Development and Evaluation of a Glucagon Sensitivity Test in Individuals With and Without Hepatic Steatosis
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 65
- 试验地点
- 1
- 主要终点
- Differences in the calculated GLUSENTIC index between individuals with or without MASLD without diabetes
研究概览
简要总结
Glucagon is secreted from pancreatic alpha-cells in response to protein-rich meals and during hypoglycemia. A physiological feedback system exists between the liver and the pancreatic alpha cells termed the liver-alpha cell axis and signifies the role between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid metabolism.
Individuals with non-alcoholic fatty liver disease have increased levels of glucagon (hyperglucagonemia) and amino acids (hyperaminoacidemia), which suggests that hepatic steatosis may uncouple glucagon's effect on amino acid metabolism (i.e. reduced glucagon sensitivity). Since hyperglucagonemia contributes to diabetes progression - due to its potentiating effects on hepatic glucose production - hepatic steatosis may create a diabetogenic circle. This study aims to develop and evaluate a test for measuring glucagon sensitivity in humans.
The investigators (Associate Prof. Nicolai J Wewer Albrechtsen and Prof. Jørgen Rungby) will investigate whether amino acid metabolism is attenuated in individuals with hepatic steatosis (assessed by magnetic resonance imaging) due to impaired hepatic glucagon sensitivity and if glucagon's effect on hepatic glucose production is intact compared to individuals without hepatic steatosis suggestive of biased signaling.
详细描述
Amino acids administered orally or intravenously stimulate glucagon secretion from the pancreas and in turn, glucagon is a powerful stimulus for hepatic amino acid turnover through transcriptional (long-term) and non- transcriptional (acute) mechanisms. Several groups including the investigators have linked glucagon secretion to hepatic amino acid metabolism suggesting a mutual feedback cycle, termed the liver-alpha cell axis. A disruption of this axis, which has been shown both pharmacologically using glucagon receptor antagonists and genetically in glucagon receptor knockout mouse models, leads to increased glucagon (hyperglucagonemia) and amino acid (hyperaminoacidemia) concentrations. This phenotype is also evident in subjects with biopsy-verified metabolic dysfunction-associated steatotic liver disease (MASLD) independent of type 2 diabetes suggesting reduced hepatic glucagon sensitivity in the presence of hepatic steatosis. Glucagon increases amino acid catabolism by potentiating ureagenesis, a pathway exclusive to the liver, and hepatic accumulation of triglycerides may reduce glucagon's ability to augment amino acid turnover. Some amino acids are more potent in stimulating glucagon secretion (glucagonotropic amino acids), including alanine, and the glucagon-alanine index is currently used as a surrogate marker for the hepatic actions of glucagon on ureagenesis. The fate of amino acid turnover depends on both glucagon and insulin dynamics by stimulating amino acid catabolism and synthesis, respectively. Studying the effects of glucagon in individuals with type 1 diabetes will allow one to differentiate between the combined effects of glucagon and insulin compared to the effects of glucagon alone.
This study aims to explore hepatic glucagon sensitivity towards amino acid metabolism in individuals with and without hepatic steatosis (based on magnetic resonance imaging (MRI)).
The investigators hypothesize that the effect of endogenous and exogenous glucagon on plasma amino acid levels are impaired in individuals with MASLD (based on hepatic steatosis measured by MRI) compared to controls.
The nomenclature for MASLD has recently been updated from non-alcoholic fatty liver disease (NAFLD) (https://pubmed.ncbi.nlm.nih.gov/37363821/).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 25 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •BMI = 18.6-25 kg/m2
- •Male or female
- •25-65 years of age
排除标准
- •Diabetes (ADA criteria)
- •Significant alcohol/drug abuse as per investigators judgement
- •Amino acid-related diseases such as phenylketonuria
- •Kidney disease
- •Cardiac problems
- •Cancer within the past 1 year
- •Severe claustrophobia
- •Pacemaker or other non-MR-compatible devices
- •Pregnancy or breastfeeding.
- •Fib4 score > 3.
- •Any medicine, acute illness (within the last two weeks) or other circumstances that in the opinion of the investigator might endanger the participants' safety or compliance with the protocol
- •Group 2 (overweight and obese individuals)
- •Inclusion Criteria:
- •BMI = 25-40 kg/m2
- •Male or female
- •25-65 years of age
- •Exclusion Criteria:
- •Diabetes (ADA criteria)
- •Significant alcohol/drug abuse as per investigators judgement
- •Amino acid-related diseases such as phenylketonuria
- •Kidney disease
- •Cardiac problems
- •Cancer within the past 1 year
- •Severe claustrophobia
- •Pacemaker or other non-MR-compatible devices
- •Pregnancy or breastfeeding
- •Abdominal diameter >70 cm
- •Fib4 score > 3.
