Glucolipotoxicity and Type 2 Diabetes

Overview

Elevations of blood glucose and lipid are thought to be deleterious to the insulin secretory function of the pancreas. This is known as glucolipotoxicity. However, few studies have examined this in detail. This investigation will examine pancreatic insulin secretory function in physiological models of glucolipotoxicity such as obese and type 2 diabetic individuals. Furthermore, healthy subjects will undergo 24 hour infusion of glucose or Intralipid to induce experimental models of glucolipotoxicity. Insulin secretion in response to intravenous infusions of glucose, GLP-1, GIP, and arginine and in response to meal ingestion, will be examined. the investigators hypothesize that experimental glucolipotoxicity will impairs pancreatic insulin secretory function to levels akin to that seen in type 2 diabetics.

Full Title of Study: “The Effects of Experimental Elevation of Plasma Glucose and Lipid on Pancreatic Beta-cell Function in Humans”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Basic Science
    • Masking: Single (Participant)
  • Study Primary Completion Date: May 2014

Interventions

  • Procedure: Glucotoxicity
    • Glucose will be infused intravenously for a 24 hour period to raise blood glucose concentrations 5 mM above basal.
  • Procedure: Lipotoxicity
    • Intralipid and heparin will be infused intravenously for a 24 hour period to raise blood free fatty acid concentrations to approximately 1 mM.

Arms, Groups and Cohorts

  • Experimental: Glucotoxicity Trial
    • Insulin secretion will be assessed using a hyperglycemic clamp combined with GLP-1, GIP, and arginine infusions. The clamp will be performed before and after 24 hours of bed rest, isocaloric meal feeding, and experimental elevation of blood glucose.
  • No Intervention: Control Trial
    • Insulin secretion will be assessed using a hyperglycemic clamp combined with GLP-1, GIP, and arginine infusions. The clamp will be performed before and after 24 hours of bed rest and isocaloric meal feeding.
  • Experimental: Lipotoxicity Trial
    • Insulin secretion will be assessed using a hyperglycemic clamp combined with GLP-1, GIP, and arginine infusions. The clamp will be performed before and after 24 hours of bed rest, isocaloric meal feeding, and experimental elevation of blood free fatty acids.

Clinical Trial Outcome Measures

Primary Measures

  • Insulin Secretion
    • Time Frame: 24 hours
    • Insulin secretion will be assessed in response to intravenous infusions of glucose, GLP-1, GIP, and arginine, and in response to meal ingestion.

Secondary Measures

  • Insulin Sensitivity
    • Time Frame: 24 hours
    • Glucose kinetics will be assesed using [6,6-2H2]glucose. Rate of glucose disappearance during glucose infusion will be quantified per unit of plasma insulin to derive an estimate of insulin sensitivity.
  • Plasma Cytokines (IL-6, TNF, IL-1beta, IL-1ra)
    • Time Frame: 24 hours
    • Cytokines will be measured in plasma: IL-6, TNF-alpha, IL-1beta, IL-1 receptor antagonist, IL-8, IL-10, Interferon gamma. Peripheral blood mononuclear cells will be isolated.

Participating in This Clinical Trial

Inclusion Criteria

  • normal glucose tolerance based on screening OGTT or – diagnosed type 2 diabetic (confirmed with OGTT) Exclusion Criteria:

  • insulin dependent diabetes – age <18 or >65 years – BMI <20 or > 35 kg/m2 – evidence of hematological, pulmonary, hepatic, renal, or cardiovascular disease – actively undergoing weight-loss (>2kg change in last 6 months) – bariatric surgery (gastric by-pass or banding) – pregnancy – smoking

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Rigshospitalet, Denmark
  • Provider of Information About this Clinical Study
    • Principal Investigator: Thomas Solomon, Group Leader – Rigshospitalet, Denmark
  • Overall Official(s)
    • Thomas P Solomon, Ph.D., Principal Investigator, Rigshospitalet, Denmark

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