scholarly journals Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments

2015 ◽  
Vol 309 (5) ◽  
pp. E474-E486 ◽  
Author(s):  
Ling Hinshaw ◽  
Ashwini Mallad ◽  
Chiara Dalla Man ◽  
Rita Basu ◽  
Claudio Cobelli ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
In Silico ◽  
Artificial Pancreas ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Action Model ◽  
The Difference ◽  
Hormone Control

Glucagon use in artificial pancreas for type 1 diabetes (T1D) is being explored for prevention and rescue from hypoglycemia. However, the relationship between glucagon stimulation of endogenous glucose production (EGP) viz., hepatic glucagon sensitivity, and prevailing glucose concentrations has not been examined. To test the hypothesis that glucagon sensitivity is increased at hypoglycemia vs. euglycemia, we studied 29 subjects with T1D randomized to a hypoglycemia or euglycemia clamp. Each subject was studied at three glucagon doses at euglycemia or hypoglycemia, with EGP measured by isotope dilution technique. The peak EGP increments and the integrated EGP response increased with increasing glucagon dose during euglycemia and hypoglycemia. However, the difference in dose response based on glycemia was not significant despite higher catecholamine concentrations in the hypoglycemia group. Knowledge of glucagon's effects on EGP was used to develop an in silico glucagon action model. The model-derived output fitted the obtained data at both euglycemia and hypoglycemia for all glucagon doses tested. Glucagon clearance did not differ between glucagon doses studied in both groups. Therefore, the glucagon controller of a dual hormone control system may not need to adjust glucagon sensitivity, and hence glucagon dosing, based on glucose concentrations during euglycemia and hypoglycemia.

691-P: Exercise Effect on Endogenous Glucose Production in Type 1 Diabetes: A Modeling Analysis

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 691-P
Author(s):  
DAVIDE ROMERES ◽  
MICHELE SCHIAVON ◽  
ROBERTO VISENTIN ◽  
ANANDA BASU ◽  
CLAUDIO COBELLI ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Modeling Analysis ◽  
Exercise Effect ◽  
Endogenous Glucose

scholarly journals The UVA/Padova Type 1 Diabetes Simulator Goes From Single Meal to Single Day

2018 ◽  
Vol 12 (2) ◽  
pp. 273-281 ◽  
Author(s):  
Roberto Visentin ◽  
Enrique Campos-Náñez ◽  
Michele Schiavon ◽  
Dayu Lv ◽  
Martina Vettoretti ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
In Silico ◽  
Artificial Pancreas ◽  
Real Life ◽  
Glucose Monitoring ◽  
Glucose Variability ◽  
Self Monitoring ◽  
Inhaled Insulin ◽  
Single Meal

Background: A new version of the UVA/Padova Type 1 Diabetes (T1D) Simulator is presented which provides a more realistic testing scenario. The upgrades to the previous simulator, which was accepted by the Food and Drug Administration in 2013, are described. Method: Intraday variability of insulin sensitivity (SI) has been modeled, based on clinical T1D data, accounting for both intra- and intersubject variability of daily SI. Thus, time-varying distributions of both subject’s basal insulin infusion and insulin-to-carbohydrate ratio were calculated and made available to the user. A model of “dawn” phenomenon based on clinical T1D data has been also included. Moreover, the model of subcutaneous insulin delivery has been updated with a recently developed model of commercially available fast-acting insulin analogs. Models of both intradermal and inhaled insulin pharmacokinetics have been included. Finally, new models of error affecting continuous glucose monitoring and self-monitoring of blood glucose devices have been added. Results: One hundred in silico adults, adolescent, and children have been generated according to the above modifications. The new simulator reproduces the intraday glucose variability observed in clinical data, also describing the nocturnal glucose increase, and the simulated insulin profiles reflect real life data. Conclusions: The new modifications introduced in the T1D simulator allow to extend its domain of validity from “single-meal” to “single-day” scenarios, thus enabling a more realistic framework for in silico testing of advanced diabetes technologies including glucose sensors, new insulin molecules and artificial pancreas.

