DNA polymorphisms of the insulin receptor gene in Japanese subjects with non-insulin-dependent diabetes mellitus

Genotypes identified by two restriction fragment length polymorphisms (RFLPs) of the insulin receptor gene (IRG) with the restriction endonuclease Sst-1 were determined in a Japanese group comprising 51 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 50 control subjects. Southern hybridization using a probe for the beta subunit of the human IRG identifies 4 alleles, termed S1(+) (5.3 kb), S1(-) (5.8 kb), S2(+) (7.0 and 2.4 kb) and S2(-) (9.4 kb). The frequencies of genotypes possessing the S1(-) allele in Japanese controls and Japanese NIDDM patients were 0.11 and 0.16, respectively. Unlike the previously reported association of the S1(-) allele with NIDDM found in Caucasians there was no significant difference in the frequency of the S1(-) allele between non-diabetic and NIDDM Japanese patients. There was a significant difference in the frequency of the S2(+) allele between Caucasian control subjects (0.14) and Japanese controls (0.0) and NIDDM patients (0.02).     

Rapid screening method of abnormal insulin-receptor gene expression: allele-specific oligonucleotide hybridization by using silent polymorphisms

An asymmetrical reduction in the levels of the insulin receptor mRNA transcribed from one allele was reported in some patients with severe insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM). To detect this abnormality, we designed the less laborious method; Allele-specific oligonucleotide hybridization of the amplified mRNA (cDNA) by using silent polymorphisms in the insulin receptor gene (nucleotide positions at 1686 and 1698). The allelic frequencies of C-1686 and T-1686 were 0.63 and 0.37, respectively (0.60 and 0.40 in 10 normal subjects, and 0.67 and 0.33 in 20 NIDDMs; n.s.). Similarly, the allelic frequencies of A-1698 and G-1698 were 0.47 and 0.53, respectively (0.50 and 0.50 in the normal subjects, and 0.45 and 0.55 in the NIDDMs; n.s.). These results suggest that these two polymorphisms are very common in Japanese. Nineteen (64%) out of 30 cases are heterozygous at one or two position(s), suggesting that it is possible to distinguish the mRNA transcribed from each of two alleles of the insulin receptor gene with using allele-specific oligonucleotide hybridization. Although we successfully measured the ratio of mRNA expression from two alleles of the gene in 20 NIDDMs, there was not patient whose mRNA transcribed from one allele of the insulin receptor gene was extremely decreased. We showed that allele-specific oligonucleotide hybridization method is useful for the screening of abnormal insulin-receptor gene expression.     

Investigation of insulin resistance gene polymorphisms in patients with differentiated thyroid cancer

We aimed to investigate insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), insulin-like growth factor binding protein-3 (IGFBP-3) genotypes, which are thought to be involved in the pathogenesis of many solid tumors and have thus far not been studied in patients with differentiated thyroid cancer (DTC). The study consisted of 93 patients diagnosed with DTC (79 females, 14 males) and 111 healthy control subjects (63 females, 48 males). The anthropometric measurements, lipid profiles, thyroid function tests and homeostatic model assessment (HOMA) as an indicator of insulin resistance (IR) of all patients were recorded. In addition IRS-1, IRS-2 and IGFBP-3 gene polymorphisms were determined by using polymerase chain reaction and restriction fragment length polymorphism. Hardy–Weinberg equilibrium was tested for each gene polymorphisms, and genetic effects were evaluated by the Chi Square test and multiple logistic regression. Homeostasis model assessment of insulin resistance (HOMA-IR), body mass index, waist circumference and serum total cholesterol levels were significantly higher in patients with DTC than in the control group. There was no difference between the two groups with respect to IRS-1, IRS-2 and IGFBP-3 gene polymorphisms. In addition, these gene polymorphisms were found to have no effect on lymph node metastases or tumor staging. While, obesity and increased HOMA-IR may be risk factors in DTC development, we suggest that IRS-1, IRS-2 and IGFBP-3 gene polymorphisms do not play an important role in pathogenesis of DTC.     

