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PubMed2006

Direct association of a promoter polymorphism in the CD36/FAT fatty acid transporter gene with Type 2 diabetes mellitus and insulin resistance.

AIMS: The membrane-bound fatty acid transporter CD36/FAT may play a role in disturbed fatty acid handling as observed in the metabolic syndrome and Type 2 diabetes mellitus (T2DM). Genetic variation in the CD36 gene may contribute to the aetiology of diabetes. METHODS: A population-based cohort in the Netherlands [age > 40 years and body mass index (BMI) > 25 kg/m2] of 675 subjects was phenotyped with respect to glucose metabolism with an oral glucose tolerance test and was genotyped for a known 478C-->T substitution and a C/T snp in the upstream promoter region (rs1527479) in the CD36 gene. RESULTS: T2DM was more prevalent in the TT genotype than in the CC genotype. This was most pronounced in women and in subjects with a high BMI (BMI > 27 kg/m2). In addition, within the group of diabetic patients, the TT genotype was commoner in subjects with increased homeostasis model assessment (HOMA) index for insulin resistance. The 478C-->T substitution, previously found in the Japanese population, was not found in our caucasian population. CONCLUSIONS: This is the first study to show a direct association of a CD36 snp with T2DM. Moreover, within the diabetic subjects, this CD36 snp was associated with insulin resistance (HOMA index).

Aged↗

PubMed2006

Relationship between common functional polymorphisms of the p22phox gene (-930A > G and +242C > T) and nephropathy as a result of Type 2 diabetes in a Chinese population.

OBJECTIVE: Genetic determinants are important in diabetic nephropathy (DN). Oxidative stress has also emerged as an important pathogenic factor in DN and vascular NADH oxidase is a major source of reactive oxygen species (ROS). Previous small studies reported a strong but contradictory association between functional genetic variation of p22(phox), an important subcomponent of NADH oxidase, and DN. We investigated the association between two common functional single nucleotide polymorphisms (SNPs) (-930 A > G and +242 C > T) and DN in a much larger group of Chinese patients with Type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Case-control study of Chinese subjects with long-standing T2DM (> 10 years). Cases (n = 306) were subjects with a spot urinary albumin : creatinine ratio (ACR) of > 113 mg/mmol or elevated serum creatinine. Control subjects (n = 306) had ACR < 3.3 mg/mmol and normal serum creatinine. Genotyping was carried out by standard PCR and restriction fragment length polymorphism analysis. RESULTS: Gender distribution, age, duration of diabetes and HbA(1c) were similar in cases and control subjects. Distribution of genotypes in the control subjects for both SNPs was consistent with the Hardy-Weinberg equilibrium. Distribution of genotypes did not differ significantly between cases and control subjects for both polymorphisms-+2424C > T: cases CC 84.6%, CT 15.0%, TT 0.4% and control subjects CC 87.6%, CT 11.8%, TT 0.6% (P = 0.45); -930 A > G: cases AA 40.5%, AG 41.8%, GG 17.7% and control subjects AA 38.2%, AG 49.0%, GG 12.8% (P = 0.12). Distribution of alleles was also similar-+2424 C > T: cases C 92.2%, T 7.8% and control subjects C 93.5%, T 6.5% (P = 0.66); -930 A > G cases A 61.4%, G 38.6% and control subjects A 62.7%, G 37.3% (P = 0.38). We estimated that our study has approximately 80% power to detect a relative risk of 1.65 (for +242 C > T) and 1.35 (for -930 A > G) conferred by the minor allele, respectively. CONCLUSIONS: In contrast with previous small studies, our data suggest that these SNPs do not confer significantly increased susceptibility to DN secondary to T2DM in Chinese subjects.

Aged↗

PubMed2006

Relationship between HbA1c and indices of glucose tolerance derived from a standardized meal test in newly diagnosed treatment naive subjects with Type 2 diabetes.

AIMS: To determine the relationship between HbA1c and other indices of glycaemic status derived during a standardized meal tolerance test (MTT) in newly diagnosed treatment-naive subjects with Type 2 diabetes (T2DM). METHODS: T2DM subjects (n = 262) consumed a standard MTT in the morning after a 10-h overnight fast. Frequent samples for plasma glucose (PG) were collected over the 4-h test period. The relationship between HbA1c and other glycaemic indices derived from the MTT were explored. The postprandial glucose exposure was calculated as the area under the incremental plasma glucose curve above the fasting level for the test period (AUC1). Excess hyperglycaemia was calculated as the AUC0-4 h above the arbitrary PG concentrations of 6.0 mmol/l (AUC2) and 5.5 mmol/l (AUC3), respectively [upper limit of fasting normoglycaemia according to World Health Organization (WHO) and American Diabetes Association (ADA), respectively]. Fasting hyperglycaemia was also estimated, being the difference between each of the above and the postprandial excursion. The participants were divided into three subgroups according to HbA1c (Group 1, 9.0%) and the relative contribution calculated of the postprandial glucose and fasting hyperglycaemia to the excess hyperglycaemia above the designated international thresholds for fasting plasma glucose. RESULTS: HbA1c was more strongly correlated with the fasting plasma glucose (r = 0.85, P < 0.001) than the overall postprandial glucose exposure (r = 0.539, P = 0.003). The contribution of fasting hyperglycaemia to excess hyperglycaemia using the WHO criteria for normal fasting plasma glucose for the three groups (Groups 1, 2 and 3) was 50.4%, 54.3% and 69.8%, respectively, and 57.8%, 58.8% and 71.4% using the ADA criteria. CONCLUSIONS: The contribution of fasting hyperglycaemia to excess hyperglycaemia increases as glycaemic control deteriorates, becoming dominant with an HbA1c in excess of 7.0%. These findings indicate which therapeutic approach needs to be adopted based on the HbA1c of the person with T2DM.

Adult↗

PubMed2004

Abnormal renal, hepatic, and muscle glucose metabolism following glucose ingestion in type 2 diabetes.

Recent studies indicate an important role of the kidney in postprandial glucose homeostasis in normal humans. To determine its role in the abnormal postprandial glucose metabolism in type 2 diabetes mellitus (T2DM), we used a combination of the dual-isotope technique and net balance measurements across kidney and skeletal muscle in 10 subjects with T2DM and 10 age-, weight-, and sex-matched nondiabetic volunteers after ingestion of 75 g of glucose. Over the 4.5-h postprandial period, diabetic subjects had increased mean blood glucose levels (14.1 +/- 1.1 vs. 6.2 +/- 0.2 mM, P < 0.001) and increased systemic glucose appearance (100.0 +/- 6.3 vs. 70.0 +/- 3.3 g, P < 0.001). The latter was mainly due to approximately 23 g greater endogenous glucose release (39.8 +/- 5.9 vs. 17.0 +/- 1.8 g, P < 0.002), since systemic appearance of the ingested glucose was increased by only approximately 7 g (60.2 +/- 1.4 vs. 53.0 +/- 2.2 g, P < 0.02). Approximately 40% of the diabetic subjects' increased endogenous glucose release was due to increased renal glucose release (19.6 +/- 3.1 vs. 10.6 +/- 2.4 g, P < 0.05). Postprandial systemic tissue glucose uptake was also increased in the diabetic subjects (82.3 +/- 4.7 vs. 69.8 +/- 3.5 g, P < 0.05), and its distribution was altered; renal glucose uptake was increased (21.0 +/- 3.5 vs. 9.8 +/- 2.3 g, P < 0.03), whereas muscle glucose uptake was normal (18.5 +/- 1.8 vs. 25.9 +/- 3.3 g, P = 0.16). We conclude that, in T2DM, 1) both liver and kidney contribute to postprandial overproduction of glucose, and 2) postprandial renal glucose uptake is increased, resulting in a shift in the relative importance of muscle and kidney for glucose disposal. The latter may provide an explanation for the renal glycogen accumulation characteristic of diabetes mellitus as well as a mechanism by which hyperglycemia may lead to diabetic nephropathy.

