Pulsatile Intravenous Insulin Therapy: Normalization of Hepatic Metabolism as a Primary
Purpose of Insulin Therapy
Mohammadreza Mirbolooki1 Victor K Knutzen2 David Scharp3 Jonathan RT Lakey2
Melanie J. Kunz4
1. Department of Surgery, University of Alberta, Edmonton, Canada
2. Clinical Islet transplant Group Inc. Edmonton Alberta Canada
3. Proto Laboratories, Irvine California, USA
4. MedEdCo, CAT (PIVIT) Protocol, Phoenix, Arizona, USA
PUBLICATION NOTICE: THIS PAPER HAS BEEN
SUBMITTED FOR PUBLICATION, AND NO DISCLOSURE OR
USE OF THIS PAPER IS ALLOWED WITHOUT THE
PERMISSION OF AN AUTHOR.
Corresponding Author:
Jonathan RT Lakey, PhD
Edmonton Alberta
Canada T6H 3Z8
Please contact: Melanie Kunz, NP, mjk1048@aol.com
Abstract
In normal subjects, insulin in the basal state and after stimulation is secreted in a pulsatile
manner. The potential clinical importance of pulsatile insulin release was understood when it was
found that persons with Type 2 diabetes demonstrated an altered plasma insulin pattern. Not all
studies showed a benefit in lowering the HbA1c with insulin administration and none of them
mimics the pulsatile fashion of normal insulin secretion. Some reports suggest a normalization of
the pulsatile pattern of insulin secretion by GLP-1, however, inhibition of gastrointestinal
motility observed with GLP-1 and its analogues should be considered. Current clinical islet
transplantation can accomplish insulin independence just for 3–5 years and with some side
effects. Pulsatile intravenous insulin therapy also referred to as chronic intermittent intravenous
insulin infusion Therapy (CIIIT) or hepatic activation is one of the treatments for diabetes
involving the delivery of insulin intravenously and in a pulsatile fashion. This review highlights
the pathophysiology of insulin secretion and the current therapies for diabetes with an emphasis
on the normalization of hepatic metabolism as a primary purpose of insulin therapy for
preventing and treating diabetes complications through pulsatile Intravenous Insulin Therapy
(PIVIT).
2
Introduction
Diabetes Mellitus is a disease with a growing prevalence worldwide. It is currently estimated that
190 million people around the world suffer from diabetes mellitus, with over 330 million
predicted to have the condition by the year 2025 [1]. Currently, diabetes mellitus affects nearly
21 million persons in the United States [2]. Both type 1 and type 2 diabetes mellitus are important
health problems. Type 1 diabetes (juvenile or insulin-dependent diabetes) is due primarily to
insulin deficiency caused by autoimmune destruction of the pancreatic beta cells. However, the
major pathogenic factor in type 2 diabetes (adult-onset or non–insulin-dependent diabetes) is
insulin resistance, resulting in a functional or relative insulin deficiency [ 3]. Consequently,
superimposed insulin resistance may influence the amount of insulin release from the pancreatic
beta cells and leads type 2 diabetics to be insulin-dependent.
Insulin discovery in 1922 has led to only partial clinical success in the treatment of
hyperglycemia and even less in preventing the development of chronic complications which play
an important role in decreasing life expectancy and adversely affecting quality of life. Failure in
the treatment of diabetes does not seem to be due to the quality of the exogenous insulin since the
introduction of human insulin [ 4 ]. However, it may be due to the inappropriateness of its
administration. The primary purpose of insulin therapy for diabetics has been to control blood
glucose since its discovery. The current insulin administration is not pulsatile and does not reach
high enough insulin concentration to the liver in a manner that can prevent impaired processing
of dietary glucose and impaired enzyme production needed for optimal liver function. This
review highlights the patho-physiology of insulin secretion and the current therapies for diabetes
3
with an emphasis on the normalization of hepatic metabolism as a primary purpose of insulin
therapy for preventing and treating diabetes complications through Pulsatile Intravenous Insulin
Therapy (PIVIT).
Physiology of insulin secretion
In subjects without diabetes, insulin in the basal state and after stimulation is secreted in a
pulsatile manner [ 5 ]. Pulsatile release of insulin provides significant oscillations of insulin
concentrations in the portal vein [ 6 ] that are much smaller but detectable in the systemic
circulation. In the fasting state, these insulin secretory bursts occur at intervals of 5–15 min [7].
