Alterations in liver, muscle, and adipose tissue insulin sensitivity in men with HIV infection and dyslipidemia

Dyslipidemia is common in patients with HIV infection. In this study, a two-stage euglycemic hyperinsulinemic clamp, with infusion of stable isotopically labeled tracers, was used to evaluate insulin action in skeletal muscle, liver, and adipose tissue in HIV-infected men with dyslipidemia (HIV-DL; plasma triglyceride >250 mg/dl and HDL <45 mg/dl; n=12), HIV-infected men without dyslipidemia (HIV w/o DL; n=12), and healthy men (n=6). Basal rates of glucose production (glucose R(a)), glucose disposal (glucose R(d)), and lipolysis (palmitate R(a)) were similar between groups. The relative suppression of glucose R(a) (63+/- 4, 77+/- 2, and 78+/- 3%, P=0.008) and palmitate R(a) (49+/-4, 63+/-3, and 68+/-3%, P=0.005) during ow-dose insulin infusion (plasma insulin approximately 30 microU/ml), and the relative stimulation of glucose R(d) (214+/-21, 390+/-25, and 393+/-46%, P=0.001) during high-dose insulin infusion (plasma insulin approximately 75 microU/ml) were lower in HIV-DL than in HIV w/o DL and healthy volunteers, respectively. Suppression of basal glucose R(a) correlated with plasma adiponectin (r=0.44, P=0.02) and inversely with plasma IL-6 (r=-0.49, P<0.001). Stimulation of glucose R(d) correlated directly with adiponectin (r=0.48, P<0.01) and inversely with IL-6 (r=-0.49, P=0.02). We conclude that dyslipidemia in HIV-infected men is indicative of multiorgan insulin resistance, and circulating adipokines may be important in the pathogenesis of impaired insulin action.     

Pioglitazone improves insulin sensitivity through reduction in muscle lipid and redistribution of lipid into adipose tissue

Hemorrhagic coagulopathy is involved in the morbidity and mortality of trauma patients. Nonetheless, many aspects of the mechanisms underlying this disorder are poorly understood. We have therefore investigated changes in fibrinogen metabolism and coagulation function after a moderate hemorrhagic shock, using a new stable isotope approach. Twelve pigs were randomly divided into the control (C) and hemorrhage (H) groups. Hemorrhage was induced by bleeding 35% total blood volume over a 30-min period. A primed constant infusion of [1-(13)C]phenylalanine (Phe), d5-phenylalanine, and alpha-[1-(13)C]-ketoisocaproate (KIC) was given to quantify fibrinogen synthesis and breakdown, together with measurements of circulating liver enzyme activities and coagulation function. Mean arterial pressure was decreased by hemorrhage from 89 +/- 4 mmHg in C to 47 +/- 4 mmHg in H (P < 0.05), followed by a rebound to 68 +/- 5 mmHg afterward. Fibrinogen fractional synthesis rate increased from 2.7 +/- 0.2%/h in C to 4.2 +/- 0.4%/h in H by Phe (P < 0.05) and from 3.1 +/- 0.4%/h in C to 4.4 +/- 0.5%/h in H by KIC (P < 0.05). Fibrinogen fractional breakdown rate increased from 3.6 +/- 1.0%/h in C to 12.9 +/- 1.8%/h in H (P < 0.05). The absolute breakdown rate accelerated from 3.0 +/- 0.4 mg x kg(-1) x h(-1) in C to 5.4 +/- 0.6 mg x kg(-1) x h(-1) in H (P < 0.05), but the absolute synthesis rate remained unchanged. These metabolic changes were accompanied by a reduction in blood clotting time to 92.7 +/- 1.6% of the baseline value by hemorrhage (P < 0.05). No changes were found in liver enzyme activities. We conclude that the observed changes in coagulation after hemorrhagic shock are mechanistically related to the acute acceleration of fibrinogen degradation.     