Effects of glycemic control on target organ responses to epinephrine in type 1 diabetes

2005 ◽  
Vol 289 (2) ◽  
pp. E258-E265 ◽  
Author(s):  
Deanna Aftab Guy ◽  
Darleen Sandoval ◽  
M. A. Richardson ◽  
Donna Tate ◽  
Stephen N. Davis
Keyword(s):  
Type 1 Diabetes ◽  
Glycemic Control ◽  
Blood Pressure Response ◽  
Severe Hypoglycemia ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Target Organ ◽  
Epinephrine Infusion ◽  
Glucose Levels

Severe hypoglycemia occurs in intensively treated patients with type 1 diabetes mellitus (T1DM) due in part to deficient epinephrine counterregulatory responses. Previously, we have found that T1DM patients demonstrated a spectrum of altered responses to epinephrine at a variety of target organs compared with nondiabetic healthy subjects. What is not known is whether intensive glycemic control further modifies target organ responses in individuals with T1DM. Therefore, the aim of this study is to assess whether there is tissue specific (liver, muscle, adipose tissue, pancreas and cardiovascular) resistance to epinephrine in intensively controlled (IC) T1DM compared with those with conventional control (CC). Eight IC patients (age 33 ± 4 yr, BMI 24 ± 2 kg/m2, Hb A1C6.7 ± 0.1%), and 11 CC patients (age 35 ± 3 yr, BMI 25 ± 1 kg/m2, Hb A1C9.6 ± 0.1%) underwent two separate randomized, single-blind, 2-h hyperinsulinemic euglycemic clamp studies with (EPI) and without (NO EPI) epinephrine infusion. Epinephrine levels during EPI were similar in all groups (5,197 ± 344 pmol/l). Glucose (5.3 ± 0.1 mmol/l) and insulin levels (515 ± 44 pmol/l) were similar in all groups during the glucose clamps. Endogenous glucose production (EGP) and glucose uptake (Rd) were determined using [3-H3]glucose. Muscle biopsy was performed at the end of each study. IC had a significantly reduced EGP and Rdresponses to EPI compared with CC. Glucagon responses to EPI were similarly blunted in both IC and CC. Free fatty acid and glycerol response to EPI was greater in CC compared with IC. There was a significantly greater systolic blood pressure response to EPI in CC. We conclude that, despite similar epinephrine, insulin, and glucose levels, intensively treated T1DM patients had reduced cardiovascular, skeletal muscle, hepatic, and adipose target organ responses to EPI compared with conventionally treated T1DM patients.

scholarly journals Run-to-Run Tuning of Model Predictive Control for Type 1 Diabetes Subjects: In Silico Trial

2009 ◽  
Vol 3 (5) ◽  
pp. 1091-1098 ◽  
Author(s):  
Lalo Magni ◽  
Marco Forgione ◽  
Chiara Toffanin ◽  
Chiara Dalla Man ◽  
Boris Kovatchev ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Insulin Sensitivity ◽  
Model Predictive Control ◽  
Predictive Control ◽  
In Silico ◽  
Insulin Pump ◽  
Artificial Pancreas ◽  
Arx Model ◽  
Starting Point

Background: The technological advancements in subcutaneous continuous glucose monitoring and insulin pump delivery systems have paved the way to clinical testing of artificial pancreas devices. The experience derived by clinical trials poses technological challenges to the automatic control expert, the most notable being the large interpatient and intrapatient variability and the inherent uncertainty of patient information. Methods: A new model predictive control (MPC) glucose control system is proposed. The starting point is an MPC algorithm applied in 20 type 1 diabetes mellitus (T1DM) subjects. Three main changes are introduced: individualization of the ARX model used for prediction; synthesis of the MPC law on top of the open-loop basal/bolus therapy; and a run-to-run approach for implementing day-by-day tuning of the algorithm. In order to individualize the ARX model, a sufficiently exciting insulin profile is imposed by splitting the premeal bolus into two smaller boluses (40% and 60%) injected 30 min before and 30 min after the meal. Results: The proposed algorithm was tested on 100 virtual subjects extracted from an in silico T1DM population. The trial simulates 44 consecutive days, during which the patient receives breakfast, lunch, and dinner each day. For 10 days, meals are multiplied by a random variable uniformly distributed in [0.5, 1.5], while insulin delivery is based on nominal meals. Moreover, for 10 days, either a linear increase or decrease of insulin sensitivity (±25% of nominal value) is introduced. Conclusions: The ARX model identification procedure offers an automatic tool for patient model individualization. The run-to-run approach is an effective way to auto-tune the aggressiveness of the closed-loop control law, is robust to meal variation, and is also capable of adapting the regulator to slow parameter variations, e.g., on insulin sensitivity.

