Modulation Of Insulin Resistance Research Articles

Evolving concepts of type 2 diabetes management with oral medications: new approaches to an old disease

ABSTRACTBackground: Type 2 diabetes is often accompanied by co-morbid conditions such as hypertension and dyslipidemia, which, coupled with persistent hyperglycemia, result in significant macrovascular and microvascular complications. Type 2 diabetes treatments focus primarily on controlling hyperglycemia, hypertension, and dyslipidemia to stabilize the disease and minimize complications. Despite treatment, control of hyperglycemia and the conditions associated with type 2 diabetes are suboptimal in the majority of patients. Research efforts have concentrated on the development of new therapies for type 2 diabetes, including agents that could be used both as monotherapy and in combination with established oral antidiabetic agents to improve glycemic control and reduce the disease burden on patients.Objective: To review published literature on oral agents in development for type 2 diabetes, with a focus on their mechanism of action and impact on concomitant risk factors.Methods: After identifying oral agents in late-stage development for type 2 diabetes using the R&D Insight database, a literature review was conducted through PubMed for studies (preferably randomized, controlled trials) on dipeptidyl peptidase-IV inhibitors, CB1 cannabinoid receptor blockers, and bile acid sequestrants. Where limited published data were available, abstracts from recent major conferences were searched. Other emerging therapies targeting pathways involved in modifying insulin resistance, glycogenolysis, and gluconeogenesis are also discussed.Conclusions: A variety of novel therapies for type 2 diabetes are in development, which will provide patients and diabetes care providers more choices for the management of this disease. Importantly, many of these treatments offer the potential to significantly improve multiple metabolic parameters.

Retinol-Binding Protein 4 and Insulin Resistance in Polycystic Ovary Syndrome

OBJECTIVE—Polycystic ovary syndrome (PCOS) is an insulin-resistant state with insulin resistance being an established therapeutic target; however, measurement of insulin resistance remains challenging. We aimed to 1) determine serum retinol-binding protein 4 (RBP4) levels (purported to reflect insulin resistance) in women with PCOS and control subjects, 2) examine the relationship of RBP4 to conventional markers of insulin resistance, and 3) examine RBP4 changes with interventions modulating insulin resistance in overweight women with PCOS.RESEARCH DESIGN AND METHODS—At baseline, 38 overweight women (BMI >27 kg/m2) with PCOS and 17 weight-matched control subjects were compared. Women with PCOS were then randomly assigned to 6 months of a higher-dose oral contraceptive pill (OCP) (35 μg ethinyl estradiol/2 mg cyproterone acetate) or metformin (1 g b.i.d.). Outcome measures were insulin resistance (total insulin area under the curve) on an oral glucose tolerance test, RBP4, and metabolic/inflammatory markers.RESULTS—Overweight women with PCOS were more insulin resistant than control subjects, yet RBP4 levels were not different in women with PCOS versus those in control subjects (35.4 ± 4.3 vs. 28.9 ± 3.1 μg/ml, P = 0.36). RBP4 correlated with cholesterol and triglycerides but not with insulin resistance. Metformin improved insulin resistance by 35%, whereas the OCP worsened insulin resistance by 33%. However, RBP4 increased nonsignificantly in both groups (43.7 ± 6.3 vs. 42.6 ± 5.5 μg/ml, P = 0.92).CONCLUSIONS—Overweight women with PCOS were more insulin resistant than control subjects, but this finding was not reflected by RBP4 levels. RBP4 correlated with lipid levels but not with insulin resistance markers. RBP4 levels did not change when insulin resistance was reduced by metformin or increased by the OCP. These data suggest that RBP4 is not a useful marker of insulin resistance in PCOS but may reflect other metabolic features of this condition.

Resistin is expressed in human hepatocytes and induces insulin resistance

Resistin, known as an adipocyte-specific secretory factor (ADSF), is implicated to modulate insulin resistance in rodents. However, the precise role of this factor for human insulin resistance has remained elusive. Here, we investigate the relationship between human resistin and insulin resistance in hepatocytes and the effect of Metformin on resistin. In this study, the expression of resistin in human hepatocytes and hepatic tissues was examined, and the human resistin eukaryotic expression vector was constructed and stably transfected in HepG2 cells. Data showed that resistin is expressed in human hepatocytes and hepatic tissues. Overexpression of human resistin impaired significantly insulin-stimulated glucose uptake and glycogen synthesis in HepG2 cells. It also decreased the expression of insulin receptor substrate 2 (IRS-2) and c-cbl associated protein (CAP), whereas increased the expression of glycogen synthetase kinase 3beta (GSK-3beta). The result suggested that human resistin induced insulin resistance in hepatocytes by blocking the two insulin signal transduction pathways of PI-3K/Akt and of CAP/c-cbl. We also concluded that Metformin reversed the effect of resistin and downregulated the expression of resistin in hepatocytes.

