Diabetes In Other Populations Research Articles

#2981 IRON DEFICIENCY AND CADMIUM LEVELS IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims A higher plasma level of cadmium, a nephrotoxic divalent heavy metal, has been associated with an increased risk of graft failure in kidney transplant recipients (KTRs). The drivers of cadmium toxicity in KTRs are incompletely understood. We hypothesize that iron deficiency (ID) increases cadmium absorption and accumulation by upregulation of divalent metal transporters. Here, we first investigated whether ID is associated with higher plasma cadmium levels. As increased cadmium levels have previously been associated with cancer, cardiovascular disease, and diabetes in other populations, we also examined whether plasma cadmium levels are associated with all-cause mortality in KTRs. Method We used data from stable KTRs ≥1 year after transplantation who participated in the TransplantLines Food and Nutrition Cohort study. Plasma cadmium and iron status parameters, i.e., ferritin, iron, and transferrin saturation (TSAT), were measured at baseline. ID was defined as TSAT<20% and ferritin <300 µg/L. Linear regression analyses were applied to study the association between iron status parameters and cadmium levels. Multivariable Cox regression analyses were used to investigate the association of plasma cadmium levels with all-cause mortality, adjusted for age, sex, BMI, smoking status, history of cardiovascular disease, glucose, HbA1c, systolic blood pressure, eGFR, cholesterol, and ID at baseline. In sensitivity analyses, we repeated these analyses using an alternative definition of ID, TSAT<20% and ferritin<100 µg/L (IDalt). Results We included 670 KTRs (age 53±13 years, 58% males, median 5.4 (IQR, 1.9-11.7) years after transplantation). KTRs with ID (30% of all KTRs, median plasma cadmium level 63 (IQR, 48-76) ng/L) had higher cadmium levels than KTRs without ID (median 56 (IQR, 42-75) ng/L, P = 0.01, Figure 1). ID was not associated with plasma cadmium after adjustment for age, sex, and smoking status. However, within the ID group, TSAT (β = -0.016, P = 0.01) and serum iron (β = -0.023, P = 0.01) were inversely associated with log-transformed cadmium levels, independently of age, sex, and smoking status. Sensitivity analysis yielded similar results: KTRs with IDalt (23% of all KTRs) had higher cadmium levels than KTRs without IDalt (median 61 (IQR, 49-76) ng/L vs median 57 (IQR, 42-75) ng/L, P = 0.03). Furthermore, in Cox regression analysis, KTRs in the highest tertile of plasma cadmium levels (70 ng/L to 330 ng/L) had an increased risk of mortality (hazard ratio 2.80, 95%CI 1.47-5.36, P = 0.01) compared to KTRs in the lowest cadmium tertile (19 ng/L to 48 ng/L) during a median follow-up of 4.9 (IQR, 3.5-5.5) years. No significant interaction by iron status was observed for the association between plasma cadmium and mortality. Conclusion KTRs with ID had higher cadmium levels than KTRs without ID, and higher plasma cadmium levels were independently associated with a higher mortality risk. The association of cadmium with mortality was not different between individuals with and without ID at baseline. Further investigations should determine whether ID correction prevents cadmium accumulation in KTRs.

Predictive Value of 1-Hour Glucose Elevations during Oral Glucose Tolerance Testing for Cystic Fibrosis-Related Diabetes

Background. In cystic fibrosis-related diabetes (CFRD) screening, oral glucose tolerance test (OGTT) thresholds for detecting prediabetes and diabetes are defined by the 2-hour glucose (2 hG). Intermediate OGTT glucoses, between 0 and 2 hours, that are ≥200 mg/dL are deemed “indeterminate,” although lower 1-hour glucose (1 hG) thresholds identify those at increased risk of type 2 diabetes in other populations, and may also better predict clinical decline in CF. Studies of 1 hG thresholds <200 mg/dL in people with CF are limited. Methods. A single center, retrospective chart review was performed of patients with 1 hG available on OGTTs collected between 2010 and 2019. In patients with ≥2 OGTTs, Kaplan–Meier analysis estimated likelihood of progression to CFRD based on a high vs. low 1 hG. In patients with ≥1 OGTT, mixed-effects models tested whether baseline 1 hG and 2 hG predicted growth and lung function trajectories. Results. A total of 243 individuals with CF were identified with at least 1 OGTT including a 1 hG, and n = 177 had ≥2 OGTTs. Baseline age (mean ± SD) was 12.4 ± 2.6 years with 3.2 ± 1.4 years of follow-up. Twenty-eight developed CFRD. All who developed CFRD had a 1 hG ≥ 155 mg/dL prior to 2 hG > 140 mg/dL. The average 1 hG was 267 mg/dL when 2 hG ≥ 200 mg/dL. In a subset with baseline 2 hG < 140 mg/dL, 1 hG ≥ 140 mg/dL conferred an increased 5 years risk of CFRD ( p = 0.036 ). Baseline 2 hG predicted decline in FEV1%predicted, but 1 hG did not. Conclusions. In youth with CF, 1 hG ≥ 140 mg/dl is an early indicator of CFRD risk. However, 2 hG, rather than 1 hG, predicted lung function decline.

