Tunekazu Umekawa

b3-adrenergic-receptor polymorphism: a genetic marker for visceral fat obesity and the insulin resistance syndrome

Summary We investigated whether the polymorphism of the β3-adrenergic receptor (β3-AR) gene, which is associated with insulin resistance in non-diabetic subjects and an earlier onset of non-insulin-dependent diabetes mellitus in Pima Indians, was associated with visceral fat obesity and features of the insulin resistance syndrome in Japanese premenopausal obese women. There was no difference between 131 obese women and 256 control subjects (0.23 vs 0.17, p = 0.112) in the frequency of the Arg64 allele. The visceral fat area measured by computerised tomography scan was greater in homozygous Arg64Arg (172 ± 17 cm2, n = 6) and heterozygous Trp64Arg (178 ± 47 cm2, n = 48) women than in women homozygous for the Trp64Trp (121 ± 46 cm2, n = 77) genotype (p < 0.01). This was also reflected by increased total body fat but not by increased body mass index. The association between the Trp64 allele and visceral fat mass by multiple regression analysis, was independent of age, body mass index and total fat mass (p < 0.004). Moreover, homozygous carriers of the Arg64 allele had higher systolic blood pressure, higher fasting and post-load glucose and insulin concentrations, higher cholesterol, and triglyceride and lower HDL-cholesterol concentrations than homozygous carriers of the Trp64 allele. Some of these differences were also observed between heterozygous Trp64Arg and homozygous Trp64Trp genotypes (glucose tolerance, insulin and cholesterol concentration). We conclude that in obese women the β3-AR polymorphism may be used as a genetic marker for visceral fat obesity and the insulin resistance syndrome. [Diabetologia (1997) 40: 200–204]

Nicotine induces uncoupling protein 1 in white adipose tissue of obese mice.

OBJECTIVE: To test the hypothesis that nicotine not only activates uncoupling protein1 (UCP1) in brown adipose tissue (BAT), but also induces UCP1 in white adipose tissue (WAT), which contributes to the mitigation of obesity in obese mice.DESIGN: Weights of the whole body, the gastrocnemius muscle, interscapular BAT and subcutaneous and retroperitoneal WAT, food intake and the mRNA and protein of UCP1 in these tissues were measured and immunohistochemistry using antiserum against UCP1 was also performed in obese yellow KK mice treated with nicotine for 6 months and control mice treated with physiological saline.RESULTS: Obese mice treated with nicotine for 6 months, compared with those injected with saline, weighed significantly less (P<0.01) and had smaller subcutaneous and retroperitoneal WAT pads (P<0.01), while obese mice that received nicotine ate less (P<0.05) than those injected with saline. In mice treated with nicotine, the mRNA and protein of UCP1 was detected not only in BAT, but also in subcutaneous and retroperitoneal WATs. Immunohistochemically, the BAT of obese mice contained large lipid droplets and appeared rather WAT-like, but changed to typical brown adipocytes after nicotine treatment. The fat pads of nicotine-treated mice contained many multilocular cells that were positive for UCP1.CONCLUSION: Nicotine not only activates UCP1 in BAT, but also induces UCP1 in WAT and decreases food intake, which contributes to the mitigation of obesity.

Beta 3-adrenoreceptor gene polymorphism: a newly identified risk factor for proliferative retinopathy in NIDDM patients.

Proliferative diabetic retinopathy is an important cause of visual impairment. We investigated whether the polymorphism of the β3-adrenoreceptor (β3-AR) gene, which is associated with insulin resistance and an earlier onset of NIDDM, was associated with proliferative diabetic retinopathy (PDR) in 215 Japanese NIDDM patients with a duration of diabetes of >10 years. The polymorphism of the β3-AR gene was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. The Trp64Arg allele of the β3-AR gene was significantly more frequent in the NIDDM patients with PDR (P = 0.002), but not in those with non-PDR (P = 0.151), than in NIDDM patients without diabetic retinopathy. Those with the mutation had an earlier onset of diabetes, a longer duration of diabetes, and higher current and maximal BMI values, compared with those without the mutation. Moreover, this mutation was also associated with higher serum triglyceride and decreased HDL-cholesterol levels. When adjustment was made for age, age at diagnosis, duration of diabetes, current BMI, systolic blood pressure, HbA1c, and serum lipids in a multiple regression analysis, a significant association was found between the Trp64Arg allele and diabetic retinopathy (P = 0.039). The Arg/Arg or Arg/Trp genotype was significantly associated with PDR, compared with the Trp/Trp genotype, with an odds ratio of 2.55 (95% CI 1.25-5.16). We concluded that the β3-AR gene polymorphism is a newly identified risk factor for PDR.

