[Show abstract][Hide abstract] ABSTRACT: To study 5-year change in computed tomography (CT)-derived visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) associated with sleep duration in 2 minority groups.
Longitudinal epidemiologic study.
Three US communities.
African Americans (N = 332) and Hispanic Americans (N = 775), aged 18-81 years, participating in the IRAS Family Study.
Abdominal CT scans and BMI obtained at a 5-year interval. Sleep duration was assessed by questionnaire at baseline and categorized as < or = 5 h, 6-7 h, and > or = 8 h. Generalized estimating equations assessed the association between sleep duration and 5-year fat accumulation with adjustment for age, race, gender, study site, baseline fat measure, physical activity, total calories, smoking status, and education. Age interacted with sleep duration to predict change in fat measures (P < 0.01). In those younger than 40 years, < or = 5 h of sleep was related to a greater accumulation of BMI (1.8 kg/m2, P < 0.001), SAT (42 cm2, P < 0.0001), and VAT (13 cm2, P > 0.01), compared to sleep duration between 6 and 7 h. Eight hours or more of sleep was also significantly related to a greater accumulation of BMI (0.8 kg/m2, P < 0.001), SAT (20 cm2, P < 0.01) and VAT (6 cm2, P < 0.05) compared to sleep duration between 6 and 7 h. No significant relationship existed between sleep duration and fat depot change in participants older than 40 years old.
In this minority cohort, extremes of sleep duration are related to increases in BMI, SAT, and VAT in persons younger than 40 years old.
[Show abstract][Hide abstract] ABSTRACT: To test the hypothesis that the thiazolidinedione agent, pioglitazone, mediates its chronic BP lowering action via improving vascular reactivity.
Lean (Fa/fa) and obese (fa/fa) Zucker rats were treated with or without pioglitazone (20 mg/ kg/day) for 4 weeks (n=8 animals per group). Pioglitazone treatment was associated with a significant improvement in oral glucose tolerance in the obese animals (p<0.05 compared with untreated obese). Pioglitazone prevented the development of hypertension seen in obese untreated rats (SBP 126+/-1 versus 138+/-1 mmHg; p<0.0001). Aortic ring preparations from pioglitazone-treated obese rats showed improved relaxation responsiveness (ED(50) 0.28 versus 1.15 U/ ml, p<0.001) to SOD, a NO potentiator, compared with untreated obese animals.
SOD-mediated vasorelaxation may contribute to the chronic antihypertensive effect and/or the improvement in insulin sensitivity following pioglitazone treatment.
[Show abstract][Hide abstract] ABSTRACT: Evaluate discs large homolog 2 (DLG2) as a positional candidate gene for disposition index (DI) in the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) African-American sample.
SNPs (n=193) were selected for genotyping in 580 African-American individuals using a modified tagging algorithm. Follow-up genotyping was carried out within regions associated with DI. A subset of highly associated, uncorrelated SNPs was used as covariates in the linkage analysis to assess their contribution to linkage.
Evidence of association with DI was observed at the DLG2 locus (admixture-adjusted P=0.050-8.7 x 10(-5)) with additional signals observed in follow-up genotyping of 17 SNPs (P=0.033-0.0012). Inclusion of highly associated, uncorrelated SNPs as covariates in the linkage analysis explained linkage at the DLG2 locus (90.8 cM) and reduced the maximal LOD score (72.0 cM) from 4.37 to 3.71.
Evidence of association and an observed contribution to evidence for linkage to DI was observed for SNPs in DLG2 genotyped on the African-American individuals from the IRAS-FS. Although not the only gene in the region, these results suggest that variation at the DLG2 locus contributes to maintenance of glucose homeostasis through regulation of insulin sensitivity and beta-cell function as measured by DI.
Diabetes research and clinical practice 11/2009; 87(1):69-76. DOI:10.1016/j.diabres.2009.10.015 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Central obesity, insulin resistance and beta cell dysfunction are independent risk factors for incident type 2 diabetes, although few studies have used detailed measures of these disorders. Our objective was to study the association of directly measured visceral and subcutaneous adipose tissue (VAT, SAT), insulin sensitivity (S (I)) and the acute insulin response (AIR) with incident type 2 diabetes.