Administration, Oral↗

PubMed2006

Inhibition of human IAPP fibril formation does not prevent beta-cell death: evidence for distinct actions of oligomers and fibrils of human IAPP.

Type 2 diabetes mellitus (T2DM) is characterized by an approximately 60% deficit in beta-cell mass, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) forms oligomers, leading to either amyloid fibrils or toxic oligomers in an aqueous solution in vitro. Either application of hIAPP on or overexpression of hIAPP in cells induces apoptosis. It remains controversial whether the fibrils or smaller toxic oligomers induce beta-cell apoptosis. Rifampicin prevents hIAPP amyloid fibril formation and has been proposed as a potential target for prevention of T2DM. We examined the actions of rifampicin on hIAPP amyloid fibril and toxic oligomer formation as well as its ability to protect beta-cells from either application of hIAPP or endogenous overexpression of hIAPP (transgenic rats and adenovirus-transduced beta-cells). We report that rifampicin (Acocella G. Clin Pharmacokinet 3: 108-127, 1978) prevents hIAPP fibril formation, but not formation of toxic hIAPP oligomers (Bates G. Lancet 361: 1642-1644, 2003), and does not protect beta-cells from apoptosis induced by either overexpression or application of hIAPP. These data emphasize that toxic hIAPP oligomers, rather than hIAPP fibrils, initiate beta-cell apoptosis and that screening tools to identify inhibitors of amyloid fibril formation are likely to be less useful than those that identify inhibitors of toxic oligomer formation. Finally, rifampicin and related molecules do not appear to be useful as candidates for prevention of T2DM.

Adenoviridae↗

PubMed2006

Calpain-10 variants and haplotypes are associated with polycystic ovary syndrome in Caucasians.

PCOS is known to be associated with an increased risk of T2DM and has been proposed to share a common genetic background with T2DM. Recent studies suggest that the Calpain-10 gene (CAPN10) is an interesting candidate gene for PCOS susceptibility. However, contradictory results were reported concerning the contribution of certain CAPN10 variants, especially of UCSNP-44, to genetic predisposition to T2DM, hirsutism, and PCOS. By means of MALDI-TOF MS technique, we genotyped an expanded single nucleotide polymorphism panel, including the CAPN10 UCSNP-44, -43, -56, ins/del-19, -110, -58, -63, and -22 in a sample of 146 German PCOS women and 606 population-based controls. Statistical analysis revealed an association between UCSNP-56 and susceptibility to PCOS with an odds ratio (OR) of 2.91 (95% CI=1.51-5.61) for women carrying an AA genotype compared with GG. As expected, the 22-genotype of the ins/del-19 variant, which is in high linkage disequilibrium (r2=0.98) with UCSNP-56, was also significantly associated (OR=2.98, 95% CI=1.55-5.73). None of the additionally tested variants alone showed any significant association with PCOS. A meta-analysis including our study (altogether 623 PCOS cases and 1,224 controls) also showed significant association only with ins/del-19. The most common haplotype TGG3AGCA was significantly associated with a lower risk for PCOS (OR=0.487, P=0.0057). In contrast, the TGA2AGCA haplotype was associated with an increased risk for PCOS (OR=3.557, P=0.0011). By investigating a broad panel of CAPN10 variants, our results pointed to an allele dose-dependent association of UCSNP-56 and ins/del-19 with PCOS.

Adult↗

PubMed2026

A validated, modifiable proteomic score from the EXSCEL trial predicts cardiovascular events in diabetes.

