Tissue-Specific Metabolic Reprogramming in Diabetic Complications

Objective: To assess steady state and dynamic metabolite changes in subjects with type 1
diabetes with and without microvascular complications and to understand intrinsic differences
from non-diabetics in metabolite levels and flux.

The hypothesis is that diabetic complications arise from tissue-specific metabolic
reprogramming resulting in alterations in fuel utilization which lead to dysfunction of the
tissue. To test this hypothesis, we will use sensitive and specific mass spectrometer based
metabolomic analysis to measure steady state metabolite levels in plasma and urine from
controls subjects and subjects with T1DM, without and with diabetic complications during
euglycemic and hyperglycemic clamp studies.

Group 1: T1DM subjects without complications:

Group 2: T1DM subjects with microalbuminuria . Group 3: T1DM subjects with advanced
diabetes complications Group 4: Age-and-sex-matched healthy control subjects .

Inclusion Criteria:

General entry criteria:

Must have type 1 diabetes > 5 years duration. 18 years of age or older

Subjects in the microalbuminuria group will have a history of urinary microalbumin to
creatinine ration between 30-300 m/g confirmed on repeat testing while the non-albuminuric
group will have a value of less than 30 mg/g.

Subjects in advanced complications group will have confirmed Retinopathy, Peripheral and/or
Autonomic Neuropathy and nephropathy.

Non diabetic individuals will be matched for age and gender and will have normal glucose
tolerance, normal lipid metabolism, and normal blood pressure.

Exclusion Criteria:

Age less than 18 . Women of child-bearing potential who may be pregnant or lactating
History of pancreas, kidney or liver transplant History of drug or alcohol use. History of
cancer other than basal cell carcinoma or squamous cell skin cancer. Presence of a
condition that in the opinion of the investigator would make it unlikely for the subject to
complete the study.