Changting Xiao

Sodium Phenylbutyrate, a Drug With Known Capacity to Reduce Endoplasmic Reticulum Stress, Partially Alleviates Lipid-Induced Insulin Resistance and β-Cell Dysfunction in Humans

OBJECTIVE Chronically elevated free fatty acids contribute to insulin resistance and pancreatic β-cell failure. Among numerous potential factors, the involvement of endoplasmic reticulum (ER) stress has been postulated to play a mechanistic role. Here we examined the efficacy of the chemical chaperone, sodium phenylbutyrate (PBA), a drug with known capacity to reduce ER stress in animal models and in vitro, on lipid-induced insulin resistance and β-cell dysfunction in humans. RESEARCH DESIGN AND METHODS Eight overweight or obese nondiabetic men underwent four studies each, in random order, 4 to 6 weeks apart. Two studies were preceded by 2 weeks of oral PBA (7.5 g/day), followed by a 48-h i.v. infusion of intralipid/heparin or saline, and two studies were preceded by placebo treatment, followed by similar infusions. Insulin secretion rates (ISRs) and sensitivity (SI) were assessed after the 48-h infusions by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively. RESULTS Lipid infusion reduced SI, which was significantly ameliorated by pretreatment with PBA. Absolute ISR was not affected by any treatment; however, PBA partially ameliorated the lipid-induced reduction in the disposition index (DI = ISR × SI), indicating that PBA prevented lipid-induced β-cell dysfunction. CONCLUSIONS These results suggest that PBA may provide benefits in humans by ameliorating the insulin resistance and β-cell dysfunction induced by prolonged elevation of free fatty acids.

Both Intestinal and Hepatic Lipoprotein Production Are Stimulated by an Acute Elevation of Plasma Free Fatty Acids in Humans

Background— Hepatic lipoprotein production has been shown previously to be regulated by free fatty acid (FFA) flux to the liver, whereas intestinal lipoprotein production is stimulated mainly by ingested fat absorbed from the intestinal lumen. Emerging evidence indicates that intestinal lipoprotein production is increased in insulin resistance and type 2 diabetes mellitus, conditions that are associated with increased levels of circulating FFAs. Here we investigated whether short-term elevation of plasma FFAs stimulates intestinal apolipoprotein (apo) B-48– and hepatic apoB-100–containing triglyceride-rich lipoprotein (TRL) production in humans in the fed state. Methods and Results— TRL apoB-48 and apoB-100 metabolism were examined in 12 healthy men during a constant fed state. The studies were as follows, respectively: (1) Intralipid/heparin was infused intravenously immediately before and during the kinetics study to induce an ≈3-fold difference in plasma FFA compared with the saline study; (2) saline was infused intravenously as a control. ApoB-48– and apoB-100–containing TRL production and clearance were determined with a 12-hour primed constant infusion of [D3]l-leucine and multicompartmental kinetic modeling. TRL apoB-48 production rate was 69% higher in the Intralipid/heparin study than in the saline control (5.95±1.13 versus 3.53±0.58 mg/kg per day; P=0.027), and there was no significant difference in TRL apoB-48 clearance. TRL apoB-100 concentrations were also increased (P<0.001) and TRL apoB-100 production rate was 35% higher in the Intralipid/heparin study compared with saline (28±4 versus 21±3 mg/kg per day; P=0.020). Conclusions— This is the first study to demonstrate that intestinal TRL apoB-48 production is increased after short-term elevation of plasma FFAs in humans in the fed state, similar to the well-described stimulation of hepatic TRL apoB100–containing particles by FFAs.

Gut-liver interaction in triglyceride-rich lipoprotein metabolism

The liver and intestine have complementary and coordinated roles in lipoprotein metabolism. Despite their highly specialized functions, assembly and secretion of triglyceride-rich lipoproteins (TRL; apoB-100-containing VLDL in the liver and apoB-48-containing chylomicrons in the intestine) are regulated by many of the same hormonal, inflammatory, nutritional, and metabolic factors. Furthermore, lipoprotein metabolism in these two organs may be affected in a similar fashion by certain disorders. In insulin resistance, for example, overproduction of TRL by both liver and intestine is a prominent component of and underlies other features of a complex dyslipidemia and increased risk of atherosclerosis. The intestine is gaining increasing recognition for its importance in affecting whole body lipid homeostasis, in part through its interaction with the liver. This review aims to integrate recent advances in our understanding of these processes and attempts to provide insight into the factors that coordinate lipid homeostasis in these two organs in health and disease.

