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PubMed2003

Barriers to the treatment of adolescent type 2 diabetes--a survey of provider perceptions.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is increasingly common among children and adolescents. However, achievement of good metabolic control has been difficult in this population. The aim of this study was to survey pediatric endocrine and diabetes specialists regarding the issues they consider to be barriers to successful treatment of adolescent T2DM. METHODS: An electronic questionnaire was administered to 220 physicians and nurses attending a conference on pediatric diabetology in 2001. RESULTS: The issues that were most strongly perceived as barriers to successful treatment of adolescents with T2DM were prevalence of high-risk lifestyle in other family members (98%), lack of immediate risk to life reducing patient motivation (89%), lack of guidelines regarding optimal treatment (73%), prevalence of behavioral and/or psychiatric disorders (71%), and cultural/language barriers (65%). The survey also revealed that in the majority of clinics, T2DM education programs were not designed specifically for type 2 patients nor delivered by a specifically trained education team. Furthermore, despite the fact that cultural and ethnic differences were identified as important barries to care, educational materials designed for particular racial and cultural groups were used in only 37% of the clinics. CONCLUSIONS: This survey identifies a number of areas perceived by clinicians to be significant barriers to successful treatment of T2DM in adolescent patients. Given the multiple challenges identified by the survey, programs addressed specifically to the characteristics of adolescents with T2DM will be necessary, including materials appropriate to the developmental stage and ethnic background of patients.

Adolescent↗

PubMed2004

Effect of taurine treatment on insulin secretion and action, and on serum lipid levels in overweight men with a genetic predisposition for type II diabetes mellitus.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) is increasing with an epidemic growth rate. Animal studies with taurine supplementation have shown increased insulin secretion and action, suggesting that taurine supplementation may have a potential to prevent T2DM. OBJECTIVE: To assess the effect of taurine treatment on insulin secretion and action, and on plasma lipid levels in overweight men with a positive history of T2DM. DESIGN: 20 nondiabetic subjects were included in a double-blinded, randomized, crossover study, receiving a daily supplementation of 1.5 g taurine or placebo for two periods of 8 weeks. The subjects were overweight first-degree relatives of T2DM patients. An intravenous glucose tolerance test (IVGTT) was used to measure first-phase insulin secretory response, and a euglycemic hyperinsulinemic clamp was used to determine peripheral insulin action. RESULTS: Mean plasma taurine concentration was 39 +/- 7 (s.d.) micromol/l after placebo and 131 +/- 62 micromol/l after taurine intervention (P < 0.0001). There was no significant difference after taurine intervention compared to placebo in incremental insulin response (Insincr.) neither during the IVGTT, nor in insulin-stimulated glucose disposal during the clamp. Insulin secretion, adjusted for insulin sensitivity, was also unchanged. There was no significant effect of taurine supplementation on blood lipid levels as well. CONCLUSION: Daily supplementation with 1.5 g taurine for 8 weeks had no effect on insulin secretion or sensitivity, or on blood lipid levels. These findings in persons with an increased risk of T2DM are in contrast to those from animal studies, and do not support the assumption that dietary supplementation with taurine can be used to prevent the development of T2DM.

Adult↗

PubMed2005

Leu7Pro polymorphism in the neuropeptide Y (NPY) gene is associated with impaired glucose tolerance and type 2 diabetes in Swedish men.