Lack of REDD1 reduces whole body glucose and insulin tolerance,and impairs skeletal muscle insulin signaling

A lack of the REDD1 promotes dysregulated growth signaling, though little has been established with respect to the metabolic role of REDD1. Therefore, the goal of this study was to determine the role of REDD1 on glucose and insulin tolerance, as well as insulin stimulated growth signaling pathway activation in skeletal muscle. First, intraperitoneal (IP) injection of glucose or insulin were administered to REDD1 wildtype (WT) versus knockout (KO) mice to examine changes in blood glucose over time. Next, alterations in skeletal muscle insulin (IRS-1, Akt, ERK 1/2) and growth (4E-BP1, S6K1, REDD1) signaling intermediates were determined before and after IP insulin treatment (10 min). REDD1 KO mice were both glucose and insulin intolerant when compared to WT mice, evident by higher circulating blood glucose concentrations and a greater area under the curve following IP injections of glucose or insulin. While the REDD1 KO exhibited significant though blunted insulin-stimulated increases (p < 0.05) in Akt S473 and T308 phosphorylation versus the WT mice, acute insulin treatment has no effect (p < 0.05) on REDD1 KO skeletal muscle 4E-BP1 T37/46, S6K1 T389, IRS-1 Y1222, and ERK 1/2 T202/Y204 phosphorylation versus the WT mice. Collectively, these novel data suggest that REDD1 has a more distinct role in whole body and skeletal muscle metabolism and insulin action than previously thought.     

Caveolin-3 knockout mice show increased adiposity and whole body insulin resistance, with ligand-induced insulin receptor instability in skeletal muscle

Caveolin-3 (Cav-3) is expressed predominantly in skeletal muscle fibers, where it drives caveolae formation at the muscle cell's plasma membrane. In vitro studies have suggested that Cav-3 may play a positive role in insulin signaling and energy metabolism. We directly address the in vivo metabolic consequences of genetic ablation of Cav-3 in mice as it relates to insulin action, glucose metabolism, and lipid homeostasis. At age 2 mo, Cav-3 null mice are significantly larger than wild-type mice, and display significant postprandial hyperinsulinemia, whole body insulin resistance, and whole body glucose intolerance. Studies using hyperinsulinemic-euglycemic clamps revealed that Cav-3 null mice exhibited 20% and 40% decreases in insulin-stimulated whole body glucose uptake and whole body glycogen synthesis, respectively. Whole body insulin resistance was mostly attributed to 20% and 40% decreases in insulin-stimulated glucose uptake and glucose metabolic flux in the skeletal muscle of Cav-3 null mice. In addition, insulin-mediated suppression of hepatic glucose production was significantly reduced in Cav-3 null mice, indicating hepatic insulin resistance. Insulin-stimulated glucose uptake in white adipose tissue, which does not express Cav-3, was decreased by 70% in Cav-3 null mice, suggestive of an insulin-resistant state for this tissue. During fasting, Cav-3 null mice possess normal insulin receptor protein levels in their skeletal muscle. However, after 15 min of acute insulin stimulation, Cav-3 null mice show dramatically reduced levels of the insulin receptor protein, compared with wild-type mice treated identically. These results suggest that Cav-3 normally functions to increase the stability of the insulin receptor at the plasma membrane, preventing its rapid degradation, i.e., by blocking or slowing ligand-induced receptor downregulation. Thus our results demonstrate the importance of Cav-3 in regulating whole body glucose homeostasis in vivo and its possible role in the development of insulin resistance. These findings may have clinical implications for the early diagnosis and treatment of caveolinopathies. limb girdle muscular dystrophy; glucose intolerance; hyperinsulinemia; insulin receptor degradation     

Adiponectin and its association with insulin resistance and type 2 diabetes

Adiponectin is an adipokine, which is expressed in adipose tissue and is thought to play an important role in glucose metabolism. Hypoadiponectinemia can cause reduction of fatty acid oxidation, decreased glucose uptake in skeletal muscle cells, and increased gluconeogenesis in hepatic cells. The level of plasma glucose can be increased. On the other hand, the decrease of fatty acid oxidation increases the level of free fatty acid (FFA), which increases the insulin resistance, and then decreases the glucose uptake, which ultimately causes increased plasma glucose and type 2 diabetes (T2D). This review describes the process from hypoadiponectinemia to T2D and the genesis of hypoadiponeetinemia at a molecular level.     