Participants were 1,230 Hispanic-Americans and African-Americans in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study who were free of type 2 diabetes at baseline (2000-2002). S (I) and AIR were determined from frequently sampled IVGTTs with minimal model analysis. VAT and SAT were determined by computed tomography. Impaired fasting glucose and type 2 diabetes were defined according to American Diabetes Association criteria.
Incident type 2 diabetes was diagnosed in 90 participants after 5 years. After adjustment for age, sex, ethnicity, centre, impaired fasting glucose, triacylglycerol, HDL-cholesterol and systolic BP, both S(I) and AIR were inversely associated with type 2 diabetes (S (I), OR 0.53, 95% CI 0.39-0.73; AIR, OR 0.22, 95% CI 0.14-0.34 per SD; both p < 0.001), while both VAT and SAT were positively associated with type 2 diabetes (VAT, OR 1.68, 95% CI 1.22-2.33; SAT, OR 1.49, 95% CI 1.13-1.99; both p < 0.01). In a model including all four factors, S (I) and AIR (S (I), OR 0.55, 95% CI 0.37-0.80; AIR, OR 0.21, 95% CI 0.13-0.33; both p < 0.01) were significant predictors of type 2 diabetes, although associations with VAT and SAT were no longer significant. A significant sex x VAT interaction indicated a stronger association of VAT with type 2 diabetes in women than in men.
Insulin resistance, beta cell dysfunction and VAT predicted incident type 2 diabetes, with evidence of a stronger association of VAT with type 2 diabetes among women.
[Show abstract][Hide abstract] ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and insulin resistance. The condition disproportionately affects Hispanic Americans. The aims of this study were to examine the risk factors and heritability of NAFLD in 795 Hispanic American and 347 African-American adults participating in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study. Computed tomography (CT) scans of the abdomen were evaluated centrally for measures of liver-spleen (LS) density ratio and abdominal fat distribution. Other measures included insulin sensitivity (SI) calculated from a frequently sampled intravenous glucose tolerance test and various laboratory measures. Statistical models which adjust for familial relationships were estimated separately for the two ethnic groups. Heritability was calculated using a variance components approach. The mean age of the cohort was 49 years (range 22-84); 66% were female. NAFLD (LS ratio<1) was more common in Hispanic Americans (24%) than African Americans (10%). NAFLD was independently associated with SI and visceral adipose tissue (VAT) area in both ethnic groups, although the proportion of explained variance was considerably higher in the Hispanic models. Adiponectin contributed significantly in the African-American models whereas triglycerides (TGs) and plasminogen activator inhibitor 1 (PAI-1) contributed only in the Hispanic models. Liver density was modestly heritable in both ethnic groups (h2 approximately 0.35). In summary, the prevalence of NAFLD was twofold greater in Hispanic than African Americans. Certain correlates of NAFLD were similar between the ethnic groups, whereas others were distinct. NAFLD was modestly heritable. These findings suggest that NAFLD may have a differing environmental and/or genetic basis in these ethnic groups.
[Show abstract][Hide abstract] ABSTRACT: Previous studies have suggested vitamin D insufficiency is associated with increased obesity; however, the relationship between 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH](2)D) and measures of adiposity has not been well characterized in minority populations.
The objective of the study was to examine the relationship between levels of 25[OH]D and 1,25[OH](2)D and measures of adiposity in Hispanic and African-Americans at baseline and on change in these measures over time.
The Insulin Resistance Atherosclerosis (IRAS) Family Study examined 917 Hispanics and 439 African-Americans at baseline and again 5.3 yr later (n = 1081 at follow-up).
25[OH]D (nanograms per milliliter) and 1,25[OH](2)D (picograms per milliliter) were measured at baseline. Abdominal sc adipose tissue (SAT), visceral adipose tissue (VAT; both determined by computed tomography scan), and body mass index (BMI) were measured at baseline and follow-up.
