For Clinicians

Introduction to Microdose Infusion

An effective means to halt and reverse diabetes complications.

Pathophysiology

It is important to preface any discussion on human metabolic physiology that Type I and Type II diabetes (T1DM, T2DM) are distinctly different diseases, however they both have tremendous overlap in their metabolic impairment that allows for congruency in many treatment paradigms, and most likely be viewed as diseases resulting from impaired carbohydrate metabolism and NOT impaired glucose control.[1,2] T2DM is an extremely complex chronic metabolic disease, as is T1DM, with myriad biochemical pathways that are impaired (polyol pathway, hexosamine pathway, PKCs signaling, oxidative stress, AGEs pathway, PARP pathway, MAPK pathway, NF-kappaB signaling, hedgehog pathways, TNF-alpha signaling, cyclooxygenase pathway, interleukins, lipoxygenase pathway just to mention a few), that render the diabetic (T1DM/T2DM) patient with improper carbohydrate metabolism that ultimately subjects them chronic disease and a shortened lifespan.[3] T2DM is ultimately a systemic bioenergetic disease of the mitochondria (as is T1DM), that subsequently leads to the development of so many of the ubiquitous symptoms that are treated by many specialists as “separate diseases” ranging from macular degeneration, cardiac myopathy, cognitive impairment, to diabetic peripheral neuropathy as separate pathology, when in fact these “separate diseases” are really simply symptoms of the core metabolic problem.[4]

Because of the impairment of these biochemical pathways, T2DM is foundationally the inability of ideal carbohydrate processing in all cells of the body due to the failure of the pancreas to properly signal the liver via delivery of insulin from the beta islet cells, in a microdose pulsatile manner, to trigger the normal hepatic enzymatic pathways and gene expression that are imperative for normal carbohydrate metabolism.[5] Failure to stimulate these normal enzymatic pathways is a direct result that the hepatic cells are not receiving the normal insulin signal from the pancreas. Normal pancreatic function revolves around microdose pulsatile spikes of insulin in response to a carbohydrate load.[6] Subcutaneous insulin administration by injection, or via insulin pumps, and IV continuous insulin infusion, only lower blood glucose—and do nothing to stimulate normal hepatic enzymatic physiology.[7-9]

The signal that the pancreas is not sending is in the form of microdose of insulin. Fortunately, when Microdose Infusion provides the missing signal, the body can many time restore or improve carbohydrate processing and the core metabolic problem is directly addressed.

With improved metabolism, there is a decrease in the high levels of lipids and free fatty acids, just to mention two of myriad biochemical changes. However, these two factors alone are known to have a directly negative systemic effect, and are a major contributor of many of the complications of diabetes through metabolic inflammation (improperly high levels of pro-inflammatory cytokines IL-6, IL-2, TNFα, NFkβ).[10] In summary deficient carbohydrate processing directly causes elevation in free fatty acids, resulting in elevated cytokines (metabolic inflammation), that subjects the patient to much higher orders of magnitude of the development of chronic disease.[11-13]

Separately, the impairment of normal carbohydrate metabolism results in significantly less cellular energy throughout all cells in the body. When a body (essentially the mitochondria) cannot properly process carbohydrates, it has approximately 70% of the normal energy of a non-diabetic person, which is a huge physical disadvantage for the cell—and ultimately for the well-being of the patient.[4] With this disadvantage in cellular energy the body adapts to a lower-calorie environment, and to conserve energy is a down regulation of metabolism in order to adapt to a lower production of ATP—a negative feedback loop.

The Missing Signal of the Pancreas: The reason for the dormant liver process of not preparing the body to convert carbohydrates ideally was not known for 70 years during which big pharma sought to chemically increase insulin or reduce insulin resistance. We now know that there is no evidence that these drugs effectuate a reduction of the complications of diabetes.[14] This is because they do not restore carbohydrate metabolism, and have been shown to actually increase insulin resistance in a negative feedback loop.[15] In fact, the first action of insulin is to signal the liver with short time period micro-dose of insulin to induce through the hepatic sinusoids via portal vein delivery essential hepatic cell signaling leading to the myriad enzymatic and gene expression cascades essential in the proper maintenance of normal circulating glucose levels.[6] The biological complexity is immense, and this microdose signaling also plays an integral role to allow optimal mitochondrial energy production via the electron transport chain (the Kreb’s Cycle). These microdose of insulin are missing in both T1DM and T2DM, but Microdose Infusion can provide this essential normal physiological signaling, and uniquely addresses the hepatocyte. With this normal insulin signaling re-established, there can be improvement and sometimes restoration of hepatocellular function levels as shown by metabolic measurement.[6] This has been demonstrated in the laboratory in both dogs and rats for more than 35 years.[5] Microdose Infusion thus effectively treats the core problem so it is logical that Microdose Infusion would stop, in some cases, and reverse the complications of diabetes in some cases, which it does. Mimicking the natural stimulation of a pancreas using a sophisticated two-signal delivery process of intravenous microdose of insulin and tailored glucose challenging can restore, or greatly improve metabolism, directly and via a natural physiologic method. Microdose Infusion has effectively restored or improved proper carbohydrate and lipid metabolism in most patients with type 1 or type 2 diabetes.[16]

