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PubMed2003

Three novel polymorphisms in the promoter region of the TIMP-3 gene are not associated with proliferative diabetic retinopathy in type 2 diabetes mellitus.

PURPOSE: Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a member of the TIMP family of proteins, playing a significant role in the control of extracellular matrix remodelling. TIMP-3 might play a role in the regulation of retinal neovascularization during progression of diabetic retinopathy. Recently, three novel polymorphisms (-899T/A, -915A/G and -1296T/C) in the promoter region of the TIMP-3 gene have been identified. The aim of the study was to investigate a possible association of these polymorphisms with proliferative diabetic retinopathy (PDR) in type 2 diabetes mellitus (T2DM). METHODS: Genotypes were detected by polymerase chain reaction and subsequent restriction with specific endonucleases. Allele frequencies were determined in an association study comprising three groups of subjects (n = 371). RESULTS: Linkage disequilibrium was found among the three polymorphisms (P < or = 0.01). Allele frequencies did not differ between neither T2DM + PDR and T2DM non-PDR subjects (P > 0.05) nor between all T2DM versus non-diabetic subjects (P > 0.05). CONCLUSIONS: Polymorphisms in the promoter region of the TIMP-3 gene were not associated with the PDR in the Caucasian T2DM patients.

Diabetes Mellitus, Type 2↗
PubMed2006

Type-2 diabetes: a cocktail of genetic discovery.

Diabetes is one of the most challenging health problems of the 21st century with an alarming increase in the prevalence of type-2 diabetes mellitus (T2DM) and associated conditions such as hypertension, dyslipidemias and obesity. T2DM is a complex genetic disease comprised of many metabolic disorders with a common phenotype of glucose intolerance. Patients with T2DM would have inherited a variety of different genetic factors that together with environmental factors combine as the primary cause. This complicates the genetic study of the disease and means that different methodological approaches are needed if we hope to identify susceptibility genes and genetic variants. The biochemical and physiological processes that underpin T2DM are still unclear although most certainly involve impairment in insulin secretion and insulin action. In this review, we will discuss the most exciting advances in understanding the genetics of T2DM by looking at recent discoveries employing human association studies and candidate genes arising from animal models.

Animals↗
PubMed2025

Screening of the key single nucleotide polymorphisms in type 2 diabetes mellitus complicated with lower extremity arterial disease by machine learning.

OBJECTIVES: Diabetic lower extremity arterial disease (LEAD) is a manifestation of diabetic lower extremity vascular complications. This study aimed to screen the key single nucleotide polymorphism (SNP) gene signature in patients with type 2 diabetes mellitus (T2DM) and LEAD. METHODS: A total of 147 patients with T2DM complicated by LEAD and 144 patients with T2DM without LEAD were enrolled for transcriptome sequencing. The Plink software was used to preprocess the data. Five machine learning methods were adopted to build the SNP diagnosis models. The receiver operating characteristic (ROC) curve was used to quantify the predicted probabilities of the model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the cluster Profiler package. Finally, regression statistical analysis was used to correlate the key SNPs with clinical information and biochemical indicators. RESULTS: A total of 24 SNPs were retained and 10 SNPs were risk allele genes. Nine SNPs (rs7412, rs1800629, rs699947, rs3918242, rs668, rs1800470, rs1800449, rs1800469, and rs1024611) were identified as the key SNPs sites. GO and KEGG pathway analyses revealed that these genes are mainly enriched in fluid shear stress and atherosclerosis. Finally, rs1800449 was associated with low-density lipoprotein cholesterol (LDL-C). With high density lipoprotein cholesterol (HDL-C), related site was rs1024611. The sites associated with total cholesterol (CHOL) were rs1800449 and rs7412.The site associated with apolipoprotein B (APOB) and apolipoprotein A1 (APOA1) were rs1800470 and rs1800469. CONCLUSION: This study authenticated nine SNPs for the diagnosis of T2DM patients with LEAD, which will be of great significance in the development of diagnostic molecular biomarkers for T2DM patients.

Humans↗
PubMed2006

Evaluation of proinflammatory cytokines and inflammation markers as biomarkers for the action of thiazolidinediones in Type 2 diabetes mellitus patients and healthy volunteers.