- •Any medicine, acute illness (within the last two weeks) or other circumstances that in the opinion of the investigator might endanger the participants' safety or compliance with the protocol
- •Group 3 (individuals with type 1 diabetes)
- •Inclusion Criteria:
- •BMI = 18.6-40 kg/m2
- •Male or female
- •C-peptide negative
- •Insulin pump user
- •25-65 years of age
- •Exclusion Criteria:
- •Type 2 diabetes
- •Closed loop user
- •Microalbuminuria (30-300 mg/g)
- •Significant alcohol/drug abuse as per investigators judgement
- •Amino acid-related diseases such as phenylketonuria
- •Kidney disease
- •Cardiac problems
- •Cancer within the past 1 year
- •Severe claustrophobia
- •Pacemaker or other non-MR-compatible devices
- •Pregnancy or breastfeeding
- •Abdominal diameter >70 cm
- •Fib4 score > 3.
- 另有 2 项未显示
结局指标
主要结局
Differences in the calculated GLUSENTIC index between individuals with or without MASLD without diabetes
时间窗: Time from the first blood sample (at time -10 minutes, following an overnight fast) until the amino acid infusion stops (45 minutes)
This index is conceptually be based on the Matsuda/composite index, and will factor in fasting and amino acid-stimulated levels of glucagon and total amino acids using the following formula: 100/(SQRT(Fasting plasma amino acids levels (mean at time -10 and 0 minutes) \* Fasting plasma glucagon levels (mean at time -10 and 0 minutes) \* Amino acid-stimulated amino acid levels (mean at time 40 and 45 minutes) \* Amino acid-stimulated glucagon levels (mean at time 40 and 45 minutes)).
次要结局
- Baseline corrected AUC for C-peptide after a bolus injection of glucagon.(Time from the glucagon injection (time 0 minutes) until time 120 minutes.)
- Baseline corrected AUC for triglycerides after a bolus injection of glucagon.(Time from the glucagon injection (time 0 minutes) until time 120 minutes.)
- Differences in total and individual amino acids between individuals with overweight or obesity without hepatic steatosis who have been BMI-matched to individuals with hepatic steatosis.(Time 0-120 minutes on the day of the glucagon injection and time 0-180 minutes on the day of the amino acid tolerance test.)
- Differences in the glucagon-alanine index(The index will be measured on samples collected after an overnight fast (12 hours))
- Glucagon's ability (exogenous glucagon) to increase amino acid disappearance (determined by baseline corrected AUC or delta) for total amino acid levels and the individual amino acids.(Time from the glucagon injection (time 0 minutes) until time 20 minutes.)
- Differences in plasma levels of glucagon following an overnight fast.(Measured on samples collected after an overnight fast (12 hours))
- Baseline corrected AUC for glucagon during and after the amino acid tolerance test.(Time from the amino acid infusion starts (time 0 minutes) until time 180 minutes.)
- Baseline corrected AUC for glucose after a bolus injection of glucagon.(Time from the glucagon injection (time 0 minutes) until time 120 minutes.)
- Baseline corrected AUC for urea after a bolus injection of glucagon.(Time from the glucagon injection (time 0 minutes) until time 120 minutes.)
- Baseline corrected AUC for C-peptide during and after the amino acid tolerance test.(Time from the amino acid infusion starts (time 0 minutes) until time 180 minutes.)
- Baseline corrected AUC for urea during and after the amino acid tolerance test.(Time from the amino acid infusion starts (time 0 minutes) until time 180 minutes.)
- Baseline corrected AUC for triglycerides during and after the amino acid tolerance test.(Time from the amino acid infusion starts (time 0 minutes) until time 180 minutes.)
- Differences in glucagon between individuals with overweight or obesity without hepatic steatosis who have been BMI-matched to individuals with hepatic steatosis.(Time time 0-180 minutes on the day of the amino acid tolerance test.)
- ROC curve analysis to evaluate cut-off value for GLUSENTIC index(Time from the first blood sample (at time -10 minutes, following an overnight fast) until the amino acid infusion stops (45 minutes))
- Differences in plasma levels of amino acids during the amino acid tolerance test (determined by baseline corrected AUC)(Time from the start of infusion (0 minutes) until time 60 minutes.)
- Differences in plasma levels of total amino acids and alanine following an overnight fast.(Measured on samples collected after an overnight fast (12 hours))
- Baseline corrected AUC for glucagon after a bolus injection of glucagon.(Time from the glucagon injection (time 0 minutes) until time 120 minutes.)
- Simple linear regression between the variables, pancreatic steatosis and amino acid stimulated glucagon or insulin levels in individuals without diabetes.(Pancreatic steatosis and time point 30 minutes on the day of the amino acid tolerance test will be used.)
- Simple linear regression between hepatic steatosis (%) and the GLUSENTIC index(Time from the first blood sample (at time -10 minutes, following an overnight fast) until the amino acid infusion stops (45 minutes))
- Baseline corrected AUC for insulin after a bolus injection of glucagon.(Time from the glucagon injection (time 0 minutes) until time 120 minutes.)
- Baseline corrected AUC for glucose during and after the amino acid tolerance test.(Time from the amino acid infusion starts (time 0 minutes) until time 180 minutes.)
- Baseline corrected AUC for insulin during and after the amino acid tolerance test.(Time from the amino acid infusion starts (time 0 minutes) until time 180 minutes.)
- Differences in the formula (plasma urea/plasma amino acids) after the amino acid tolerance test.(Time from the amino acid infusion stops (time 45 minutes) until time 180 minutes.)
研究者
Nicolai Jacob Wewer Albrechtsen
Associate Professor, MD, PhD
University of Copenhagen