Cardiovascular and metabolic effects of CPAP in obese obstructive sleep apnoea patients

To the Editors: In a recent issue of the European Respiratory Journal , Coughlin et al. 1 demonstrated that, in Caucasians with untreated obstructive sleep apnoea (OSA), continuous positive airway pressure (CPAP) can improve baroreceptor responsiveness and reduce waking blood pressure within 6 weeks, but that this treatment period was insufficient to modify insulin resistance or change the metabolic profile. This is the first randomised placebo-controlled blinded crossover trial comparing cardiovascular and metabolic outcomes after 6 weeks of therapeutic and sham CPAP in obese symptomatic Caucasians with OSA. We have found similar CPAP effects in obese Japanese OSA patients (table 1⇓). The authors suggested that there is a need to offer multiple modalities of treatment to obese OSA patients if their cardiovascular risk profile is to be successfully modified. We totally agree with their conclusion. However, it may be necessary to address the following unresolved issues. View this table: Table 1— Effect of 6-week continuous positive airway pressure …

A new variation in the promoter region, the −604 C>T, and the Leu72Met polymorphism of the ghrelin gene are associated with protection to insulin resistance

Previous studies suggested that polymorphisms in the coding region of the preproghrelin were involved in the etiology of obesity and might modulate glucose-induced insulin secretion. We evaluated the association of a new variation, -604C>T, in the promoter region of the ghrelin gene, of Leu72Met (247C>A) and of Gln90Leu (265A>T), all haplotype-tagging single nucleotide polymorphisms (SNPs), with measures of insulin sensitivity in 1420 adult individuals. The three SNPs were genotyped using ABI PRISM 7900 HT Sequence Detection System. We used multiple linear regression analysis for quantitative traits and THESIAS software for haplotype analysis. We observed a protective effect exerted by Met72 variant of Leu72Met SNP on insulin resistance parameters; a significant decreasing trend from Leu/Leu to Leu/Met and to Met/Met homozygous subjects in triglycerides, fasting insulin levels and HOMA-IR index (P=0.02, 0.01 and 0.003, respectively), and, consistently, an increase in ghrelin levels (P=0.003) was found. A significant decrease from CC to TC and to TT genotypes in insulin levels and HOMA-IR index was also detected (P=0.00l for both), but only in subjects homozygous for Leu72, where the protective effect of Met72 was not present. The haplotype analysis results supported the data obtained by the evaluation of each single SNP, showing the highest value of insulin levels and HOMA-IR index in the -604(c)247(c) haplotype intermediate value in -604(T)247(C) and lowest value in -604(C)247(A). Our observations suggest a protective role of the Met72 variant and of -604 T allele in modulating insulin resistance. These SNPs or an unknown functional variant in linkage disequilibrium could increase ghrelin levels and probably insulin sensitivity.

Insulin action on glucose and protein metabolism during L-carnitine supplementation in maintenance haemodialysis patients

Impaired protein anabolism and insulin resistance are characteristic features of maintenance haemodialysis patients. We have used a randomised, matched-paired, double-blind, placebo-controlled experimental design to determine the capability of intravenous L-carnitine supplementation to modify insulin resistance and protein catabolism in non-diabetic patients with end-stage renal disease (ESRD) undergoing chronic haemodialysis treatment. L-carnitine (20 mg x kg(-1)) (n = 9) or placebo (n = 10) were given intravenously at the end of seven consecutive dialysis sessions. Whole-body protein and glucose metabolism were assessed on interdialytic days by the L[1-(13)C]leucine and the [2,2-(2)H(2)]glucose kinetic models in the postabsorptive state and during euglicemic hyperinsulinemic clamp studies at baseline and at the end of the treatment period. L-carnitine supplementation was associated with lower (P < 0.05) rates of leucine oxidation (-11 +/- 12%) and appearance from proteolysis (-6 +/- 2%) during the clamp studies than after placebo supplementation. The rates of glucose appearance in the postabsorptive state did not change significantly in the patients receiving L-carnitine treatment. Insulin-mediated glucose disappearance was improved by L-carnitine only in those patients (n = 5) (+18 +/- 3%, P < 0.05 vs placebo group, n = 5) with greater baseline insulin resistance, selected according to the median value of insulin sensitivity before treatment. L-carnitine supplementation was associated with protein-sparing effects in maintenance haemodialysis patients during hyperinsulinemia.

