Effect of Pulsatile IV Insulin on Circulating Risk Markers of Vascular and Metabolic Complications in Pts With Diabetes

Insulin produces vasodilatory, anti inflammatory and anti thrombotic effects (1-4). .
However the effects of pulsatile intravenous insulin delivery on circulating risk factors
for vascular and metabolic disease is unknown. This study is used to evaluate circulating
risk markers of vascular and metabolic disease compared to a matched control group.

Protocol Patients selected have diabetes mellitus, 20 years of age and older, and are
treated with oral agents and/or insulin. The study is for a minimum of 12 months and may
continue for 2-3 years if a significant difference is shown following the initial 12 months.
Blood markers will be determined every 12 months for the first year, and every 12 months
after that. They may include the following: BNP, fructosamine, PAI-1, fibrinogen,
homocysteine, endothelin 1, aldosterone, VCAM, ICAM, IGF-1, TGF-beta, TNF-alpha, hs-CRP, and
IL-6). The results are compared to an age and fructosamine matched control group.

Endpoints; Changes in markers Statistics: ANOVA Blood: 2 purple, 2 red, 2 blue tops

The respiratory quotient (RQ) is a measurement of CO2 exhaled and O2 inhaled and is
proportionate to the fuel sources being used by the body, primarily the liver over short
periods of time. The higher the RQ, the more glucose and less alternative fuel sources are
being utilized. Following the RQ change helps determine the effectiveness of physiological
insulin administration in increasing anabolic functions in diabetic individuals. By
improving the body's glucose metabolism and thereby causing beneficial effects of anabolic
factors, the possibility of serious complications can be decreased. In addition the use of
oral carbohydrate at the same time along with the physiologic insulin administration
stimulates the appropriate gut hormones which augment this effect, a response which cannot
be duplicated with intravenous glucose. The purpose of our studies is to determine whether
the physiologic administration of pulsatile intravenous insulin along with the augmenting
effect of oral carbohydrates will normalize metabolism in diabetic patients and improve
their quality of life indices.

The RQ is determined by the use of a metabolic cart. Individuals breathe into a mask for 3-5
minutes after a rest period of 30 or more minutes. The ratio of exhaled volume of CO2 to the
inhaled volume of O2 is determined as the RQ. The physiologic range is 0.7 to1.3.
Individuals using fat as a primary fuel have a ratio of 0.7, protein or mixed fuels is
0.8-0.9 and carbohydrate is 0.9-1.0. Those taking excessive calories will have RQ's higher
than 1.05. The RQ can be followed serially and this is done twice, before and after each
treatment, during the 3 successive sessions on a single treatment day. The amount of
intravenous insulin and oral glucose given is determined by the RQ changes during the
previous session.

Pusatile intravenous insulin delivery is a process which encourages the glucose metabolism
in diabetics to normalize in multiple organs, especially muscle, retina, liver, kidney and
nerve endings. The process fundamentally requires the administration of high dose
intravenous insulin pulses similar to those found in non diabetic humans by their pancreas
into the surrounding portal circulation. Oral carbohydrates are given simultaneously to
augment the process and prevent hypoglycemia. The process is monitored by frequent glucose
level measurements and respiratory quotients (RQ). RQ is measured by a metabolic cart which
determines the ratio VCO2/ VO2. This ratio is specific for the fuel used at any one time by
the body. The glucose levels are monitored to keep glucose levels appropriate and the RQ
determines the need to readjust the infusion protocol in each patient for subsequent insulin
infusion sessions. Pulsatile intravenous insulin delivery is done over 1-hour periods with a
up to a 1-hour rest period between each session for three courses each day of activation.

References:

Katakam PVG, Tulbert CD, Snipes JA, Erdos B, Miller AW, Busija DW, Impaired Insulin-induced
Vasodilation in Small Coronary Arteries of Zucker Obese rats is Mediated by Reactive Oxygen
Species, AJP-Heart 288:854-60, 2005.

Chakraborty K Sinha AK, The Role of Insulin as an Antithrombotic Humoral Factor, BioEssays
26:91-98, 2003.

Elias AN, Eng S, Homocysteine Concentrations in Patients with Diabetes Mellitus-Relationship
to Microvascular and Macrovascular Disease, Diabetes, Obesity and Metabolism 7:117-21, 2005.

Patiag D, Qu X, Gray S, Idris I, Wilkes M, Seale JP, Donnely R, Possible Interactions
between Angiotensin II and Insulin:Effects on Glucose and Lipid Metabolism in vivi and in
vitro, Journal of Endocrinology 167: 525-31, 2000

Inclusion Criteria:

- We will include up to 500 patients both male and female over the age of 21 diagnosed
with type 1 or type 2 diabetes mellitus

- All patients must have secondary complications caused by the diabetes and not
responding to conventional medical management

- Under an Endocrinologists supervision for their diabetes management

- Endocrinologist must assess and approve patient for participation in this study

- Ability to swallow without difficulty

- Ability to commit to the weekly time requirements associated with the study

Exclusion Criteria:

- Other causes of complications not related to diabetes

- Lack of intravenous access

- Pregnancy

- Alcohol abuse, drug addiction or the use of illegal drugs

- Positive HIV

- Inability to perform breathe into machine for respiratory quotients