Search PubMed⌕ Search

Biomedical subjects

Fausto Machicao

Publications and source records attributed to Fausto Machicao.

9 recordsLinked to original sources
PubMed2003

Increased insulin clearance in peroxisome proliferator-activated receptor gamma2 Pro12Ala.

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPARgamma(2)) is associated with reduced risk for type 2 diabetes. Although increased insulin sensitivity of glucose disposal and lipolysis has been reported, the exact mechanism by which the risk reduction is conferred is not clear. Because the conclusion of greater insulin sensitivity hinged upon lower insulin levels in some studies, it is possible that more efficient insulin clearance is involved. We therefore estimated insulin clearance during a euglycemic hyperinsulinemic clamp (insulin infusion rate divided by steady-state insulin concentration, 229 normal glucose tolerant [NGT] subjects), an oral glucose tolerance test (OGTT) (mean C-peptide divided by mean insulin concentrations, 406 NGT, 54 impaired glucose tolerant or mildly diabetic subjects), and a hyperglycemic clamp (120 minutes, 10 mmol/L, C-peptide divided by insulin in the steady-state, 56 NGT subjects). In the carriers of the Ala allele (prevalence approximately 24%), insulin clearance in all 3 protocols was significantly greater ( approximately 10%), than in controls. While the results from the euglycemic clamp reflect both hepatic and peripheral insulin clearance, those from the OGTT and the hyperglycemic clamp reflect mainly hepatic insulin extraction. Free fatty acids (FFA) during the steady state of the euglycemic hyperinsulinemic clamp were significantly lower in carriers of the Ala allele (26 +/- 5 micromol/L) than in controls (46 +/- 3 micromol/L, P =.02). In conclusion, the Pro12Ala polymorphism is associated with increased insulin clearance. This could be the result of reduced FFA delivery, which has been shown to improve hepatic insulin removal and sensitivity. Because PPARgamma(2) is mainly expressed in adipose tissue, one of the main regulatory effects of the polymorphism may well be the more efficient suppression of (possibly intra-abdominal) lipolysis.

Adult↗
PubMed2003

Assessing the shape of the glucose curve during an oral glucose tolerance test.

OBJECTIVE: The oral glucose tolerance test (OGTT) is used to define the status of glucose tolerance based on the plasma glucose level at 120 min. The purpose of the present study was to identify parameters that determine the shape of the plasma glucose course measured at 0, 30, 60, 90, and 120 min during an OGTT. RESEARCH DESIGN AND METHODS: OGTT data from 551 subjects (485 with normal glucose tolerance [NGT] and 66 with impaired glucose tolerance [IGT]) were analyzed. We distinguished between "monophasic," "biphasic," and unclassified glucose shapes. A "shape" index based on the extent and the direction of the plasma glucose change in the second hour allowed us to treat shape as a continuous variable. RESULTS: In the biphasic group, the NGT-to-IGT ratio was slightly higher (173/20 vs. 209/40, P = 0.08) and the male-to-female ratio was lower (60/133 vs. 120/129, P = 0.0003). Subjects with a biphasic shape had significantly lower age, BMI, waist-to-hip ratio (WHR), HbA(1c), plasma glucose, and area under the insulin curve (insulin(AUC)) and a better estimated insulin sensitivity and secretion (using validated indexes) than monophasic subjects (all P < 0.05). By adjusting this shape index for glucose(AUC) (as continuous measure of glucose tolerance), correlations with age, BMI, WHR, HbA(1c), and insulin(AUC) were completely abolished. The adjusted shape index was still higher in female than in male subjects but lower in IGT than in NGT subjects (both P = 0.0003). Finally, we tested common polymorphisms in insulin receptor substrate (IRS)-1, IRS-2, calpain-10, hepatic lipase, and peroxisome proliferator-activated receptor-gamma for association with the shape index. CONCLUSIONS: We conclude that the plasma glucose shape during an OGTT depends on glucose tolerance and sex. In addition, genetic factors seem to play a role. The shape index may be a useful metabolic screening parameter in epidemiological and genetic association studies.