Résistance à l’insuline et alimentation

Several chronic diseases, such as type II diabetes, hypertension, dyslipidemia and cardiovascular disease, are the consequences of insulin resistance. An adapted nutritional programme can modify insulin resistance. Indeed, diets high in red meat, saturated fat and high glycemic index carbohydrates induce insulin resistance; whereas diets rich in vegetables, fish, fruits, polyunsaturated fat and low glycemic index carbohydrates improve insulin resistance.

The importance of free fatty acids in the development of Type 2 diabetes

The recent increase in the prevalence of obesity has been associated with a coincident rise in the prevalence of Type 2 diabetes, whereas weight loss has been shown to decrease the risk of Type 2 diabetes. The pathophysiological mechanisms that have been proposed to explain this link are fundamentally concerned with insulin resistance and the decline in pancreatic B-cell function that accompanies an increase in visceral obesity. They involve the rise in the plasma concentrations of free fatty acids (FFAs) that are associated with an increase in fat mass. Elevated levels of FFAs can lead to insulin resistance, and evidence is growing that B-cell function is impaired through lipotoxicity. Factors such as tumour necrosis factor-alpha (TNF-alpha) and adiponectin, released from adipose tissue, can also modulate insulin resistance. Many interventions that are helpful in treating or preventing Type 2 diabetes, such as weight loss and certain pharmacological interventions, reduce circulating FFA concentrations to a greater or lesser extent. Recent study results suggest that peroxisome proliferator-activated receptor (PPAR)gamma agonists have an effect on the development of Type 2 diabetes. However, in light of concerns over the apparent increase in congestive heart failure with PPARgamma agonists, their place in the prevention of Type 2 diabetes remains to be determined.

Role of Dietary Proteins and Amino Acids in the Pathogenesis of Insulin Resistance

Dietary proteins and amino acids are important modulators of glucose metabolism and insulin sensitivity. Although high intake of dietary proteins has positive effects on energy homeostasis by inducing satiety and possibly increasing energy expenditure, it has detrimental effects on glucose homeostasis by promoting insulin resistance and increasing gluconeogenesis. Varying the quality rather than the quantity of proteins has been shown to modulate insulin resistance induced by Western diets and has revealed that proteins derived from fish might have the most desirable effects on insulin sensitivity. In vitro and in vivo data also support an important role of amino acids in glucose homeostasis through modulation of insulin action on muscle glucose transport and hepatic glucose production, secretion of insulin and glucagon, as well as gene and protein expression in various tissues. Moreover, amino acid signaling is integrated by mammalian target of rapamycin, a nutrient sensor that operates a negative feedback loop toward insulin receptor substrate 1 signaling, promoting insulin resistance for glucose metabolism. This integration suggests that modulating dietary proteins and the flux of circulating amino acids generated by their consumption and digestion might underlie powerful new approaches to treat various metabolic diseases such as obesity and diabetes.

Graded Doses of Exercise and Insulin Resistance in Nondiabetic Post-Menopausal Women

