Modulation Of Insulin Action Research Articles

Tissue specificity on insulin action and resistance: past to recent mechanisms

Insulin resistance is the most important pathophysiological feature in many pre-diabetic states. Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion by pancreatic β-cells. The creation of monogenic or polygenic genetically manipulated mice models in a tissue-specific manner was of great help to elucidate the tissue specificity of insulin action and its contribution to the overall insulin resistance. However, a complete understanding of the molecular bases of insulin action and resistance requires the identification of intracellular pathways that regulate insulin-stimulated proliferation, differentiation and metabolism. Accordingly, cell lines derived from insulin target tissues such as brown adipose tissue, liver and beta islets lacking insulin resistance or sensitive candidate genes such as IRS-1, IRS-2, IRS-3, IR and PTP1B have been developed. Indeed, these cell lines have also been very useful to understand the tissue specificity of insulin action and inaction. Obesity is a risk factor for several components of the metabolic syndromes such as type 2 diabetes, dyslipidaemia and systolic hypertension, because white and brown adipose tissues as endocrine organs express and secrete a variety of adipocytokines that can act at both local and systemic levels, modulating the insulin sensitivity. Recent studies revealed that the subjects with the highest transcription rates of genes encoding TNF-α and IL-6 were prone to develop obesity, insulin resistance and type 2 diabetes. Accordingly, we specifically focus in this review on the impact of those adipocytokines on the modulation of insulin action in skeletal muscle.

Novel adiponectin-resistin (AR) and insulin resistance (IRAR) indexes are useful integrated diagnostic biomarkers for insulin resistance, type 2 diabetes and metabolic syndrome: a case control study

BackgroundAdiponectin and resistin are adipokines which modulate insulin action, energy, glucose and lipid homeostasis. Meta-analyses showed that hypoadiponectinemia and hyperresistinemia are strongly associated with increased risk of insulin resistance, type 2 diabetes (T2DM), metabolic syndrome (MS) and cardiovascular disease. The aim of this study was to propose a novel adiponectin-resistin (AR) index by taking into account both adiponectin and resistin levels to povide a better indicator of the metabolic homeostasis and metabolic disorders. In addition, a novel insulin resistance (IRAR) index was proposed by integration of the AR index into an existing insulin resistance index to provide an improved diagnostic biomarker of insulin sensitivity.MethodsIn this case control study, anthropometric clinical and metabolic parameters including fasting serum total adiponectin and resistin levels were determined in 809 Malaysian men (208 controls, 174 MS without T2DM, 171 T2DM without MS, 256 T2DM with MS) whose ages ranged between 40-70 years old. Significant differences in continuous variables among subject groups were confirmed by ANCOVA or MANCOVA test using 1,000 stratified bootstrap samples with bias corrected and accelerated (BCa) 95% CI. Spearman's rho rank correlation test was used to test the correlation between two variables.ResultsThe AR index was formulated as 1+log10(R0)-log10(A0). The AR index was more strongly associated with increased risk of T2DM and MS than hypoadiponectinemia and hyperresistinemia alone. The AR index was more strongly correlated with the insulin resistance indexes and key metabolic endpoints of T2DM and MS than adiponectin and resistin levels alone. The AR index was also correlated with a higher number of MS components than adiponectin and resistin levels alone. The IRAR index was formulated as log10(I0G0)+log10(I0G0)log10(R0/A0). The normal reference range of the IRAR index for insulin sensitive individuals was between 3.265 and 3.538. The minimum cut-off values of the IRAR index for insulin resistance assessment were between 3.538 and 3.955.ConclusionsThe novel AR and IRAR indexes are cost-effective, precise, reproducible and reliable integrated diagnostic biomarkers of insulin sensitivity for screening subjects with increased risk of future development of T2DM and MS.

