Acute Effect of HP-211 (Axulin) on Blood Glucose and Serum Insulin Responses in Healthy Lean and Overweight Humans
Condition: Insulin Resistance, Diabetes
MeSH terms: Overweight; Insulin Resistance
Study type: Interventional
Phase: Phase 1

Summary: 
      Blood sugar levels are controlled by insulin, a hormone made by cells in the pancreas. After
      a meal, carbohydrates are broken down into glucose (blood sugar) which is absorbed from the
      intestine into the blood leading to a rise in glucose which triggers the secretion of
      insulin. Insulin binds to cells in the liver, muscle and fat, triggering them to take up
      glucose and bring the blood glucose level back to normal.

      A high blood sugar level is known as diabetes. The most common form of diabetes, type 2
      diabetes, is caused by insulin resistance; that is, a reduced ability of insulin to stimulate
      glucose uptake into cells. The body compensates for insulin resistance by making more
      insulin; type 2 diabetes occurs when the pancreas can no longer make enough insulin to
      control blood glucose. The high blood glucose and insulin levels lead to long-term
      complications such as heart attacks, kidney failure, reduced sensation and poor circulation
      in the feet and legs. Reducing blood glucose levels with oral medications and insulin reduces
      risk of diabetic complications. There are several types of oral medications available for
      treating diabetes; however, they do not always control blood glucose adequately. In addition,
      these drugs have complications and are not used to treat insulin resistance and prediabetes -
      a condition when blood glucose is higher than normal but not high enough to be classified as
      diabetes. Prediabetes often progresses to diabetes over a period of months or years.
      Effective and safe treatments for prediabetes could prevent or delay the onset of diabetes.

      Axulin is a natural health product consisting of a mixture of extracts - derived from herbs
      and vegetables present in normal diets - which has been shown in cell culture and in animal
      studies to increase the ability of insulin to stimulate glucose uptake into cells. The active
      ingredient in Axulin is a botanical extract designated HP-211. Thus, HP-211 may reduce the
      blood glucose and insulin levels of subjects without diabetes after eating. HP-211 may also
      reduce glucose and insulin responses to a larger extent in insulin-resistant as compared to
      insulin-sensitive subjects.

      Subjects will take 0g, 2g, or 4g of capsules or tablets in the morning after an overnight
      fast; 40 minutes later they will consume 75g glucose dissolved in 300ml water. Blood glucose,
      insulin and fats will be measured before and for 2 hours after the glucose drink.
    

Detailed description: 
      After consumption of a meal, pancreatic secretions of various digestive enzymes results in
      the breakdown of carbohydrates into monosaccharides including glucose. These sugars are
      subsequently absorbed through the intestinal lumen, resulting in an increased plasma glucose
      concentration. In response to high glucose levels, pancreatic beta-cells are stimulated to
      release the hormone insulin which circulates through the bloodstream and binds to
      insulin-responsive cells including adipocytes (fat tissue), myocytes (muscle tissue), and
      hepatocytes (liver). The resulting insulin-mediated signaling cascade initiates intracellular
      glucose uptake within peripheral tissues leading to a corresponding decrease in circulating
      plasma glucose.

      In insulin responsive cells glucose uptake stimulation begins after the binding of insulin to
      Insulin Receptors (IR), which are found on the membrane surface of cells in insulin
      responsive tissues such as fat, muscle and liver. The IR consists of an extracellular domain
      which binds to insulin, and an intracellular domain that has a protein tyrosine kinase
      activity. The binding of Insulin to the IR initiates a series of auto-phosphorylation events
      within the protein kinase domain that permit interaction and phosphorylation of downstream
      signaling proteins in the cell that mediate the cellular response to insulin. The resulting
      signaling complex includes proteins in the Insulin Receptor Substrate (IRS) family known as
      IRS-1 and IRS-2. These key targets of the insulin signaling pathway link IR activation to
      downstream signaling cascades that mediate intracellular processes including GLUT4-mediated
      glucose uptake.

      Prediabetes and Type II diabetes involve an impaired post-receptor response to insulin that
      hinders the glucose uptake response after meal consumption. Chronic hyperglycemia and the
      resulting compensatory hyperinsulinemia promote a cohort of acute and chronic sequelae
      including cardiovascular disease, liver complications, central nervous system degeneration
      and hyperglycemic osmotic stress. Axulin is a natural health product consisting of a mixture
      of extracts from herbs and vegetables present in normal diets which was identified by
      screening more than 100,000 compounds and extracts in a patented cell-culture based assay
      system targeting the IRS proteins. In vitro, Axulin's active ingredient, HP-211, has marked
      effects on the IRS-2 branch of the insulin signaling cascade to enhance downstream insulin
      signaling. HP-211 has been shown in animal models to increase glucose uptake in peripheral
      tissues and decrease circulating blood glucose and triglyceride concentrations. Regular
      supplementation of the diet with Axulin would be expected to reduce the incidence of
      associated prediabetic and diabetic complications, resulting in an increased quality of life
      for patients without resorting to current anti-diabetic prescription drugs such as metformin
      and others that may have substantial unwanted side effects in patients.

      HYPOTHESES Axulin will reduce postprandial glucose and insulin responses in a dose-dependent
      fashion in healthy subjects without diabetes. The reduction in glucose and insulin will be
      relatively greater in insulin-resistant than insulin-sensitive subjects.

      Subjects will take 0g, 2g, or 4g of capsules or tablets in the morning after an overnight
      fast; 40 minutes later they will consume 75g glucose dissolved in 300ml water. Blood glucose,
      insulin and triglycerides will be measured fasting and at intervals for 2 hours after the
      glucose drink.
    

Intervention name(s): Placebo capsules; 2g capsules; 4g capsules; Water Control; 2g tablets; 4g tablets
Intervention type(s): Other; Other; Other; Other; Other; Other
Intervention description(s): 250ml water with 16 x 250mg placebo capsules; 250ml water with 8 x 250mg capsules containing Axulin powder plus 8 x 250mg placebo capsules; 250ml water with 16 x 250mg capsules containing Axulin powder; 250ml water; 250ml water with 2 x 1g tablets containing Axulin powder; 250ml water with 4 x 1g tablets containing Axulin powder
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Each participant in 2 participant groups will undergo each of 6 treatments
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment