Medical Student Research Fellowship for Summer 2003

Mentor: Philip Raskin, M.D.
Department: Internal Medicine
Room number: G5.238
Mail Code: 8858
Phone number: (214)648-2017
E-mail: Philip.Raskin@UTSouthwestern.edu
Project Title: Comparison of the Inhibitory Effects of Prolonged Hyperglycemia on Insulin Secretion in Idiopathic Type 1 and Type 2 Diabetes
Human subjects IRB approved project number: 0403-241
Project Type: patient-based research
Brief Description of Project:
I. Purpose: To further explore the differences between idiopathic type 1 and type 2 diabetes, specifically what makes the first group prone to unprovoked ketosis and/or ketoacidosis while those with typical type 2 diabetes are not.
II. Background: The new diabetes nomenclature acknowledges idiopathic type 1 diabetes mellitus as insulin-requiring diabetes without markers for autoimmunity, in contrast to the "classic" type 1 diabetes which has an autoimmune etiology. While the idiopathic type 1 group biochemically resembles the "classic" type 1 group in the acute setting in that they often present in diabetic ketoacidosis, phenotypically, this idiopathic group looks more like type 2 diabetes. We and others have observed that after recovery from this initial clearly defective insulin secretory stage, as well as years after presentation, people classified as having idiopathic type 1 diabetes not only resemble those with type 2 diabetes in their physical appearances, but also in terms of their insulin secretion and sensitivity.
The effects of sustained hyperglycemia (in the fasted state while on a glucose infusion) on C-peptide secretion have been studied in healthy volunteers. Significant hyperglycemia (blood glucose around 225 mg/dL) over an extended period of time (close to 72 hours) has been shown to reduce glucose-stimulated insulin secretion and cause ß-cell desensitization in non-diabetic subjects. In contrast, milder hyperglycemia for less than 72 hours is not enough to decrease insulin secretion in the same population. Recognizing that the average diabetic patient has a blood glucose in the 150-200 mg/dL range, we are interested in making an adaptation of this prolonged hyperglycemia study to address the biochemical and clinical response in obese ketosis-prone diabetic individuals, challenging them with higher than average sustained blood glucose levels. The rationale of this study is to objectively assess the insulin secretory response in idiopathic type 1 diabetes as compared to those with typical type 2 diabetes.
Our primary hypothesis is that individuals with idiopathic type 1 diabetes are more sensitive to the toxic effects of glucose on insulin secretion than are individuals with type 2 diabetes who never had ketoacidosis. Results confirming this hypothesis might result in an increased awareness within the medical community about the importance of sustained insulin therapy in idiopathic type 1 diabetes. A secondary hypothesis is that idiopathic type 1 diabetes and type 2 diabetes have a similar response to non-glucose stimuli for insulin secretion, such as the amino acid arginine.
III. Summary: This study has two steps. First, a 20% glucose solution will be
infused at a variable rate designed to keep plasma glucose concentrations at 300 mg/dL for 72 hours while subjects are in the fasting state. Insulin secretion will be assessed with C-peptide measurements every 30 minutes. Second, insulin secretion will be stimulated with L-arginine hydrochloride under hyperglycemia.

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