ES2362420T3 - INSULIN FOR USE IN A DOSAGE SCHEME. - Google Patents

Abstract

Insulin for use in a treatment procedure of a patient with poor hepatic glucose processing, said procedure comprising the steps of: ingestion by the patient of a meal containing carbohydrates; supply to the patient of a series of pulses of said insulin by means of an infusion device, in which the amount of said insulin in each pulse, the interval between pulses and the amount of time to deliver each pulse to the patient are chosen so that the Circulating glucose level in the patient, controlled by a control device, is initially raised and then falls by an amount equal to 50 mg / dl or more.

Description

Field of the Invention

The present invention relates to insulin for use in a method of treating a patient with poor liver glucose processing.

Background of the invention

Diabetic retinopathy is one of the main causes of blindness. While early detection and major advances in laser therapies have had a significant impact on this chronic complication of diabetes, the number of diabetic patients suffering from diabetic retinopathy continues to increase.

Glucose control is typically measured by a blood test that determines the level of hemoglobin A1c, which has been the desired result of insulin therapy in diabetic patients for many years. However, it is clear that the tight control of circulating glucose was insufficient in 25% or more of the study participants to protect them from the increase or progression of diabetic retinopathy, nephropathy or neuropathy.

An important cause of death in patients with diabetes saccharin is cardiovascular disease in its various forms. Current evidence indicates that diabetic patients are particularly susceptible to heart failure, mainly associated with atherosclerosis of the coronary arteries and autonomic neuropathy. There is little doubt that a metabolic component is present in various forms of cardiovascular disease in diabetic patients. Cardiac dysfunction (lower systolic volume, cardiac index and ejection fraction and increased left ventricular telediastolic pressure) frequently manifested by patients with diabetes, can be explained at least partially by metabolic abnormalities, and is probably secondary to insulin deficiency since Proper administration of insulin can restore normal cardiac metabolism models (Avogaro et al., Am J Physiol 1990, 258: E606-18).

The pathophysiology of diabetic nephropathy is only partially understood. The most consistent morphological conclusion in diabetic nephropathy is the enlargement of the mesangium, which can compress the glomerular capillaries and, thereby, alter intraglomerular hemodynamics.

Diabetes is the number one cause of non-traumatic amputations. Common sources of amputations are wounds that do not heal and progress to necrosis and gangrene. Generally, it is observed that diabetic patients have greater difficulty in healing and overcoming infections.

It is thought that diabetes, in general, and poor control of circulating glucose, in particular, are causally related to poor wound healing in diabetic patients. Poor control of circulating glucose is also the source of a lack of energy and a feeling of general malaise.

As reported in Diabetes mellitus and the risk of dementia A. Ott., RP. Stolk, F. Van Harskamp, The Rotterdam Study, Neurology, 1999, vol. 53, p. 1937-1942, patients with diabetes have an increased risk of dementia. Having diabetes almost doubled the risk of having dementia (the risk was 1.9 times higher). The risk of diabetics from getting Alzheimer's disease was also almost double. And in diabetics taking insulin, the risk was more than 4 times that of non-diabetics. Even after the adjustment of the possible effects of sex, age, educational level and other measured factors, the conclusions were the same. Therefore, it can be concluded that diabetes is a risk factor in the development of dementias, including Alzheimer's disease.

What is an insulin dosage regimen by which: the metabolism can be restored; Oxidation of retinal and neuronal glucose can be increased by enhancing the activity of pyruvate dehydrogenase; Retinopathy and central nervous system disorders can be treated; systolic volume can be increased, which improves the cardiac index; and the ejection fraction can be increased, and the ventricular telediastolic pressure decreases, thus improving cardiac function, as well as improving the quality of life in diabetic patients. An insulin dosing regimen is also needed to significantly reverse the common cardiac dysfunction in diabetic patients with heart disease. The same treatment should be able to provide improved blood glucose control measured by hemoglobin A1c. In addition, an insulin dosing regimen is needed to improve the complete metabolic process and through its multiplicity of effects on neurovascular reactivity, intraglomerular pressure and hemodynamics, stop the progression of symptomatic diabetic nephropathy, improve intraglomerular hemodynamics, and thus stop the progression of diabetic nephropathy and reduce the risk of developing end-stage renal failure (ESRD). In addition, an insulin dosing regimen also needs to increase glucose oxidation in the affected areas and, therefore, provide more energy while consuming less oxygen to treat wounds, promote healing and avoid lower limb amputations. in diabetic patients as in

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non-diabetic patients An insulin dosing regimen is required to improve the metabolism in the brain of patients suffering from any of the various diseases that cause senile dementia and, consequently, improve the mental function of patients suffering from senile dementia.