Insulin sensitivity and secretion in young, healthy subjects are not changed by Zone and Mediterranean diets

The Zone diet (ZD) is centreed primarily on protein intake. Previous findings have assessed the role of ZD on glucose metabolism, but the outcomes have been conflicting. So far, there is no clear evidence of the effects of ZD on insulin response. Furthermore, the effect of ZD on insulin sensitivity has never been clearly determined yet. Our aim was to evaluate in healthy subjects how ZD acts on body composition, lipid profile and overall on insulin sensitivity and secretion in dynamic conditions. We also compared ZD effects with those of the Mediterranean diet (MD). Twelve volunteers were studied. Subjects were randomized either to MD or to ZD for 8 weeks. A wash-out period followed. Afterwards, subjects were crossed over to the other diet for other 8 weeks. At any end-point subjects underwent standard 75 g oral glucose tolerance test for measurements of glucose, insulin, C-peptide, proinsulin and glucagon. Lipids and free fatty acids were determined at fasting. Insulin sensitivity was assessed by the oral glucose insulin sensitivity index. Insulin secretion was determined by mathematical modelling of insulin and C-peptide data. No significant differences were observed following both diets in body weight, fat mass and plasma glucose, insulin, C-peptide, proinsulin and glucagon levels. Similarly, insulin sensitivity and secretion were not different in both absolute values and changes from baseline. Decrease in triglyceride and increase in HDL–cholesterol levels were observed after ZD compared with MD. Thus, it was determined that intake of high-protein diet for 2 months does not modify insulin action and secretion, but improves lipid profile.

Glucagon-Like Peptide-1 Receptor Knockout Mice Are Protected from High-Fat Diet-Induced Insulin Resistance

Glucagon-like peptide-1 augments nutrient-stimulated insulin secretion. Chow-fed mice lacking the glucagon-like peptide-1 receptor (Glp1r) exhibit enhanced insulin-stimulated muscle glucose uptake but impaired suppression of endogenous glucose appearance (endoRa). This proposes a novel role for the Glp1r to regulate the balance of glucose disposal in muscle and liver by modulating insulin action. Whether this is maintained in an insulin-resistant state is unknown. The present studies tested the hypothesis that disruption of Glp1r expression overcomes high-fat (HF) diet-induced muscle insulin resistance and exacerbates HF diet-induced hepatic insulin resistance. Mice with a functional disruption of the Glp1r (Glp1r-/-) were compared with wild-type littermates (Glp1r+/+) after 12 wk on a regular chow diet or a HF diet. Arterial and venous catheters were implanted for sampling and infusions. Hyperinsulinemic-euglycemic clamps were performed on weight-matched male mice. [3-(3)H]glucose was used to determine glucose turnover, and 2[14C]deoxyglucose was used to measure the glucose metabolic index, an indicator of glucose uptake. Glp1r-/- mice exhibited increased glucose disappearance and muscle glucose metabolic index on either diet. This was associated with enhanced activation of muscle Akt and AMP-activated protein kinase and reduced muscle triglycerides in HF-fed Glp1r-/- mice. Chow-fed Glp1r-/- mice exhibited impaired suppression of endoRa and hepatic insulin signaling. In contrast, HF-fed Glp1r-/- mice exhibited improved suppression of endoRa and hepatic Akt activation. This was associated with decreased hepatic triglycerides and impaired activation of sterol regulatory element-binding protein-1. These results show that mice lacking the Glp1r are protected from HF diet-induced muscle and hepatic insulin resistance independent of effects on total fat mass.

Zucker fatty rat hepatocytes have impaired regulation of gene expression mediated by insulin and retinoids

The mechanism of insulin resistance at gene expression level is still unrevealed. We demonstrated retinoids synergize with insulin (INS) to induce glucokinase (Gck) expression in primary hepatocytes, showing their roles in modulating insulin action. Herein, we compared the responses of Gck, Srebf‐1c, Pck1 and Pklr in hepatocytes isolated from Zucker lean (ZL) and fatty (ZF) rats to INS (0 to 100nM) without or with 5 uM all trans retinoic acid (RA). The mRNA levels of these genes were analyzed by real time PCR. For Gck, RA started to synergize with INS at 1nM to induce its expression in ZL and ZF hepatocytes, but the induction folds by INS were higher in ZL than in ZF cells with or without RA. The Srebf‐1c mRNA was only induced in ZL, but not ZF hepatocytes. The Pck1 mRNA levels were decreased more in ZL than in ZF cells by 1 and 10nM INS without RA, and by 1nM INS with RA. The Pklr mRNA level was higher in ZF cells at basal state. It was not responsive to INS, RA or INS + RA in both ZL and ZF hepatocytes. We showed here ZL hepatocytes respond to INS and RA more robustly in regulation of gene expression than ZF cells, suggesting a potential model to study insulin resistance at gene expression level.Grant Funding Source: American Heart Association

