Glucose tolerance stages in Cystic Fibrosis are idenfied by a unique pattern of defects of Beta-cell function

To assess the order of severity of the defects of three direct determinants of glucose regulation, i.e., beta-cell function, insulin clearance and insulin sensitivity, in patients with CF categorized according their glucose tolerance status, including early elevation of mid-OGTT glucose values (>140 and < 200 mg/dL), named AGT140

Ethnic differences in beta cell function occur independently of insulin sensitivity and pancreatic fat in black and white men

Introduction It is increasingly recognized that type 2 diabetes (T2D) is a heterogenous disease with ethnic variations. Differences in insulin secretion, insulin resistance and ectopic fat are thought to contribute to these variations. Therefore, we aimed to compare postprandial insulin secretion and the relationships between insulin secretion, insulin sensitivity and pancreatic fat in men of black West African (BA) and white European (WE) ancestry.Research design and methods A cross-sectional, observational study in which 23 WE and 23 BA men with normal glucose tolerance, matched for body mass index, underwent a mixed meal tolerance test with C peptide modeling to measure beta cell insulin secretion, an MRI to quantify intrapancreatic lipid (IPL), and a hyperinsulinemic-euglycemic clamp to measure whole-body insulin sensitivity.Results Postprandial insulin secretion was lower in BA versus WE men following adjustment for insulin sensitivity (estimated marginal means, BA vs WE: 40.5 (95% CI 31.8 to 49.2) × 103 vs 56.4 (95% CI 48.9 to 63.8) × 103 pmol/m2 body surface area × 180 min, p=0.008). There was a significantly different relationship by ethnicity between IPL and insulin secretion, with a stronger relationship in WE than in BA (r=0.59 vs r=0.39, interaction p=0.036); however, IPL was not a predictor of insulin secretion in either ethnic group following adjustment for insulin sensitivity.Conclusions Ethnicity is an independent determinant of beta cell function in black and white men. In response to a meal, healthy BA men exhibit lower insulin secretion compared with their WE counterparts for their given insulin sensitivity. Ethnic differences in beta cell function may contribute to the greater risk of T2D in populations of African ancestry

Interleukin-6 as a potential positive modulator of human beta-cell function: an exploratory analysis-the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 6

Recent studies in mouse models of T2D showed that interleukin-6 (IL-6), released from skeletal muscle, is associated with increased glucose-dependent insulin secretion. Few data currently exist exploring the relationship between IL-6 and beta-cell function in humans. We investigated whether IL-6 is positively associated with beta-cell function in newly diagnosed T2D. We extended the same analyses to IL-10, because it regulated similarly to IL-6 in skeletal muscle, and TNF-\u3b1 and C-reactive protein (CRP), as general biomarkers of inflammation

Is common genetic variation at IRS1, ENPP1 and TRIB3 loci associated with cardiometabolic phenotypes in type 2 diabetes? An exploratory analysis of the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 5

Background and Aims - Insulin resistance is a hallmark of type 2 diabetes (T2DM), it is often accompanied by defective beta-cell function (BF) and is involved in the pathophysiology of cardiovascular disease (CVD). Commonalities among these traits may recognize a genetic background, possibly involving the genetic variation of insulin signaling pathway genes. We conducted an exploratory analysis by testing whether common genetic variability at IRS1, ENPP1 and TRIB3 loci is associated with cardiovascular risk traits and metabolic phenotypes in T2DM.Methods and Results - In 597 drug-na\uefve, GADA-negative, newly-diagnosed T2DM patients we performed: 1) genotyping of 10 independent single-nucleotide polymorphisms covering ~90% of common variability at IRS1, ENPP1 and TRIB3 loci; 2) carotid artery ultrasound; 3) standard ECG (n=450); 4) euglycaemic insulin clamp to assess insulin sensitivity; 5) 75g-OGTT to estimate BF (derivative and proportional control) by mathematical modeling. False discovery rate of multiple comparisons was set at 0.20. After adjustment for age, sex and smoking status, rs4675095-T (IRS1) and rs4897549-A (ENPP1) were significantly associated with carotid atherosclerosis severity, whilst rs7265169-A (TRIB3) was associated with ECG abnormalities. Rs858340-G (ENPP1) was significantly associated with decreased insulin sensitivity, independently of age, sex and body-mass-index. No consistent relationships were found with BF.Conclusion - Some associations were found between intermediate phenotypes of CVD and common genetic variation of gatekeepers along the insulin signaling pathway. These results need be replicated to support the concept that in T2DM the CVD genetic risk clock may start ticking long before hyperglycemia appears. ClinicalTrials.gov Identifier: NCT01526720

In patients with newly-diagnosed type 2 diabetes beta cell function is an independent predictor of glucose control evolution over 18 months