Moderate-intensity aerobic exercise has been shown to be effective in modulating insulin resistance (IR) in diabetic populations; however, the effect of graded doses of exercise on IR in nondiabetic populations is unclear. PURPOSE: To examine the effects of graded exercise doses on fasting insulin, glucose and HOMA-IR (homeostasis model of assessment of IR) in nondiabetic women in the DREW (Dose Response to Exercise in Women Aged 45–75y) study. METHODS: Data from 374 previously sedentary, overweight (BMI 25–40 kg/m2), nondiabetic (fasting glucose <126 mg/dL) post-menopausal women with elevated BP (SBP 120–159 mm Hg, DBP ≤99 mm Hg) was used for analysis. Participants were randomized into a control group (A, n = 83) or 1 of 3 exercising groups: B) low dose (4 kcals/kg/week-KKW, n = 123), C) moderate dose (8 KKW, n = 80), or D) high dose (12 KKW, n = 88). Participants in the exercise groups completed 3–5 exercise sessions/ week at a HR associated with 50% VO2peak for 6 months. Fasting blood samples were obtained at baseline and post-intervention, analyzed for glucose and insulin levels, and HOMA was calculated [(insulin (μU/mL) X glucose (mM))/22.5]. The distribution of insulin and HOMA values were skewed and, thus, logarithmically transformed to normalize distribution of the residuals. Post-intervention log insulin, glucose and log HOMA were compared across groups using the SAS general linear model after adjustment for age and baseline values. RESULTS: Post-intervention fasting glucose was significantly (P < 0.01) lower for all exercise groups (94 ±0.6, 93 ±0.8, and 92 ± 0.8 mg/dL for B, C and D) versus controls (96 ± 0.8). Insulin levels were significantly (P < 0.04) lower in the high dose group (9.7 ± 1.0) and marginally lower (P < 0.06) in the moderate dose group (9.8 ± 1.0 μU/mL) relative to controls (10.9 ± 1.0) following intervention. Post-intervention HOMA was significantly lower in the moderate (P < 0.03) and high dose (P < 0.02) groups (2.2 ±1.0 and 2.2 ±1.0 Units) versus controls (2.6 ± 1.0). The trend across groups was significant for glucose, insulin and HOMA (P < 0.0001). CONCLUSIONS: Moderate-intensity aerobic exercise, specifically at or above doses recommended by the U.S. Surgeon General (8 KKW), improves IR in nondiabetic post-menopausal women. Supported by NIH grant HL66262 and equipment grants from Life Fitness.

Cardiovascular and metabolic effects of CPAP in obese males with OSA

Obstructive sleep apnoea is associated with increased blood pressure and other features of the metabolic syndrome. The aim of the present study was to determine the relative effectiveness of continuous positive airway pressure (CPAP) in modifying these outcomes. A randomised placebo-controlled blinded crossover trial comparing cardiovascular and metabolic outcomes after 6 weeks of therapeutic and sham CPAP was performed in 34 CPAP-naïve patients (mean+/-SD body mass and respiratory disturbance indices were 36.1+/-7.6 and 39.7+/-13.8, respectively). Mean waking systolic and diastolic blood pressure fell by 6.7 and 4.9 mmHg, respectively, when compared with sham CPAP. No change was observed in glucose, lipids, insulin resistance or the proportion of patients with metabolic syndrome. In CPAP-compliant patients the fall in blood pressure was greater and the baroreceptor sensitivity improved significantly but no metabolic variable changed. In obese Caucasians with untreated obstructive sleep apnoea, continuous positive airways pressure can improve baroreceptor responsiveness and reduce waking blood pressure within 6 weeks, but this treatment period was insufficient to modify insulin resistance or change the metabolic profile. The mechanisms underlying this difference in the time course of blood pressure and metabolic response to continuous positive airway pressure in obstructive sleep apnoea requires further exploration.

ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome

Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE-/- mice. Transplantation with ATM-/- as compared to ATM+/+ bone marrow increased vascular disease. Jun N-terminal kinase (JNK) activity was increased in ATM-deficient cells. Treatment of ATM+/+apoE-/- mice with low-dose chloroquine, an ATM activator, decreased atherosclerosis. In an ATM-dependent manner, chloroquine decreased macrophage JNK activity, decreased macrophage lipoprotein lipase activity (a proatherogenic consequence of JNK activation), decreased blood pressure, and improved glucose tolerance. Chloroquine also improved metabolic abnormalities in ob/ob and db/db mice. These results suggest that ATM-dependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease.