Relationship of the angiotensin-converting enzyme gene polymorphism to glucose intolerance, insulin resistance, and hypertension in NIDDM

The deletion (D) allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been shown to be associated with cardiovascular and renal diseases in diabetes mellitus, but the mechanism underlying this association is not known. In addition, recent studies of the effect of the ACE gene on blood pressure have yielded conflicting results. Therefore, we studied the association of the ACE gene I/D polymorphism with glucose intolerance and insulin resistance, and the contribution of this locus to genetic susceptibility to hypertension in non-insulin-dependent diabetic mellitus (NIDDM). We analysed the ACE genotype in 84unrelated NIDDM patients with a known disease duration of less than 1year and in 115age- and sex-matched controls. The I/D polymorphism was determined by the polymerase chain reaction. There were no differences in ACE genotype distribution and allele frequencies between patients with NIDDM and nondiabetic controls. The frequencies of the D and Ialleles in both groups were identical, viz., 0.65 and 0.35, respectively. The NIDDM patients with the DD genotype had significantly higher blood glucose levels in the oral glucose tolerance test than those with the other genotypes; the incremental glucose area under the curve in the order of II, ID, and DD was 7.2 ± 2.4, 9.2 ± 4.0, and 10.7 ± 2.7mmol/l · h (II vs ID vs DD, P=0.0066 by ANOVA). No significant difference was found between the ACE genotype and serum insulin values. Similarly, there were no differences in body mass index, blood pressure, or serum lipids between the three genotypes. Among the nondiabetic controls, there was no statistically significant association of the I/D polymorphism with serum lipids, blood glucose levels, serum insulin concentrations, or blood pressure values. In conclusion, NIDDM patients with the DD genotype have higher blood glucose levels and are more glucose intolerant; this may help to explain the reported association between the Dallele and vascular complications in NIDDM. Received: 15 September 1997 / Accepted: 13 November 1997     

Prevalence of vitamin D receptor gene polymorphism in a Uruguayan population and its relation to type 1 diabetes mellitus

Vitamin D has important immuno-modulatory properties and it influences insulin secretion. It acts through a vitamin D receptor (VDR), for which several gene polymorphisms have been described. The Uruguayan population presents several epidemiological characteristics that make it different from that of other counties, including other Latin-American countries. It went through miscegenation processes, with a tri-hybrid European, Amerindian and African origin, with no contribution from isolated Amerindian communities. Such differences have important consequences for the relationship between frequencies of several genes in the general population and their association with the diabetes mellitus. We examined the prevalence of VDR gene polymorphisms in the general population and their relation to type 1 diabetes in a parent-case design. One hundred unrelated individuals from the general population and 45 parent-patient triads with a child affected with type 1 diabetes were genotyped for FokI, BsmI and TaqI VDR gene polymorphisms by RFLP-PCR. We used a transmission disequilibrium test to assess preferential transmission of parents to affected offspring. The prevalence of the three VDR polymorphisms was: allele F = 48%, B = 35%, T = 64%. The f, b, T alleles and heterozygous genotypes were found at a high frequency in this population. Among 36 informative heterozygous parental genotypes, 30 transmitted the F allele (probability of transmission = 83%). The other two polymorphisms did not show significant transmission. We suggest that FokI polymorphism indicates susceptibility to type 1 diabetes mellitus in the Uruguayan population.     

Altered expression of the two naturally occurring human insulin receptor variants in isolated adipocytes of non-insulin-dependent diabetes mellitus patients.

