Insulin resistance in Chinese patients with type 2 diabetes is associated with C-reactive protein independent of abdominal obesity

Background

Patients with diabetes mellitus (DM) have high risk of heart failure. Whether some of the risk is directly linked to metabolic derangements in the myocardium or whether the risk is primarily caused by coronary artery disease (CAD) and hypertension is incompletely understood. Echocardiographic tissue Doppler imaging was therefore performed in DM patients without significant CAD to examine whether DM per se influenced cardiac function.

Methods

Patients with a left ventricular (LV) ejection fraction (EF) > 35% and without significant CAD, prior myocardial infarction, cardiac pacemaker, atrial fibrillation, or significant valve disease were identified from a tertiary invasive center register. DM patients were matched with controls on age, gender and presence of hypertension.

Results

In total 31 patients with diabetes and 31 controls were included. Mean age was 58 ± 12 years, mean LVEF was 51 ± 7%, and 48% were women. No significant differences were found in LVEF, left atrial end systolic volume, or left ventricular dimensions. The global longitudinal strain was significantly reduced in patients with DM (15.9 ± 2.9 vs. 17.7 ± 2.9, p = 0.03), as were peak longitudinal systolic (S') and early diastolic (E') velocities (5.7 ± 1.1 vs. 6.4 ± 1.1 cm/s, p = 0.02 and 6.1 ± 1.7 vs. 7.7 ± 2.0 cm/s, p = 0.002). In multivariable regression analyses, DM remained significantly associated with impairments of S' and E', respectively.

Conclusion

In patients without significant CAD, DM is associated with an impaired systolic longitudinal LV function and global diastolic dysfunction. These abnormalities are likely to be markers of adverse prognosis.     

Insulin resistance in the defense against obesity

In the face of the current obesity epidemic, the nature of the relationship between overnutrition and type 2 diabetes is of great importance. Obesity can be considered a state of excessive insulin action that elicits a series of cellular homeostatic responses, producing systemic insulin resistance. These responses occur in four steps: homologous desensitization to insulin action, leptin secretion, inflammation, and, finally, a counter-inflammatory phase that serves to conserve energy storage. The molecular mechanisms underlying these steps are discussed in the context of potential new therapeutic approaches.     

地塞米松诱发的大鼠胰岛素抵抗模型

目的：建立一种简便可靠的大鼠胰岛素抵抗模型。方法：对大鼠进行不同剂量地塞米松腹腔注射,观察不同时间各组大鼠糖代谢相关变化。结果：大鼠空腹葡萄糖、胰岛素、胰岛素抵抗程度呈地塞米松给药时间及剂量依赖性,后两者改变先于前者改变。结论：一定剂量的地塞米松空腹注射将诱发大鼠胰岛素抵抗,这种模型简便、可靠,可用于相关课题的研究。     

Insulin resistance in nonobese patients with polycystic ovary syndrome

OBJECTIVES: Most patients with polycystic ovary syndrome (PCOS) are obese and known to have insulin resistance. Obesity per se is a cause of insulin resistance. This study was performed to determine whether insulin resistance occurs in patients with PCOS in the absence of obesity and acanthosis nigricans. METHOD: For this purpose, an euglycemic hyperinsulinemic clamp study was performed in 12 nonobese patients with PCOS and in 10 healthy control subjects matched for age and weight. RESULTS: The mean serum testosterone and luteinizing hormone (LH) levels were significantly elevated (4.09 +/- 1.32 vs. 1.18 +/- 0.53 pg/ml, p < 0.001, and 11.63 +/- 5.37 vs. 4.98 +/- 2.73 mIU/ml, p < 0.001, respectively), and the serum sex hormone binding globulin level was significantly reduced (40.96 +/- 14.94 vs. 73.98 +/- 30.40 nmol/l, p < 0.001) in patients with PCOS as compared with the values in control subjects. The mean serum insulin level was also elevated in patients with PCOS as compared with control subjects (32.33 +/- 4.98 vs. 19.56 +/- 2.21 microU/ml, p < 0.05). The insulin sensitivity was lower in patients with PCOS as compared with the control subjects (200 +/- 27.8 vs. 427.8 +/- 88.9 micromol x kg(-1) x min(-1), p < 0.001). In patients with PCOS, the serum levels of free testosterone (r = -0.89, p < 0.001) and LH were inversely correlated with the insulin sensitivity (r = -0.63, p < 0.05). Serum follicle-stimulating hormone, prolactin, and dehydroepiandrosterone sulfate levels were similar in both groups. CONCLUSIONS: These results indicate that a significant degree of insulin resistance exists in nonobese patients with PCOS and that this insulin resistance is significantly related to serum LH and free testosterone levels. Thus, measures to decrease insulin resistance may have to be considered earlier to decrease the potential risks of developing diabetes mellitus and coronary artery disease at later ages of life in these patients.     

