Association of the CD36 gene with impaired glucose tolerance, impaired fasting glucose, type-2 diabetes, and lipid metabolism in essential hypertensive patients

Essential hypertension is a common disorder that can increase the risk of type 2 diabetes (T2D). CD36 has been studied in patients with diabetes and hypertension extensively; however, few studies have focused on the relationship of the CD36 gene with impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) or T2D in essential hypertension patients. To identify rs1049673 and rs1527483 in the CD36 gene conferring susceptibility to IFG/IGT and T2D, we conducted a case-control study in 1257 essential hypertension patients among the Han Chinese population (control: 676; IGT/IFG: 468; T2D: 113). We also evaluated the impact of two loci on insulin sensitivity, glucose tolerance and serum lipid. The major findings of this study were that rs1049673 was found associated with IFG/IGT and T2D in essential hypertension patients (Pco = 0.028; Pdom = 0.015). The rs1049673 G carriers showed significant higher Glu0 (βdom = 0.08 (0.01~0.16), Pdom = 0.045) and Lp(a) (βco = 0.04 (0.002~0.07), Pco = 0.041; βdom = 0.06 (0.01~0.12), Pdom = 0.032), and lower HDL by the linear regression with the adjustment for gender, age, BMI, and mean blood pressures. These findings provided evidence that the CD36 gene may play some role in the pathogenesis of IFG/IGT and T2D in essential hypertension patients.     

Type 2 diabetes risk alleles demonstrate extreme directional differentiation among human populations, compared to other diseases

Many disease-susceptible SNPs exhibit significant disparity in ancestral and derived allele frequencies across worldwide populations. While previous studies have examined population differentiation of alleles at specific SNPs, global ethnic patterns of ensembles of disease risk alleles across human diseases are unexamined. To examine these patterns, we manually curated ethnic disease association data from 5,065 papers on human genetic studies representing 1,495 diseases, recording the precise risk alleles and their measured population frequencies and estimated effect sizes. We systematically compared the population frequencies of cross-ethnic risk alleles for each disease across 1,397 individuals from 11 HapMap populations, 1,064 individuals from 53 HGDP populations, and 49 individuals with whole-genome sequences from 10 populations. Type 2 diabetes (T2D) demonstrated extreme directional differentiation of risk allele frequencies across human populations, compared with null distributions of European-frequency matched control genomic alleles and risk alleles for other diseases. Most T2D risk alleles share a consistent pattern of decreasing frequencies along human migration into East Asia. Furthermore, we show that these patterns contribute to disparities in predicted genetic risk across 1,397 HapMap individuals, T2D genetic risk being consistently higher for individuals in the African populations and lower in the Asian populations, irrespective of the ethnicity considered in the initial discovery of risk alleles. We observed a similar pattern in the distribution of T2D Genetic Risk Scores, which are associated with an increased risk of developing diabetes in the Diabetes Prevention Program cohort, for the same individuals. This disparity may be attributable to the promotion of energy storage and usage appropriate to environments and inconsistent energy intake. Our results indicate that the differential frequencies of T2D risk alleles may contribute to the observed disparity in T2D incidence rates across ethnic populations.     

Expression of PE_PGRS 62 protein in Mycobacterium smegmatis decrease mRNA expression of proinflammatory cytokines IL-1β, IL-6 in macrophages

Involvement of mitochondrial and nuclear gene mutations in the development of type 2 diabetes (T2D) has been established well in various populations around the world. Previously, we have found the mitochondrial A>G transition at nucleotide position 3243 and 8296 in the T2D patients of Coimbatore population. This study is aimed to screen for the presence of various mitochondrial and nuclear DNA mutations in the T2D patients of Coimbatore to identify most prevalent mutation. This helps in identifying the susceptible individuals based on their clinical phenotype in future. Blood samples were collected from 150 unrelated late-onset T2D patients and 100 age-matched unrelated control samples according to World Health Organization criteria. Genotyping for the selected genes was done by polymerase chain reaction–single strand confirmation polymorphism, direct sequencing, and polymerase chain reaction–restriction fragment length polymorphism. The mitochondrial T>C transition at 8356 and nuclear-encoded GLUT1 gene mutation were found in the selected T2D patients. The T8356C mutation was found in two patients (1.3%), and the clinical characteristics were found to be similar in both the patients whereas GLUT1 gene mutation was found in seven patients. Four out of seven patients showed homozygous (?) genotype and three patients showed heterozygous (±) genotype for the mutant allele XbaI. Among these three patients, one patient was found to have elevated level of urea and creatinine with the history of kidney dysfunction and chronic T2D. Our results suggest that the T8356C and GLUT1 gene mutations may have an important role in developing late-onset T2D in Coimbatore population. Particularly, individuals with GLUT1 gene may develop kidney dysfunction at their later age.     