The human insulin receptor gene is expressed in two variant isoforms which differ by the absence (HIR-A) or presence (HIR-B) of 12 amino acids in the COOH-terminus of the extracellular alpha-subunit as a consequence of alternative splicing of exon 11. Expression of the two variant isoforms is regulated in a tissue-specific manner. In this study, we have measured the levels of the two receptor variants in isolated adipocytes from 10 non-insulin-dependent diabetes mellitus (NIDDM) and 11 normal subjects using an immunological assay, based on the ability of a human anti-receptor autoantibody to discriminate between HIR-A and HIR-B. Results indicate that levels of HIR-B variant are increased in NIDDM patients.     

DNA polymorphism analysis of candidate genes for type 2 diabetes mellitus in a Mexican ethnic group

Type 2 diabetes mellitus is a complex metabolic disorder resulting from the action and interaction of many genetic and environmental factors. It has been reported that polymorphisms in genes involved in the metabolism of glucose are associated with the susceptibility to develop type 2 diabetes mellitus. Although the risk of developing type 2 diabetes mellitus increases with age, as well as with obesity and hypertension, its prevalence and incidence are different among geographical regions and ethnic groups. In Mexico, a higher prevalence and incidence has been described in the south of the country, and differences between urban and rural communities have been observed.We studied 73 individuals from Santiago Jamiltepec, a small indigenous community from Oaxaca State, Mexico. This population has shown a high prevalence of type 2 diabetes mellitus, and the aim of this study was to analyze the relationship between the Pst I (insulin gene), Nsi I (insulin receptor gene) and Gly972Arg (insulin receptor substrate 1 gene) polymorphisms and type 2 diabetes mellitus, obesity and hypertension in this population. Clinical evaluation consisted of BMI and blood pressure measurements, and biochemical assays consisted of determination of fasting plasma insulin and glucose levels. PCR and restriction enzyme digestion analysis were applied to genomic DNA to identify the three polymorphisms. From statistical analysis carried out here, individually, the Pst I, Nsi I and Gly972Arg polymorphisms were not associated with the type 2 diabetes, obese or hypertensive phenotypes in this population. Nevertheless, there was an association between the Nsi I and Pst I polymorphisms and increased serum insulin levels.     

Association of the insulin-receptor variant Met-985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands: a population-based study.

One of the characteristics of non-insulin-dependent diabetes mellitus (NIDDM) is the presence of insulin resistance. Most NIDDM patients have a normal sequence of the insulin receptor, indicating that, if insulin-receptor mutations contribute to the development of NIDDM, they will be present only in a minor fraction of the NIDDM population. The goal of the present study was to examine whether insulin-receptor mutations contribute to the development of NIDDM. We examined 161 individuals with NIDDM and 538 healthy controls from the population-based Rotterdam study for the presence of mutations in the insulin-receptor gene by SSCP. A heterozygous mutation changing valine-985 into methionine was detected in 5.6% of diabetic subjects and in 1.3% of individuals with normal oral glucose tolerance test. Adjusted for age, gender, and body-mass index, this revealed a relative risk for diabetes of 4.49 (95% confidence interval 1.59-12.25) for Met-985 carriers. When the total study group was analyzed, the prevalence of the mutation increased with increasing serum glucose levels (test for trend P < .005). We conclude that the Met-985 insulin-receptor variant associates with hyperglycemia and represents a risk factor for NIDDM.     

High frequency of polymorphism but no mutations found in the GLUT1 glucose transporter gene in NIDDM and familial obesity by SSCP analysis