Result of Restoring the Kreb’s Cycle: When proper carbohydrate metabolism is restored, many biochemical interactions are upregulated and improved, but two of them occur that need to be elucidated. First, normal levels of cellular energy are restored, or greatly improved, reducing the 30% deficit of intra- cellular energy, and secondly, improved carbohydrate metabolism stops the decreases the systemic levels of inflammatory cytokines and other markers of inflammation. Improvement in lipid metabolism is believed to be the mechanism of seeing reductions in circulating free fatty acids. Because lipid metabolism is the “back-up” system of providing nutrients to the cells, it was never meant to be the primary source of energy as it is with T1DM and T2DM. Constant high lipid utilization automatically results in elevated lipids and free fatty acids, causing much of the entire diabetic milieu.[10]

Treating diabetes with Microdose Infusion – A Reversible Metabolic Dysfunction.

Effectiveness: The proprietary insulin pump that achieves Microdose Infusion (MDI) is US FDA- cleared. This is a safe and effective way to address the core problem of T1DM and T2DM, and in some cases reverse the chronic complications of diabetes and other diseases of impaired metabolism.[5-7, 9] It is equally effective for both T1DM and T2DM patients–even for the most severely impaired patients.

strong>Schematic Overview of T1DM and T2DM Complications: Clemens and colleagues published the following overview of diabetes and its “poor outcomes” which sets forth the direct causational relationship of improper carbohydrate metabolism and disability/death. It also shows the origins of all complications, the inability to properly process and metabolize glucose within the cells. Conventional therapies are not able to reestablish proper metabolism of carbohydrates by the mitochondria in the cell, and thus with any excess glucose, the patient has increased blood glucose.

The best approach to normalization of this impaired metabolism is obtained by replicating normal pancreatic stimulation of the liver. This is precisely what PII does.

Current Pharmacologic Approaches: The stated goal of all current drugs in the treatment of T1DM and T2DM is simply to reduce blood glucose, something that is not the core problem—but rather the symptom. These drugs and their pharmacodynamics can be seen in the figure below:

A Misleading Surrogate Symptom: It is well proven that not controlling blood glucose is harmful, but intensive blood sugar control does NOT stop the complications of diabetes. This has was proven by the Mayo Clinic in September 2016 when it was announced:

Over 90 per cent of experts were saying that controlling blood sugars tightly was associated with a reduction in your risk of going blind or of needing dialysis or having to undergo an amputation,”

Montori said. “But when we looked at the evidence for that, we could not see any signal that would suggest that is true despite the question being asked at least since the 1970s. [14]

And, this was not the first verification of the shortcomings of simply glucose control. The huge DCCT, and ACCORD Studies are also consistent:

DCCT: “while not controlling glucose worsens complications, tight control does not prevent 25% to 40% of diabetic patients from developing overt secondary complications within 10 years.”[17]

ACCORD (Action to Control Cardiovascular Risks in Diabetes): “Tight blood glucose control is also not the best treatment for diabetic cardiovascular disease.” This glycemia trial showed that tight blood glucose control was actually worse than keeping higher glucose levels. This caused the glycemia trial to be terminated early due to accelerated deaths and was reported in the New England Journal of Medicine in 2008.[18]

Better than any drug: It can be strongly argued that no pharmaceutical agent to date can establish improve, or normal cellular energy levels, coupled with the automatic reduction of lipid metabolism and thus the reversal of diabetic inflammatory processes, like what is seen with Microdose infusion. No drug achieves these outcomes because no other technology mimics the normal pancreas signals to the liver and body.

All Published Studies since after 2000 have uniformly shown that normal pancreas secretion is in “bursts every 4 to 6 minutes, with an amplitude of 660% of baseline.

Butler published the groundbreaking study showing that “all insulin is secreted in bursts of 660% of basal. (see Publication Abstracts).

Microdose Infusion treatment uniquely provides this microdose. By mimicking normal, a large number of other processes usually not measured or quantified become more normal, and the human body knows how to repair itself much more efficiently and quickly than imagined. This is why outcomes such as reversal of neuropathy occur sometimes in just days. Body-wide energy becomes normalized, and a host of other processes are moved toward normal.