Heritability of Serum Resistin and Its Genetic Correlation with Insulin Resistance-Related Features in Nondiabetic Caucasians

Serum levels of resistin are believed to modulate insulin resistance in humans. The aim of this study was to investigate whether serum resistin levels are genetically controlled and whether this control is shared with other insulin resistance traits. The study cohort included 264 nondiabetic probands, Caucasian from Italy, and their 473 adult family members. Phenotypic characterization included anthropometric variables, blood pressure, fasting glucose and insulin, lipid profile, and resistin levels. Genotypes were determined at position g.-420C-->G (rs1862513), IVS2+181G-->A (rs3745367), and GAT((n)) polymorphisms of the resistin (RETN) gene. In the 264 unrelated probands, resistin levels were significantly (P < 0.01) correlated with adiposity, blood pressure, C-reactive protein, and the metabolic syndrome score. In a variance component analysis of the 264 probands and their 473 relatives, about 70% of the observed variation of serum resistin levels was heritable (P < 0.0001). A small, but significant (P = 0.004) proportion of this variance was explained by the G-->A variation at position IVS2+181 of the RETN gene. Significant genetic correlations (P < 0.05) were observed between resistin and body mass index (rho(g) = 0.30), waist circumference (rho(g) = 0.32), the insulin resistance index HOMA(IR) (rho(g) = 0.28), and the metabolic syndrome score (rho(g) = 0.35). These data indicate that serum resistin is highly heritable and has some common genetic background with traits related to insulin resistance, reinforcing the hypothesis that this adipokine may play a pathogenic role in insulin resistance-related abnormalities, including type 2 diabetes and cardiovascular disease.

Nutrient intake of women with and without gestational diabetes with a specific focus on fatty acids

Objective Diet therapy is the cornerstone for the management of gestational diabetes mellitus (GDM). Women with GDM are commonly given dietary advice that broadly focuses on a reduction of total energy and fat consumption. We compared nutrient intake and specifically fatty acids of women with GDM who had received individualized nutritional counseling with those of non-diabetic women who did not. Method Women with GDM ( n = 44) and healthy pregnant women ( n = 44) with uncomplicated singleton pregnancies were recruited during the third trimester. Women with GDM were given consultation on diet, health, and macronutrient content of foods commonly consumed by the individual. The non-diabetic group did not receive any dietary advice. Both groups were asked to keep a detailed record of all of foods and fluid consumed over a 4-d period. Results After dietary counseling, the GDM group had lower intakes of energy ( P < 0.05), refined sugar ( P < 0.0001), total and saturated fats ( P < 0.0001), and monounsaturated ( P < 0.01) and trans ( P < 0.0001) fatty acids and higher levels of docosahexaenoic acid and fiber ( P < 0.05) compared with the non-diabetic group. Conclusions Individualized dietary advice was associated with a lower consumption of the target nutrients in women with GDM. Another benefit of the advice was a slight increase in intake of eicosapentaenoic and docosahexaenoic acids, although consumption of ω-3 fatty acids by both groups was well below the recommendations for pregnancy. There is evidence that docosahexaenoic acid modulates insulin resistance and that it is vital for neurovisual development. We suggest that dietary management for women with GDM should foster the current recommendations for essential fatty acids in pregnancy.

Inhibition of the phosphatidylinositol 3′-kinase signaling pathway leads to decreased insulin-stimulated adiponectin secretion from 3T3-L1 adipocytes

Adiponectin is a protein secreted by adipocytes, which modulates insulin resistance and is thought to confer protection from atherosclerosis. Decreased circulating adiponectin is seen in states of insulin resistance, yet the cause of this decrease remains unclear. We investigated the role of insulin in adiponectin secretion and the effect of selective insulin resistance on insulin-stimulated adiponectin secretion by 3T3-L1 adipocytes. Inhibition of the phosphatidylinositol 3′-kinase (PI3K) insulin-signaling pathway was induced with wortmannin (WT) or with a kinase-inactive Akt adenoviral construct (Akt-KD), and inhibition of the mitogen-activated protein kinase pathway was induced with PD98059 or with a dominant-negative ras adenoviral construct (DNras). The PI3K pathway was activated with a constitutively active Akt adenoviral construct (Akt-myr). Adiponectin was measured by Western blot, and adiponectin messenger RNA (mRNA) levels were determined by real-time reverse transcription–polymerase chain reaction. Insulin treatment increased adiponectin secretion and decreased intracellular adiponectin. Treatment with 100 nmol/L insulin for 24 hours resulted in a 78% increase in secreted adiponectin ( P < .05). Insulin had no effect on adiponectin mRNA. WT or Akt-KD, but not PD98059 or DNras, inhibited insulin-stimulated adiponectin secretion ( P < .05). Activation of the PI3K pathway resulted in increased insulin-independent adiponectin secretion. Inhibition of the PI3K- or mitogen-activated protein kinase–dependent pathway decreased adiponectin mRNA by 50% ( P < .01). We demonstrate a decrease in insulin-stimulated adiponectin secretion with selective inhibition of the PI3K pathway. These results suggest a mechanism for the observed decreased adiponectin levels associated with insulin resistance, when defects in the PI3K-dependent insulin-signaling pathway lead to decreased adiponectin production, inadequate adiponectin secretion, and therefore low circulating adiponectin levels.

