APT® NEUROPATHY BENEFITED BY APT  (FEB 18 2016)

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Natural Course of Diabetic Neuropathy In Patients Receiving Intravenous Burst Insulin Therapy (Artificial Pancreas Treatment)​

José Hernán Martínez, MD, FACP, G Ford Gilbert, PhD.

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 Diabetes Mellitus is a major public health problem in many countries around the world.  The long term chronic complications (microvascular and macrovascular) can and do cause increased morbidity and mortality in those patients afflicted.  Likewise the increased direct and indirect cost impose in third party payees and government resources result in considerable economic burden when dealing with such complications. 

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            One of the leading microvascular complications of diabetes mellitus is diabetic neuropathy1 (DN).  The prevalence of DN varies greatly but it is estimated to be some where around 30-60% in most studies.  In the classic study of Pirart2 in which 4,400 patients were evaluated the prevalence approximated 45% after 25 years.  In the Rochester Diabetes Project, MN3, the prevalence of any neuropathy was 66% in type1 and 59% for type 2 diabetes.  Ten to twenty percent (10-20%) of patients with diabetes may experience diabetic peripheral neuropathic pain (DPNP), and 30-60% of patients with DPN may have DPNP.  In some patients the symptoms and signs of DN may precede the appearance of clinical diabetes mellitus.

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            Symptoms of Diabetic Peripheral Neuropathy depend on the distribution of involved nerves but the most common form is distal symmetric polyneuropathy although frequently, autonomic, focal and diffuse neuropathies can co-exist.       Multiple metabolic pathways can contribute to DN4  Hyperglycemia is the leading abnormality causing activation of the PKCβ enzyme, increased oxidative stress, protein glycosylation (AGE) and abnormal polyol metabolism resulting in direct neurotoxicity and ischemic changes at the nerve cell membrane and vasa nervorum.  Genetic, immunological and environmental factors also play a role. Risk factors for the development of DN includes age, duration of diabetes, male sex, height, hypertension and smoking5. 

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            In 1988 The San Antonio Consensus Statement6 defines DN as “A descriptive term meaning a demonstrable disorder, either clinically evident or subclinical, that occurs in the setting of diabetes mellitus without other causes for peripheral neuropathy.  The neuropathic disorder includes manifestations in the somatic and/or autonomic parts of the peripheral nervous system”.  The members of above consensus meeting also confirmed that neuropathy could not be diagnosed without a careful clinical examination, because of lack of symptoms could not be parallel with absence of neuropathy, due to frequent occurrence of asymptomatic neuropathy.

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            Tight or strict blood glucose and blood pressure control have shown reduction on the risk of retinopathy, nephropathy, neuropathy, microalbuminuria, such as those seen in the DCCT7, Kumamoto8 and UKPDS9 clinical trials.  However in spite of these results considerable percentage of patients develops the long term complications of diabetes.

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            In the last years, direct and indirect objective studies have confirmed the paramount role of chronic burst intravenous insulin therapy (Artificial Pancreas Treatment® – APT)  in the amelioration and improvement of the microvascular and macrovascular complications of diabetes.10

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            In order to prevent the progression of diabetic neuropathy, one must control the formation of advanced glycogen end products and other possible related mechanism which would decreased vascular endothelial growth factors.11 We believe that the infusion of insulin intravenously via burst insulin therapy (APT)  would a) stabilize the blood glucose levels and b) reduce the diabetes related complications of diabetic neuropathy.

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            The purpose of the study is to document the progression of diabetic neuropathy, using standardized quantitative measures, in patients undergoing APT.

Patients and Methods 

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            This is a single site, prospective, observational study, of all treated diabetics patients, no exclusions, undergoing burst intravenous insulin therapy via the Artificial Pancreas Treatment, in Puerto Rico.

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            The study was designed to run for a minimum of 12 months.  All participants gave written informed consent under appropriate institutional approval policies.

Study Subjects

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            A total of 25 patients with Type 2 and one (1) patient with Type 1 diabetes and clinical evidence of diabetic neuropathy were enrolled in this study.  Patients eligible to participate were a) Hispano-American, male and female b) at least 18 years of age c) with diagnoses of type 1 or type 2 diabetes d) which qualify for burst intravenous insulin therapy.

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            Exclusion criteria –included:

a)    Patient unable or unwilling to manage their diabetes

b)    Pregnant women

c)    Terminal cancer, chronic hepatic disease, HIV

Study Procedures

            A complete history, physical and neurologic examination, neuropathy, quality of life and psychological well being questionnaire as well as EMG/NCV (lower extremities) were done at baseline and at the end of 12 months of therapy (PIVIT).

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            Blood and urine were drawn for complete blood count, glycohemoglobin, bun, creatinine, lipids, co2, potassium, blood sugar and creatinine clearance and urinary mircroalbumin determination using commercial laboratory at baseline and every 3 months there after.

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            Patients were encouraged to perform self blood glucose monitoring regularly and to adhere to their diet, insulin, oral hypoglycemic, antihypertensive and antineuropathic medications as prescribed by their primary care physicians.

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            Weekly appointments for APT therapy were given to patients at our center (Integrative Diabetes Research) on an outpatient basis. 

