Effect of Leptin Administration on Circulating Apolipoprotein CIII levels in Patients With Lipodystrophy.

CONTEXT: Apolipoprotein CIII (apoCIII), an inhibitor of lipoprotein lipase, plays an important role in triglyceride metabolism. However, the role of apoCIII in hypertriglyceridemia in lipodystrophy and the effects of leptin replacement on apoCIII levels are unknown. OBJECTIVE: The objective of the study was to test the hypotheses that apoCIII is elevated in hypertriglyceridemic patients with lipodystrophy and that leptin replacement in these patients lowers circulating apoCIII. DESIGN, SETTING, STUDY PARTICIPANTS, INTERVENTION, AND OUTCOME MEASURES: Using a post hoc cross-sectional case-control design, we compared serum apoCIII levels from patients with lipodystrophy not associated with HIV (n = 60) and age-, gender-, race-, and ethnicity-matched controls (n = 54) participating in ongoing studies at the National Institutes of Health. In a prospective, open-label, ongoing study, we studied the effects of 6­12 months of leptin replacement on apoCIII in lipodystrophy patients as an exploratory outcome. RESULTS: ApoCIII was higher in lipodystrophy patients (geometric mean [25th and 75th percentiles]) (23.9 mg/dL [14.6, 40.3]) compared with controls (14.9 mg/dL [12.3, 17.7]) (P < .0001). ApoCIII and triglyceride levels were positively correlated in patients with lipodystrophy (R = 0.72, P < .0001) and healthy controls (R = 0.6, P < .0001). Leptin replacement (6­12 mo) did not significantly alter apoCIII (before leptin: 23.4 mg/dL [14.5, 40.1]; after leptin: 21.4 mg/dL [16.7, 28.3]; P = .34). CONCLUSIONS: Leptin replacement in lipodystrophy did not alter serum apoCIII levels. Elevated apoCIII may play a role in the hypertriglyceridemia of lipodystrophy independent of leptin deficiency and replacement.

Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.

The lipodystrophies represent a class of diseases characterized by leptin deficiency. Leptin deficiency is associated with a severe form of the metabolic syndrome characterized by dyslipidemia, insulin resistance, diabetes, and ovarian dysfunction. Metreleptin is the pharmaceutical derived product that has been approved by the Food and Drug Administration (FDA) to treat the severe metabolic abnormalities of the generalized forms of lipodystrophy. Herein we describe the properties of metreleptin, its use in patients, which includes the administration of the drug and how it may be acquired by medical professionals as well as its safety, tolerability, and properties. Finally, we speculate on future uses and development of metreleptin.

EGF regulates survivin stability through the Raf-1/ERK pathway in insulin-secreting pancreatic ß-cells.

BACKGROUND: Postnatal expansion of the pancreatic ß-cell mass is required to maintain glucose homeostasis immediately after birth. This ß-cell expansion is regulated by multiple growth factors, including glucose, insulin, insulin-like growth factor (IGF-1) and epidermal growth factor (EGF). These mitogens signal through several downstream pathways (AKT, ERK, STAT3, and JNK) to regulate the survival and proliferation of ß-cells. Survivin, an oncofetal protein with both pro-proliferative and anti-apoptotic properties, is a known transcriptional target of both IGF-1 and EGF in cancer cells. Here, we analyzed the effects of the ß-cell mitogens IGF-1 and EGF on survivin regulation in the established pancreatic ß-cell model cell lines, MIN6 and INS-1 and in primary mouse islets. RESULTS: In pancreatic ß-cells, treatment with glucose, insulin, or EGF increased survivin protein levels at early time points. By contrast, no significant effects on survivin were observed following IGF-1 treatment. EGF-stimulated increases in survivin protein were abrogated in the presence of downstream inhibitors of the Raf-1/MEK/ERK pathway. EGF had no significant effect on survivin transcription however it prolonged the half-life of the survivin protein and stabilized survivin protein levels by inhibiting surviving ubiquitination. CONCLUSIONS: This study defines a novel mechanism of survivin regulation by EGF through the Raf-1/MEK/ERK pathway in pancreatic ß-cells, via prolongation of survivin protein half-life and inhibition of the ubiquitin-mediated proteasomal degradation pathway. This mechanism may be important for regulating ß-cell expansion after birth.

Atorvastatin effect on the distribution of high-density lipoprotein subfractions and human paraoxonase activity.

