Aoki Diabetes Research Institute

Published Research Articles

Metabolic activation therapy (MAT) and pulsatile therapy are other names for chronic intermittent intravenous insulin therapy (CIIIT).

Overview

Chronic intermittent intravenous insulin therapy: A new frontier in diabetes therapy. Aoki TT, Grecu EO, Arcangeli MA, Benbarka MM, Prescott P, Ahn JH. Diabetes Technology and Therapeutics 2001; 3(1): 111-123.

The novel approach to insulin therapy know as chronic intermittent intravenous insulin, CIIIT, delivers insulin in a pulsatile fashion and achieves physiologic concentrations of insulin in the portal vein. Done as a weekly outpatient procedure combined with daily intensive subcutaneous insulin therapy, this procedure has been shown to 1) significantly improve glycemic control while decreasing the incidence of hypoglycemic events 2) improve hypertension control, 3) slow the progression of overt diabetic nephropathy, and 4) reverse some manifestations of diabetic autonomic neuropathy.

Nephropathy

1. Effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy. Dailey GE, Boden GH, Creech RH, Johnson DG, Gleason RE, Kennedy FP, Weinrauch LA, Weir M, D'Elia JA. Metabolism 2000; 49: 1491-1495.

A multi-center randomized controlled trial in patients with Type 1 diabetes and diabetic nephropathy compared outcomes in 23 patients treated with pulsatile intravenous insulin therapy (CIIIT) plus intensive insulin therapy compared to 26 patients treated with intensive insulin therapy alone. Blood pressure was controlled in both groups and patients were seen weekly. Hemoglobin A1c levels declined significantly in both groups. However, the rate of decline of the Creatinine Clearance level was significantly less (2.2 mL/min/yr) in the treatment group(CIIIT plus intensive insulin therapy) as compared to 7.7 mL/min/yr in the control group( intensive insulin therapy alone.) Projected average-time-until-dialysis/transplant is 5.2 years for the control group and 18.2 years for the CIIIT treatment group. Conclusion: Pulsatile intravenous insulin therapy (CIIIT) appears to markedly reduce the progression of diabetic nephropathy.

2. Effect of intensive insulin therapy on progression of overt nephropathy in patients with Type I diabetes mellitus. Aoki TT, Grecu EO, Gollapudi GM, Barber RA, Arcangeli MA, Benbarka MM, Prescott P, Meisenheimer R. Endocrine Practice 1999; 5: 174-8.

In patients with advanced diabetic kidney disease, the gradual deterioration of kidney function (decrease of creatinine clearance [CrCl] by 8-10 ml/min/year) cannot be arrested with "routine" insulin therapy. This study reports the treatment outcome of an average of 37 months (range 1-7 years) of CIIIT in 31 patients with Type I diabetes and advanced diabetic renal disease. The CrCl at the end of the treatment period was essentially unchanged, suggesting that adding weekly CIIIT to daily intensive insulin therapy could arrest or markedly delay progression to the end stage renal disease, when kidney dialysis or transplantation is required.

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Hypoglycemia

1. Long-term intermittent intravenous insulin therapy and type I diabetes mellitus. Aoki TT, Benbarka MM, Okimura MC, Arcangeli MA, Walter RM Jr., Wilson LD, Truong MP, Barber AR, Kumagai.  Lancet 1993; 342: 515-8.

A study of 20 diabetic patients over 42 months showed that hepatic activation (CIIIT) resulted in a 98 percent decrease in major hypoglycemic reactions. On treatment with CIIIT, patients with "brittle" diabetes and "hypoglycemia unawareness" gradually regained the ability to detect falling blood glucose levels. These patients went from an average of 3 severe hypoglycemic reactions (requiring outside intervention) per month to an average of 0.1 episodes per month. The average frequency of hypoglycemic reactions returned to three per month when CIIIT was stopped.

Hypertension

  1. Chronic intermittent intravenous insulin therapy for patients with high blood pressure led to a 46% decrease in the amount of medication required to control the patients' blood pressure.

2. Effect of intensive insulin therapy on abnormal circadian blood pressure pattern in patients with Type 1 diabetes mellitus. Aoki, TT, Grecu EO, Arcangeli MA, Meisenheimer R. The Online Journal of Current Clinical Trials, 1995; Dec. 13: Doc. No.199.

Patients with severe diabetes often have increased night time blood pressure, a condition that may worsen the complications of diabetes. Patients in randomized, controlled clinical trials comparing two treatments 1) four subcutaneous insulin injections daily, vs 2) weekly CIIIT added to the four subcutaneous injections daily had monthly measures of 24 hour ambulatory blood pressure. The group on weekly CIIIT in addition to four subcutaneous insulin injections daily had a 3% decline in the night/day blood pressure ratio. In contrast, those on only four subcutaneous injections daily had a 3% increase in night/day blood pressure ratio. In addition, the group on CIIIT had an significant improvement in the average HbA1c levels.

 

Hypotension

1. Chronic intermittent intravenous insulin therapy corrects orthostatic hypotension of diabetes. Aoki TT, Grecu EO, Arcangeli MA. Amer.  J. Med. 1995; 99: 683-4.

On CIIIT therapy, patients reported complete relief from dizziness and fainting when they stood up and blood pressure no longer dropped precipitously with upright posture.

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Obstetrics

1. The effect of chronic intermittent intravenous insulin therapy of pregnancy outcome in insulin dependent diabetes mellitus. Field N, Boe N, Gilbert W, Benbarka M, Aoki T.  Journal Soc. Gynecol. Invest. 1997; 4(1, supplement): 196A.

A group of 3 insulin-dependent diabetic pregnant patients received CIIIT in addition to the usual regimen of 3 insulin shots per day and home glucose monitoring. Compared to 15 matched controls, the CIIIT group all had normal hemoglobin A1c levels at delivery, none developed hypertensive complications requiring early delivery, and none required extra antepartum hospital days. Infants of the CIIIT group were not hypoglycemic, and 2 of the 3 were discharged at the same time as their mothers.

Quality of Life

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Physiology and Biochemistry

1. Acute insulin effects on plasma homocysteine levels in patients with diabetes mellitus. Aoki TT, Grecu EO, Medina M, Goodman M.  J Invest Med (in Press).

2. IGF-1 and IGFBP-1 blood levels in type 1 diabetes mellitus on intensive intravenous insulin therapy.  Aoki TT, Grecu EO.  J Invest Med, 1999; 47(2) 78 A.(abstract).

3. Restoration of glucose homeostasis in insulin-dependent diabetic subjects. An inducible process. Foss MC, Vlachokosta FV, Cunningham LN, Aoki TT.  Diabetes 1982; 31: 46-52.

4. Role of muscle in CO2 production after oral glucose administration in man. Meistas MT, Vlachokosta FV, Gleason RE, Arcangeli M, Aoki TT.  Diabetes 1985; 34: 960-63.

5.  Aoki TT, Vlachokosta FV, Foss MC, Meistas MI.  Evidence for restoration of hepatic glucose processing in type I diabetes mellitus. Journal of Clinical Investigation 1983; 71:837-839.

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 Osteoporosis