In a prior patent, US Pat. No. 4,826,810, the author of the invention describes a method of sending insulin pulses to a patient after ingestion of a meal containing glucose. Insulin pulses are adjusted to produce a series of peaks in the concentration of free insulin so that there is successively an increase in the minimum concentration of free insulin between said peaks. To do this, a viable treatment is needed for clinical purposes that is a simple, low-cost way to measure free insulin to determine such peaks to ensure that the correct levels are present to ensure that hydrate processing capabilities are activated. Food carbon from the patient's liver.

Summary of the invention

The present invention is defined in claim 1.

The subclaims define additional features of the invention.

The infusion device supplies a series of insulin pulses to the individual over a period of time accompanied by the ingestion of glucose in the form of a meal containing carbohydrates. The amount of insulin in each pulse, the interval between pulses and the amount of time to deliver each pulse to an individual such as a patient are chosen so that hepatic glucose processing is restored in the individual. Initially, after ingestion of the food containing carbohydrates, the individual's blood glucose level rises.

Coinciding with or shortly after the establishment of elevated glucose levels in the patient, the first pulse of insulin supply is administered. This pulse results in a maximum concentration of "free" insulin in the blood represented by peak E (see Fig. 3). When the concentration of "free" insulin decreases by approximately 90% for Y, the next pulse is administered, which results in peak F. When the concentration of "free" insulin decreases again by approximately 90% for Z is administered the next pulse resulting in the peak G. The repetition of this process will result in an increase in the concentration of "free" insulin between peaks indicated by the H line. The pulses are regulated so that the concentration of "free" insulin between peaks it increases by 10 to 500 µU / ml from one pulse to the next. To activate the liver, an increase in the concentration of “free” insulin between peaks is required after ingestion of a meal containing carbohydrates to activate the liver and to allow the circulating blood glucose level to drip 50 mg / l in individuals with poor liver glucose processing. However, there are times that although "free" insulin levels rise between spikes, they do not rise fast enough to activate the liver. In these circumstances the drop in circulating glucose will not reach 50 mg / dl.

It is desirable to administer the minimum amount of insulin according to the activation of hepatic glucose processing, even the amount of insulin required to activate a patient will vary from one patient to another patient or even from one day to another day in the same patient. For the same patient in one day, a pulse regimen will achieve activation of hepatic glucose processing while the same patient the next day requires significantly more insulin per pulse, or more frequent pulses, to achieve activation. Measuring "free" insulin levels in the blood is an expensive and time-consuming procedure, which cannot provide the necessary information in real time. What is described in the present invention is a way of measuring in real time when the patient has actually activated liver glucose processing to allow positive confirmation of a satisfactory response and signal by the patient when it is no longer necessary to administer the pulses

In individuals in whom liver glucose processing has been restored there is a subsequent drop in circulating blood glucose levels of 50 mg / dl or more, directly as a result of glucose processing being restored in the liver Hepatic This circulating glucose signal is easy to obtain and inexpensive, it can be easily done by the patient in a home health care environment without the help of a doctor and provides real-time information that the liver function has been re-established. Patients are normally well trained and fully capable of obtaining their own circulating glucose levels without the need for a doctor to help with the procedure and assess the results. Other means to determine if the liver has been activated are expensive, do not provide real-time information, require a doctor's evaluation or cannot be used in a home health care setting. There must be a minimum of more than two pulses in the insulin pulse series; for example, three, four, five or six. In the preferred embodiment, the device is a pump that supplies a series of ten pulses over a period of one hour. The pump is preferably controlled by a programmable processing unit, which controls the amount of insulin in each pulse, the time to distribute each pulse and the time between pulses. Circulating blood glucose levels can be measured by any appropriate method of measuring circulating glucose including finger pricking methods.

Drawings

Below is a description of the drawings:

Fig. 1 is a schematic block diagram of a programmable insulin pump using a syringe with a plunger-type mechanism and programmed to deliver insulin;

Fig. 2 is a schematic block diagram of a programmable insulin pump with a rotating plunger mechanism and programmed to deliver insulin according to the present invention; Y

Fig. 3 is a graph showing the relationship between blood insulin concentration and time in a series of insulin pulses.

