Early-onset Type 2 Diabetes Research Articles

Nephropathy in Youth and Young Adults with Type 2 Diabetes

The occurrence and progression of nephropathy associated with early onset type 2 diabetes (T2D) is a consequence of the ongoing epidemic of childhood obesity. Minimal evidence regarding treatment effectiveness of renovascular comorbidities in youth with early onset T2D is available, due to the relatively recent emergence of T2D in youth and young adults. Extrapolation of adult therapy guidelines is not an ideal approach to making therapeutic decisions in this population. Evolving management and intervention strategies are based on accumulating longitudinal data from cohorts of well characterized youth and young adults with T2D. The degree of similarity in histologic findings and disease specific characteristics of kidney disease in patients with early onset T2D and albuminuria compared with affected adults is not well characterized. Early aggressive therapies to minimize the impact of nephropathy are indicated as the evidence for best therapies in youth with T2D are further explored.

Oxidized Fatty Acids: A Potential Pathogenic Link Between Fatty Liver and Type 2 Diabetes in Obese Adolescents?

In this study, we sought to investigate the putative association of the oxidized metabolites derived from linoleic acid (OXFAs) with pediatric nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We studied 80 obese adolescents (age 13.3 ± 3.31 years; body mass index 33.0 ± 6.79 kg/m(2)), who underwent an oral glucose tolerance test, a magnetic resonance imaging (MRI) to measure the hepatic fat content, and the measurement of OXFAs and caspase-cleaved Citokeratin18 fragment (CK-18), a robust biomarker of liver injury. In this study, we show that only in subjects with hepatic steatosis, the OXFAs are associated with the CK-18 and that this association is modulated by the PNPLA3 rs738409 variant. We also show that most of the OXFAs are associated with a lower insulin secretion and that adolescents with T2D have higher levels of OXFAs than subjects with impaired or normal glucose tolerance. These observations lead to the hypothesis that the OXFAs may be the pathogenic link between liver injury and T2D and that the novel therapeutic opportunities targeting the OXFAs are possible in adolescents with early-onset NAFLD and T2D.

Preliminary analysis of immune activation in early onset type 2 diabetes

IntroductionFirst Nations and other Aboriginal children are disproportionately affected by cardiometabolic diseases, including type 2 diabetes (T2D). In T2D, the disruption of insulin signalling can be driven by pro-inflammatory immunity. Pro-inflammatory responses can be fueled by toll-like receptors (TLR) on immune cells such as peripheral blood mononuclear cells (PBMC, a white blood cell population). TLR4 can bind to lipids from bacteria and food sources activating PBMC to produce cytokines tumour necrosis factor (TNF)-α and interleukin (IL)-1β. These cytokines can interfere with insulin signalling. Here, we seek to understand how TLR4 activation may be involved in early onset T2D. We hypothesized that immune cells from youth with T2D (n=8) would be more reactive upon TLR4 stimulation relative to cells from age and body mass index (BMI)-matched controls without T2D (n=8).MethodsSerum samples were assayed for adipokines (adiponectin and leptin), as well as cytokines. Freshly isolated PBMC were examined for immune reactivity upon culture with TLR4 ligands bacterial lipopolysaccharide (LPS, 2 and 0.2 ng/ml) and the fatty acid palmitate (200 µM). Culture supernatants were evaluated for the amount of TNF-α and IL-1β produced by PBMC.ResultsYouth with T2D displayed lower median serum adiponectin levels compared to controls (395 vs. 904 ng/ml, p<0.05). PBMC isolated from youth with and without T2D produced similar levels of TNF-α and IL-1β after exposure to the higher LPS concentration. However, at the low LPS dose the T2D cohort exhibited enhanced IL-1β synthesis relative to the control cohort. Additionally, exposure to palmitate resulted in greater IL-1β synthesis in PBMCs isolated from youth with T2D versus controls (p<0.05). These differences in cytokine production corresponded to greater monocyte activation in the T2D cohort.ConclusionThese preliminary results suggest that cellular immune responses are exaggerated in T2D, particularly with respect to IL-1β activity. These studies aim to improve the understanding of the biology behind early onset T2D and its vascular complications that burden First Nations people.