BACKGROUNDAdults with type 2 diabetes mellitus (T2DM) are at increased risk for stroke, myocardial infarction, and cardiovascular death, yet individual risk is heterogeneous and incompletely captured by clinical models.METHODSIn the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), adults with T2DM were randomized to a GLP-1 RA (exenatide) or a placebo and followed longitudinally for major adverse cardiovascular events (MACE). High-throughput discovery proteomics was done in plasma collected at baseline and 12 months. Proteins associated with time to MACE were identified using multivariable regression and incorporated into supervised machine learning models. A multi-protein score was developed and externally validated in 2 independent population-based and trial cohorts.RESULTSThe proteomic score showed incremental improvement in cardiovascular risk discrimination beyond clinical factors alone, and several proteins were consistently prioritized across modeling approaches. The protein score and a top-ranked protein, tetranectin, were modified by GLP-1 RA treatment, and a decrease in protein score was associated with improved outcomes, supporting modifiability of MACE risk.CONCLUSIONExternal validation confirmed generalizability across cohorts with and without diabetes. Together, these findings demonstrate that plasma proteomic signatures can enhance cardiovascular risk stratification and identify treatment-responsive biomarkers in T2DM, supporting their potential role in precision prevention strategiesFUNDINGThe EXSCEL study was funded by Amylin Pharmaceuticals. This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, and grants R01HL146145, U01HL080295, U01HL130114, R01HL172803, and R01HL144483 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging.

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PubMed2005

Effects of the PPARgamma agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus.

Elevated plasma levels of VLDL triglycerides (TGs) are characteristic of patients with type 2 diabetes mellitus (T2DM) and are associated with increased production rates (PRs) of VLDL TGs and apoB. Lipoprotein lipase-mediated (LPL-mediated) lipolysis of VLDL TGs may also be reduced in T2DM if the level of LPL is decreased and/or the level of plasma apoC-III, an inhibitor of LPL-mediated lipolysis, is increased. We studied the effects of pioglitazone (Pio), a PPARgamma agonist that improves insulin sensitivity, on lipoprotein metabolism in patients with T2DM. Pio treatment reduced TG levels by increasing the fractional clearance rate (FCR) of VLDL TGs from the circulation, without changing direct removal of VLDL particles. This indicated increased lipolysis of VLDL TGs during Pio treatment, a mechanism supported by our finding of increased plasma LPL mass and decreased levels of plasma apoC-III. Lower apoC-III levels were due to reduced apoC-III PRs. We saw no effects of Pio on the PR of either VLDL TG or VLDL apoB. Thus, Pio, a PPARgamma agonist, reduced VLDL TG levels by increasing LPL mass and inhibiting apoC-III PR. These 2 changes were associated with an increased FCR of VLDL TGs, almost certainly due to increased LPL-mediated lipolysis.

Adiponectin↗

PubMed2004

Genes and pathophysiology of type 2 diabetes: more than just the Randle cycle all over again.

The Randle cycle, which has been invoked to explain the reciprocal relationship between fatty acid oxidation and glucose oxidation, has long been implicated as a potential mechanism for hyperglycemia and type 2 diabetes mellitus (T2DM). Now genetic, functional genomic, and transgenic approaches have identified PPARgamma coactivators (PGC-1alpha and PGC-1beta) as key regulators of mitochondrial number and function. They regulate adaptive thermogenesis as well as glucose and fat oxidation in muscle and fat tissue, gluconeogenesis in liver, and even glucose-regulated insulin secretion in beta cells. PGC-1alpha and PGC-1beta mRNA levels and the mitochondrial genes they regulate are decreased in muscle of people with prediabetes and T2DM. A new report indicates that PGC-1alpha and PGC-1beta mRNA levels decrease with age in individuals with a genetic variant in PGC-1alpha, and these decreases correlate with alterations in whole-body glucose and fatty acid oxidation. These findings provide insights into how aging modifies genetic susceptibility to alterations in oxidative phosphorylation and T2DM.

Age Factors↗

PubMed2026

BRAIN-Diabetes: Acceptability of an adapted FINGER multidomain intervention among adults living with type 2 diabetes in rural border regions across the island of Ireland.

