A Novel Insulin/Glucose Model after a Mixed-Meal Test in Patients with Type 1 Diabetes on Insulin Pump Therapy

Current closed-loop insulin delivery methods stem from sophisticated models of the glucose-insulin (G/I) system, mostly based on complex studies employing glucose tracer technology. We tested the performance of a new minimal model (GLUKINSLOOP 2.0) of the G/I system to characterize the glucose and insulin dynamics during multiple mixed meal tests (MMT) of different sizes in patients with type 1 diabetes (T1D) on insulin pump therapy (continuous subcutaneous insulin infusion, CSII). The GLUKINSLOOP 2.0 identified the G/I system, provided a close fit of the G/I time-courses and showed acceptable reproducibility of the G/I system parameters in repeated studies of identical and double-sized MMTs. This model can provide a fairly good and reproducible description of the G/I system in T1D patients on CSII, and it may be applied to create a bank of "virtual" patients. Our results might be relevant at improving the architecture of upcoming closed-loop CSII systems

Glomerular filtration rate decline in T2DM following diagnosis. The Verona newly diagnosed diabetes study-12

Aims: Nephropathy is a complication of type 2 diabetes, with increased albuminuria and reduced glomerular filtration rate (GFR) as biomarkers. Rates of progression to end-stage-renal disease are variable among patients. In this study we have examined the GFR decline in newly diagnosed T2DM. Methods: A cohort of 410 patients with newly diagnosed T2DM and with at least four serum creatinine during the follow-up period were recruited. A linear model was used to calculate the decline in eGFR. A multivariable logistic model was used to identify independent predictors of rapid eGFR decline. Results: Average follow-up was 12.4 years. The eGFR change was −0.80 ± 2.23 ml/min/1.73 m2 per year. Patients were arbitrarily stratified into rapid decliners (≤-3.0 ml/min/1.73 m2 per year), moderate decliners (-2.9/-1 ml/min/1.73 m2 per year) and slow/no decliners (>-1.0 ml/min/1.73 m2 per year). Subjects in the 3 categories were 11.4%, 27.3%, and 61.3%, respectively. Albuminuria was the stronger predictor of rapid eGFR decline. Conclusions: A rapid decline in eGFR occurs in approximately 1 out of 10 newly diagnosed subjects. This rapid decline can be predicted by widely accessible clinical features, such as albuminuria. Identification of rapid decliners may help to reduce progression toward advanced stages of nephropathy

Insulin resistance and beta-cell dysfunction in newly diagnosed type 2 diabetes: Expression, aggregation and predominance. Verona Newly Diagnosed Type 2 Diabetes Study 10

We investigated quantitative expression, mutual aggregation and relation with hyperglycemia of insulin resistance (IR) and beta-cell dysfunction (BCD) in newly diagnosed type 2 diabetes

Chronic complications in patients with newly diagnosed type 2 diabetes: prevalence and related metabolic and clinical features: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 9

INTRODUCTION: We explored the presence of chronic complications in subjects with newly diagnosed type 2 diabetes referred to the Verona Diabetes Clinic. Metabolic (insulin secretion and sensitivity) and clinical features associated with complications were also investigated.RESEARCH DESIGN AND METHODS: The comprehensive assessment of microvascular and macrovascular complications included detailed medical history, resting ECG, ultrasonography of carotid and lower limb arteries, quantitative neurological evaluation, cardiovascular autonomic tests, ophthalmoscopy, kidney function tests. Insulin sensitivity and beta-cell function were assessed by state-of-the-art techniques (insulin clamp and mathematical modeling of glucose/C-peptide curves during oral glucose tolerance test).RESULTS: We examined 806 patients (median age years, two-thirds males), of whom prior clinical cardiovascular disease (CVD) was revealed in 11.2% and preclinical CVD in 7.7%. Somatic neuropathy was found in 21.2% and cardiovascular autonomic neuropathy in 18.6%. Retinopathy was observed in 4.9% (background 4.2%, proliferative 0.7%). Chronic kidney disease (estimated glomerular filtration rate <60mL/min/1.73 m2) was found in 8.8% and excessive albuminuria in 13.2% (microalbuminuria 11.9%, macroalbuminuria 1.3%).Isolated microvascular disease occurred in 30.8%, isolated macrovascular disease in 9.3%, a combination of both in 9.1%, any complication in 49.2% and no complications in 50.8%.Gender, age, body mass index, smoking, hemoglobin A1c and/or hypertension were independently associated with one or more complications. Insulin resistance and beta-cell dysfunction were associated with macrovascular but not microvascular disease.CONCLUSIONS: Despite a generally earlier diagnosis for an increased awareness of the disease, as many as ~50% of patients with newly diagnosed type 2 diabetes had clinical or preclinical manifestations of microvascular and/or macrovascular disease. Insulin resistance might play an independent role in macrovascular disease.TRIAL REGISTRATION NUMBER: NCT01526720