Advancing Diabetes Prevention and Control in American Indians and Alaska Natives.

As with many Indigenous populations globally, American Indians and Alaska Natives (AI/ANs) experience high rates of type 2 diabetes. Prevention efforts, ongoing medical care, patient self-management education, and support to prevent and reduce the risk of long-term complications must be developed to limit the impact of diabetes on individuals, families, and communities. Diabetes prevention and control require both individual- and community-level efforts as well as policies that attempt to mitigate contributing adverse socioeconomic factors. Congressional funding since 1998 continues to address the epidemic of diabetes in AI/AN groups with the Special Diabetes Program for Indians (SDPI), which has resulted in significant outcomes and key lessons that can inform new efforts to prevent diabetes in other populations and communities. The purpose of this review is to understand the context behind the epidemic of diabetes in AI/ANs, review the impact of the SDPI on prevention and control of diabetes as well as the translation of these strategies into clinical practice and their influence on health practice, and identify lessons learned for future efforts to address this ongoing challenge for AI/AN and other communities suffering from type 2 diabetes.

Elevated Levels of Organochlorine Pesticides in South Asian Immigrants Are Associated With an Increased Risk of Diabetes.

ObjectiveRates of diabetes mellitus are higher in South Asians than in other populations and persist after migration. One unexplored cause may be higher exposure to persistent organic pollutants associated with diabetes in other populations. We compared organochlorine (OC) pesticide concentrations in South Asian immigrants and European whites to determine whether the disease was positively associated with OC pesticides in South Asians.Research Design and MethodsSouth Asians of Tamil or Telugu descent (n = 120) and European whites (n = 72) were recruited into the London Life Sciences Population Study cohort. Blood samples as well as biometric, clinical, and survey data were collected. Plasma levels of p,p′-dichlorodiphenyldichloroethylene (DDE), p,p′- dichlorodiphenyltrichloroethane, β-hexachlorohexane (HCH), and polychlorinated biphenyl-118 were analyzed by gas chromatography-mass spectrometry. South Asian cases and controls were categorized by binary exposure (above vs below the 50th percentile) to perform logistic regression.ResultsTamils had approximately threefold to ninefold higher levels of OC pesticides, and Telugus had ninefold to 30-fold higher levels compared with European whites. The odds of exposure to p,p′-DDE above the 50th percentile was significantly greater in South Asian diabetes cases than in controls (OR: 7.00; 95% CI: 2.22, 22.06). The odds of exposure to β-HCH above the 50th percentile was significantly greater in the Tamil cases than in controls (OR: 9.35; 95% CI: 2.43, 35.97).ConclusionsSouth Asian immigrants have a higher body burden of OC pesticides than European whites. Diabetes mellitus is associated with higher p,p′-DDE and β-HCH concentrations in this population. Additional longitudinal studies of South Asian populations should be performed.

PSMD9 gene variants within NIDDM2 may rarely contribute to type 2 diabetes

Multiple genome-wide scans in different populations have linked the chromosome 12q24 region, known as NIDDM2 (non-insulin-dependent-diabetes, locus 2), to type 2 diabetes. Within NIDDM2 we examined the PSMD9 (proteasome modulator 9/Bridge-1) gene that encodes a PDZ-domain transcriptional coactivator of insulin production. Our goal was to identify a potential contribution of the PSMD9 gene to type 2 diabetes in Italians. We directly sequenced the entire gene PSMD9 in Italian type 2 diabetes patients (n = 237) and controls subjects (n = 215) and performed an association study with the identified gene variants. We found five single nucleotide polymorphisms (SNPs), A17V, IVS1+nt29, IVS3+nt460, IVS3+nt437, and E197G, which are not associated with disease in our case-control study. Furthermore, we identified two PSMD9 gene variants in type 2 diabetes patients, which produced nonconservative amino acid substitutions S143G and N166S within the PDZ domain and two other gene variants. Three out of four of these variants are absent from the control subjects screened. We propose that the three PSMD9 gene variants (S143G, N166S and G > A at IVS3+nt102), absent in control subjects, contribute rarely to late-onset type 2 diabetes in Italians. In fact, the frequency rate of such variants in unrelated cases equals 0.016. We may not exclude that PSMD9 gene variants may contribute, either commonly or rarely, to an increased risk of type 2 diabetes in other populations.

Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population

India has the greatest number of diabetic subjects in any one country, but the genetic basis of type 2 diabetes mellitus in India is poorly understood. Common non-coding variants in the transcription factor 7-like 2 gene (TCF7L2) have recently been strongly associated with increased risk of type 2 diabetes in European populations. We investigated whether TCF7L2 variants are also associated with type 2 diabetes mellitus in the Indian population. We genotyped type 2 diabetes patients (n = 955) and ethnically matched control subjects (n = 399) by sequencing three single nucleotide polymorphisms (SNPs) (rs7903146, rs12255372 and rs4506565) in TCF7L2. We observed a strong association with all the polymorphisms, including rs12255372 (odds ratio [OR] 1.50 [95% CI = 1.24-1.82], p = 4.0 x 10(-5)), rs4506565 (OR 1.48 [95% CI = 1.24-1.77], p = 2.0 x 10(-5)) and rs7903146 (OR 1.46 [95% CI = 1.22-1.75], p = 3.0 x 10(-5)). All three variants showed increased relative risk when homozygous rather than heterozygous, with the strongest risk for rs12255372 (OR 2.28 [95% CI = 1.40-3.72] vs OR 1.43 [95% CI = 1.11-1.83]). We found no association of the TCF7L2 genotypes with age at diagnosis, BMI or WHR, but the risk genotype at rs12255372 was associated with higher fasting plasma glucose (p = 0.001), higher 2-h plasma glucose (p = 0.0002) and higher homeostasis model assessment of insulin resistance (HOMA-R; p = 0.012) in non-diabetic subjects. Our study in Indian subjects replicates the strong association of TCF7L2 variants with type 2 diabetes in other populations. It also provides evidence that variations in TCF7L2 may play a crucial role in the pathogenesis of type 2 diabetes by influencing both insulin secretion and insulin resistance. TCF7L2 is an important gene for determining susceptibility to type 2 diabetes mellitus and it transgresses the boundaries of ethnicity.

Association of Amino Acid Variants in the Activating Transcription Factor 6 Gene (ATF6) on 1q21-q23 With Type 2 Diabetes in Pima Indians

Activating transcription factor 6 (ATF6) is important for protective cell response to accumulation of unfolded and misfolded proteins in endoplasmic reticulum, and disturbances of this process can contribute to beta-cell apoptosis. We analyzed the structural gene located within a region on 1q21-q23 linked with type 2 diabetes in several populations for variants in the Pima Indians. Functionally important segments of ATF6 were sequenced in 15 diabetic and 15 nondiabetic Pimas and representative single nucleotide polymorphisms (SNPs) tested for association with type 2 diabetes in 900-1,000 subjects. We identified 20 variants including three amino acid substitutions [Met(67)Val, Pro(145)Ala, and Ser(157)Pro]. Pro(145)Ala and Ser(157)Pro were in a complete linkage disequilibrium and showed a nominal association with type 2 diabetes (P = 0.05; odds ratio 2.3 [95% CI 1.0-5.2]) and with 30-min plasma insulin during oral glucose tolerance test in 287 nondiabetic individuals (P = 0.045). Although the associations with type 2 diabetes and plasma insulin levels are marginal and their functional consequences are yet unknown, all three amino acid substitutions are located in a functionally important part of ATF6. Because these variants are not unique to the Pimas, it will be feasible to investigate their association with type 2 diabetes in other populations to better evaluate their significance for a predisposition to the disease.