Background and aims: We asked the question whether the metabolic phenotype at baseline and/or a number of type 2 diabetes mellitus (T2DM) risk genes may predict the evolution of glucose control (GC) within the first 18 months after diagnosis of the disease. Materials and methods: 593 GAD-antibodies negative patients with newly diagnosed T2DM (age: 59\ub10.4 yrs; BMI: 30.0\ub10.2 kg/m2) were studied with: 1. Prolonged (5-hours) frequently sampled OGTT to assess beta cell function(BCF) by state of art mathematical modelling of glucose and C-peptide; 2. Standard euglycemic insulin clamp to assess insulin sensitivity (SI); 3. Genotyping the common T2DM risk variants of the following genes: ADAMTS9, CDKAL1, FTO, G6PC2, GCK, GCKR, GNPDA2, HHEX, HNF1B, IGF2BP2, IRS1, JAZF1, KCNJ11, MTNR1B, NOTCH2, PPARG, SCL30A8, TCFL2, THADA,TMEM18, TSPAN and WFS1. GC evolution was defined as the difference between HbA1c at diagnosis (7.0\ub10.1%) and HbA1c at 18 months (6.5\ub10.1%). Results: 141 patients were lost to follow-up, thereby leaving 452 patients for evaluation. In all multivariate regression models, basal HbA1c (standardizedbeta [stBETA]: 0.92, p<0.0001) was the strongest positive predictor of favourable GC evolution (i.e. the higher HbA1c at diagnosis, the greater its fall within 18 months). No role for T2DM risk gene variants, either as a single SNP or as a genetic score derived from all SNPs, could be detected. BCF(stBETA: 0.26) and eGFR (stBETA: 0.08), but not age nor BMI nor SI nor pharmacological therapy, were positive independent predictors of favourable GC evolution (p<0.001 e p<0.01, respectively). Conclusion: Thus, better BCF at diagnosis, but not SI nor the T2DM genotype assessed in this study, is an independent predictor and a putative determinantof more desirable short-term (18 months) GC evolution

A low "genetic load" of risk variants for type 2 diabetes is associated to better beta cell function in patients with newly diagnosed type 2 diabetes

This study evaluates the association of a low "genetic load" of risk variants for type 2 diabetes with better beta cell function in patients with newly diagnosed type 2 diabete

Changes induced by metabolic surgery on the main components of glucose/insulin system in patients with diabetes and obesity

Bariatric surgery is able to induce remission of type 2 diabetes (T2D). Several studies reported an improvement of insulin sensitivity after surgery [1], but data about insulin secretion and insulin clearance are less abundant and somewhat controversial. Aim of our study was to assess the changes of the determinants of glucose regulation, i.e., insulin secretion, insulin sensitivity and insulin clearance in a group of T2D patients with obesity one month and over 1 year after metabolic surgery

Central role of the β-cell in driving regression of diabetes after liver transplantation in cirrhotic patients

Background & Aims: Diabetes occurring as a direct consequence of loss of liver function is usually characterized by non-diabetic fasting plasma glucose (FPG) and haemoglobin A 1c (HbA 1c ) levels and should regress after orthotopic liver transplantation (OLT). This observational, longitudinal study investigated the relationship between the time-courses of changes in all 3 direct determinants of glucose regulation, i.e., β-cell function, insulin clearance and insulin sensitivity, and diabetes regression after OLT. Methods: Eighty cirrhotic patients with non-diabetic FPG and HbA 1c levels underwent an extended oral glucose tolerance test (OGTT) before and 3, 6, 12 and 24 months after OLT. The OGTT data were analysed with a mathematical model to estimate derivative control (DC) and proportional control (PC) of β-cell function and insulin clearance (which determine insulin bioavailability), and with the Oral Glucose Insulin Sensitivity (OGIS)-2 h index to estimate insulin sensitivity. Results: At baseline, 36 patients were diabetic (45%) and 44 were non-diabetic (55%). Over the 2-year follow-up, 23 diabetic patients (63.9%) regressed to non-diabetic glucose regulation, whereas 13 did not (36.1%); moreover, 4 non-diabetic individuals progressed to diabetes (9.1%), whereas 40 did not (90.9%). Both DC and PC increased in regressors (from month 3 and 24, respectively) and decreased in progressors, whereas they remained stable in non-regressors and only PC decreased in non-progressors. Insulin clearance increased in all groups, apart from progressors. Likewise, OGIS-2 h improved at month 3 in all groups, but thereafter it continued to improve only in regressors, whereas it returned to baseline values in the other groups. Conclusions: Increased insulin bioavailability driven by improved β-cell function plays a central role in favouring diabetes regression after OLT, in the presence of a sustained improvement of insulin sensitivity. Lay summary: Diabetes occurring in cirrhosis as a direct consequence of loss of liver function should regress after transplantation of a new functioning liver, though the pathophysiological mechanisms are unclear. This is the first study evaluating the contribution of all 3 direct determinants of insulin-dependent glucose regulation using a sophisticated mathematical model. Results show that β-cell function is the key process governing favourable or detrimental changes in glucose regulation in cirrhotic patients undergoing transplantation, pointing to the need to develop therapies to sustain β-cell function in these individuals. Trial registration: ClinicalTrials.gov, NCT02038517

Crosstalk between genetic variability of adiponectin and leptin, glucose-insulin system and subclinical atherosclerosis in patients with newly diagnosed type 2 diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study 14