The neuropeptide Y (NPY) is a neuropeptide with a role in the regulation of satiety and energy balance of body weight, insulin release, cardiovascular and central endocrine systems. In order to evaluate whether the NPY gene variations contribute to development of type 2 diabetes (T2DM), we have performed a genetic association study for Leu7Pro (T1128 C) polymorphism of the NPY gene in impaired glucose tolerance (IGT) and T2DM. Genotyping experiments for this non-synonymous single nucleotide polymorphism (SNP) in 263 patients with T2DM, 309 subjects with IGT and 469 non-diabetic healthy individuals in Swedish Caucasians were performed by using Dynamic Allele Specific Hybridisation (DASH). We found that the frequencies of the "risk" allele C in the subjects with IGT and the patients with T2DM in Swedish men were 13 % (p = 0.002, OR = 3.70, 1.65 - 8.29 95 % CI) and 10 % (p = 0.007, OR = 4.80, 1.47 - 11.33 95 % CI) respectively, which were significantly higher than the C allele frequency in non-diabetic controls (6 %). Furthermore, we found that the carriers with TC and CC genotypes in the subjects with IGT in Swedish men had significantly higher fasting plasma glucose in comparison with the TT carriers (5.6 +/- 0.7 mmol/l vs. 5.2 +/- 0.7 mmol/l, p = 0.021). The present study thus provides the evidence that Leu7Pro polymorphism in the NPY gene is associated with IGT and T2DM in Swedish men, and indicates that the NPY gene variations contribute to development of T2DM. Questions of gender specificity may be explained by genetic backgrounds, sense of coherence for stress and other factors in environment.

Adult↗

PubMed2004

The G/G genotype of a resistin single-nucleotide polymorphism at -420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3.

Insulin resistance is a major cause of type 2 diabetes mellitus (T2DM). Resistin, an adipocyte-secreted hormone, antagonizes insulin. Transgenic mice that overexpress the resistin gene (Retn) in adipose tissue are insulin-resistant, whereas Retn (-/-) mice show lower fasting blood glucose, suggesting that the altered Retn promoter function could cause diabetes. To determine the role of RETN in human T2DM, we analyzed polymorphisms in its 5' flanking region. We found that the -420G/G genotype was associated with T2DM (397 cases and 406 controls) (P=.008; adjusted odds ratio = 1.97 [by logistic regression analysis]) and could accelerate the onset of disease by 4.9 years (P=.006 [by multiple regression analysis]). Meta-analysis of 1,888 cases and 1,648 controls confirmed this association (P=.013). Linkage disequilibrium analysis revealed that the -420G/G genotype itself was a primary variant determining T2DM susceptibility. Functionally, Sp1 and Sp3 transcription factors bound specifically to the susceptible DNA element that included -420G. Overexpression of Sp1 or Sp3 enhanced RETN promoter activity with -420G in Drosophila Schneider line 2 cells that lacked endogenous Sp family members. Consistent with these findings, fasting serum resistin levels were higher in subjects with T2DM who carried the -420G/G genotype. Therefore, the specific recognition of -420G by Sp1/3 increases RETN promoter activity, leading to enhanced serum resistin levels, thereby inducing human T2DM.

Aged↗

PubMed2003

Algorithmic evaluation of metabolic control and risk of severe hypoglycemia in type 1 and type 2 diabetes using self-monitoring blood glucose data.

The optimization of metabolic control in Type 1 and Type 2 diabetes mellitus (T1DM and T2DM, respectively) [i.e., the maintenance of near-normal hemoglobin A(1c) (HbA(1c)) without increasing the risk of hypoglycemia] could be enhanced by analysis of self-monitoring blood glucose (SMBG) data assessing complementary processes: exposure to hyperglycemia and hypoglycemia. We present algorithms that simultaneously estimate HbA(1)c and risk for significant hypoglycemia using 45-60 days of SMBG. The algorithms were developed using a primary data for 96 subjects with T1DM (n = 48) and T2DM, and were validated in an external data for 520 subjects with T1DM (n = 231) and T2DM. All subjects were on insulin. In the primary (external) data the estimation of HbA(1c) had absolute error of 0.5 (0.7) units of HbA(1c) and percent error of 6.8% (8.1%); 96% (96%) of all estimates were within 20% from reference HbA(1c). The SMBG-estimated value of HbA(1c) was closer to current reference HbA(1c) than a reference HbA(1c) value taken only 2-3 months ago. The results in T1DM and T2DM were similar. Linear model predicted future significant hypoglycemia (R(2) = 62%, p < 0.0001). The leading predictor was a previously introduced Low Blood Glucose Index, which alone had R(2) = 55%. Probability model assessed accurately the odds for future moderate/severe hypoglycemia (coefficients of determination 92%/94%). Four risk categories were identified; within moderate- and high-risk category, there was no difference between T1DM and T2DM in the occurrence of prospective significant hypoglycemia. SMBG data allow for accurate estimation of the two most important markers of metabolic control in T1DM and T2DM - HbA(1c) and risk for hypoglycemia.