Administration, Oral↗
PubMed2002

Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes.

The adipocyte-derived hormone adiponectin seems to protect from insulin resistance, a key factor in the pathogenesis of type 2 diabetes. Genome-wide scans have mapped a susceptibility locus for type 2 diabetes and the metabolic syndrome to chromosome 3q27, where the adiponectin gene is located. A common silent T-G exchange in nucleotide 94 (exon 2) of the adiponectin gene has been associated with increased circulating adiponectin levels. Metabolic abnormalities associated with the G allele have not been reported. We therefore assessed whether this polymorphism alters insulin sensitivity and/or measures of obesity using the Tübingen Family Study database (prevalence of the G allele, 28%). In 371 nondiabetic individuals, we found a significantly greater BMI in GG + GT (25.5 +/- 0.7 kg/m(2)) compared with TT (24.1 +/- 0.3 kg/m(2); P = 0.02). Insulin sensitivity (determined by euglycemic clamp, n = 209) was significantly lower in GG + GT (0.089 +/- 0.007 units) compared with TT (0.112 +/- 0.005 units; P = 0.02). This difference disappeared completely on adjustment for BMI. Because our population contains a relatively high proportion of first-degree relatives of patients with type 2 diabetes, we stratified by family history (FHD). Much to our surprise, the genotype differences in BMI and insulin sensitivity in the whole population were attributable entirely to differences in the subgroup without FHD, whereas in the subgroup with FHD, the G allele had absolutely no effect. Moreover, individuals without FHD had a significantly lower BMI than individuals with FHD (25.2 +/- 0.4 vs. 26.2 +/- 0.5 kg/m(2); P = 0.01), which was not the case for the GG + GT subgroup without FHD (27.0 +/- 0.9 kg/m(2); NS). This suggests that in individuals without familial predisposition for type 2 diabetes, the adiponectin polymorphism may mildly increase the obesity risk (and secondarily insulin resistance). In contrast, in individuals who are already burdened by other genetic factors, this small effect may be very hard to detect.

Adipocytes↗
PubMed2002

Troglitazone downregulates delta-6 desaturase gene expression in human skeletal muscle cell cultures.

Delta-6 Desaturase, one of the rate-limiting enzymes, catalyzes the conversion of linoleic acid (C18:2 omega6) into gamma-linolenic acid (C18:3 omega6), arachidonic acid (C20:4 omega6), and further metabolites. Recently, it has been shown that human Delta-6 desaturase is expressed not only in liver but in a variety of human tissues, including muscle. Skeletal muscle is a major site of insulin action, and insulin sensitivity may be related to the fatty acid composition of muscle lipids. We examined the effects of troglitazone on the regulation of Delta-6 desaturase gene expression in human muscle cell cultures obtained from muscle biopsies (n = 15). Delta-6 Desaturase mRNA and peroxisome proliferator-activated receptor gamma2 (PPARgamma2) mRNA were quantified by two-step RT-PCR, and the activity of the Delta-6 desaturase enzyme was estimated by gas chromatographic analysis of the omega 6-C18:3/C18:2 fatty acids ratio. In cells treated with 11.5 micromol troglitazone for 4 days, PPARgamma2 mRNA levels were significantly increased (301.0 +/- 51.5%, P < 0.05) and Delta-6 desaturase mRNA levels were significantly decreased (41.7 +/- 5.9%, P < 0.0005) compared with the untreated controls. In accordance with the decrease of Delta-6 desaturase mRNA, there was a significant decrease in the omega6-C18:3/C18:2 ratio down to 47.4 +/- 7.5% in cholesterol esters, 54.2 +/- 7.4% in phospholipids, 56.7 +/- 6.5% in nonesterified fatty acids, and 67.7 +/- 5.9% in triglycerides. The troglitazone-induced decrease in Delta-6 desaturase mRNA is associated with a change in the unsaturated fatty acid composition of the muscle cells. These results add new aspects to the known thiazolidinedione effects on lipid metabolism.

