Genetic variability in insulin action inhibitor Ikkbeta (IKBKB) does not play a major role in the development of type 2 diabetes

Recent evidence indicates that IkappaB kinase beta (Ikkbeta) may be a mediator of acquired forms of insulin-resistance. In this study, we examined whether genetic variability at the Ikkbeta locus (IKBKB) contributes to the development of genetic forms of early-onset type 2 diabetes transmitted with an autosomal dominant mode of inheritance. Linkage with four markers flanking the IKBKB gene was evaluated in 32 multigenerational families. Included in the study were 233 diabetic (mean age at Dx = 37 +/- 18) and 152 nondiabetic subjects. The overall LOD scores were negative (-54.9 and -46.2 on the centromeric and telomeric sides, respectively) indicating that variability in IKBKB was not a major determinant of diabetes in these families. Positive values, however, were observed for selected pedigrees. All 17 families for which linkage with the IKBKB locus could not be excluded were screened for sequence differences in the 22 exons and 1.6 kb of the 5' flanking region by dideoxyfingerprinting or direct sequencing. Polymorphisms were identified in the 5' flanking region (-1775del/insC and -1547T > A), exon 11 (c.1083A > G, L361L) and in intron 12 (IVS12+14t > a). However, no mutations segregating with diabetes could be found in these families. Furthermore, all four polymorphisms had similar allele frequencies in the 32 family probands, 171 individuals with common, later-onset type 2 diabetes, and 182 nondiabetic controls. We conclude that sequence differences in the IKBKB gene do not play a major role in either early-onset, autosomal dominant type 2 diabetes, or common forms with a later-onset.     

NOCTURNAL 8mg DEXAMETHASONE SUPPRESSION TEST: A PRACTICAL AND ACCURATE TEST FOR IDENTIFICATION OF THE CAUSE OF ENDOGENOUS CUSHING'S SYNDROME

SUMMARY The efficacy of a nocturnal 8mg dexamethasone suppression test (nocturnal DST) was compared with that of the standard high-dose dexamethasone suppression test (standard DST) in identifying the cause of endogenous Cushing's syndrome in 10 proven cases with Cushing's disease, 20 with adrenal tumours, and one with ectopic ACTH syndrome. The nocturnal test compared serum cortisol concentration at 8am before and after administration of a single dose of 8mg dexamethasone at 11pm. Suppression of serum cortisol level to <50% of the baseline value indicated a diagnosis of Cushing's disease, while a lack of suppression below that limit indicated one of the other two causes of Cushing's syndrome: glucocorticoid-secreting adrenal tumour or ectopic ACTH syndrome. The nocturnal DST had a sensitivity of 90%, a specificity of 100%, an accuracy of 96.8%, a positive predictive value of 100%, and a negative predictive value of 95.5%. These values are comparable to the efficacy of the standard DST in distinguishing Cushing's disease from glucocorticoid-secreting adrenocortical tumour or ectopic ACTH syndrome. Furthermore, this rapid test does not require hospitalisation or urine collection like the standard DST. The nocturnal 8mg dexamethasone suppression test is practical, fairly reliable, and an effective alternative with which to identify the cause of endogenous Cushing's syndrome.     

The prevalence and risk factors of hypertension in Klong Toey slum and Klong Toey government apartment houses

We have investigated the prevalence and factors associated with hypertension in 976 residents of Klong Toey Slum and 909 residents of government apartment houses, aged 30 and above, selected by probability sampling after systematic household surveys with an average response rate of over 80%. Hypertensives were those who had, on at least three measurements, average diastolic blood pressure equal to or above 95 mmHg and/or systolic blood pressure equal to or above 160 mmHg or had blood pressure below 160/95 mmHg but were currently on antihypertensive medication. The prevalence of total hypertensives were found to be 17.3% and 14.0% for residents of slum and government apartment houses respectively. Men and women had more or less equal mean blood pressure and similar prevalence of hypertension. The mean systolic blood pressure increased with age while the mean diastolic blood pressure, after an initial rise with age in lower age groups, tended to level off from the age group 55-64 years upwards. Only one quarter to one third were aware of their illness and less than 15% were receiving treatment. Significant risk factors include age, duration of smoking, duration of alcohol intake, high body mass index, high Cholesterol, high Triglyceride, high Low Density Lipoprotein Cholesterol (LDLC), low High Density Lipoprotein Cholesterol (HDLC), high Total Cholesterol (TC) to High Density Lipoprotein ratio (TC/HDLC), high LDLC to HDLC ratio and diabetes mellitus. The data suggested that hypertension was an important public health problem in low socioeconomic groups in Bangkok. Some of the risk factors were related to an unhealthy lifestyle which should receive due consideration in planning for appropriate control.     