Adult↗

PubMed2005

Use of chromium picolinate and biotin in the management of type 2 diabetes: an economic analysis.

This paper addresses the potential economic benefits of chromium picolinate plus biotin (Diachrome) use in people with Type 2 diabetes (T2DM). The economic model was developed to estimate the impact on health care systems' costs by improved HbA1C levels with chromium picolinate plus biotin (Diachrome). Lifetimes cost savings were estimated by adjusting a benchmark from the literature, using a price index to adjust for inflation. The cost of diabetes is highly dependent on the HbA1C level with higher initial levels and higher annual increments increasing the cost. Improvement in glycemic control has proven to be cost-effective in delaying the onset and progression of T2DM, reducing the risk for diabetes-associated complications and lowering utilization and cost of care. Chromium picolinate plus biotin (Diachrome) showed greater improvement of glycemic control in poorly controlled T2DM patients (HbA(1C) > or = 10%) compared to their better controlled counterparts (HbA(1C) < 10%). This improvement was additive to that achieved by oral hypoglycemic medications and correlates to calculated levels of cost savings. Average 3-year cost savings for chromium picolinate plus biotin (Diachrome) use could range from 1,636 dollars for a poorly controlled patient with diabetes without heart diseases or hypertension, to 5,435 dollars for a poorly controlled patient with diabetes, heart disease, and hypertension. Average 3-year cost savings was estimated to be between 3.9 billion dollars and 52.9 billion dollars for the 16.3 million existing patients with diabetes. Chromium picolinate plus biotin (Diachrome) use among the 1.17 million newly diagnosed patients with T2DM each year could deliver lifetime cost savings of 42 billion dollars, or 36,000 dollars per T2DM patient. Affordable, safe, and convenient, chromium picolinate plus biotin (Diachrome) could prove to be a cost-effective complement to existing pharmacological therapies for controlling T2DM.

Biotin↗

PubMed2006

Assessing progression to impaired glucose tolerance and type 2 diabetes mellitus.

BACKGROUND: A prospective evaluation of the relationship between insulin secretion and insulin sensitivity, derived from the fasting state, is needed in clinical practice in order to identify the worsening of glucose metabolism. In this study the authors examine whether the product of insulin sensitivity and insulin secretion, assessed from the fasting state, predicts progression from normal glucose tolerance (NGT) to impaired fasting glucose (IFG) and from impaired glucose tolerance (IGT) to type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A cohort of 300 subjects with NGT and 75 subjects with IGT were followed up over a 5-year period. Insulin sensitivity was calculated using the Belfiore index (B) and insulin secretion by the homeostasis model analysis beta-cell (HOMA-beta cell) index: the product of B-beta is expressed as: (40 x Ins(0) pmol L(-1))/Glu(0) mmol L(-1){[(Glu(0) mmol L(-1)x Ins(0) pmol L(-1)) + 1] - 3.5[(Glu(0) mmol L(-1) x Ins(0) pmol L(-1)) - 1]}, where Glu(0) is fasting glucose and Ins(0) is fasting insulin. RESULTS: From baseline at the end of the follow-up period, the product B-beta decreased 10.7% and 52.2% in progressors to IGT and T2DM, respectively. The product B-beta predicts the progression from NGT to IGT [relative risk (RR) 2.7, CI(95%) 1.2-9.1] and from IGT to T2DM (RR 5.3, CI(95%) 1.3-8.55). The cut-off point for the product B-beta that better predicts progression from NGT to IGT is 0.25 (sensitivity 88%, specificity 92%) and from IGT to T2DM 0.15 (sensitivity 92%, specificity 95%). CONCLUSIONS: Adaptation of insulin secretion to compensate for decreased insulin sensitivity during transition to IGT and T2DM can be successfully assessed with simple measures derived from the fasting state. The product B-beta predicts the development to IGT and T2DM.