To evaluate whether a structural defect in the human glucose transporter gene GLUT1 could be involved in the aetiology of insulin resistance, a key factor of non-insulin-dependent diabetes mellitus (NIDDM) and obesity, we performed single-strand conformation polymorphism (SSCP) analysis in 40 subjects (20 NIDDM patients and 20 subjects with familial obesity). The GLUT1 gene, which is involved in basal glucose transport in most tissues, consists of ten exons and encodes a 492 amino acid protein. Population studies have shown a strong association between the X1 allele of an XbaI restriction fragment length polymorphism of the GLUT1 gene and NIDDM. We therefore performed SSCP analysis in NIDDM subjects known to carry at least one X1 allele. Variant SSCP patterns were detected in exons 2, 4, 5 and 9. Sequence analysis of the SSCP variants revealed the presence, in all exons examined, of silent mutations consisting of single-nucleotide substitutions with no amino acid changes. Both NIDDM and obese patients showed a high frequency of polymorphism in the sequence (50% and 35%, respectively). We conclude that the GLUT1 gene is unlikely to play a role in the aetiology of NIDDM and obesity. However, the strong association between the GLUT1 gene and NIDDM, together with the recent family studies showing linkage between chromosome 1p and NIDDM warrant further studies on this chromosomal region. Received: 18 August 1997 / Accepted: 10 December 1997     

Characterization of the insulin resistance in liver cirrhosis: a comparison with non-insulin dependent diabetes mellitus.

To characterize the mechanisms of insulin resistance in liver cirrhosis (LC), we estimated the peripheral tissue sensitivity and responsiveness to insulin using the euglycemic clamp technique and determined the insulin binding to erythrocytes in patients with compensated LC as well as in patients with non-insulin dependent diabetes mellitus (NIDDM). The insulin dose-response curves of the glucose metabolic clearance rates (MCR) were shifted to the right and downward both in patients with LC and NIDDM, indicating a reduced sensitivity and responsiveness to insulin. In the cirrhotics, MCR at the maximally effective insulin level, an index of insulin responsiveness, was correlated with fasting insulin levels (r = -0.57, P < 0.01) and sigma BG in 75 gOGTT (r = -0.43, P < 0.05), but no correlations were found between them and the diabetics. Although specific insulin bindings to erythrocytes were significantly lower in patients both with LC and NIDDM, Scatchard analysis revealed a significant decrease in the number of insulin receptors in the cirrhotics, and a decrease in the empty-site affinity in the diabetics. These findings suggest that insulin resistance in LC consists of a combination of binding and postbinding defects. The latter defect may be caused by basal hyperinsulinemia and contribute to the development of glucose intolerance. Although binding and postbinding abnormalities are also found in NIDDM, the mechanisms of insulin resistance in LC and NIDDM may be different.     

The importance of ERα and ERβ gene polymorphisms in PCOS

Estrogens act through binding to estrogen receptor α (ERα) and β (ERβ). Studies in knockout mice have shown that the absence of ERα leads to the polycystic ovary syndrome (PCOS) phenotype. Furthermore, the expression of ERβ gene is lower in follicles derived from women with PCOS compared with healthy women. The aim of this study was to investigate the importance of ERα and ERβ gene polymorphisms in PCOS. A cohort of 180 women with PCOS and 140 healthy controls were recruited, and the PvuII and XbaI polymorphisms of ERα, as well as, the AluI and RsaI polymorphisms of ERβ were genotyped. No difference was found in the distribution of these polymorphisms between patients and healthy controls. However, in PCOS women, carriers of TC and TT genotypes of PvuII polymorphism had lower fasting glucose to insulin ratio compared with carriers of CC genotype (p = 0.029). In addition, the presence of AA genotype of XbaI polymorphism was associated with lower levels of follicle-stimulating hormone (FSH) compared with the presence of AG and GG genotypes (p = 0.03). The association of ERα polymorphisms with insulin resistance indices and FSH levels emphasizes the importance of ERα as a genetic modifier of the PCOS phenotype.     

