Which is a better treatment for hypertensive patients with diabetes: a combination of losartan and hydrochlorothiazide or a maximum dose of losartan?

BACKGROUND: This 12-month study compared the effects of a combination of losartan 50 mg and hydrochlorothiazide 12.5 mg with a maximum dose of losartan (100 mg) in hypertensive patients with diabetes. METHODS: This was a multicenter randomized open-label study. RESULTS: A similar reduction in systolic/diastolic blood pressure from baseline to month 3 was observed in both groups. There was also a similar decrease in UACR in both groups. A significant decrease in uric acid was observed in the maximum-dose group only. eGFR decreased in the combination group after 1 year. CONCLUSIONS: The combination of losartan and a diuretic may be a useful option in such hypertensive patients with diabetes, provided that metabolic parameters are closely monitored. In patients with hyperuricemia and impaired renal function, a maximum dose of losartan may be more beneficial.

Relationship between the Thyroid Function and Cognitive Impairment in the Elderly in Japan.

Objective The reference ranges of serum thyroid hormone levels are determined by the values of normal subjects aged 15 or 20 to 60 years old in Japan and may differ from the values in elderly patients. In addition, the relationship between the thyroid function and cognitive function remains controversial. We assessed the thyroid function of elderly subjects ≥60 years old and its impact on the cognitive function in Japanese adults. Methods We compared the thyroid function by age group and gender and investigated the effects of cognitive impairment on the thyroid function. This study was a cross-sectional, multi-institutional joint study. Patients The serum concentrations of thyroid hormones in 1,136 patients were measured; however, those taking thyroid hormones, anti-thyroid drugs, and steroid hormones were excluded. Among them, 1,016 cases in which the cognitive function was evaluated were divided into five groups according to their free thyroxine (FT4) levels. Results Excluding overt thyroid dysfunction (5.8%), the average age of the 1,070 remaining patients was 77.5 years old. The rate of cognitive impairment was lowest at FT4 levels of 1.1-1.2 ng/dL and highest at FT4 levels <0.9 ng/dL for both genders. Thyroid-stimulating hormone (TSH) levels in the elderly varied widely by age group and gender. The upper limit of the reference range of TSH for those ≥60 years old may be higher (7.7-9.2 mIU/L for men; 8.2-8.6 mIU/L for women) than the current range for those <60 years old (4.23 mIU/L). Conclusion The thyroid function seemed to be slightly higher (lower TSH and higher FT4) in the population without cognitive impairment than in those with cognitive impairment, except for men in their 90s.

A Novel homozygous missense mutation of melanocortin-4 receptor (MC4R) in a Japanese woman with severe obesity.

The melanocortin-4 receptor (MC4R) is a member of the seven membrane-spanning G protein-coupled receptor superfamily and signals through the activation of adenylyl cyclase. The MC4R mutations are the most common known monogenic cause of human obesity. However, no such mutations have been found in Japanese obese subjects. Here we report a novel homozygous missense mutation of MC4R (G98R) in a nondiabetic Japanese woman with severe early-onset obesity, which is located in its second transmembrane domain. Her birth weight was 3,360 g, and she gained weight progressively from 10 months of age. At 40 years of age, her weight reached 160 kg and a BMI of 62 kg/m(2). Her parents, who are heterozygous for the mutation, have BMIs of 26 and 27 kg/m(2). In vitro transient transfection assays revealed no discernable agonist ligand binding and cAMP production in HEK293 cells expressing the mutant receptor, indicating a severe loss-of-function mutation. This study represents the first demonstration of a pathogenic mutation of MC4R in Japan and will provide further insight into the pathophysiologic role of the hypothalamic melanocortin system in human obesity.

Central pontine and extrapontine myelinolysis associated with type 2 diabetic patient with hypokalemia.

Central pontine myelinolysis (CPM) is a demyelinating disease of the pons often associated with the demyelination of extrapontine areas of the central nervous system. Although the etiology and pathogenesis are unclear, CPM is usually associated with hyponatremia or its rapid correction, and chronic alcoholism is also a common underlying condition. We observed a 43-year-old man with diabetes mellitus who developed central pontine and extrapontine myelinolysis with no apparent evidence of hyponatremia, serum hyperosmolality or associated rapid correction, or history of alcohol abuse. On admission, the patient was lethargic with dysarthria, dysphagia, and mild tetraparesis and his face and lower extremities were severely edematous. Laboratory examination showed normoglycemia and normonatremia, although hypokalemia, elevated HbA1c, and nephrotic syndrome were also present. Magnetic resonance imaging (MRI) revealed abnormal signal intensity in the pons, the deep layers of the cerebral cortex, and the adjacent white matter consistent with central pontine and extrapontine myelinolysis. Generalized edema was reduced by the use of diuretics and extracorporeal ultrafiltration without significant changes of serum sodium or osmolality. His consciousness level and paresis gradually improved within a few weeks. Our patient is a rare case of CPM associated with diabetes without apparent evidence of sodium or glucose imbalances.

Pathophysiogical role of leptin in lifestyle-related diseases. Studies with transgenic skinny mice overexpressing leptin.

Leptin is a major adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure. Plasma leptin concentrations are elevated in obese subjects, suggesting its pathophysiological role in obesity-related lifestyle-related diseases. We have recently succeeded in the generation of transgenic skinny mice overexpressing leptin. They exhibit increased glucose metabolism and insulin sensitivity accompanied by a significant increase in insulin signaling for glucose utilization in the skeletal muscle and liver. They also show blood pressure elevation through the sympathetic activation. Introduction of the lethal yellow agouti (A(y)) allele into transgenic skinny mice results in late-onset obesity and diabetes with blood pressure elevation similar to those found in nontransgenic agouti mice (A(y)/+ mice). After caloric restriction, blood pressure elevation is reversed but insulin resistance still remains in A(y)/+ mice in parallel with a reduction of plasma leptin concentrations. By contrast, blood pressure elevation is sustained but insulin resistance is reversed in transgenic mice overexpressing leptin with the A(y) allele (Tg/+:A(y)/+ mice), which remain hyperleptinemic. Collectively, our data suggest the pathophysiologic and therapeutic implication of leptin in obesity-related insulin resistance and hypertension.

[Obesity induced by abnormality in leptin receptor and melanocortin-4 receptor].

Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. It increases a risk of cardiovascular and metabolic diseases such as diabetes, hypertension, and hyperlipidemia. Recent molecular genetic studies have disclosed some monogenic forms of obesity in humans. Leptin directly exerts its anorexigenic effects on hypothalamic arcuate nucleus. alpha-melanocyte stimulating hormone (alpha-MSH) derived from proopiomelanocortin (POMC) and melanocortin-4 receptor (MC4-R) have been reported to be involved in the downstream of leptin actions. In this paper, we summarize the clinical characteristics and the mechanisms of obesity caused by genetic abnormalities in leptin receptor and melanocortin-4 receptor.