The discovery of plasma insulin oscillations dates back to 1977 from studies in the fasting
monkey [8] and were demonstrated shortly thereafter in humans [5]. The appearance of regular
plasma insulin oscillations in the portal vein requires not only coordination of the beta cells in the
islet but also coordination between the islets of the pancreas. When the endogenous insulin
production is suppressed by somatostatin, pulsatile delivery of insulin has a greater hypoglycemic
effect than continuous delivery [ 9], although this effect is not universal [ 10 ]. The greater
hypoglycemic action of pulsatile delivery is probably related to the expression of insulin
receptors on target tissue. An important step towards resolving the nature of the oscillations came
with the demonstration that the isolated perfused pancreas produced pulsatile release of insulin
[11]. The pulses were amplitude-regulated and the duration was approximately 6 minutes. An
important observation was that similar oscillations returned in patients with diabetes following
their receipt of a transplanted pancreas [12]. The pulsatile pattern was further traced to the
individual isolated islet, which also showed amplitude-regulated oscillations of insulin release
with similar durations as previously described in the perfused pancreas and in vivo [13].
In a pancreatic beta cell, glucose is phosphorylated to glucose- 6-phosphate by glucokinase. After
conversion of glucose-6-phosphate to fructose-6-phosphate there is further phosphorylation to
4
fructose-1,6-bisphosphate by phosphofructokinase. The oscillatory behavior of phosphofructokinase induces corresponding variations in the glycolytic and mitochondrial ATP production,
which in turn drive the ratio of the cytoplasmic concentrations of ATP and ADP (ATP/ADP)
vary rhythmically. Oscillations in the ATP/ADP ratio induce corresponding rhythmic changes in
the permeability of the ATP-sensitive K+-channels. These regular membrane depolarizations
cause openings of the voltage-dependent calcium channels. The periodic influx of Ca2+ ions
produces the oscillations in the cytoplasmic Ca2+ concentration [14]. These periodic and coordinated increases in the ATP/ADP ratio and cytoplasmic Ca2+ concentration produce episodic
exocytosis of insulin granules [ 15 ] (Fig. 1). The intermittent high cytoplasmic Ca2+
concentrations are adequate for triggering exocytosis but decrease the risks for an intracellular
overload of Ca2+ in the beta cell and inhibits the initiation of apoptotic signals in the cell [16].
Insulin Secretion in Diabetes
The relevance of the variations in plasma insulin was implicated when the rhythm has been
reported to be deranged in persons with Type 2 diabetes [17], which may be a contributing factor
to the development of insulin resistance and glucose intolerance. Furthermore, in persons with
diabetes, pulsatile delivery of insulin has been shown to be superior to continuous delivery [18].
Indeed, in one study, 40% less insulin was required when insulin was infused in a pulsatile
fashion [19]. Supporting such a view, the regularity of plasma insulin pulses from the perfused
pancreas was decreased when the neurotoxin tetrodotoxin was included in the perfusate [20]. The
poor secretory response of the islets and the gradual reduction of the amplitude of the insulin
pulses observed in the type 2 diabetes islet responding to the sulfonylurea support the idea that
type 2 diabetes is associated with an inadequate supply of energy in the beta cell to maintain
secretion. However, in one of the very few studies with islets from glucose-intolerant individuals,
glucose-induced oscillations in Ca2+ were recorded with similar frequency as in normal
5
individuals [21]. The main finding of the study is that all 20 individual islets isolated from three
subjects with type 2 diabetes released insulin in a pulsatile manner [22].
While it appears that insulin release remains occilatory in Type 2 diabetes, the less accentuated
plasma oscillatory pattern could lead to down-regulation of insulin receptors. The finding that the
beta cell is equipped with insulin receptors [23] made conditions with altered insulin receptor
signaling relevant also for the insulin-producing cell. It was recently demonstrated in a mouse
model that a selective inactivation of the gene encoding the insulin receptor of the beta cell was
associated with loss of insulin secretion in response to glucose and a progressive impairment of
glucose tolerance [24]. Based on these results, we suggest that not only mutations of the insulin
receptor of the beta cell could lead to deranged plasma insulin pattern in humans, but also altered
oscillations of insulin sensing by the beta cell’s insulin receptor can lead to ongoing deterioration
in insulin release responses to glucose levels.
The potential clinical importance of pulsatile insulin release was understood when it was found
that persons with Type 2 diabetes demonstrated an altered plasma insulin pattern [17]. Also,
relatives of persons with Type 2 as well as Type 1 diabetes were found to have derangements in
their plasma insulin oscillations [25]. Such findings have raised the idea to use analysis of the
kinetics of plasma insulin release as a diagnostic tool since these changes in the rhythmicity of
plasma insulin oscillations could be an early marker for the development of diabetes [26]. An
interpretation of the observations of `brief irregular oscillations' [17] in plasma insulin from
persons with diabetes has been that there is a defective pulse generation in the beta cell. For this
reason much attention has been placed on finding the pulse generating mechanism with the
intention to restore it in these patients.