A defective intramolecular autoactivation cascade may cause the reduced kinase activity of the skeletal muscle insulin receptor from patients with non-insulin-dependent diabetes mellitus

The insulin receptor purified from skeletal muscle of patients with non-insulin-dependent diabetes mellitus (NIDDM) displayed a 25-55% reduction in insulin-stimulated autophosphorylation and tyrosyl-specific phosphotransferase activity relative to controls. This decrease was not explained by alterations of muscle fiber composition, insulin binding affinity or capacity, or the Km values for ATP; the lower kinase activity was entirely attributed to a decrease in the Vmax of the enzyme. Phosphorylation sites in the beta-subunit of the control and diabetic receptor were identified by tryptic digestion and reverse-phase high performance liquid chromatography. Autophosphorylation occurred primarily in two regions of the beta-subunit: the regulatory region containing Tyr-1146, Tyr-1150, and Tyr-1151, and the C terminus containing Tyr-1316 and 1322. Autophosphorylation of the regulatory region at all three tyrosyl residues (tris-phosphorylation) appears to be necessary to activate the receptor kinase (White, M. F., Shoelson, S. E., Stepman, E. W., Keutmann, H. & Kahn, C. R. (1988) J. Biol. Chem. 263, 2969-2980). The receptor from NIDDM patients showed a decreased level of tris-phosphorylation of the regulatory region which was closely associated (r2 = 0.97) with the decreased kinase activity. In contrast, weak associations were found between kinase activity and the bis-phosphorylated forms of the regulatory region (r2 = 0.51) and the C terminus (r2 = 0.35). Therefore, the reduced formation of the tris-phosphorylated regulatory region in the diabetic receptors suggests that a defective autophosphorylation cascade leading to tris-phosphorylation of the regulatory region may cause, in part, the reduced insulin-stimulated kinase activity of the insulin receptor in muscle of NIDDM patients.     

Is the insulin resistance of patients with noninsulin-dependent diabetes mellitus secondary to insulin deficiency?

Defects in both insulin secretion and action have been documented in patients with noninsulin-dependent diabetes mellitus (NIDDM), leading to the suggestion that both fasting hyperglycemia and insulin resistance in NIDDM are secondary to insulin deficiency. In order to test this hypothesis, insulin secretion (plasma insulin response to oral glucose) and insulin action (insulin clamp) were determined in 25 patients with NIDDM. The results documented relationships between incremental plasma insulin response to glucose and degree of fasting hyperglycemia (r = -.045, P less than 0.05) and insulin-stimulated glucose utilization (r = 0.25, P = NS). These data indicate that differences in insulin secretory response accounted for only approximately 20% of the variance in fasting plasma glucose level and 6% of the variance in insulin resistance in NIDDM. Thus, differences in insulin-secretory response contribute modestly to magnitude of glycemia, and not at all to variations in insulin resistance in NIDDM, permitting rejection of the hypothesis that insulin resistance is secondary to insulin deficiency.     

GLUT-4, tumor necrosis factor, essential fatty acids and daf-genes and their role in insulin resistance and non-insulin dependent diabetes mellitus.

It is now believed that the GLUT-4 receptor, tumor necrosis factor-alpha (TNF-alpha), essential fatty acids (EFAs) and their metabolites and daf-genes have an important role in the development of obesity and non-insulin dependent diabetes mellitus (NIDDM). The protein encoded by daf-2 is 35% identical to the human insulin receptor, daf-7 codes a transforming growth factor-beta (TGF-beta) type signal and daf-16 can enhance superoxide dismutase (SOD) expression. EFAs and their metabolites can alter the cell membrane fluidity and enhance the expression of GLUT-4 and insulin receptors. EFAs can suppress TNF-alpha production and secretion, a mechanism that may have relevance to the role of these fatty acids in the pathogenesis of insulin resistance, obesity and NIDDM. Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. Based on this evidence, it is proposed that GLUT-4, TNF-alpha, EFAs, daf-genes, melatonin and leptin interact with each other in ways which may have relevance to the development or abrogation of insulin resistance, obesity, NIDDM, complications due to NIDDM, longevity and ageing.     

High-frequency DNA sequence polymorphisms in the insulin receptor gene detected by denaturing gradient gel blots.