Uric acid is a biomarker of beta cell function in patients with newly diagnosed type 2 diabetes

Background and aims: The relationship between uric acid and insulin resistance has been widely studied, whereas little is known about a potential interaction between uric acid and beta-cell function. Goal of this study was to investigate the relationship, if any, between uricaemia and beta-cell function in patients with newly diagnosed type 2 diabetes. Materials and methods: In 569 GAD negative, drug naive patients (median [interquartile range]: age 60 [52-66] years, BMI 29.3 [26.6-32.9] kg/m2, HbA1c 6.6 [6.1-7.4]%, uric acid 0.32 [0.27-0.37] mmol/L) with newly diagnosed type 2 diabetes we assessed insulin sensitivity by the euglycemic insulin clamp (M clamp: 605 [381-845] \u3bcmol\ub7min-1\ub7m-2 BSA) and beta-cell function by state-of-art modelling of glucose/C-peptide curves during an oral glucose tolerance test (OGTT). There are two main outputs of the model: derivative control (DC: amount of insulin secreted in response to the rate of plasma glucose increase; median [interquartile range]: 444 [66-929] [pmol\ub7m-2 BSA]/ [mM\ub7min-1]) and proportional control of beta-cell function (PC: stimulusresponse curve linking glucose concentration to insulin secretion rate; mean \ub1 SD at the preselected glucose concentrations of 5.5, 8.0, 11.0, 15.0 and 20.0 mM: 158\ub167, 228\ub1124, 376\ub1229, 602\ub1397, 889\ub1623 pmol\ub7min-1\ub7m-2 BSA). Results: In univariate analysis, serum uric acid concentration was positively related to both DC (p<0.01) and PC (p<0.01) of beta-cell function. In multiple regression analysis, after adjusting for age, gender, BMI, insulin sensitivity and glomerular filtration rate, this positive relationship stayed statistically significant (p<0.01 e p<0.01 for DC and PC respectively). Consistently with this result, uricaemia was inversely correlated to HbA1c (p<0.01), fasting glucose (p<0.01), 1-hour and 2-hour OGTT glucose (p<0.01 and p<0.01 respectively). Patients in the 3rd tertile of uric acid had a 37% increase in DC (p<0.01) and a 21-30% increase in PC (p<0.01) of beta-cell function, when compared to those in the 1st tertile. Conclusions: In patients with newly diagnosed type 2 diabetes there exists a strong positive correlation between serum uric acid concentration and betacell function. This finding might reflect antioxidant activity of uric acid. However, to determine whether uric acid improves beta-cell function per se or through other factors, mechanistic studies will be required

"Presence and titer of GAD antibodies are determinants of beta cell function in patients with newly diagnosed type 2 diabetes mellitus: further insights in the metabolic phenotype of LADA patients"

Latent Autoimmune Diabetes in Adults (LADA) is a metabolic disorder at the crossroad between type 1 (T1DM) and type 2 diabetes (T2DM). Aim of our study was to carefully assess beta cell function and insulin sensitivity in patients with LADA, in comparison to patients with either type 2 diabetes clinically undistinguishable from LADA or typical type 2 diabetes. In 35 (M/F=19/16) patients (mean\ub1SEM: age 57.4\ub11.6 years, BMI 27.5\ub10.9 kg/m2) with newly diagnosed LADA were compared to 35 patients with newly diagnosed T2DM matched for age, gender, BMI and HbA1c (LADA-like). The latter group was extracted from the database of the Verona Newly Diagnosed Type 2 diabetes (VNDS; N=589 GADA-negative patients) The rest of VNDS patients herein represent typical T2DM. LADA patients were further divided in two groups according to GADA levels (median 4 kU/L): low GAD-LADA (GADA 4 kU/L). In all patients we performed on separate days: 1. prolonged (5-hours) frequently sampled OGTT to assess derivative control (DC) and proportional control (PC) of beta cell function by state of art mathematical modeling of glucose and C-peptide curves; 2. standard euglycemic insulin clamp to assess insulin sensitivity (SI). SI was not statistically different (p<0.12) in LADA-like and in LADA patients, but in the latter was higher (+28%) than in VNDS (812\ub1SEM vs 635\ub1SEM \ub5mol.min-1.m-2 BSA, respectively; p=0.01). The DC of beta cell function was impaired in LADA compared to LADA-like (p<0.01) and to VNDS (p<0.05). The PC in LADA was similar to LADA-like (p=0.42), but it was reduced when compared to VNDS (p<0.03). High GAD- and low GAD-LADA had similar SI, but the former had worse PC of beta cell function than the latter (p<0.01). In conclusion, patients with newly diagnosed LADA display more severe defects in beta cell function even when compared to LADA-like patients with newly diagnosed T2DM; furthermore, the higher the GADA titer, the worse is beta cell dysfunction. These data may be of help in optimizing metabolic therapy and in refining metabolic prognosis of these patients

