Gupta, R. | bioRxiv Science

bioRxiv2018

Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: an overview of the data from the epidemiological studies within the IMI DIRECT Consortium

Abstract/SummaryO_ST_ABSBackground and aimsC_ST_ABSUnderstanding the aetiology, clinical presentation and prognosis of type 2 diabetes (T2D) and optimizing its treatment might be facilitated by biomarkers that help predict a persons susceptibility to the risk factors that cause diabetes or its complications, or response to treatment. The IMI DIRECT (Diabetes Research on Patient Stratification) Study is a European Union (EU) Innovative Medicines Initiative (IMI) project that seeks to test these hypotheses in two recently established epidemiological cohorts. Here, we describe the characteristics of these cohorts at baseline and at the first main follow-up examination (18-months).\n\nMaterials and methodsFrom a sampling-frame of 24,682 European-ancestry adults in whom detailed health information was available, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm and enrolled into a prospective cohort study (n=2127) undertaken at four study centres across Europe (Cohort 1: prediabetes). We also recruited people from clinical registries with recently diagnosed T2D (n=789) into a second cohort study (Cohort 2: diabetes). The two cohorts were studied in parallel with matched protocols. Endogenous insulin secretion and insulin sensitivity were modelled from frequently sampled 75g oral glucose tolerance (OGTT) in Cohort 1 and with mixed-meal tolerance tests (MMTT) in Cohort 2. Additional metabolic biochemistry was determined using blood samples taken when fasted and during the tolerance tests. Body composition was assessed using MRI and lifestyle measures through self-report and objective methods.\n\nResultsUsing ADA-2011 glycaemic categories, 33% (n=693) of Cohort 1 (prediabetes) had normal glucose regulation (NGR), and 67% (n=1419) had impaired glucose regulation (IGR). 76% of the cohort was male, age=62(6.2) years; BMI=27.9(4.0) kg/m2; fasting glucose=5.7(0.6) mmol/l; 2-hr glucose=5.9(1.6) mmol/l [mean(SD)]. At follow-up, 18.6(1.4) months after baseline, fasting glucose=5.8(0.6) mmol/l; 2-hr OGTT glucose=6.1(1.7) mmol/l [mean(SD)]. In Cohort 2 (diabetes): 65% (n=508) were lifestyle treated (LS) and 35% (n=271) were lifestyle + metformin treated (LS+MET). 58% of the cohort was male, age=62(8.1) years; BMI=30.5(5.0) kg/m2; fasting glucose=7.2(1.4)mmol/l; 2-hr glucose=8.6(2.8) mmol/l [mean(SD)]. At follow-up, 18.2(0.6) months after baseline, fasting glucose=7.8(1.8) mmol/l; 2-hr MMTT glucose=9.5(3.3) mmol/l [mean(SD)].\n\nConclusionThe epidemiological IMI DIRECT cohorts are the most intensely characterised prospective studies of glycaemic deterioration to date. Data from these cohorts help illustrate the heterogeneous characteristics of people at risk of or with T2D, highlighting the rationale for biomarker stratification of the disease - the primary objective of the IMI DIRECT consortium.\n\nAbbreviations

epidemiology↗

bioRxiv2018

Understanding the role of alterations in cortical D1 receptor sensitivity in shaping working memory maintenance through mesocortical dynamics

The dopamine (DA) hypothesis of cognitive deficits suggests that too low or too high extracellular DA concentration in the prefrontal cortex (PFC) can severely impair the working memory (WM) maintenance during delay period. Thus, there exists only an optimal range of DA where the sustained-firing activity, the neural correlate of WM maintenance, in the cortex possesses optimal firing frequency as well as robustness against noisy distractions. Empirical evidences demonstrate changes even in the D1 receptor (D1R)-sensitivity to extracellular DA, collectively manifested through D1R density and DA-binding affinity, in the PFC under neuropsychiatric conditions such as ageing and schizophrenia. However, the impact of alterations in the cortical D1R-sensitivity on WM maintenance has yet remained poorly addressed. Using a quantitative neural mass model of the prefronto-mesoprefrontal system, the present study reveals that higher D1R-sensitivity may not only effectuate shrunk optimal DA range but also shift of the range to lower concentrations. Moreover, higher sensitivity may significantly reduce the WM-robustness even within the optimal DA range and exacerbates the decline at abnormal DA levels. These findings project important clinical implications, such as dosage precision and variability of DA-correcting drugs across patients, and failure in acquiring healthy WM maintenance even under drug-controlled normal cortical DA levels.

neuroscience↗

bioRxiv2018

Methionine coordinates a hierarchically organized anabolic program through GCN4

Methionine availability during overall amino acid limitation metabolically reprograms cells to support proliferation, the underlying basis for which remains unclear. Here, we construct the organization of this methionine mediated anabolic program, using yeast. Combining comparative transcriptome analysis, biochemical and metabolic flux based approaches, we discover that methionine rewires overall metabolic outputs by increasing the activity of three key regulatory nodes. These are: the pentose phosphate pathway coupled with reductive biosynthesis, and overall transamination capacity, including the synthesis of glutamate/glutamine. These provides the cofactors or substrates that enhance subsequent rate-limiting reactions in the synthesis of costly amino acids, and nucleotides, which are also induced in a methionine dependent manner. This thereby results in a biochemical cascade establishing an overall anabolic program. For this methionine mediated anabolic program leading to proliferation, cells co-opt a \"starvation stress response\" regulator, Gcn4p. Collectively, our data suggest a hierarchical metabolic framework explaining how methionine mediates an anabolic switch.

systems biology↗