Insulin Secretion in Diabetes

The objective of this project is to understand defects in insulin secretion that contribute
to abnormal glucose metabolism in patients with diabetes. Diabetes is a major problem for
patients receiving care at VA medical centers among whom 20% are affected. Specifically,
this project will seek to determine the mechanism(s) by which the incretin effect is
impaired in diabetic patients. The incretin effect refers to the action of GI hormones and
neural stimuli to increase insulin secretion after food intake, and accounts for
approximately 50% of postprandial insulin secretion in nondiabetic humans. There are
several studies indicating that this response is severely impaired in patients with type 2
diabetes. The mechanism(s) by which this occurs has not been explained. There is some
evidence to suggest that secretion of the important incretins, glucagon-like peptide 1
(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), may be impaired in diabetic
individuals. There is also some data to suggest that the -cells in persons with diabetes
are insensitive to the incretins. The problem with the current state of knowledge in this
area is that previous work has involved small numbers of diabetic subjects, and did not
directly test mechanisms by which the incretin effect is altered in diabetes.

In this project we will: 1) determine the role of reduced GIP and GLP-1 levels in mediating
postprandial insulin secretion in diabetic subjects. Subjects with type 2 diabetes and
nondiabetic controls will have the incretin effect measured on separate occasions using test
meals that cause different levels of circulating incretins. This will allow the role of
reduced incretin levels in diabetes to be assessed; 2) determine the role of endogenous
GLP-1 to stimulate insulin secretion in diabetic subjects. Subjects with type 2 diabetes and
nondiabetic controls will have the incretin effect measured on two occasions, with and
without infusion of a GLP-1 receptor antagonist. This study will compare the role of GLP-1
signaling to stimulate postprandial insulin secretion in diabetic and nondiabetic humans; 3)
determine the role of hyperglycemia to impair the incretin effect. Groups of type 2
diabetic subjects will have the incretin effect measured before and after intensified
diabetes treatment. This study will test the effect of chronic hyperglycemia on incretin
mediated insulin secretion. In all studies, the incretin effect will be measured before and
after these interventions using studies with a within subjects design. A combined glucose
clamp/meal tolerance test protocol will be used to quantify the incretin effect.

These studies will allow the role of incretin secretion, incretin action, and overall
metabolic milieu, on postprandial insulin secretion to be defined. The results of these
studies will add important new information for understanding abnormal -cell function in
diabetes. By identifying the sites where the incretin effect is impaired this project will
provide the basis for new approaches to treat diabetic patients. This is especially
relevant with the recent availability of new medications that target the incretin pathways
to lower blood glucose.

The blood samples will be drawn and processed in the GCRC. The samples will be frozen and
stored in Building 15, Room 401. Samples will be shipped to the Genome Research Institute
by staff trained in IATA shipping procedures.

Inclusion Criteria:

- Aim 1:

- (non-diabetics)

- male/female 30-65 yrs old,

- free of active medical disease,

- no history of diabetes.

- (diabetics)

- HbA1c=6.5-8.5,

- treated with metformin, a sulfonylurea, or combination,

- Stable body wt with BMI 28-40.

- Aim 2: Same as above

- Aim 3: Diabetic with HgA1c 8.0-9.5

Exclusion Criteria:

- Aim 1: For both groups: no history of: pancreatitis, cardiac, gastrointestinal, renal
or liver disease.

- Aim 2: Same as above

- Aim 3: Same as above, plus a diagnosis of incipient diabetic nephropathy severe
nonproliferative, or proliferative retinopathy.