Insulin resistance in patients with cirrhosis and portal hypertension

Insulin resistance (IR) is involved in the pathogenesis of endothelial dysfunction and is also present in patients with cirrhosis. Intrahepatic endothelial dysfunction plays a major role, increasing hepatic vascular resistance and promoting portal hypertension (PH). In addition, β-adrenergic agonists and insulin share several intracellular signaling pathways. Thus IR may influence the response to β-blockers. This study aimed at evaluating the relationship between IR and hepatic hemodynamics in patients with cirrhosis and with the portal pressure response to acute β-blockade. Forty-nine patients with cirrhosis and PH were included. Hepatic and systemic hemodynamics were measured, and IR was estimated by using the updated homeostasis model assessment (HOMA)-2 index. Patients with HOMA-2 > 2.4 were considered IR. In patients with hepatic venous pressure gradient (HVPG) ≥ 10 mmHg) [clinically significant PH (CSPH)], hemodynamic measurements were performed again 20 min after intravenous propranolol. Mean HOMA-2 index was 3 ± 1.4. Fifty-seven percent of patients had IR. A weak correlation between HOMA-2 index and HVPG was observed. Eighty-six percent of patients had CSPH. HOMA-2 index was an independent predictor of CSPH. However, in patients with CSPH, the correlation between HOMA-2 index and HVPG was lost. HVPG, but not IR, predicted the presence of esophageal varices. Response to propranolol was not different between patients with or without IR. In nondiabetic patients with cirrhosis, HOMA-2 index is directly associated with the presence of CSPH and indirectly with varices, but does not allow either grading HVPG or predicting its response to propranolol.     

Sedentary behavior is not associated with cardiometabolic risk in adults with abdominal obesity

Objective

The primary aim of this study was to determine whether time spent in sedentary behaviors (SED) was associated with 2-hour glucose and insulin resistance in adults with abdominal obesity. We also examined the association between light physical activity (LPA) and sporadic (accumulated in bouts <10 minutes in duration) moderate-to-vigorous physical activity (MVPA) with glucose metabolism.

Methods

Participants were 135 inactive, abdominally obese adults recruited from Kingston, Canada. SED and physical activity were determined by accelerometry over 7 days and summarized as SED (accelerometer counts/min <100), LPA (counts/min 100–1951), and MVPA (counts/min ≥1952). A 75 g oral glucose tolerance test was used to ascertain 2-hour glucose; the homeostasis model of assessment was used to determine insulin resistance (HOMA-IR); lipid, lipoproteins and blood pressure were determined using standard protocols. Secondary analyses considered the association between SED and physical activity with other cardiometabolic risk factors.

Results

Participants spent 627.2±82.9 min/d in SED, 289.0±91.7 min/d in LPA and 19.2±13.5 min/d in MVPA. Neither SED nor the physical activity variables were associated with 2-hour glucose or HOMA-IR (p>0.05). In secondary analyses, SED was not associated with any cardiometabolic risk factor (p>0.1); with the exception of blood pressure (p<0.05), LPA was not associated with any cardiometabolic risk factor (p>0.1); and MVPA was independently associated with total cholesterol and triglycerides (p<0.05).

Conclusions

Objectively measured SED was not associated with 2-hr glucose or HOMA-IR. Our findings also suggest that the accumulation of LPA and sporadic MVPA is not associated with glucose metabolism in adults with abdominal obesity.     

The role of production of adipsin and leptin in the development of insulin resistance in patients with abdominal obesity

We investigated the tissue-specific features of the production of adipokines (leptin and adipsin) by adipose tissue in obese patients depending on the degree of obesity and the state of carbohydrate metabolism. An increase in the content of adipsin and leptin in the blood plasma was found. In patients with varying degrees of obesity with and without type 2 diabetes mellitus (DM 2), we determined the level of tissue-specific expression of LEP and CFD genes encoding leptin and adipsin, respectively. The contribution of different adipose tissue depots to the blood plasma level of adipsin and leptin in obese patients with and without DM 2 was established. The disturbance of reciprocal relationships between adipsin and leptin in obesity is associated with the development of insulin resistance.     