Psychophysiology of perceived effort during physical tasks

Arterial stiffness (AS) and baroreflex sensitivity (BRS) are subclinical markers of vascular diseases in type 2 diabetes (T2D). We evaluated the effects of aerobic interval training (AIT), with loads prescribed according to individual heart rate and lactate profiling obtained during a baseline treadmill test (TRIMPi method), on AS and BRS in patients with early-onset T2D without cardiovascular complications.Twenty-two sedentary overweight T2D patients (aged 57 ± 7 years) were randomized to 12-weeks open-label of supervised AIT by TRIMPi (n = 8) or unsupervised physical activity as per usual care (SOC) (n = 11). Following parameters were evaluated (pre- and post-): anthropometrics; six-minute walking test (6MWT); fasting glucose, insulin, HbA1c; Pulse Wave Velocity (PWV) and Augmentation Index (AIxHR75) using radial approach (SphigmoCor System); BRS using Finapress method.Both interventions significantly improved distance walked during 6MWT (AIT 52 ± 21 m; SOC 39 ± 24 m, p < 0.001 for both). PWV significantly improved with AIT (p < 0.001) whereas did not vary with SOC (p = 0.47). Similar trend was observed for AIxHR75. Resulting percent changes from baseline were significantly better for AIT vs SOC, in both PWV (− 15.8 ± 2.1 vs + 1.50 ± 3.4%, p < 0.001) and AIxHR75 (− 28.9 ± 3.2% vs + 12.7 ± 2.4%, p < 0.001). BRS similarly improved in both groups (p < 0.001 for both), as well as body weight, HbA1c and blood pressure.In sedentary T2D patients, 12-weeks AIT individualized by TRIMPi method improved AS to a greater extent than usual recommendation on physical activity, whilst exerting comparable effects on exercise capacity, glycemic control and body weight. Further researches are needed to ascertain durability of these effects.

Early-onset type 2 diabetes: higher burden of atherogenic apolipoprotein particles during statin treatment

To determine the burden of atherogenic apolipoprotein particles in early-onset type 2 diabetes (T2D) compared to those with later-onset disease during statin treatment. Early and later-onset T2D was defined as current age below and above 40 years respectively. Conventional lipid profile, LDL, non-HDL cholesterol, apolipoprotein B and A1 were determined in those without cardiovascular disease treated with simvastatin to achieve LDL cholesterol <2 mmol/l. Fifty subjects were recruited (early-onset n=24 and later-onset n=26). The mean age was 34.5 and 59.6 years and mean age of diagnosis was 29.1 and 49.1 years for early and later-onset T2D respectively. Obesity, dyslipidaemia, microalbuminuria, glycaemic control and diabetes complication burden were similar in both cohorts. Early-onset subjects received non-significantly higher simvastatin dose (37.5 vs. 31.9 mg daily, p=NS). On-treatment LDL cholesterol was similar in both cohorts (early vs. later-onset; 2.12 vs. 1.97 mmol/l, p=NS). Fasting triglyceride, non-HDL, apo B and B/A1 ratio were significantly higher in early-onset cohort. There was no difference in apo A1, HDL and total cholesterol/HDL ratio. Apo B level remained significantly higher among early-onset subjects after adjustment for insulin treatment. Lower current age and age of diagnosis were significant predictors of higher apo B level. The burden of atherogenic apolipoprotein particles was greater in early-onset T2D despite adequate statin treatment indicating an adverse phenotype for vascular disease.