Most importantly of all, the beauty of Microdose Infusion delivering burst insulin is that the treatment is like a normal healthy body and normal healthy pancreas stimulation of the rest of the body:

As shown above, the Microdose Infusion treatment provides the exactly normal-like insulin waves and was doing so over 10 years before it was widely known that the pancreas delivered all insulin in micro-dose causing normal oscillations. This is totally unlike and very different from conventional subcutaneous insulin by either shots or a wearable pump.

  1. Hallberg SJ, Gershuni VM, Hazbun TL, Athinarayanan SJ: Reversing Type 2 Diabetes:A Narrative Review of the Evidence. Nutrients 2019, 11(4).
  2. Taylor R, Valabhji J, Aveyard P, Paul D: Prevention and reversal of Type 2 diabetes: highlights from a symposium at the 2019 Diabetes UK Annual ProfessionalConference. Diabet Med 2019, 36(3):359-365.
  3. Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK, Kalita J, Manna P: Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol 2018, 833:472-523.
  4. Berthiaume JM, Kurdys JG, Muntean DM, Rosca MG: Mitochondrial NAD(+)/NADHRedox State and Diabetic Cardiomyopathy. Antioxid Redox Signal 2019, 30(3):375-398.
  5. Matthews DR, Naylor BA, Jones RG, Ward GM, Turner RC: Pulsatile insulin has greater hypoglycemic effect than continuous delivery. Diabetes 1983, 32(7):617-621.
  6. Wahren J, Kallas A: Loss of pulsatile insulin secretion: a factor in the pathogenesis of type 2 diabetes? Diabetes 2012, 61(9):2228-2229.
  7. Paolisso G, Scheen AJ, Giugliano D, Sgambato S, Albert A, Varricchio M, D’Onofrio F, Lefebvre PJ: Pulsatile insulin delivery has greater metabolic effects than continuous hormone administration in man: importance of pulse frequency. J Clin Endocrinol Metab 1991, 72(3):607-615.
  8. Paolisso G, Sgambato S, Gentile S, Memoli P, Giugliano D, Varricchio M, D’Onofrio F: Advantageous metabolic effects of pulsatile insulin delivery in noninsulin-dependentdiabetic patients. J Clin Endocrinol Metab 1988, 67(5):1005-1010.
  9. Paolisso G, Sgambato S, Torella R, Varricchio M, Scheen A, D’Onofrio F, Lefebvre PJ: Pulsatile insulin delivery is more efficient than continuous infusion in modulating islet cell functioning normal subjects and patients with type 1 diabetes. J Clin Endocrinol Metab 1988, 66(6):1220- 1226.
  10. Piro S, Anello M, Di Pietro C, Lizzio MN, Patane G, Rabuazzo AM, Vigneri R, Purrello M, Purrello F: Chronic exposure to free fatty acids or high glucose induces apoptosis inrat pancreatic islets: possible role of oxidative stress. Metabolism 2002, 51(10):1340-1347.
  11. Liao YF, Yin S, Chen ZQ, Li F, Zhao B: High glucose promotes tumor cell proliferationand migration in lung adenocarcinoma via the RAGENOXs pathway. Mol Med Rep 2018, 17(6):8536-8541.
  12. Schroter D, Hohn A: Role of Advanced Glycation End Products in Carcinogenesis andtheir Therapeutic Implications. Curr Pharm Des 2018, 24(44):5245-5251.
  13. Sharma A, Chari ST: Pancreatic Cancer and Diabetes Mellitus. Curr Treat Options Gastroenterol 2018, 16(4):466-478.
  14. Rodriguez-Gutierrez R, Montori VM: Glycemic Control for Patients With Type 2 Diabetes Mellitus: Our Evolving Faith in the Face of Evidence. Circ Cardiovasc Qual Outcomes2016, 9(5):504-512.
  15. Mishriky BM, Cummings DM, Tanenberg R, Pories WJ: Re-examining insulin compared to non-insulin therapies for type 2 diabetes: when in the disease trajectory is insulin preferable? Postgrad Med 2018, 130(8):653-659.
  16. Mirbolooki MR, Taylor GE, Knutzen VK, Scharp DW, Willcourt R, Lakey JR: Pulsatile intravenous insulin therapy: the best practice to reverse diabetes complications? Med Hypotheses 2009, 73(3):363-369.
  17. Chrisholm DJ: The Diabetes Control and Complications Trial (DCCT). A milestonein diabetes management. Med J Aust 1993, 159(11-12):721-723.
  18. Dluhy RG, McMahon GT: Intensive glycemic control in the ACCORD and ADVANCEtrials. N Engl J Med 2008, 358(24):2630-2633.