Changes in Features of the Metabolic Syndrome and Incident Impaired Glucose Regulation or Type 2 Diabetes in a Chinese Population

The current understanding of the pathogenesis of type 2 diabetes is mainly based on a large number of cross-sectional and prospective studies (1– 4) in which nondiabetic individuals were followed for several years to determine incident cases of diabetes without repeating assessment of other metabolic characteristics except for assay of plasma glucose during follow-up. In fact, only the studies in the Pima Indian population (5–7) have examined the changes in anthropometric characteristics, insulin secretion, and insulin action during the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to diabetes. Thus far, no study has directly addressed the effects of changes in the components of the metabolic syndrome on the transition to diabetes in other populations. The purpose of this study was to investigate the changes in the features of the metabolic syndrome during the transition from one state of glucose homeostasis to another in a cohort of Chinese people and to understand the relative contributions of these changes to the development of impaired glucose regulation (IGR) or type 2 diabetes. RESEARCH DESIGN AND METHODS — A total of 627 subjects without diabetes at baseline who participated in the National Diabetes Survey in 1994 and the follow-up survey in 1999 in the Beijing area (8) were included in this study. All of the subjects had measurements of BMI, blood pressure, fasting serum total cholesterol, triglecerides, insulin, plasma fasting glucose, and 2-h postload glucose (2-hPG) at baseline and follow-up separately. Past medical history, family history of diabetes, history of pharmacological treatment, smoking status, education, and occupation were determined with a standardized questionnaire. Obesity was defined as BMI 25.0 kg/m 2 , according to the recommendations for Asians (9). Hy

The association of specific HLA class I and II alleles with type 1 diabetes among Filipinos.

The genetic predisposition to type 1 diabetes among Filipinos was examined by PCR/SSOP HLA class I and II typing of 90 patients and 94 general population controls. The HLA-DRB1, DQB1, and the A, B, and C loci were typed using the reverse SSO probe line-blot method while the DPB1 and DPA1 loci were typed using the SSO probe dot blot method. The Filipino population has a distinctive frequency distribution of HLA class II alleles as well as linkage disequilibrium patterns: a DR-DQ haplotype, unique to Filipinos, contains a DRB1 allele (*0405) positively associated with type 1 diabetes in other populations and DQA1 and DQB1 alleles (*0101-*0503) that are negatively associated in other populations. Specific DR-DQ haplotypes or alleles could be identified as susceptible, neutral or protective based on the distribution among Filipino patients and controls. The DR9 and DR3 haplotypes showed the most dramatic increase among patients (0.156 vs 0.063) and (0.172 vs 0.042), respectively. Among Filipinos, the DR3/9 genotype confers approximately the same risk as the well-known high-risk DR3/4 genotype, similar to that for DR3/3 and DR9/9. The common DR2 haplotype in the Philippines (DRB1*1502-DQB1*0502) was only slightly decreased in type 1 diabetic patients (0.200 in patients vs 0.270 in controls). Another DR2 haplotype, DRB1*1502-DQB1*0501, was significantly decreased among patients. In addition, haplotypes containing DQB1*06 alleles, such as the DRB1*0803-DQB1*0601 (OR = 0.1), are strongly protective. The DR4 allele group was also increased in Filipino patients compared to controls. In this population there is, as in other populations, a hierarchy of type 1 diabetes associations among the many different DR4 haplotypes (n = 15). The high-risk haplotypes in this population are the very rare DRB1*0405-DQB1*0302 and DQB1*0405-DQB1*0201, followed by the more common DRB1*0405-DQB1*0401 and DRB1*0405-DQB1*0402. The DRB1*0403-DQB1*0302 is protective. The DRB1*0405-DQB1*05031 haplotype, which is unique to Filipinos, appears to be "neutral". HLA-DPB1*0202 was significantly increased among patients (0.056 vs 0.011; with OR = 5.3); this increase does not appear to simply reflect linkage disequilibrium with high risk DR-DQ haplotypes. The observed distribution of HLA class II alleles among Filipino patients and controls strongly supports the notion that specific combinations of alleles at the DRB1, DQB1, DQA1, and DPB1 loci are critical in determining the risk for type 1 diabetes. Specific HLA class I alleles also show significant associations with type 1 diabetes in this population. HLA-A*2402 and *2403 were increased among patients; however, 2407 was decreased. Inaddition, A *1101 was significantly decreased among patients (OR = 0.51). Moreover, these HLA-A associations do not appear attributable to linkage disequilibrium with the DR-DQ region. The allele B*5801 was increased in patients while B*1301 was decreased; both of these associations, however, reflected linkage disequilibrium with high-risk and with protective DR-DQ haplotypes, respectively. The HLA-C*0102 and *0302 alleles were increased (0.089 vs 0.037 and 0.122 vs 0.064) while C*1502 and *0702 (0.028 vs 0.080 and 0.217 vs 0.330) were decreased. The observed associations of C*0102 and C*1502 do not simply reflect linkage disequilibrium with high-risk DR-DQ haplotypes. Thus, specific HLA class I-A and C alleles were associated with type 1 diabetes in the Filipinos and may, in combination with high risk DR-DQ haplotypes, significantly modify disease risk.