Quantitation of the roles played by the main determinants of meal glucose tolerance in patients with type 1 diabetes on insulin pump therapy

The relative roles of each component of the glucose (G)/insulin (I) system in determining after meal hyperglycemia in type 1 diabetes (T1DM) are still under debate. Metabolic Control Analysis (MCA) quantifies the control exerted by each component of a system on a variable of interest, by computing the relevant coefficients of control (CCs), which are systemic properties. We applied MCA to a mixed meal test (MMT) to quantify the CCs of the main components of the G/I system on G concentration. 7 T1DM patients (age: 41\ub15 yrs; BMI: 24.3\ub10.6 kg.m-2; HbA1c: 7.9\ub10.2%) on insulin pump therapy and continuous glucose monitoring (CGM) participated in 2 separate studies:1. A standard euglycemic insulin (240 pmol.min-1.m-2 BSA) clamp (duration: 120 min, M value: 1209\ub1169 \ub5mol.min-1.m-2 BSA) including CGM; 2. A standardized MMT (292 Kcal; 38.9 g complex CHO, 8.9 g lipids, 14 g proteins) with plasma I/G monitoring and CGM. With our modeling strategy, data from the clamp and from the MMT are sufficient to build an in silico replica (\u201cvirtual patient\u201d) of the G/I system of each patient (CGM included), which behaves as the real patient during the MMT. Virtual patients were used to compute the CCs of plasma G and G measured by CGM. During the MMT, plasma glucose and insulin peaked at (time ) and at (time ), respectively, and leveled at and at time 300\u2019. The CCs exerted by some primary components of the G/I system on plasma G are summarized in the Table. Size of s.c. insulin depot had the highest CCs (p<0.01 or less vs other CCs). The CCs of meal insulin bolus peaked at 300\u2019 (p<0.01 vs CCs at 30\u2019-60\u2019). The CCs of CHO transit time across the gut, including also absorption, was relevant in the first half and became negligible in the second half of the meal (p<0.01 CCs 180-300\u2019 vs CCs 30\u2019-120\u2019). The CCs of CGM measured G were parallel, but not superimposable to CCs of plasma G, with some statistically significant difference (p<0.03-0.01) in CCs exerted by gut CHO transit time. Conclusions. In patients with T1DM on insulin pump therapy, after a mixed meal: 1. the most relevant factor of after meal G may be the size of subcutaneous insulin depot; 2. Pre-meal insulin bolus may be much more influential in the last 3 than in the initial 2 hours. These findings may have important implications for the development and the refinement of closed loop control of insulin delivery systems

Glycated haemoglobin is inversely related to serum vitamin d levels in type 2 diabetic patients.

OBJECTIVE: A correlation between glucose control and 25(OH)D metabolism has been suggested by previous studies. However, this correlation has not yet been evaluated considering the impact of chronic complications of type 2 diabetes, especially the presence of nephropathy. Thus, the aim of this study was to determine the correlation between A1C and 25(OH)D in a well characterized cohort of type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We cross-sectionally examined the association between A1C and serum 25(OH) D in 715 type 2 diabetic patients attending our clinic during the years 2011-2012. The average age was 68\ub112 years (range 26-94 years). The relation between A1C and serum 25(OH)D levels was modelled by multiple linear regression analyses. RESULTS: Serum 25(OH)D levels were inversely associated with A1C levels (r\u200a=\u200a-0.116, p\u200a=\u200a.003). This relation maintains its independence in the multivariate analysis after adjusting for age, sex, A1C, BMI, treatment and duration of diabetes and nephropathy. CONCLUSIONS: In type 2 diabetic patients, high A1C levels are associated with low concentrations of serum 25(OH)D independently of duration of diabetes, diabetic treatment and nephropathy. Future studies are needed to clarify the biological relation between glucose control and vitamin D metabolism in type 2 diabetes

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

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