scholarly journals Control of Blood Glucose Level for Type 1 Diabetes Mellitus using Improved Hovorka Equations: Comparison between Clinical and In-Silico Works

2020 ◽  
Author(s):  
Nur’Amanina Mohd Sohadi ◽  
Ayub Md Som ◽  
Noor Shafina Mohd Nor ◽  
Nur Farhana Mohd Yusof ◽  
Sherif Abdulbari Ali ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Blood Glucose Level ◽  
Type 1 Diabetes Mellitus ◽  
Glucose Level ◽  
In Silico ◽  
Artificial Pancreas ◽  
The Body

AbstractBackgroundType 1 diabetes mellitus (T1DM) occurs due to inability of the body to produce sufficient amount of insulin to regulate blood glucose level (BGL) at normoglycemic range between 4.0 to 7.0 mmol/L. Thus, T1DM patients require to do self-monitoring blood glucose (SMBG) via finger pricks and depend on exogenous insulin injection to maintain their BGL which is very painful and exasperating. Ongoing works on artificial pancreas device nowadays focus primarily on a computer algorithm which is programmed into the controller device. This study aims to simulate so-called improved equations from the Hovorka model using actual patients’ data through in-silico works and compare its findings with the clinical works.MethodsThe study mainly focuses on computer simulation in MATLAB using improved Hovorka equations in order to control the BGL in T1DM. The improved equations can be found in three subsystems namely; glucose, insulin and insulin action subsystems. CHO intakes were varied during breakfast, lunch and dinner times for three consecutive days. Simulated data are compared with the actual patients’ data from the clinical works.ResultsResult revealed that when the patient took 36.0g CHO during breakfast and lunch, the insulin administered was 0.1U/min in order to maintain the blood glucose level (BGL) in the safe range after meal; while during dinner time, 0.083U/min to 0.1 U/min of insulins were administered in order to regulate 45.0g CHO taken during meal. The basal insulin was also injected at 0.066U/min upon waking up time in the early morning. The BGL was able to remain at normal range after each meal during in-silico works compared to clinical works.ConclusionsThis study proved that the improved Hovorka equations via in-silico works can be employed to model the effect of meal disruptions on T1DM patients, as it demonstrated better control as compared to the clinical works.

scholarly journals Effects of Growth Hormone and Free Fatty Acids on Insulin Sensitivity in Patients with Type 1 Diabetes

2009 ◽  
Vol 94 (9) ◽  
pp. 3297-3305 ◽  
Author(s):  
Burak Salgin ◽  
Maria L. Marcovecchio ◽  
Rachel M. Williams ◽  
Sarah J. Jackson ◽  
Leslie J. Bluck ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Growth Hormone ◽  
Type 1 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Endogenous Glucose