AIMS: Thiazolidinediones (TZDs) not only enhance cellular glucose transport but are reported to have potent anti-inflammatory effects. These effects may play an important role in the insulin sensitizing mechanism, and possibly precede the effects on parameters of glucoregulation. We sought to investigate whether these anti-inflammatory effects could yield early responding biomarkers for TZD action in Type 2 diabetes mellitus (T2DM) patients and healthy volunteers (HV) to expedite early clinical development of novel compounds. METHODS: We investigated the timing of treatment effects on several proinflammatory cytokines and markers of inflammation in comparison with effects on typical measures of glucoregulation in T2DM patients and HV receiving rosiglitazone 4 mg or placebo twice daily for 6 weeks. RESULTS: We found a significant reduction in interleukin (IL)-6 [-39.4%, confidence interval (CI) - 60.0, - 8.2] and white blood cell count (-18.4%, CI - 30.2, - 4.5) after 4 weeks of treatment in the T2DM group. These anti-inflammatory effects did not precede the effects on typical parameters of glucoregulation in the T2DM group and there was no significant anti-inflammatory response in the HV group. CONCLUSION: We could not identify biomarkers that precede the effects of rosiglitazone on parameters of glucoregulation in T2DM or that have a significant response in HV. However, the IL-6 response observed in this study indicates a potential role for this cytokine as complementary biomarker in clinical 'proof of concept' studies with novel TZDs.

Adult↗
PubMed2006

An educational programme for peer review groups to improve treatment of chronic heart failure and diabetes mellitus type 2 in general practice.

RATIONALE, AIMS AND OBJECTIVES: Peer review groups are considered helpful for quality improvement in primary care. An interactive educational programme for small peer groups was developed, focusing on the implementation of newly developed treatment guidelines. The aim is to evaluate the effect of the programme on adherence to treatment guidelines in general practice. METHODS: A cluster randomized trial using a balanced incomplete block design was used; one arm received a programme on treatment of chronic heart failure (CHF), the other on hypertension treatment in diabetes mellitus type 2 (T2DM). A random sample of 10 CHF and 10 T2DM patients per GP was drawn, for whom data were extracted from electronic patient records 1 years before and 6 months after the intervention. The outcomes were prescribing of ACE inhibitors, and antihypertensive treatment in T2DM. The effect was analysed separately for both programmes using multilevel regression models. RESULTS: All 27 peer review groups in one region in the Netherlands were randomized, of which 16 participated. No significant effects were observed in the CHF group or in the T2DM group. The opportunity for change was limited, as only 53% of the CHF patients and 60% of the T2DM patients had a contact with their GP between the intervention and follow-up measurement. CONCLUSION: The peer review programme was not successful for changing the treatment of chronic patients, although the programme focused on dealing with barriers perceived by the participants. Not all problems perceived can be solved in a peer group discussion.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Thiazolidinedione therapy in the prevention/delay of type 2 diabetes in patients with impaired glucose tolerance and insulin resistance.

AIM: The second-generation thiazolidinediones (TZDs), rosiglitazone and pioglitazone, significantly decrease fasting plasma glucose and glycosylated haemoglobin (HbA(1c)) levels in patients with diabetes. Recent studies suggest that early treatment with TZDs may prevent the progression from insulin resistance (IR) to type 2 diabetes mellitus (T2DM). This prospective analysis examined the effect of early TZD treatment in the prevention or delay of T2DM in a multiethnic population with impaired glucose tolerance (IGT) and IR. METHODS: The analysis included 172 patients (aged 29-86 years) with IGT and IR (normal or borderline HbA(1c), C-peptide levels > 2 mg/ml, fasting blood sugar 100-125 mg/dl, and 2-h postprandial blood glucose levels 140-200 mg/dl). Patients in the active treatment group (n = 101) had received troglitazone for an average of 10 months before being randomly switched to rosiglitazone (4 mg/day) or pioglitazone (30 mg/day). Patients were switched when troglitazone was withdrawn from the US market because of liver toxicity concerns. Patients with IGT and IR who received no antidiabetic medication served as a control group (n = 71). HbA(1c) and C-peptide levels were measured at baseline (2 years) and study end point (3 years). Kaplan-Meier testing, using time to outcome as the main outcome variable, determined risk reduction in the TZD group relative to the control group. RESULTS: Mean HbA(1c) and C-peptide levels decreased for patients receiving either TZD at the 2-year assessment, and reductions were maintained at study end point. After 2 years, none of the patients receiving TZD therapy progressed to T2DM; three patients progressed to T2DM by study end point. In the control group, 11 patients became diabetic after 2 years and 19 patients became diabetic by the end of the study. The incidence (risk reduction) of diabetes after 3 years was 88.9% lower in the TZD group compared with the control group (p < 0.001). CONCLUSIONS: The TZDs, rosiglitazone and pioglitazone, were effective in reducing HbA(1c) and C-peptide levels in patients with IGT/IR. Progression of IR/IGT to T2DM appears to be significantly delayed or prevented with early TZD treatment.

