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The changing spectrum of diabetes in Mexican American youth.

Type 2 diabetes (T2DM) is now a pediatric disease. As in adults, it disproportionately affects ethnic and racial minorities, including Hispanics. The preponderance of Hispanics in south Texas are of Mexican American (MA) heritage. Over the past 16 years, we have accumulated a large cohort of children with diabetes. We have noted distinct differences in numerous parameters between MA children with T2DM and those with type 1 diabetes (T1DM). In order to explore these observations, we have reviewed the records of all children diagnosed with diabetes (n = 669) during the 9 years between January, 1990 and December, 1998 and seen by our pediatric diabetes group. In this cohort were 329 MA, 287 non-Hispanic whites (EA) and 53 African Americans. Compared to EA children with T1DM, MA children were more likely to have a parent with diabetes, to be hospitalized at the time of diagnosis and to lack health insurance. The differences between MA children with T1DM and T2DM were significant: specifically, children with T2DM were more likely to be female and pubertal with a body mass index >25 kg/m(2) and have acanthosis nigricans. Slightly more than 2/3 of the MA children with T2DM had at least one parent already diagnosed with T2DM. Less than 1/3 of the children with T2DM required hospitalization at the time of diagnosis and only a 1/4 have private health insurance. Over this 9-year interval, the apparent incidence of diabetes almost tripled in south Texas with the great majority of that increase due to the increasing numbers of children with T2DM.

Child↗

Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) and hypertension (HT) commonly coexist. While endothelial nitric oxide synthase (eNOS) haplotypes have been associated with HT, it is unknown whether eNOS genotypes/haplotypes are associated with altered susceptibility to HT in patients with T2DM. We studied the distribution of three eNOS genetic polymorphisms: a single nucleotide polymorphism in the promoter region (T(-786)C), in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4(b/a). Genotypes were determined for 102 healthy controls, 119 patients with HT, 66 patients with T2DM, and 113 patients with T2DM+HT. In addition, we also compared the distribution of eNOS haplotypes in the four groups of subjects. No differences were found in genotype and allele distribution among the four groups. Conversely, the haplotypes "C Glu b" and "C Asp b" were, respectively, more and less common in healthy controls than in HT or in T2DM+HT groups (24% versus 6% and 5%, respectively; both P<0.00625; and 8% versus 18% and 18%, respectively; both P<0.00625). Moreover, DM patients presented an overall distribution of eNOS haplotypes that was not different from healthy controls (P>0.05). Additionally, the haplotypes "C Glu b" and "C Asp b" were, respectively, more and less common in T2DM group than in T2DM+HT group (19% versus 5%; and 7% versus 18%, respectively; both P<0.00625). Our findings suggest a protective effect for eNOS haplotype "C Glu b" against the development of hypertension, and that haplotype "C Asp b" increases the susceptibility to hypertension in patients without or with T2DM.

Alleles↗

Association of interleukin-10 A-592C and T-819C polymorphisms with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is the most common form of diabetes. The association of low interleukin (IL)-10 production capacity with the metabolic syndrome and T2DM was recently established. Approximately 75% of the variation in IL-10 secretion capacity in humans derives from genetic factors that contribute to disease susceptibility. Based on the facts that IL-10 secretion ability is tightly controlled at the transcription level and the low production capacity of IL-10 is associated with T2DM, it seemed tempting to investigate if polymorphisms in the IL-10 gene promoter contribute to T2DM. IL-10 promoter polymorphisms at positions -592 and -819 among 370 consecutive patients with T2DM seen at the Department of Internal Medicine, Chung Shan Medical University Hospital, were examined using polymerase chain reaction restriction fragment length polymorphism. Though no significant association was detected between either the A-592C (p=0.088) or T-819C (p=0.160) polymorphism and T2DM, significantly more T2DM subjects carried -592*C (34.28%, p=0.027) and -819*C (32.57%, p<0.001) alleles, which were associated with high levels of IL-10 production. Nevertheless, no association was observed between these two polymorphisms and biochemical markers for T2DM. Our study suggests that IL-10 genetic polymorphisms may play a specific role(s) in determining diabetic susceptibility, but do not seem to be important in the clinical manifestations of diabetes.

