p53 and rapamycin are additive

Mechanistic target of rapamycin (mTOR) is a kinase found in a complex (mTORC1) that enables macromolecular synthesis and cell growth and is implicated in cancer etiology. The rapamycin-FK506 binding protein 12 (FKBP12) complex allosterically inhibits mTORC1. In response to stress, p53 inhibits mTORC1 through a separate pathway involving cell signaling and amino acid sensing. Thus, these different mechanisms could be additive. Here we show that p53 improved the ability of rapamycin to: 1) extend mouse life span, 2) suppress ionizing radiation (IR)-induced senescence-associated secretory phenotype (SASP) and 3) increase the levels of amino acids and citric acid in mouse embryonic stem (ES) cells. This additive effect could have implications for cancer treatment since rapamycin and p53 are anti-oncogenic.     

Health-seeking behaviour of the elderly living alone in an urbanised low-income community in Singapore

INTRODUCTION:Elderly persons who live alone are more likely to be socially isolated and at increased risk of adverse health outcomes, unnecessary hospital re-admissions and premature mortality. We aimed to understand the health-seeking behaviour of elderly persons living alone in public rental housing in Singapore.METHODS:In-depth interviews were conducted using a semi-structured question guide. Participants were selected using a purposive sampling approach. Interviews were conducted until theme saturation was reached. Qualitative data collected was analysed using manual thematic coding methods.RESULTS:Data analysis revealed five major themes: accessibility of healthcare services and financial assistance schemes; perceived high cost of care; self-management; self-reliance; and mismatch between perceived needs and services.CONCLUSION:Elderly persons living in one-room rental flats are a resilient and resourceful group that values self-reliance and independence. Most of the elderly who live alone develop self-coping mechanisms to meet their healthcare needs rather than seek formal medical consultation. The insightful findings from this study should be taken into consideration when models of healthcare delivery are being reviewed and designed so as to support the disadvantaged elderly living alone.     

Common genetic variation in the glucokinase gene (GCK) is associated with type 2 diabetes and rates of carbohydrate oxidation and energy expenditure

Aims/hypothesis

Glucokinase (GCK) plays a role in glucose metabolism and glucose-stimulated insulin secretion. Rare mutations in GCK cause MODY. We investigated whether common variation (minor allele frequency ≥0.01) in GCK is associated with metabolic traits and type 2 diabetes.

Methods

Four exonic single-nucleotide polymorphisms (SNPs) and three SNPs predicted to cause loss of promoter function were identified in whole-genome sequence data from 234 Pima Indians. These seven tag SNPs and rs4607517, a type 2 diabetes variant established in other studies, were analysed in 415 full-heritage non-diabetic Pima Indians characterised for metabolic traits, and 7,667 American Indians who had data on type 2 diabetes and BMI.

Results

A novel 3′ untranslated region (3′UTR) SNP, chr7:44184184-G/A, was associated with the rate of carbohydrate oxidation post-absorptively (β?=?0.22 mg [kg estimated metabolic body size (EMBS)]^?1?min^?1, p?=?0.005) and during a hyperinsulinaemic–euglycaemic clamp (β?=?0.24 mg [kg EMBS]^?1?min^?1, p?=?0.0002), the rate of carbohydrate oxidation in a respiratory chamber (β?=?311 kJ/day, p?=?0.03) and 24 h energy expenditure, which was attributable to the thermic effect of food (β?=?520 kJ/day, p?=?3.39?×?10^?6). This 3′UTR SNP was also associated with diabetes (OR 1.36, 95% CI 1.11, 1.65, p?=?0.002), where the A allele (allele frequency 0.05) was associated with a lower rate of carbohydrate oxidation, lower 24 h energy expenditure and higher risk for diabetes. In a Cox proportional hazards model, a rate of insulin-stimulated carbohydrate oxidation lower than the mean rate at baseline predicted a higher risk for developing diabetes than for those above the mean (hazard rate ratio 2.2, 95% CI 1.3, 3.6, p?=?0.002).

Conclusions/interpretation

Common variation in GCK influences the rate of carbohydrate oxidation, 24 h energy expenditure and diabetes risk in Pima Indians.