Liver Glycogen and Hypoglycemia in Humans

May 1, 2020 updated by: Jason Winnick

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

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

Interventional

Enrollment (Anticipated)

40

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • Ohio
      • Cincinnati, Ohio, United States, 45267
        • Recruiting
        • University of Cincinnati
        • Contact:
          • Rebecca Cason, BS

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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:
  • SRIF
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.
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:
  • SRIF
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.
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:
  • SRIF
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.
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

This is where you will find people and organizations involved with this study.

Sponsor

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 2, 2018

Primary Completion (Anticipated)

May 31, 2022

Study Completion (Anticipated)

May 31, 2022

Study Registration Dates

First Submitted

August 4, 2017

First Submitted That Met QC Criteria

August 4, 2017

First Posted (Actual)

August 7, 2017

Study Record Updates

Last Update Posted (Actual)

May 5, 2020

Last Update Submitted That Met QC Criteria

May 1, 2020

Last Verified

May 1, 2020

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

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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