Aged↗

Microalbuminuria and abnormal ambulatory blood pressure in adolescents with type 2 diabetes mellitus.

OBJECTIVE: To determine whether risk factors for cardiovascular disease and diabetic nephropathy, as evidenced by abnormalities of ambulatory blood pressure (ABP), dyslipidemia, and microalbuminuria (MA), are present in adolescents with type 2 diabetes mellitus (T2DM). STUDY DESIGN: We enrolled 26 minority adolescents recently diagnosed with T2DM and 13 obese control subjects without diabetes mellitus. ABP monitoring was performed, and a 24-hour urine, a fasting lipid profile, blood urea nitrogen, creatinine, homocysteine, and hemoglobin A 1 c levels were obtained. The patients with T2DM underwent echocardiograms. RESULTS: Forty percent of the patients with T2DM had MA (> or = 30 mg of microalbumin/day), compared with none of the control subjects ( P < .05). There were no significant differences between patients with T2DM who had MA and patients with T2DM who didn't have MA in demographics, characteristics, casual BP, echocardiographic findings, and hemoglobin A 1 c levels. Average daytime systolic BP was greater in patients with T2DM with MA than patients without MA (129 versus 121 mm Hg, P = .03) and compared with the control subjects (113 mm Hg, P = .01). Patients with MA had an average daytime systolic BP load that was higher than patients without MA (37.1 versus 5.1%, P = .008) and compared with the control subjects (2.6%, P < .001). CONCLUSION: As in adults, adolescents with T2DM exhibit abnormalities of ABP, dyslipidemia, and microalbuminuria.

Adolescent↗

Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease.

A number of well-designed epidemiological studies have linked type 2 diabetes mellitus (T2DM) with an increased risk of Alzheimer's disease (AD). Several mechanisms could help to explain this proposed link, including insulin and insulin resistance, inflammatory cytokines, and oxidative stress. Obesity or physical inactivity might also influence AD through effects on hypertension, insulin sensitivity or inflammation. Typical AD pathology, such as amyloid-beta deposits, might be exacerbated by insulin dysregulation, T2DM itself, or microvascular disease that is a consequence of T2DM. T2DM patients are not routinely evaluated for cognitive outcomes, and cognitive impairment in T2DM is rarely treated. Similarly, AD patients are not routinely evaluated for T2DM or hyperinsulinemia. Current treatments for AD have only modest benefits, and several drugs that target metabolic and inflammatory pathways are being evaluated, most notably the statins, which reduce LDL and inflammation but might not influence amyloid- deposition, an important precursor for AD. Although some evidence supports a potentially important role for peroxisome proliferative activated receptor agonists such as glitazones, at present there are no published randomized clinical trials in AD patients of any drugs that target insulin or insulin resistance. Clinical implications of the T2DM-AD link include cognitive evaluations of patients with T2DM, and potential benefits for such patients through treatment with statins or diabetes drugs that target insulin.

Age of Onset↗

Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients.