Early-onset type 2 diabetes: High risk for premature diabetic retinopathy

Aim To examine the relationship between early-onset type 2 diabetes (T2D) and retinopathy in relation to the burden, severity, the extent of its premature development and associated predictive risk factors. Methods A cross sectional study using the hospital diabetes register and eye screening database to identify T2D subjects and to ascertain retinopathy severity. Early and later-onset cohort were defined as age of diagnosis <40 and >40 years respectively. Results 2516 subjects were identified of which 455 were diagnosed below 40 years. After 10 years of diagnosis, the prevalence of overall retinopathy was significantly higher in the early-onset cohort ( p < 0.05). For significant retinopathy (SigDR), there was a non-significant trend of higher prevalence with increasing diabetes duration in the early-onset cohort. The rate of increase for SigDR was greater in the early-onset cohort who experienced similar burden of SigDR up to 20 years earlier than the later-onset cohort. Hypertension ( p < 0.05), suboptimal glycaemic control ( p < 0.05) and long diabetes duration ( p < 0.05) were associated with risk of retinopathy whilst lower age of diagnosis and dyslipidaemia were not significant predictive factors. Conclusions Early-onset T2D subjects are at risk of developing premature retinopathy driven predominantly by hypertension and prolonged exposure to suboptimal diabetes control.

Implication of genetic variants near SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, FTO, TCF2, KCNQ1, and WFS1 in Type 2 Diabetes in a Chinese population

BackgroundRecently, several genome-wide and candidate gene association studies have identified many novel genetic loci for type 2 diabetes (T2D); among these genes, CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 are the most important. We aimed to determine the effects of these genetic loci associated with T2D in the Chinese Han population of China.MethodsSingle-nucleotide polymorphisms (SNPs) in or near CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 genes were genotyped in a case-control Chinese Han sample living in Beijing, China involving 1024 patients with T2D and 1005 control subjects.ResultsIn Chinese Han, we replicated the associations between 7 genetic loci and T2D, with risk allele-specific odds ratios (ORs) as follows: 1.27 (95% CI, 1.11-1.45; p = 0.0008) for CDKAL1-rs10946398, 1.26 (95% CI, 1.08-1.47; p = 0.003) for IGF2BP2-rs4402960, 1.19 (95% CI, 1.04-1.37; p = 0.009) for SLC30A8-rs13266634, 1.22 (95% CI, 1.06-1.41; p = 0.005) for CDKN2A/B-rs10811661, 1.20 (95% CI, 1.01-1.42; p = 0.03) for HHEX-rs5015480, 1.37 (95% CI, 1.19-1.69; p = 1.0 × 10-4) for KCNQ1-rs2237892, and 1.24 (95% CI, 1.01-1.52; p = 0.046) for FTO-rs8050136 after adjustment for age, gender, and body mass index. Not only did an association between WFS1-rs6446482 and early-onset T2D exist in the subgroup analysis, but TCF2-rs7501939 and WFS1-rs6446482 were also confirmed to confer risk for T2D in this meta-analysis. Moreover, the relationship between FTO-rs8050136 and body mass index, together with the effect of CDKAL1-rs10946398 on beta cell function, was also observed in the control individuals.ConclusionsOur findings support the important contribution of these genetic loci to susceptibility for T2D in the Chinese Han population in Beijing of China.

TheTRIB3Q84R Polymorphism and Risk of Early-Onset Type 2 Diabetes

The prevalence of type 2 diabetes (T2D), particularly among young adults, has been rising steadily during the past 2 decades. T2D, especially in its early-onset subtype, is under genetic control. TRIB3 inhibits insulin-stimulated Akt phosphorylation and subsequent insulin action. A TRIB3 gain-of-function polymorphism, Q84R (rs2295490), impairs insulin signaling. The objective of the study was to verify the association of TRIB3 Q84R with: 1) T2D, either subtyped or not according to age at diagnosis (early-onset, <45 yr, or >or= 45 yr); 2) insulin secretion and sensitivity in nondiabetic individuals; or 3) in vitro insulin secretion from isolated human islets. Four different case-control samples comprising a total of 5,469 whites were examined. Insulinogenic and insulin sensitivity indexes and their interplay (disposition index) were assessed in 645 nondiabetic individuals at oral glucose tolerance test, glucose (16.7 mmol/liter)-induced in vitro insulin secretion was assessed in islets isolated from 54 nondiabetic donors. In the whole sample, the R84 variant was nominally associated with T2D (odds ratio 1.17, 95% confidence interval 1.00-1.36, P = 0.04). When stratifying according to age of diabetes onset, R84 carriers had an increased risk of early-onset T2D (odds ratio 1.32, 95% confidence interval 1.10-1.58, P = 0.002). Among 645 nondiabetic subjects, R84 carriers had higher glucose levels (P = 0.005) and lower insulinogenic (P = 0.03) and disposition index (P = 0.02) during the oral glucose tolerance test. R84 islets were more likely to display relatively low glucose-stimulated insulin release (P = 0.04). The TRIB3 R84 variant is associated with early-onset T2D in whites. Alteration in the insulin secretion/insulin sensitivity interplay appears to underlie this association.