Context: Because GH stimulates lipolysis, an increase in circulating free fatty acid levels, as opposed to a direct effect of high GH levels, could underlie the development of insulin resistance in type 1 diabetes (T1D). Our aim was to explore the relative contributions of GH and free fatty acids to the development of insulin resistance in patients with T1D. Patients: Seven (four females, three males) nonobese patients with T1D aged 21–30 yr were studied on four occasions in random order. On each visit, overnight endogenous GH production was suppressed by octreotide. Three 1-h pulses of recombinant human GH (rhGH) or placebo were administered on two visits each. Acipimox, an antilipolytic drug, or a placebo were ingested every 4 h on two visits each. Stable glucose and glycerol isotopes were used to assess glucose and glycerol turnover. The overnight protocol was concluded by a two-step hyperinsulinemic euglycemic clamp on each visit. Main Outcome: rhGH administration led to increases in the insulin infusion rate required to maintain euglycemia overnight (P = 0.008), elevated basal endogenous glucose production (P = 0.007), decreased basal peripheral glucose uptake (P = 0.03), and reduced glucose uptake during step 1 of the clamp (P < 0.0001). Coadministration of rhGH and acipimox reversed these effects and suppression of lipolysis in the absence of GH replacement led to further increases in insulin sensitivity. Results: GH pulses were associated with an increase in endogenous glucose production and decreased rates of peripheral glucose uptake, which was entirely reversed by acipimox. Therefore, GH-driven decreases in insulin sensitivity are mainly determined by the effect of GH on lipolysis. Growth hormone decreases insulin sensitivity through increases in free fatty acid levels.

scholarly journals Long-Term Improvement in Glucose Control and Counterregulation by Islet Transplantation for Type 1 Diabetes

2016 ◽  
Vol 101 (11) ◽  
pp. 4421-4430 ◽  
Author(s):  
Michael R. Rickels ◽  
Amy J. Peleckis ◽  
Eileen Markmann ◽  
Cornelia Dalton-Bakes ◽  
Stephanie M. Kong ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
University Of Pennsylvania ◽  
Symptom Recognition ◽  
Endogenous Glucose ◽  
The University

Context: Islet transplantation has been shown to improve glucose counterregulation and hypoglycemia symptom recognition in patients with type 1 diabetes (T1D) complicated by severe hypoglycemia episodes and symptom unawareness, but long-term data are lacking. Objective: To assess the long-term durability of glucose counterregulation and hypoglycemia symptom responses 18 months after intrahepatic islet transplantation and associated measures of glycemic control during a 24-month follow-up period. Design, Setting, and Participants: Ten patients with T1D disease duration of approximately 27 years were studied longitudinally before and 6 and 18 months after transplant in the Clinical & Translational Research Center of the University of Pennsylvania and were compared to 10 nondiabetic control subjects. Intervention: All 10 patients underwent intrahepatic islet transplantation according to the CIT07 protocol at the Hospital of the University of Pennsylvania. Main Outcome Measures: Counterregulatory hormone, endogenous glucose production, and autonomic symptom responses derived from stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-2H2-glucose. Results: Near-normal glycemia (HbA1c ≤ 6.5%; time 70–180 mg/dL ≥ 95%) was maintained for 24 months in all patients, with one returning to low-dose insulin therapy. In response to insulin-induced hypoglycemia, glucagon secretion was incompletely restored at 6 and 18 months, epinephrine was improved at 6 months and normalized at 18 months, and endogenous glucose production and symptoms, absent before, were normalized at 6 and 18 months after transplant. Conclusions: In patients with T1D experiencing problematic hypoglycemia, intrahepatic islet transplantation can lead to long-term improvement of glucose counterregulation and hypoglycemia symptom recognition, physiological effects that likely contribute to glycemic stability after transplant.

scholarly journals Pharmacokinetic and Pharmacodynamic Head-to-Head Comparison of Clinical, Equivalent Doses of Insulin Glargine 300 units/mL and Insulin Degludec 100 units/mL in Type 1 Diabetes

2020 ◽  
Author(s):  
Paola Lucidi ◽  
Paola Candeloro ◽  
Patrizia Cioli ◽  
Anna Marinelli Andreoli ◽  
Chiara Pascucci ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Steady State ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucagon Suppression ◽  
Bolus Insulin ◽  
Design And Methods ◽  
Single Blind ◽  
Randomized Crossover Study