Description of preferred embodiments

Accordingly, the present invention includes an infusion device for administering insulin to diabetic patients by infusing a series of insulin pulses in the patient at regular intervals. At the same time, the patient ingests a meal containing carbohydrates and measures of circulating glucose are taken periodically to ensure that proper hepatic glucose processing has been restored.

Liquid or food containing glucose is consumed by the patient to prevent the patient from becoming hypoglycemic. The preferred glucose-containing liquid or food is 4 to 10 ounces of GLUCOLA for diabetic patients that translates into 40 to 100 grams of glucose, but the patient can be given any similar type of high-glycemic liquid or food that contains glucose, including cakes and bread, but not limited only to them. For non-diabetic patients, the amounts of glucose ingested are greater and need to be adjusted for each patient.

In the preferred embodiment of the invention, a programmable insulin pump is programmed to deliver intravenous insulin in accurately measured pulses, is programmed to deliver each of those pulses in a minimum amount of time, and is programmed to leave timed intervals between each pulse. However, any method of infusing measured amounts of insulin that includes simple injections with a syringe is also acceptable. The preferred means of delivering insulin is a programmable infusion device capable of providing measured pulses of insulin at a pre-established interval, provided there is sufficient blood glucose to prevent the patient from becoming hypoglycemic. It is also preferable that the infusion device is capable of delivering insulin pulses in the shortest possible period of time, without adversely affecting the vein at the infusion site used. A preferred infusion device is the Bionica MD-110. However, less safe and slower devices, which include a simple syringe, can send the pulses and achieve the necessary infusion profile.

In one embodiment, a programmable manual pump uses a conventional syringe for use in medicine to infuse insulin. In relation to Fig. 1, the syringe 11 is attached to the pump by clips 13 and 14 and the plunger 15 is activated by a syringe driver 16. The syringe driver is an actuator driven by any of several possible actuator configurations. known to those skilled in the art. Any conventional infusion tube connection device can be used to connect the infusion tube to the syringe. The programmed values can be loaded to a control processor by means of the keyboard 17, through a manufacturer's microprogram in the pump or by a computer program via a communications link 18 to a higher level computer or any other appropriate loading method . An instrument that measures the glucose in circulation, configured to communicate directly with the pump through the communications link can provide timely values of glucose in circulation. Alternatively, wireless communication systems can send information from a circulating glucose sensor automatically to the pump without operator intervention. Typical circulating glucose sensors include but are not limited to finger pricking devices, non-invasive instruments that use near-infrared or radiofrequency spectroscopy, and implanted sensors. Alternatively, the circulating glucose signal may come from an implantable system to control the electrical activity of beta pancreatic cells in a patient to obtain a measure of the patient's insulin demand and the level of circulating glucose. Any other method to directly or indirectly obtain an accurate measure of the change in circulating glucose levels is also acceptable. Communications links can be used to send alarm and status messages to a higher level computer by any acceptable protocol and means of communications.

When the pump is activated, it dispenses the programmed insulin pulse in the amount of time programmed to the individual. Insulin circulates through the infusion tube 19, to the needle 10, which is inserted intravenously into the individual at any convenient part but preferably in the forearm. The time to supply each pulse should be as short as possible and, at most, less than one minute and, preferably, on the order of seconds. Pump status, alarm status and circulating glucose levels, among other system parameters, can be displayed on display panel 12.

In the preferred embodiment, the circulating glucose levels in the individual are measured periodically and are used automatically or manually to load changes in the parameters of the pump that supplies the insulin. Then, adjustments of ingested insulin and infused insulin are made to produce the desired results of activating the liver without the unwanted side effects of hypoglycemia or hyperglycemia.

In another embodiment, instead of a syringe type pump, see Fig. 2, the infusion pump comprises a cassette cartridge pump device, consisting of a cartridge 22, a housing 24, a plunger 25, an area of reservoir 27 inside the cartridge where insulin is contained, and an open mouth for connecting the cartridge to an infusion tube 21 to an infusion needle, which is inserted intravenously into the individual at any convenient part but preferably in the forearm. The pumping mechanism comprises a gear connection 26, a motor 28 and a pumping device 29. When the cartridge 22 is engaged in the housing 24, the cartridge is carved in place by a rotational engagement of male threads of the cartridge and female threads of the housing. The cartridge is optionally manufactured from glass, ceramic, steel or plastic. The pumping mechanism is used to rotate the piston-type piston 25 and 23 inside the cassette cartridge. The pumping mechanism can be operated by methods that include but are not limited to any motor that rotates the piston or housing, by a coordinated hand-eye movement or by a manual movement through a series of "snap" points. The plunger rotates in relation to the cassette housing walls. As the plunger 25 is rotatably rotated, the device infuses insulin to the individual. Preferably, the pumping mechanism is controlled by a programmable processor that controls the amount of insulin to be infused, the timing between pulses and the period of time to infuse a single pulse. The diameter of the deposit area and the depth at which the plunger moves at each rotation of the plunger are selected to provide very precise pulse sizes delivered in a time as short as possible safely. The programmed values can be loaded to a control processor by means of the keyboard, through a microprogram of the manufacturer in the pump or by a computer program by means of a communication link 30 from a higher level computer or any other appropriate loading method. Automated entry of blood glucose levels can be achieved as described above. The same communications link can be used to send alarm and status messages to a higher level computer using any acceptable communications protocol and means. Pump status, alarm status and circulating glucose levels, among other system parameters can be presented on a display panel of the pumping device 29.

