Alpha to Beta Cell Communication in Health and Disease
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Insulin secretion
研究概览
简要总结
Glucagon secretion from α-cells has long been viewed as primarily a counterregulatory mechanism - e.g. an agent with a role to prevent blood sugar from decreasing to levels that compromise function. Our group, along with other researchers, have begun to identify a much more complex role for α-cells, raising questions about when and how glucagon may influence blood glucose levels. This proposal looks to detail proglucagon peptide secretion from α-cells and the impact this has on β-cell function and glucose tolerance, in preclinical studies of human islets and translational studies in human subjects.
This protocol registration describes Aim 2 from this NIH grant which involves 2 study populations and separate protocols but addresses a common question. Aim 3 in the grant is focused on a separate hypothesis and will be conducted and published separately from Aim 2.
详细描述
Subjects will undergo screening for medical history, medication usage, and blood work; those who qualify will be offered participation. Study participation will last approximately 4-5 weeks depending on appointment availability.
Aim 2A: Each participant will have two 5-hour hyperglycemic clamp procedures to test the effect of fasting glucagon-like peptide 1 (GLP-1) action before and after experimental insulin resistance. The effect of endogenous proglucagon peptides (glucagon and GLP-1) to stimulate insulin secretion will be determined by blockade of the GLP-1 receptor with the antagonist exendin-9 (Ex-9) during glucose infusions. Insulin secretion experiments will be repeated before and after induction of insulin resistance. To induce insulin resistance, subjects will take dexamethasone, a synthetic glucocorticoid that has been shown in published studies and in a pilot study by our group to reduce insulin sensitivity by ~30%.
Aim 2B: This study will recruit non-diabetic subjects with obesity. They will be studied on two occasions using a 4.5-hour procedure with a hyperglycemic clamp to measure insulin secretion, followed by a hyperinsulinemic, euglycemic clamp to measure insulin sensitivity. This procedure will be done 2 times, once with saline infused during hyperglycemia as a control, and once with exendin-9 given during hyperglycemia to determine the role of GLP-1 receptor action.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Aim 2A: Inclusion Criteria:
- •Age 18-45
- •Body Mass Index (BMI) < 27.0
- •Fasting plasma glucose of ≤ 95 mg/dL or HbA1c value ≤ 5.8% as measured at screening visit
排除标准
- •Active medical disease: e.g. active infectious, inflammatory, neurodegenerative or mental health disorders
- •Personal history of diabetes or pancreatitis
- •Personal history of cardiac, gastrointestinal, renal or liver disease
- •Immediate family history of diabetes
- •Renal insufficiency (eGFR < 60 mL/kg/min)
- •Anemia (hematocrit < 34%) as measured at screening visit
- •Pregnant females
- •Poor vein access
- •Consumption of daily medications that alter glucose metabolism of GI function (glucocorticoids, psychotropics, narcotics, metoclopramide)
- •Apparent sensitivity to the study peptide as determined by the skin test
- •Aim 2B: Inclusion Criteria:
- •Age 35-60
- •Body Mass Index (BMI) ≥ 27.0
- •Fasting plasma glucose of < 126 mg/dL or HbA1c value < 6.5% as measured at screening visit
- •Exclusion Criteria:
- •Active medical disease: e.g. active infectious, inflammatory, neurodegenerative or mental health disorders
- •Personal history of diabetes or pancreatitis
- •Personal history of cardiac, gastrointestinal, renal or liver disease
- •Immediate family history of diabetes
- •Renal insufficiency (eGFR < 60 mL/kg/min)
- •AST and/or ALT levels > 3x the upper limit of the normal range
- •Anemia (hematocrit < 34%) as measured at screening visit
- •Pregnant females
- •Poor vein access
- •Consumption of daily medications that alter glucose metabolism of GI function (glucocorticoids, psychotropics, narcotics, metoclopramide)
- •Apparent sensitivity to the study peptide as determined by the skin test
研究组 & 干预措施
Aim 2A: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockade
Aim 2A: Each subject will have a 5 hr experiment with sequential hyperglycemic clamps separated by a 90-minute washout. Blood glucose will be increased with an intravenous (IV) infusion of 20% dextrose and maintained stable at a level of 2.5-3.0 mM above fasting glucose for 90 minutes. Following the washout, a second, identical hyperglycemic clamp will be performed. Subjects will receive either saline or exendin-9 (600 pmol/kg/min) during the clamps; in 10 subjects the saline/clamp will be first and in 10 subjects the exendin-9/clamp will be first; the orders will be assigned randomly.
