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

Abstracts of 51st EASD Annual Meeting

Background and aims: Presence and frequency of beta cell (BC) dysfunction(BCD) and insulin resistance (IR) in patients with newly diagnosedtype 2 diabetes mellitus (NDT2D) are imperfectly known, becauseprevious studies used small cohorts and/or only surrogate indexes of BCfunction and IR.We sought to assess BC function and IR with state-of-artmethods in the VNDS.Materials and methods: In 712 GADA-negative, drug naïve, consecutiveItalian NDT2D patients we assessed: 1. standard parameters; 2. insulinsensitivity (IS) by the euglycaemic insulin clamp); 3. BC functionby state-of-art modeling of prolonged (5 hours) OGTT-derived glucose/C-peptide curves. Thresholds for BCD and IR were the 25th percentilesof BC function and IS assessed with the same methods of the VNDS inItalian subjects with normal glucose regulation of the GENFIEV (n=340)and GISIR (n=386) studies, respectively.Results: In the VNDS, 89.8% [95% C.I.: 87.6 - 92.0%] and87.8% [85.4 - 90.2] patients had BCD and IR, respectively. Patientswith only one defect were 19.7% [16.8 - 22.6]. IsolatedBCD and isolated IR were present in 10.9% [8.6 - 13.2] and8.9% [6.8 - 11.0] patients, respectively. Coexistence of BCDand IR was observed in 78.9% [75.9 - 81.9] of the patients.1.4% [0.5 - 2.3] of the patients had no detectable alterations inBC function and IS. Patients (19.7%) with only one metabolicdefect had lower BMI, fasting glucose, HbA1c, triglycerides andBC function, and higher HDL-cholesterol and IS than patientswith both BCD and IR (p<0.01 or less after Bonferroni’scorrection).Conclusion: In conclusion, in NDT2DM patients: 1. at least 75.9% haveboth BCD and IR; 2. At least 87.6% and 85.4% have BCD and IR,respectively; 3. At least 16.8% have only one defect and a significantlydifferent (milder) metabolic phenotype compared to patients with bothdefects. These findings may be relevant to therapeutic strategies centeredon the metabolic phenotype of the patient.Clinical Trial Registration Number: NCT00879801; NCT01526720Supported by: University of Veron

Quantificazione del ruolo svolto dai principali fattori determinanti la glicemia durante un pasto misto, nei pazienti affetti da diabete mellito tipo 1 in terapia con microinfusore insulinico associato a glucosensore