Adult↗

PubMed2005

Neuropsychiatric disorders at the presentation of type 2 diabetes mellitus in children.

OBJECTIVES: To estimate the frequency of neuropsychiatric disease (NPD) in an urban pediatric type 2 diabetes mellitus (T2DM) population, to compare demographic characteristics of affected patients with those unaffected with NPD, and to determine the frequency of psychotropic medication treatment. STUDY DESIGN: Retrospective chart review of patients with T2DM at the Children's Hospital of Philadelphia. RESULTS: Of 237 patients with T2DM, 46 (19.4%) were found to have NPD at the presentation of diabetes. Diagnoses by report included depression, attention-deficit hyperactivity disorder (ADHD), neurodevelopmental disorders, schizophrenia, and bipolar disorder. Those affected were 63% females and 37% males, with a mean age of 14.6 yr and body mass index (BMI) of 34.3 kg/m(2) at diagnosis of T2DM. Patients were 79% African American, 13% Caucasian, 4.3% Hispanic, and 4.3% Asian. There were no statistically significant differences in demographic characteristics or BMI between those affected and unaffected with NPD. Twenty-nine patients (63%) were on psychotropic medication and were prescribed 58 medications, most commonly mood stabilizers (n = 20) and atypical antipsychotics (n = 17). CONCLUSIONS: Our data reveal a high frequency of NPD among pediatric patients with T2DM at presentation to a tertiary care, urban medical center. Many affected patients are receiving psychotropic medication. These data have implications for screening regimens for pediatric populations at high risk for T2DM and for therapeutic interventions, including lifestyle measures.

Adolescent↗

PubMed2006

Prolonged deterioration of endothelial dysfunction in response to postprandial lipaemia is attenuated by vitamin C in Type 2 diabetes.

BACKGROUND: Endothelial dysfunction (ED) has been described in Type 2 diabetes (T2DM). We have described previously a diminution of flow-mediated arterial dilatation and, by implication, further ED in T2DM in response to postprandial lipaemia (PPL) at 4 h. This is possibly mediated by oxidative stress/alteration of the nitric oxide (NO) pathway. T2DM subjects tend to exhibit both exaggerated and prolonged PPL. We therefore studied the relationship of PPL to the duration of ED in T2DM subjects and oxidative stress with or without the antioxidant, vitamin C. METHODS: Twenty subjects with T2DM with moderate glycaemic control (mean HbA1c 8.4%) were studied. After an overnight fast, all subjects consumed a standard fat meal. Endothelial function (EF), lipid profiles, and venous free radicals were measured in the fasting, peak lipaemic phase (4 h) and postprandially to 8 h. The study was repeated in a double-blinded manner with placebo, vitamin C (1 g) therapy for 2 days prior to re-testing and with the fat meal. Oxidative stress was assessed by lipid-derived free radicals in plasma, ex vivo by electron paramagnetic resonance spectroscopy (EPR) and by markers of lipid peroxidation (TBARS). Endothelial function was assessed by flow-mediated vasodilatation (FMD) of the brachial artery. RESULTS: There was a significant decrease in endothelial function in response to PPL from baseline (B) 1.3 +/- 1.3% to 4 h 0.22 +/- 1.1% (P < 0.05) and 8 h 0.7 +/- 0.9% (P < 0.05) (mean +/- sem). The endothelial dysfunction seen was attenuated at each time point with vitamin C. Baseline EF with vitamin C changed from (fasting) 3.8 +/- 0.9-2.8 +/- 0.8 (at 4 h) and 2.9 +/- 1.3 (at 8 h) in response to PPL. Vitamin C attenuated postprandial (PP) oxidative stress significantly only at the 4-h time point [301.1 +/- 118 (B) to 224.7 +/- 72 P < 0.05] and not at 8 h 301.1 +/- 118 (B) to 260 +/- 183 (P = NS). There were no changes with placebo treatment in any variable. PPL was associated with a PP rise in TG levels (in mmol/l) from (B) 1.8 +/- 1 to 2.7 +/- 1 at 4 h and 1.95 +/- 1.2 at 8 h (P = 0.0002 and 0.33, respectively). CONCLUSION: PPL is associated with prolonged endothelial dysfunction for at least 8 h after a fatty meal. Vitamin C treatment improves endothelial dysfunction at all time points and attenuates PPL-induced oxidative stress. This highlights the importance of low-fat meals in T2DM and suggests a role for vitamin C therapy to improve endothelial function during meal ingestion.