Focus: Preventive Medicine: Undiagnosed Hypertension and Undiagnosed Type 2 Diabetes among Overweight and Obese Marshallese Participants in a Diabetes Prevention Program

Hypertension and type 2 diabetes (T2D) are major public health issues that disproportionately affect minority communities, including Native Hawaiians and Pacific Islanders (NHPI). Minority communities are also more likely to have undiagnosed hypertension and T2D. Marshallese Pacific Islanders have been shown to have high proportions of diagnosed and undiagnosed hypertension and T2D. Using survey and biometric data collected from 378 overweight/obese Marshallese Pacific Islander adults, this study documents the prevalence of hypertension and T2D, as well as the prevalence of undiagnosed hypertension and T2D. The study also examines associations between undiagnosed hypertension and undiagnosed T2D and age group, sex, health care access (defined by foregone care due to cost and health insurance status), and body mass index (BMI). Among participants with blood pressure readings indicative of hypertension, 68.4% were undiagnosed, and among participants with HbA1c indicative of T2D, 31.6% were undiagnosed. A quarter of participants (24.5%) had blood pressure and HbA1c measures indicative of both undiagnosed hypertension and undiagnosed T2D. Undiagnosed hypertension was significantly associated with age group (p’s<0.0001) and sex (p=0.028). Undiagnosed T2D was significantly associated with age group (p’s<0.05), forgone care due to cost (p=0.018), health insurance status (p=0.035), and BMI (p=0.001). Participants in this study had high proportions of undiagnosed hypertension and undiagnosed T2D. These findings will be immediately useful for those working to address hypertension and T2D disparities among Marshallese and other NHPI populations.     

Mitochondrial haplogroup N9a confers resistance against type 2 diabetes in Asians

Because mitochondria play pivotal roles in both insulin secretion from the pancreatic beta cells and insulin resistance of skeletal muscles, we performed a large-scale association study to identify mitochondrial haplogroups that may confer resistance against or susceptibility to type 2 diabetes mellitus (T2DM). The study population comprised 2,906 unrelated Japanese individuals, including 1,289 patients with T2DM and 1,617 controls, and 1,365 unrelated Korean individuals, including 732 patients with T2DM and 633 controls. The genotypes for 25 polymorphisms in the coding region of the mitochondrial genome were determined, and the haplotypes were classified into 10 major haplogroups (i.e., F, B, A, N9a, M7a, M7b, G, D4a, D4b, and D5). Multivariate logistic-regression analysis with adjustment for age and sex revealed that the mitochondrial haplogroup N9a was significantly associated with resistance against T2DM (P=.0002) with an odds ratio of 0.55 (95% confidence interval 0.40-0.75). Even in the modern environment, which is often characterized by satiety and physical inactivity, this haplogroup might confer resistance against T2DM.     

Hypertension associated with neurocognitive performance among persons with type 2 diabetes: a brief report

Background Among persons with type 2 diabetes (T2DM) it is not known whether the presence of hypertension could have a detrimental effect on learning ability and whether repeated exposure to information changes the amount of information retained. The aim of this study was to determine cross-sectional evidence for a differential burden to cognitive functioning among persons with T2DM and comorbid hypertension (HTN).Methods This study performed a cross-sectional, retrospective analysis, by medical chart review, of patients with a diagnosis of T2DM.Results Medical records information for history of HTN, age, gender and cognitive performance scores were recorded and analysed for 112 T2DM patients, with an average age of 60 years (SD = 13.84). Differences in cognitive performance scores were compared between patients with and without a history of HTN. The results show that participants who were diagnosed with hypertension produced lower average Rey Auditory–Verbal Learning Test scores than individuals who are not diagnosed with hypertension. Trial 2 was the only trial to prove significant with a P-value of 0.041.Conclusions Our results support previous studies showing that HTN is associated with increased risk to learning and memory functioning, although the degree of interference with these cognitive functions could not be determined from our research. Recognising that people diagnosed with HTN may be at risk for poorer learning and memory skills, future research can investigate how the length of time with the diseases affects learning and memory, and how medication management can attenuate cognitive learning and memory performance.     

