PET Scan Imaging of Beta Cell Mass

Both Type 1 and Type 2 diabetes (T1DM and T2DM) develop when there is impaired insulin production. The amount of insulin that can be produced, the amount of insulin producing beta cells in thepancreas and level of insulin and glucose in the blood are, however, imperfectly correlated. The development of a reliable method to noninvasively quantitate the beta cell mass (BCM) would be of great benefit by providing an important endpoint for the development of new treatments of T1DM and T2DM. We have previously identified a specific marker on islet cells called VMAT2 that we now propose to use in positron emission tomography (P.E.T.) scanning to determine islet cell mass. This radioligand, [11C]DTBZ, has been used previously in human subjects in clinical trials evaluating P.E.T scanning of the brain in patients with bipolar illness and schizophrenia compared to healthy control subjects. We hypothesize that P.E.T scans will be able to differentiate between normal, reduced or increased BCM in human subjects. Subjects with normal BCM will be recruited from among normal weight nondiabetic people with plasma insulin levels within the normal range. Subjects with predicted reduced BCM will be recruited from among patients with T1DM who have with low or not measurable insulin levels. If results from the nondiabetic subjects and the subjects with T1DM are found to differ significantly, subjects with increased BCM will be recruited from among patients with hyperinsulinemia including those with obesity and the metabolic syndrome. PET scan measurements of the pancreas will be obtained and compared in people predicted, on the basis of biochemical testing, to have normal or reduced, or increased BCM.

An important determinant of progression to diabetes is beta cell mass (BCM). Measurement of plasma insulin has been used as a surrogate marker but insulin levels often do not correlate well with beta cell mass and development of means to assess BCM would provide an important endpoint. For example, highrisk individuals could be monitored prior to onset of diabetes or patients could be monitored prospectively to determine the progression of their disease and response to therapy. We have previously identified a specific marker on beta cells called VMAT2. We propose to use a radioligand, [11C]DTBZ, that binds to VMAT2 in positron emission tomography (P.E.T.) scanning to assess whether P.E.T. can measure beta cell masses. This radioligand, [11C]DTBZ, has been used previously in human subjects in clinical trials evaluating P.E.T scanning of the brain in patients with bipolar illness and schizophrenia compared to healthy control subjects. We hypothesize that P.E.T. with [11C]DTBZ will differentiate between normal, reduced or increased beta cell mass in human subjects. Subjects with predicted normal beta cell mass will be recruited from among normal weight nondiabetic people with plasma insulin levels within the normal range. Subjects with predicted reduced beta cell mass will be recruited from among patients with Type 1 diabetes who have low or not measurable insulin levels. Subjects with predicted increased beta cell mass will be recruited from among obese nondiabetic patients with hyperinsulinemia. Measurements of [11C]DTBZ uptake in the pancreas will be obtained and compared in the study population.

Potential subjects with diabetes will be recruited from among the patients cared for at the Naomi Berrie Diabetes Center. Nondiabetic subjects will either be referred by their physicians or by word of mouth. Primary care physicians will be made aware of the study by fliers.

• Type 1 Diabetes
• Obesity

• A. Healthy Controls
  subjects w/ predicted normal BCM (healthy, normalweight, nondiabetic individuals who have stimulated insulin and cpeptide levels within the normal range);
• B. Longstanding T1D
  subjects with predicted reduced beta cell mass (subjects with established T1DM who have low or not measurable stimulated insulin and c peptide levels);
• C. Obese Subjects
  subjects with predicted increased beta cell mass (euglycemic obese subjects with fasting hyperinsulinemia).

• Souza F, Simpson N, Raffo A, Saxena C, Maffei A, Hardy M, Kilbourn M, Goland R, Leibel R, Mann JJ, Van Heertum R, Harris PE. Longitudinal noninvasive PET-based beta cell mass estimates in a spontaneous diabetes rat model. J Clin Invest. 2006 Jun;116(6):1506-13. Epub 2006 May 18.
• Simpson NR, Souza F, Witkowski P, Maffei A, Raffo A, Herron A, Kilbourn M, Jurewicz A, Herold K, Liu E, Hardy MA, Van Heertum R, Harris PE. Visualizing pancreatic beta-cell mass with [11C]DTBZ. Nucl Med Biol. 2006 Oct;33(7):855-64.
• Murthy R, Harris P, Simpson N, Van Heertum R, Leibel R, Mann JJ, Parsey R. Whole body [11C]-dihydrotetrabenazine imaging of baboons: biodistribution and human radiation dosimetry estimates. Eur J Nucl Med Mol Imaging. 2008 Apr;35(4):790-7. Epub 2007 Dec 4.

Inclusion Criteria:

Potential participants must meet all of the following inclusion criteria:

1. Informed consent obtained from participants
2. Age 18-45 years
3. Healthy nondiabetic subjects will have normal fasting blood sugar (<100 mg/dl), BMI 18.5-24.9, no history of type 2 diabetes in first degree relative
4. Type 1 diabetes defined by: ADA criteria or judgment of physician; diabetes onset younger than age 18, duration >5 - years, BMI 18.5-24.9. Insulin dose <0.8 units/kg/day. Fasting cpeptide < 0.1 ng/ml
5. Obese hyperinsulinemic subjects will have BMI > 30 and fasting insulin>20 and cpeptide> 4.6 ng/ml and normal fasting blood sugar <100 mg/dl.
6. Able to tolerate PET imaging: not claustrophobic, able to lie supine for 1.5 hours
7. Normal liver and renal function tests including normal spot urine microalbumin/creatinine; normal CBC including hematocrit >31.8% in women, >36.7% in men, WBC count >3.4 K/mm3 and platelet count >162 K/mm3
8. Adequate collateral circulation in the wrist as assessed by Allen Test.

Exclusion Criteria:

Potential participants must not have any of the following exclusion criteria:

1. Previous or current treatment with drugs influencing beta cell function or insulin sensitivity (e.g. oral hypoglycemic agents, glucocorticoids); or with antipsychotic, antianxiety, or antidepressant medications (eg MAO inhibitors, 5HT inhibitors, tricyclic antidepressants); or treatment with reserpine; or treatment with beta2receptor agonists (eg, terbutaline); or treatment with anticoagulant medication.
2. History of movement disorder such as Parkinson's Disease or Huntington's Disease
3. History of or psychiatric illness such as depression, bipolar disease, anxiety or schizophrenia.
4. If a female of childbearing age, currently pregnant, breastfeeding or not using a form of birth control
5. Previous or current use of cocaine, methamphetamine, ecstasy ( MDMA, 34 methylenedioxymethamphetamine)
6. Current daily intake of caffeine >500 mg/day (>45 cups of coffee; >10 12oz cans of soda)
7. Current history of cigarette smoking
8. Consumption of more than 1 alcoholic drink per day
9. Evidence of chronic infection
10. History of malignancy
11. Any prior participation in other research protocols within the past year that involve radiation, with the exception of plain radiography studies (i.e., chest xrays).
12. Medical implant -