Pathophysiology of Gouty Diathesis and Uric Acid Nephrolithics: Role of Insulin Resistance
Aim 1 Lvl 1
Subjects: 50 stone formers (SF), 100 type II diabetes mellitus (DM), 200 normals. Urine: 24 hour urine. 2 additional 24-hour urines and 3 spot urines will be collected. Blood: Fasting blood. Anthropometric Measurements: Height, weight, waist and hip circumference, skinfold thickness. Spectroscopy: 12 normal and 12 DM subjects will have an optional kidney MRS.
Aim 1 Lvl 2
Subjects: 30 SF, 30 type II DM, 30 normals. Diet: Days 1-5, subjects will eat a frozen diet at home. Days 6-9, subjects will eat the same diet at the CTRC. Urine: Days 6 and 7, urine will be collected. Blood: Day 7, fasting blood sample. Anthropometric Measurements: As in Aim 1 Level 1. A DEXA will be done for total body fat. Spectroscopy: Optional MRS of the kidneys. Acid Load: Day 7, subjects fast overnight. Day 8, breakfast is withheld. Urine collected hourly from 7am to 1200. At 8am, NH4Cl is be given orally in up to three doses (up to 4 10mEq pills per dose) based on weight (1mEq/kg), not to exceed 120mEq and not be less than 50mEq, with 250 ml of water. Blood samples drawn. Insulin/Glucose Infusion: Day 8, subjects fast overnight. Patients with type 2 DM get an insulin-glucose infusion from 1800 to 0600 to maintain their plasma glucose. Euglycemic Clamp: Day 9, breakfast withheld. Two catheters placed intravenously; one for infusion of glucose and insulin and the other for blood sampling. At 0800, an infusion of human insulin will be started and continued for 2 hours. A 20% glucose infusion will be started after 4 minutes of insulin infusion. Blood for plasma glucose will be drawn every 5 minutes. The rate of glucose infusion will be altered based on glucose concentration. Blood will be drawn every 10 minutes from –30 to 0 and 80 to 120 minutes. Three 2-hour urine specimens will be collected from 0600 to 1200.
Subjects: 20 SF and 20 subjects with insulin resistance. Subjects are blindly randomized into two groups to receive pioglitazone, 30 mg once a day for 24 weeks, or placebo. After 12 weeks of treatment, subjects, while continuing the same treatment, will participate in weight reduction lasting 12 weeks. During weeks 12 and 24, subjects will have the same 9 day study as described in Aim 1 Level 2. Diet: During weight reduction, energy intake is calculated by subtracting a total of 750 Kcal from the daily caloric intake required to maintain a constant body weight. Urine and Blood: Visits for fasting blood samples and a 24-hour urine collection will be done at weeks 4, 8, 16, and 20.
Subjects: 3 subjects with type II DM and 3 normals. Diet: Days 1-3 – frozen diet with 100mEq Na. Days 4-6 – fresh diet with 100mEq Na. Days 6-7 – frozen diet with 150mEq Na. Days 8-9 – frozen diet with 200mEq Na. Days 10-11 – frozen diet with 300mEq Na. Day 12 – fresh diet with 300mEq Na. Urine: Day 4, a 24 hour urine collection. Day 5, urine will be collected in 4 hour intervals starting at 0600. Days 6-11 subjects will collect their urine in 24 hour pools. Day 12, a 24-hour urine collection will be obtained as an inpatient. On day 13, urine will be collected in 2 hour intervals from 0600 to 1200. Blood: Fasting labs will be obtained day 4 and day 12. Saline Infusion: A catheter will be placed day 4. Day 5, Subjects will collect urine for a 4 hour period from 0600 to 1000. Blood will be drawn at 1000 and 1400. At 1000 two liters of 0.9 % saline will be infused until 1400. Blood pressure will be monitored every 15 minutes. Urine will be collected f
Aims 1 - 6 - Age 21 or older. Aim 7 - Age between 18 and 65
Aim 1: Uric acid stone-formers: Patients with documented gouty diathesis, defined as pure uric acid or mixed uric acid/calcium oxalate nephrolithiasis. Non-stone formers with type 2 diabetes mellitus or glucose intolerance: Patients with type-2 diabetes mellitus or glucose intolerance with fasting plasma glucose 110-180mg/dl and no documented history of kidney stones who are treated with diet or oral agents alone, but are not on insulin. Normal volunteers (non-stone former, non-diabetic): Normal subjects, matched for age, gender, body mass index, ethnicity, and endogenous creatinine clearance to patients.
Aim 2: Subjects from Aim 1, who have both peripheral insulin resistance (Glucose Disposal Rate ≤ 6 mg/min/kg by the euglycemic study) and defective ammonium excretion (to be defined from percentiles from Aim 1 results).
Aim 3: Normal subjects with normal insulin sensitivity as determined by the euglycemic clamp study in Aim 1. Aim 4: Normal subjects will be included in
Aim 4. Inclusion criteria are as in Aim 1.
Aim 5: Patients that have undergone a renal transplant will be included. These subjects will have no history of diabetes mellitus and have a fasting blood glucose < 110mg/dL. The BMI will be > 18.5 kg/m2. Subjects will have intact renal function with a serum creatinine < 2 mg/dl.
Aim 6: Normal subjects and diabetic patients with newly diagnosed type-2 diabetes mellitus or impaired glucose tolerance as defined in Aim 1.
Aim 7: Hypercalciuric calcium stone formers and normal subjects.