Pathogenesis of the Cardiometabolic Risk in Youth With Type 1 Diabetes

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.

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.

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.

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

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