Clinical Effects of Pulsatile Insulin Delivery on Cognitive Function- Phase 1

NCT ID: NCT00228865

Last Updated: 2016-08-10

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-06-30
• Study Completion Date: 2009-08-31

Brief Summary

To determine if restoring normal metabolic function in patients with either Type I or Type II Diabetes can improve overall cognitive function. Patients are treated once a week with pulsatile intravenous insulin therapy mimicking normal insulin secretion and high amounts of oral glucose consumption.

Detailed Description

It is known that the glucose metabolic pathway (glycolysis) is the primary fuel generator in the brain and nerve tissue, the heart and vascular tissue, the eye, the kidney and the liver Deficient metabolic states such as seen in the glucose metabolism of diabetics can lead to sequelae. These damaging effects are exacerbated by altered cellular metabolites, specifically the increase in catabolic and decrease in anabolic factors. It has been shown over the past twenty years that normalization of metabolism in diabetic patients can be accomplished by mimicking the normal endogenous insulin pattern (ie., in pulses). Pulsatile insulin infusion has been demonstrated to reverse the diabetic metabolic state from primary fat utilization to carbohydrate utilization. This has been correlated with a stabilization of kidney function in patients with overt diabetic nephropathy, stabilization of blood glucoses, stabilization of blood pressure patterns, and reversal of hypoglycemic unawareness.

In patients with cognitive disorders (Alzheimer's type), infusion of intravenous insulin over a short interval (hours) improves cognitive function. Patients with this type of disorder have fewer insulin receptors in the affected areas of brain and insulin resistance by measurement of insulin and glucose levels in spinal fluid. This study is designed to study the effects of Pulsatile insulin on patients with diabetes mellitus and impaired cognitive function.

Diabetic individuals without other primary causes of cognitive impairment (brain tumor, previous neurosurgery, medications impairing memory) and able to swallow without difficulty will undergo pulsatile insulin treatments weekly over a period of 6-12 months with renewals for successive six month periods. Serial cognitive studies using Mindstream testing, Wechsler Memory Scale II and other localizing cognitive function tests will be done before the start of of treatment and every 3 months thereafter.This study began in 2002 and is continuing.

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 induce the physiologic administration of insulin along with the augmenting effect of oral carbohydrates, and by returning the normal fuel and organ metabolism as noted by RQ changes, evaluate its effectiveness in altering the deleterious effects on bodily functions in diabetic individuals.

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 before and after each treatment. Three treatments are given during each visit to the center. The amount of intravenous insulin and oral glucose given is determined by the RQ changes during the previous treatment.

The treatment 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 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 levels 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.

Conditions

Diabetes Mellitus

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

Testing performed on diabetic patients with decline in cognitive function at baseline and quarterly after the start of receiving pulsatile intravenous insulin therapy to assess continuing cognitive function ability.

Group Type: EXPERIMENTAL

Pulsatile IV insulin therapy

Intervention Type: PROCEDURE

Diabetic pts are given pulsatile iv insulin on a weekly basis determined by weekly phys orders based on pt response and insulin resistance. Cognitive testing is performed quarterly to track progress

Effects of Pulsatile IV Insulin on Cognitive functions

Intervention Type: PROCEDURE

Diabetic patients receive weekly treatment of Pulsatile Intravenous Insulin therapy. Dosage is determined each week by the patient's Endocrinologist based upon the patient's response and insulin resistance.

Interventions

Pulsatile IV insulin therapy

Diabetic pts are given pulsatile iv insulin on a weekly basis determined by weekly phys orders based on pt response and insulin resistance. Cognitive testing is performed quarterly to track progress

Intervention Type: PROCEDURE

Effects of Pulsatile IV Insulin on Cognitive functions

Diabetic patients receive weekly treatment of Pulsatile Intravenous Insulin therapy. Dosage is determined each week by the patient's Endocrinologist based upon the patient's response and insulin resistance.

Intervention Type: PROCEDURE

Other Intervention Names

Insulin includes Humulin, Humulog, Novolog and Epidra; Humulin, Humulog

Eligibility Criteria

Inclusion Criteria

• diagnosed with type 1 or type 2 diabetes mellitus.
• Self reporting or diagnosed with memory changes
• Taking oral agents and/or insulin for diabetic control
• Under Endocrinologist's supervision for 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 cognitive impairment not related to diabetes
• Inability to take cognitive testing
• Lack of intravenous access
• Pregnancy
• Alcohol abuse, drug addiction or the use of illegal drugs
• Positive HIV
• Inability to breathe into machine for respiratory quotients

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Advanced Diabetes Treatment Centers

OTHER

Sponsor Role: collaborator

Florida Atlantic University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Betty Tuller, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Florida Atlantic University

Locations

Florida Atlantic University

Boca Raton, Florida, United States

Countries

United States

References

Hammond GS, Aoki TT. Measurement of health status in diabetic patients. Diabetes impact measurement scales. Diabetes Care. 1992 Apr;15(4):469-77. doi: 10.2337/diacare.15.4.469.

Reference Type: BACKGROUND

PMID: 1499460 (View on PubMed)

Stewart R, Liolitsa D. Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med. 1999 Feb;16(2):93-112. doi: 10.1046/j.1464-5491.1999.00027.x.

Reference Type: BACKGROUND

PMID: 10229302 (View on PubMed)

Gregg EW, Yaffe K, Cauley JA, Rolka DB, Blackwell TL, Narayan KM, Cummings SR. Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch Intern Med. 2000 Jan 24;160(2):174-80. doi: 10.1001/archinte.160.2.174.

Reference Type: BACKGROUND

PMID: 10647755 (View on PubMed)

Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? J Alzheimers Dis. 2005 Feb;7(1):63-80. doi: 10.3233/jad-2005-7107.

Reference Type: BACKGROUND

PMID: 15750215 (View on PubMed)

Watson GS, Craft S. Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease. Eur J Pharmacol. 2004 Apr 19;490(1-3):97-113. doi: 10.1016/j.ejphar.2004.02.048.

Reference Type: BACKGROUND

PMID: 15094077 (View on PubMed)

Other Identifiers

H09-66-COG

Identifier Type: -

Identifier Source: org_study_id