25[OH]D was inversely associated with BMI, VAT, and SAT in both populations at baseline (P < 0.001). 25[OH]D was marginally inversely associated with baseline visceral fat to sc fat ratio in African-Americans (P = 0.049) but not Hispanics. 1,25[OH](2)D was inversely associated with BMI (P < 0.0001, P = 0.002) and VAT (P = 0.0005, P = 0.012) in Hispanics and African-Americans, respectively, whereas 1,25[OH](2)D was inversely associated with SAT in Hispanics (P < 0.0001) and with visceral fat to sc fat ratio in African-Americans (P = 0.02). Adjusting for 25[OH]D attenuated these associations; 1,25[OH](2)D remained associated with BMI in both populations (P < 0.05) and with SAT (P = 0.004) in Hispanics. No significant associations between 5-yr change in adiposity and 25[OH]D or 1,25[OH](2)D were seen. Conclusions: Vitamin D levels were inversely associated with baseline BMI, SAT, and VAT in Hispanic and African-Americans but were not associated with 5-yr change in adiposity.
The Journal of Clinical Endocrinology and Metabolism 06/2009; 94(9):3306-13. DOI:10.1210/jc.2009-0079 · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several observational studies have recently suggested an inverse association of circulating levels of vitamin D with blood pressure. These findings have been based mainly on Caucasian populations; whether this association also exists among Hispanic and African Americans has yet to be definitively determined. This study investigates the association of 25-hydroxyvitamin D (25[OH]D) with blood pressure in Hispanic and African Americans.
The data source for this study is the Insulin Resistance Atherosclerosis Family Study (IRASFS), which consists of Hispanic- and African-American families from three US recruitment centers (n =1,334). A variance components model was used to analyze the association of plasma 25[OH]D levels with blood pressure.
An inverse association was found between 25[OH]D and both systolic (beta for 10 ng/ml difference = -2.05; P < 0.01) and diastolic (beta for 10 ng/ml difference = -1.35; P < 0.001) blood pressure in all populations combined, after adjusting for age, sex, ethnicity, and season of blood draw. Further adjustment for body mass index (BMI) weakened this association (beta for 10 ng/ml difference = -0.94; P = 0.14 and beta for 10 ng/ml difference = -0.64; P = 0.09, respectively).
25[OH]D levels are significantly inversely associated with blood pressure in Hispanic and African Americans from the IRASFS. However, this association was not significant after adjustment for BMI. Further research is needed to determine the role of BMI in this association. Large, well-designed prospective studies of the effect of vitamin D supplementation on blood pressure may be warranted.
American Journal of Hypertension 06/2009; 22(8):867-70. DOI:10.1038/ajh.2009.88 · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE
To describe the 5-year change in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas.
RESEARCH DESIGN AND METHODS
Absolute change in VAT and SAT measured by abdominal computed tomography scans has been obtained at a 5-year interval from African Americans (n = 389) and Hispanic Americans (n = 844), aged 20–69 years, in 10-year age-groups.
Mean 5-year increases in VAT areas in women were 18, 7, 4, 0.4, and −3 cm2 for African Americans and 13, 7, 3, 1, and −15 cm2 for Hispanics, across the 5 age decades (trend not significant). Mean 5-year increases in SAT areas in women were 88, 46, 19, 17, and 14 cm2 for African Americans and 53, 20, 17, 12, and 1 cm2 for Hispanics, across the 5 age decades (P < 0.05 for both). Similar trends have been observed in men.
Accumulation of abdominal fat is greatest in young adulthood. These data may be useful in identifying subgroups at risk of type 2 diabetes.
Diabetes care 06/2009; 32(8):1553-5. DOI:10.2337/dc09-0336 · 8.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study sought to identify genes and regions in the human genome that are associated with the acute insulin response to glucose (AIRg), an important predictor of type 2 diabetes, in Hispanic-American participants from the Insulin Resistance Atherosclerosis Family Study (IRAS FS).