BackgroundIndividuals with type 2 diabetes mellitus (T2DM) face increased risk of cognitive decline and dementia. Multidomain lifestyle interventions offer a non-pharmacological strategy to support brain health in this high-risk group.ObjectiveThis study examined the acceptability of a culturally adapted FINGER-based intervention among adults living with T2DM in rural border regions of Ireland (BRAIN-Diabetes Trial).MethodsA 6-month pilot randomized controlled trial was conducted. The intervention group received a multidomain program targeting diet, physical activity, and computerized cognitive training (CCT). The control group received standard care. Acceptability was assessed using questionnaires (all participants) and semi-structured interviews (intervention participants). Quantitative data were analyzed descriptively and qualitative data using template analysis, guided by four a-priori themes: trial participation and engagement, dietary behavior change, exercise behavior change, and CCT behavior change.ResultsQuestionnaire data (intervention: n = 28; control: n = 36) indicated high overall acceptability. Dietary and exercise components were rated most positively, while CCT component was less well received. Interviews (n = 25) highlighted facilitators to trial engagement, including perceived health improvements, and social connection, with time constraints and limited personalization as barriers. Dietary change was supported by tailored guidance but hindered by cost and availability. Facilitators for exercise included accessible resources and perceived benefits, with barriers including competing priorities. CCT engagement was mixed, with challenges including digital access and repetitiveness.ConclusionsThe Brain-Diabetes intervention was acceptable and feasible among adults with T2DM. Personalized support and accessible resources were key to engagement. Future work should refine delivery to enhance scalability and long-term adherence among high-risk groups.

Humans↗

PubMed2004

Efficacy and tolerability of initial combination therapy with nateglinide and metformin in treatment-naïve patients with type 2 diabetes.

OBJECTIVE: To assess the efficacy and tolerability of the combination of nateglinide (120 mg, ac) and metformin (500 mg, tid) as initial treatment in drug-naïve patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: This study reports data from the treatment-naïve (TN) subgroup of patients in a previously published, randomized, multicenter, placebo-controlled, 24- week trial that compared nateglinide, metformin, and the combination therapy (CT) in 701 patients with T2DM with baseline HbA(1c) between 6.8% and 11.0%. Of the 401 TN patients, 104, 104, 89, and 104 patients received nateglinide (120 mg, ac), metformin (500 mg, tid), CT, and placebo, respectively. The baseline characteristics of each group were similar, with mean age, BMI, duration of diabetes, HbA(1c), and fasting plasma glucose (FPG) levels of approximately 58 years, 30 kg/m(2), 4 Gastrointestinal side effects occurred in 27% of years, 8.2%, and 10.2 mmol/L, respectively. RESULTS: In patients receiving initial CT, HbA(1c) decreased substantially (Delta = -1.6 +/- 0.1%, p < 0.0001 vs. baseline or placebo) from a mean baseline of 8.2 +/- 0.1%, an effect significantly greater than the 0.8% reduction observed with both monotherapies (p < 0.001); whereas, in placebo-treated patients, HbA(1c) increased modestly (Delta = +0.3 +/- 0.1%, p < 0.05) from an identical baseline value. Seventy percent of CT-treated patients achieved a target HbA(1c) of < 7.0%. Both fasting plasma glucose (FPG) and the 2-hour postprandial glucose excursion (PPGE) after a liquid meal challenge decreased by 2.3 mmol/L in patients receiving CT, while the changes from baseline values in FPG and PPGE were +0.2 +/- 0.3 mmol/L and -0.5 +/- 0.2 mmol/L, respectively, in placebo-treated patients. The incremental 30-minute post-load insulin levels increased by 88 +/- 32 pmol/L (p = 0.006) in patients receiving CT and did not change significantly in placebo-treated patients. patients receiving CT (vs. 27.9% in the metformin monotherapy, and 14.4% in the placebo groups). Confirmed hypoglycemia (glucose <or= 2.8 mmol/L) occurred in 3.4% of patients receiving CT. CONCLUSIONS: Initial CT with the rapid-acting insulinotropic agent, nateglinide, and metformin, an agent with insulin-sensitizing effects in the liver and periphery, is a safe and effective means of achieving glycemic targets in TN patients with T2DM.