Hepatic glucose processing includes the proper absorption of glucose in liver cells, the oxidation of glucose by liver cells, the storage of glucose in the form of hepatic glycogen in liver cells, and the transformation of glucose into fat or Alanine, an amino acid, by liver cells. Liver processing is poor when the liver fails to produce liver enzymes (specifically hepatic glucokinase, phosphofructokinase and pyruvatokinase) necessary in the proper glucose processing. Poor glucose processing is the fundamental condition of type 1 and type 2 diabetic patients, of patients whose pancreas is not producing enough insulin, and of patients experiencing significant insulin resistance, or a combination of these factors. After glucose ingestion, even with intravenous insulin administration, decreased glucose oxidation, low alanine production, and insufficient formation and deposition of glycogen in the liver in a timed manner are all indications that the processing of the liver glucose is deficient. Glucose tolerance tests and hemoglobin A1c measurements can be used as indications that hepatic glucose processing has been deficient.

In a preferred embodiment, insulin pulses are sent to a patient who uses Chronic Intermittent Intravenous Insulin Therapy as follows. On the morning of the procedure, the patient sits, preferably, in a blood collection chair and is inserted, preferably in a vein of the hand or forearm, a 23-gauge needle or catheter to obtain vascular access. However, any similar access system can achieve the necessary result, including permanent catheters, PICC lines and PortaCaths. After a short period of equilibration, the patient is asked to make a measurement of the glucose in circulation before starting the actual insulin infusion. It is preferable that patients have circulating glucose levels close to 200 mg / dL before using the infusion device. In the case of pregnant diabetic women, however, every attempt is made to maintain the maximum level of glucose in circulation at 180 mg / dl or less.

After the measurement of circulating glucose has been taken and the patient has the appropriate starting glucose level, the patient is asked to consume a liquid or food containing glucose. The amount of glucose given to the diabetic patient ranges from 60 to 100 grams or 6 to 10 ounces of GLUCOLA, but for small people the amount can be as low as 40 grams of glucose or 4 ounces of GLUCOLA. However, the amount of initial glucose given to the patient may vary. In the non-diabetic patient, more glucose may be required than in the diabetic patient, but the other parameters should remain the same, including the need for a pulsed supply. Insulin pulses are then administered intravenously at pre-established time intervals, usually every six minutes, however other intervals can be used from as little as every three minutes to every 30 minutes. For diabetic patients the amount of insulin in each pulse is 10-200 milliunits of insulin per kilogram of body weight; for slightly less diabetic patients.

Measures of circulating glucose are made as frequently as possible. When finger pricks are used, due to patient discomfort, it is recommended that readings be taken every 30 minutes. When less invasive methods of measuring circulating glucose are used, readings can be taken more frequently, preferably after the infusion of each insulin pulse. It is recommended to leave a period of one to two minutes after each pulse infusion before circulating glucose levels are measured. The circulating glucose level will typically rise by approximately 100 to 150 mg / dl before beginning to fall. In patients whose liver glucose processing has been restored there will be a drop in circulating glucose levels of approximately 50-100 mg / dl. In patients who still have to obtain the appropriate hepatic glucose processing, there will be no fall or there will be a fall considerably less than 50 mg / dl. The drop in circulating glucose levels, which indicate the restoration of hepatic glucose processing, is generally achieved at the time of the start of the first insulin pulse using the preferred embodiment of this invention; however, the time required may be shorter or longer than one hour. It is possible to decrease the amount of insulin in each pulse and lengthen the time between pulses so that an excess of two or even three hours or more takes place for a 50 mg / dl drop to occur. The longer the time it takes to activate the patient, however, the longer the patient should be under treatment and the less desirable the treatment for the patient. This decrease in circulating glucose is caused by the combination of increased glucose utilization by the muscles and the use of glucose by the liver.