Exenatide, a Glucagon-like Peptide-1 Receptor Agonist, Acutely Inhibits Intestinal Lipoprotein Production in Healthy Humans

Objectives—Incretin-based therapies for the treatment of type 2 diabetes mellitus improve plasma lipid profiles and postprandial lipemia, but their exact mechanism of action remains unclear. Here, we examined the acute effect of the glucagon-like peptide-1 receptor agonist, exenatide, on intestinal and hepatic triglyceride-rich lipoprotein production and clearance in healthy humans. Methods and Results—Fifteen normolipidemic, normoglycemic men underwent 2 studies each (SC 10 &mgr;g exenatide versus placebo), 4 to 6 weeks apart, in random order, in which triglyceride-rich lipoprotein particle kinetics were examined with a primed, constant infusion of deuterated leucine and analyzed by multicompartmental modeling under pancreatic clamp conditions. A fed state was maintained during each study by infusing a high-fat, mixed macronutrient, liquid formula at a constant rate directly into the duodenum via a nasoduodenal tube. Exenatide significantly suppressed the plasma concentration and production rate of triglyceride-rich lipoprotein-apolipoprotein B-48, but not of triglyceride-rich lipoprotein-apolipoprotein B-100. Conclusions—These results suggest a possible direct effect of exenatide on intestinal lipoprotein particle production, independent of changes in weight gain and satiety as seen in long-term studies and independent of changes in gastric emptying. This finding expands our understanding of the effects of exenatide in metabolic regulation beyond its primary therapeutic role in regulation of glucose homeostasis. Clinical Trial Registration—URL: http://www.clinicaltrials.gov, NCT01056549.

High-Dose Resveratrol Treatment for 2 Weeks Inhibits Intestinal and Hepatic Lipoprotein Production in Overweight/Obese Men

Objective—Overproduction of hepatic apolipoprotein B (apoB)-100 containing very low-density lipoprotein particles and intestinal apoB-48 containing chylomicrons contributes to hypertriglyceridemia seen in conditions such as obesity and insulin resistance. Some, but not all, preclinical and clinical studies have demonstrated that the polyphenol resveratrol ameliorates insulin resistance and hypertriglyceridemia. Here, we assessed intestinal and hepatic lipoprotein turnover, in humans, after 2 weeks of treatment with resveratrol (1000 mg daily for week 1 followed by 2000 mg daily for week 2) or placebo. Approach and Results—Eight overweight or obese individuals with mild hypertriglyceridemia were studied on 2 occasions, 4 to 6 weeks apart, after treatment with resveratrol or placebo in a randomized, double-blinded, crossover study. Steady-state lipoprotein kinetics was assessed in a constant fed state with a primed, constant infusion of deuterated leucine. Resveratrol treatment did not significantly affect insulin sensitivity (homeostasis model of assessment of insulin resistance), fasting or fed plasma triglyceride concentration. Resveratrol reduced apoB-48 production rate by 22% (P=0.007) with no significant effect on fractional catabolic rate. Resveratrol reduced apoB-100 production rate by 27% (P=0.02) and fractional catabolic rate by 26% (P=0.04). Conclusions—These results indicate that 2 weeks of high-dose resveratrol reduces intestinal and hepatic lipoprotein particle production. Long-term studies are needed to evaluate the potential clinical benefits of resveratrol in patients with hypertriglyceridemia, who have increased concentrations of triglyceride-rich lipoprotein apoB-100 and apoB-48. Clinical Trial Registration—URL: www.clinicaltrials.gov. Unique identifier: NCT01451918.

Insulin Acutely Inhibits Intestinal Lipoprotein Secretion in Humans in Part by Suppressing Plasma Free Fatty Acids

OBJECTIVE Intestinal lipoprotein production has recently been shown to be increased in insulin resistance, but it is not known whether it is regulated by insulin in humans. Here, we investigated the effect of acute hyperinsulinemia on intestinal (and hepatic) lipoprotein production in six healthy men in the presence and absence of concomitant suppression of plasma free fatty acids (FFAs). RESEARCH DESIGN AND METHODS Each subject underwent the following three lipoprotein turnover studies, in random order, 4–6 weeks apart: 1) insulin and glucose infusion (euglycemic-hyperinsulinemic clamp) to induce hyperinsulinemia, 2) insulin and glucose infusion plus Intralipid and heparin infusion to prevent the insulin-induced suppression of plasma FFAs, and 3) saline control. RESULTS VLDL1 and VLDL2-apoB48 and -apoB100 production rates were suppressed by 47–62% by insulin, with no change in clearance. When the decline in FFAs was prevented by concomitant infusion of Intralipid and heparin, the production rates of VLDL1 and VLDL2-apoB48 and -apoB100 were intermediate between insulin and glucose infusion and saline control. CONCLUSIONS This is the first demonstration in humans that intestinal apoB48-containing lipoprotein production is acutely suppressed by insulin, which may involve insulins direct effects and insulin-mediated suppression of circulating FFAs.

Regulation of chylomicron production in humans.

