- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03241706
Liver Glycogen and Hypoglycemia in Humans
Effect of Liver Glycogen Content on Hypoglycemic Counterregulation
The purpose of this research study is to learn more about how sugar levels in the liver affect the ability of people both with and without type 1 diabetes. People with type 1 diabetes do not make their own insulin, and are therefore required to give themselves injections of insulin in order to keep their blood sugar under control. However, very often people with type 1 diabetes give themselves too much insulin and this causes their blood sugar to become very low, which can have a negative impact on their health. When the blood sugar becomes low, healthy people secrete hormones such as glucagon and epinephrine (i.e., adrenaline), which restore the blood sugar levels to normal by increasing liver glucose production into the blood. However, in people with type 1 diabetes, the ability to release glucagon and epinephrine is impaired and this reduces the amount of sugar the liver is able to release.
People with type 1 diabetes also have unusually low stores of sugar in their livers. It has been shown in animal studies that when the amount of sugar stored in the liver is increased, it increases the release of glucagon and epinephrine during insulin-induced hypoglycemia. In turn, this increase in hormone release boosts liver sugar production. However, it is not known if increased liver sugar content can influence these responses in people with and without type 1 diabetes. In addition, when people with type 1 diabetes do experience an episode of low blood sugar, it impairs their responses to low blood sugar the next day. It is also unknown whether this reduction in low blood sugar responses is caused by low liver sugar levels.
The investigators want to learn more about how liver sugar levels affect the ability to respond to low blood sugar.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
There is universal agreement that iatrogenic hypoglycemia is the single most prominent barrier to the safe, effective management of blood sugar in people with type 1 diabetes (T1D). The typical patient with T1D is required to "count" the number of carbohydrates they consume, estimate their own insulin doses and deliver this insulin subcutaneously to manage their own glycemic level. With these multiple degrees of freedom, it is not surprising that people with T1D frequently over-insulinize, thereby putting themselves at increased risk of developing hypoglycemia and its associated comorbidities.
As the glycemic level falls in people who are generally healthy (i.e., non-T1D), the first response is an abatement of insulin secretion. This reduction is then followed by an increase in the release of the counterregulatory hormones glucagon and epinephrine as glycemia continues to fall. Collectively, this hormonal milieu causes an increase in liver glycogen mobilization and gluconeogenesis such that hepatic glucose production (HGP) increases, thereby preventing serious hypoglycemia from occurring. However, people with T1D are unable to reduce their own insulin levels (due to subcutaneous insulin delivery) and often have a diminished capacity to secrete both glucagon and epinephrine during insulin-induced hypoglycemia. Predictably, the HGP response to hypoglycemia in people with T1D is a fraction of that seen in non-T1D controls, thereby increasing the depth and duration of the hypoglycemic episode.
Liver glycogen is the first substrate used to defend against hypoglycemia. Interestingly, hepatic glycogen levels in people with T1D are lower than those of non-T1D controls and their ability to mobilize liver glycogen to combat insulin-induced hypoglycemia is also diminished. Because of this, we carried out experiments in dogs to determine whether hepatic glycogen content is a determinant of the HGP response to insulin-induced hypoglycemia. Results of those studies showed that a 75% increase in liver glycogen (such as occurs in a non-T1D individual over the course of a day) generated a signal in the liver that was transmitted to the brain via afferent nerves which, in turn, led to an increase in the secretion of both epinephrine and glucagon. As expected, this increase in counterregulatory hormone secretion caused a 2.4-fold rise in HGP, despite insulin levels that were ~ 400 µU/mL at the liver.
The finding that an acute increase in hepatic glycogen can augment hypoglycemic counterregulation has important clinical implications. However, despite the potential of this therapeutic avenue to reduce the risk of iatrogenic hypoglycemia, it remains unclear at this point if such a strategy translates to humans with T1D. Therefore, the overarching theme of this proposal is to determine whether an acute increase in liver glycogen content can augment the hepatic and hormonal responses to insulin-induced hypoglycemia in humans with and without T1D. Herein we are proposing studies that will advance the field, with the specific aims being as follows:
Specific Aim #1: To determine the effect of increasing liver glycogen deposition on insulin-induced hypoglycemic counterregulation in humans with and without T1D.
The discovery of ways by which the risk of iatrogenic hypoglycemia can be reduced in people with T1D is a priority. The proposed experiments will improve our understanding of the mechanisms by which increased glycogen improves hypoglycemic counterregulation. If hypoglycemia is reduced by increased glycogen, it will focus attention on the ways in which liver glycogen levels can be normalized in people with T1D. This would be a significant step forward in the ongoing effort to reduce the risk of iatrogenic hypoglycemia in people with T1D.
Study Type
Enrollment (Estimated)
Phase
- Phase 1
Contacts and Locations
Study Contact
- Name: Jason Winnick, PhD
- Phone Number: 5135584437
- Email: jason.winnick@uc.edu
Study Contact Backup
- Name: Rebecca Nelson, BS
- Phone Number: 5135583427
- Email: nelsonr8@ucmail.uc.edu
Study Locations
-
-
Ohio
-
Cincinnati, Ohio, United States, 45267
- University of Cincinnati
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Males and females of any race or ethnicity.
- Aged 21-40 years.
- Non-obese (BMI <28 kg/m2).
Exclusion Criteria:
- Pregnant women.
- Cigarette smoking.
- Taking inflammation-targeting steroids (e.g., prednisone).
- Taking medications targeting adrenergic signaling (e.g., beta-blockers, bronchodilators).
- Abnormal hematocrit or electrolyte levels.
- The presence of cardiovascular or peripheral vascular disease.
- The presence of neuropathy, retinopathy or nephropathy.
- Any metal in the body that would make magnetic resonance spectroscopy dangerous.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Controls-saline
Each subject from Group 1 will undergo a metabolic study where saline is infused so as to not stimulate liver glucose uptake and glycogen deposition.
|
Saline given as a comparison to fructose.
IV infusion of somatostatin (60 ng/kg/min)
Other Names:
IV infusion of insulin between 20-60 mU/m2/min.
IV glucagon (0.65 ng/kg/min).
IV dextrose to clamp the plasma glucose at the desired level.
Other Names:
|
Active Comparator: Controls-high fructose
A second group of control subjects will undergo a single metabolic study using a higher dose of fructose (6.5 mg/kg/min).
|
IV infusion of somatostatin (60 ng/kg/min)
Other Names:
IV infusion of insulin between 20-60 mU/m2/min.
IV glucagon (0.65 ng/kg/min).
IV dextrose to clamp the plasma glucose at the desired level.
Other Names:
IV fructose (1.3 mg/kg/min)
|
Active Comparator: Controls-low fructose
Each subject from Group 1 will undergo another metabolic study where fructose (1.3 mg/kg/min) is infused so as to stimulate liver glucose uptake and glycogen deposition.
|
IV infusion of somatostatin (60 ng/kg/min)
Other Names:
IV infusion of insulin between 20-60 mU/m2/min.
IV glucagon (0.65 ng/kg/min).
IV dextrose to clamp the plasma glucose at the desired level.
Other Names:
IV-fructose (6.5 mg/kg/min)
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Epinephrine
Time Frame: 2 hours
|
Hormone
|
2 hours
|
Glucagon
Time Frame: 2 hours
|
Hormone
|
2 hours
|
Glucose Infusion Rate
Time Frame: 2 hours
|
Whole-body responses
|
2 hours
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Liver Glycogen
Time Frame: 2 hours
|
Amount of sugar stored in the liver
|
2 hours
|
Hepatic Glucose Production
Time Frame: 2 hours
|
Amount of glucose released
|
2 hours
|
Peripheral Glucose Uptake
Time Frame: 2 hours
|
Amount of glucose being metabolized
|
2 hours
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Jason Winnick, PhD, University of Cincinnati
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2016-7982
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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