Another indication that liver liver activation has been restored is that gradually the amount of insulin required to reduce circulating glucose levels by 50 mg / dl or more will decrease over time. The decrease in hemoglobin A1c levels is another manifestation, in the medium term, that hepatic processing has been restored. Long-term manifestations are seen in the reduction of several diabetes-related complications, including retinopathy, nephropathy, neuropathy, hypoglycemia, cardiovascular disease and hypertension, but not limited to them.

The phase during which a series of insulin pulses are administered and glucose is ingested typically lasts 56 minutes (ten pulses with a six minute pulse interval) and is followed by a rest period of, usually, one or two hours. . The rest period allows high insulin levels to be returned to the baseline. During periods when insulin is not being infused, the intravenous site is preferably changed to a key with heparin or saline. The entire process is repeated until the desired effect is obtained. Typically, the procedure is repeated three times for each day of treatment, but it can be repeated as little as twice and up to 8 times a day. Before the patient is discarded from the procedure, both in the clinic and in the home environment, in the preferred embodiment the circulating glucose levels are stabilized at 100-200 mg / dl for approximately 30-45 minutes.

Accordingly, the present invention provides an insulin dosing regimen that increases the oxidation of retinal or neuronal glucose by enhancing the activity of pyruvate dehydrogenase and, therefore, treats retinopathy and disorders of the central nervous system in both diabetic non-diabetic cone patients. . One method of controlling oxidation of retinal and neuronal glucose is that of PET scans (positronic emission tomography). Alternatively, the stabilization / inversion of diabetic retinopathy can be sought. In terms of neuronal function, there will be an improvement in peripheral neuropathy manifested as increased perception of sensation, especially in the feet, and a loss of the painful sensation of "burning" or "pins and needles" in the feet. There will also be an improvement in autonomic neuropathy, especially gastroparesis and an improvement in postural or orthostatic hypotension.

Diabetic heart disease is one of the most common complications of diabetes experienced by diabetic patients of both types I and II. Experts generally agree that the main fuel for both a normal and diabetic heart is free of fatty acids, a fuel that requires more oxygen on a calorie basis than glucose as fuel. As a consequence, the heart of both diabetic and non-diabetic individuals is particularly vulnerable to ischemia. If the affected tissue has been using mainly free fatty acids for energy generation, even a slight or temporary decrease in blood flow or oxygen supply would be catastrophic. On the other hand, if that tissue has been oxidizing glucose more than free fatty acids, for the generation of an equivalent amount of energy, a temporary interruption of the blood or oxygen supply would not be as harmful, since the tissue's oxygen requirements They would be minor. Therefore, for the same amount of oxygen sent to the myocardium, the use of glucose rather than the use of free fatty acid would result in increased energy generation (ATP). The present invention is capable of improving the processing capacity of the food fuel to allow more glucose to burn or oxidize and correct the overuse of free fatty acids associated with heart disease and cardiovascular disease in both diabetic and non-diabetic patients.

Furthermore, the present invention is capable of improving the complete metabolic process and, through its multiplicity of effects on neurovascular reactivity, intraglomerular pressure and hemodynamics, of stopping the progression of symptomatic diabetic nephropathy, of improving intraglomerular hemodynamics, stopping Therefore, the progression of diabetic nephropathy, and reducing the risk of development of ESRD in both diabetic and non-diabetic patients.

In addition, the present invention is capable of increasing glucose oxidation in an affected area and thereby providing more energy with the same oxygen supply for wounds, promoting healing and preventing amputations in both diabetic and non-diabetic patients. . The rational thing about this improved healing is that the tissue surrounding the affected area suffers from inadequate blood supply, leading to insufficient oxygenation. When this tissue is fueled through enhanced glucose oxidation instead of the use of free fatty acid, thereby changing from a fuel economy predominantly based on lipids to one based more on glucose oxidation, more Energy is available for wound healing for the same amount of blood flow and, consequently, more healing from the amount of oxygen distributed. In addition, the ability to achieve more energy from less oxygen, thus leads to a general malaise associated with diabetic individuals who have energy levels that are lower than normal.