Smad5 regulates Akt2 expression and insulin-induced glucose uptake in L6 myotubes

Insulin-induced glucose uptake by skeletal muscle results from Akt2 activation and is severely impaired during insulin resistance. Recently, we and others have demonstrated that BMP9 improves glucose homeostasis in diabetic and non-diabetic rodents. However, the mechanism by which BMP9 modulates insulin action remains unknown. Here we demonstrate that Smad5, a transcription factor activated by BMP9, and Akt2, are upregulated in differentiated L6 myotubes. Smad5, rather than Smad1/8, is downregulated “in vivo” and “in vitro” by dexamethasone. Smad5 knockdown decreased Akt2 expression and serine phosphorylation and insulin-induced glucose uptake, and increased the expression of the lipid phosphatase Ship2. Additionally, binding of Smad5 to Akt2 gene is decreased in dexamethasone-treated rats and increased in L6 myotubes compared to myoblasts. The present study indicates that Smad5 regulates glucose uptake in skeletal muscle by controlling Akt2 expression and phosphorylation. These finding reveals Smad5 as a potential target for the therapeutic of type 2 diabetes.

Modulation of Insulin Action by Botanical Therapeutics

Modulation of Insulin Action by Botanical Therapeutics

Abstract 5160: Apelin Modulates Adipocyte and Inflammatory Cell Processes to Inhibit Atherosclerosis

Background: The G-protein coupled receptor APJ and its ligand apelin have many physiological roles in the cardiovascular system, although its overall impact and mechanism of effect on atherosclerosis remain controversial. Methods and Results: Apelin knockout male mice were bred with ApoE knockout (ApoE KO) mice to generate double knockout (DKO) mice. DKO and ApoE KO mice were fed a normal diet for 20 weeks, and atherosclerotic lesions were analyzed histologically in the aortic sinus and by en face analysis. DKO mice developed more atherosclerosis in the thoracoabdominal aorta than ApoE-KO mice (percent plaque area; 5.36±0.55 vs. 2.53±0.54, p<0.05). Lesion area in the aortic sinus was also increased in DKO compared to ApoE-KO (0.30±0.14 vs. 0.15±0.04 mm2, p<0.05). Histological analysis showed that there was no difference in macrophage or smooth muscle content between genotypes, and studies of reactive oxygen species also did not show a significant difference. Because of recent evidence that the apelin-APJ pathway modulates insulin action, we investigated metabolic parameters and those associated with insulin resistance in the mouse models. DKO mice had significantly greater body weight and fat weight, and glucose tolerance testing showed the DKO mice to be insulin resistant. Also, the mRNA expression of TNF-a, IL-6, and MCP-1 in visceral fat tissue was increased in DKO compared with ApoE KO mice. Similarly, in cultured NIH 3T3 cells, apelin treatment decreased LPS-induced MCP-1 mRNA expression. In related studies, we investigated macrophage function in a foam cell assay, and found there was increased CD36 mRNA in aorta, and increased oil red O positive staining cells in peritoneal macrophage preparations from DKO mice compared with those from ApoE-KO mice. Conclusion: Apelin-APJ signaling inhibits atherosclerosis through multiple mechanisms, including modulation of inflammation and metabolic effects in macrophages and adipose tissues.

No need to sweat: is dieting enough to alleviate insulin resistance in obesity?

No need to sweat: is dieting enough to alleviate insulin resistance in obesity?

