A novel study is underway to comprehensively evaluate the metabolic effects of imeglimin, an investigational drug for type 2 diabetes, utilizing a sophisticated two-step hyperinsulinemic-euglycemic glucose clamp technique. The research aims to dissect imeglimin's impact on insulin sensitivity across different tissues and its broader effects on glucose metabolism.
The study employs an artificial endocrine pancreas (STZ-55; Nikkiso Co., Ltd.) to precisely control glucose levels during the clamp procedure. Participants adhere to a strict dietary and exercise regimen in the days leading up to the clamp, ensuring minimal variability in metabolic parameters. This includes a standardized weight-maintenance diet for three days prior and abstaining from alcohol the day before. Physical activity is monitored using accelerometers (Lifecorder; SUZUKEN Co., Ltd.) to maintain activity levels within ±10% of their mean daily activity.
The two-step hyperinsulinemic-euglycemic glucose clamp involves a primed and continuous infusion of [6,6-²H₂]glucose to measure fasting endogenous glucose production (EGP). Subsequently, insulin is infused at two different rates (20 mU/m²/min and 40 mU/m²/min) to assess insulin sensitivity. Plasma glucose levels are maintained at <95 mg/dl through a variable 20% glucose infusion. Blood samples are collected at 10-minute intervals to measure various biochemical parameters.
Key Measurements and Calculations
The study focuses on several key metabolic parameters: EGP suppression during the first step as an index of hepatic insulin sensitivity, glucose disposal rate (Rd) during the second step as an index of muscle insulin sensitivity, and free fatty acid (FFA) suppression during the first step as an index of adipose tissue insulin sensitivity. Insulin clearance is calculated using the formula: insulin clearance = (IIR/[SSSI − (BSI × SSSC/BSC)]), where IIR is the insulin infusion rate, SSSI is the steady-state serum insulin concentration, BSI is basal serum insulin, SSSC is steady-state serum C-peptide concentration, and BSC is basal serum C-peptide concentration. Feedback inhibition of insulin secretion is also assessed.
Clinical Significance
Type 2 diabetes is a growing global health concern, characterized by insulin resistance and impaired glucose metabolism. Understanding the precise mechanisms by which imeglimin improves glycemic control is crucial for optimizing its use in clinical practice. This study's rigorous methodology and comprehensive assessment of metabolic parameters promise to provide valuable insights into imeglimin's therapeutic potential.