On many occasions patients who have been diabetic as well as have dementia have been treated with insulin pulses. Dementia seems to be related to poor glucose metabolism in the brain, which may well be the result of a sudden narrowing of blood flow. This mediocre metabolism is at least partly the cause of dementia. The use of the treatment regimen according to the present invention in patients suffering from senile dementia has clearly shown an improvement in the state of confusion, weakness, disorientation, cognitive function and lack of memory associated with dementia as well as an improvement in the management of blood glucose Sudden narrowing of blood flow to the brain is also frequent in patients with dementia without diabetes and the device of the present invention also provides an improved metabolism to these patients and, therefore, is effective in the treatment of both patients with dementia, with And without diabetes.

In the preferred embodiment, the first week three treatments are carried out two consecutive days with a new patient. For patients who continue, the procedure is performed once a week. For patients who need / require a more intensive procedure, the procedure can be repeated 3 or more times, including continuously, every week until the desired clinical result is achieved.

The following non-limiting examples are given by way of illustration only.

Example 1

A study was conducted to evaluate the effects of Chronic Intermittent Intravenous Insulin Therapy (CIIT) on the progression of diabetic nephropathy in patients with type 1 diabetes saccharin (DM). This prospective multicenter controlled study affected 49 type 1 DM patients with kidney disease who were following the intensive therapy (IT) regimen of the Diabetes Control and Complications Test (DCCT). Of these, 26 patients formed the control group C, which continued with the IT, while 23 patients formed the treatment group (T) and weekly experienced the CIIT in addition to the IT. All patients in the study were observed in the clinic, weekly, for 18 months, had monthly checked HbA1C glycohemoglobin, and every 3 months the urinary protein excretion and creatinine elimination (CrCl) determinations. CrCl decreased significantly in both groups as expected, but the rate of CrCl decrease in group T (2.21 ± 1.62 ml / min / year) was significantly lower than in group C (7, 69 ± 1.88 ml / min / year, P = 0.0343). The conclusion is that when CIIIT is added to IT in type 1 DM patients with symptomatic nephropathy, the progression of diabetic nephropathy seems to be significantly reduced.

Example 2

A middle-aged woman with Type 1 diabetes for more than 22 years suffered from polyneuropathy. He had widespread pain and was unable to walk or even wear socks due to pain. After receiving treatment with the device of the present invention the pain had reduced to the point that the woman enjoyed a rigorous exercise such as roller skating.

Example 3

A middle-aged woman with Type 1 diabetes for more than 30 years had severe peripheral neuropathy, had constant pain under the knees and had difficulty sleeping at night. After receiving treatment with the device of the present invention, he no longer has pain medication and has no stitches of pain in his legs. He has been using the treatment for eight years.

Example 4

A middle-aged woman with type 2 diabetes for 17 years was suffering from severe congestive cardiomyopathy (expulsion fraction 14-19%). It was placed on the list to receive a heart transplant before prior treatment with the device of the present invention. After receiving the treatment, the individual reduced his insulin intake from 150 units per day to 24-26 units / day, and stabilized to the point that he no longer required a heart transplant and, in effect, was removed from the heart transplant list. The patient has been receiving treatment for 9 years and is still off the list of heart transplants. Its expulsion fraction is currently 29-32%.

Example 5

A middle-aged male with type 1 diabetes for 38 years suffered from macular degeneration (retinopathy). He was unable to drive at night. After receiving treatment with the device of the present invention, the sight of this male improved to the point that driving at night was no longer a problem. The patient has been receiving treatment for 4 years.

Example 6

A middle-aged type 2 male diabetic patient had severe heart disease that included congestive heart failure and severe arteriosclerotic heart disease. The patient was scheduled for cardiac surgery but due to his poor condition the surgeons refused to operate. After using the device of the present invention, doctors were convinced that it could withstand bypass surgery on four blood vessels. The patient had a normal postoperative recovery, of which there is almost no news in diabetic patients with their state of heart disease.

Example 7

An elderly type 2 diabetic male patient was exercising and had excellent control of circulating glucose under intensive insulin therapy that included 3-4 injections a day of subcutaneous insulin. Even so, his diabetes-related kidney disease had progressed to the point that he was eliminating

1,500 milligrams of protein over a 24-hour period and the growth rate was 500 milligrams / 24 hours / year. After using the device of the present invention, the patient's proteinuria was reduced to 600-800 milligrams / 24 hours. He has been using the device for 5 years.

Example 8

An elderly type 1 diabetic female patient who was diabetic from the age of 5 was scheduled for a coronary artery bypass graft to correct her diabetes-related heart disease. Surgeons were reluctant to operate in the state in which it was due to its advanced diabetes-related atherosclerosis. It was programmed for a graft in a single blood vessel. After using the device of the present invention, its condition improved to the point that doctors performed two grafts instead of one. He had a normal recovery. He continued to use the device of the present invention for several years after surgery with no further deterioration in his diabetes-related heart disease.