The relationship between basal serum tumor necrosis factor alpha (TNFalpha) levels and peripheral tissue (muscle) sensitivity to insulin was examined in 63 subjects with normal glucose tolerance (NGT), 18 subjects with impaired glucose tolerance (IGT), and 123 patients with type 2 diabetes mellitus (T2DM). The BMI was similar in NGT (28.8+/-0.7 kg/m(2)), IGT (31.1+/-1.0), and T2DM (30.0+/-0.4) groups. The fasting serum TNFalpha concentration in T2DM (4.4+/-0.2 pg/ml) was significantly higher than in NGT (3.1+/-0.2) and IGT (3.4+/-0.2; both P<0.05). In T2DM the fasting plasma glucose (FPG=183+/-5 mg/dl) and insulin (FPI=17+/-1 micro U/ml) concentrations were significantly higher than in NGT (FPG=95+/-1; FPI=10+/-1) and IGT (FPG=100+/-2; FPI=13+/-1; all P<0.01). The rate of total body insulin-mediated glucose disposal (Rd; 40 mU/m(2) min euglycemic insulin clamp in combination with (3)H-glucose) was reduced in T2DM (102+/-3 mg/m(2) min) compared with NGT (177+/-10) and IGT (151+/-14; both P<0.01). The serum TNFalpha concentration was inversely correlated with Rd (r=-0.47, P<0.0001) and positively correlated with both FPG (r=0.32, P=0.004) and FPI (r=0.32, P=0.004) in NGT plus IGT. No correlation was observed between serum TNFalpha and Rd (r=-0.02), FPG (r=0.15), or FPI (r=0.15) in T2DM. In stepwise multiple regression analysis using age, sex, BMI, FPG, FPI and serum TNFalpha concentration as independent variables, only BMI and serum TNFalpha concentration were significant and independent predictors of Rd (r(2)=0.29, P<0.0001) in the NGT plus IGT group, while FPG and FPI were significant and independent predictors of Rd (r(2)=0.13, P<0.0001) in T2DM. These results suggest that: (i) an increase in circulating TNFalpha concentration is associated with peripheral insulin resistance and increased plasma glucose and insulin levels prior to the onset of type 2 diabetes; and (ii) the further deterioration in peripheral insulin resistance in T2DM (compared with NGT and IGT) is unrelated to the increase in serum TNFalpha concentration.

Adult↗

The SREBF-1 locus is associated with type 2 diabetes and plasma adiponectin levels in a middle-aged Austrian population.

CONTEXT: The sterol regulatory element-binding protein-1c (SREBP-1c) is a transcription factor involved in the regulation of lipid and glucose metabolism and has been implicated in the pathophysiology of type 2 diabetes mellitus (T2DM). OBJECTIVE: We aimed to confirm associations of the SREBF-1 gene with T2DM in an Austrian population and to study possible associations with diabetes-related quantitative traits. DESIGN, SETTINGS AND PARTICIPANTS: We genotyped a diabetic cohort (n=446) along with a control group (n=1524) for a common C/G variation that is located in exon 18c (rs2297508) and has been associated with obesity and T2DM in French populations. MAIN OUTCOME MEASURES: Body mass index (BMI), indices of insulin sensitivity and beta-cell function, plasma adiponectin, T2DM and single-nucleotide polymorphism rs2297508. RESULTS: Genotype distributions associated with rs2297508 differed by T2DM status (P=0.0045), but not by BMI. The variant G allele was associated with a modest, but significant, increase in the prevalence of T2DM after adjustment for age, sex and BMI (G/G: odds ratios (OR) (95% confidence intervals)=1.45 (0.99-2.11) and G/C: OR=1.37 (1.04-1.81)). In a cross-sectional population of non-diabetic subjects, associations of rs2297508 genotypes with plasma adiponectin levels adjusted for age, sex and BMI (P=0.0017) were observed in that the risk G/G genotype displayed the lowest adiponectin levels. CONCLUSIONS: We observed associations of rs2297508 with T2DM prevalence and plasma adiponectin. SREBP-1c has been implicated in the regulation of adiponectin gene expression. Our results therefore raise the possibility that sequence variations at the SREBF-1 gene locus might contribute to T2DM risk, at least in part, by altering circulating adiponectin levels.

Adiponectin↗

Plasma proteome profiling identifies XPNPEP3 as a novel biomarker associated with metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus.