Adult↗
PubMed2005

Association between Pro12Ala polymorphism of the PPAR-gamma2 gene and insulin sensitivity in Brazilian patients with type-2 diabetes mellitus.

AIM: Peroxisome-proliferator-activated receptor-gamma2 (PPAR-gamma2) is a nuclear receptor that plays an important role in lipid metabolism and insulin sensitivity. The purpose of this study is to investigate the association of Pro12Ala polymorphism at the PPAR-gamma2 gene in Brazilian patients with type-2 diabetes mellitus (T2Dm) and controls (CG). METHODS: Genomic DNA was obtained from 207 unrelated white people presenting with T2Dm and from 170 controls. Anthropometric data included body mass index and waist to hip ratio. Biochemical parameters included fasting plasma glucose, total cholesterol, high- and low-density lipoprotein cholesterol, triglycerides, glycated haemoglobin and insulin. Systolic and diastolic blood pressures were also measured. Screening for mutations in the entire coding region of the PPAR-gamma gene was performed by means of polymerase chain reaction (PCR), single-strand conformational polymorphism and sequencing. Pro12Ala polymorphism was analysed by using PCR-RFLP (restriction fragment-length polymorphism). RESULTS: One base substitution was identified - a C to G substitution in exon B of the PPAR-gamma2 gene. The frequency of the Ala12 allele in T2Dm (0.09) was similar to that found in CG (0.06, p = 0.185). In the T2Dm group, Ala12 allele was associated with lower fasting plasma insulin levels (p = 0.036) and higher insulin sensitivity (p = 0.049) by means of homeostasis model assessment. Among obese people, there was no association between any of the T2Dm or obesity-related traits and the Pro12Ala polymorphism. CONCLUSIONS: The results of our study suggest that people with the Ala12 allele of the PPAR-gamma2 gene could be more sensitive to insulin than those carriers of the Pro12 allele among Brazilian Caucasians.

Adult↗
PubMed2006

Common promoter polymorphism in monocyte differentiation antigen CD14 is associated with serum triglyceride levels and body mass index in non-diabetic individuals.

AIMS: Growing evidence supports the hypothesis that chronic low-grade inflammation related to innate immunity may play an important role in the pathophysiology of Type 2 diabetes mellitus (T2DM). The monocyte differentiation antigen CD14 gene (CD14) acts as the receptor for lipopolysaccharide (LPS) and augments monocyte/macrophage inflammatory responses. METHODS: We have sequenced the gene, including all exons, exon/intron boundaries, and the -1.5 kb of the 5' flanking region. Two common loci (minor allele frequency > 0.05) were genotyped in 775 T2DM patients and 316 control subjects recruited in the Korean T2DM Study. RESULTS: Eight polymorphisms, including four non-synonymous forms, were identified in CD14. No polymorphisms were found in association with T2DM. However, one common promoter SNP (-260T>C) was significantly associated with both the serum triglyceride level (TG) and body mass index (BMI) in non-diabetic control subjects. Individuals who carried the minor allele (C) had higher TG levels (1.65 +/- 0.81 vs. 1.46 +/- 0.80 mmol/l; P = 0.0007) and BMI (23.96 +/- 3.00 vs. 23.28 +/- 3.22 kg/m(2); P = 0.04) as compared with subjects carrying T/T genotypes. CONCLUSION: Our data suggest that lipid metabolism and obesity, important pathophysiological elements of T2DM and the metabolic syndrome, are regulated by complex mechanisms that include the CD14 gene polymorphism-mediated genetic propensity to non-specific inflammatory responses.