Acylated and nonacylated ghrelin levels and their associations with insulin resistance in obese and normal weight children with metabolic syndrome

Ghrelin, a peptide mainly derived from the stomach, plays a pivotal role in the regulation of food intake, energy metabolism, and storage, as well as in insulin sensitivity. Ghrelin circulates in acylated (A-Ghr) and nonacylated (NA-Ghr) forms, and their potential differential associations with insulin resistance (IR) in childhood obesity remain undefined. We investigated the associations of ghrelin forms with IR in normal weight and obese children and the impact of metabolic syndrome (MS) on their plasma values. A total of 210 children in four subgroups of normal weight/obese children with and without components of MS were studied. Fasting blood glucose, insulin, lipid profile, and acylated and total ghrelin were examined. IR was determined by a homeostasis model assessment (HOMA) of IR. In the entire population, plasma insulin and HOMA-IR were associated negatively with T-Ghr and NA-Ghr, but positively with the ratio of A/NA-Ghr after adjustment for age, gender, and Tanner stage. Obese metabolically abnormal children had lower T-Ghr and NA-Ghr, but comparable A-Ghr and a higher A/NA-Ghr ratio than obese metabolically normal subjects. Compared with lean healthy children, lean metabolically abnormal subjects had higher A-Ghr and the A/NA-Ghr ratio, but comparable T-Ghr and NA-Ghr. A multiple regression analysis showed that A-Ghr and the A/NA-Ghr ratios were positively associated with HOMA-IR, independent of age, gender, Tanner stage, and body mass index (or waist circumference) and other components of MS. A-Ghr excess may negatively modulate insulin action in obese and nonobese children, and may contribute to the association of IR and MS.

Adiponectin is required to mediate rimonabant-induced improvement of insulin sensitivity but not body weight loss in diet-induced obese mice

The increase in adiponectin levels in obese patients with untreated dyslipidemia and its mRNA expression in adipose tissue of obese animals are one of the most interesting consequences of rimonabant treatment. Thus, part of rimonabant's metabolic effects could be related to an enhancement of adiponectin secretion and its consequence on the modulation of insulin action, as well as energy homeostasis. The present study investigated the effects of rimonabant in adiponectin knockout mice (Ad(-/-)) exposed to diet-induced obesity conditions. Six-week-old Ad(-/-) male mice and their wild-type littermate controls (Ad(+/+)) were fed a high-fat diet for 7 mo. During the last month, animals were administered daily either with vehicle or rimonabant by mouth (10 mg/kg). High-fat feeding induced weight gain by about 130% in both wild-type and Ad(-/-) mice. Obesity was associated with hyperinsulinemia and insulin resistance. Treatment with rimonabant led to a significant and similar decrease in body weight in both Ad(+/+) and Ad(-/-) mice compared with vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad(+/+) mice compared with Ad(+/+) vehicle-treated mice by decreasing hepatic glucose production and increasing glucose utilization index in both visceral and subcutaneous adipose tissue. In contrast, rimonabant failed to improve insulin sensitivity in Ad(-/-) mice, despite the loss in body weight. Rimonabant's effect on body weight appeared independent of the adiponectin pathway, whereas adiponectin seems required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.

The emerging role of TRIB3 as a gene affecting human insulin resistance and related clinical outcomes

Type 2 diabetes is becoming epidemic. The personal and social burden imposed by diabetes will increase in the close future as its prevalence is expected to double in the next 15-20 years. Type 2 diabetes is caused by the combination of resistance to insulin action and inadequate insulin secretion. Despite the role of profound changes in individual environmental exposure is incontrovertible, several findings clearly indicate that type 2 diabetes and insulin resistance are also heritable. Among the several inhibitors of insulin signalling, which have been recently proposed as determinants of insulin resistance, is TRIB3, a mammalian tribbles homolog which affects insulin signalling at the level of Akt-2, a key modulator of insulin action in target cells. We here report data on a prevalent Q84R TRIB3 missense single nucleotide polymorphism (rs2295490) we first described few years ago. Several lines of evidences indicate that this amino-acid change is, in fact, a gain of function mutation with the potential to affect insulin signalling and thus, to increase the risk of insulin resistance and related clinical outcomes.