A two-stage genome-wide association scan (GWAS) was performed in IRAS FS Hispanic-American samples. In the first stage, 317K single nucleotide polymorphisms (SNPs) were assessed in 229 Hispanic-American DNA samples from 34 families from San Antonio, TX, USA. SNPs with the most significant associations with AIRg were genotyped in the entire set of IRAS FS Hispanic-American samples (n = 1,190). In chromosomal regions with evidence of association, additional SNPs were genotyped to capture variation in genes.
No individual SNP achieved genome-wide levels of significance (p < 5 x 10(-7)); however, two regions (chromosomes 6p21 and 20p11) had multiple highly ranked SNPs that were associated with AIRg. Additional genotyping in these regions supported the initial evidence of variants contributing to variation in AIRg. One region resides in a gene desert between PXT1 and KCTD20 on 6p21, while the region on 20p11 has several viable candidate genes (ENTPD6, PYGB, GINS1 and RP4-691N24.1).
A GWAS in Hispanic-American samples identified several candidate genes and loci that may be associated with AIRg. These associations explain a small component of variation in AIRg. The genes identified are involved in phosphorylation and ion transport, and provide preliminary evidence that these processes are important in beta cell response.
[Show abstract][Hide abstract] ABSTRACT: We report a patient with type 2 diabetes mellitus who, while treated with the antitumor necrosis factor-alpha blocking agent etanercept for severe plaque psoriasis, experienced persistent hypoglycemia requiring the lowering and eventual elimination of his previous insulin regimen. After 20 months of therapy on etanercept, his plaque psoriasis markedly improved, whereas both his fasting blood sugars and glycosylated hemoglobin A(1c) decreased. Hypoglycemia can be a serious side effect of etanercept in patients already on antidiabetic medications known to cause hypoglycemia, such as sulfonylureas, meglitinides, and insulin. Thus, it is important for dermatologists treating patients with diabetes and antitumor necrosis factor-alpha agents for psoriasis to be aware of potential hypoglycemia and to adjust antidiabetes therapy accordingly.
Journal of the American Academy of Dermatology 03/2009; 60(6):1032-6. DOI:10.1016/j.jaad.2008.12.012 · 5.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ATP-sensitive potassium channels are composed of pore-forming (Kir6.x) and regulatory sulfonylurea receptor (SURx) subunits and have been implicated in the maintenance of glucose homeostasis. Kir6.2 and SUR1 are expressed in a broad range of tissues, and no contemporary studies have addressed the physiological impact of variants in Hispanic-Americans and African-Americans carefully phenotyped for components of glucose homeostasis.
The objective of this study was to evaluate two nonsynonymous variants in Kir6.2 (E23K) and SUR1 (A1369S) and determine their role in vivo.
The Insulin Resistance Atherosclerosis Family Study (IRAS-FS) is a community-based study of Hispanic-Americans (San Antonio, TX, and San Luis Valley, CO) and African-Americans (Los Angeles, CA).
A total of 1,040 Hispanic-Americans and 500 African-American individuals formed the basis of this study.
The primary glucose homeostasis phenotypes of interest in this study were derived from the frequently sampled iv glucose tolerance test and included insulin sensitivity (S(I)), acute insulin response, and disposition index. Results: In African-Americans, both variants were associated with a significant reduction in insulin secretion in glucose-tolerant carriers of the minor alleles (additive P = 0.00053). S(I), a measure of insulin sensitivity, was not associated. In Hispanic-Americans, there was no association with measures of glucose homeostasis.
We conclude that variation marked by the Kir6.2 E23K and SUR1 A1369S mutations is associated with alterations in glucose-stimulated insulin secretion but not with other measures of glucose homeostasis in an African-American population.
[Show abstract][Hide abstract] ABSTRACT: We examined the relationship between visceral adipose tissue (VAT), independent of overall adiposity, and prevalent hypertension among adults enrolled in the Insulin Resistance Atherosclerosis (IRAS) Family Study. We also examined the role of insulin sensitivity (S(I)) upon hypertension. This was a cross-sectional epidemiological study in which African-American and Hispanic-American families were recruited from three clinical sites. The main outcome measure was prevalent hypertension, as defined by standardized protocol.