Base Sequence↗
PubMed2006

The Gly482Ser variant of the PPARGC1 gene is associated with Type 2 diabetes mellitus in northern Chinese, especially men.

AIMS: To investigate the prevalence of the Gly482Ser polymorphism of the PPARGC1 gene in a northern Chinese population and to clarify the susceptibility of individuals with the Gly482Ser polymorphism to insulin resistance and related diseases. METHODS: We studied the association of the Gly482Ser polymorphism identified in the PPARGC1 gene with Type 2 diabetes mellitus (T2DM) in 390 unrelated patients with T2DM and 525 control subjects with normal glucose tolerance. Clinical parameters and measures of insulin resistance were recorded. Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, which was further confirmed by direct sequencing in 20 randomly selected cases. RESULTS: The Gly482Ser polymorphism was common in the northern Chinese population. Univariate analysis indicated no statistically significant differences in allele frequencies or genotype frequencies of the Gly482Ser polymorphism in diabetic and control subjects (minor 482Ser allele frequency 44.4 vs. 41.4%, P = 0.169). However, logistic regression analysis demonstrated a positive 1.645-fold higher risk of the Ser/Ser genotype for T2DM (P = 0.039, 95% CI = 1.026-2.632). After stratification by gender, the risk of Type 2 diabetes in men was increased 1.852-fold (95% CI = 1.125-3.049) in those with the Ser/X genotype compared with those with the Gly/Gly genotype (P = 0.015). No associations were observed between the Gly482Ser polymorphism and parameters of insulin resistance, obesity and hypertension. CONCLUSION: The Gly482Ser variant of the PPARGC1 gene might contribute to susceptibility to T2DM in northern Chinese subjects. The Ser/X genotype of the Gly482Ser polymorphism in the PPARGC1 gene appears to be a risk factor for T2DM in northern Chinese men.

Adult↗
PubMed2006

Antihypertensive efficacy of Irbesartan/HCTZ in men and women with the metabolic syndrome and type 2 diabetes.

This subgroup analysis of the Irbesartan/Hydrochlorothiazide (HCTZ) Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial evaluated the efficacy and safety of irbesartan/HCTZ fixed combinations in adults with uncontrolled systolic blood pressure (SBP) (140-159 mm Hg; 130-159 mm Hg for type 2 diabetes mellitus [T2DM]) after >or=4 weeks of antihypertensive monotherapy. Treatment was sequential: placebo (4-5 weeks), HCTZ 12.5 mg (2 weeks), irbesartan/HCTZ 150/12.5 mg (8 weeks), and irbesartan/HCTZ 300/25 mg (8 weeks). In the intent-to-treat analysis, mean change from baseline (end of placebo phase) off all previous therapy to Week 18 (study end) in T2DM patients (n=227) was -18.2+/-14.1 mm Hg for SBP (primary end point; p<0.001) and -8.7+/-8.2 mm Hg for diastolic blood pressure (p<0.001). Mean SBP/diastolic blood pressure changes in patients with the metabolic syndrome (n=345) were -21.0+/-14.3/-10.4+/-8.5 mm Hg (p<0.001). Overall, 56% (95% confidence interval, 49%-62%) of T2DM and 73% (95% confidence interval, 68%-77%) of metabolic syndrome patients achieved SBP goal (<140 mm Hg; <130 mm Hg for T2DM). Goal attainment rates were significantly higher among women with the metabolic syndrome than men. Treatments appeared to be well tolerated. Irbesartan/HCTZ fixed combinations achieved SBP goals in over half of the T2DM patients and nearly three quarters of patients with the metabolic syndrome, with SBP uncontrolled on antihypertensive monotherapy.

Adult↗
PubMed2004

Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes.

