ABSTRACT
Development of low glycemic-foods is important in the prevention and management of type 2 diabetes. In this context, we prepared four test foods (TFs) (two mixed mini-meals and two breakfast items) with low glycemic-components and assessed their glycemic index (GI) in young healthy non-diabetic volunteers with mean age of 29 yr, body mass index of 24 kg/m2, and fasting plasma glucose levels less than 4.62 mmol/L. Volunteers were given 50 g of glucose, as a reference food (RF) on the first day, and TFs, i.e. TF1 (mixed mini meal: roti made of wheat flour and chana dal+ curd), TF2 [mixed mini meal made of wheat, pearl barley, and Bengal gram flour (besan) mix with chana whole (unhusked chana+curd)], TF3 (pearl barley rawa upma), and TF4 (wheat rawa upma) were given 2-day intervals in the same order. Glucose levels at fasting conditions and after the consumption of RF and TFs at different time intervals (15, 30, 45, 60, 90, and 120 min) were measured, and the incremental area under curve (IAUC) for glucose and GI of the TFs were calculated. The glucose IAUC values at different time points were highest for TF2 (GI=71.9±7.4), while all other TFs had comparable GI in the range of 53.7~54.9. Among the various TFs, TF1, TF3, and TF4 exerted low to moderate glycemic response, and thus can be classified as low glycemic-foods. Nevertheless, these foods need to be tested for their efficacy in controlling and/or managing hyperglycemia and glucose over-load in diabetic subjects.
ABSTRACT
Distinct protein phosphorylation levels in interphase and M phase require tight regulation of Cdk1 activity [1, 2]. A bistable switch, based on positive feedback in the Cdk1 activation loop, has been proposed to generate different thresholds for transitions between these cell-cycle states [3-5]. Recently, the activity of the major Cdk1-counteracting phosphatase, PP2A:B55, has also been found to be bistable due to Greatwall kinase-dependent regulation [6]. However, the interplay of the regulation of Cdk1 and PP2A:B55 in vivo remains unexplored. Here, we combine quantitative cell biology assays with mathematical modeling to explore the interplay of mitotic kinase activation and phosphatase inactivation in human cells. By measuring mitotic entry and exit thresholds using ATP-analog-sensitive Cdk1 mutants, we find evidence that the mitotic switch displays hysteresis and bistability, responding differentially to Cdk1 inhibition in the mitotic and interphase states. Cdk1 activation by Wee1/Cdc25 feedback loops and PP2A:B55 inactivation by Greatwall independently contributes to this hysteretic switch system. However, elimination of both Cdk1 and PP2A:B55 inactivation fully abrogates bistability, suggesting that hysteresis is an emergent property of mutual inhibition between the Cdk1 and PP2A:B55 feedback loops. Our model of the two interlinked feedback systems predicts an intermediate but hidden steady state between interphase and M phase. This could be verified experimentally by Cdk1 inhibition during mitotic entry, supporting the predictive value of our model. Furthermore, we demonstrate that dual inhibition of Wee1 and Gwl kinases causes loss of cell-cycle memory and synthetic lethality, which could be further exploited therapeutically.