OBJECTIVE: To identify plasma protein differences between type 2 diabetes mellitus (T2DM) patients with and without metabolic dysfunction-associated steatotic liver disease (MASLD), and to evaluate the diagnostic potential of X-prolyl aminopeptidase 3 (XPNPEP3) for identifying MASLD in T2DM patients. METHODS: Twenty T2DM inpatients were categorized into groups with and without MASLD and their plasma samples&#xa0;were analyzed using data-independent acquisition mass spectrometry, followed by bioinformatics analysis to identify differentially expressed proteins. The cohort was then expanded to 84 patients, and plasma XPNPEP3 levels were validated by enzyme-linked immunosorbent assay. Correlation between XPNPEP3 and clinical indicators were evaluated, and diagnostic performance was determined via receiver operating characteristic (ROC) analysis. Immunohistochemistry was employed to compare hepatic XPNPEP3 expression between the two groups. RESULTS: Proteomic analysis identified 176 differentially expressed proteins, with XPNPEP3 exhibiting the most significant down-regulation by fold change. In the validation cohort, plasma XPNPEP3 was significantly lower in T2DM+MASLD versus T2DM alone. XPNPEP3 levels were negatively correlated with diabetes duration, liver function markers, and triglyceride levels, and was identified as an independent factor inversely associated with MASLD in T2DM.ROC analysis demonstrated strong diagnostic performance for XPNPEP3, further enhanced when combined with BMI and diabetes duration.&#xa0; Immunohistochemistry confirmed reduced hepatic XPNPEP3 expression in T2DM+MASLD patients. CONCLUSIONS: Lower plasma XPNPEP3 is independently associated with MASLD in T2DM patients and demonstrates strong diagnostic potential, positioning XPNPEP3 as a promising biomarker for diagnosing MASLD in T2DM patients and a novel target for non-invasive diagnostic tool development.

Humans↗

A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27.

Prevalence of coronary heart disease (CHD), of type 2 diabetes (T2DM) and of the metabolic syndrome are in Mauritius amongst the highest in the world. As T2DM and CHD are closely associated and have both a polygenic basis, we conducted a 10 cM genome scan with 403 microsatellite markers in 99 independent families of North-Eastern Indian origin including 535 individuals. Families were ascertained through a proband with CHD before 52 years of age and additional sibs with myocardial infarction (MI) or T2DM. Model-free two-point and multipoint linkage analysis were performed using the Mapmarker-Sibs (MLS) and maximum-likelihood-binomial (MLB) programs for autosomal markers and the Aspex program for chromosome X markers. In a second step, additional markers were studied to increase the genetic map density in three regions on chromosomes 3, 8 and 16 where initial indication for linkage was found. Our data show suggestive linkage with CHD on chromosome 16p13-pter with the MLS statistics at 8.69 cM (LOD = 3.06, P = 0.00017) which partially overlaps with a high pressure (HBP) peak. At the same locus, a nominal indication for linkage with T2DM was found in 35 large T2DM Pondicherian families also having Indian origin. With respect to region 8q23, we found suggestive linkage with T2DM (LOD = 2.55, P = 0.00058) as well as with HBP. On 3q27, we replicated previous indication for linkage found in Caucasians (for the metabolic syndrome and for diabetes) according to the categorized trait for CHD and MI with the MLB statistics (LOD = 2.13, P = 0.0009). The genome scan also revealed nominal evidence of linkage with CHD on 10q23 (LOD = 2.06, P = 0.00188). Interestingly, we detected in the same region overlapping linkages with three QTLs: age of onset of CHD (LOD = 2.03), HDL cholesterol (LOD = 1.48) and LDL/HDL ratio (LOD = 1.34). Ordered-subset analysis based on family body mass index ranking replicated finding on 2q37 for T2DM (at Calpain 10 locus). These results show the first evidence for susceptibility loci that predispose to CHD, T2DM and HBP in the context of the metabolic syndrome.

Chromosome Mapping↗

Beta-cell autoantibodies in children with type 2 diabetes mellitus: subgroup or misclassification?

