Cersósimo, Eugênio

Growth hormone (GH) excess stimulates lipolysis, but its role in the hierarchy of lipolysis regulation is not clear. We studied whether pulsatile GH delivery is required for its lipolytic effect. With use of the pancreatic clamp, eight subjects were randomized to three protocols: protocol A, GH deficiency; protocol B, constant GH infusion; protocol C, pulsatile GH delivery (same total GH as protocol B). Pulsatile GH was given in four consecutive bursts, with symmetric peak width (60 min), amplitude of 10.7 (men) and 15 (women) ng.kg-1.min-1, and peak width at half-height of 15 min. Palmitate flux (PF) was measured at baseline and in the last hour of each study with [3H]palmitate. GH (ng/ml) decreased from approximately 3.5 to 2.0 in protocol A (P < 0.05), it remained between 3.2 and 4.0 in protocol B (P < 0.05), but in protocol C it fluctuated between approximately 2.7 and approximately 5.0 (P < 0.05). Palmitate concentration (in mumol/l) was approximately 150 at baseline; it did not change in protocols A and B (137 +/- 17 and 136 +/- 12, respectively) but increased to 198 +/- 16 (P < 0.05) in protocol C. PF (mumol.kg-1.min-1) was approximately 2.7 at baseline and did not change in protocol B (2.4 +/- 0.2); it decreased to 2.2 +/- 0.1 in protocol A (P < 0.05); it increased to 3.1 +/- 0.3 (P < 0.05) in protocol C. These experiments provide evidence that pulsatile secretion of GH is required for its lipolytic effect.

To examine whether hyperglycemia is an independent regulator of adipose tissue lipolysis, we measured palmitate flux ([3H]palmitate) on two occasions in eight volunteers with insulin-dependent diabetes. On one. occasion, euglycemia was maintained for 4 h continuously; on a different occasion, hyperglycemia (plasma glucose, 12 mmol/l) was induced after 2 h of euglycemia. Palmitate flux decreased from 1.39 +/- 0.22 to 1.25 +/- 0.18 mumol.kg-1 x min-1 during sustained euglycemia and from 1.43 +/- 0.24 to 1.13 +/- 0.19 mumol.kg-1 x min-1 during the transition from the euglycemic to the hyperglycemic study intervals. There were no significant differences between the changes in palmitate flux from the first to the second study interval on the control (euglycemia-euglycemia) and experimental (euglycemia-hyperglycemia) study days and no difference between palmitate flux on different study days. Thus, in the face of euinsulinemia, euglucagonemia, and the absence of somatostatin, no effect of hyperglycemia on free fatty acid metabolism could be detected in humans.

AbstractAimsThe molecular mechanisms by which muraglitazar (peroxisome proliferator‐activated receptor γ/α agonist) improves insulin sensitivity in Type 2 diabetes mellitus are not fully understood. We hypothesized that muraglitazar would increase expression of 5′‐monophosphate‐activated protein kinase and genes involved in adiponectin signalling, free fatty acid oxidation and mitochondrial function in skeletal muscle.MethodsSixteen participants with Type 2 diabetes received muraglitazar, 5 mg/day (n = 12) or placebo (n = 4). Before and after 16 weeks, participants had vastus lateralis muscle biopsy followed by 180 min euglycaemic hyperinsulinaemic clamp.ResultsMuraglitazar increased plasma adiponectin (9.0 ± 1.1 to 17.8 ± 1.5 μg/ml, P < 0.05), while no significant change was observed with placebo. After 16 weeks with muraglitazar, fasting plasma glucose declined by 31%, fasting plasma insulin decreased by 44%, insulin‐stimulated glucose disposal increased by 81%, HbA1c decreased by 21% and plasma triglyceride decreased by 39% (all P < 0.05). Muraglitazar increased mRNA levels of 5′‐monophosphate‐activated protein kinase, adiponectin receptor 1, adiponectin receptor 2, peroxisome proliferator‐activated receptor gamma coactivator–1 alpha and multiple genes involved in mitochondrial function and fat oxidation. In the placebo group, there were no significant changes in expression of these genes.ConclusionsMuraglitazar increases plasma adiponectin, stimulates muscle 5′‐monophosphate‐activated protein kinase expression and increases expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation. These changes represent important cellular mechanisms by which dual peroxisome proliferator‐activated receptor agonists improve skeletal muscle insulin sensitivity.