Human serum paraoxonase-1 (PON1) protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low-density lipoprotein (LDL); therefore, it may protect against atherosclerosis. Changes in the ratio of high-density lipoprotein (HDL) subfractions may alter the stability and the antioxidant capacity of PON1. The aim of the study was to examine the effect of atorvastatin treatment on the distribution of HDL subfractions, LDL size, cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and PON1 activity. In all, 33 patients with type IIa and IIb hypercholesterolemia were involved in the study. LDL sizes and HDL subfractions were determined by gradient gel electrophoresis. CETP, LCAT, and PON1 activities were measured spectrophotometrically. Three months of treatment with atorvastatin 20 mg daily significantly increased the HDL3 (+8.13%) and decreased the HDL2a and HDL2b subfractions (-1.57% and -6.55%, respectively). The mean LDL size was significantly increased (+3.29%). The level of oxidized LDL was significantly decreased (-46.0%). The PON1 activity was augmented by the atorvastatin treatment (+5.0%). The CETP activity positively correlated with the HDL2b level and negatively correlated with the HDL3 and HDL2a levels. Atorvastatin alters the HDL subfractions, which may improve its antiatherogenic effect via enhancement of the PON1 activity.

Uncoupling protein-2 modulates the lipid metabolic response to fasting in mice.

Uncoupling protein-2 (UCP2) regulates insulin secretion by controlling ATP levels in beta-cells. Although UCP2 deficiency improves glycemic control in mice, increased expression of UCP2 interferes with glucose-stimulated insulin secretion. These observations link UCP2 to beta-cell dysfunction in type 2 diabetes with a perplexing evolutionary role. We found higher residual serum insulin levels and blunted lipid metabolic responses in fasted ucp2(-/-) mice, supporting the concept that UCP2 evolved to suppress insulin effects and to accommodate the fuel switch to fatty acids during starvation. In the absence of UCP2, fasting initially promotes peripheral lipolysis and hepatic fat accumulation at less than expected rates but culminates in protracted steatosis, indicating diminished hepatic utilization and clearance of fatty acids. We conclude that UCP2-mediated control of insulin secretion is a physiologically relevant mechanism of the metabolic response to fasting.

The effect of atorvastatin therapy on lecithin:cholesterol acyltransferase, cholesteryl ester transfer protein and the antioxidant paraoxonase.

OBJECTIVES: The aim of our study was to examine the influence of atorvastatin on lipid parameters, particularly on HDL, and on the activity of LCAT and CETP and how they affect the activity of the HDL-associated antioxidant enzyme paraoxonase. DESIGN AND METHODS: Thirty-three patients with types II.a and II.b primary hyperlipoproteinemia were enrolled into our study. The patients received atorvastatin, 20 mg daily, for 3 months. We measured the serum paraoxonase activity and concentration, oxidized LDL, LCAT and CETP activities. RESULTS: Atorvastatin significantly reduced the levels of cholesterol, triglyceride, LDL-C and apoB, while it did not influence the levels of HDL-C and apo A-I. The increases in serum PON-specific activity, PON/HDL ratio and LCAT activity were significant, while oxLDL and CETP activities were significantly decreased. CONCLUSION: Atorvastatin may influence the composition and function of HDL, thereby possibly increasing the activity of paraoxonase and preventing atherosclerosis.

The association between angiotensin II-induced free radical generation and membrane fluidity in neutrophils of patients with metabolic syndrome.

Angiotensin II (Ang II) is able to induce free radical generation in neutrophils, which is more elevated in neutrophils of patients with hypercholesterolemia (HC). In addition, the signal processing through angiotensin I (Ang I) receptors is altered. In present study, we compared the Ang II-triggered free radical generation of neutrophils obtained from patients with relatively isolated forms of metabolic syndrome (MS) with membrane-bound cholesterol content and membrane fluidity. We determined the enhancement of Ang II-induced superoxide anion and leukotriene C(4) (LTC(4)) generation, membrane fluidity and cell-bound cholesterol content of neutrophils obtained from 12 control subjects, 11 patients with obesity (Ob), 10 patients with type 2 diabetes mellitus (t2-DM) and 12 patients with HC. The alteration of signal processing was studied after preincubation with different inhibiting drugs. Superoxide anion, LTC(4) production and membrane rigidity were increased in the following order: control < Ob < t2-DM < HC. Both Ang II-induced superoxide anion and LTC(4) generation were decreased in control cells by pertussis toxin and fluvastatin (Flu), whereas in each patient group, mepacrin, verapamil and Flu were effective, suggesting alterations in signal pathways, which may be attributed to isoprenylation. The enhancement of superoxide anion and LTC(4) generation correlated significantly with membrane rigidity, independently from the experimental groups and membrane-bound cholesterol content. Membrane rigidity of neutrophils, obtained from patients with MS, plays a role in Ang II-induced free radical generation independent of intracellular cholesterol homeostasis.