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            APT consist of the administration of insulin intravenously at a rate of 7-10 pulses per hour, which mimics the normal secretory insulin burst of the pancreas in order to achieve high portal insulin concentrations as seen in the non diabetic individual.12  Frequent capillary blood sugar determinations were done (every 30 minutes) and glucose orally was given to maintain blood sugar levels over 150 mg/dl to avoid hypoglycemia.  This is repeated three (3) times over a period of 5-6 hours once a week. Detailed description is found elsewhere.  Respiratory quotient measurement, using a metabolic cart, was obtained at the start and end of each one hour therapy to maintain an increase in carbohydrate production from pre-treatment which signifies proper glucose oxidation.  Blood pressure measurement, pulse, weight were recorded weekly at each clinic visit.

Results

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            Of the 26 patients enrolled, eighteen completed the one year APT protocol.  A drop of 8 patients occurred due to poor protocol compliance. 

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            Ten patients were female and 8 were males.  Mean age of the female group was 68.3 years and that of the male group was 61.1 years.  The duration of diabetes span from 8 to 35 years.

            The most important comorbidities seen in our patients were hypertension in ten (10), renal disease in six (mild to moderate in 4 and severe in 2) and retinopathy which became stable in six (6).  Eleven patients were using insulin and 7 patients were on oral hypoglycemic agents. Seven of the 11 patients using insulin were concomitantly on oral hypoglycemic drugs.

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            Glycosylated hemoglobin (HbA1c) at baseline range from 6.50% to 11.2% - mean 8.94%.  After 12 months of treatment HbA1c mean value was 8.69% (range 7.10%-10.3%).  Seventy five percent (75%) of patients were obese (BMI >30.0), however at the end of 12 months period of treatment fifty percent (50%) lost from one (1) to three (3) kilograms and the other fifty percent (50%) weight remained unchanged.

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            Blood pressure at baseline was 136/76 (mean) and 135/76 (mean) after 12 months of therapy.  In five patients antihypertensive medications were reduced substantially and 4 patients had a reduction of insulin units and oral hypoglycemic drugs.

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              Results of EMG/NCV of lower extremities showed:

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a)    Eighteen patients treated, 17 evaluated

b)    Nerve conduction velocity improvement in 11 patients, latency difference 4-9m/sec.

c)    Eight (8) patients – Tibial NCV improved, latency difference 4-10 m/sec.

d)    Two (2) patients:  Sural SNAP amplitude and conduction velocity improved.

e)    Five (5):  Failed to show improvement in conduction velocity of motor nerves. These five (5) patients had more advanced neuropathy with marked sensory loss.  The sural nerves were absent in all except one in this group.  The peroneal/tibial CMAP amplitudes were less than 1MV, correlating with severe axonal damage.

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            The above findings revealed a sixty five (65%) percent improvement in nerve conduction velocity in our patients. 

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            There was a marked dramatic improvement in all eighteen patients soon after the institution of PIVIT regarding neuropathic symptoms, improvement in quality of life, sleep patterns and decreased depressive symptoms as measured by respective questionnaires.  Interestingly three patients (17%) completely discontinued all analgesics and antineuropathic medications due to complete absence of neuropathic pain while on therapy.

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Discussion

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            In non-diabetic individuals, insulin is secreted from beta cells almost exclusively in secretory burst or oscillatory pulses every four to six minutes, achieving high portal vein concentration (ranging from 200 to 1,000m u/ml) and maximum levels outside portal vein of 75 mu/ml.13-15 This insulin portal concentration is important in order to activate enzymes responsible (glucokinase) for proper glucose oxidation and metabolism as well as the suppression of hepatic glucose production. So in normal men after glucose administration, CO2 production (and consequently the RQ) increase (0.9-1.0) indicating that glucose has become the primary source of energy. The amount of increase of carbohydrate use is verified as part of the study and treatment.  On the other hand in diabetic patients on Insulin treatment no such increase in CO2 production is observed.  This is due to the fact that subcutaneous insulin administration increased portal insulin concentration scarcely to 20 to 30 mu/ml and peripherally to 40 mu/ml and consequently poor insulin depended glucose enzymes activation.  This last pattern promotes oxidation of fat and protein fuel instead of normal carbohydrate metabolism seen in normal individuals.16

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            The respiratory quotient (RQ: VCO2/VO2) as an index of indirect calorimetry is about 0.9-1.0 in normal person when glucose oxidation is the main source of energy production.  It drops to (0.7-0.8) when fat oxidation becomes the primary source of metabolism.

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            Poor response to subcutaneous insulin or pharmaceutical treatments in diabetics is not due to quality or quantity of insulin but rather inappropriateness in the route and manner of administration.

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            Burst insulin (APT) has been used in the treatment and prevention of diabetes, its complications and comorbidities.  Reports of the effectiveness of APT on patients with “brittle diabetes”, diabetic nephropathy, hypoglycemia unawareness, autonomic neuropathy, hypertension, orthostatic hypotension are well documented.10

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            At the end of our study period (12 months of weekly PIVIT) 65% of our patients with severe symptomatic distal symmetric polyneuropathy had a prominent increased in nerve conduction velocity as compared to base line values.  More importantly seventeen percent (17%) discontinued all medications to relieve neuropathy pain and symptoms.

