Evaluation of the Effects of Intranasal Glucagon on Endogenous Glucose Production in Humans
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 10
- 主要终点
- Endogenous glucose production following intranasal glucagon compared to placebo
研究概览
简要总结
Peripheral glucagon action increases hepatic glucose production. In rodents hypothalamic action of glucagon paradoxically suppresses glucose production. Intranasally administered peptides have been shown to preferentially enter the central nervous system. We assessed the effects of intranasal glucagon on hepatic glucose production
详细描述
Fifteen healthy, lean, non-diabetic males and females will undergo two studies each (single blinded crossover), in random order, 4-6 weeks apart.
Study A. Intranasal placebo administration with measurement of endogenous glucose production under pancreatic clamp conditions.
Study B. Intranasal glucagon (glucagon, Eli Lilly, Canada) administration with measurement of endogenous glucose production under pancreatic clamp conditions Each study participant will be admitted to the Metabolic Test Centre of the Toronto General Hospital the day before the study at 12pm. They will be provided with a standardized dinner (consisting of 7 Kcal/kg; 50% carbohydrate, 30% fat, and 20% protein) and will then be required to fast for 12 hr overnight (can have water but no other food or drinks).
At 7am (t=0) the next day, we will begin a primed, constant intravenous infusion of [6,6-2H2]glucose (D2 glucose; Cambridge Isotope Laboratories, MA; a stable isotope of glucose, the enrichment of which can be measured by GC/MS, allowing us to calculate endogenous glucose production rates). The infusion will continue for 8 hours.
At the same time (7am) a pancreatic clamp will be started for 8 hours in order to suppress pancreatic hormone secretion with somatostatin while providing basal infusions of pancreatic hormones and growth hormone by intravenous infusion. This method will permit us to study the effect of intranasal glucagon on hepatic glucose and TRL production without the confounding effects it may have on pancreatic hormone secretion. A simultaneous infusion of somatostatin (Sandostatin, Novartis Pharma, Miss, ON 30mcg/hr), insulin (Humulin R, Eli Lilly, Scarborough, ON, 0.05mU/kg/min), glucagon (Eli Lilly, Miss, ON 0.325ng/kg/min) and growth hormone (Humatrope, Eli Lilly, Mississauga, ON 3ng/kg/min) will be started and continued throughout the study. All hormones were diluted in 1 liter of normal saline and infused with a syringe pump (B. Braun Medical Inc., Bethlehem, PA). Autologous serum (3 mL), freshly prepared from the subject's blood, was added to the saline as carrier prior to hormone dilution.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Men and women, aged 18 to 60 years
- •Body mass index 20 to 27 kg/m2
- •Hemoglobin in the normal range.
- •Normal glucose tolerance in response to a 75gram glucose
排除标准
- •Study participant with a history of hepatitis/hepatic disease that has been active within the previous two years.
- •Any current or previous history of biliary disease (including gall stones, biliary atresia and cholecystitis) or pancreatitis.
- •Any current or previous history of endocrine disease, dyslipidemia or malignancy
- •Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal, genitourinary, hematological systems, or has severe uncontrolled treated or untreated hyper/ hypotension (sitting diastolic > 100 or systolic > 180 or systolic<100) or proliferative retinopathy
- •Use of immunosuppressive agents at any time during the study
- •Allergy to any study medication
- •Pregnancy or breastfeeding
- •Heavy smoker
- •Fasting blood glucose > 6.0 mmol/l or known diabetes.
- •Any history of a MI or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on ECG, unstable angina, or decompensated heart failure.
- •Any nasal pathology.
- •Abnormal liver and thyroid function
- •Current addiction to alcohol or substances of abuse as determined by the investigator or of any mental illness.
- •Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation
- •Taking any regular prescription or non-prescription medications at the time of the study. Occasional use of medications such as acetoaminophen or Tylenol 1 or any use of natural health products may be permitted at the discretion of the investigator.
- •Will not donate blood three months prior to and three months post study procedures
研究组 & 干预措施
Intranasal placebo
placebo comparator
干预措施: Intranasal placebo (Drug)
Intranasal glucagon
active intervention
干预措施: Intranasal glucagon (Drug)
结局指标
主要结局
Endogenous glucose production following intranasal glucagon compared to placebo
时间窗: 6 hours
Stable isotope infusion (D2 glucose) will enable assessment of endogenous glucose production by measuring glucose enrichment in plasma by gas chromatogaphy mass spectrometry. During steady state, rate of glucose appearance (Ra) = rate of glucose disappearance (Rd), where Ra = tracer infusion rate /plasma tracer enrichment. Endogenous glucose production (EGP) rate = Ra - glucose infusion rate
次要结局
未报告次要终点