BACKGROUND: In adults, a fraction of diabetic individuals with beta-cell autoantibodies has initially non-insulin requiring diabetes clinically appearing as type 2 diabetes mellitus (T2DM), named latent autoimmune diabetes in adulthood (LADA). The occurrence of beta-cell autoantibodies in European children and adolescents with T2DM has not been reported so far. METHODS: The frequency of beta-cell autoantibodies (anti-GAD, anti-IA-2, and anti-ICA) was determined in 7050 diabetic children and adolescents. The type of diabetes was classified by paediatric diabetic specialists based on the clinical presentation. Children with non-insulin dependent T2DM over a one year period were studied separately. RESULTS: A total of 6922 children were clinically classified as having type 1 diabetes (T1DM) and 128 children as having T2DM. Thirty six per cent of the children with T2DM had at least one detectable beta-cell autoantibody. These children did not differ significantly from the children with T2DM and without autoantibodies in respect of age, gender, weight status, lipids, blood pressure, C-peptide, glucose, and HbA1c at manifestation, as well as frequency of anti-thyroidal antibodies and insulin treatment during follow up. In the subgroup of the 38 children with T2DM without insulin requirement over a one year period, autoantibodies occurred in 32%. These 12 children were predominantly obese (67%), female (67%), and in the pubertal age range. CONCLUSION: beta-cell autoantibodies were detectable in a subgroup of initially non-insulin dependent diabetic children and adolescents with the clinical appearance of T2DM. Following the terminology "latent autoimmune diabetes in adulthood (LADA)", this subgroup might be classified as "LADY" (latent autoimmune diabetes in youth).

Adolescent↗

Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes.

UNLABELLED: Type 2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue (AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysaccharide (LPS) activates toll-like receptors (TLRs) to cause inflammation. For this study, we 1) examined activation of TLRs and adipocytokines by LPS in human abdominal subcutaneous (AbdSc) adipocytes, 2) examined blockade of NF-kappaB in human AbdSc adipocytes, 3) examined the innate immune pathway in AbdSc AT from lean, obese, and T2DM subjects, and 4) examined the association of circulating LPS in T2DM subjects. The findings showed that LPS increased TLR-2 protein expression twofold (P<0.05). Treatment of AbdSc adipocytes with LPS caused a significant increase in TNF-alpha and IL-6 secretion (IL-6, CONTROL: 2.7+/-0.5 vs. LPS: 4.8+/-0.3 ng/ml; P<0.001; TNF-alpha, CONTROL: 1.0+/-0.83 vs. LPS: 32.8+/-6.23 pg/ml; P<0.001). NF-kappaB inhibitor reduced IL-6 in AbdSc adipocytes ( CONTROL: 2.7+/-0.5 vs. NF-kappaB inhibitor: 2.1+/-0.4 ng/ml; P<0.001). AbdSc AT protein expression for TLR-2, MyD88, TRAF6, and NF-kappaB was increased in T2DM patients (P<0.05), and TLR-2, TRAF-6, and NF-kappaB were increased in LPS-treated adipocytes (P<0.05). Circulating LPS was 76% higher in T2DM subjects compared with matched controls. LPS correlated with insulin in controls (r=0.678, P<0.0001). Rosiglitazone (RSG) significantly reduced both fasting serum insulin levels (reduced by 51%, P=0.0395) and serum LPS (reduced by 35%, P=0.0139) in a subgroup of previously untreated T2DM patients. In summary, our results suggest that T2DM is associated with increased endotoxemia, with AT able to initiate an innate immune response. Thus, increased adiposity may increase proinflammatory cytokines and therefore contribute to the pathogenic risk of T2DM.

Adipocytes, White↗

Data-mining analysis suggests an epigenetic pathogenesis for type 2 diabetes.