Acquired obesity is associated with increased liver fat, intra-abdominal fat, and insulin resistance in young adult monozygotic twins

We determined whether acquired obesity is associated with increases in liver or intra-abdominal fat or impaired insulin sensitivity by studying monozygotic (MZ) twin pairs discordant and concordant for obesity. We studied nineteen 24- to 27-yr-old MZ twin pairs, with intrapair differences in body weight ranging from 0.1 to 24.7 kg [body mass index (BMI) range 20.0-33.9 kg/m2], identified from a population-based FinnTwin16 sample. Fat distribution was determined by magnetic resonance imaging, percent body fat by dual-energy X-ray absorptiometry, liver fat by proton spectroscopy, insulin sensitivity by measuring the fasting insulin concentration, and whole body insulin sensitivity by the euglycemic insulin clamp technique. Intrapair differences in BMI were significantly correlated with those in intra-abdominal fat (r = 0.82, P < 0.001) and liver fat (r = 0.57, P = 0.010). Intrapair differences in fasting insulin correlated with those in subcutaneous abdominal (r = 0.60, P = 0.008), intra-abdominal (r = 0.75, P = 0.0001) and liver (r = 0.49, P = 0.048) fat. Intrapair differences in whole body insulin sensitivity correlated with those in subcutaneous abdominal (r = -0.72, P = 0.001) and intra-abdominal (r = -0.55, P = 0.015) but not liver (r = -0.20, P = 0.20) fat. We conclude that acquired obesity is associated with increases in intra-abdominal and liver fat and insulin resistance, independent of genetic factors.     

Insulin resistance induced by loop diuretics and hyperosmolarity in perfused rat liver.

Insulin-induced cell swelling was recently suggested to reflect an independent signal for metabolic insulin effects such as inhibition of hepatic proteolysis, which is transmitted at the level of autophagosome formation via p38MAPK activation [H?ussinger et al., Gastroenterology 116 (1999), 921-935]. Here, the role of insulin-induced cell swelling in the overall context of insulin signalling towards proteolysis inhibition was studied in perfused rat liver. Loop diuretics and hyperosmolarity, which impair insulin-stimulated cell swelling, strongly blunt Erk-2 and p38MAPK activation as well as proteolysis inhibition by insulin, but are without effect on insulin-induced tyrosine phosphorylation of IR-beta and IRS-1. Inhibitors of phosphatidylinositol-3-kinase (PI3-kinase) also block insulin-induced cell swelling, MAP kinase activation and proteolysis inhibition, but the antiproteolytic response to hypoosmolarity remains unaffected. We suggest that PI3-kinase-mediated cell swelling induced by insulin is required to amplify the insulin signal to MAP kinases and thus proteolysis regulation. The perturbation of insulin-induced cell swelling may be of pathophysiological relevance for the development of insulin resistance in clinical situations associated with hyperosmotic dehydration and loop diuretic treatment.     

Leptin resistance in obesity is characterized by decreased sensitivity to proopiomelanocortin products

Obesity in normal animals has been demonstrated to be associated with a decrease in sensitivity to leptin especially as it relates to leptin's capacity to increase sympathetic nerve activity and enhance cardiovascular dynamics. In normal animals leptin has been demonstrated to exert significant regulatory responses by its capacity to increase proopiomelanocortin (POMC) expression and especially the increase in alpha melanocyte stimulating hormone (alphaMSH). These responses to leptin are blocked by a melanocortin-4 (MC-4) receptor antagonist. In this study we investigated the responsiveness of the sympathetic nervous system and cardiovascular system of high fat fed obese animals to the intracerebroventricular (ICV) administration of the POMC products alphaMSH and beta-endorphin (beta-END). We further investigated these responses in obese animals following leptin administration in the presence of MC-4 receptor and opioid receptor blockade. The ICV administration of leptin resulted in an increase in lumbar sympathetic nerve activity (LSNA) and mean arterial pressure (MAP) in normals but decreased it in the obese. The ICV administration of alphaMSH increased the LSNA and MAP in normal animals but to a lesser degree in obese animals. On the other hand beta-endorphin decreased the LSNA and MAP in normal animals but increased it in obese animals. Additionally ICV leptin administration in obese animals in the presence of MC-4 or opioid receptor blockade resulted in an increase in sympathetic activity and a pressor response. From these studies we conclude that obesity in high fat fed animals is characterized by a decreased sensitivity to alphaMSH and a paradoxical response to beta-endorphin and this altered responsiveness may be a factor in the altered leptin resistance characteristic of obese animals.     

Insulin resistance is not conserved in myotubes established from women with PCOS

Background

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among premenopausal women, who often develop insulin resistance. We tested the hypothesis that insulin resistance in skeletal muscle of patients with polycystic ovary syndrome (PCOS) is an intrinsic defect, by investigating the metabolic characteristics and gene expression of in vitro differentiated myotubes established from well characterized PCOS subjects.