<b>OBJECTIVE</b> <p><b> </b></p> <p>To prove equivalence of individual, clinically-titrated basal insulin doses of Gla-300 and Deg-100 under steady-state conditions in a single-blind, randomized, crossover study, on the glucodynamics (PD) in people with type 1 diabetes (T1DM).</p> <p><b>RESEARCH DESIGN AND METHODS</b></p> <p>T1DM subjects [N=22, 11 males M, age 44.3±12.4 years, disease duration 25.5±11.7 years, A1C 7.07±0.63% (53.7±6.9 mmol/mol), BMI 22.5±2.7 kg/m<sup>2</sup>], naïve to Gla-300 and Deg-100, underwent 24-h euglycemic clamps with individual clinical doses of Gla-300 (0.34±0.08 U.Kg<sup>-1</sup>) and <a>Deg-100 </a>(0.26±0.06 U.Kg<sup>-1</sup>), (dosing at 20.00h), after 3 months of optimal titration of basal (and bolus) insulin.</p> <p><b>RESULTS</b></p> <p>At the end of 3 months, Gla-300 and Deg-100 reduced slightly and similarly A1C vs baseline. Clamp average plasma glucose (0-24h) was euglycemic with both insulins. The area under curve of glucose infused [AUC-GIR<sub>(0-24h)</sub>] was equivalent for the two insulins (ratio 1.04, 90% CIs 0.91, 1.18). Suppression of endogenous glucose production, free fatty acids (FFA), glycerol and b-hydroxybutyrate was 9%, 14%, 14% and 18% greater respectively, with Gla-300 as compared with Deg-100, during the first 12 h, while glucagon suppression was no different. Relative within-day PD variability was 23% lower with Gla-300 vs Deg-100 (ratio 0.77, 90% CI 0.63, 0.92).</p> <p><b>CONCLUSIONS</b></p> <p>In T1DM, individualized, clinically titrated doses of Gla-300 and Deg-100 at steady-state result in similar glycemic control and PD equivalence during euglycemic clamps. Clinical doses of Gla-300 as compared with Deg-100 are higher, and associated with quite similar even 24h distribution of PD and anti-lipolytic effects.</p>

scholarly journals Separating Insulin-Mediated and Non-Insulin-Mediated Glucose Uptake during Aerobic Exercise in People with Type 1 Diabetes

2020 ◽  
Author(s):  
Thanh-Tin P. Nguyen ◽  
Peter G. Jacobs ◽  
Jessica Castle ◽  
Leah M. Wilson ◽  
Kerry Kuehl ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Aerobic Exercise ◽  
Glucose Uptake ◽  
Area Under The Curve ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Intense Exercise ◽  
Muscle Work ◽  
Exercise Period

Aerobic exercise in type 1 diabetes (T1D) causes rapid increase in glucose utilization due to muscle work during exercise, followed by increased insulin resistance after exercise. Better understanding of these changes is necessary for models of exercise in T1D. Twenty-six individuals with T1D underwent three studies at three insulin rates (100%, 150%, 300% of basal). After 3-hours run-in, participants performed 45 minutes aerobic exercise (moderate or intense). We determined area-under-the-curve for endogenous glucose production (AUCEGP) and rate of glucose disappearance (AUCRd) over 45 minutes from exercise start. A novel application of linear regression of Rd across the three insulin studies allowed separation of insulin-mediated from non-insulin-mediated glucose uptake before, during and after exercise. ­AUCRd increased 12.45 mmol/L (CI=10.33-14.58, p<0.001) and 13.13 mmol/L (CI=11.01-15.26, p<0.001) while AUCEGP increased 1.66(CI=1.01-2.31, p<0.001) and 3.46 mmol/L (CI=2.81-4.11, p<0.001) above baseline during moderate and intense exercise respectively. AUCEGP increased during intense exercise by 2.14 mmol/L (CI=0.91-3.37, p<0.001) compared to moderate exercise. There was significant effect of insulin infusion rate on AUCRd equal to 0.06 mmol/L per % above basal rate (CI=0.05-0.07, p<0.001). Insulin-mediated glucose uptake rose during exercise and persisted hours afterward, while non-insulin mediated effect was limited to the exercise period. To our knowledge, this method of isolating dynamic insulin and non-insulin mediated uptake has not been previously employed during exercise. These results will be useful in informing glucoregulatory models of T1D. The study has been registered at www.clinicaltrials.gov (ID: NCT03090451).

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