Introduzione. Il microinfusore insulinico ed i sistemi di monitoraggio in continuo del glucosio possono essere combinati per formare un \u201csistema integrato\u201d (sensor augmented pump, SAP) dove il microinfusore, oltre ad infondere insulina, \ue8 dotato anche di un ricevitore dei valori di glucosio rilevati in \u201creal time\u201d dal glucosensore e orienta le scelte di posologia insulinica. Il trattamento SAP \ue8 attualmente il gold standard per i pazienti affetti da diabete mellito tipo 1 (DMT1) in quanto, determina una riduzione di HbA1c, una minore variabilit\ue0 glicemica ed un miglioramento della qualit\ue0 di vita, rispetto alla terapia multi-iniettiva standard. L\u2019integrazione completa richiede lo sviluppo di un algoritmo di controllo, che calcoli la velocit\ue0 di infusione dell\u2019insulina in funzione della concentrazione di glucosio rilevata dal sensore, realizzando cos\uec un sistema ad ansa chiusa: il pancreas artificiale. Il ruolo di ciascun componente del sistema glucosio/insulina (G/I) nel determinare la glicemia post-prandiale in soggetti con DMT1 in trattamento con SAP, non \ue8 ancora completamente noto. Obiettivo. L\u2019obiettivo del presente studio \ue8 stato quello di quantificare, attraverso l\u2019analisi di controllo metabolico (MCA) il grado di controllo sulla glicemia plasmatica post-prandiale di ciascun componente del sistema glucosio/insulina (G/I), attraverso il calcolo dei rispettivi coefficienti di controllo (CC), durante pasto misto (MMT). Disegno Sperimentale. E\u2019 stata applicata la MCA per stimare la distribuzione dei CC del glucosio plasmatico (CCG) in 10 soggetti (7 maschi e 3 femmine) con DMT1, in terapia con SAP (media \ub1 SEM: et\ue0 39.8 \ub1 3.9 anni; BMI 23.3 \ub1 0.7 kg/m2; HbA1c 7.8 \ub1 0.2%) studiati in due sessioni separate: 1. clamp euglicemico iperinsulinemico (240 pmol/min/m2 BSA; durata: 120\u2019; M clamp: 1091 \ub1 133 pmol/min/m2 BSA); 2. Pasto misto (MMT) costituito da polenta e parmigiano: 292 Kcal derivanti da 38.9 g di CHO complessi, 8.9 g di lipidi e 14 g di proteine. Mediante analisi modellistica, sono stati utilizzati i dati ricavati dal clamp e da MMT per costruire una fenocopia in silico dei pazienti reali, in cui, mediante simulazioni ripetute, si sono calcolati i CCG. Risultati. Le concentrazioni di glicemia plasmatica ed insulinemia erano rispettivamente di 10.7\ub11.3 mM e 68.8\ub17.7 pM al basale (tempo 0 dello studio) e raggiungevano il picco di 12.7\ub11.1 mM e di 150\ub115 pM, rispettivamente dopo 90\u2019 e 60\u2019. Tra i principali CCG calcolati \ue8 emerso che il tempo di transito medio dell\u2019insulina nel sottocute aveva il CCG pi\uf9 elevato. Il CCG del quantitativo di CHO assunti aveva un ruolo significativo durante tutta la durata del pasto (p<0.001), mentre il CCG del tempo di transito intestinale era rilevante nella prima met\ue0 del pasto stesso (p<0.01). Conclusioni. In pazienti con DMT1 in terapia con SAP il tempo di transito medio dell\u2019insulina nel tessuto sottocutaneo svolge, in alcuni pazienti, un ruolo preponderante nell\u2019escursione glicemica durante MMT. Inoltre, la quantit\ue0 di CHO assunti risulta un determinante rilevante della glicemia post-prandiale. Questi risultati potrebbero avere importanti implicazioni per lo sviluppo e perfezionamento di un algoritmo di controllo per il pancreas artificiale.Title: Quantitation of the roles played by the main determinants of meal glucose tolerance in patients with type 1 diabetes on sensor-augmented insulin-pump therapy. Background. Glucose sensor augmented insulin pump therapy (SAP), in which patients wear both a pump for subcutaneous insulin delivery (CSII) and a subcutaneously installed glucose sensor for continuous glucose monitoring (CGM) is nowadays the gold standard but not yet the optimal treatment of type 1 diabetes (T1DM). The relative roles of each component of the glucose (G)/ insulin (I) system in determining post-meal hyperglycaemia in T1DM are still under debate. The use of Metabolic Control Analysis (MCA) allows to compute the coefficients of control of plasma glucose (CCG), which quantify the control exerted by each component of the G/I system on glucose concentration. Aim. Aim of this research was to quantify the CCG of the main components of the G/I system during the mixed meal test (MMT). Materials and Methods. 10 T1DM patients (7 males and 3 females; age: 39.8 \ub1 3.9 years; BMI 23.3 \ub1 0.7 Kg/m2; HbA1c 7.8 \ub1 0.2%) on insulin pump and continuous glucose monitoring (CGM) participated in two studies: 1. Euglycemic Insulin (240 pmol/min/m2 BSA) clamp (duration: 120 minutes, M value 1091 \ub1 133 pmol/min/m2 BSA); 2. MMT (292 Cal; 38.9 g complex CHO, 8.9 g lipids and 14 g proteins) with plasma insulin, plasma glucose and interstitial glucose assessment for 360 minutes. With our modelling strategy, data from both clamp and MMT are used to build an in silico replica (\u201cvirtual patients\u201d) of the G/I system of each patient, which behaves as the real patient during the MMT. Virtual patients were used to compute the CCG of plasma glucose. Results. During the MMT, plasma glucose and insulin started from 10.7 \ub1 1.3 mM and 68.8 \ub1 7.7 pM and peaked at 12.7 \ub1 1.1 mM (time: +90\u2019) and at 150 \ub1 15 pM (time: + 60\u2019) respectively. The CCG of key components of the G/I system were calculated. The insulin mean transit time across subcutaneous tissue had the highest CCG among all. The CCG of the meal carbohydrates (CHO) content was remarkable during the whole time of the MMT (p<0.001). The CCG of CHO transit time across the gut was noticeable in the first half and became negligible in the second half of the MMT (p<0.01). Conclusions. In patients with T1DM on SAP therapy, the insulin mean transit time across subcutaneous tissue was a primary determinant of plasma glucose in some patients, after a MMT. The meal CHO content was also remarkable in determining post-meal hyperglycaemia in T1DM. These findings may have important implications for the development and the refinement of closed loop control of subcutaneous insulin delivery systems