Chylomicrons (CM), secreted by the intestine in response to fat ingestion and to a lesser extent during the postabsorptive state (lipid poor CM), are the major vehicles whereby ingested lipids are transported to and partitioned in energy-storing and energy-utilizing tissues of the body. CM contribute significantly, although not exclusively, to postprandial lipemia. Intestinal CM production is upregulated in humans under conditions of insulin resistance and CM overproduction in such conditions contributes to the highly prevalent dyslipidemia of these conditions. In addition, CM remnants possess direct atherogenic properties. CM assembly and secretion is regulated by many factors apart from ingested fat (the primary stimulus for their secretion), including a number of nutritional, hormonal, metabolic and genetic factors. Understanding the mechanisms that regulate CM production in health and disease may lead to treatments and prevention of atherosclerosis and cardiovascular disease. This review aims to summarize current understanding of CM production in humans. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

Hypertriglyceridemia in the genomic era: a new paradigm.

Hypertriglyceridemia (HTG) is a highly prevalent condition that is associated with increased cardiovascular disease risk. HTG may arise as a result of defective metabolism of triglyceride-rich lipoproteins and their remnants, ie, impaired clearance, or increased production, or both. Current categorization of HTG segregates primary and secondary cases, implying genetic and nongenetic causes for each category. Many common and rare variants of the genes encoding factors involved in these pathways have been identified. Although monogenic forms of HTG do occur, most cases are polygenic and often coexist with nongenetic conditions. Cumulative, multiple genetic variants can increase the risks for HTG, whereas environmental and lifestyle factors can force expression of a dyslipidemic phenotype in a genetically susceptible person. HTG states are therefore best viewed as a complex phenotype resulting from the interaction of cumulated multiple susceptibility genes and environmental stressors. In view of the heterogeneity of the HTG states, the absence of a unifying metabolic or genetic abnormality, overlap with the metabolic syndrome and other features of insulin resistance, and evidence in some patients that accumulation of numerous small-effect genetic variants determines whether an individual is susceptible to HTG only or to HTG plus elevated low-density lipoprotein cholesterol, we propose that the diagnosis of primary HTG and further delineation of familial combined hyperlipidemia from familial HTG is neither feasible nor clinically relevant at the present time. The hope is that with greater understanding of genetic and environmental causes and their interaction, therapy can be intelligently targeted in the future.

C-reactive protein impairs hepatic insulin sensitivity and insulin signaling in rats: role of mitogen-activated protein kinases.

Plasma C‐reactive protein (CRP) concentration is increased in the metabolic syndrome, which consists of a cluster of cardiovascular disease risk factors, including insulin resistance. It is not known, however, whether CRP is merely a marker of accompanying inflammation or whether it contributes causally to insulin resistance. The objective of this study is to investigate the role that CRP may play in the development of insulin resistance. We examined the effect of single‐dose intravenous administration of purified human (h)CRP on insulin sensitivity in Sprague‐Dawley rats using the euglycemic, hyperinsulinemic clamp technique. hCRP was associated with impaired insulin suppression of endogenous glucose production with no reduction in peripheral tissue glucose uptake, suggesting that hCRP mediated insulin resistance in the liver but not extrahepatic tissues. We further assessed components of the insulin signaling pathway and mitogen‐activated protein kinases (MAPKs) in the liver. Liver tissues derived from hCRP‐treated rats showed reduced insulin‐stimulated insulin receptor substrate (IRS) tyrosine phosphorylation, IRS/phosphatidylinositol 3‐kinase (PI3K) association, and Akt phosphorylation, consistent with hCRP‐induced impairment of hepatic insulin signaling. Furthermore, hCRP enhanced phosphorylation of extracellular signal‐regulated kinase (ERK)1/2 and p38 MAPK as well as IRS‐1 Ser612. Finally, we observed in primary cultured rat hepatocytes that U0126 (a selective inhibitor of MAPK/ERK kinase1/2) corrected hCRP‐induced impairment of insulin signaling. Conclusions: hCRP plays an active role in inducing hepatic insulin resistance in the rat, at least in part by activating ERK1/2, with downstream impairment in the insulin signaling pathway. (HEPATOLOGY 2011)

Intranasal Insulin Suppresses Endogenous Glucose Production in Humans Compared With Placebo in the Presence of Similar Venous Insulin Concentrations

Intranasal insulin (INI) has been shown to modulate food intake and food-related activity in the central nervous system in humans. Because INI increases insulin concentration in the cerebrospinal fluid, these effects have been postulated to be mediated via insulin action in the brain, although peripheral effects of insulin cannot be excluded. INI has been shown to lower plasma glucose in some studies, but whether it regulates endogenous glucose production (EGP) is not known. To assess the role of INI in the regulation of EGP, eight healthy men were studied in a single-blind, crossover study with two randomized visits (one with 40 IU INI and the other with intranasal placebo [INP] administration) 4 weeks apart. EGP was assessed under conditions of an arterial pancreatic clamp, with a primed, constant infusion of deuterated glucose and infusion of 20% dextrose as required to maintain euglycemia. Between 180 and 360 min after administration, INI significantly suppressed EGP by 35.6% compared with INP, despite similar venous insulin concentrations. In conclusion, INI lowers EGP in humans compared with INP, despite similar venous insulin concentrations. INI may therefore be of value in treating excess liver glucose production in diabetes.