Metabolic Effects of Resveratrol in Mammals - a Link Between Improved Insulin Action and Aging

Resveratrol, a polyphenol found in several vegetal sources, has been shown to possess lifespan-promoting properties in yeast and metazoans, including small mammals. While in yeast and low metazoans resveratrol acts mainly by activating the histone deacetylase Sir2, in mammals it appears to target - besides the Sir2 homolog SIRT1 - several crucial pathways for the control of metabolism, including the AMPK and the insulin-IGF1 receptors axis. The action of resveratrol on these pathways has been linked to its capability to i) prolong lifespan following chronic administration to mice and ii) protect from the development of diet-induced obesity and obesity-dependent metabolic disorders. Here we summarise the current understanding on how resveratrol displays its remarkable properties by acting on the control of insulin secretion and by modulation of insulin action in pheripheral insulin-responsive tissues. Since resveratrol has the potential for pharmacological exploitation to prevent the establishment of insulin-resistance and thus postpone - or even prevent - the onset of type 2 diabetes, toxicologic and pharmacodynamics studies in humans have been initiated. These studies show that resveratrol is non-toxic and easily absorbed by humans. As a drawback, its bioavailability is very limited due to the fast metabolic alterations to which it is subjected in the plasma. Therefore, we also review here the efforts that have been made - in the drug discovery field - to identify new molecules endowed with resveratrol-like pharmacological properties but with better bioavailability, which could prove to possess therapeutic potential.

Mechanisms of macrophage activation in obesity-induced insulin resistance

Chronic inflammation is now recognized as a key step in the pathogenesis of obesity-induced insulin resistance and type 2 diabetes mellitus. This low-grade inflammation is mediated by the inflammatory (classical) activation of recruited and resident macrophages that populate metabolic tissues, including adipose tissue and liver. These findings have led to the concept that infiltration by and activation of macrophages in adipose tissue are causally linked to obesity-induced insulin resistance. Studies have shown, however, that alternatively activated macrophages taking residence in adipose tissue and liver perform beneficial functions in obesity-induced metabolic disease. Alternatively activated macrophages reduce insulin resistance in obese mice by attenuating tissue inflammation and increasing oxidative metabolism in liver and skeletal muscle. The discovery that distinct subsets of macrophages are involved in the promotion or attenuation of insulin resistance suggests that pathways controlling macrophage activation can potentially be targeted to treat these comorbidities of obesity. Thus, this Review focuses on the stimuli and mechanisms that control classical and alternative activation of tissue macrophages, and how these macrophage activation programs modulate insulin action in peripheral tissues. The functional importance of macrophage activation is further discussed in the context of host defense to highlight the crosstalk between innate immunity and metabolism.

Acute Dipeptidyl Peptidase-4 Inhibition Rapidly Enhances Insulin-Mediated Suppression of Endogenous Glucose Production in Mice

Pharmacological approaches that enhance incretin action for the treatment of type 2 diabetes mellitus have recently been developed, i.e. injectable glucagon-like peptide-1 receptor (GLP-1R) agonists with prolonged plasma half-lives and orally available inhibitors of dipeptidyl peptidase (DPP)-4, the main enzyme responsible for the rapid degradation of circulating glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. The mechanism(s) underlying the glucose-lowering effect of these two pharmacotherapies differs and is not yet fully understood. Here we investigated whether acute GLP-1R activation (exendin-4) or DPP-4 inhibition (des-F-sitagliptin) modulates insulin action in mice using a hyperinsulinemic euglycemic clamp. A single iv bolus of des-F-sitagliptin (11 mg/kg) was administered to mice 15 min after the start of the clamp, and its effect was compared with a 50-ng bolus of exendin-4 or the same volume of saline. Despite matched levels of plasma glucose and insulin, within 15 min the glucose infusion rate required to maintain euglycemia was significantly greater after des-F-sitagliptin compared with saline or exendin-4. This difference was entirely due to enhancement of insulin-mediated suppression of endogenous glucose production by des-F-sitagliptin, with no difference in glucose disposal rate. These findings illustrate that DPP-4 inhibition modulates glucose homeostasis through pathways distinct from those used by GLP-1R agonists in mice.

