposed to 120 nM amylin for 1 hr, there was a marked decrease in both basal and submaxmally insulin-stimulated rates of glycogen synthesis, which resulted in significant reduction in the rates of insulin-stimulated glucose uptake. In muscles treated with amylin there was no response at the concentration of insulin required to stimulate glucose uptake half-maximally in untreated (control) muscles. In marked contrast, amylin had no effect on either basal or insulinstimulated rates of glucose incorporation into either CO2 or triacylglycerol in isolated adipocytes. Therefore, amylin may be a factor in the etiology of the insulin resistance in type 2 diabetes mellitus, as both deposition of the peptide in islet amyloid and decreased rates of glucose uptake and glycogen synthesis in skeletal muscle are characteristic of this condition.

This study examines the mechanisms of glucocorticoid-induced insulin resistance in rat soleus muscle. Glucocorticoid excess was induced by administration of dexamethasone to rats for 5 days. Dexamethasone decreased the sensitivity of 3-O-methylglucose transport, 2-deoxyglucose phosphorylation, glycogen synthesis and glucose oxidation to insulin. The total content of GLUT4 glucose transporters was not decreased by dexamethasone ; however, the increase in these transporters in the plasma membrane in response to insulin (100 m-units\litre) was lessened. In contrast, the sensitivity of lactate formation to insulin was normal. The content of 2-deoxyglucose in the dexamethasonetreated muscle was decreased at 100 m-units\litre insulin, while the contents of glucose 6-phosphate and fructose 2,6-bisphosphate were normal at all concentrations of insulin studied. The maximal activity of hexokinase in the soleus muscle was not

1. The effects of the nitric oxide (NO) donor sodium nitroprusside (SNP) on the rates of glucose transport and utilization and its interaction with insulin were investigated in rat soleus muscle in vitro. SNP stimulated the rate of 2-deoxyglucose transport and insulin-mediated (100 mu-units/ml) rates of both net and [14C]lactate release and the rate of glucose oxidation. The effects of SNP were independent of the concentration-dependent effects of insulin on glucose metabolism. 2. SNP stimulated the insulin-stimulated rates of net and [14C]lactate release and glucose oxidation in a concentration-dependent manner. The rate of [14C]lactate release was also stimulated by another NO donor, (Z)-1-(N-[aminopropyl]-N-[4-(3-aminopropylammonio) butyl]-amino)-diazen-l-ium-1,2-diolate (spermine NONOate). 3. SNP at 5, 10 and 15 mM inhibited the insulin-stimulated rate of glycogen synthesis and this rate was further decreased at 20 and 25 mM SNP. SNP did not affect the rate of glycogen synthesis in the absence of insulin. 4. Haemoglobin, which is a NO scavenger, prevented the stimulation of the rates of [14C]lactate release by SNP or spermine NONOate. 5. The cGMP content was increased maximally (by approx. 80-fold) within 15 min by SNP (15 mM). The cGMP content, raised maximally by SNP, was significantly decreased by the guanylate cyclase inhibitor LY-83583 (10 microM). The cGMP analogue 8-bromo-cGMP (100 microM) significantly increased the rate of net lactate release. 6. LY-83583 significantly inhibited SNP-stimulated rates of 2-deoxyglucose transport, [4C]lactate release and glucose oxidation. Methylene Blue (another guanylate cyclase inhibitor) also inhibited SNP-stimulated rates of [14C]lactate release. 7. The results suggest that in rat skeletal muscle: (a) nitric oxide (from SNP or spermine NONOate) increases the rate of glucose transport and metabolism, an effect independent of insulin; (b) SNP inhibits insulin-mediated rates of glycogen synthesis; (c) SNP stimulates cGMP formation, which mediates, at least partly, the effects on glucose metabolism; (d) nitric oxide-mediated stimulation of glucose utilization might occur in fibre contraction. The implications of the effects of NO on glucose metabolism are discussed.