Muscle insulin resistance develops when plasma free fatty acids (FFAs) are acutely increased to supraphysiological levels (approximately 1,500-4,000 micromol/l). However, plasma FFA levels >1,000 micromol/l are rarely observed in humans under usual living conditions, and it is unknown whether insulin action may be impaired during a sustained but physiological FFA increase to levels seen in obesity and type 2 diabetes mellitus (T2DM) (approximately 600-800 micromol/l). It is also unclear whether normal glucose-tolerant subjects with a strong family history of T2DM (FH+) would respond to a low-dose lipid infusion as individuals without any family history of T2DM (CON). To examine these questions, we studied 7 FH+ and 10 CON subjects in whom we infused saline (SAL) or low-dose Liposyn (LIP) for 4 days. On day 4, a euglycemic insulin clamp with [3-3H]glucose and indirect calorimetry was performed to assess glucose turnover, combined with vastus lateralis muscle biopsies to examine insulin signaling. LIP increased plasma FFA approximately 1.5-fold, to levels seen in T2DM. Compared with CON, FH+ were markedly insulin resistant and had severely impaired insulin signaling in response to insulin stimulation. LIP in CON reduced insulin-stimulated glucose disposal (Rd) by 25%, insulin-stimulated insulin receptor tyrosine phosphorylation by 17%, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 by 20%, and insulin-stimulated glycogen synthase fractional velocity over baseline (44 vs. 15%; all P < 0.05). In contrast to CON, a physiological elevation in plasma FFA in FH+ led to no further deterioration in Rd or to any additional impairment of insulin signaling. In conclusion, a 4-day physiological increase in plasma FFA to levels seen in obesity and T2DM impairs insulin action/insulin signaling in CON but does not worsen insulin resistance in FH+. Whether this lack of additional deterioration in insulin signaling in FH+ is due to already well-established lipotoxicity, or to other molecular mechanisms related to insulin resistance that are nearly maximally expressed early in life, remains to be determined.

Adult↗
PubMed2002

Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus.

We examined the relationship between peripheral/hepatic insulin sensitivity and abdominal superficial/deep subcutaneous fat (SSF/DSF) and intra-abdominal visceral fat (VF) in patients with type 2 diabetes mellitus (T2DM). Sixty-two T2DM patients (36 males and 26 females, age = 55 +/- 3 yr, body mass index = 30 +/- 1 kg/m2) underwent a two-step euglycemic insulin clamp (40 and 160 mU. m(-2). min(-1)) with [3-3H]glucose. SSF, DSF, and VF areas were quantitated with magnetic resonance imaging at the L(4-5) level. Basal endogenous glucose production (EGP), hepatic insulin resistance index (basal EGP x FPI), and total glucose disposal (TGD) during the first and second insulin clamp steps were similar in male and female subjects. VF (159 +/- 9 vs. 143 +/- 9 cm2) and DSF (199 +/- 14 vs. 200 +/- 15 cm(2)) were not different in male and female subjects. SSF (104 +/- 8 vs. 223 +/- 15 cm2) was greater (P < 0.0001) in female vs. male subjects despite similar body mass index (31 +/- 1 vs. 30 +/- 1 kg/m2) and total body fat mass (31 +/- 2 vs. 33 +/- 2 kg). In male T2DM, TGD during the first insulin clamp step (1st TGD) correlated inversely with VF (r = -0.45, P < 0.01), DSF (r = -0.46, P < 0.01), and SSF (r = -0.39, P < 0.05). In males, VF (r = 0.37, P < 0.05), DSF (r = 0.49, P < 0.01), and SSF (r = 0.33, P < 0.05) were correlated positively with hepatic insulin resistance. In females, the first TGD (r = -0.45, P < 0.05) and hepatic insulin resistance (r = 0.49, P < 0.05) correlated with VF but not with DSF, SSF, or total subcutaneous fat area. We conclude that visceral adiposity is associated with both peripheral and hepatic insulin resistance, independent of gender, in T2DM. In male but not female T2DM, deep subcutaneous adipose tissue also is associated with peripheral and hepatic insulin resistance.

Abdomen↗
PubMed2003

Presentation and 5-year follow-up of type 2 diabetes mellitus in African-American and Caribbean-Hispanic adolescents.