HNF1A mutation in a Thai patient with maturity-onset diabetes of the young: A case report

BACKGROUND Maturity-onset diabetes of the young(MODY) is the most common form of monogenic diabetes. The disease is transmitted in autosomal dominant mode and diabetes is usually diagnosed before age 25 year. MODY 3 is caused by mutation of hepatocyte nuclear factor(HNF) 1 A genes and is the most common MODY subtype. Diagnosis of MODY 3 is crucial since glycemic control can be accomplished by very low dose of sulfonylurea. In this report we described a Thai MODY 3 patient who had excellence plasma glucose control by treating with glicazide 20 mg per day and insulin therapy can be discontinued.CASE SUMMARY A 31-year-old woman was diagnosed diabetes mellitus at 14 years old. The disease was transmitted from her grandmother and mother compatible with autosomal dominant inheritance. Sanger sequencing of proband's DNA identified mutation of HNF1 A at codon 203 which changed amino acid from arginine to cysteine(R203 C). This mutation was carried only by family members who have diabetes. The patient has been treated effectively with a combination of oral hypoglycemic agents and must include a very low dose of glicazide(20 mg/d). Insulin therapy was successfully discontinued.CONCLUSION We demonstrated a first case of pharmacogenetics in Thai MODY 3 patient. Our findings underscore the essential role of molecular genetics in diagnosis and guidance of appropriate treatment of diabetes mellitus in particular patient.     

Evidence of a novel type 2 diabetes locus 50 cM centromeric to NIDDM2 on chromosome 12q.

To replicate the recent finding of a type 2 diabetes locus (NIDDM2) on 12q, families segregating early-onset autosomal-dominant type 2 diabetes were screened for linkage. Included were 26 Caucasian and 6 non-Caucasian pedigrees with an average age at diabetes diagnosis of 37 +/- 18 years. Affected (n = 233) and nonaffected (n = 152) family members were genotyped for 17 markers covering 90 cM on chromosome 12q. While no evidence for linkage was detected at the NIDDM2 locus, a linkage peak was observed 50 cM centromeric to NIDDM2 at markers D12S375 and D12S1052. In a nonparametric analysis, the Z(all) score was 2.9 (P = 0.015) at D12S375, and increased to 3.8 (P = 0.007) among Caucasian families. Further increase in significance was observed in pedigrees with poor insulin response, with a maximum Z(all) of 6.2 (P = 0.002) at D12S375. Suggestive evidence of linkage was also detected by the parametric analysis, with the heterogeneity logarithm of odds score peaking at 2.5 (alpha = 0.15) between D12S375 and D12S1052. In summary, our data indicate that the NIDDM2 locus does not play a major role in early-onset autosomal-dominant type 2 diabetes. Rather, they strongly suggest that a previously undetected type 2 diabetes locus exists 50 cM from NIDDM2 on 12q.     

PRIMARY THYROID CARCINOMA AND THYROTOXICOSIS

A 60-year-old man noticed rapid enlargement of a long-standing thyroid goitre, with dysphagia and difficulty in breathing. Thyrotoxicosis was diagnosed. Chest X-ray revealed multiple pulmonary metastases. He underwent near-total thyroidectomy. The histopathology revealed an undifferentiated thyroid carcinoma with some areas of papillary carcinoma and its follicular variant. Postoperative ¹³¹l total body scan showed residual thyroid tissue in the neck and one functioning metastasis in the right rib, posteriorly. The patient's condition deteriorated rapidly and he died from pneumonia. The autopsy showed widespread metastases of undifferentiated thyroid carcinoma. Only the right rib contained the follicular variant of papillary carcinoma.     

Detection of CAPN10 copy number variation in Thai patients with type 2 diabetes by denaturing high performance liquid chromatography and real‐time quantitative polymerase chain reaction

Aims/Introduction

A combination of multiple genetic and environmental factors contribute to the pathogenesis of type 2 diabetes. Copy number variations (CNVs) are associated with complex human diseases. However, CNVs can cause genotype deviation from the Hardy–Weinberg equilibrium (HWE). A genetic case–control association study in 216 Thai diabetic patients and 192 non-diabetic controls found that, after excluding genotyping errors, genotype distribution of calpain 10 (CAPN10) SNP44 (rs2975760) deviated from HWE. Here, we aimed to detect CNV within the CAPN10 SNP44 region.

Materials and Methods

CNV within the CAPN10 SNP44 region was detected using denaturing high-performance liquid chromatography, and the results confirmed by real-time quantitative polymerase chain reaction with SYBR Green I.

Results

Both methods successfully identified CNV in the CAPN10 SNP44 region, obtaining concordant results. Correction of genotype calling based on the status of identified CNVs showed that the CAPN10 SNP44 genotype is in good agreement with HWE (P > 0.05). However, no association between CNV genotypes and risk of type 2 diabetes was observed.

Conclusions

Identified CNVs for CAPN10 SNP44 genotypes lead to deviation from HWE. Furthermore, both denaturing high-performance liquid chromatography and real-time quantitative polymerase chain reaction are useful for detecting CNVs.