Glucolipotoxicity and Type 2 Diabetes

The Effects of Experimental Elevation of Plasma Glucose and Lipid on Pancreatic Beta-cell Function in Humans

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Procedure: Glucotoxicity; Procedure: Lipotoxicity

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Centre of Inflammation and Metabolism, Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: SINGLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Procedure: Glucotoxicity; Glucose will be infused intravenously for a 24 hour period to raise blood glucose concentrations 5 mM above basal.
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.	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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Sensitivity	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.	24 hours
Plasma Cytokines (IL-6, TNF, IL-1beta, IL-1ra)	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.	24 hours

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (ACTUAL): May 1, 2014
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: June 14, 2011
• First Submitted That Met QC Criteria: June 16, 2011
• First Posted (ESTIMATE): June 17, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): December 3, 2014
• Last Update Submitted That Met QC Criteria: December 2, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: diabetes; incretin; beta-cell function; glucagon-like peptide 1; glucolipotoxicity; glucose-dependent insulinotropic polypeptide
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: H-3-2010-127