Intracellular Counter-regulatory Mechanisms Following Low Blood Glucose
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(1,2), 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.
Diabetes Mellitus Type I.
Counter-regulatory Mechanisms During Hypoglycemia.
Drug: Insulin (Insuman Rapid)
|Study Design:||Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single Blind (Subject)
Primary Purpose: Basic Science
|Official Title:||Intracellular Counter-regulatory Mechanisms Following Low Blood Glucose|
- 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 ] [ Designated as safety issue: No ]Change in phosphorylation of target proteins and mRNA expression of target genes assessed with western blotting technique.
- 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 ] [ Designated as safety issue: No ]Assessed by Western blotting.
- Metabolism. [ Time Frame: measured twice on each study day (arm) at t= -30-0 min. and t= 50-80 min. ] [ Designated as safety issue: No ]Assessment of glucose metabolism by forearm pletysmography and heated hand technique (duration of pletysmography = 30 min.)
- Ghrelin [ Time Frame: Measured at t = -30min., t= 30min., t= 75min. and t=110min. on each study day (arm) ] [ Designated as safety issue: No ]
- Metabolism [ Time Frame: once per study day (arm): t 45min - 105min. ] [ Designated as safety issue: No ]A palmitic acid tracer will be given once per trial day to estimate fatty acid metabolism. Duration 1 hour.
|Study Start Date:||August 2013|
|Estimated Study Completion Date:||October 2014|
|Estimated Primary Completion Date:||October 2014 (Final data collection date for primary outcome measure)|
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.
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|
|Institute of Clinical Medicine|
|Aarhus, Aarhus C, Denmark, 8000|
|Study Chair:||Niels Møller, MD||Aarhus University / Aarhus University Hospital|
|Principal Investigator:||Thomas Voss, MD||Aarhus University / Aarhus University Hospital|