Trunk muscle electromyography and whole body vibration

By measuring the electromyographic (EMG) activity of the paraspinal muscles, we have estimated the average and peak-to-peak torque imposed on the spine during whole body vibration. Six subjects had surface electrodes placed on their erector spinae muscles at the L3 level. The EMG-torque relationship was estimated by having each subject perform isometric horizontal pulls in an upright seated posture. The subject was then vibrated vertically and sinusoidally in a controlled, flexed, slightly lordotic seated posture, in 1 Hz increments from 3 to 10 Hz at a 0.1 g RMS seat acceleration level. Between vibration readings taken at each frequency, a static reading was also taken with the subject maintaining the same posture. The entire vibration-static 3-10 Hz test was repeated for reliability purposes. Specialized digital signal processing techniques were developed for the EMG signals to enhance the measured cyclic muscle activity and to allow automatic measurement of the time relationship between the mechanical displacement and the estimated torque. We found significantly more average and peak-to-peak estimated torque at almost all frequencies for vibration vs static sitting.     

Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism

Insulin resistance is viewed as an insufficiency in insulin action, with glucocorticoids being recognized to play a key role in its pathogenesis. With insulin resistance, metabolism in multiple organ systems such as skeletal muscle, liver, and adipose tissue is altered. These metabolic alterations are widely believed to be important factors in the morbidity and mortality of cardiovascular disease. More importantly, clinical and experimental studies have established that metabolic abnormalities in the heart per se also play a crucial role in the development of heart failure. Following glucocorticoids, glucose utilization is compromised in the heart. This attenuated glucose metabolism is associated with altered fatty acid supply, composition, and utilization. In the heart, elevated fatty acid use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in "lipotoxicity". In the present article, we review the action of glucocorticoids, their role in insulin resistance, and their influence in modulating peripheral and cardiac metabolism and heart disease.     

Exercise-induced increase in muscle insulin sensitivity.

Exercise/muscle contraction activates glucose transport. The increase in muscle glucose transport induced by exercise is independent of insulin. As the acute effect of exercise on glucose transport wears off, it is replaced by an increase in insulin sensitivity. An increase in insulin sensitivity results in a shift in the insulin dose-response curve to the left, with a decrease in the concentration of insulin needed to induce 50% of the maximal response. This phenomenon, which plays a major role in rapid muscle glycogen accumulation after exercise, is not mediated by amplification of the insulin signal. Development of the increase in insulin sensitivity after contractions does not require protein synthesis or activation of p38 MAPK. It does require the presence of a serum protein during the period of contractile activity. The effect of exercise on muscle insulin sensitivity is mimicked by hypoxia and by treatment of muscles with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside to activate AMP-activated protein kinase. The postexercise increase in sensitivity of muscle glucose transport to activation is not specific for insulin but also involves an increased susceptibility to activation by a submaximal contraction/hypoxia stimulus. The increase in insulin sensitivity is mediated by translocation of more GLUT4 glucose transporters to the cell surface in response to a submaximal insulin stimulus. Although the postexercise increase in muscle insulin sensitivity has been characterized in considerable detail, the basic mechanisms underlying this phenomenon remain a mystery.     

Activin B regulates islet composition and islet mass but not whole body glucose homeostasis or insulin sensitivity

Based on the phenotype of the activin-like kinase-7 (ALK7)-null mouse, activins A and B have been proposed to play distinct roles in regulating pancreatic islet function and glucose homeostasis, with activin A acting to enhance islet function and insulin release while activin B antagonizes these actions. We therefore hypothesized that islets from activin B-null (BBKO) mice would have enhanced glucose-stimulated insulin secretion. In addition, we hypothesized that this enhanced islet function would translate into increased whole body glucose tolerance. We tested these hypotheses by analyzing glucose homeostasis, insulin secretion, and islet function in BBKO mice. No differences were observed in fasting glucose or insulin levels, glucose tolerance, or insulin sensitivity compared with weight-matched young or older males. Similarly, there were no significant differences in insulin secretion comparing islets from WT or BBKO males at either age. However, BBKO islets were more sensitive to activin A, myostatin (MSTN), and follistatin (FST) treatments, so that activin A and FST inhibited and MSTN enhanced glucose stimulated insulin secretion. While mean islet area and the distribution of islet areas were not different between the genotypes, islet mass, islet number, and the proportion of α-cells/islet were significantly reduced in BBKO islets. These results indicate that activin B does not antagonize activin A to influence whole body glucose homeostasis or β-cell function but does influence islet mass and proportion of α-cells/islet. Therefore, loss of activin B signaling alone does not account for the ALK7-null phenotype, but activin B may have important roles in modulating islet mass, islet number, and the cellular composition of islets.     