CHOP T/C and C/T haplotypes contribute to early‐onset type 2 diabetes in Italians

Type 2 diabetes (T2D) is characterized by impaired insulin secretion, insulin insensitivity and decreased beta-cell mass. Multiple genes contribute to T2D. The chromosome 12q13.1 region is in linkage to T2D in different populations, including our Italian dataset. CHOP is a candidate gene for the linkage, as it is located in the chromosome 12q13.1 region, and may contribute to T2D by increasing beta-cell apoptosis susceptibility and by impairing insulin sensitivity. Our goal was to identify any potential CHOP gene variants contributing to T2D in our Italian early-onset T2D families, which show linkage to the CHOP region. We directly sequenced the CHOP gene in 28 Italian probands of the linked T2D families and in 115 control subjects. We performed genotype and haplotype association tests with T2D of the identified single nucleotide polymorphisms (SNPs). We performed model-free and parametric association haplotype tests with T2D. We identified three SNPs [5'UTR-c.279T > C, 5'UTR-c.120A > G and + nt30C > T (F10F)] in CHOP. These SNPs are in complete linkage disequilibrium. The genotype association test showed an association trend with T2D of TT (F10F) and AG (-c.120A > G). The haplotype association test provided significant results for the haplotypes T/C (frequency = 0.33) and C/T (frequency = 0.01) (at 5'UTR-c.279T > C and + nt30C > T, respectively) under non-parametric analysis (P-value = 0.0000), recessive model (P-value = 0.0000) and additive model (P-value = 0.0014). Our data show that CHOP described haplotypes T/C and C/T, as an additive and as a homozygous variant, contribute significantly to T2D in our Italian early-onset group. We conclude that the CHOP T/C and C/T haplotype contributes to our T2D linkage signal on chromosome 12q13.1.

Linkage studies for T2D in Chop and C/EBPbeta chromosomal regions in Italians

The genes causing type 2 diabetes (T2D), a complex heterogeneous disorder, differ and/or overlap in various populations. Among others there are two loci in linkage to T2D, the chromosomes 20q12-13.1 and 12q15. These two regions harbor two genes, C/EBPbeta and CHOP, which are excellent candidate genes for T2D. In fact, C/EBPbeta protein cooperates with HNF4alpha (MODY1, monogenic form of diabetes) and 1alpha (MODY3, monogenic form of diabetes). C/EBPbeta mediates suppression of insulin gene transcription in hyperglycemia and may contribute to insulin-resistance. It interacts in a complex pathway with the CHOP protein. CHOP may play a role in altered beta-cell glucose metabolism, in beta-cell apoptosis, and in lack of beta-cell replication. Thus, both C/EBPbeta and CHOP genes may independently and interactively contribute to T2D. The chromosomal regions targeting C/EBPbeta and CHOP genes have never been previously explored in T2D. We planned to identify their potential contribution to T2D in Italians. We have genotyped a group of affected siblings/families with both late- and early-onset T2D around the C/EBPbeta and the CHOP genes. We have performed non-parametric linkage analysis in the total T2D group, in the late-onset and the early-onset group, separately. We have identified a suggestive linkage to T2D in the CHOP gene locus in the early-onset T2D group (P = 0.04). We identified the linkage to T2D in the chromosome 12q15 region in the early-onset T2D families and specifically target the CHOP gene. Our next step will be the identification of CHOP gene variants, which may contribute to the linkage to T2D in Italians.