The relationship between VAT and prevalent hypertension was examined in adjusted marginal models among 1,582 participants. All continuous variables were standardized.
A significant VAT by gender interaction prompted separate analyses for VAT according to gender. Further adjustment for S(I) was performed to determine its potential roles in the VAT-hypertension relationship. The mean age (s.d.) of the sample was 41.3 (13.8) years, with a mean body mass index (BMI) (s.d.) of 28.7 (6.0) kg/m2. Women comprised 58.5% of the sample (N = 925), and Hispanic Americans comprised 69.2% of the sample (N = 1,095). One in five participants (21.2%) had prevalent hypertension. In women, VAT was significantly associated with hypertension, independent of BMI (odds ratio (OR) = 1.49, P = 0.006). African-American women demonstrated increased odds of prevalent hypertension compared to Hispanic-American women (OR = 3.08, P < 0.001). Among men, VAT was not associated with hypertension independent of BMI, and BMI explained a significant amount of the variation in hypertension.
A significant relationship may exist between VAT and hypertension among women, but not among men. The relationship between VAT and hypertension in women was not associated with insulin resistance.
American Journal of Hypertension 06/2008; 21(8):910-6. DOI:10.1038/ajh.2008.213 · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Evaluate type 2 diabetes susceptibility variants identified from genome-wide association studies in Hispanic Americans and African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) for association with quantitative measures of glucose homeostasis and determine their biological role in vivo.
Seventeen type 2 diabetes-associated single nucleotide polymorphisms (SNPs) were genotyped in 1,268 Hispanic- and 581 African-American participants from the IRAS-FS. SNPs were tested for association with quantitative measures of glucose homeostasis, including insulin sensitivity index (S(I)), acute insulin response (AIR), and disposition index.
Previously identified risk variants in cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1 (CDKAL1) were associated with reduced AIR (P < 0.0046) in Hispanic Americans. Additionally in Hispanic Americans, the variant in a hypothetical gene (chromosome 11; LOC387761) was significantly associated with AIR (P = 0.0046) with the risk allele showing protective effects, i.e., increased AIR. In both Hispanic- and African-American populations, risk variants at the solute carrier family 30, member 8 (SLC30A8) locus were nominally associated with decreased disposition index (P < 0.078). Risk variants in the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) locus were associated with a decreased disposition index (P = 0.011) exclusively in Hispanic Americans.
These data indicate a distinct, limited number of diabetes-related genes, more specifically the SNPs in the genes identified in European-derived populations, with modest evidence for association with glucose homeostasis traits in Hispanic Americans and African Americans. We observe evidence that diabetes risk for CDKAL1, SLC30A8, IGF2BP2, and LOC387761 is specifically mediated through defects in insulin secretion. The mechanisms of other predisposing genes remain to be elucidated.
[Show abstract][Hide abstract] ABSTRACT: We previously detected an association between a region of the estrogen receptor-alpha (ESR1) gene and type 2 diabetes in an African-American case-control study; thus, we investigated this region for associations with the metabolic syndrome and its component traits in African-American families from the Insulin Resistance Atherosclerosis Family Study.
A total of 17 single nucleotide polymorphisms (SNPs) from a contiguous 41-kb intron 1-intron 2 region of the ESR1 gene were genotyped in 548 individuals from 42 African-American pedigrees. Generalized estimating equations were computed using a sandwich estimator of the variance and exchangeable correlation to account for familial correlation.
Significant associations were detected between ESR1 SNPs and the metabolic syndrome (P = 0.005 to P = 0.029), type 2 diabetes (P = 0.001), insulin sensitivity (P = 0.0005 to P = 0.023), fasting insulin (P = 0.022 to P = 0.033), triglycerides (P = 0.021), LDL (P = 0.016 to P = 0.034), cholesterol (P = 0.046), BMI (P = 0.016 to P = 0.035), waist circumference (P = 0.012 to P = 0.023), and subcutaneous adipose tissue area (P = 0.016).