Genome-wide scanning for type 2 diabetes susceptibility in Canadian Oji-Cree, using 190 microsatellite markers.

We undertook a genome-wide scan using 190 markers with an average separation of 20 cM in 49 Canadian Oji-Cree sib pairs affected with type 2 diabetes. Four of these markers, one each on chromosomes 6, 8, 16, and 22, showed both suggestive linkage and suggestive association with type 2 diabetes in the Oji-Cree. None of these markers corresponded to any chromosomal region or marker that has so far been linked with type 2 diabetes in other populations. Thus, there might be several genetic loci that confer susceptibility to type 2 diabetes in this study sample. We are following up on these preliminary leads by increasing the density of the markers within these linked and associated regions, and also by increasing the number of study subjects. Also, we found instances in which there were wide disparities between the Oji-Cree and reference Caucasians with respect to marker heterozygosity. This suggests that a particular set of markers for genome-wide scanning will have different informativeness in different ethnic groups. Thus, different marker sets will likely be required for different ethnic groups in order to maximize their information content for linkage calculations.

Diabetic neuropathy in Mauritius: prevalence and risk factors

The study of diabetic neuropathy has been primarily in Europids, despite the high prevalence of diabetes in other populations. We set out to ascertain the prevalence of diabetic neuropathy and its risk factors in the island nation of Mauritius. Population surveys were carried out in 1987 and 1992 in Mauritius to establish the prevalence of Type 2 diabetes. In the second survey, vibration perception threshold (VPT) was also measured at the great toe in 847 subjects with diabetes, 204 subjects with impaired glucose tolerance and 127 subjects with normal glucose tolerance. Neuropathy was defined as levels of VPT exceeding the mean plus 2 standard deviations defined separately for three age groups of Mauritian non-diabetic subjects. Risk factors for neuropathy were identified cross sectionally from the 1992 data, and longitudinally from the 1987 data. Neuropathy was detected in 8.3% of the 847 diabetic subjects (12.7% of those with known diabetes, and 3.6% of those with newly diagnosed diabetes). Logistic regression identified diabetes duration (odds ratio [95% CI]; 1.08 [1.04–1.13] per year, P=0.0002), treatment with insulin or oral hypoglycaemic agents (2.63 [1.36–5.09], P=0.004) and greater height (1.36 [1.19–1.57] per 5 cm, P<0.001) as risk factors for neuropathy, in the cross sectional analysis. In the longitudinal analysis, diabetes duration (1.11 [1.05–1.18] per year, P=0.001), fasting glucose (1.12 [1.03–1.22] per mmol/l, P=0.01) and height (1.23 [1.03–1.45] per 5 cm, P=0.02) were associated with neuropathy. A lower 2-h plasma insulin was also associated with neuropathy in the longitudinal analysis. The prevalence of diabetic neuropathy in Mauritius is the lowest reported for any population, but the risk factors associated with it are similar to those previously found.

Incidence of proteinuria in type 2 diabetes mellitus in the Pima Indians

Little is known of the natural history of nephropathy in type 2 (non-insulin-dependent) diabetes, yet type 2 diabetes is a major cause of end-stage renal disease in the United States. The incidence rate of heavy proteinuria was determined in Pima Indians participating in a longitudinal population study of diabetes and its complications. Heavy proteinuria was defined by a urine protein (g/liter) to urine creatinine (g/liter) ratio greater than or equal to 1.0 (greater than or equal to 113 mg protein/nmol creatinine), a level which corresponds to a urine protein excretion rate of about 1 g/day. The incidence rates of proteinuria in diabetic Pimas were 4, 12, 37, and 106 cases/1,000 person-years at risk in the periods 0 to 5, 5 to 10, 10 to 15, and 15 to 20 years after the diagnosis of diabetes. The cumulative incidence rates were 2%, 8%, 23%, and 50% at 5, 10, 15, and 20 years, respectively. The duration of diabetes, severity of diabetes as determined by the degree of hyperglycemia and type of treatment, and blood pressure were risk factors for proteinuria. The presence of heavy proteinuria was strongly associated with the development of renal insufficiency, defined by serum creatinine greater than or equal to 2.0 mg/dl (greater than or equal to 177 mumol/liter). The incidence of proteinuria in type 2 diabetes in Pima Indians was as high as that reported in type 1 diabetes in other populations and represents a frequent, serious complication of the disease.