Cyclohexanes↗

PubMed2005

CARDS on the table: should everybody with type 2 diabetes take a statin?

BACKGROUND: Vascular complications are a major cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The recently published Collaborative Atorvastatin Diabetes Study (CARDS) showed that atorvastatin (10 mg, once daily vs. placebo) markedly reduces vascular events in this high-risk population. The participants (n = 2838) were fairly typical T2DM = 2838) patients without cardiovascular disease and with at least one other risk factor: hypertension, retinopathy, albuminuria or current smoking. In the treatment group, coronary events were reduced by 36% (p = 0.001) and stroke by 48% (p = 0.001). The trial was terminated two years early on ethical grounds. The number needed to treat (NNT) was 27 for four years to prevent one event. However, the benefit may have been greater since a proportion of the placebo group received statin therapy. The benefit from statin treatment was independent of sex, age, baseline lipid levels, was independent of sex, age, baseline lipid levels, systolic blood pressure, retinopathy, albuminuria, systolic blood pressure, retinopathy, albuminuria, smoking or HbA smoking or HbA(1c). The frequency of adverse events did not differ between the groups. These findings support those of other statin trials. SCOPE: CARDS does not comment on renal function. However, other trials suggest that statins preserve renal function in those with and without DM. We discuss the CARDS study in this context in this brief overview paper. CONCLUSIONS: the evidence shows that we need to control glucose to prevent microvascular complications, to lower cholesterol to prevent macrovascular disease and to lower blood pressure to prevent both. It may be that the benefit of statins extends beyond a threshold low-density lipoprotein cholesterol level in patients with T2DM. More trials are needed in this field.

Atorvastatin↗

PubMed2006

Beta2-adrenergic receptor and UCP3 variants modulate the relationship between age and type 2 diabetes mellitus.

BACKGROUND: It is widely accepted that Type 2 Diabetes Mellitus (T2DM) and other complex diseases are the product of complex interplay between genetic susceptibility and environmental causes. To cope with such a complexity, all the statistical and conceptual strategies available should be used. The working hypothesis of this study was that two well-known T2DM risk factors could have diverse effect in individuals carrying different genotypes. In particular, our effort was to investigate if a well-defined group of genes, involved in peripheral energy expenditure, could modify the impact of two environmental factors like age and obesity on the risk to develop diabetes. To achieve this aim we exploited a multianalytical approach also using dimensionality reduction strategy and conservative significance correction strategies. METHODS: We collected clinical data and characterised five genetic variants and 2 environmental factors of 342 ambulatory T2DM patients and 305 unrelated non-diabetic controls. To take in account the role of one of the major co-morbidity conditions we stratified the whole sample according to the presence of obesity, over and above the 30 Kg/m2 BMI threshold. RESULTS: By monofactorial analyses the ADRB2-27 Glu27 homozygotes had a lower frequency of diabetes when compared with Gln27 carriers (Odds Ratio (OR) 0.56, 95% Confidence Interval (CI) 0.36 - 0.91). This difference was even more marked in the obese subsample. Multifactor Dimensionality Reduction method in the non-obese subsample showed an interaction among age, ADRB2-16 and UCP3 polymorphisms. In individuals that were UCP3 T-carriers and ADRB2-16 Arg-carriers the OR increased from 1 in the youngest to 10.84 (95% CI 4.54-25.85) in the oldest. On the contrary, in the ADRB2-16 GlyGly and UCP3 CC double homozygote subjects, the OR for the disease was 1.10 (95% CI 0.53-2.27) in the youngest and 1.61 (95% CI 0.55-4.71) in the oldest. CONCLUSION: Although our results should be confirmed by further studies, our data suggests that, when properly evaluated, it is possible to identify genetic factors that could influence the effect of common risk factors.

Adult↗

PubMed2005

An IGF-I promoter polymorphism modifies the relationships between birth weight and risk factors for cardiovascular disease and diabetes at age 36.