It appears likely that ESR1 contributes to type 2 diabetes and CVD risk via pleiotropic effects, leading to insulin resistance, a poor lipid profile, and obesity.
[Show abstract][Hide abstract] ABSTRACT: Hypoadiponectinemia has emerged as an independent risk factor for type 2 diabetes and cardiovascular disease. Although associations of adiponectin with central obesity and insulin resistance have been reported, very little data are available from studies using detailed measures of insulin sensitivity (S(I)) and/or body fat distribution in ethnic groups at high risk for metabolic disease.
The aim of the study was to identify the correlates of adiponectin in 1636 nondiabetic Hispanics and African-Americans.
A cross-sectional analysis of participants in the Insulin Resistance Atherosclerosis Family Study was conducted. S(I) was determined from frequently sampled iv glucose tolerance tests with minimal model analysis. Subcutaneous and visceral adipose tissues (SAT, VAT, respectively) were determined with computed tomography. Triglyceride, high-density lipoprotein, C-reactive protein, and adiponectin were measured in fasting samples. Generalized estimating equation (GEE) models were used to identify factors associated with adiponectin concentration.
A multicenter study using a family-based design was conducted.
A total of 1636 nondiabetic Hispanic and African-American subjects participated.
Circulating adiponectin concentration was measured.
Age, female gender, high-density lipoprotein, SAT, and S(I) were positive independent correlates of adiponectin, whereas glucose, CRP, and VAT were negative independent correlates (all P < 0.05). Ethnicity was not an independent correlate of adiponectin in this model (P = 0.27); however, an ethnicity by VAT interaction term was retained, indicating a stronger negative association of VAT with adiponectin in African-Americans compared with Hispanics.
Directly measured S(I), VAT, and SAT were independently correlated with adiponectin in Hispanic and African-American subjects. The inverse association of VAT with adiponectin was stronger in African-Americans compared with Hispanics, a finding that suggests possible ethnic differences in the effects of visceral obesity.
[Show abstract][Hide abstract] ABSTRACT: Focal adhesion kinase (FAK) is important to cellular functions such as proliferation, migration, and survival of anchorage-dependent cells. We investigated the role of FAK in modulating normal cellular responses, specifically cell survival in response to inflammatory stimuli and serum withdrawal, using FAK-knockout (FAK(-/-)) embryonic fibroblasts. FAK(-/-) fibroblasts were more vulnerable to TNF-alpha-induced apoptosis, as measured by terminal deoxynucleotidyl transferase positivity. FAK(-/-) fibroblasts also demonstrated increased procaspase-3 cleavage to p17 subunit, whereas this was undetectable in FAK(+/+) fibroblasts. Insulin receptor substrate-1 expression was completely abolished and NF-kappaB activity was reduced, with a concomitant decrease in abundance of the anti-apoptotic protein Bcl-x(L) in FAK(-/-) cells. Upon serum withdrawal, FAK(+/+) cells exhibited marked attenuation of basal ERK phosphorylation, while FAK(-/-) cells, in contrast, maintained high basal ERK phosphorylation. Moreover, inhibition of ERK phosphorylation potentiated serum withdrawal-induced caspase-3 activity. This was paralleled by increased insulin receptor substrate (IRS)-2 expression in FAK(-/-) cells, although both insulin- and IGF-1-mediated phosphorylation of Akt/PKB and GSK-3 were impaired. This suggests that IRS-2 protects against apoptosis upon serum withdrawal via the ERK signaling pathway. The specific role of FAK to protect cells from apoptosis is regulated by activation and phosphorylation of NF-kappaB and interaction between activated growth factor anti-apoptotic signaling pathways involving both phosphatidylinositol 3-kinase/Akt and MAPK/ERK1/2. We demonstrate that FAK is necessary for upregulation of the anti-apoptotic NF-kappaB response, as well as for normal expression of growth factor signaling proteins. Thus we propose a novel role for FAK in protection from cytokine-mediated apoptosis.