Administration, Oral↗

PubMed2005

Tracking ancient pathways to a modern epidemic: diabetic end-stage renal disease in Saskatchewan aboriginal people.

BACKGROUND: Saskatchewan aboriginal people are experiencing an epidemic of type 2 diabetes (T2DM) and diabetic end-stage renal disease (DESRD). The purpose of these investigations was to study the role of the intrauterine environment in the emergence of these diseases. METHODS: Epidemiologic studies were carried out using data from the Provincial Department of Health databases, the Saskatoon Health Region obstetrical unit, the Saskatchewan Renal Transplant Program, surveys of Saskatchewan aboriginal communities, and the Canadian Organ Replacement Registry. Parameters analyzed included rates, risk factors, and outcomes of T2DM, gestational diabetes (GDM), and DESRD; birth registration information; anthropometric measurements; and human leukocyte antigen profiles. RESULTS: Aboriginal ethnicity is an independent predictor of GDM. High rates of GDM appear in remote aboriginal communities before the significant appearance of T2DM and are associated with increasing rates of high birth weight. A significant relationship between high-birth-weight rates and T2DM has strengthened over several decades. Finally, higher birth weights and older mother's age (both associated with GDM), and increased frequencies of the human leukocyte antigen-A2/DR4 and A2/DR8 haplotypes are associated with DESRD among aboriginal people. CONCLUSION: It is likely that diabetic pregnancies play a key role in the initiation, progression, and perpetuation of the T2DM epidemic among Canadian aboriginal peoples, and may additionally increase the risk for DESRD. We speculate that an ancient survival advantage that promoted caloric conservation in young women and their unborn children is now a risk factor for prepregnancy obesity, GDM, and excess fetal nutrition. Infants are often large and have an increased risk for T2DM and its complications (hefty fetal-type hypothesis).

Adult↗

PubMed2003

Basal and dynamic proinsulin-insulin relationship to assess beta-cell function during OGTT in metabolic disorders.

The fasting proinsulin-to-insulin ratio is a currently used marker of beta-cell dysfunction. This ratio is calculated at the basal condition, but its behavior in dynamic conditions, i.e., during glucose stimulation, could be more informative. Given the different kinetics of the peptides, a mathematical model was necessary to analyze the oral glucose tolerance test (OGTT) data of insulin, C-peptide, and proinsulin in 55 healthy (NGT), 30 impaired glucose-tolerant (IGT), and 31 type 2 diabetic (T2DM) subjects. The model provided for secretion and disappearance of the peptides and an index of beta-cell function under dynamic conditions. Total proinsulin secretion during the OGTT was not different (P > 0.053) among NGT (0.17 +/- 0.01 mmol/l in 3 h), IGT (0.22 +/- 0.02), and T2DM (0.21 +/- 0.02) subjects. The proinsulin-to-insulin molar ratio measured from basal samples was higher (P < 0.0001) in T2DM (0.39 +/- 0.05) than in NGT (0.14 +/- 0.01) and IGT (0.13 +/- 0.02) subjects, and similar results (P < 0.003) were found by the dynamic index (0.27 +/- 0.04, 0.14 +/- 0.01, 0.15 +/- 0.01 in T2DM, NGT, IGT subjects, respectively). The basal ratio significantly correlated with the dynamic index, and the regression line slope was lower than 1 (0.43 +/- 0.08, 0.61 +/- 0.10, and 0.56 +/- 0.03 in NGT, IGT, and T2DM subjects, respectively, P < 0.0001). Impaired beta-cell function in T2DM could then be indicated by proinsulin-to-insulin indexes at both basal and dynamic phases.