OBJECTIVE: To investigate whether IGF-I promoter polymorphism was associated with birth weight and risk factors for cardiovascular disease (CVD) and type 2 diabetes (T2DM), and whether the birth weight--risk factor relationship was the same for each genotype. DESIGN AND PARTICIPANTS: 264 subjects (mean age 36 years) had data available on birth weight, IGF-I promoter polymorphism genotype, CVD and T2DM risk factors. Student's t-test and regression analyses were applied to analyse differences in birth weight and differences in the birth weight--risk factors relationship between the genotypes. RESULTS: Male variant carriers (VCs) of the IGF-I promoter polymorphism had a 0.2 kg lower birth weight than men with the wild type allele (p = 0.009). Of the risk factors for CVD and T2DM, solely LDL concentration was associated with the genotype for the polymorphism. Most birth weight--risk factor relationships were stronger in the VC subjects; among others the birth weight--systolic blood pressure relationship: 1 kg lower birth weight was related to an 8.0 mmHg higher systolic blood pressure CONCLUSION: The polymorphism in the promoter region of the IGF-I gene is related to birth weight in men only, and to LDL concentration only. Furthermore, the genotype for this polymorphism modified the relationships between birth weight and the risk factors, especially for systolic and diastolic blood pressure.

Journal Article↗

PubMed2004

Vasa vasorum in plaque angiogenesis, metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: a malignant transformation.

BACKGROUND: Vascularization is an exciting and complex mechanism involving angiogenesis and arteriogenesis. The metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) are associated with multiple metabolic toxicities, which result in reactive oxygen species (ROS) due to an elevated tension of oxidative-redox stress and an accelerated atherosclerosis termed atheroscleropathy. RESULTS: This atheroscleropathy is associated with accelerated angiogenesis within the vulnerable, thin-cap fibro-atheroma, prone to rupture resulting in acute coronary syndromes (ACS). The resulting intimopathy with its neovascularization due to angiogenesis of the adventitial vasa vasorum (Vv) is prone to intraplaque hemorrhage (IPH). These IPH are associated with destabilization of the vulnerable plaques resulting in plaque erosion and plaque rupture resulting in ACS. In atheroscleropathy the adventitial Vv invades the plaque in a malignant-like fashion and concurrently is associated with chronic inflammation, as macrophages are being deposited within the shoulder regions of these vulnerable plaques. These angiogenic Vv provide a custom delivery vascular network for multiple detrimental substrates, which further accelerates the growth of these vulnerable plaques and atheroscleropathy. There exists a vascularization paradox in MS and T2DM, in that, angiogenesis within the plaque is induced and arteriogenesis is impaired. CONCLUSION: This review will attempt to provide a database of knowledge regarding the vascularization process (angiogenesis and arteriogenesis) and its mechanisms to better understand the increased cardiovascular risk and the increased morbidity and mortality associated with MS and T2DM.

Journal Article↗

PubMed2006

Will availability of inhaled human insulin (Exubera) improve management of type 2 diabetes? The design of the Real World trial.