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            To our knowledge this is the first report relating dramatic improvement in symptoms as well as objective improvement of nerve conduction velocities in patients with DN, which occurred and continued for 12 months.  Likewise there was a gradual and constant improvement in energy levels, sleeping patterns, emotional and mood stability in all patients shortly after institution of therapy.

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            The exact mechanism by which APT slows the progression of symptomatic DN is not well understood.  It appears to have correlation to the production of adenosine triphosphate as carbohydrate production provides a higher level of ATP than non-carbohydrate production with the mitochondria and ATP relationship being well understood.17

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            The fact that HbA1c and blood pressure levels did not change markedly at the end of the 12 months of therapy in our patients and that in three (3) complete resolution of symptoms, improvement in NCV, quality of life and discontinuation of analgesics, suggest that clinical improvement is independent of glycohemoglobin or blood pressure levels.

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            Other possible mechanisms includes a direct effect of insulin on nerves function    and    structure,    decreased    mesangium   proliferation,   restoration   of  Na-KATpase activity, increased in blood flow with diminished A-V shunting and nerve hypoxia.

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            In two patients with advanced diabetic nephropathy APT retarded any further renal deterioration during the twelve months period as judged by stable creatinine clearance and urinary protein excretion.  Patients with diabetic retinopathy did not experience any deterioration in their visual acuity and stabilized.  We believe that these preliminary results are encouraging.

            In summary Receiving Intravenous Burst Insulin Therapy (Artificial Pancreas Treatment) is a safe treatment alternative in diabetic patients with microvascular complications and specifically in those with diabetic peripheral neuropathy. 

    

References:

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1. Association of glycaemia with macrovascular and microvascular  complications of type 2 diabetes (UKPDS 35): prospective observational study: BMJ 2000;321:405

2. J Pirart, Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973 Diabetes care, 1978 - Am Diabetes Assoc. Diabete et Metabolisme (vol. 3: 97–107, 173–182, 245–256; 1977).
   Nathan, David M. "Long-term complications of diabetes mellitus." New England Journal of Medicine 328.23 (1993): 1676-1685.

3. Palumbo, P. J., L. R. Elveback, and D. C. Connolly. "Coronary heart disease in the diabetic: epidemiological aspects: The Rochester Diabetes Project." Clinical cardiology and diabetes 1 (1981): 13-27.

4. Sheetz, Matthew J., and George L. King. "Molecular understanding of hyperglycemia's adverse effects for diabetic complications." Jama 288.20 (2002): 2579-2588.

5. Cameron, N. E., Eaton, S. E. M., Cotter, M. A., & Tesfaye, S. (2001). Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia, 44(11), 1973-1988.     

6. American Diabetes Association, and American Academy of Neurology. "Report and recommendations of the San Antonio conference on diabetic neuropathy." Diabetes Care 11.7 (1988): 592-597.

7. Control, The Diabetes, and Complications DCCT Research Group. "Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial." Kidney International 47.6 (1995): 1703-1720.

8. Shichiri, Motoaki, et al. "Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients." Diabetes care 23 (2000): B21.

9. Group, UK Prospective Diabetes Study. "Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38." BMJ: British Medical Journal (1998): 703-713.

10. Wahren J, Kallas A. Loss of Pulsatile Insulin Secretion: A Factor in the Pathogenesis of type 2 Diabetes. Diabetes (2012) 61:2228-2229
    Helman, B et. al. Pulsatility of Insulin Release- A Clinically Important Phenomenon. Upsala Journal of Medical Sciences (2009) 114:193-205
    Marvel Logan-Darrough; Pulsatile I.V. Insulin Therapy for Severely Out of Control Diabetes. Journal of Intravenous Nursing (1995) 18:124-128.
    Gilbert, G. The Medical Necessity of of Mimicking Normal Human Burst Insulin via the Artificial Pancreas Treatment. (2015) 42:125-147

11. Goldin, Alison, et al. "Advanced glycation end products sparking the development of diabetic vascular injury." Circulation 114.6 (2006): 597-605.

12. Feingold, Vladimir, and Peter C. Allworth. "Infusion pump." U.S. Patent No. 4,919,650. 24 Apr. 1990. Zaias, Nardo, and Gregory F. Gilbert. "Medical infusion and aspiration system." U.S. Patent No. 6,565,535. 20 May 2003 add’l pending.

13. Pørksen, Niels, et al. "In humans at least 75% of insulin secretion arises from punctuated insulin secretory bursts." American Journal of Physiology-Endocrinology And Metabolism 273.5 (1997): E908-E914.

14. Pørksen, Niels, Butler P. et al "Pulsatile insulin secretion: detection, regulation, and role in diabetes." Diabetes 51.suppl 1 (2002): S245-S254.

15. Song, Soon H., et al. "Direct Measurement of Pulsatile Insulin Secretion from the Portal Vein in Human Subjects 1." The Journal of Clinical Endocrinology & Metabolism 85.12 (2000): ​