Adult↗

PubMed2005

Delayed threshold for active cutaneous vasodilation in patients with Type 2 diabetes mellitus.

Epidemiological evidence suggests decreased heat tolerance in patients with Type 2 diabetes mellitus (T2DM), but it is not known whether the mechanisms involved in thermoregulatory control of skin blood flow are altered in these patients. We tested the hypothesis that individuals with T2DM have a delayed internal temperature threshold for active cutaneous vasodilation during whole body heating compared with healthy control subjects. We measured skin blood flow using laser-Doppler flowmetry (LDF), internal temperature (T or) via sublingual thermocouple, and mean arterial pressure via Finometer at baseline and during whole body heating in 9 T2DM patients and 10 control subjects of similar age, height, and weight. At one LDF site, sympathetic noradrenergic neurotransmission was blocked by local pretreatment with bretylium tosylate (BT) to isolate the cutaneous active vasodilator system. Whole body heating was conducted using a water-perfused suit. There were no differences in preheating T(or) between groups (P > 0.10). Patients with T2DM exhibited an increased internal temperature threshold for the onset of vasodilation at both untreated and BT-treated sites. At BT-treated sites, T or thresholds were 36.28 +/- 0.07 degrees C in controls and 36.55 +/- 0.05 degrees C in T2DM patients (P < 0.05), indicating delayed onset of active vasodilation in patients. Sensitivity of vasodilation was variable in both groups, with no consistent difference between groups (P > 0.05). We conclude that altered control of active cutaneous vasodilation may contribute to impaired thermoregulation in patients with T2DM.

Adrenergic Antagonists↗

PubMed2004

Advances in the treatment of diabetic renal disease: focus on losartan.

Diabetic nephropathy is the leading cause of end stage renal disease (ESRD), and given that treating this condition is a considerable economic burden, the prevention of ESRD is a major public health goal. The renin-angiotensin system (RAS) is aberrantly activated in patients with diabetes. Angiotensin II (AII), a downstream effector of the RAS, has haemodynamic and non-haemodynamic effects that contribute to the development and progression of nephropathy. For patients with type 2 diabetes mellitus (T2DM) and hypertension, an AII receptor blocker (AIIRB) is recommended as the first drug that should be used. This review will focus on the rationale for the use of losartan as a treatment for nephropathy associated with T2DM. In animal models of diabetes, losartan reduced proteinuria and conferred renal protection. In RENAAL (Reduction in Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan), the first major randomised trial that investigated the benefit of losartan in patients with T2DM and nephropathy, losartan significantly reduced the risk of a doubling of serum creatinine and progression to ESRD, significantly lowered the levels of proteinuria and slowed the rate of decline in glomerular filtration rate. This review also discusses other clinical trials of losartan and other AIIRBs in T2DM, and considers alternative mechanisms by which losartan may be exerting its effects. The collective experience in treatment trials highlighted in this review indicate that losartan and other AIIRBs can reduce blood pressure and the progression of proteinuria in diabetic renal disease. However, losartan is thus far the only AIIRB that has been shown to reduce significantly the risk of ESRD and cardiovascular events in patients with T2DM. Its use in hypertensive patients with T2DM and nephropathy may play an important role in reducing the burden of ERSD.

Angiotensin Receptor Antagonists↗

PubMed2024

Association between OX40L polymorphism and type 2 diabetes mellitus in Iranians.