Modulation of Insulin Action by Advanced Glycation Endproducts: A New Player in the Field

Insulin resistance is characterized by an impaired responsiveness to the action of insulin at its multiple target organs. The accumulation of advanced glycation endproducts (AGEs) has been demonstrated in clinical settings of insulin resistance such as in diabetes, hypertension, and obesity. In this review we have focused on advanced glycation as a modulator of insulin resistance. Structural and functional abnormalities of the insulin molecule by glycation and methylglyoxal may contribute to the pathogenesis of insulin resistance. In addition, it is likely that AGEs interfere in the complex molecular pathways of insulin signaling and as such in insulin resistance.

The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies

BackgroundConsidering that a portion of the heterogeneity amongst previous replication studies may be due to a variable proportion of obese subjects in case-control designs, we assessed the association of genetic variants with type 2 diabetes (T2D) in large groups of obese and non-obese subjects.MethodsWe genotyped RETN, KCNJ11, HNF4A, HNF1A, GCK, SLC30A8, ENPP1, ADIPOQ, PPARG, and TCF7L2 polymorphisms in 1,283 normoglycemic (NG) and 1,581 T2D obese individuals as well as in 3,189 NG and 1,244 T2D non-obese subjects of European descent, allowing us to examine T2D risk over a wide range of BMI.ResultsAmongst non-obese individuals, we observed significant T2D associations with HNF1A I27L [odds ratio (OR) = 1.14, P = 0.04], GCK -30G>A (OR = 1.23, P = 0.01), SLC30A8 R325W (OR = 0.87, P = 0.04), and TCF7L2 rs7903146 (OR = 1.89, P = 4.5 × 10-23), and non-significant associations with PPARG Pro12Ala (OR = 0.85, P = 0.14), ADIPOQ -11,377C>G (OR = 1.00, P = 0.97) and ENPP1 K121Q (OR = 0.99, P = 0.94). In obese subjects, associations with T2D were detected with PPARG Pro12Ala (OR = 0.73, P = 0.004), ADIPOQ -11,377C>G (OR = 1.26, P = 0.02), ENPP1 K121Q (OR = 1.30, P = 0.003) and TCF7L2 rs7903146 (OR = 1.30, P = 1.1 × 10-4), and non-significant associations with HNF1A I27L (OR = 0.96, P = 0.53), GCK -30G>A (OR = 1.15, P = 0.12) and SLC30A8 R325W (OR = 0.95, P = 0.44). However, a genotypic heterogeneity was only found for TCF7L2 rs7903146 (P = 3.2 × 10-5) and ENPP1 K121Q (P = 0.02). No association with T2D was found for KCNJ11, RETN, and HNF4A polymorphisms in non-obese or in obese individuals.ConclusionGenetic variants modulating insulin action may have an increased effect on T2D susceptibility in the presence of obesity, whereas genetic variants acting on insulin secretion may have a greater impact on T2D susceptibility in non-obese individuals.

Uncoupling protein 1 expression in murine skeletal muscle increases AMPK activation, glucose turnover, and insulin sensitivity in vivo

Uncoupling of oxidative phosphorylation represents a potential target for the treatment of hyperglycemia and insulin resistance in obesity and type 2 diabetes. The present study investigated whether the expression of uncoupling protein 1 in skeletal muscles of transgenic (mUCP1 TG) mice modulates insulin action in major insulin target tissues in vivo. Euglycemic-hyperinsulinemic clamps (17 pM x kg lean body mass(-1) x min(-1)) were performed in 9-mo-old hemizygous male mUCP1 TG mice and wild-type (WT) littermates matched for body composition. mUCP1 TG mice exhibited fasting hypoglycemia and hypoinsulinemia compared with WT mice, whereas fasting hepatic glucose production rates were comparable in both genotypes. mUCP1 TG mice were markedly more sensitive to insulin action compared with WT mice and displayed threefold higher glucose infusion rates, enhanced skeletal muscle and white adipose tissue glucose uptake, and whole body glycolysis rates. In the absence of alterations in plasma adiponectin concentrations, acceleration of insulin-stimulated glucose turnover in skeletal muscle of mUCP1 TG mice was accompanied by increased phosphorylated Akt-to-Akt and phosphorylated AMP-activated protein kinase (AMPK)-to-AMPK ratios compared with WT mice. UCP1-mediated uncoupling of oxidative phosphorylation in skeletal muscle was paralleled by AMPK activation and thereby stimulated insulin-mediated glucose uptake in skeletal muscle.