Regulation of insulin sensitivity by adipose tissue-derived hormones and inflammatory cytokines

PURPOSE OF REVIEW: The aim of this review is to assess the role of adipose tissue-derived hormones and inflammatory cytokines in the pathogenesis of obesity-linked type II diabetes, with a special focus on articles published between December 2002 and December 2003. RECENT FINDINGS: Insulin resistance is widely recognized as a fundamental defect seen in obesity and type II diabetes. Although the molecular mechanisms triggering the development of insulin resistance remain elusive, recent studies have suggested that adipose tissue and adipose tissue-derived hormones and inflammatory cytokines play essential roles in the overall insulin sensitivity in vivo. Dysfunctions of adipose tissue can lead to systemic insulin resistance. SUMMARY: Understanding the regulation of the metabolic and secretory functions of adipose tissue, as well as its subsequent impact on overall insulin sensitivity, is becoming increasingly important given the therapeutic potential of targeting the root causes of insulin resistance in the treatment of type 2 diabetes and its associated complications, such as cardiovascular and cerebrovascular diseases.     

Influence of PPAR-alpha agonist fenofibrate on insulin sensitivity and selected adipose tissue-derived hormones in obese women with type 2 diabetes

PPAR-alpha agonists improve insulin sensitivity in rodent models of obesity/insulin resistance, but their effects on insulin sensitivity in humans are less clear. We measured insulin sensitivity by hyperinsulinemic-isoglycemic clamp in 10 obese females with type 2 diabetes before and after three months of treatment with PPAR-alpha agonist fenofibrate and studied the possible role of the changes in endocrine function of adipose tissue in the metabolic effects of fenofibrate. At baseline, body mass index, serum glucose, triglycerides, glycated hemoglobin and atherogenic index were significantly elevated in obese women with type 2 diabetes, while serum HDL cholesterol and adiponectin concentrations were significantly lower than in the control group (n=10). No differences were found in serum resistin levels between obese and control group. Fenofibrate treatment decreased serum triglyceride concentrations, while both blood glucose and glycated hemoglobin increased after three months of fenofibrate administration. Serum adiponectin or resistin concentrations were not significantly affected by fenofibrate treatment. All parameters of insulin sensitivity as measured by hyperinsulinemic-isoglycemic clamp were significantly lower in an obese diabetic group compared to the control group before treatment and were not affected by fenofibrate administration. We conclude that administration of PPAR-alpha agonist fenofibrate for three months did not significantly affect insulin sensitivity or resistin and adiponectin concentrations in obese subjects with type 2 diabetes mellitus. The lack of insulin-sensitizing effects of fenofibrate in humans relative to rodents could be due to a generally lower PPAR-alpha expression in human liver and muscle.     

Reduced Expression of FOXC2 and Brown Adipogenic Genes in Human Subjects with Insulin Resistance

Objective: We investigated subcutaneous adipose tissue expression of FOXC2 and selected genes involved in brown adipogenesis in adult human subjects in whom we have previously identified a reduced potential of precursor cell commitment to adipose‐lineage differentiation in relation to insulin resistance. Research Methods and Procedure: Gene expression was studied using quantitative real time polymerase chain reaction. The relation between the expression of brown adipogenic genes and the genes involved in progenitor cell commitment, adipose cell size, and insulin sensitivity in vivo was analyzed. Results: The expression of FOXC2, MASK, MAP3K5, retinoblastoma protein (pRb), peroxisome proliferator‐activated protein gamma (PPARγ), and retinoid X receptor gamma (RXRγ) was decreased in the insulin‐resistant compared with insulin‐sensitive subjects, whereas PPARγ‐2 and CCAAT/enhancer binding protein alpha (C/EBPα) showed no differential expression. The FOXC2 expression correlated with that of Notch and Wnt signaling genes, as well as of the genes studied participating in brown adipogenesis, including MASK, MAP3K5, PPARγ, pRb, RXRγ, and PGC‐1. A second‐level correlation between PPARγ and UCP‐1 was also significant. In addition, the expression of MASK, MAP3K5, pRb, RXRγ, and PGC‐1 inversely correlated with adipose cell mass and also correlated with the glucose disposal rate in vivo. Discussion: Our results suggest that a reduced brown adipose phenotype is associated with insulin resistance and that a basal brown adipose phenotype may be important for maintaining normal insulin sensitivity.     