The frequency, when it can be resolved, of plasma insulin oscillations in persons with diabetes is
very similar to that observed in normal persons [27]. However, the ability of entrainment to
6
oscillations in the plasma glucose concentration with different frequencies seems to be lost in
persons with diabetes. Recently, insulin oscillatory activity with a period of 10 min was described
in persons with Type 2 diabetes [27]. Smaller amplitudes of the insulin pulses in persons with
Type 2 diabetes [28] give a smaller signal-to-noise ratio and makes it more difficult to discern the
pulses. The observation that the lowering of the amplitude of the plasma insulin oscillation while
retaining the normal frequency after baboons were exposed to streptozotocin [29] supports the
importance of the role of reduction in pulse amplitude of the insulin pulses in diabetes rather than
alterations in rhythmicity.
Current therapies for diabetes
Current strategies to treat diabetes cover a broad base of approaches. These include reducing
insulin resistance using glitazones, supplementing insulin supplies with exogenous insulin,
increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic
glucose production through biguanides, and limiting postprandial glucose absorption with alphaglucosidase inhibitors. Biological targets are also emerging such as insulin sensitizers including
protein tyrosine phosphatase-1B (PTP-1B) and glycogen synthase kinase 3 (GSK3), inhibitors of
gluconeogenesis like pyruvate dehydrogenase kinase (PDH) inhibitors, lipolysis inhibitors, fat
oxidation including carnitine palmitoyltransferase (CPT) I and II inhibitors, and energy
expenditure by means of beta 3-adrenoceptor agonists [ 30 ]. Agents that stimulate insulin
secretion (glucose [31], sulfonylureas [32], and incretin hormones [33]) increase burst mass,
whereas inhibitory factors (like somatostatin [34]) lead to a decrement.
Repaglinide augments first-phase insulin secretion as well as high-frequency insulin secretory
burst mass and amplitude during glucose entrainment in patients with Type 2 diabetes, while
regularity of the insulin release process was unaltered [35]. The sulfonylurea agent gliclazide
augments insulin secretion by concurrently increasing pulse mass and basal insulin secretion
7
without changing secretory burst frequency or regularity. However, the treatment of individuals
with type 2 diabetes with sulfonyl- ureas has its obvious limitations in not alleviating the problem
with impaired metabolism. The reports suggest a possible relationship between the improvement
in short-term glycemic control and the acute improvement of regularity of the in vivo insulin
release process [ 36 ]. In healthy subjects receiving a continuous glucose infusion, GLP-1
specifically increased the secretory burst mass and amplitude of pulsatile insulin secretion,
whereas burst frequency was not affected [33]. Some reports suggest a normalization of the
pulsatile pattern of insulin secretion by GLP-1, which supports the future therapeutic use of GLP1–derived agents [37]. However, inhibition of gastrointestinal motility observed with GLP-1 and
its analogues should be considered [38] in trying to adapt GLP-1 as an approved agent for
diabetes treatment.
Insulin Therapy
Banting and Best first used insulin extracted from bovine pancreata to treat a boy with Type 1
diabetes in Toronto in 1922 [39]. Until the 1990s, the most commonly prescribed insulins were
extracted from bovine or porcine pancreata. There was a concern then that beef or pork insulin
would lead to the production of antibodies, increasing insulin resistance. Human insulin
(Humulin line) was then manufactured in 1981 using recombinant DNA technology to synthesize
the alpha and beta chains of insulin within Escherichia coli. The newest insulins are insulin
analogs [40] or designer insulins. These insulins are no longer classified as “long-acting” or
“short-acting,” but rather are made to mimic the action of endogenous insulin and are classified
as basal (fasting) or bolus (mealtime) insulins. The rapid-acting bolus insulins include Eli Lilly's
Humalog (lispro), Novo Novodisk's Novolog (aspart), and Sanofi-Aventis' Apidra (glulisine).
