CACNA1E Variants Affect Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 3

Background: Genetic variability of the major subunit (CACNA1E) of the voltage-dependent Ca 2+ channel Ca V2.3 is associated to risk of type 2 diabetes, insulin resistance and impaired insulin secretion in nondiabetic subjects. The aim of the study was to test whether CACNA1E common variability affects beta cell function and/or insulin sensitivity in patients with newly diagnosed type 2 diabetes. Methodology/Principal Findings: In 595 GAD-negative, drug naïve patients (mean6SD; age: 58.5610.2 yrs; BMI: 29.965 kg/m 2, HbA1c: 7.061.3) with newly diagnosed type 2 diabetes we: 1. genotyped 10 tag SNPs in CACNA1E region reportedly covering,93 % of CACNA1E common variability: rs558994, rs679931, rs2184945, rs10797728, rs3905011, rs12071300, rs175338, rs3753737, rs2253388 and rs4652679; 2. assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp and beta cell function by state-of-art modelling of glucose/C-peptide curves during OGTT. Five CACNA1E tag SNPs (rs10797728, rs175338, rs2184945, rs3905011 and rs4652679) were associated with specific aspects of beta cell function (p,0.0520.01). Both major alleles of rs2184945 and rs3905011 were each (p,0.01 and p,0.005, respectively) associated to reduced proportional control with a demonstrable additive effect (p,0.005). In contrast, only the major allele of rs2253388 was related weakly to more severe insulin resistance (p,0.05). Conclusions/Significance: In patients with newly diagnosed type 2 diabetes CACNA1E common variability is strongl

A local glucose-and oxygen concentration-based insulin secretion model for pancreatic islets

<p>Abstract</p> <p>Background</p> <p>Because insulin is the main regulator of glucose homeostasis, quantitative models describing the dynamics of glucose-induced insulin secretion are of obvious interest. Here, a computational model is introduced that focuses not on organism-level concentrations, but on the quantitative modeling of local, cellular-level glucose-insulin dynamics by incorporating the detailed spatial distribution of the concentrations of interest within isolated avascular pancreatic islets.</p> <p>Methods</p> <p>All nutrient consumption and hormone release rates were assumed to follow Hill-type sigmoid dependences on local concentrations. Insulin secretion rates depend on both the glucose concentration and its time-gradient, resulting in second-and first-phase responses, respectively. Since hypoxia may also be an important limiting factor in avascular islets, oxygen and cell viability considerations were also built in by incorporating and extending our previous islet cell oxygen consumption model. A finite element method (FEM) framework is used to combine reactive rates with mass transport by convection and diffusion as well as fluid-mechanics.</p> <p>Results</p> <p>The model was calibrated using experimental results from dynamic glucose-stimulated insulin release (GSIR) perifusion studies with isolated islets. Further optimization is still needed, but calculated insulin responses to stepwise increments in the incoming glucose concentration are in good agreement with existing experimental insulin release data characterizing glucose and oxygen dependence. The model makes possible the detailed description of the intraislet spatial distributions of insulin, glucose, and oxygen levels. In agreement with recent observations, modeling also suggests that smaller islets perform better when transplanted and/or encapsulated.</p> <p>Conclusions</p> <p>An insulin secretion model was implemented by coupling local consumption and release rates to calculations of the spatial distributions of all species of interest. The resulting glucose-insulin control system fits in the general framework of a sigmoid proportional-integral-derivative controller, a generalized PID controller, more suitable for biological systems, which are always nonlinear due to the maximum response being limited. Because of the general framework of the implementation, simulations can be carried out for arbitrary geometries including cultured, perifused, transplanted, and encapsulated islets.</p

ContrAzioni di presidio e mitigazione

Partendo dalla concezione di "rischio" e contrapponendola a quella di "azzardo", il testo introduce il lavoro di indagine e le proposte interattive nate durante e in seguito dell'esperienza del Laboratorio del cammino che nel 2021 attraversavai territori in contrazione delle province di Torino e Biella.Starting from the concept of "risk" and opposing it with that of "hazard", the text introduces the investigation work and the interactive proposals developed during and following the experience of the "Laboratorio del Cammino" which in 2021 crossed the shrinking territories of the Turin and Biella provinces

Assessement of 1th and snd phase of insulin secretion during OGTT and IVGTT

We recently assessed 1st and 2nd phase f-cell insulin secretion by applying the same model of glucose-induced insulin secretion to plasma glucose and C-peptide curves during both IVGTTs and hyperglicemic clamps. In the present study we have extended the same modeling strategy to standard OGTT (time 0\u2019-120\u2019). We performed in 31 subjects (18 with normal glucose regulation [NGR], 7 with impared glucose regulation [IGR], and 6 with newly diagnosed type 2 diabetes [T2DM]) a standard OGTT (blood samples for plasma glucose/C-peptide were collected every 5\u2019-20\u2019 from 0\u2019 to 120\u2019), and an IVGTT (12 g per m2 of BSA; blood samples collected every 1\u2019-20\u2019 from 0\u2019 to 180\u2019-240\u2019) on 2 separate day. We have applied the same modeling strategy to both tests and obtained a fairly good fit of the data in both the IVGTT and the OGTT. We thus estimated first (\uf0731st) and second (\uf0732nd) phase insulin secretion during both tests. Results are normalized per m2 of BSA. In the pooled data, OGTT \uf0731st and \uf0732nd (2996\ub1299 e 96.1\ub17.37, respectively) were significantly higher (p<0.01) than IVGTT \uf0731st and \uf0732nd (467\ub167 e 43.8\ub14.3), reflecting the well known potentiating effect of oral glucose on \uf062-cell response. Moreover, OGTT \uf0731st and \uf0732nd were positively and significantly correlated to IVGTT \uf0731st and \uf0732nd (r=0.50 e r=0.52, respectively; p<0.01 for both). Finally, in NGR, IGR and T2DM subjects OGTT \uf0731st (3609\ub1430, 2439\ub1437 e 1807\ub1220) and \uf0732nd (112\ub19.5, 80.8\ub113 e 66.2\ub1 11.5, respectively) showed a similar declining pattern as the one observed with the IVGTT (624\ub183, 427\ub1112 and 42.8\ub127.8 for IVGTT \uf0731st; 44.8\ub16.5, 48.3\ub19.1 and 35.5\ub15 for IVGTT \uf0732nd, respectively). These data demonstrate that is feasible to assess 1st and the 2nd insulin secretion phase during a standard OGTT and provide a physiological tool to measure f-cell function in states of normal and/or altered glucose regulation