Methylenetetrahydrofolate reductase gene polymorphism is not related to diabetic nephropathy in Japanese Type 2 diabetic patients.

The development of diabetic nephropathy varies among individuals, because genetic factors as well as metabolic control contributes to its pathogenesis [1]. Methlenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the re-methylation of homocysteine to methionine [2], and reduced activity can cause hyperhomocysteinemia [3], which in turn promotes atherothrombotic vascular disease [4]. Although a common MTHFR gene (C677T) mutation is associated with hyperhomocysteinemia [5], it does not appear to be a significant, independent risk factor for atherothrombotic vascular disease [6]. The possible association of this mutation and diabetic nephropathy is controversial [7–11]. We therefore examined the association between this MTHFR gene mutation and diabetic nephropathy in Japanese Type 2 diabetic patients. A total of 342 subjects with Type 2 diabetes were enrolled for the study. To avoid the interference of retinopathy, subjects with advanced retinopathy were excluded. Diabetic nephropathy was defined according to the urinary albumin : creatinine ratio and the subjects were subdivided into a normoalbuminuria group (< 30 mg/g.Cr), a microalbuminuria group (30–300 mg/ g.Cr), and a macroalbuminuria group (> 300 mg/g.Cr). The C677T mutation in the MTHFR gene was analysed by real time polymerase chain reaction (PCR) as described previously [12]. As shown in Table 1, the allelic frequency of C677T mutation of MTFHR gene in the total study population was 0.37. Genotype frequencies were in accordance with the Hardy– Weinberg equation (C/C, 39.8%; C/T, 46.5%; T/T, 13.7%). The genotype distribution of C/C allele, C/T allele, and T/T allele in patients with microand macro-albuminuria were not significantly different from those with normoalbuminuria. Allele frequencies for T allele were also similar among the groups. Glycosylated haemoglobin (HbA 1c ), systolic blood pressure, plasma triglyceride were elevated in patients with microalbumiuria compared with those with normoalbuminuria. The patients with macroalbuminuria had longer diabetic duration and higher blood urea and creatinine compared with those with normoalbuminuria. It is hypothesized that individuals homozygous for MTHFR gene mutation (C677T) would be predisposed to develop diabetic nephropathy, as the latter is associated with increased plasma homocysteine levels [13]. Some report an association between this mutation and nephropathy [7–9], whereas others did not [10,11]. In the present study, we found no differences in genotype and allele frequency of MTHFR mutations between patients with and without diabetic nephropathy. Logistic analysis showed significant associations between nephropathy and HbA 1c level or duration of diabetes, but not C677T mutation of MTHRF gene. These conflicting results may be due to differences in ethnic and clinical characteristics. Serum folate concentrations may be another determinate, because high serum folate restores plasma homocysteine levels to normal and so overcomes decreased MTHFR activity accompanied by the MTHFR gene mutation [14]. We have recently reported no association between the C677T MTHFR gene mutation and diabetic retinopathy as another diabetic

A case of primary hyperparathyroidism that had been treated under a diagnosis of depression for 10 years

Abstract A 66 year old man who had been treated under a diagnosis of depression for 10 years was referred to the Kyoto Prefectural University of Medicine, Kyoto because of general fatigue and appetite loss. The patient was diagnosed as having primary hyperparathyroidism (PHPT) based on the increased parathyroid hormone (PTH) and serum calcium levels. Computed tomography revealed solitary adenoma of parathyroid gland. The resection of this solitary adenoma improved the PTH and serum calcium concentrations to normal ranges, which resulted in an improvement in his depressive state. This case suggests that ionic calcium levels contribute to the mental symptoms associated with PHPT. As PHPT is curable, the possibility of PHPT should be taken into account when patients have depressive symptoms.