INTRODUCTION: Diabetes mellitus (DM) is one of the leading causes of morbidity and mortality worldwide. It is a multifactorial disease that genetic and environmental factors contribute to its development. The aim of the study was to investigate the association of OX40L promoter gene polymorphisms with type 2 diabetes mellitus (T2DM) in Iranians. MATERIALS AND METHODS: Three hundred and sixty-eight subjects including 184 healthy subjects and 184 T2DM patients were enrolled in our study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied to detect genotype and allele frequencies of rs3850641, rs1234313 and rs10912580. In addition, SNPStats web tool was applied to estimate haplotype frequency and linkage disequilibrium (LD). RESULTS: The distribution of tested polymorphisms was statistically different between the T2DM patients and healthy subjects (P < 0.01). rs1234313 AG (OR = 0.375, 95% CI = 0.193-0.727, P = 0.004) and rs10912580 AG (OR = 0.351, 95% CI = 0.162-0.758, P = 0.008) genotypes were associated with the decreased risk of T2DM in Iranians. Moreover, our prediction revealed that AAG (OR = 0.46, 95% CI= (0.28-0.76), P = 0.0028) and GAG (OR = 0.24, 95% CI= (0.13-0.45), P < 0.0001) haplotypes were related to the reduced risk of the disease. However, the tested polymorphisms had no effect on biochemical parameters and body mass index (BMI) in the patient group (P > 0.05). CONCLUSION: Our findings revealed that OX40L promoter gene polymorphisms are associated with T2DM. Moreover, genotype and allelic variations were related to the decreased risk of T2DM in Iranians. Further studies are recommended to show whether these polymorphic variations could affect OX40/OX40L interaction or OX40L phenotype.

Adult↗

PubMed2002

Perspective: the search for genes for type 2 diabetes in the post-genome era.

Twin and family studies have demonstrated a strong genetic component to type 2 diabetes mellitus (T2DM), but mapping the susceptibility genes that account for this risk has proved difficult. At least seven single gene defects are known to cause T2DM, often with early onset and insulin deficiency, but these causes account for 5% or less of all T2DM. A large number of candidate genes have been evaluated for typical T2DM, but few have been confirmed in multiple studies, and among these, the effect on individual risk is modest. A large number of genome-wide scans have been published in the last few years, and at least four regions show evidence in multiple studies. However, only NIDDM1 has been mapped to a single gene, and that gene (calpain 10) appears to have a major role only in selected populations. Work is ongoing in many laboratories and multiple populations to map additional regions, but T2DM and other complex diseases have proved recalcitrant to current methodology. In addition to the ongoing progress in completing the genome sequence and in developing a comprehensive map of single nucleotide polymorphisms, new statistical models will be needed to incorporate the multiple loci with modest effect and the known environmental interactions that characterize the susceptibility to T2DM.

Animals↗

PubMed2004

Body mass index and C-174G interleukin-6 promoter polymorphism interact in predicting type 2 diabetes.

Increased levels of IL-6 add further risk to the impact of obesity in respect to the development of type 2 diabetes mellitus (T2DM). A C-174G polymorphism within the IL-6 promoter region was shown to influence transcription rate of IL-6. We made use of a nested case-control study within the European Prospective Investigation into Cancer and Nutrition-Potsdam cohort of 27,548 individuals, selecting 188 T2DM cases and 376 controls to investigate this polymorphism in respect to development of T2DM. This polymorphism was found to modify the correlation between body mass index (BMI) and IL-6 by showing a much stronger increase of IL-6 at increased BMI for CC genotypes compared with GG genotypes. Interestingly, C-174G polymorphism was found to be an effect modifier for the impact of BMI regarding T2DM. Whereas BMI greater than or equal to 28 kg/m(2) increased the risk of T2DM 3.44-fold [95% confidence interval (CI), 1.34- to 8.24-fold] for GG genotypes and 2.94-fold (95% CI, 1.56- to 5.56-fold) for GC genotypes, we found a 17.68-fold (95% CI, 3.57- to 87.66-fold) increase in risk for CC genotypes. In conclusion, obese individuals with BMI greater than or equal to 28 kg/m(2) carrying the CC genotype showed a more than 5-fold increased risk of developing T2DM compared with the remaining genotypes and, hence, might profit most from weight reduction.

Body Mass Index↗

PubMed2004

Fluvastatin slow-release lowers platelet-activating factor acetyl hydrolase activity: a placebo-controlled trial in patients with type 2 diabetes.