Hepatic steatosis and insulin resistance: Does etiology make a difference?

To ascertain whether the etiology of hepatic steatosis modulates insulin resistance (IR) and to determine the predictors of IR. We studied IR through HOMA IR in 146 subjects, 99 of whom had ultrasonographic and/or histologic steatosis. Twenty-two had familial heterozygous hypobetalipoproteinemia (FHBL), 48 had non-alcoholic fatty liver disease (NAFLD), 34 HCV infection (17 with HCV1b, 17 with HCV3a) and 42 were healthy controls without steatosis. Steatosis was present in 77.3% of FHBL and, by enrolment criteria, in all NAFLD and HCV cases. Overall HOMA-IR correlated with BMI and GGT (P<0.01). FHBL and healthy groups had similar HOMA-IR and GGT values, whereas higher levels were observed in HCV and NAFLD. HCV3a and FHBL patients were hypolipidemic. HOMA-IR was similar in FHBL patients and controls and lower than in HCV and NAFLD. FHBL patients had a high extent of steatosis, similar to that observed in HCV3a, but lower grading and staging than NAFLD and HCV. At multivariate analysis, steatosis and GGT predicted HOMA-IR. Data suggest that not all hepatic fat associates with IR. FHBL patients, for some aspects, resemble HCV3a infection, possibly suggesting a shared steatogenic mechanism. Among steatotic patients serum GGT levels is the independent predictor of IR.

Combined adipocyte-macrophage fatty acid-binding protein deficiency improves metabolism, atherosclerosis, and survival in apolipoprotein E-deficient mice.

The adipocyte fatty acid-binding protein (FABP) aP2 is expressed by adipocytes and macrophages and modulates insulin resistance, glucose and lipid metabolism, and atherosclerosis. Insulin sensitivity is improved in obese but not in lean aP2-deficient mice. A second fatty acid-binding protein, mal1, also is expressed in adipocytes and macrophages, and mal1 deficiency produces similar effects on insulin resistance. We tested the hypothesis that combined aP2 and mal1 deficiency would produce synergistic effects on metabolism and reduce atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. Male and female apoE-/- mice null for both aP2 and mal1 (3KO) and apoE-/- controls were fed a low-fat chow diet for 16 or 56 weeks. Lean 3KO mice had significantly lower serum cholesterol and triglycerides as well as improved insulin and glucose tolerance as compared with controls. Analysis of atherosclerotic lesions in the 3KO mice showed dramatic reductions in both early (20 weeks) and late-stage (60 weeks) atherosclerosis. Strikingly, survival in the 3KO mice was improved by 67% as compared with apoE-/- controls when challenged with the Western diet for 1 year. Combined aP2 and mal1 deficiency improved glucose and lipid metabolism, reduced atherosclerosis, and improved survival in apoE-/- mice, making these proteins important therapeutic targets for the prevention of the cardiovascular consequences of the metabolic syndrome.

Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) represents an advanced stage of fatty liver disease developed in the absence of alcohol abuse. Its increasing prevalence in western countries, the diagnostic difficulties by noninvasive tests, and the possibility of progression to advanced fibrosis and even cirrhosis make NASH a challenge for hepatologists. NASH is frequently associated with type 2 diabetes and the metabolic syndrome, and several genetic and acquired factors are involved in its pathogenesis. Insulin resistance plays a central role in the development of a steatotic liver, which becomes vulnerable to additional injuries. Several cyclic mechanisms leading to self-enhancement of insulin resistance and hepatic accumulation of fat have been recently identified. Excess intracellular fatty acids, oxidant stress, tumor necrosis factor-alpha, and mitochondrial dysfunction are causes of hepatocellular injury, thereby leading to disease progression and to the establishment of NASH. Intestinal bacterial overgrowth also plays a role, by increasing production of endogenous ethanol and proinflammatory cytokines. Therapeutic strategies aimed at modulating insulin resistance, normalizing lipoprotein metabolism, and downregulating inflammatory mediators with probiotics have promising potential.

