Meal Glucose Regulation in Type 1 Diabetes on Insulin Pump Therapy: Towards a Better Understanding of the Glucose-Insulin System.
试验速览
- 阶段
- 不适用
- 入组人数
- 20
- 试验地点
- 4
- 主要终点
- 1. Composite plasma glucose and hormone responses to a mixed meal; 2. Glucose control coefficients
研究概览
简要总结
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.
详细描述
BACKGROUND: Ideally, optimal treatment of T1DM should achieve near-normal glucose with no hypoglycemias and preserved quality of life. In the clinical arena, even the currently available most complex strategy, i.e. glucose sensor augmented insulin pump therapy, in which patients wear both a pump for subcutaneous insulin delivery (CSII) and a subcutaneous glucose sensor for continuous glucose monitoring (CGM), does not fully meet the patients' needs. Artificial pancreas (AP) or integrated closed loop control (CLC) algorithms -which take into account CGM readings and the effects of previous insulin infusions to continuously compute the amount of insulin dose to be administered- aim to minimize, in real time, glucose variability and prevent extreme glucose excursions. A number of research groups have been brilliantly working for years to develop a wearable AP to partially, or totally, free the patient (and/or the caregiver) from the burden of the open loop control. However, a perfect glucose control is still lacking, especially in post-meal glycemic excursions. Further insights might be gained by studies of the substrate/hormone responses to meals in T1DM patients on sensor augmented CSII, possibly compared with the gold standard of normal physiology, with special regard to the relative role played by a number of factors of the glucose-insulin pump system in controlling glucose levels.
Metabolic control analysis (MCA) is a theoretical framework which aims at quantitatively describing metabolic systems and at gauging distribution of control. MCA quantifies the role of each component of a system (e.g.: absorption rate of the fast insulin analogue, carbohydrate absorption through the gut, etc.) in controlling a variable of interest, most notably fluxes or concentrations, of the system itself, by computing the scaled coefficient of controls (CCs). CCs typically range from -1 to +1, and the greater their absolute value, the stronger is the control. Application of MCA to T1DM patients on CGM/CSII could quantify the individual role played by each components of the system, and may help in understanding and potentially overcome the hindrances to achieve stable and tight glucose control and to further develop CLC algorithms for optimal management of the disease.
AIM: To investigate characteristics and determinants of the glucose-insulin pump system in patients with T1DM with CGM with particular emphasis on the system level (i.e. glucose CCs). We will perform single mixed meal tolerance tests as well as 24-hour studies in T1DM patients and in healthy controls. We will apply mathematical modelling tools developed by us and will create virtual patients and virtual controls from this database to gain further insights into the alterations of the glucose-insulin pump system in patients.
SPECIFIC AIMS:
- AIM 1: To outline and compare the features of the glucose-insulin system in T1DM patients and in healthy controls during breakfast meals of different sizes
- AIM 2: To test the reproducibility of model assessed glucose-insulin pump system in T1DM patients
- AIM 3: To outline and compare the features of the glucose-insulin system in T1DM patients and in healthy controls during 24-hour periods
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
结局指标
主要结局
1. Composite plasma glucose and hormone responses to a mixed meal; 2. Glucose control coefficients
时间窗: 24 months
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.
次要结局
- Composite plasma free fatty and amino acid responses to a mixed meal(24 months)