Pathogenesis of the Cardiometabolic Risk in Youth With Type 1 Diabetes

NCT ID: NCT04101045

Last Updated: 2023-02-13

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: NA
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-21
• Study Completion Date: 2022-03-30

Brief Summary

The purpose of this study is to quantitate hepatic de novo lipogenesis (DNL) in youth with poorly-controlled type 1 diabetes (T1D) (HbA1c >8.5%), youth with T1D who achieve targeted glycemic control (HbA1c <7.5%) and lean controls. Hypothesis: Youth with poor glycemic control experience higher fractional hepatic DNL during the fasting and the postprandial states than youth who achieve targeted glycemic control and lean controls.

Detailed Description

What is not known, is whether hepatic de novo lipogenesis (DNL) contributes to dyslipidemia in this in patients with type 1 diabetes (T1D). The aim of the study is to test the hypothesis that an enhanced rate of DNL largely contributes to dyslipidemia occurring in youth with poorly-controlled T1D. According to this hypothesis, youth with poorly-regulated T1D experience a state of persistent insulin independent, highly variable fluctuations of glucose, and other sugars, through the glycolytic pathway that result in an enhancement of hepatic DNL and an increased production of triglycerides (TG). Newly-formed TG are packaged into large-VLDL that are secreted into the circulation contributing to an increase in plasma TG. When the TG concentration in the hepatocytes exceeds the ability of the liver to secrete TG, the latter start accumulating leading to hepatic steatosis.

Conditions

Type 1 Diabetes; De Novo Lipogenesis

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Poorly-controlled T1D

Patients in this group will have poorly-controlled T1D (HbA1c \>8.5%).

Group Type: ACTIVE_COMPARATOR

Oral Glucose Tolerance Test

Intervention Type: DIAGNOSTIC_TEST

Each participant consumes a dinner scaled to his/her energy needs which is prepared by the metabolic kitchen. Dinner will be provided beforehand if patient does this portion at home. The participant consumes the first of three doses of D2O. Two additional doses of D20 are given at on day 1 and on day 2. The total D2O given (3 ml per kg of body water) is designed to raise body deuterium levels to 0.3% and is administered as described above to maintain steady state until the end of the study. At the HRU, an IV catheter will be inserted in order to collect blood to assess DNL. Blood draws begin during the fasting state to assess basal rates of DNL and then for six hours after the consumption of a glucose/fructose beverage (75g glucose and 25g fructose ) to assess postprandial rates of DNL. Blood draws will be taken 15 minutes before ingestion of the sugar beverage, then for every half hour for 6 hours.

Controlled T1D

Patients in this group will have T1D and achieve targeted glycemic control (HbA1c \<7.5%).

Group Type: ACTIVE_COMPARATOR

Oral Glucose Tolerance Test

Intervention Type: DIAGNOSTIC_TEST

Each participant consumes a dinner scaled to his/her energy needs which is prepared by the metabolic kitchen. Dinner will be provided beforehand if patient does this portion at home. The participant consumes the first of three doses of D2O. Two additional doses of D20 are given at on day 1 and on day 2. The total D2O given (3 ml per kg of body water) is designed to raise body deuterium levels to 0.3% and is administered as described above to maintain steady state until the end of the study. At the HRU, an IV catheter will be inserted in order to collect blood to assess DNL. Blood draws begin during the fasting state to assess basal rates of DNL and then for six hours after the consumption of a glucose/fructose beverage (75g glucose and 25g fructose ) to assess postprandial rates of DNL. Blood draws will be taken 15 minutes before ingestion of the sugar beverage, then for every half hour for 6 hours.

Lean controls

Patients in this group will not have T1D.

Group Type: ACTIVE_COMPARATOR

Oral Glucose Tolerance Test

Intervention Type: DIAGNOSTIC_TEST

Each participant consumes a dinner scaled to his/her energy needs which is prepared by the metabolic kitchen. Dinner will be provided beforehand if patient does this portion at home. The participant consumes the first of three doses of D2O. Two additional doses of D20 are given at on day 1 and on day 2. The total D2O given (3 ml per kg of body water) is designed to raise body deuterium levels to 0.3% and is administered as described above to maintain steady state until the end of the study. At the HRU, an IV catheter will be inserted in order to collect blood to assess DNL. Blood draws begin during the fasting state to assess basal rates of DNL and then for six hours after the consumption of a glucose/fructose beverage (75g glucose and 25g fructose ) to assess postprandial rates of DNL. Blood draws will be taken 15 minutes before ingestion of the sugar beverage, then for every half hour for 6 hours.

Interventions

Oral Glucose Tolerance Test

Each participant consumes a dinner scaled to his/her energy needs which is prepared by the metabolic kitchen. Dinner will be provided beforehand if patient does this portion at home. The participant consumes the first of three doses of D2O. Two additional doses of D20 are given at on day 1 and on day 2. The total D2O given (3 ml per kg of body water) is designed to raise body deuterium levels to 0.3% and is administered as described above to maintain steady state until the end of the study. At the HRU, an IV catheter will be inserted in order to collect blood to assess DNL. Blood draws begin during the fasting state to assess basal rates of DNL and then for six hours after the consumption of a glucose/fructose beverage (75g glucose and 25g fructose ) to assess postprandial rates of DNL. Blood draws will be taken 15 minutes before ingestion of the sugar beverage, then for every half hour for 6 hours.

Intervention Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

• HbA1c >8.5% for the group with poorly controlled diabetes
• HbA1c <7.5% for the well-controlled patients
• T1D for at least 12 months (T1D groups only)
• Negative pregnancy test (all groups)

Exclusion Criteria

• Baseline creatinine >1
• Being on medications affecting glucose concentrations other than insulin
• Positive pregnancy test
• Endocrinopathies

• Minimum Eligible Age: 13 Years
• Maximum Eligible Age: 22 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Juvenile Diabetes Research Foundation

OTHER

Sponsor Role: collaborator

Yale University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nicola Santoro, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Assistant Professor of Pediatrics (Endocrinology)

Locations

Yale University School of Medicine

New Haven, Connecticut, United States

Countries

United States

References

Monga Kravetz A, Testerman T, Galuppo B, Graf J, Pierpont B, Siebel S, Feinn R, Santoro N. Effect of Gut Microbiota and PNPLA3 rs738409 Variant on Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Youth. J Clin Endocrinol Metab. 2020 Oct 1;105(10):e3575-85. doi: 10.1210/clinem/dgaa382.

Reference Type: DERIVED

PMID: 32561908 (View on PubMed)

Other Identifiers

2000025170

Identifier Type: -

Identifier Source: org_study_id