Replication and Identification of Novel Variants at TCF7L2 Associated with Type 2 Diabetes in Hong Kong Chinese

Variations at a large linkage disequilibrium (LD) block of transcription factor 7-like 2 gene (TCF7L2) were reported to be associated with type 2 diabetes (T2D) in Icelandic, Danish and European-American populations and further replicated in other populations of European, African, and Asian ancestries. However, data for Chinese and comprehensive survey of the whole gene are lacking. We attempted to examine 22 tagging single-nucleotide polymorphisms (SNPs) spanning across the TCF7L2 gene for association with T2D in Hong Kong Chinese. We first studied a case-control sample involving 433 hospital cases with familial early-onset T2D and 419 normal controls and further studied the associated SNPs in 450 members of 142 diabetic families. Two of the previously reported risk alleles at rs11196205 (C) and rs7903146 (T) were rare in Chinese (0.013 and 0.024, respectively, in controls). Rs11196205 was associated with T2D [odds ratio (OR) [95% confidence interval (CI)] = 2.11 (1.04-4.26)], whereas the association for rs7903146 [OR (95% CI) = 1.27 (0.71-2.29)] was not significant in the case-control sample. Interestingly, another SNP (rs11196218 G allele) located in adjacent LD block conferred independent risk for T2D [OR (95%CI) =1.43 (1.14-1.79)] and contributed high-population attributable risk of 42%. The association finding of rs11196218 and its haplotype for T2D was also replicated in the family sample (P < 0.05). Our results are consistent with others' findings that variations at TCF7L2 contribute to T2D, including Chinese. The presence of association signals spanning several LD blocks warrants further examination of extended regions to reveal the causal variant(s) for this important T2D gene.

Clinical characteristics of early-onset type 2 diabetes and risk factors associated with its chronic complications

To investigate the clinical characteristics of early-onset type 2 diabetes (EOD) and the risk factors associated with its chronic complications. A total of 2713 T2DM patients were recruited and divided into two groups: early- and late-onset groups EOD group (diagnosed at the age <or= 40) and late-onset type 2 diabetes (LOD) group (diagnosed at the age > 40). The clinical characteristics were compared between two groups, and the risk factors were analyses within the early-onset group. (1) The EOD patients were characterized by significantly higher levels of triglycerides (2.5 +/- 2.4 mmol/L vs 1.9 +/- 1.5mmol/L, P < 0.01) and BMI (24.4 kg/m(2) +/- 4.6 kg/m(2) vs 23.6 kg/m(2) +/- 3.7 kg/m(2), P < 0.01), higher rates of smoking (29.2% vs 22.0%, P < 0.01), family history of diabetes (28.6% vs 13.1%, P < 0.01), and higher prevalence of metabolic syndrome (18.9% vs 10.7%, P < 0.01), higher proportion of patients with unacceptable HbA1c (>7.0%) (77.3% versus 72.7%, P < 0.05) and fasting blood glucose >or= 7.0 mmol/L, (80.8% versus 74.6%, P < 0.05). (2) The prevalence rates of microvascular complications were higher than those of macrovascular complications in the EOD group, and the prevalence rates of pain, anesthesia, diarrhea, and nephropathy were 10.6%, 6.20%, 6.00%, and 13.00% respectively, all significantly higher than those of the LOD group (7.10%, 2.80%, 3.70%, and 8.00% respectively, P < 0.05, < 0.01, < 0.05, and < 0.01). Linear regression analysis showed that certain subsets of chronic complications were associated with onset age, diabetes duration, hypertension, family history and high level of triglyceride. Early-onset DM patients present the clinical features of poorer metabolic profiles, which may contribute to the development of certain subsets of microvascular complications. Late-onset patients tend to be complicated with macrovascular diseases, such as cerebrovascular disease, angiocardiopathy, etc. Multiple factor comprehensive control is important for the prevention of the complications.