Fluvastatin reduces atherogenic dense low-density lipoprotein (dLDL) in patients with type 2 diabetes mellitus (T2DM). dLDLs are associated with platelet-activating factor acetyl hydrolase (PAF-AH), an enzyme involved in inflammation and related to coronary artery disease (CAD). The association of preexisting CAD and PAF-AH and the effect of fluvastatin on enzyme activity is investigated in a placebo-controlled trial in patients with T2DM. A multicenter, double-blind, randomized comparison of fluvastatin XL (80 mg) (n = 42) and placebo (n = 47), each given once-daily for 8 wk, in 89 patients with T2DM, was conducted. At baseline and on treatment, lipoproteins, including lipoprotein (a) [Lp(a)] and LDL subfractions, and the activity of PAF-AH were measured. Increasing PAF-AH activity was significantly associated with a positive history of CAD (+0.7% per IU/liter PAH-AH; P = 0.010), the odds ratio estimate adjusted for age, gender, and body mass index of the highest quartile being 10.6 (P = 0.036). At baseline and at study end, PAF-AH activity was associated with the apolipoprotein B (apoB) content in dLDL (LDL-5 and LDL-6) (r = 0.447; P < 0.001 and r = 0.651; P < 0.001, respectively) and with non-HDL cholesterol at baseline (r = 0.485; P < 0.001). However, after additional adjustment for apoB in dLDL and non-HDL cholesterol at baseline, the odds ratio increment for CAD across PAF-AH quartiles was 2.09 (95% confidence interval, 1.02-4.29; P = 0.043). Fluvastatin treatment decreased the activity of PAF-AH by 22.8% compared with an increase of 0.4% in the placebo group (P < 0.001). This effect was independent of changes of Lp(a) concentrations. In patients with T2DM, PAF-AH activity is associated with a positive history of CAD. Fluvastatin not only decreases atherogenic dLDL but also PAF-AH activity, emphasizing the significance of fluvastatin treatment in T2DM. The antiatherogenic potential of fluvastatin in T2DM may thus be greater than expected from its effects on LDL-C and triglycerides alone.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2005

Beta-cell function, insulin sensitivity, and glucose tolerance in obese diabetic and nondiabetic adolescents and young adults.

CONTEXT: Type 2 diabetes mellitus (T2DM) is estimated to account for 10-45% of incident pediatric diabetes cases. OBJECTIVE: Our objective was to characterize the metabolic defects underlying T2DM in adolescents and young adults. DESIGN, SETTING, AND PATIENTS: We conducted a cross-sectional study of islet function and insulin sensitivity in 16 adolescents with T2DM and 13 obese (OB) and 13 lean (LN) age-matched nondiabetic subjects at a University Medical Center. INTERVENTION: We provided oral and iv glucose tolerance tests. MAIN OUTCOME MEASURES: We measured insulin and glucagon levels, insulin sensitivity, acute insulin responses to iv glucose, and the ratio of proinsulin to immunoreactive insulin. RESULTS: The diabetic subjects had elevated fasting insulin levels and significantly reduced insulin sensitivity (P < 0.05). The acute insulin response to iv glucose was comparable in the T2DM and LN groups (P < 0.05 for the OB vs. LN and T2DM), but insulin secretion adjusted for insulin resistance, the disposition index, was severely impaired in the diabetic subjects (P < 0.05 for the T2DM vs. LN and OB). The ratio of proinsulin to immunoreactive insulin did not differ among the three groups in the basal or stimulated state. Plasma glucagon levels were comparable before and after ingestion of glucose. CONCLUSIONS: These findings demonstrate that diabetic adolescents have significant insulin resistance, even compared with subjects of similar obesity and body fatness, and impaired insulin secretion relative to their degree of insulin resistance. However, the adolescent diabetic subjects retained a first-phase insulin response to glucose that was comparable to lean controls and did not have hyperproinsulinemia or hyperglucagonemia.

Adolescent↗