Adiponectin Concentrations in Type 2 Diabetic Patients with or without Metabolic Syndrome

Background: Adipocytes produce several adipokines that modulate insulin action as well as glucose and lipid metabolism. The aim of this study was to evaluate the relationship between serum adiponectin concentrations and metabolic syndrome (MS) in patients with type 2 diabetes mellitus. Methods: This study included 127 type 2 diabetic patients (males 63, females 64). The subjects were divided into two groups as with or without metabolic syndrome (MS(+) or MS(-)). The MS was diagnosed by International Diabetes Federation. Serum adiponectin, leptin, fasting plasma insulin, glucose, glycated hemoglobin, lipid profile, white blood corpuscle (WBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), uric acid and C-reactive protein (CRP) were examined. Results: Serum adiponectin concentrations were significantly lower in MS(+) than MS(-) (4.8 ± 2.4 μg/mL vs 7.6 ± 5.8 μg/mL, 7.6 ± 3.7 μg/mL vs 11.5 ± 7.2 μg/mL, P < 0.05 in males and females). After adjustment for age and body mass index (BMI), in MS (+), the serum levels of adiponectin correlated positively with high density lipoprotein - cholesterol (HDL-C) and negatively wi th height, body weight, ALT and CRP. In MS(-), the serum levels of adiponectin correlated positively with HDL-C and negatively with diastolic blood pressure (DBP), triglyceride and CRP. By multiple regression analysis, no parameters were independently correlated with serum adiponectin concentrations in MS(+), while DBP and HDL-C were independently related to serum adiponectin concentrations in MS(-). Conclusion: Serum adiponectin concentrations were lower in type 2 diabetic patients with MS than without MS. There were no significant parameters related to decrease serum adiponectin concentrations in MS. But further study is needed to confirm this result. (KOREAN DIABETES J 32:224-235, 2008)

Accretion of visceral fat and hepatic insulin resistance in pregnant rats

Insulin resistance (IR) is a hallmark of pregnancy. Because increased visceral fat (VF) is associated with IR in nonpregnant states, we reasoned that fat accretion might be important in the development of IR during pregnancy. To determine whether VF depots increase in pregnancy and whether VF contributes to IR, we studied three groups of 6-mo-old female Sprague-Dawley rats: 1) nonpregnant sham-operated rats (Nonpreg; n = 6), 2) pregnant sham-operated rats (Preg; n = 6), and 3) pregnant rats in which VF was surgically removed 1 mo before mating (PVF-; n = 6). VF doubled by day 19 of pregnancy (Nonpreg 5.1 +/- 0.3, Preg 10.0 +/- 1.0 g, P < 0.01), and PVF- had similar amounts of VF compared with Nonpreg (PVF- 4.6 +/- 0.8 g). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp in late gestation in chronically catheterized unstressed rats. Glucose IR (mg.kg(-1).min(-1)) was highest in Nonpreg (19.4 +/- 2.0), lowest in Preg (11.1 +/- 1.4), and intermediate in PVF- (14.7 +/- 0.6; P < 0.001 between all groups). During the clamp, Nonpreg had greater hepatic insulin sensitivity than Preg [hepatic glucose production (HGP): Nonpreg 4.5 +/- 1.3, Preg 9.3 +/- 0.5 mg.kg(-1).min(-1); P < 0.001]. With decreased VF, hepatic insulin sensitivity was similar to nonpregnant levels in PVF- (HGP 4.9 +/- 0.8 mg.kg(-1).min(-1)). Both pregnant groups had lower peripheral glucose uptake compared with Nonpreg. In parallel with hepatic insulin sensitivity, hepatic triglyceride content was increased in pregnancy (Nonpreg 1.9 +/- 0.4 vs. Preg 3.2 +/- 0.3 mg/g) and decreased with removal of VF (PVF- 1.3 +/- 0.4 mg/g; P < 0.05). Accretion of visceral fat is an important component in the development of hepatic IR in pregnancy, and accumulation of hepatic triglycerides is a mechanism by which visceral fat may modulate insulin action in pregnancy.