ACEI/ARB Underused in Patients with Type 2 Diabetes in Chinese Population (CCMR-3B Study)

ObjectiveIn patients with diabetic kidney disease, it is well documented that RAS blockade is associated with an improved outcome. This observational, multicenter study examined the “real-world” use of ACEI/ARB in patients with type 2 diabetes (T2DM) in China.MethodData from the China Cardiometabolic Registries on blood pressure, blood lipid and blood glucose in Chinese T2DM patients (CCMR-3B) were used for the present study. Consecutive outpatients with T2DM for more than 6 months were recruited to this non-interventional, observational, cross-sectional study. Albuminuria was defined as urine albumin creatinine ratio (ACR) ≥ 30mg/g.ResultsA total of 25,454 outpatients with T2DM from 6 regions in China were enrolled, 47.0% were male, and 59.8% had hypertension. ACR was measured in 6,383 of these patients and 3,231 of them ≥ 30mg/L. Among patients with hypertension, 73.0% were on antihypertensives, and 39.7% used ACEI/ARB. Of the 2,157 patients with hypertension and albuminuria, only 48.3% used ACEI/ARB. Among the non-hypertensive patients with albuminuria, ACEI/ARB usage was < 1%. Multivariate analysis revealed that comorbidities, region, hospital tier, physician specialty and patient’s educational level were associated with ACEI/ARB use.ConclusionIn T2DM with hypertension and albuminuria in China, more than half of them were not treated with ACEI/ARB. This real world evidence suggests that the current treatment for patients with diabetes coexisting with hypertension and albuminuria in China is sub-optimal.     

Frequency of heterozygous complete hydatidiform moles,estimated by locus-specific minisatellite and Y chromosome-specific probes

Summary Restriction fragment length polymorphisms identified with three locus-specific minisatellite probes and banding patterns with Y chromosome-specific probes have been examined in 39 cases of complete hydatidiform mole (CHM) and the parents. All 39 cases were shown to be androgenetic. Of the 39 cases, 8 were identified as heterozygous CHM using the minisatellite probes. Estimates for the total number of heterozygous CHM in the series ranged from 23%–29%, higher than previously reported. Of the eight identified heterozygous CHM, six had Y chromosome-specific sequences whereas two were female; this is not significantly different from the 2:1 ratio expected. The low frequency of 46,XX heterozygous CHM in the literature may reflect difficulties in distinguishing them from 46,XX homozygous CHM. Examination of RFLPs with a small panel of locus-specific minisatellite probes provides a powerful method of classifying hydatidiform mole, enabling the rare heterozygous 46,XX CHM to be accurately identified.     

Impact of Hypertension on the Association of BMI with Risk and Age at Onset of Type 2 Diabetes Mellitus: Age- and Gender-Mediated Modifications

Aims

Given that BMI correlates with risk of Type 2 diabetes mellitus (T2DM), and that hypertension is a common comorbid condition, we hypothesize that hypertension augments significantly the impact of obesity on T2DM onset.

Methods

We obtained data on T2DM in Kuwaiti natives from Kuwait Health Network Registry. We considered 1339 comorbid individuals with onset of hypertension preceding that of T2DM, and 3496 non-hypertensive individuals but with T2DM. Multiple linear regressions, ANOVA tests, and Cox proportional hazards models were used to quantify the impact of hypertension on correlation of BMI with age at onset and risk of T2DM.

Results

Impact of increasing levels of BMI on age at onset ot T2DM is seen augmented in patients diagnosed with hypertension. We find that the slope of the inverse linear relationship between BMI and onset age of T2DM is much steep in hypertensive patients (−0.69, males and −0.39, females) than in non-hypertensive patients (−0.36, males and −0.17, females). The decline in onset age for an unit increase of BMI is two-fold in males than in females. Upon considering BMI as a categorical variable, we find that while the mean onset age of T2DM in hypertensive patients decreases by as much as 5–12 years in every higher BMI categories, significant decrease in non-hypertensive patients exists only when severely obese. Hazard due to hypertension (against the baseline of non-hypertension and normal weight) increases at least two-fold in every obese category. While males have higher hazard due to hypertension in early adulthood, females have higher hazard in late adulthood.