Association of the human adiponectin gene and insulin resistance.

Adiponectin is an adipocyte-secreted protein that modulates insulin sensitivity and whose low circulating concentration is associated with insulin resistance. In the present study, we analysed the association between two single-nucleotide polymorphisms (SNPs) in the adiponectin gene and insulin resistance in 253 nondiabetic subjects. In addition, we investigated whether this association is modulated by body mass index (BMI) levels. The SNPs +45T>G and +276G>T in the human adiponectin gene were detected in real-time PCR with LightCycler. No association was found with the +45T>G SNP. The +276G>T SNP was associated with higher BMI (P<0.01), plasma insulin (P<0.02) and HOMA(IR) (P<0.02). To analyse the possible interaction between BMI and the adiponectin gene on insulin resistance, the study group was divided into two subgroups, according to the BMI below or above the median of 26.2 kg/m(2). In both subgroups, subjects carrying the +276G>T SNP had higher HOMA(IR); however, the difference was highly significant among leaner (P<0.001), but not among heavier individuals, indicating that BMI status and the adiponectin gene interact in modulating insulin resistance. Among individuals with BMI <26.2 kg/m(2), the relative risk of insulin resistance was 9.7 (CI: 1.32-87.7, P<0.035). In a subgroup of 67 subjects, carriers of the +276G>T SNP had significantly (P<0.05) lower mean serum adiponectin levels (25.7 ng/ml) compared to noncarriers (37.0 ng/ml), suggesting a possible influence of the +276G>T SNP on adiponectin levels. In summary, we observed an association between the +276G>T SNP in the adiponectin gene and insulin resistance. In particular, among leaner individuals, the adiponectin gene appears to determine an increased risk to develop insulin resistance.

Hepatic insulin sensitizing substance: a novel 'sensocrine' mechanism to increase insulin sensitivity in anaesthetized rats.

1. We recently described the sensory nitrergic nature of the hepatic insulin sensitizing substance (HISS) mechanism linked to postprandial activation of anterior hepatic plexus fibres in rabbits. This study is designed to assess the involvement of the sensory pathways in this mechanism. 2. Selective sensory denervation of the anterior hepatic plexus (AHP) was achieved by a 3-day perineurial treatment with 2% capsaicin solution in Wistar rats (230-250 g). After 1 week, hyperinsulinaemic (100 micro U kg(-1)) euglycaemic (5.5 mmol kg(-1)) glucose clamp studies were performed to estimate insulin sensitivity. 3. The rats with regional AHP sensory denervation exhibited a significantly decreased insulin sensitivity, that is, 9.1+/-1.0 mg kg(-1) min(-1) glucose reinstalled euglycaemia vs 13.3+/-1.9 mg kg(-1) min(-1) glucose (P<0.01) in control rats. 4. Acute partial hepatic denervation by AHP cut was without effect on insulin sensitivity, whereas chronic hepatic denervation induced insulin resistance was similar to that achieved by regional AHP capsaicin treatment. 5. Intraportal administration of L-NAME (10 mg kg(-1)) decreased, whereas capsaicin (0.3 mg kg(-1) min(-1)) increased insulin sensitivity. Neither atropine (1 mg kg(-1)) nor acetylcholine (1-10 micro g mg min(-1)) produced any significant effect. In animals with preceding regional capsaicin desensitization, none of the pharmacological manoeuvres modified the resulting insulin-resistant state. 6. Cysteamine (200 mg kg(-1) s.c.) is known to cause functional somatostatin depletion-induced insulin resistance similar to that produced by either chronic partial hepatic denervation or perineurial AHP capsaicin desensitization. Intraportal capsaicin (0.3 mg kg(-1) min(-1)) was unable to modify insulin resistance achieved by cysteamine. 7. We conclude that capsaicin-sensitive sensory fibres play a crucial role in neurogenic insulin sensitization known as the HISS mechanism without involvement of anatomical reflex-mediated circuits. The results also suggest that HISS is identical to somatostatin of AHP sensory neural origin.