Apolipoprotein A-I improves pancreatic ß-cell function independent of the ATP-binding cassette transporters ABCA1 and ABCG1.

Apolipoprotein A-I (apoA-I), the main protein constituent of HDLs, increases insulin synthesis and insulin secretion in pancreatic ß cells. ApoA-I also accepts cholesterol that effluxes from cells expressing ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1). Mice with conditional deletion of ABCA1 and ABCG1 in ß cells [ß-double knockout (DKO) mice] have increased islet cholesterol levels and reduced glucose-stimulated insulin secretion (GSIS). The project asks whether metabolic pathways are dysregulated in ß-DKO mouse islets and whether this can be corrected, and GSIS improved, by treatment with apoA-I. ß-DKO mice were treated with apoA-I or PBS, and islets were isolated for determination of GSIS. Total RNA was extracted from ß-DKO and control mouse islets for microarray analysis. Metabolic pathways were interrogated by functional enrichment analysis. ApoA-I treatment improved GSIS in ß-DKO but not control mouse islets. Plasma lipid and lipoprotein levels and islet cholesterol levels were also unaffected by treatment with apoA-I. Cholesterol metabolism, glucose metabolism, and inflammation pathways were dysregulated in ß-DKO mouse islets. This was not corrected by treatment with apoA-I. In summary, apoA-I treatment improves GSIS by a cholesterol-independent mechanism, but it does not correct metabolic dysregulation in ß-DKO mouse islets.-Hou, L., Tang, S., Wu, B. J., Ong, K.-L., Westerterp, M., Barter, P. J., Cochran, B. J., Tabet, F., Rye, K.-A. Apolipoprotein A-I improves pancreatic ß-cell function independent of the ATP-binding cassette transporters ABCA1 and ABCG1.

Apolipoprotein A-I Protects Against Pregnancy-Induced Insulin Resistance in Rats.

Objective- Insulin resistance and inflammation in pregnancy are risk factors for gestational diabetes mellitus. Increased plasma HDL (high-density lipoprotein) and apo (apolipoprotein) A-I levels have been reported to improve glucose metabolism and inhibit inflammation in animals and humans. This study asks whether increasing plasma apoA-I levels improves insulin sensitivity and reduces inflammation in insulin-resistant pregnant rats. Approach and Results- Insulin-resistant pregnant rats received intravenous infusions of lipid-free apoA-I (8 mg/kg) or saline on days 6, 9, 12, 15, and 18 of pregnancy. The rats were then subjected to a euglycemic-hyperinsulinemic clamp. Glucose uptake was increased in white and brown adipose tissue by 57±13% and 32±10%, respectively ( P<0.05 for both), and in quadriceps and gastrocnemius muscle by 35±9.7% and 47±14%, respectively ( P<0.05 for both), in the apoA-I-treated pregnant rats relative to saline-infused pregnant rats. The pregnant rats that were treated with apoA-I also had reduced plasma TNF-α (tumor necrosis factor-α) levels by 57±8.4%, plasma IL (interleukin)-6 levels by 67±9.5%, and adipose tissue macrophage content by 54±8.2% ( P<0.05 for all) relative to the saline-treated pregnant rats. Conclusions- These studies establish that apoA-I protects against pregnancy-induced insulin resistance in rats by increasing insulin sensitivity in adipose tissue and skeletal muscle and inhibiting inflammation. This identifies apoA-I as a potential target for preventing pregnancy-induced insulin resistance and reducing the incidence of gestational diabetes mellitus.

Relationship of fibroblast growth factor 21 with kidney function and albuminuria: multi-ethnic study of atherosclerosis.

BACKGROUND: Fibroblast growth factor 21 (FGF21) may play a role in the development of chronic kidney disease (CKD). We therefore investigated the relationship of plasma FGF21 levels with kidney function and albuminuria in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: The analysis included 5724 MESA participants ages 45-84 years between 2000 and 2002, free of clinically apparent cardiovascular disease (CVD). Participants were followed up in person at four additional clinic visits over 10 years. Plasma FGF21 levels were measured at baseline examination by enzyme-linked immunosorbent assay. Kidney function was assessed by estimated glomerular filtration rate (eGFR). Outcomes were urinary albumin:creatinine ratio (UACR) progression, incident CKD by eGFR (reaching eGFR <60 mL/min/1.73 m2 with eGFR loss rate ≥1 mL/min/1.73 m2 per year) and rapid kidney function decline (eGFR decline >5%/year). RESULTS: At baseline, higher FGF21 levels, assessed as both continuous and categorical quartile variables, were significantly associated with lower eGFR and higher UACR, after adjusting for demographic, socioeconomic and other confounding factors [adjusted mean differences of -2.63 mL/min/1.73 m2 in eGFR and 0.134 in log normally transformed UACR (mg/g) for the highest FGF21 quartile compared with the lowest quartile, all P < 0.001]. However, in longitudinal analyses, baseline FGF21 levels did not predict incident CKD by eGFR, rapid kidney function decline or UACR progression. No significant interaction with sex and race/ethnicity was found (all P > 0.05). CONCLUSIONS: Our study does not support a role of FGF21 as a biomarker for predicting kidney function decline or albuminuria in adults free of clinically apparent CVD at baseline.