BACKGROUND: Common deterrents to insulin therapy for both physicians and patients are the complexity and burden of daily injections. In January 2006, the first inhaled human insulin (INH, Exubera (insulinhuman [rDNA origin])InhalationPowder) was approved for use in adult patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) in the United States and European Union. Results from the INH clinical trial program have shown comparable efficacy of INH to subcutaneous (s.c.) insulin and superior efficacy versus oral antidiabetic agents; thus providing effective glycemic control in adult patients with T2DM without the requirement for preprandial injections. However, because subjects in those trials were randomized to either INH or an alternative, the studies could not estimate the effect of INH on patient acceptance of insulin therapy. Therefore, traditional study designs cannot provide answers to important and practical questions regarding real world effectiveness, which is influenced by psychological and other access barriers. METHODS: To overcome these limitations, the Real World Trial was designed to estimate the effect of the availability of INH as a treatment option for glycemic control. A total of approximately 700 patients from Canada, France, Germany, Italy, Spain, United Kingdom, and the United States with T2DM poorly controlled by oral agent therapy will be randomized to two different treatment settings. Patients and clinicians in both groups (A & B) may choose from all licensed therapies for diabetes including SC insulin delivered by pens; INH will be an additional treatment option only available in Group A. The Real World Trial (Protocol A2171018) has been registered with ClincalTrials.gov, registration id NCT00134147. RESULTS: The primary outcome for the trial will be the difference in mean glycosylated hemoglobin (HbA1c) at 6 months between groups. The design was based on a preceding feasibility study examining the theoretical effects of inhaled insulin availability on treatment choice in 779 patients. In that study, patients were three times more likely to choose insulin therapy when inhaled insulin was available. CONCLUSION: Innovations in study designs may provide an opportunity to reveal unbiased answers to important treatment questions that are more relevant to prescribers, funding agencies, and healthcare policymakers.

Journal Article↗

PubMed2006

A systematic review and meta-analysis of the relationship between lipoprotein lipase Asn291Ser variant and diseases.

This systematic review attempted to summarize the associations between the Asn291Ser variant in the lipoprotein lipase (LPL) gene and dyslipidemia, the risk of type 2 diabetes mellitus (T2DM), and coronary heart disease (CHD). In addition, the relationships between the Asn291Ser variant and other metabolic diseases such as obesity and high blood pressure were also investigated in this systematic review. We systematically reviewed the literature by means of a meta-analysis. Twenty-one articles, including 19,246 white subjects, were selected for this meta-analysis. The summary standardized mean difference (SMD) of plasma triglyceride (TG) for carriers compared with noncarriers of the Asn291Ser variant was 3.23 (P < 0.00001). The summary SMD of plasma HDL-cholsterol (HDL-C) for carriers compared with noncarriers of the Asn291Ser variant was -3.42 (P < 0.0001). The summary SMD of the association of the Asn291Ser variant with plasma TG increased with increasing age and weight gain. Significant interactions between the LPL Asn291Ser variant and fasting glucose, T2DM, and CHD were seen (P = 0.02, 0.04, and 0.01, respectively). No significant interactions were seen between the LPL Asn291Ser variant and body mass index, waist-hip ratio, and blood pressure (P > 0.05). This meta-analysis indicates that the Asn291Ser variant in the LPL gene is a risk factor for dyslipidemia, characterized by hypertriglyceridemia and low HDL-C levels. And the Asn291Ser variant in the LPL gene predisposes to more severe dyslipidemia with increasing age and weight gain. Also, this meta-analysis shows that the LPL Asn291Ser variant is associated with CHD and T2DM.

Amino Acid Substitution↗

PubMed2006

High postprandial triglyceridemia in patients with type 2 diabetes and microalbuminuria.

Microalbuminuria (MA) is an independent risk factor for atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Postprandial lipemia is also associated with excess cardiovascular risk. However, the association between MA and postprandial lipemia in diabetes has not been investigated. A total of 64 patients with T2DM, 30 with and 34 without MA, were examined. Plasma total triglycerides (TGs), triglycerides contained in chylomicrons (CM-TG), and TGs in CM-deficient plasma were measured at baseline and every 2 h for 6 h after a mixed meal. Postheparin LPL and HL activities were also determined. Plasma levels of apolipoprotein A-V (apoA-V), apoC-II, and apoC-III were measured in the fasting state and 2 h postprandially. Patients with MA had higher postprandial total TG levels than those without MA (P < 0.001); this increase been attributed mainly to CM-TG. LPL activity and fasting concentrations of the measured apolipoproteins were not different between the studied groups, whereas HL activity was higher in the patients with MA. ApoC-II and apoC-III levels did not change postprandially in either study group, whereas apoA-V increased more in the patients with MA. These data demonstrate for the first time that MA is characterized by increased postprandial lipemia in patients with T2DM and may explain in part the excess cardiovascular risk in these patients.

Aged↗