The etiological origin of type 2 diabetes mellitus (T2DM) has long been controversial. The body of literature related to T2DM is vast and varied in focus, making a broad epidemiological perspective difficult, if not impossible. A data-mining approach was used to analyze all electronically available scientific literature, over 12 million Medline records, for "objects" such as genes, diseases, phenotypes, and chemical compounds linked to other objects within the T2DM literature but were not themselves within the T2DM literature. The goal of this analysis was to conduct a comprehensive survey to identify novel factors implicated in the pathology of T2DM by statistically evaluating mutually shared associations. Surprisingly, epigenetic factors were among the highest statistical scores in this analysis, strongly implicating epigenetic changes within the body as causal factors in the pathogenesis of T2DM. Further analysis implicates adipocytes as the potential tissue of origin, and cytokines or cytokine-like genes as the dysregulated factor(s) responsible for the T2DM phenotype. The analysis provides a wealth of literature supporting this hypothesis, which-if true-represents an important paradigm shift for researchers studying the pathogenesis of T2DM.

Journal Article↗

[Incidence of type 2 diabetes and its diagnosis process in the decade 1991-2000 in a primary health care centre].

BACKGROUND AND OBJECTIVE: To determine the annual incidence and reasons for diagnosing type 2 diabetes mellitus (T2DM) from 1991 to 2000. PATIENTS AND METHOD: We performed a retrospective, longitudinal study. The clinical records of all new cases of T2DM registered in an urban primary care center over a 10-year period were reviewed. The annual incidence and prevalence in the population aged more than 14 years old were calculated. Statistical analyses of temporal trends and periodicity (monthly, seasonal and annual) were performed with ARIMA models (Box-Jenkins), Poisson parametrical regression and semiparametrical (GAM) models. RESULTS: There were 598 true new cases of T2DM (mean age [SD]: 59.7 [11.4] years; 51.3% women). The most frequent associated cardiovascular risk factors were obesity (58.5%) and hypertension (68.2%). The main reasons for diagnosing T2DM were the presence of previous hyperglycemia (64.7%) and the application of protocols for other cardiovascular risk factors (12.4%).The annual incidence was 37.9 per 10,000 persons (95% CI, 34.9-40.9) with no differences between sexes. The prevalence of T2DM at the beginning and end of the study period was 4.4 (95% CI, 2.0-4.8) and 5.5% (95% CI, 5.2-5.9) (25% relative increase). There was no significant temporal trend in the incidence of T2DM over the years. CONCLUSIONS: The observed incidence of T2DM is high compared with that reported in other studies. The increase in prevalence was not related to a progressive increase in the incidence. The most frequent reasons for diagnosing T2DM were previous hyperglycemia and the application of protocols for other cardiovascular risk factors. This finding seems to be related to an early diagnosis and could benefit these patients.

Adult↗

Homozygous combination of calpain 10 gene haplotypes is associated with type 2 diabetes mellitus in a Polish population.

OBJECTIVE: The polymorphisms of two genes have recently been associated with complex forms of type 2 diabetes mellitus (T2DM): calpain 10 and peroxisome proliferator-activated receptor-gamma (PPARgamma). Calpain 10 is a member of a large family of intracellular proteases. It was shown in Mexican-Americans and other populations that variants of three single nucleotide polymorphisms (SNPs), -43, -19, and -63, of this ubiquitously expressed protein influence susceptibility to T2DM. However, substantial differences were shown between ethnic groups in at risk alleles and haplotypes as well as in their attributable risk. Thus, it is important to determine the role of calpain 10 in various populations. AIM: To examine the role of calpain 10 SNPs -43, -19, and -63 in genetic susceptibility to T2DM in a Polish population. METHODS: Overall, 377 individuals were examined: 229 T2DM patients and 148 control individuals. The groups were genotyped for calpain 10 SNP-43, SNP-19, and SNP-63. SNP-19 was examined by electrophoresis of the PCR product on agarose gel by size, while the restriction fragment length polymorphism (RFLP) method was used for the two other markers. Differences in allele, genotype, haplotype, and haplotype combination distribution between the groups were examined by chi(2) test. RESULTS: Distributions of alleles, genotypes, and haplotypes at three loci defined by examined SNPs were not significantly different between the groups. However, the homozygote combination of 121 haplotype was more prevalent in the T2DM group than in the controls (17.9% vs 10.1%, P=0.039). No difference was observed in the 112/121 haplotype distribution. This heterozygous haplotype combination was associated with increased risk of T2DM in several populations. CONCLUSION: The results of our study suggest the association of calpain 10 121/121 haplotype combination created by SNPs -43, -19, and -63 with T2DM in a Polish population. However, we were not able to confirm the previously described role of the heterozygous 112/121 haplotype combination in susceptibility to T2DM.