In vivo PET imaging with [(18)F]FDG to explain improved glucose uptake in an apolipoprotein A-I treated mouse model of diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by decreased HDL levels, as well as the level of apolipoprotein A-I (apoA-I), the main apolipoprotein of HDLs. Pharmacological elevation of HDL and apoA-I levels is associated with improved glycaemic control in patients with type 2 diabetes. This is partly due to improved glucose uptake in skeletal muscle. METHODS: This study used kinetic modelling to investigate the impact of increasing plasma apoA-I levels on the metabolism of glucose in the db/db mouse model. RESULTS: Treatment of db/db mice with apoA-I for 2 h significantly improved both glucose tolerance (AUC 2574 ± 70 mmol/l × min vs 2927 ± 137 mmol/l × min, for apoA-I and PBS, respectively; p < 0.05) and insulin sensitivity (AUC 388.8 ± 23.8 mmol/l × min vs 194.1 ± 19.6 mmol/l × min, for apoA-I and PBS, respectively; p < 0.001). ApoA-I treatment also increased glucose uptake by skeletal muscle in both an insulin-dependent and insulin-independent manner as evidenced by increased uptake of fludeoxyglucose ([(18)F]FDG) from plasma into gastrocnemius muscle in apoA-I treated mice, both in the absence and presence of insulin. Kinetic modelling revealed an enhanced rate of insulin-mediated glucose phosphorylation (k 3) in apoA-I treated mice (3.5 ± 1.1 × 10(-2) min(-1) vs 2.3 ± 0.7 × 10(-2) min(-1), for apoA-I and PBS, respectively; p < 0.05) and an increased influx constant (3.7 ± 0.6 × 10(-3) ml min(-1) g(-1) vs 2.0 ± 0.3 × 10(-3) ml min(-1) g(-1), for apoA-I and PBS, respectively; p < 0.05). Treatment of L6 rat skeletal muscle cells with apoA-I for 2 h indicated that increased hexokinase activity mediated the increased rate of glucose phosphorylation. CONCLUSIONS/INTERPRETATION: These findings indicate that apoA-I improves glucose disposal in db/db mice by improving insulin sensitivity and enhancing glucose phosphorylation.

Fibroblast growth factor 21 in chronic kidney disease.

The association between fibroblast growth factor 21 (FGF21) and kidney function has been extensively studied in recent years in both animal and human studies. However, the exact functional role of FGF21 in the kidney remains unclear. Previous animal studies have shown that administration of FGF21 ameliorates kidney function, morphological glomerular abnormalities, dyslipidemia, hyperglycemia, insulin resistance, oxidative stress and obesity. In human studies, FGF21 levels negatively correlated with estimated glomerular filtration rate. FGF21 levels were elevated in patients with end-stage renal disease. The elevation of FGF21 levels in presence of kidney disease has also raised questions as to whether FGF21 is a potential biomarker for detecting a decline in renal function. In recent clinical trials, an FGF21 analogue reduced insulin levels and body weight, and ameliorated dyslipidemia in patients with type 2 diabetes mellitus and obesity, all of which are well-known risk factors for kidney disease. Thus, FGF21 may be a potential therapeutic target for the treatment of kidney disease, although adverse side effects should also be considered when administering FGF21 since FGF21 may affect bone development and reproduction. This review will assess current knowledge on the relationship between FGF21 and kidney function.

Apolipoprotein A-I enhances insulin-dependent and insulin-independent glucose uptake by skeletal muscle.

Therapeutic interventions that increase plasma high density lipoprotein (HDL) and apolipoprotein (apo) A-I levels have been reported to reduce plasma glucose levels and attenuate insulin resistance. The present study asks if this is a direct effect of increased glucose uptake by skeletal muscle. Incubation of primary human skeletal muscle cells (HSKMCs) with apoA-I increased insulin-dependent and insulin-independent glucose uptake in a time- and concentration-dependent manner. The increased glucose uptake was accompanied by enhanced phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), the serine/threonine kinase Akt and Akt substrate of 160 kDa (AS160). Cell surface levels of the glucose transporter type 4, GLUT4, were also increased. The apoA-I-mediated increase in glucose uptake by HSKMCs was dependent on phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt, the ATP binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-B1). Taken together, these results establish that apoA-I increases glucose disposal in skeletal muscle by activating the IR/IRS-1/PI3K/Akt/AS160 signal transduction pathway. The findings suggest that therapeutic agents that increase apoA-I levels may improve glycemic control in people with type 2 diabetes.

The role of fibroblast growth factor 21 in atherosclerosis.

The metabolic properties of the endocrine fibroblast growth factor 21 (FGF21) have been extensively studied in the past decade. Previous studies have demonstrated the lipid-lowering, anti-inflammatory and anti-oxidant properties of FGF21. FGF21 is mainly secreted in the liver and adipose tissue in response to a range of physiological and pathological stimuli. In animal and in vitro studies, FGF21 has been shown to improve lipid profiles and inhibit key processes in the pathogenesis of atherosclerosis. It exerts its effects on the cardiovascular system via adiponectin dependent and independent mechanisms. However, the signalling pathways by which FGF21 exerts its effects on endothelial cells remains unknown and needs to be further investigated. The elevation of circulating FGF21 levels in cardiovascular disease has also raised questions as to whether FGF21 can be used as a biomarker to predict subclinical atherosclerosis and cardiovascular events. Recent findings from population studies must be validated in independent cohorts before FGF21 can be used as a biomarker in the clinical setting. The anti-atherosclerotic effects of FGF21 have been investigated in two recent clinical trials, where treatment with an FGF21 analog significantly improved the cardiometabolic profile in obese patients with type 2 diabetes. This review will evaluate recent advances that suggest there may be a role for FGF21 in atherosclerosis.

Impact of Perturbed Pancreatic ß-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism.

Elevated pancreatic ß-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased ß-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in ß-cells (ß-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The ß-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of ß-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify ß-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes.