Ignite Creation Date:
2025-12-26 @ 2:38 PM
Ignite Modification Date:
2026-01-01 @ 1:02 AM
Study NCT ID:
NCT03241706
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2025-07-25
First Post:
2017-08-04
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Liver Glycogen and Hypoglycemia in Humans
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D007003', 'term': 'Hypoglycemia'}, {'id': 'D003922', 'term': 'Diabetes Mellitus, Type 1'}], 'ancestors': [{'id': 'D044882', 'term': 'Glucose Metabolism Disorders'}, {'id': 'D008659', 'term': 'Metabolic Diseases'}, {'id': 'D009750', 'term': 'Nutritional and Metabolic Diseases'}, {'id': 'D003920', 'term': 'Diabetes Mellitus'}, {'id': 'D004700', 'term': 'Endocrine System Diseases'}, {'id': 'D001327', 'term': 'Autoimmune Diseases'}, {'id': 'D007154', 'term': 'Immune System Diseases'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D012965', 'term': 'Sodium Chloride'}, {'id': 'D013004', 'term': 'Somatostatin'}, {'id': 'D007328', 'term': 'Insulin'}, {'id': 'D005934', 'term': 'Glucagon'}, {'id': 'D066248', 'term': 'High Fructose Corn Syrup'}], 'ancestors': [{'id': 'D002712', 'term': 'Chlorides'}, {'id': 'D006851', 'term': 'Hydrochloric Acid'}, {'id': 'D017606', 'term': 'Chlorine Compounds'}, {'id': 'D007287', 'term': 'Inorganic Chemicals'}, {'id': 'D017670', 'term': 'Sodium Compounds'}, {'id': 'D010905', 'term': 'Pituitary Hormone Release Inhibiting Hormones'}, {'id': 'D007028', 'term': 'Hypothalamic Hormones'}, {'id': 'D036361', 'term': 'Peptide Hormones'}, {'id': 'D006728', 'term': 'Hormones'}, {'id': 'D006730', 'term': 'Hormones, Hormone Substitutes, and Hormone Antagonists'}, {'id': 'D010187', 'term': 'Pancreatic Hormones'}, {'id': 'D009479', 'term': 'Neuropeptides'}, {'id': 'D010455', 'term': 'Peptides'}, {'id': 'D000602', 'term': 'Amino Acids, Peptides, and Proteins'}, {'id': 'D009419', 'term': 'Nerve Tissue Proteins'}, {'id': 'D011506', 'term': 'Proteins'}, {'id': 'D011384', 'term': 'Proinsulin'}, {'id': 'D061385', 'term': 'Insulins'}, {'id': 'D052336', 'term': 'Proglucagon'}, {'id': 'D000073417', 'term': 'Dietary Sugars'}, {'id': 'D004040', 'term': 'Dietary Carbohydrates'}, {'id': 'D002241', 'term': 'Carbohydrates'}, {'id': 'D000073893', 'term': 'Sugars'}, {'id': 'D064427', 'term': 'Nutritive Sweeteners'}, {'id': 'D013549', 'term': 'Sweetening Agents'}, {'id': 'D005421', 'term': 'Flavoring Agents'}, {'id': 'D005503', 'term': 'Food Additives'}, {'id': 'D000074385', 'term': 'Food Ingredients'}, {'id': 'D020313', 'term': 'Specialty Uses of Chemicals'}, {'id': 'D020164', 'term': 'Chemical Actions and Uses'}, {'id': 'D005502', 'term': 'Food'}, {'id': 'D000066888', 'term': 'Diet, Food, and Nutrition'}, {'id': 'D010829', 'term': 'Physiological Phenomena'}, {'id': 'D019602', 'term': 'Food and Beverages'}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE1'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'SINGLE', 'whoMasked': ['PARTICIPANT'], 'maskingDescription': 'The subjects will not be informed which treatment they will receive for a given trial.'}, 'primaryPurpose': 'BASIC_SCIENCE', 'interventionModel': 'CROSSOVER'}, 'enrollmentInfo': {'type': 'ESTIMATED', 'count': 40}}, 'statusModule': {'overallStatus': 'ACTIVE_NOT_RECRUITING', 'startDateStruct': {'date': '2018-08-02', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2025-07', 'completionDateStruct': {'date': '2028-05-31', 'type': 'ESTIMATED'}, 'lastUpdateSubmitDate': '2025-07-23', 'studyFirstSubmitDate': '2017-08-04', 'studyFirstSubmitQcDate': '2017-08-04', 'lastUpdatePostDateStruct': {'date': '2025-07-25', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2017-08-07', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2028-05-31', 'type': 'ESTIMATED'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Epinephrine', 'timeFrame': '2 hours', 'description': 'Hormone'}, {'measure': 'Glucagon', 'timeFrame': '2 hours', 'description': 'Hormone'}, {'measure': 'Glucose Infusion Rate', 'timeFrame': '2 hours', 'description': 'Whole-body responses'}], 'secondaryOutcomes': [{'measure': 'Liver Glycogen', 'timeFrame': '2 hours', 'description': 'Amount of sugar stored in the liver'}, {'measure': 'Hepatic Glucose Production', 'timeFrame': '2 hours', 'description': 'Amount of glucose released'}, {'measure': 'Peripheral Glucose Uptake', 'timeFrame': '2 hours', 'description': 'Amount of glucose being metabolized'}]}, 'oversightModule': {'oversightHasDmc': False, 'isFdaRegulatedDrug': True, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'keywords': ['hypoglycemia', 'type 1 diabetes', 'liver glucose metabolism'], 'conditions': ['Hypoglycemia; Iatrogenic']}, 'descriptionModule': {'briefSummary': '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.\n\nPeople 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.\n\nThe investigators want to learn more about how liver sugar levels affect the ability to respond to low blood sugar.', 'detailedDescription': '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.\n\nAs 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.\n\nLiver 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.\n\nThe 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:\n\nSpecific Aim #1: To determine the effect of increasing liver glycogen deposition on insulin-induced hypoglycemic counterregulation in humans with and without T1D.\n\nThe 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.'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT'], 'maximumAge': '40 Years', 'minimumAge': '21 Years', 'healthyVolunteers': True, 'eligibilityCriteria': 'Inclusion Criteria:\n\n* Males and females of any race or ethnicity.\n* Aged 21-40 years.\n* Non-obese (BMI \\<28 kg/m2).\n\nExclusion Criteria:\n\n* Pregnant women.\n* Cigarette smoking.\n* Taking inflammation-targeting steroids (e.g., prednisone).\n* Taking medications targeting adrenergic signaling (e.g., beta-blockers, bronchodilators).\n* Abnormal hematocrit or electrolyte levels.\n* The presence of cardiovascular or peripheral vascular disease.\n* The presence of neuropathy, retinopathy or nephropathy.\n* Any metal in the body that would make magnetic resonance spectroscopy dangerous.'}, 'identificationModule': {'nctId': 'NCT03241706', 'briefTitle': 'Liver Glycogen and Hypoglycemia in Humans', 'organization': {'class': 'OTHER', 'fullName': 'University of Cincinnati'}, 'officialTitle': 'Effect of Liver Glycogen Content on Hypoglycemic Counterregulation', 'orgStudyIdInfo': {'id': '2016-7982'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'PLACEBO_COMPARATOR', 'label': 'Controls-saline', 'description': '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.', 'interventionNames': ['Drug: Saline', 'Drug: Somatostatin', 'Drug: Insulin', 'Drug: Glucagon', 'Drug: Dextrose solution']}, {'type': 'ACTIVE_COMPARATOR', 'label': 'Controls-high fructose', 'description': 'A second group of control subjects will undergo a single metabolic study using a higher dose of fructose (6.5 mg/kg/min).', 'interventionNames': ['Drug: Low Fructose', 'Drug: Somatostatin', 'Drug: Insulin', 'Drug: Glucagon', 'Drug: Dextrose solution']}, {'type': 'ACTIVE_COMPARATOR', 'label': 'Controls-low fructose', 'description': '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.', 'interventionNames': ['Drug: Somatostatin', 'Drug: Insulin', 'Drug: Glucagon', 'Drug: Dextrose solution', 'Drug: High Fructose']}], 'interventions': [{'name': 'Low Fructose', 'type': 'DRUG', 'description': 'IV fructose (1.3 mg/kg/min)', 'armGroupLabels': ['Controls-high fructose']}, {'name': 'Saline', 'type': 'DRUG', 'description': 'Saline given as a comparison to fructose.', 'armGroupLabels': ['Controls-saline']}, {'name': 'Somatostatin', 'type': 'DRUG', 'otherNames': ['SRIF'], 'description': 'IV infusion of somatostatin (60 ng/kg/min)', 'armGroupLabels': ['Controls-high fructose', 'Controls-low fructose', 'Controls-saline']}, {'name': 'Insulin', 'type': 'DRUG', 'description': 'IV infusion of insulin between 20-60 mU/m2/min.', 'armGroupLabels': ['Controls-high fructose', 'Controls-low fructose', 'Controls-saline']}, {'name': 'Glucagon', 'type': 'DRUG', 'description': 'IV glucagon (0.65 ng/kg/min).', 'armGroupLabels': ['Controls-high fructose', 'Controls-low fructose', 'Controls-saline']}, {'name': 'Dextrose solution', 'type': 'DRUG', 'otherNames': ['d20'], 'description': 'IV dextrose to clamp the plasma glucose at the desired level.', 'armGroupLabels': ['Controls-high fructose', 'Controls-low fructose', 'Controls-saline']}, {'name': 'High Fructose', 'type': 'DRUG', 'description': 'IV-fructose (6.5 mg/kg/min)', 'armGroupLabels': ['Controls-low fructose']}]}, 'contactsLocationsModule': {'locations': [{'zip': '45267', 'city': 'Cincinnati', 'state': 'Ohio', 'country': 'United States', 'facility': 'University of Cincinnati', 'geoPoint': {'lat': 39.12711, 'lon': -84.51439}}], 'overallOfficials': [{'name': 'Jason Winnick, PhD', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'University of Cincinnati'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'NO'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Jason Winnick', 'class': 'OTHER'}, 'responsibleParty': {'type': 'SPONSOR_INVESTIGATOR', 'investigatorTitle': 'Assistant Professor', 'investigatorFullName': 'Jason Winnick', 'investigatorAffiliation': 'University of Cincinnati'}}}}