Intracellular Counter-regulatory Mechanisms Following Low Blood Glucose

NCT01919788 | Completed

• 2 other identifiers: VEK journal nr.: M-2013-113-13VEK Journal nr. M-2013-113-13
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Diabetes mellitus type I (DMI) is characterized by lack of endogenous insulin and these patients are 100% dependent on insulin substitution to survive. Diabetes mellitus type II (DMII) is characterized by reduced insulin sensitivity and sometimes also reduced insulin production, thus patients with DMII might also be dependent on insulin substitution. Insulin is produced in- and secreted from the pancreas when blood glucose concentration rises during- and after a meal. Insulin increases cellular uptake of glucose leading to lower blood glucose concentration. Substitution with insulin is/can be necessary in DM, but at the same time it induces the risk of hypoglycemia. This makes treatment with insulin a balancing act between hyper- and hypoglycemia. A hypoglycemic episode is a dreaded consequence of insulin overdosing, and also a very frequent reason for hospital admission in patients with DM. Examples of hypoglycemic symptoms may be; shaking, a sense of hunger, sweating, irritability progressing to lack of relevant cerebral responses and eventually coma, convulsions and possibly death. People with diabetes lose the ability to sense of low blood glucose with time, because of a lack of appropriate counter-regulatory responses, hereby increasing the risk of severe hypoglycemia. Understanding normal physiologic counter regulatory mechanisms during hypoglycemia is of major importance to patients with DM and has the potential to change medical treatment in diabetes, to reduce the risk of hypoglycemia. Hypothesis: Hypoglycemia counteracts insulin signaling via hormone-dependent intracellular counter-regulatory mechanisms, involving phosphorylation of specific signaling proteins. Aim: To define counter-regulatory mechanisms in muscle- and fat tissue during hypoglycemia, and to investigate the effect of insulin on lipid metabolism in healthy- and type I diabetic subjects.

Conditions

Diabetes Mellitus Type I; Hypoglycemia

Keywords

Diabetes Mellitus Type I; Hypoglycemia; Counter-regulatory mechanisms

Outcome Measures

Primary Outcomes (1)

• Insulin and growth hormone signalling, expressed as CHANGE in phosphorylation of intracellular target proteins and mRNA expression of target genes in muscle- and fat-tissue.

  Change in phosphorylation of target proteins and mRNA expression of target genes assessed with western blotting technique.

  Biopsies obtained on each study day (arm). Muscle biopsies: time (t)= -30min, t= 30min and t= 75min. Fat biopsies: t= 30min and t= 75min

Secondary Outcomes (4)

• Intracellular markers of lipid metabolism in muscle- and fat tissue biopsies.

  Biopsies obtained on each study day (arm). Muscle biopsies: time (t)= -30min, t= 30min and t= 75min. Fat biopsies: t= 30min and t= 75min

• Metabolism.

  measured twice on each study day (arm) at t= -30-0 min. and t= 50-80 min.

• Ghrelin

  Measured at t = -30min., t=0min, t=15min, t= 30min., t=45min., t=60min., t= 75min., t=90min. and t=105min. on each study day (arm)

• Metabolism

  once per study day (arm): t 45min - 105min.

Study Arms (3)

Control

PLACEBO COMPARATOR

No insulin administered. Instead of insulin infusion, a small amount of saline is administered to keep the subject blinded. Three muscle biopsies and two fat biopsies will be obtained. A palmitic acid tracer will be given to estimate fatty acid metabolism. Forearm pletysmography will be performed twice.

Other: Saline

Insulin

EXPERIMENTAL

Insulin (Insuman Rapid) is administered once as a bolus of 0,1 IU/kg. Three muscle biopsies and two fat biopsies will be obtained. A palmitic acid tracer will be given to estimate fatty acid metabolism Forearm pletysmography will be performed twice

Drug: Insulin (Insuman Rapid)

Insulin and glucose

EXPERIMENTAL

Insulin (Insuman rapid) is administered once as a bolus injection of 0,1 IU/kg and glucose is given at the same time to avoid hypoglycemia in this arm. Three muscle biopsies and to fat biopsies is obtained. A palmitic acid tracer is given to estimate fatty acid metabolism Forearm pletysmography will be performed twice

Drug: Insulin (Insuman Rapid); Drug: Glucose

Interventions

Insulin (Insuman Rapid) DRUG

Insulin; Insulin and glucose

Glucose DRUG

Insulin and glucose

Saline OTHER

Control

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Epilepsy
• Cardiac arrythmia
• Ischemic heart disease
• Other medical illness

Sponsors & Collaborators

• University of Aarhus: lead

Study Sites (1)

Institute of Clinical Medicine

Aarhus, Aarhus C, 8000, Denmark

Location

Related Publications (2)

• Voss TS, Vendelbo MH, Kampmann U, Hingst JR, Wojtaszewski JFP, Svart MV, Moller N, Jessen N. Acute Hypoglycemia in Healthy Humans Impairs Insulin-Stimulated Glucose Uptake and Glycogen Synthase in Skeletal Muscle: A Randomized Clinical Study. Diabetes. 2017 Sep;66(9):2483-2494. doi: 10.2337/db16-1559. Epub 2017 Jun 8.

  PMID: 28596236 DERIVED

• Voss TS, Vendelbo MH, Kampmann U, Pedersen SB, Nielsen TS, Johannsen M, Svart MV, Jessen N, Moller N. Effects of insulin-induced hypoglycaemia on lipolysis rate, lipid oxidation and adipose tissue signalling in human volunteers: a randomised clinical study. Diabetologia. 2017 Jan;60(1):143-152. doi: 10.1007/s00125-016-4126-x. Epub 2016 Oct 12.

  PMID: 27734104 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Hypoglycemia

Interventions

Insulin; Glucose; Sodium Chloride

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Hexoses; Monosaccharides; Sugars; Carbohydrates; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Niels Møller, MD

  Aarhus University / Aarhus University Hospital

  STUDY CHAIR

• Thomas Voss, MD

  Aarhus University / Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: August 5, 2013
• First Posted: August 9, 2013
• Study Start: August 1, 2013
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: September 27, 2019

Record last verified: 2019-09

Locations

DK (1)