Mixed Meal Test in Type 1 Diabetes on Insulin Pump Therapy: Optimization of Artificial Pancreas

NCT02003274 | Unknown

• 1 other identifier: Verona Artificial Pancreas
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

BACKGROUND. Optimal glucose control can prevent/relent tissue damage in patients with type 1 diabetes mellitus (T1DM). Ongoing efforts aim at developing closed loop control (CLC) algorithms linking subcutaneous continuous glucose monitoring (CGM) and insulin delivery (CSII). Substantial improvement towards an effective artificial pancreas system is still needed, especially in the regulation of post-meal glucose. Application of metabolic control analysis (MCA) can unveil and quantify distortions in the system properties of the glucose-insulin (pump) system (GIS), by measuring the coefficients of control (CCs) of glucose. Our approach rely on previous experience with our previous pilot protocol (NCT01800734). AIM. We will outline and compare features of GIS in T1DM patients and in healthy controls during differently sized breakfast meals and during 24-hour periods. The reproducibility of our approach will also be assessed. METHODOLOGY. Three protocols will be carried out. All T1DM patients will be on CGM/CSII therapy. In all three protocols, study 1 will be an euglycemic insulin clamp in T1DM patients and a frequently sampled intravenous glucose tolerance test (IVGTT) in healthy controls.

• Protocol 1: 10 T1DM patients on CGM/CSII and 10 control subjects will ingest a mixed meal of different size (320 and 640 kcal) on two separate occasions.
• Protocol 2: 5 T1DM patients will ingest two repeat 320 kcal meals, whereas other 5 T1DM patients will ingest two 640 kcal meals on two separate occasions.
• Protocol 3: 10 T1DM patients and 10 controls will be monitored for 24 hours, during which they will ingest 3 mixed meals. Substrate (including CGM)/hormone responses will be measured in all studies. Comprehensive single meal and 24-hour models of GIS will be built, MCA will be applied and the CCs of glucose assessed, thereby allowing to outline and to compare the CCs of glucose between patients and controls. EXPECTED RESULTS. Our data will be of use in devising novel clinical strategies in T1DM, including, but not limited to, development and refinement of CLC algorithms along the path towards an effective artificial pancreas system.

Conditions

Type 1 Diabetes Mellitus

Keywords

Mixed Meal Test; Insulin Pump; Continuous Glucose Monitoring; Metabolic Control Analysis; Closed Loop Control; Artificial Pancreas

Outcome Measures

Primary Outcomes (1)

• 1. Composite plasma glucose and hormone responses to a mixed meal; 2. Glucose control coefficients

  1. Timed curves of composite plasma glucose, meal-derived glucose, endogenous glucose, insulin, glucagon and incretin hormone concentrations in response to a mixed meal. 2. Composite glucose control coefficients (CCs) of each component of the glucose-insulin system at each time point of the mixed meal.

  24 months

Secondary Outcomes (1)

• Composite plasma free fatty and amino acid responses to a mixed meal

  24 months

Study Arms (2)

Clamp-Mixed Meal Arm

OTHER

Twenty adult patients with type 1 diabetes, regularly attending the Division of Endocrinology and Metabolic Diseases of University of Verona School of Medicine, using continuous subcutaneous fast insulin analogue infusion (CSII) through a permanent pump and on subcutaneous glucose sensing will be enrolled.

Other: Clamp-Mixed Meal

IVGTT-Mixed Meal Arm

OTHER

Twenty healthy adult volunteers will be recruited.

Other: IVGTT-Mixed Meal Arm

Interventions

Clamp-Mixed Meal OTHER

Standard clinical parameters will be assessed in all patients. Metabolic tests: A. Euglycemic insulin clamp. A standard euglycemic insulin clamp will be carried out in type 1 diabetic patients to assess insulin sensitivity, as previously described (1). B. Mixed meal test. All participants will ingest a standardized mixed meal and will be monitored for 300 minutes thereafter. Right before meal ingestion, a s.c. fast insulin analogue bolus will be administered by the pump This test will determine the time courses of: 1\. plasma glucose, 2. 13C/12C glucose ratio (hence, meal-derived and endogenous glucose), 3. insulin, 4. free fatty acids, 5. aminoacids, 6. glucagon, 7. incretin hormones 8. glucose control coefficients (CCs) during a mixed meal.

Clamp-Mixed Meal Arm

IVGTT-Mixed Meal Arm OTHER

Standard clinical parameters will be assessed in all subjects. Metabolic tests: A. IVGTT. A frequently sampled intravenous glucose tolerance test (IVGTT) in healthy controls will be carried out in study 1 and study 3 to assess insulin sensitivity. B. Mixed meal test. All participants will ingest a standardized mixed meal and will be monitored for 300 minutes thereafter. This test will determine the time courses of: 1\. plasma glucose, 2.13C/12C glucose ratio (hence, meal-derived and endogenous glucose), 3. insulin, 4. free fatty acids, 5. aminoacids, 6. glucagon, 7. incretin hormones 8. glucose control coefficients (CCs) during a mixed meal.

IVGTT-Mixed Meal Arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• patient must be aged between 18 (inclusive) and 65 years old;
• patient must have been diagnosed with type 1 diabetes(positive islet cell antibodies;
• use of an insulin pump to treat his/her diabetes for at least 1 year;
• actively using a carbohydrate/insulin ratio for insulin bolus adjustments in order to keep blood glucose in a predefined range;
• patient HbA1c is between 6,0% and 9,0% (standardized with DCCT);
• patient must be willing to avoid consumption of acetaminophen containing products during the study involving DexCom (one CGM system which will be employed in this study) use;
• patient must demonstrate proper mental status and cognition for the study;
• patient has signed informed consent from prior to study entry.

