Intracellular Counter-regulatory Mechanisms Following Low Blood Glucose

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus Type I.; Hypoglycemia.	Drug: Insulin (Insuman Rapid); Drug: Glucose; Other: Saline	Not Applicable

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	9 participants
Allocation:	Randomized
Intervention Model:	Factorial Assignment
Masking:	Single (Participant)
Primary Purpose:	Basic Science
Official Title:	Intracellular Counter-regulatory Mechanisms Following Low Blood Glucose
Study Start Date :	August 2013
Actual Primary Completion Date :	April 2014
Actual Study Completion Date :	April 2014

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Placebo Comparator: Control; 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
Experimental: Insulin; 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)
Experimental: Insulin and glucose; 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

Outcome Measures

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Primary Outcome Measures :

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. [ Time Frame: Biopsies obtained on each study day (arm). Muscle biopsies: time (t)= -30min, t= 30min and t= 75min. Fat biopsies: t= 30min and t= 75min ]
   Change in phosphorylation of target proteins and mRNA expression of target genes assessed with western blotting technique.

Secondary Outcome Measures :

1. Intracellular markers of lipid metabolism in muscle- and fat tissue biopsies. [ Time Frame: Biopsies obtained on each study day (arm). Muscle biopsies: time (t)= -30min, t= 30min and t= 75min. Fat biopsies: t= 30min and t= 75min ]
   Assessed by Western blotting.
2. Metabolism. [ Time Frame: measured twice on each study day (arm) at t= -30-0 min. and t= 50-80 min. ]
   Assessment of glucose metabolism by forearm pletysmography and heated hand technique (duration of pletysmography = 30 min.)
3. Ghrelin [ Time Frame: 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) ]
4. Metabolism [ Time Frame: once per study day (arm): t 45min - 105min. ]
   A palmitic acid tracer will be given once per trial day to estimate fatty acid metabolism. Duration 1 hour.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	Yes

Criteria

• BMI > 19 and < 26
• Written Consent

Exclusion Criteria:

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

Contacts and Locations

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Locations

Denmark
Institute of Clinical Medicine
Aarhus, Aarhus C, Denmark, 8000

Sponsors and Collaborators

University of Aarhus

Investigators

Study Chair:	Niels Møller, MD	Aarhus University / Aarhus University Hospital
Principal Investigator:	Thomas Voss, MD	Aarhus University / Aarhus University Hospital

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Voss TS, Vendelbo MH, Kampmann U, Hingst JR, Wojtaszewski JFP, Svart MV, Møller 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.

Voss TS, Vendelbo MH, Kampmann U, Pedersen SB, Nielsen TS, Johannsen M, Svart MV, Jessen N, Møller 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. Epub 2016 Oct 12.

Responsible Party:	Thomas Schmidt Voss, MD, University of Aarhus
ClinicalTrials.gov Identifier:	NCT01919788 History of Changes
Other Study ID Numbers:	VEK journal nr.: M-2013-113-13; VEK Journal nr. M-2013-113-13 ( Other Identifier: VEK )
First Posted:	August 9, 2013
Last Update Posted:	February 24, 2016
Last Verified:	February 2016

Keywords provided by Thomas Schmidt Voss, University of Aarhus:

Diabetes Mellitus Type I; Hypoglycemia; Counter-regulatory mechanisms

Additional relevant MeSH terms:

Diabetes Mellitus; Hypoglycemia; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases	Autoimmune Diseases; Immune System Diseases; Insulin, Globin Zinc; Insulin; Hypoglycemic Agents; Physiological Effects of Drugs