Conclusion

Pre-existing condition of hypertension augments the association of BMI with Type 2 diabetes onset in both males and females. The presented results provide health professionals directives on the extent of weight-loss required to delay onset of Type 2 diabetes in hypertensive versus non-hypertensive patients.     

RT-qPCR assay on the vitamin D receptor gene in type 2 diabetes and hypertension patients in Turkey

RT-qPCR was used to analyze the vitamin D receptor (VDR) gene TaqI polymorphism in 100 Turkish patients with type 2 diabetes mellitus (T2DM) and hypertension compared with 100 healthy subjects, to determine whether VDR could be considered as one of the susceptibility genes for T2DM and hypertension. Genotyping was done with PCR, followed by melting curve analysis with specific fluorescent hybridization probes. The results showed that distributions for TT, Tt and tt genotypes were 51, 46 and 3% in the patient group, and 35, 49 and 16% in the control group, respectively. The frequency of the T allele in patients was also significantly higher than that in controls. Based on the results, the relationship between the VDR gene TaqI polymorphism and T2DM patients in the Turkish population was compared. In terms of the genotype distributions and allele frequencies of the VDR gene TaqI polymorphism, there was no statistically significant difference (P > 0.05) between the T2DM and hypertension patients and controls. Application of RT-qPCR method enabled us to assess the prevalence of the VDR gene TaqI polymorphism and its association with type 2 diabetes and hypertension.     

Decreased Circulating Levels of APRIL: Questioning Its Role in Diabetes

Diabetes mellitus is a chronic disease that affects over 382 million people worldwide. Type-1 Diabetes (T1D) is classified as an autoimmune disease that results from pancreatic β-cell destruction and insulin deficiency. Type-2 Diabetes (T2D) is characterized principally by insulin resistance in target tissues followed by decreased insulin production due to β-cell failure. It is challenging to identify immunological markers such as inflammatory molecules that are triggered in response to changes during the pathogenesis of diabetes. APRIL is an important member of the TNF family and has been linked to chronic inflammatory processes of various diseases since its discovery in 1998. Therefore, this study aimed to evaluate APRIL serum levels in T1D and T2D. For this, we used the ELISA assay to measure serum APRIL levels of 33 T1D and 30 T2D patients, and non-diabetic subjects as control group. Our data showed a decrease in serum APRIL levels in T1D patients when compared with healthy individuals. The same pattern was observed in the group of T2D patients when compared with the control. The decrease of serum APRIL levels in diabetic patients suggests that this cytokine has a role in T1D and T2D. Diabetes is already considered as an inflammatory condition with different cytokines being implicated in its physiopathology. Our data suggest that APRIL can be considered as a potential modulating cytokine in the inflammatory process of diabetes.     

Long-Term Risk of Incident Type 2 Diabetes and Measures of Overall and Regional Obesity: The EPIC-InterAct Case-Cohort Study

Background

Waist circumference (WC) is a simple and reliable measure of fat distribution that may add to the prediction of type 2 diabetes (T2D), but previous studies have been too small to reliably quantify the relative and absolute risk of future diabetes by WC at different levels of body mass index (BMI).

Methods and Findings

The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident T2D cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. We used Prentice-weighted Cox regression and random effects meta-analysis methods to estimate hazard ratios for T2D. Kaplan-Meier estimates of the cumulative incidence of T2D were calculated. BMI and WC were each independently associated with T2D, with WC being a stronger risk factor in women than in men. Risk increased across groups defined by BMI and WC; compared to low normal weight individuals (BMI 18.5–22.4 kg/m²) with a low WC (<94/80 cm in men/women), the hazard ratio of T2D was 22.0 (95% confidence interval 14.3; 33.8) in men and 31.8 (25.2; 40.2) in women with grade 2 obesity (BMI≥35 kg/m²) and a high WC (>102/88 cm). Among the large group of overweight individuals, WC measurement was highly informative and facilitated the identification of a subgroup of overweight people with high WC whose 10-y T2D cumulative incidence (men, 70 per 1,000 person-years; women, 44 per 1,000 person-years) was comparable to that of the obese group (50–103 per 1,000 person-years in men and 28–74 per 1,000 person-years in women).

Conclusions

WC is independently and strongly associated with T2D, particularly in women, and should be more widely measured for risk stratification. If targeted measurement is necessary for reasons of resource scarcity, measuring WC in overweight individuals may be an effective strategy, since it identifies a high-risk subgroup of individuals who could benefit from individualised preventive action. Please see later in the article for the Editors'' Summary