Methods

Using radiotracer techniques, RT-PCR and enzyme kinetic analysis we examined myotubes established from PCOS subjects with or without pioglitazone treatment, versus healthy control subjects who had been extensively metabolically characterized in vivo. Results Myotubes established from PCOS and matched control subjects comprehensively expressed all insulin-sensitive biomarkers; glucose uptake and oxidation, glycogen synthesis and lipid uptake. There were no significant differences between groups either at baseline or during acute insulin stimulation, although in vivo skeletal muscle was insulin resistant. In particular, we found no evidence for defects in insulin-stimulated glycogen synthase activity between groups. Myotubes established from PCOS patients with or without pioglitazone treatment also showed no significant differences between groups, neither at baseline nor during acute insulin stimulation, although in vivo pioglitazone treatment significantly improved insulin sensitivity. Consistently, the myotube cultures failed to show differences in mRNA levels of genes previously demonstrated to differ in PCOS patients with or without pioglitazone treatment (PLEK, SLC22A16, and TTBK).

Conclusion

These results suggest that the mechanisms governing insulin resistance in skeletal muscle of PCOS patients in vivo are not primary, but rather adaptive.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00145340","term_id":"NCT00145340"}}NCT00145340     

Insulin resistance is associated with DNA damage in peripheral blood cells in non-diabetic patients with genotype 1 chronic hepatitis C

Abstract

Background. In chronic liver diseases of different etiologies, including viral hepatitis, genotoxic effects of oxidative stress have been shown, both in clinical and in experimental conditions, suggesting that this mechanism may contribute to the evolution of the disease. Aim. To evaluate DNA damage in the peripheral blood of untreated non-diabetic patients with chronic hepatitis C and control subjects, and its correlation with demographic, anthropometric, biochemical, and histological parameters in the patient sample. Patients and methods. This study comprised 100 subjects of both genders, 60 of whom were treatment-naïve patients with positive serology for genotype 1 hepatitis C. The remaining 40 were blood donors with negative serology for hepatitis who were used as control subjects, and matched by gender, age, weight, and BMI. DNA damage was determined using the comet assay in the total peripheral blood. Results. The DNA damage evaluated by the comet assay revealed higher values in the group of patients with hepatitis compared with that in the control group. The relationships of the comet assay with the studied variables were assessed using multivariate analysis; significant correlations were only identified with insulin (r = 0.343, p = 0.008) and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) (r = 0.331, p = 0.011). Conclusion. Patients with genotype 1 chronic hepatitis C have higher rates of DNA damage, as determined by comet assay and this alteration is correlated with the HOMA index of insulin resistance.     

Protein kinase-C involvement in thymocyte apoptosis induced by hydrocortisone

The involvement of protein kinase-C in thymocytes death induced by hydrocortisone was studied. Thymus cells were incubated 6 hr or in the presence of hydrocortisone, labeled with Acridine orange, and the DNA content of each nuclei was estimated by cytofluorimetry. The results indicate that hydrocortisone-induced DNA fragmentation can be prevented by adding the protein kinase-C inhibitor H-7 to the cell suspension. Incubation of the H-A 1004, an inhibitor of c-AMP-dependent protein kinase, with low effect on on protein kinase-C, did not interfere with the cortisone-mediated DNA fragmentation. Therefore, it can be concluded that protein kinase-C plays an important role in the process of lympholysis mediated by corticoids.     

The association of PNPLA3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat

Background and Aims

A polymorphism in adiponutrin/patatin-like phospholipase-3 gene (PNPLA3), rs738409 C->G, encoding for the I148M variant, is the strongest genetic determinant of liver fat and ALT levels in adulthood and childhood obesity. Aims of this study were i) to analyse in a large group of obese children the role of the interaction of not-genetic factors such as BMI, waist circumference (W/Hr) and insulin resistance (HOMA-IR) in exposing the association between the I148M polymorphism and ALT levels and ii) to stratify the individual risk of these children to have liver injury on the basis of this gene-environment interaction.

Methods

1048 Italian obese children were investigated. Anthropometric, clinical and metabolic data were collected and the PNPLA3 I148M variant genotyped.

Results

Children carrying the 148M allele showed higher ALT and AST levels (p = 0.000006 and p = 0.0002, respectively). Relationships between BMI-SDS, HOMA-IR and W/Hr with ALT were analysed in function of the different PNPLA3 genotypes. Children 148M homozygous showed a stronger correlation between ALT and W/Hr than those carrying the other genotypes (p: 0.0045) and, therefore, 148M homozygotes with high extent of abdominal fat (W/Hr above 0.62) had the highest OR (4.9, 95% C. I. 3.2–7.8, p = 0.00001) to develop pathologic ALT.

Conclusions

We have i) showed for the first time that the magnitude of the association of PNPLA3 with liver enzymes is driven by the size of abdominal fat and ii) stratified the individual risk to develop liver damage on the basis of the interaction between the PNPLA3 genotype and abdominal fat.