You may not qualify if:

• diabetic ketoacidosis within the 6 months prior to enrollment;
• severe hypoglycemia resulting in seizure or loss of consciousness in the 12 months prior to enrollment;
• pregnancy and breast feeding;
• uncontrolled microvascular (diabetic)complications (other than diabetic non-proliferative retinopathy)such as history of laser coagulation, proliferative diabetic retinopathy, known diabetic nephropathy (other than microalbuminuria with normal creatinine) or neuropathy requiring treatment;
• uncontrolled arterial hypertension (diastolic blood pressure \>90 mmHg and/or systolic blood pressure \>160 mmHg);
• conditions which may increase the risk of hypoglycemia such as uncontrolled coronary artery disease during the previous year (e.g. history of myocardial infarction, acute coronary syndrome, therapeutic coronary intervention, coronary bypass or stenting procedure, stable or unstable angina, episode of chest pain of cardiac etiology with documented EKG changes, or positive stress test or catheterization with coronary blockages \>50%), congestive heart failure, history of cerebrovascular event, seizure disorder, syncope, adrenal insufficiency, neurologic disease or atrial fibrillation;
• drugs affecting glucose metabolism (oral steroids, thiazide diuretic, beta-blockers,beta-agonist, nicotinic acid, immunosuppressant agents, antiretroviral drugs and antipsychotics);
• impaired hepatic function measured as alanine aminotransferase or aspartate aminotransferase \> three times the upper reference limit;
• impaired renal function measured as creatinine \>1.2 times above the upper limit of normal; anticoagulant therapy other than aspirin;
• known current or recent alcohol or drug abuse;
• psychiatric disorders that would interfere with study tasks (e.g. inpatient psychiatric treatment within 6 months prior to enrollment);
• mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation.

Sponsors & Collaborators

• Azienda Ospedaliera Universitaria Integrata Verona: lead
• Universita di Verona: collaborator
• European Foundation for the Study of Diabetes: collaborator

Study Sites (2)

Clinical Research Center-University Hospital of Verona

C/o Policlinico G.B. Rossi - Piazzale L.A. Scuro, 10, Verona, 37134, Italy

Location

Division of Endocrinology and Metabolic Diseases - University Hospital of Verona

Piazzale Stefani 1-Pad. 22, Verona, 37126, Italy

Location

Related Publications (6)

• Bonetti S, Trombetta M, Boselli ML, Turrini F, Malerba G, Trabetti E, Pignatti PF, Bonora E, Bonadonna RC. Variants of GCKR affect both beta-cell and kidney function in patients with newly diagnosed type 2 diabetes: the Verona newly diagnosed type 2 diabetes study 2. Diabetes Care. 2011 May;34(5):1205-10. doi: 10.2337/dc10-2218. Epub 2011 Mar 16.

  PMID: 21411509 BACKGROUND

• Trombetta M, Boselli L, Cretti A, Cali A, Vettore M, Caruso B, Dorizzi R, Avogaro A, Muggeo M, Bonora E, Bonadonna RC. Type 2 diabetes mellitus: a disease of the governance of the glucose-insulin system: an experimental metabolic control analysis study. Nutr Metab Cardiovasc Dis. 2013 Jan;23(1):23-30. doi: 10.1016/j.numecd.2011.05.006. Epub 2011 Sep 19.

  PMID: 21937205 BACKGROUND

• Fell DA. Metabolic control analysis: a survey of its theoretical and experimental development. Biochem J. 1992 Sep 1;286 ( Pt 2)(Pt 2):313-30. doi: 10.1042/bj2860313. No abstract available.

  PMID: 1530563 BACKGROUND

• Cobelli C, Toffolo GM, Dalla Man C, Campioni M, Denti P, Caumo A, Butler P, Rizza R. Assessment of beta-cell function in humans, simultaneously with insulin sensitivity and hepatic extraction, from intravenous and oral glucose tests. Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E1-E15. doi: 10.1152/ajpendo.00421.2006. Epub 2007 Mar 6.

  PMID: 17341552 BACKGROUND

• Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981 Dec;68(6):1456-67. doi: 10.1172/jci110398.

  PMID: 7033284 BACKGROUND

• Marchetti L, Reali F, Dauriz M, Brangani C, Boselli L, Ceradini G, Bonora E, Bonadonna RC, Priami C. A Novel Insulin/Glucose Model after a Mixed-Meal Test in Patients with Type 1 Diabetes on Insulin Pump Therapy. Sci Rep. 2016 Nov 8;6:36029. doi: 10.1038/srep36029.

  PMID: 27824066 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Riccardo C Bonadonna, Assoc Prof

  Division of Endocrinology and Metabolic Diseases, University Hospital of Verona

  PRINCIPAL INVESTIGATOR

• Enzo Bonora, Full Prof

  Division of Endocrinology and Metabolic Diseases, University Hospital of Verona

  STUDY DIRECTOR

• Maddalena Trombetta, Asst Prof

  Division of Endocrinology and Metabolic Diseases, University Hospital of Verona

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 3, 2013
• First Posted: December 6, 2013
• Study Start: October 1, 2013
• Primary Completion: October 1, 2016
• Study Completion: October 31, 2017
• Last Updated: July 2, 2017

Record last verified: 2017-03

Locations

IT (2)