Clinical trial NCT00228904: Effects of Pulsatile Intravenous Insulin Delivery on Diabetic Neuropathy in pATIENTS (Pts) With Type 1 and Type 2 Diabetes
Official title: Effects of Pulsatile IV Insulin Delivery on Peripheral Diabetic Neuropathy
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
PHASE3
Conditions: Diabetic Neuropathy
Keywords: Pulsatile intravenous insulin
Oral carbohydrate loading
Respiratory Quotients
Hypoglycemia
Diabetic Neuropathy
Diabetes Mellitus, with complications
Lead sponsor: Florida Atlantic University
Sponsor class: OTHER
Collaborators: name: Advanced Diabetes Treatment Centers
name: Global Infusions
First posted: 2005-09-29
Enrollment: 0
Sex: ALL
Minimum age (years): 20
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Diabetic neuropathy is a progressive complication causing serious problems in 25-40% of diabetic patients. Anecdotal reports have indicated improvement with pulsatile IV insulin therapy in affected patients otherwise resistant to all conventional therapies. Significant complications produce painful peripheral dysesthesias, loss of sensation and gastroparesis. This study is designed to test the effectiveness of pulsatile IV insulin therapy on diabetic neuropathy.

Detailed description: Diabetic neuropathy (DN) is a progressive complication causing serious problems in 25%-40% of diabetic patients. Significant complications produce painful peripheral dysesthesias, loss of sensation, and gastroparesis. DN may affect the peripheral motor and sensory nerves in addition to the autonomic nervous system (1-3). Treatment strategies for patients with DN have generally concentrated on pain relief, without addressing the underlying pathophysiology of the disease (4). Anecdotal reports from patients treated with pulsatile IV insulin therapy for other complications suggest that this treatment may show efficacy in patients with DN. This study is designed to compare patients with DN who receive pulsatile IV insulin therapy with a control group.

Pulsatile IV insulin therapy 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 secreted by 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 measuring of 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. Pulsatile IV insulin therapy is done over 1-hour periods with a 1-hour rest period between each treatment. Three treatments are given during a patient visit to the center.

Frequent monitoring of RQ is necessary as these levels change rapidly, depending on the fuel being utilized by the body. IV insulin given in pulses shifts metabolism from primarily fatty acid metabolism to primarily glucose metabolism. This shift is reflected by the increase in respiratory quotient. However during rest periods the RQ may fall back to lower levels. Therefore RQs are done at the beginning and at the end of each insulin infusion session in order to appropriately monitor and adjust insulin and carbohydrate loads to reach optimal activation in each session.

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 carbohydrates 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 insulin along with the augmenting effect of oral carbohydrates will normalize metabolism in diabetic patients and correlate with an improvement in their manifestations of diabetic neuropathy.

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 to 1.3. 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 RQs higher than 1.05. The amount of intravenous insulin and oral glucose given is determined by the RQ changes during the previous session.

1. Tesfaye S, Chaturvedi N, Eaton SEM, Ward JD, Manes C, Ionescu-Tirgoviste C, witte DR, Fuller JH, Vascular Risk factors and Diabetic Neuropathy N Engl J Med 352:341-50, 2005.
2. Neuropathy Trust, Diabetic Neuropathy: Prevalence, www.neurocentre.com.
3. Potter PJ, Maryniak O, Yamorski R, Jones IC, Incidence of Peripheral Neuropathy in the Contralateral Limb of Persons with Unilateral Amputation due to Diabetes, Journal of Rehabilitation Research and Development 35:335-39, 1998.
4. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengan, Duloxetine versus Placebo in Patients with Painful Diabetic Neuropathy, Pain 116:109-18, 2005.

Eligibility criteria: Inclusion Criteria:

* Up to 500 patients both male and female between the ages of 20 and 90 diagnosed with type 1 or type 2 diabetes mellitus.
* All patients were diagnosed by their endocrinologists as having diabetic neuropathy.
* All patients had failed conventional treatment for diabetic neuropathy.
* All patients are taking oral agents and/or insulin for diabetic control.
* All patients are under an endocrinologist's supervision for their diabetes management.
* Endocrinologist must assess and approve patient for participation in this study.
* All patients must demonstrate the ability to swallow without difficulty and the 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
* HIV positive
* Inability to breathe into machine for respiratory quotients

Primary outcomes:
measure: To evaluate objective testing performed including nerve conduction velocity in diabetic patients treated with pulsatile intravenous insulin therapy
timeFrame: at baseline and every six months
Secondary outcomes:
measure: To obtain patient questionnaires and perform objective testing to analyze, compare and measure progress
timeFrame: prior to start of pulsatile intravenous insulin therapy and every six months thereafter
Other outcomes:
Locations:
city: Boca Raton
country: United States
facility: Florida Atlantic University Center for Complex Systems and Brain Sciences
state: Florida
Study officials:
affiliation: Florida Atlantic University
name: Betty Tuller, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gill G, Moulik P. Mortality and diabetic neuropathy. Diabet Med. 2005 Sep;22(9):1289. doi: 10.1111/j.1464-5491.2005.01729.x. No abstract available.
citation: Moghtaderi A, Bakhshipour A, Rashidi H. Validation of Michigan neuropathy screening instrument for diabetic peripheral neuropathy. Clin Neurol Neurosurg. 2006 Jul;108(5):477-81. doi: 10.1016/j.clineuro.2005.08.003. Epub 2005 Sep 16.
citation: Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH; EURODIAB Prospective Complications Study Group. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005 Jan 27;352(4):341-50. doi: 10.1056/NEJMoa032782.
citation: Potter PJ, Maryniak O, Yaworski R, Jones IC. Incidence of peripheral neuropathy in the contralateral limb of persons with unilateral amputation due to diabetes. J Rehabil Res Dev. 1998 Jul;35(3):335-9.
citation: Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005 Jul;116(1-2):109-18. doi: 10.1016/j.pain.2005.03.029.