A limiting factor in the study of genetic determinants of human disorders is the availability of informative DNA markers. In this report, we describe an application of the denaturing gradient gel blot method for detecting high-frequency DNA sequence polymorphisms in the human insulin receptor locus. Using two restriction enzymes and cDNA probes for the insulin receptor, we found five DNA polymorphisms. The probe that contained exons 4-10 of the insulin receptor gene detected two two-allelic polymorphisms in HinfI digests, one at denaturant concentrations of 38%/39% and the other at 46%/48%. The probe that contained exons 14-22 detected three two-allelic polymorphisms in Sau96I digests, the first at denaturant concentrations of 34%/35%, the second at 38%/39%, and the third at 46%/47%. All these DNA polymorphisms segregated in families in a Mendelian fashion, and the allelic distribution for each of them did not deviate from Hardy-Weinberg equilibrium. The identified polymorphisms were in linkage equilibrium and provided sufficient genetic information to determine parental haplotypes at the insulin receptor locus in small two-generation families. The denaturing gradient gel blot method is a very sensitive technique for identifying sequence polymorphisms in genomic DNA; its application will facilitate the search for genes involved in the development of many inherited disorders.     

多巴胺D4受体基因与注意缺损多动障碍

为探讨注意缺损多动障碍（ADHD）与多巴胺D4受体基因（dopamine D4 receptor gene,DRD4)间的关系,采用Amp-FLP的方法检测了上海地区汉族人群中68例ADHD患及其父母DRD4的多态性,数据采用基于单体型的单体型相对风险（HHRR）及传递不平衡检验（TDT）进行遗传关联分析。结果表明HHRR分析和复等位基因的TDT检验,均未显示出与ADHD的遗传关联性（P＞0．05）。提示上海地区人群中DRD4基因与ADHD无显性关联。     

Genetic aspects of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common heterogenous endocrine disorder associated with amenorrhoea (or oligomenorrhoea), hyperandrogenism, hirsutism, obesity, insulin resistance, and an approximately 7-fold increased risk of type 2 diabetes mellitus (NIDDM - non-insulin dependent diabetes mellitus). It is a leading cause of female infertility. The prevalence of PCOS among reproductive-age women has been estimated at 4%-12%. Familial aggregation of this syndrome is well established. There are also ethnic and racial variations in the prevalence of the syndrome and its symptoms. Multiple biochemical pathways have been implicated in the pathogenesis of PCOS. Several genes from these pathways have been tested include genes involved in steroid hormone biosynthesis and metabolism (StAR, CYP11, CYP17, CYP19 HSD17B1-3, HSD3B1-2), gonadotropin and gonadal hormones action (ACTR1, ACTR2A-B, FS, INHA, INHBA-B, INHC, SHBG, LHCGR, FSHR, MADH4, AR), obesity and energy regulation (MC4R, OB, OBR, POMC, UCP2-3), insulin secretion and action (IGF1, IGF1R, IGFBPI1-3, INS VNTR, IR, INSL, IRS1-2, PPARG) and many others. Most women with PCOS, both obese and lean, have a degree of insulin resistance. The minisatellite of insulin gene (INS VNTR), especially class III alleles and III/III genotypes might not only determine the predisposition to anovulatory PCOS but also the concomitant risk for development of type 2 diabetes. The function of the insulin receptor (IR) is probably normal in woman with PCOS. However abnormal serine phosphorylation in the receptor may impair signal transduction accounting for a post-binding defect in insulin action. Serine phosphorylation is also involved in the postranslational regulation of 17,20-lyase activity (CYP17). There may be a common aetiology for both insulin resistance and hyperandrogenism. Polymorphic alleles of both IRS-1 and IRS-2 (insulin receptor substrate 1 - 2), alone or in combination, may have a functional impact on the insulin-resistant component of PCOS. There is no evidence to suggest that follistatin gene polymorphisms play a role in the pathogenesis of insulin resistance in PCOS women. PCOS appears to be associated with the absence of the four-repeat-units allele in a polymorphic region of pentanucleotide (TTTTA)n repeats within CYP11A gene, which encodes cytochrome P450scc. It has been hypothesized that up-regulation of this enzyme could lead to increased androgen production. There is no evidence of any association of alleles of CYP19 gene (encoding cytochrome P450arom) with PCOS. Association exists between androgen receptor gene (AR) polymorphisms an androgens action in PCOS. Increased hirustism and decreased CAG repeat length within AR gene has been also demonstrated in women with normal testosterone levels. Expression of estrogen receptor (ERs) as well as 5-alpha-reeducates (SRD5A1-2 genes) activity was analysed in granulosa (GC) and theca cells (TC). The results of this study demonstrate that there are significant alterations in the expression of ERalpha and ERbeta in PCOS that may be related to abnormal follicular development. On the other hand elevated SRD5A activity in polycystic ovaries supported the hypothesis that 5-alpha-reduced androgens may play a role in the pathogenesis of the syndrome. The genetic aetiology of PCOS remains unknown. There are a number of interlinking factors that affects expression of PCOS. Single cause of PCOS is unlikely. Other possible mechanisms in pathogenesis of PCOS are discussed.     