OBJECTIVE: We report the presentation and 5-year follow-up of 89 African-American (AA) and Caribbean-Hispanic (CH) youths with type 2 diabetes mellitus (T2DM) followed at the Montefiore Medical Center, Bronx, N.Y., USA, from 1990 to 2000. METHODS: The medical records of 89 patients with T2DM diagnosed between 1990 and 2000 were reviewed. RESULTS: Over a 10-year period, the number of pediatric patients less than 18 years of age diagnosed with T2DM at the Montefiore Medical Center increased tenfold. At presentation, the mean age was 14 +/- 2.3 years, the mean body mass index (BMI) was 34.4 +/- 9 kg/m(2), the female/male ratio was 1.6:1, and all these patients were pubertal. Acanthosis nigricans was present in 89% of the patients, polyuria and polydipsia occurred in 48%, weight loss occurred in 22%, and nearly 30% of the patients were asymptomatic at diagnosis. Diabetic ketoacidosis occurred in 5 patients. By 5 years after diagnosis, 45% of the patients were able to maintain an HgbA1C <7% with oral medications (metformin and/or glipizide); 18% required insulin (<0.4 U/kg/day) in addition to oral medications, and 37% did not require any medication. The mean insulin level, BMI and HgbA1C at the time of diagnosis did not predict treatment requirements for 3 years after diagnosis. CONCLUSIONS: Because the incidence of T2DM is increasing in adolescents, the natural history and optimal therapy for adolescents with T2DM need to be established.

Adolescent↗
PubMed2006

Prevention and treatment of type 2 diabetes in youth.

Parallel to the increase in obesity worldwide, there has been a rise in the prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents. The etiology of T2DM in youth, similar to adults, is multifactorial including genetic and environmental factors, among them obesity, sedentary lifestyle, family history of the disease, high-risk ethnicity and insulin resistance phenotype playing major roles. Treatment of T2DM should not have a glucocentric approach; it should rather target improving glycemia, dyslipidemia, hypertension, weight management and the prevention of short- and long-term complications. Prevention strategies, especially in high-risk groups, should focus on environmental change involving participation of families, schools, the food and entertainment industries and governmental agencies. Presently, limited pharmacotherapeutic options need to be expanded both for childhood T2DM and obesity. The coming decades will prove very challenging for healthcare providers battling socioeconomic waves conducive to obesity and T2DM. Evidence-based research and clinical experience in pediatrics, possibly modeled after adult trials, need to be developed if this public health threat is to be contained.

Adolescent↗
PubMed2005

Diabetes, the metabolic syndrome, and angiographic progression of coronary arterial disease in postmenopausal women.

OBJECTIVE: Although the metabolic syndrome (MS) is associated with increased cardiovascular risk, its relationship with atherosclerotic progression is less well defined. We sought to determine whether the MS predicts angiographic progression of coronary heart disease in a cohort of postmenopausal women. METHODS AND RESULTS: A total of 309 postmenopausal women entered the Estrogen Replacement and Atherosclerosis trial, of whom 248 underwent baseline angiography and completed follow-up angiography after an average of 3.2 years. Women were identified as having type 2 diabetes mellitus (T2DM) or the MS (National Cholesterol Education Panel diagnostic criteria). In adjusted models, participants with T2DM and the MS had greater angiographic progression [change in minimal diameter (DeltaMD): -0.15] than women without T2DM or the MS (DeltaMD: -0.08; P<0.05) or with MS alone (DeltaMD: -0.07; P<0.005); there was no difference in progression by MS status in women without T2DM (P=0.54)]. In adjusted logistic regression models, T2DM predicted coronary heart disease events [odds ratio, 2.79 (95% CI, 1.29 to 6.02)], and the MS demonstrated a similar trend [odds ratio, 1.98 (95% CI, 0.90 to 4.33)]. CONCLUSIONS: Among postmenopausal women with coronary heart disease, the presence of diabetes predicted disease progression, but the MS did not.