Example 9

An elderly type 2 diabetic male suffering from autonomic neuropathy had very high blood pressure readings of 200/120 despite a rigorous program to regulate his circulating glucose using intensive insulin therapy of 3 to 4 daily subcutaneous insulin injections . As a result of using the device of the present invention, his blood pressure decreased to 120/80. He has been using the device for 5 years.

Example 10

An elderly type 2 diabetic male patient had an amputated leg as a result of diabetes-related ulcers in that leg. He had developed ulcers on the other leg that did not respond to any available therapy and was in danger of losing the other leg by amputation. As a result of using the device of the present invention, the ulcers in his second leg healed, and the leg was saved from amputation. This patient used the device of the present invention for several more years, and no further ulcers formed.

Example 11

A middle-aged type 1 diabetic female patient had developed severe ulcers on both legs, which did not heal with any available treatment. As a result of using the device of the present invention, the ulcers healed and did not reappear. The patient has been using the device of the present invention for 13 years.

Example 12

A middle-aged type 2 diabetic male patient had proliferative diabetic retinopathy with severe bleeding. Multiple photocoagulation signals made additional photocoagulation impossible. As a result of using the device of the present invention, the bleeding was stopped, and there was no further deterioration of the retina, preserving the remaining view. The patient has been using the device of the present invention for 5 years, and has not

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had no hemorrhage more than the retina and no additional photocoagulation.

Example 13

An elderly type 2 diabetic female patient had severe painful peripheral neuropathy to the point that she was unable to walk and used a wheelchair. After six months of using the device of the present invention, the pain had subsided to the point that he no longer used a wheelchair. Due to financial reasons, he stopped therapy. As a result, the neuropathy reappeared and had to use the wheelchair again.

Example 14

A middle-aged type 1 diabetic female patient had severe neuropathy. She was a mother with two children who was bedridden with autonomic neuropathy before using the device of the present invention two years ago. His muscles had atrophied, he couldn't digest his diet, he had been told that his nerves were dying inside her as a result of his diabetes. He pointed out that if he had to take care of two children, he would have taken care of his life. He had to leave his job, remained disabled and was often entering and leaving the hospital. He had hives in his head that caused hair loss. He had no sensation in his feet, had constant nausea, and could not sleep at night due to pain. He had insulin absorption problems and tried all the different ways to improve the absorption of insulin in his body. For several years he was injected intramuscularly because he felt he achieved better insulin absorption in that way. Since using the device of the present invention they have reversed all their illnesses to the point that their disability has disappeared and they have paid work. Since then he has not returned to a hospital. His sensation of sleeping legs has disappeared. If you skip the treatment for a week, you may feel that the feeling of sleeping legs reappears. His gastroparesis reversed, and he no longer suffers the symptoms. Apart from using the device of the present invention, it currently has no medical expenses.

Example 15

A 79-year-old diabetic woman who was suffering from advanced senile dementia moved to a nursing home due to her excessive confusion, weakness, disorientation and lack of memory. Because the nursing home was not following the strict four-point regimen that the patient needed for diabetic blood sugar control, the patient's children removed the patient from the nursing home. The doctor on call recommended Hepatic Activation. Once the patient was activated, he totally returned to an independent lifestyle. He had a significant improvement in his motor skills, memory and cognitive function. Hepatic Activation clearly had a positive effect on his senile dementia.

For all the examples listed above, a few days after the start of treatment, patients underwent treatment once a week, each day of treatment consisted of three infusions of insulin accompanied by ingestion of carbohydrates. The pump device used to infuse insulin was the Bionica MD-110 pump described in Fig. 1 without the circulating glucose sensor. Typically, there were ten pulses given over a period of one hour, and a one-hour rest period was stored between insulin infusions. The way in which carbohydrates were ingested changed from time to time and the intake of high glycemic foods was included but not limited to bread and sweets. The circulating glucose of the patients was measured once every thirty minutes by the finger prick method commonly used by most diabetic patients. Circulating glucose levels initially rose during each treatment and then fell between 50 and 100 mg / dl during each series of insulin infusions indicating that, in fact, the liver had been activated. Table 1 below summarizes by the previous examples the number of insulin units per pulse administered and the amount of glucose ingested for each series of pulses:

The preferred embodiments described herein are illustrative only, and although the examples given include many of the specificities, it is understood that they are illustrative of only a few possible embodiments of the invention. Without any doubt, other embodiments and modifications will take place for those skilled in the art. The examples given should be interpreted only as illustrations of some of the preferred embodiments of the invention, and the full scope of the invention should be determined by the appended claims.