Influence of obesity and insulin sensitivity on insulin signaling genes in human omental and subcutaneous adipose tissue

Obesity and insulin resistance are independent risk factors for metabolic syndrome, diabetes, and cardiovascular disease. Adipose tissue samples from nonobese (NO), insulin-sensitive obese (ISO), and insulin-resistant obese (IRO) subjects from subcutaneous (SC) and omental (OM) adipose tissue (n = 28) were analyzed by microarray and confirmed by real-time PCR. Insulin signaling gene expression changes were greater in OM than in SC tissue and were related to insulin resistance rather than to obesity; few genes correlated with body mass index. Insulin receptor and insulin receptor substrate 1 (IRS-1) increased in the IRO versus pooled insulin-sensitive (NO+ISO) subjects. In glucose transport, PI3Kalpha and PDK2 decreased in IRO subjects, whereas PI3Kgamma, Akt2, GLUT4, and GLUT1 increased. IRS-1 regulators Jnk and IKK increased in IRO (P < 0.01 and P < 0.001 respectively). In protein synthesis, most genes examined were downregulated in IRO subjects, including mTor, Rheb, and 4EBP and eIF members (all P < 0.05). In proliferation, SHC, SOS, and Raf1 (P < 0.05) were increased, whereas Ras and MEK1/2 kinase 1 (P < 0.05) were decreased, in IRO subjects. Finally, in differentiation, PPARgamma, CEBPalpha, and CEBPbeta decreased, whereas PPARdelta, CEBPgamma, and CEBPepsilon increased, in IRO subjects (P < 0.05). Together, microarray and real-time PCR data demonstrate that insulin resistance rather than obesity is associated with altered gene expression of insulin signaling genes, especially in OM adipose tissue.     

Maximal activities of enzymes involved in adenosine metabolism in muscle and adipose tissue of rats under conditions of variations in insulin sensitivity

The maximal activities of 5'-nucleotidase, adenosine deaminase and adenosine kinase were measured in quadriceps or soleus muscle from animals in which the sensitivity to insulin was changed. Most conditions caused no effect on the activities but exercise-training increased the activity of adenosine deaminase and cold exposure increased the activity of 5'-nucleotidase in soleus muscle: in addition, ageing decreased markedly the activities of all three enzymes in both muscles. When the activities are based on mg protein they are much higher in both white and brown adipose tissue than in muscle, suggesting that changes in adenosine concentration may be important in changing insulin sensitivity in adipose tissue whereas changes in adenosine receptor number may be more important in muscle.     

Decreased sensitivity to insulin in white adipose tissue from adrenalectomised rats

The ability of insulin to increase both [14C]-glucose incorporation into fatty acids and pyruvate dehydrogenase activity in incubated rat epididymal adipose tissues was considerably lessened after adrenalectomy. Insulin antagonism of adrenaline-stimulated lipolysis in isolated fat cells was abolished after adrenalectomy. Percentage stimulation of lipolysis above basal by adrenaline was not appreciably altered by adrenalectomy.     

A novel index of whole body antilipolytic insulin action

Objective:

Assessment of antilipolytic insulin action is important in obesity research, but extensive isotopic tracer studies are not always feasible. We evaluated whether an index of antilipolytic insulin action could be derived from readily available insulin and glycerol concentrations obtained during clamps or oral glucose tolerance tests (OGTT).

Design and Methods:

We evaluated data collected from 29 subjects who had undergone a 3‐stage hyperinsulinemic‐euglycemic clamp (4, 8, and 40 mU/m²/min) with infusion of [²H₅]glycerol to calculate the glycerol rate of appearance (GLY_RA). Exponential decay curves for GLY_RA across insulin concentrations were generated for each individual and suppression of lipolysis was calculated as the insulin concentration needed to half‐maximally suppress GLY_RA (GLY_RA EC₅₀). Areas under the curve for glycerol (GLY_AUC) and insulin (INS_AUC) were calculated and their products (INS_AUC × GLY_AUC) were calculated as an index of insulin suppression of lipolysis.

Results:

The clamp index was highly correlated with GLY_RA EC₅₀ (r = 0.862, P < 0.001), as was an OGTT‐derived index (r = 0.720, P < 0.01).

Conclusions:

These findings suggest that the products of the insulin and glycerol AUC from either a clamp or an OGTT are good biomarkers of the antilipolytic action of insulin and are comparable with direct measurement by isotopic tracer methods.