Insulin continues to induce plasminogen activator inhibitor 1 gene expression in insulin-resistant mice and adipocytes

BACKGROUND: Although the association between insulin resistance and cardiovascular risk is well established, the underlying molecular mechanisms are poorly understood. The antifibrinolytic molecule plasminogen activator inhibitor 1 (PAI-1) is a cardiovascular risk factor that is consistently elevated in insulin-resistant states such as obesity and non-insulin-dependent diabetes mellitus (NIDDM). The strong positive correlation between this elevated PAI-1 and the degree of hyperinsulinemia not only implicates insulin itself in this increase, but also suggests that PAI-1 is regulated by a pathway that does not become insulin resistant. The data in this report supports this hypothesis. MATERIALS AND METHODS: We show that insulin stimulates PAI-1 gene expression in metabolically insulin-resistant ob/ob mice and in insulin-resistant 3T3-L1 adipocytes. Moreover, we provide evidence that glucose transport and PAI-1 gene expression are mediated by different insulin signaling pathways. These observations suggest that the compensatory hyperinsulinemia that is frequently associated with insulin-resistant states, directly contribute to the elevated PAI-1. CONCLUSIONS: These results provide a potential mechanism for the abnormal increases in cardiovascular risk genes in obesity, NIDDM, and polycystic ovary disease.     

Glucocorticoid receptor gene polymorphisms in premenopausal women with major depression.

Glucocorticoid receptor gene polymorphisms are associated with glucocorticoid hypersensitivity and visceral obesity. Perturbations in HPA axis sensitivity to glucocorticoids implicated in the pathogenesis of major depression may result from functional alterations in the glucocorticoid receptor gene. We 1) examined the prevalence of genotype distribution of specific polymorphisms of the glucocorticoid receptor gene (Bcl1, N363S, rs33388, rs33389) in a subset of women from the P.O.W.E.R. Study (which enrolled 21- to 45-year-old premenopausal women with major depression and healthy controls) and 2) explored whether such polymorphisms were associated with visceral obesity and insulin resistance. Women with major depression had a higher body mass index, a higher waist:hip ratio, and more body fat than did controls. No differences were observed in plasma and urinary cortisol or in insulin sensitivity. The G/G genotype of the Bcl1 polymorphism was significantly more common (p<0.03) in women with major depression (n=52) than in controls (n=29). In addition, GG homozygotes (depressed n=10; controls n=2) had higher waist:hip ratios than did non-GG carriers (p<0.02). N363S, rs33388, and rs33389 polymorphisms were not different between groups. In conclusion, premenopausal women with both major depression and the GG genotype of the Bcl1 polymorphism had greater abdominal obesity compared with non-GG carriers.