Table 1

Summary of the previous examples: The number of insulin units per pulse administered and the amount of glucose ingested for each series of pulses

Example Number

Number of milliunits of insulin / kg of body weight per pulse Grams of Glucose per Insulin Pulse Series

pulse

one*

15-195 40-100 grams

2

30-45 50-60 grams

3

35-50 40-60 grams

4

45-60 40-60 grams

5

30-45 50-60 grams

6

70-100 50-70 grams

7

40-60 50-70 grams

8

15-45 50-70 grams

9

40-55 50-70 grams

10

45-60 40-60 grams

eleven

15-45 50-70 grams

12

130-170 50-70 grams

13

30-60 50-70 grams

14

30-60 50-70 grams

fifteen

30-60 50-70 grams

* This study included 23 patients in the treatment group with varying amounts of insulin per pulse and variable glucose intake. Therefore, the general limits of what they used are included

Claims (20)

1.-Insulin for use in a treatment procedure of a patient with poor hepatic glucose processing, said procedure comprising the steps of: ingestion by the patient of a meal containing carbohydrates; supply to the patient of a series of pulses of said insulin by means of an infusion device, wherein the amount of said insulin in each pulse, the interval between pulses and the amount of time to deliver each pulse to the patient are chosen such that the level of glucose circulating in the patient, controlled by a control device, is initially rises and then falls by an amount equal to 50 mg / dl or more. 2. Insulin according to claim 1, wherein the treatment is to improve the energy levels of the individual. 3. Insulin according to claim 1, wherein the treatment is the improvement of one or more of the states of confusion, weakness, disorientation, cognitive function or lack of memory in patients suffering from dementia. 4. Insulin according to claim 1, wherein the treatment is to stop the progression of nephropathy by reducing the risk of end-stage renal disease. 5. Insulin according to claim 1, wherein the treatment is to correct the overuse of fatty acids associated with heart disease and cardiovascular disease. 6. Insulin according to claim 1, wherein the treatment is to stabilize or reverse the progression of retinopathy. 7. Insulin according to claim 1, wherein the treatment is to improve the symptoms of autonomic neuropathy including gastroparesis and orthostatic hypotension. 8. Insulin according to claim 1, wherein the treatment is to improve or stop the progression of peripheral neuropathy. 9. Insulin according to claim 1, wherein the treatment is to decrease hypertension and / or decrease the amount of antihypertensive medication required. 10. Insulin according to claim 1, wherein the treatment is wounds to promote healing and prevent amputations. 11. Insulin according to any of claims 1 to 10, wherein said infusion device comprises a cartridge (22) containing liquid insulin and a plunger (15; 25), and in which the plunger can rotate to dispense insulin. 12. Insulin according to any of claims 1 to 10, wherein said infusion device comprises a syringe (11) for sending insulin pulses. 13. Insulin according to any of claims 1 to 10, wherein the drop in the level of circulating glucose in the patient in an amount equal to 50 mg / dl or more, occurs within two hours of administering the First pulse of the pulse series. 14. Insulin according to any of claims 1 to 10, wherein the insulin pulses are administered intravenously. 15. Insulin according to any of claims 1 to 10, wherein the amount of insulin in each pulse is between 10 and 200 milliunits per kilogram of body weight. 16. Insulin according to any of claims 1 to 10, wherein said infusion device comprises a programmable processing unit and the amount of insulin in each pulse, the time interval between pulses and the amount of time to deliver each Patient pulse are controlled by said programmable processing unit. 17. Insulin according to any one of claims 1 to 10, wherein one of said series of pulses is supplied over a period of 6 to 180 minutes. 18. Insulin according to any of claims 1 to 10, wherein each pulse of said series of pulses is supplied every 3 to 30 minutes. 19. Insulin according to any of claims 1 to 10, wherein said food containing carbohydrates contains between 40 and 100 grams of glucose. 20. Insulin according to any of claims 1 to 10, wherein said supply of said series 5 of pulses is done 2 to 8 times a day. 21. Insulin according to any of claims 1 to 10, wherein the information is automatically transferred between a blood glucose meter and a pump. 22. Insulin according to any of the preceding claims, wherein said patient suffers from diabetes 10