Adult↗

Acute plasma glucose increase, but not early insulin response, regulates plasma ghrelin.

OBJECTIVE: The independent role of glucose and insulin in ghrelin regulation is still controversial; this is also because in healthy subjects it is difficult to isolate the increase of glucose from that of insulin. The aim of this study was to discriminate the effect of glucose increase alone and early insulin response on plasma ghrelin, comparing ghrelin variation after i.v. glucose between healthy subjects and type 2 diabetic (T2DM) subjects, in whom the early insulin response to i.v. glucose is abolished. METHODS: Plasma glucose, insulin and ghrelin levels were measured 0, 3, 5, 10, 30, 45 and 60 min after a 5 g glucose i.v. bolus in seven healthy control subjects and eight T2DM subjects. RESULTS: There were no significant differences in body mass index, basal insulin and basal ghrelin between T2DM and healthy subjects. Basal glucose levels were higher in T2DM subjects than in controls. After i.v. glucose administration, plasma glucose increased significantly in both groups and the glucose peak was higher in T2DM subjects than in controls (9.67+/-1.25 (s.d.) vs 6.88+/-1.00 mmol/l, P<0.01). Insulin increased rapidly in controls, while in T2DM subjects, plasma insulin did not rise in the first 10 min. After the glucose bolus, plasma ghrelin showed a significant reduction both in controls and in T2DM subjects after 5 min. CONCLUSION: These findings indicate that a low-dose i.v. glucose bolus reduces ghrelin both in controls and in T2DM subjects and therefore that early insulin response does not affect plasma ghrelin.

Adult↗

Novel Insights into Immune Cell Function in Type 2 Diabetes Mediated by Gut Microbiota: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: The role of immune cells in type 2 diabetes mellitus (T2DM) development is well-studied, but their interactions with the gut microbiota and the mediating role in this process remain unclear. METHODS: We analyzed 731 immune cell phenotypes (3,757 Europeans), 473 gut microbiota traits (5,959 Finns), and T2DM data (over 400,000 Finns). Mendelian randomization (MR) was based on three assumptions: the instrumental variable (IV) is associated with exposure, IV is not influenced by confounding, and IV affects the outcome only through exposure. We selected single-nucleotide polymorphisms (SNPs) from genome-wide association studies as instrumental variables (IVs) to infer causal effects in two-sample MR analysis. RESULTS: We identified 36 immune cell phenotypes associated with T2DM, including 29 protective factors and seven risk factors, as well as 10 gut microbiota significantly linked to T2DM, with eight protective factors and two risk factors. MR revealed that five gut microbiota mediated the relationship between immune cells and T2DM. For example, the effects of CD3 on resting Treg (OR: 1.0136), CD3 on CM CD4+ (OR: 1.0180), and CD3 on naive CD4+ cells (OR: 1.0150) in T2DM were found to be partially mediated by the species Bacillus. AYThe corresponding mediation effect proportions were 8.99%, 11.8%, and 11.4%. DISCUSSION: MR analysis identified multiple gut microbiota mediators in the relationship between immune cells and T2DM, addressing previous observational evidence. Limitations included the European ancestry bias, among others. CONCLUSION: This study has highlighted the gut microbiota as a mediator between immune cells and T2DM, offering new insights for its early prevention and intervention.