Aim: To evaluate the relationship of genetic variability of adiponectin (ADIPOQ), leptin (LEP) and leptin receptor (LEPR) genes with glucose-insulin system and markers of subclinical atherosclerosis (ATS) in patients with newly diagnosed type 2 diabetes.Materials and methods: In 794 subjects we performed: 1) euglycemic hyperinsulinemic clamp to assess insulin sensitivity; 2) mathematical modelling of a 5h-OGTT to estimate ss-cell function; 3) resting ECG; 4) carotid artery and lower limb artery ecodoppler sonography to identify ATS; 5) genotyping of tag-SNPs within ADIPOQ, LEP and LEPR gene.Results: Regression analyses showed: 1) adiponectin levels were negatively associated with BMI, waist-to-hip ratio and triglycerides and positively with HDL and insulin sensitivity (p-all&lt;0.03); 2) leptin levels were positively associated with BMI, HDL-cholesterol and plasma triglycerides and negatively with insulin sensitivity (p- all&lt;0.001). Two SNPs (rs1501299 and rs2241767) within ADIPOQ gene were associated with circulating levels of adiponectin. The ADIPOQ-GAACA haplotype was associated with plasma adiponectin (p=0.034; ss=-0.24), ECG abnormalities ( p=0.012; OR=2.76), carotid ATS (p= 0.025; OR=2.00) and peripheral limb artery ATS ( p=0.032; OR=1.90). The LEP-CTA haplotype showed an association with ischemic ECG abnormalities (p=0.017; OR= 2.24). Finally, LEPR-GAACGG was associated with circulating leptin (p=0.005; ss=-0.31) and worst ss-cell function ( p=0.023; ss=-15.10). Omnibus haplotype analysis showed that ADIPOQ haplotypes were associated with levels of adiponectin and common carotid artery ATS, LEP with peripheral limb artery ATS, whereas LEPR haplotypes influenced circulating levels of leptin.Conclusions: Results of this study reinforce knowledge on adipokines' role in regulating glucose metabolism; in particular highlighted the potential atherogenic role of leptin and the anti atherogenic role of adiponectin

A parsimonious model of a mixed-meal test in patients with type 1 diabetes in insulin pump therapy

Background and aims: Currently available closed-loop insulin deliverysystems stem from sophisticated models of the glucose-insulin (G/I) systemmostly based on complex studies employing glucose tracer technology.We asked the question whether simpler studies based on the minimalmodeling approach (Bergman, 1981; Cobelli, 2007) could likewise reliablydescribe the G/I system during a mixed meal test (MMT) in patientswith type 1 diabetes (T1D). If effective, this approach would expedite thecreation of large bio-banks of virtual patients to develop robust models\u201cto close the loop\u201d. To this end, we tested the performance of a minimalmodel of the G/I system to characterize the glucose (G) and insulin (I)dynamics during MMT in T1D patients on insulin pump therapy (CSII).Materials and methods: In six T1D patients on CSII enrolled in theMMT-T1D Pilot Study we assessed on three separate days: (1) insulinsensitivity, by the hyperinsulinemic euglycemic clamp (HEC); (2) the G/Itime-courses during a standardized 5 h-MMT (MMT1: 292 Kcal; 38.9 gcomplex CHO, 8.9 g lipids, 14 g proteins); (3) theG/I time-courses duringa second identical (3 patients) or double-sized (3 patients) MMT(MMT2). The parameters estimated by modeling of the HEC were usedto cast a comprehensiveMMTmodel (GLUKINSLOOP.2), including theinsulin delivery system and the metabolic G/I system of each patient.GLUKINSLOOP.2 was implemented and run in the SAAM2.1 software.Results: The GLUKINSLOOP.2 model identified the G/I system parameters(among others: insulin sensitivity, SI; glucose effectiveness, SG;glucose distribution volume, Vd; time of oral carbohydrate appearancein the peripheral circulation, expressed as ICMTT, Intestinal CarbohydrateMean Transit Time) and provided a good fit of the G/I timecoursesin all studies, as proved by the analysis of mean weighted residuals(WR, mean \ub1 SD; MMT1: WR(G)=-0.03\ub10.71; WR(I)=0.33\ub11.04; MMT2: WR(G)=0.09\ub10.86; WR(I)=0.01\ub11.37). Both the identicaland double-sized repeated MMT2s showed good reproducibility ofthe G/I system parameters (mean\ub1SEM; MMT1: SI=0.57\ub10.12(mL\u2d9min-1)/(pmol\u2d9L-1); SG=15.6\ub110.1 mL\u2d9min-1; Vd=11,482\ub11,131 mL; ICMTT=105\ub114 min; MMT2: SI=0.57\ub10.13; SG=38.2\ub113.6; Vd=11,609\ub11,031; ICMTT=101\ub111).Conclusion: The GLUKINSLOOP.2 model herein presented can providea fairly good and reproducible description of the G/I system in T1Dpatients on CSII and it may be used to build a bank of \u201cvirtual patients\u201d.Our results might be relevant to strategies directed to improve the architectureof upcoming closed-loop CSII systems.Clinical Trial Registration Number: NCT01800734Supported by: EFSD/Novo Nordis