Metabolic Effects of Exercise

Exercise has a powerful action on metabolism, and adaptation of the body to changes induced by exercise is fundamental to be able to provide the energy required for muscle contraction and physiological functions of vital tissues. Depending on the intensity and duration of exercise, different mechanisms are called on to make energy available, and under homeostatic control, this is guaranteed by rapid and coordinated changes in the secretion of several hormones. Molecular mechanisms controlling muscle function and fiber phenotype are related to the specific mode of muscle activation. We can distinguish between two fundamental types of physical activity, endurance exercise and strength exercise, although there is a continuum between these exercise modalities. Besides the acute changes induced by a single exercise session, regular exercise may induce chronic adaptations, improving exercise capacity and affecting energy metabolism. Notably, although acute metabolic effects of exercise are mostly due to insulin-independent effects, exercise training may improve muscle insulin sensitivity and is considered a key tool in the prevention and treatment of metabolic disorders. This chapter focuses on the biochemistry of energy supply to the exercising muscle, on molecular mechanisms involved and on the physiology of energy metabolism during exercise in healthy subjects and patients with insulin resistance and/or 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

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±12 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 = -0.116, p = .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

Prevalence of neuropathy in type 2 diabetic patients and its association with other diabetes complications: The Verona Diabetic Foot Screening Program.

AIMS:Somatic neuropathy is a chronic complication of diabetes. The purpose of our study was to determine prevalence and clinical variables associated with somatic neuropathy applying a simple screening method.METHODS:All outpatients with type 2 diabetes attending our diabetic clinic were offered to participate into a diabetic foot screening program, in the period January 2004-December 2012. A total of 3,591 diabetic patients (55.5% men, age 68\ub110years) underwent detection of somatic neuropathy using the Michigan Neuropathy Screening Instrument in its parts of symptoms (administering a questionnaire) and clinical assessment slightly modified (evaluating foot inspection, vibration sensation by biothesiometer, ankle reflexes).RESULTS:The prevalence of somatic neuropathy was 2.2% in men and 5.5% in women (p<0.001) when assessed by symptom questionnaire, whereas it was 30.5% in men and 30.8% (p=NS) in women when identified by clinical assessment. In subjects with somatic neuropathy macro- and microvascular complications of diabetes were significantly more common. In multivariate logistic regression analyses BMI, HbA1c and ankle/brachial index independently predicted the presence of neuropathy.CONCLUSION:The prevalence of somatic neuropathy in type 2 diabetes is nearly 30% when searched with clinical examination. Poor metabolic control, excess body weight and peripheral arteriopathy are independent markers of somatic neuropathy

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

Relationship of Chronic Vascular Complications with Beta-Cell Dysfunction and Insulin Resistance in Newly Diagnosed Type 2 Diabetes: The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS)

The prevalence of vascular complications in newly-diagnosed type 2 diabetes (NDT2D) and their relationships with beta cell function (BF) and insulin sensitivity (IS) defects are poorly known. In 712 GADA-negative, drug na\uefve, consecutive VNDS participants we measured: 1) IS, by euglycemic insulin clamp; 2) BF, by mathematical modeling of 5h-OGTT; 3) microvascular complications (MIC): diabetic retinopathy, cardiac autonomic and sensorymotor neuropathy (SMN, by biothesiometer and tendon reflexes), e-GFRMDRD &lt;60 mL/min/1.73 m2 or albuminuria &gt;30 mg/24 h; and 4) macrovascular complications (MAC): prior cardiovascular disease, ischemic ECG, lowerlimb artery stenosis or carotid stenosis &gt;40% at US-scans. Thresholds for defective BF and IS were the 25th percentiles of BF and IS assessed with the same methods of VNDS in subjects with normal glucose regulation of the GENFIEV (n=340) and GISIR (n=386) studies, respectively. The prevalence of combined BF and IS defects was 78.9%, while that of isolated BF and IS was 10.8% and 8.8%, respectively. Overall, the prevalence of MIC andMAC was 48.2% and 18.6%. The most frequent MIC and MAC were SMN (28.5%) and prior cardiovascular disease (11%), respectively. Notably, the prevalence of isolated or combined IS and BF defects did not significantly differ between patients with and without complications. Logistic regression analysis revealed that reduced IS, older age, male sex and smoking independently predicted MAC, but not MIC, after adjusting for BMI, blood pressure, LDL-cholesterol and A1c. BF was not associated with any complication. Our study shows that patients with NDT2D have a high prevalence of MIC and MAC, the latter being independently associated with reduced IS. These findings highlight the clinical importance of a systematic screening for chronic complications in the earliest disease stages. ClinicalTrial.gov ID: NCT00879801, NCT01526720