Appearance Of Insulin Resistance Research Articles

Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases

Oxidized LDL (oxLDL) increase in patients affected by type-2 diabetes, obesity, and metabolic syndrome. Likewise, insulin resistance, an impaired responsiveness of target tissues to insulin, is associated with those pathological conditions. To investigate a possible causal relationship between oxLDL and the onset of insulin resistance, we evaluated the response to insulin of 3T3-L1 adipocytes treated with oxLDL. We observed that oxLDL inhibited glucose uptake (-40%) through reduced glucose transporter 4 (GLUT4) recruitment to the plasma membrane (-70%), without affecting GLUT4 gene expression. These findings were associated to the impairment of insulin signaling. Specifically, in oxLDL-treated cells insulin receptor (IR) substrate-1 (IRS-1) was highly degraded likely because of the enhanced Ser(307)phosphorylation. This process was largely mediated by the activation of the inhibitor of kappaB-kinase beta (IKKbeta) and the c-Jun NH(2)-terminal kinase (JNK). Moreover, the activation of IKKbeta positively regulated the nuclear content of nuclear factor kappaB (NF-kappaB), by inactivating the inhibitor of NF-kappaB (IkappaBalpha). The activated NF-kappaB further impaired per se GLUT4 functionality. Specific inhibitors of IKKbeta, JNK, and NF-kappaB restored insulin sensitivity in adipocytes treated with oxLDL. These data provide the first evidence that oxLDL, by activating serine/threonine kinases, impaired adipocyte response to insulin affecting pathways involved in the recruitment of GLUT4 to plasma membranes (PM). This suggests that oxLDL might participate in the development of insulin resistance.

Stress oxidativo e seus efeitos na insulino-resistência e disfunção das células Beta-pancreáticas: relação com as complicações da diabetes mellitus tipo 2.

Type 2 diabetes mellitus, the most prevalent and serious metabolic disease worldwide, is believed to result from the interaction between genetical and lifestyle factors. In genetically predisposed people, the combination of a hypercaloric ingestion and reduced physical activity is responsible for the appearance of insulin resistance. This state can be overcomed, until a certain point, with increments of insulin secretion (hyperinsulinemia). However, an insufficient compensation leads to a state of glucose intolerance, which can evolve to diabetes, according to actual knowledge. The noxious effects of the hyperglycemia, allied with the possible increase of free fatty acids, are mediated by highly reactive molecules, oxygen and nitrogen free radicals species (ROS and RNS). Recent data suggests that these reactive species are signalling molecules and are involved in the regulation of the cellular function, being its increased production or reduced elimination a cause of oxidative stress. Indeed, those free radicals act directly through oxidative damage on macromolecules (proteins, lipids, DNA) or indirectly, activating single transduction pathways sensible to stress mechanisms. In this review, we will consider the pathways recognized as the more significant in stress mechanisms, namely: NF-kB, JNK/SAPK, p38 MAPK, PKC, AGE/RAGE, hexosamines and poliol. These signalling cascades are believed to be responsible for the insulin resistance and reduced insulin secretion, therefore the use of innocuous antioxidant substances such as vitamin C, E and the a-lipoic acid, is seen as a possible step for type 2 diabetic complications management. We will also discuss acetylsalicylic acid potentialities in the above-mentioned pathologies.

Incidence of and Risk Factors for Insulin Resistance in Treatment-Naive HIV-Infected Patients 48 Weeks after Starting Highly Active Antiretroviral Therapy