Intervention: The interventions here are the experimental hyperglycemia with and without exendin-9
干预措施: Exendin-9 is a 30 amino acid peptide that is an established competitive antagonist of the GLP-1 receptor. Subjects will receive exendin-9 by intravenous infusion at a rate of 600 pmol/kg/min (Drug)
Glucose stimulated insulin secretion with or without GLP-1 receptor blockade and insulin resistance
Aim 2A: Subjects will be treated with 6 mg dexamethasone once daily for 7 days to induce insulin resistance before repeating the 5 hr glucose clamp study. The infusion of glucose with saline and exendin-9 will be performed identically to the first study.
Intervention: The intervention in this arm is the induction of insulin resistance with dexamethasone treatment.
干预措施: Exendin-9 is a 30 amino acid peptide that is an established competitive antagonist of the GLP-1 receptor. Subjects will receive exendin-9 by intravenous infusion at a rate of 600 pmol/kg/min (Drug)
Aim 2B: Glucose stimulated insulin secretion and insulin sensitivity
Aim 2B: Each subject will have a 3-hour experiment with a 90-minute hyperglycemic clamp at a level of 2.5-3.0 mM above fasting glucose followed by a 60 minute hyperinsulinemic (80 units/meter2 Body Surface Area/minute), euglycemic clamp.
干预措施: Dexamethasone (Drug)
Aim 2B: Glucose stimulated insulin secretion with GLP-1 receptor blockade and insulin sensitivity
Aim 2B: Subjects will have an identical hyperglycemic clamp but with infusion of exendin-9 (600 pmol/kg/min). Exendin-9 infusion will be stopped before the following hyperinsulinemic clamp that will be conducted identically to the control arm. Allocation of subjects in Aim 2B to the study with and without exendin-9 will be randomized.
Intervention: The intervention in this study is the administration of exendin-9 during experimental hyperglycemia.
干预措施: Exendin-9 is a 30 amino acid peptide that is an established competitive antagonist of the GLP-1 receptor. Subjects will receive exendin-9 by intravenous infusion at a rate of 600 pmol/kg/min (Drug)
结局指标
主要结局
Insulin secretion
时间窗: Insulin secretion rates will be measured on both days of study in subjects participating in Aims 2A and 2B. Studies will be completed over a period of 4-5 weeks
Insulin secretion rates will be computed from deconvolution of C-peptide concentrations measured from plasma samples taken during the hyperglycemic clamps.
Insulin secretion with and without exendin-9: Aims 2A and 2B
时间窗: 4-5 weeks
Insulin secretion rates derived from deconvolution of C-peptide will be the primary outcome for insulin secretion. This measure will be compared within subjects in Aim 2A with the difference between the saline and exendin-9 clamps on each day used as the measure of fasting GLP-1 receptor mediated insulin secretion. Comparison of GLP-1 receptor mediated insulin secretion between the placebo and dexamethasone studies will be used to determine the effect of insulin resistance. Insulin secretion rates will also be compared within subjects in Aim 2B. Here the two different study days, one with saline and one with exendin-9 will be used.
次要结局
- Insulin sensitivity: Aim 2B(Insulin sensitivity will be measured in subjects participating in Aim 2B during the hyperinsulinemic clamp in each of the two days of study. The two experiments will be completed in a 4-5 week period.)
研究者
David D'Alessio, M.D.
Professor of Medicine Duke University, Director Division of Endocrinology
Duke University