[Show abstract][Hide abstract] ABSTRACT: Integrins mediate interactions between cells and extracellular matrix proteins that modulate growth factor signaling. Focal adhesion kinase (FAK) is a key multifunctional integrin pathway protein. We recently reported that disruption of FAK impairs insulin-mediated glycogen synthesis in hepatocytes. To test the hypothesis that FAK regulates skeletal muscle insulin action, we reduced FAK expression in L6 myotubes using FAK antisense. In untransfected myotubes, insulin stimulated both FAK tyrosine phosphorylation and kinase activity. Cells treated with antisense FAK showed 78 and 53% reductions in FAK mRNA and FAK protein, respectively, whereas insulin receptor substrate 1/2 and paxillin abundance were unaffected. Insulin-stimulated U-(14)C-glucose incorporation into glycogen was abolished by FAK antisense, and 2-deoxy-glucose uptake and glucose transporter 4 (GLUT4) translocation were both markedly attenuated. Antisense FAK did not alter GLUT1 or GLUT3 protein abundance. Immunofluorescence staining showed decreased FAK Tyr(397) phosphorylation and reduced actin stress fibers. Thus, in skeletal myotubes, FAK regulates the insulin-mediated cytoskeletal rearrangement essential for normal glucose transport and glycogen synthesis. Integrin signaling may play an important regulatory role in muscle insulin action.
[Show abstract][Hide abstract] ABSTRACT: The usefulness of metformin as an oral antidiabetic agent is widely accepted. However, several other classes of oral antidiabetic agents have been recently introduced, raising the need to evaluate the role of metformin as initial therapy and in combination with these newer drugs for treatment of type 2 diabetes mellitus (DM).
Synthesis of information was preceded by a comprehensive review of the English language literature using Medline. We also reviewed bibliographies of relevant articles. The studies most pertinent to the mechanism of action, efficacy, toxicity and administration of metformin were selected for citation in this review.
Metformin acts by increasing tissue sensitivity to insulin, principally in the liver. Beneficial properties of metformin include weight reduction, favourable effects on the lipid profile and the fibrinolytic pathway, and improvement of ovarian function in some insulin-resistant women. It does not cause hyperinsulinaemia or hypoglycaemia. Metformin is effective as monotherapy and, in combination with both insulin secretagogues and thiazolidinediones (TZDs), may obviate the need for insulin treatment. Several fixed-dose combination pills containing metformin and other agents are available. A protocol for the initiation of therapy with contemporary oral agents for type 2 DM is presented, with emphasis on the continuing central role of metformin.
Metformin remains a safe and effective agent for the therapy of patients with type 2 DM. It is useful as monotherapy or in combination regimens with the newer insulin secretagogues, TZDs or insulin. It is still in most circumstances the agent of choice for initial therapy of the typical obese patient with type 2 DM and mild to moderate hyperglycaemia.
[Show abstract][Hide abstract] ABSTRACT: Leptin has been shown to improve insulin sensitivity and glucose metabolism in obese diabetic ob/ob mice, yet the mechanisms remain poorly defined. We found that 2 d of leptin treatment improved fasting but not postprandial glucose homeostasis, suggesting enhanced hepatic insulin sensitivity. Consistent with this hypothesis, leptin improved in vivo insulin receptor (IR) activation in liver, but not in skeletal muscle or fat. To explore the cellular mechanism by which leptin up-regulates hepatic IR activation, we examined the expression of the protein tyrosine phosphatase PTP1B, recently implicated as an important negative regulator of insulin signaling. Unexpectedly, liver PTP1B protein abundance was increased by leptin to levels similar to lean controls, whereas levels in muscle and fat remained unchanged. The ability of leptin to augment liver IR activation and PTP1B expression was also observed in vitro in human hepatoma cells (HepG2). However, overexpression of PTP1B in HepG2 cells led to diminished insulin-induced IR phosphorylation, supporting the role of PTP1B as a negative regulator of IR activation in hepatocytes. Collectively, our results suggest that leptin acutely improves hepatic insulin sensitivity in vivo with concomitant increases in PTP1B expression possibly serving to counterregulate insulin action and to maintain insulin signaling in proper balance.