to assess the incidence and risk factors for insulin resistance (IR) in a cohort of naive HIV-infected patients 48 weeks after starting highly active antiretroviral therapy (HAART). prospective, two centre, observational, cohort study. One-hundred and thirty-seven patients who started HAART and maintained the same regimen for 48 weeks were included. IR was determined by the homeostasis model assessment (HOMA-IR) method. Individuals with a HOMA-IR value >3.8 were defined as insulin resistant. Independent associations with the development of IR at 48 weeks were evaluated. Seventeen (12.4%) individuals showed a HOMA-IR value >3.8 at baseline and were excluded for incidence analyses. Fifteen patients developed IR at 48 weeks of HAART, giving an incidence of 13%. Independent predictors of the development or IR were indinavir exposure (beta-coefficient 5.45, 95% confidence interval [CI] 1.30-22.8; P=0.02), and hepatitis C virus (HCV) antibody positivity (beta-coefficient 5.22, 95% CI 1.34-20.33; P=0.01). The appearance of IR was associated with a higher BMI (beta-coefficient 1.72 for each 2 kg/m2 increase, 95% CI 1.54-1.94; P=0.02) and with the presence of lipodystrophy at 48 weeks (beta-coefficient 5.59, 95% CI 1.45-21.5; P=0.01). HAART induces the development of IR in previously naive non-insulin-resistant HIV-infected individuals, with an incidence of 13% in the first year of therapy. Indinavir exposure, and HCV coinfection are associated with an increased risk of developing IR.

Mannose-binding lectin gene polymorphisms are associated with gestational diabetes mellitus.

Insulin resistance is a feature of gestational diabetes mellitus (GDM). Inverse correlations between indexes of insulin sensitivity and serum markers of inflammation have been observed and, particularly, TNF-alpha has been shown to be associated with the appearance of insulin resistance in pregnancy. Mannose-binding lectin (MBL) is a protein member of the collectin family. Its deficiency is genetically determined and predisposes to recurrent infections and chronic inflammatory diseases. To test the hypothesis that a genetic predisposition to a proinflammatory state could favor the appearance of GDM during pregnancy, we studied R52C and G54D polymorphisms of MBL2 gene and plasma MBL levels from 105 consecutive GDM women and 173 healthy pregnant women. An association was found between G54D and GDM [odds ratio, 2.03 (1.18-3.49); P < 0.01], and this association remained significant when the presence of both mutated alleles was considered [odds ratio, 1.76 (1.04-2.96); P < 0.05] but not for the R52C. GDM patients who carried the G54D mutation required insulin therapy more frequently (56.4 vs. 30.4%, chi(2) =5.83; P = 0.027) and had heavier infants (3326.4 +/- 546.9 vs. 3087.5 +/- 395.5 g; P < 0.05) than GDM women homozygous for the wild-type allele. An inverse correlation in GDM patients between neonatal weight and plasma MBL levels (r = -0.320; P = 0.002) was found, remaining significant after adjustment for confounding variables. In conclusion, pregnant women bearing the G54D MBL allele have a greater risk for developing GDM and having heavier infants.

Insulin resistance precedes the appearance of albuminuria in non-diabetic subjects: 6 years follow up study

Microalbuminuria is a marker of increased risk of cardiovascular mortality in type 1 and type 2 diabetes, and in non-diabetic subjects. Little is known about the association between prospective changes of microalbuminuria and the risk factors of atherosclerosis, or gene polymorphism in non-diabetic subjects. We conducted a 6-year prospective study of risk factors for progression of albuminuria in non-diabetic subjects. The participants were 116 non-diabetic subjects who consecutively underwent medical examinations for Japanese-Americans living in Hawaii. In the baseline examination in 1992, normoalbuminuria was found in all subjects. After 6 years, 101 subjects remained normoalbuminuria (non-progressors), 15 subjects changing from normoalbuminuria to microalbuminuria or proteinuria and were defined as progressors. In progressors, compared with non-progressors, the fasting insulin level and HOMA-R were significantly higher at 3 years follow-up, and the systolic and diastolic pressure and Σ insulin level were significantly higher at 6 years follow-up. Insulin resistance appeared earlier than the appearance of hypertension and albuminuria. In progressors, there was no significant correlation with angiotensin-converting enzyme (ACE) genotype or angiotensinogen (AGT) genotype compared with non-progressors. Therefore, the appearance of insulin resistance should be regarded as a remarkable mediator of albuminuria.