Diabetes Mellitus, Type 2↗

Platelet nitrate responsiveness in fasting and postprandial type 2 diabetes.

Vascular responsiveness to exogenous nitrates in type 2 diabetes (T2DM) is attenuated in brachial and coronary vessels. We determined platelet responsiveness to nitric oxide (NO) in T2DM and control subjects. We examined whether the postprandial (PP) state affected platelet sensitivity to NO donors in T2DM patients and the extent of correlation between this and measures of oxidative stress, compared to changes in endothelial function. Twelve T2DM subjects were studied fasting and four hours after a test meal and compared with 15 healthy controls. We assessed the inhibitory effects of NO donors on adenosine 5'-diphosphate (ADP)-induced platelet aggregation. Oxidative stress was assessed by lipid-derived free radicals, ex vivo by electron paramagnetic resonance spectroscopy and markers of lipid peroxidation. Endothelial function was assessed by flow-mediated vasodilatation (FMD) of the brachial artery. Results are expressed as (mean +/- SEM). Fasting platelet aggregation was increased in diabetics versus controls (14.86 +/- 1.1 Ohms vs. 10.76 +/- 1.1 Ohms, p < 0.05). Sodium nitroprusside (SNP) and glyceryl trinitrate (GTN) inhibited ADP-induced aggregation by 73.1 +/- 5.9% and 50.3 +/- 7.7% in healthy controls compared to 15.4 +/- 7% and 19.5 +/- 8.2% in T2DM (p < 0.05). Fasting and postprandial inhibition of platelet aggregation with NO donors in T2DM was similar. T2DM patients had higher levels of oxidative stress in the fasting state and postprandially. There were no PP correlations with platelet NO resistance. In conclusion, there is platelet hyporesponsiveness to NO donors (SNP/GTN) in T2DM compared to controls, with increased ADP-induced platelet aggregation. Platelet abnormalities were associated with increased oxidative stress.

Adenosine Diphosphate↗

Mendelian Randomization Analysis of NETs-Associated Inflammatory Traits and Type 2 Diabetes and its Complications.

Neutrophil extracellular traps (NETs) -associated inflammatory traits play a significant role in type 2 diabetes mellitus (T2DM) and its complications. Notably, IL-6, a key inflammatory cytokine, is intricately linked to the formation of NETs and the pathogenesis of T2DM and its complications. This study aimed to explore the causal association between NETs-associated inflammatory traits and T2DM, as well as its complications, using a Mendelian Randomization (MR) approach. This study utilized a two-sample MR design with data from Genome-Wide Association Studies (GWAS), comprising a large European population-based meta-analysis for T2DM and its complications. The primary method of analysis was the inverse variance weighted (IVW) approach, complemented by MR-Egger regression, weighted median, and weighted mode methods. Sensitivity analyses included MR-Egger, MR-PRESSO, Cochran's Q, and leave-one-out methods to assess the robustness of the findings. The study indicated that genetically predicted levels of interleukin-6 (IL-6) were inversely associated with diabetic coronary artery disease (CAD) (OR = 0.8997, 95% CI: 0.8257-0.9803, P = 0.0158). Additionally, NETs showed significant associations with T2DM with renal complications (OR=0.97, 95% CI 0.9428-0.998, P = 0.0358) and T2DM with peripheral circulatory complications(OR = 1.0342, 95% CI 1.002-1.0673, P = 0.037). The significant IVW associations showed no evidence of heterogeneity or horizontal pleiotropy. This study suggests that genetically predicted NETs-associated inflammatory traits are associated with specific T2DM complications. Genetically predicted IL-6 was inversely associated with diabetic CAD, whereas NETs were associated with renal and peripheral circulatory complications in T2DM.

Diabetes Mellitus, Type 2↗