Adult↗
PubMed2002

The prevalent Glu23Lys polymorphism in the potassium inward rectifier 6.2 (KIR6.2) gene is associated with impaired glucagon suppression in response to hyperglycemia.

Genetic factors play an important role in the pathogenesis of type 2 diabetes. The relevance to type 2 diabetes of the common polymorphism Glu23Lys in the potassium inward rectifier 6.2 (KIR6.2) gene is still controversial. The aim of this study was to assess whether this polymorphism influences beta-cell function, alpha-cell function, or insulin action. We therefore studied 298 nondiabetic subjects using an oral glucose tolerance test (OGTT) and 75 nondiabetic subjects using a hyperglycemic clamp (10 mmol/l) with additional glucagon-like peptide (GLP)-1 and arginine stimulation. The prevalence of the Lys allele was approximately 37%, and the Lys allele was associated with higher incremental plasma glucose during the OGTT (P = 0.03, ANOVA). Neither first- nor second-phase glucose-stimulated C-peptide secretion was affected by the presence of the polymorphism; nor were maximal glucose-, GLP-1-, or arginine-induced C-peptide secretion rates; nor was insulin sensitivity (all P > 0.7). However, the relative decrease in plasma glucagon concentrations during the 10 min after the glucose challenge was reduced in carriers of the Lys allele (10 +/- 3% decrease from baseline in Lys/Lys, 18 +/- 2% in Glu/Lys, and 20 +/- 2% in Glu/Glu; P = 0.01, ANOVA). In conclusion, our findings suggest that the common Glu23Lys polymorphism in KIR6.2 is not necessarily associated with beta-cell dysfunction or insulin resistance but with diminished suppression of glucagon secretion in response to hyperglycemia. Our findings thus confirm its functional relevance for glucose metabolism in humans.

Adult↗
PubMed2002

Retraction.

Explore the source record for details and available documents.

Retraction Notice↗
PubMed2001

Interaction effect between common polymorphisms in PPARgamma2 (Pro12Ala) and insulin receptor substrate 1 (Gly972Arg) on insulin sensitivity.

The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma2 gene is associated with a reduced risk of type 2 diabetes. A beneficial effect on insulin sensitivity is reported in some but not all populations. It is possible that this genetic variant produces a characteristic phenotype only against a certain genetic background. We therefore tested the hypothesis that carriers of the Ala allele of PPARgamma2 exhibit a different phenotype against the background of the Gly972Arg polymorphism in the insulin receptor substrate (IRS) 1. We determined insulin sensitivity in the four combinations defined by the absence or presence of the polymorphic allele (healthy, glucose tolerant subjects), by the oral glucose tolerance test (OGTT; using a validated index, n=318) and hyperinsulinemic clamp ( n=201). Insulin sensitivity was not or was only marginally different between Pro/Pro and X/Ala in the overall population. Interestingly, using the OGTT index, insulin sensitivity was significantly greater in X/Ala (PPARgamma2) + X/Arg (IRS-1) than in Pro/Pro (PPARgamma2) + X/Arg (IRS-1). On the other hand, insulin sensitivity was similar in the X/Ala (PPARgamma2) + Gly/Gly (IRS-1 972) and the Pro/Pro (PPARgamma2) + Gly/Gly (IRS-1). The results were practically identical using insulin sensitivity from the clamp. In conclusion, the Arg972 (IRS-1) background produced a marked difference in insulin sensitivity between X/Ala and Pro/Pro (PPARgamma) which was not present in the whole population or against the Gly972 (IRS-1) background. This suggests that the Ala allele of PPARgamma2 becomes particularly advantageous against the background of an additional, possibly disadvantageous genetic polymorphism. Allowing for gene-gene interaction effects may reveal novel information regarding metabolic effects of genetic variants.

Amino Acid Substitution↗