Aged↗
PubMed2004

G(-30)A polymorphism in the pancreatic promoter of the glucokinase gene associated with angiographic coronary artery disease and type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of coronary artery disease (CAD). A G(-30)A polymorphism in the beta-cell-specific promoter of glucokinase (GK-30PM) has been implicated in reduced pancreatic beta-cell function. Its impact on CAD has not been examined. METHODS AND RESULTS: The glucokinase G(-30)A variant was determined in 2567 patients with angiographic CAD and in 731 individuals in whom CAD had been ruled out by angiography. In carriers of the A allele, the adjusted OR of CAD was 1.39 (95% CI, 1.15 to 1.70). Corresponding ORs were 1.27 (95% CI, 1.02 to 1.59) and 1.92 (95% CI, 1.26 to 2.93) in individuals without and with T2DM, respectively. The prevalence of the A allele increased in parallel with the Friesinger coronary score. Patients with T2DM were more frequent among carriers of > or =1 A allele (OR, 1.17; 95% CI, 1.00 to 1.28). This association was stronger if CAD patients only were considered. The A allele was associated with higher glucose (fasting, P=0.002; 2 hours after oral glucose, P=0.017) and glycohemoglobin (HbA1c; P=0.002). Furthermore, presence of 1 A allele was negatively related to beta-cell function, estimated by beta percent (P=0.012) and by the ratios of proinsulin to insulin (P=0.025) and proinsulin to C peptide (P=0.019). CONCLUSIONS: The A allele of the pancreatic promoter of glucokinase increases the risk of CAD in individuals with and without T2DM. Furthermore, at least in CAD, it is associated with an augmented prevalence of T2DM.

Aged↗
PubMed2004

Subclinical coronary atherosclerosis in asymptomatic Filipino and white women.

BACKGROUND: Coronary heart disease (CHD) is the leading cause of morbidity and mortality in persons with type 2 diabetes mellitus (T2DM). Electron-beam computed tomography (EBCT) detects coronary artery calcium (CAC), a marker of atherosclerotic plaque. Few studies have described EBCT-defined CHD among ethnic minorities with elevated T2DM prevalence. The objective of this study was to compare EBCT-defined CAC in Filipino and white women without known cardiovascular disease. METHODS AND RESULTS: Subjects were participants aged 55 to 78 years in the Rancho Bernardo Study (n=196) and the University of California at San Diego's Filipino Women's Health Study (n=181). Glucose, blood pressure, lipids, anthropometric measurements, and lifestyle factors were measured from 1995 to 1999. EBCT-defined CAC scores, visceral and subcutaneous fat, and statin use were assessed in 2001 to 2002. Compared with whites, Filipinas had a significantly higher prevalence of T2DM (32.6% versus 6.1%, P<0.001) and the metabolic syndrome (32.6% versus 13.8, P<0.001). Filipinas were younger (64.4 versus 66.7 years), had higher triglyceride levels (155 versus 135 mg/dL), had a higher ratio of total cholesterol to HDL cholesterol (4.3 versus 3.5), more frequently used statins (31% versus 19%), and had more visceral fat (69.4 versus 62.1 cm3) and lower HDL cholesterol levels (54 versus 66 mg/dL) than whites. Exercise frequency, body mass index, and waist girth did not differ by ethnicity. Nevertheless, extensive (CAC score > or =400; 9% versus 9%) and moderate (CAC score 150 to 399; 13% versus 11%) atherosclerotic plaque did not differ by ethnicity, even after adjustment for age, T2DM, hypertension, estrogen use, statin use, smoking, lipids, and visceral fat. CONCLUSIONS: Filipinas had no excess of subclinical atherosclerosis despite their significantly higher prevalence of T2DM, the metabolic syndrome, hypertension, and visceral adiposity.

Adipose Tissue↗
PubMed2006

Dominant Western health care: type 2 diabetes mellitus.

Diabetes is a major public health problem with serious complications. In 2002, the Centers for Disease Control estimated that 18.2 million people in the United States had diabetes. One in every 400 to 500 adolescents is diagnosed with type 1 diabetes mellitus (T1DM), and pediatric type 2 diabetes mellitus (T2DM) represents an emerging public health concern. The Children's Hospital of Philadelphia (CHOP) identified 337 children with T2DM through 2004. These children were mostly female and obese with a strong family history of T2DM. One patient's course of treatment for 1.5 years after initial presentation is described. Nineteen percent of the patients at CHOP were diagnosed with a neuropsychiatric illness before T2DM onset, further complicating their treatment. There is an imperative need for large-scale studies investigating the pathophysiology, treatment, and complications of T2DM in adolescents and youth.

Adolescent↗