These designer insulins differ from human insulin in that certain amino acids in the insulin
molecule itself are rearranged or substituted to allow a faster onset of activity and shorter
8
duration. Lispro differs from regular insulin in that the 28th and 29th amino acids of the betachain of insulin are reversed to form lys-pro instead of pro-lys [41]. Aspart is a recombinant
human insulin in which aspartic acid is substituted for proline at B28. Glulisine has a lysine
substituted for arginine at B3 and glutamic acid replaces lysine at B29. Of designer basal insulins,
Glargine (Lantus by Sanofi-Aventis) has no onset of action or peak as a result of the addition of 2
arginines at the carboxyterminal end of the beta chain (B31 and B32) and the substitution of
glycine for asparaginase at A21, which delays its solubility at physiological pH. Another basal
analog insulin is Detemir (Novo Nordisk). This analog created by fatty acid acylation within the
insulin molecule is like NPH and is used twice a day, but has less of a peak. In preliminary
testing among Type 1 and 2 patients with diabetes, Detemir led to improved glycemic control
without weight gain, which could prove to be a substantial advantage over other insulins and
insulin secretagogues. Most studies comparing human and analog insulin use found that
postprandial glucoses were lower and hypoglycemic episodes were lower, particularly overnight,
with the newer analogs [42]. Cefalu reported that after a 3-month study in 26 patients with Type
2 diabetes, there was no significant change in pulmonary function, whereas blood sugar control
improved when patients were switched from orals or insulin injections to inhaled insulin use at
mealtimes and bedtime [43]. The inhaler delivered consistent doses of insulin, similar to injected
insulin in bioavailability and potency. Intrapulmonary insulin delivery has been preferred to
intranasal delivery, because the latter would require the use of surfactants to allow insulin to
cross the nasal mucosa, since the bioavailability of the dose is low at no more than 10%.
Insulin use is associated with weight gain. In the Diabetes Control and Complications Trial
(DCCT) trial, the patients on intensive insulin regimens gained 5.1 kg versus those on
conventional therapy who gained 2.4 kg [44]. In the UKPDS study, those on insulin or insulin
9
secretagogues gained weight (10.4 kg for insulin users and 3.7 kg for those using sulfonylureas)
[45]. Not all studies showed a benefit in lowering the HbA1c with insulin administration.
Most importantly, none of these approaches mimics the pulsatile fashion of normal insulin
secretion. With the observations that derangements in the amplitude of normal pulsatile insulin
secretion most likely have important patho-physiologic consequences in the ongoing
development of Type 2 diabetes, it has become critical to find new ways to study and to observe
treatments of patients that focus on restoring the amplitude of physiologic insulin secretion to
normal. These opportunities exist in patients following pancreas and islet transplantation and in
those receiving pulsatile intravenous insulin therapy (PIVIT).
Islet Transplantation
Conventional insulin therapy with intermittent injections or pump delivery accomplishes
imperfect glycemic control with attendant risks of hypoglycemia and micro-vascular
complications as well as considerable personal inconvenience [44]. Thus, beta cell replacement is
an attractive potential therapy for Type 1 diabetes. Pancreas transplantation is frequently
performed with kidney transplantation and allows longstanding insulin independence in most
patients [46]. However, whole-pancreas transplantation carries significant surgical morbidities
and finite mortality risks. Intrahepatic islet transplantation via the portal vein is a relatively safe
procedure. Potential advantages of the intrahepatic route of islet transplantation include delivery
of insulin directly to the liver. In health, insulin is secreted into the portal venous circulation to
the liver, which extracts more than 80% during the first passage. Thus, the physiological balance
between hepatic and extrahepatic insulin exposure requires portal delivery of insulin [47]. Insulin
signaling and insulin extraction by the liver may be optimized by a pulsatile mode of insulin
delivery. It’s been reported that insulin secretion in islet transplant recipients is pulsatile and that
glucose-induced insulin secretion is accomplished through amplification of pulse size.
10
Furthermore, it’s been also observed via a direct transhepatic catheterization approach that
hepatic first-pass insulin extraction is similar in patients after intraportal islet autotransplantation
and healthy control subjects, implying that insulin secreted from islet grafts is delivered into
hepatic sinusoids rather than into the hepatic central vein [48].
Current clinical islet transplantation can accomplish insulin independence just for 3–5 years [49].
Proposed hypotheses are that the intrahepatic environment is toxic as a consequence of exposure
of islets to high concentrations of immunosuppressive drugs (first pass) and/or relatively low
oxygen concentrations [50]. Exposure of the liver sinusoids to high local concentrations of
insulin secreted from intraportal islet grafts may have other metabolic consequences. Hepatic
steatosis occurs in a subgroup of patients after successful intraportal islet transplantation [51].
Graft failure was associated with reversal of this lesion [52]. Such findings could indicate that
insulin released by intraportal islet grafts into the liver sinusoids induces lipid deposition, e.g., via
promoting the esterification of free fatty acids within the hepatocytes.
While these specific
problems with intra-portal vein islet transplantation are continuing to be approached, the
observations that islet and pancreas transplantation restore towards normal the amplitude of
insulin delivery from beta cells is an important confirmation of the potential importance of
restoring normal pulsatile insulin delivery in diabetes.
PIVIT
Pulsatile intravenous insulin therapy also referred to as chronic intermittent intravenous insulin
infusion Therapy (CIIIT) or hepatic activation is one of the treatments for diabetes involving the
delivery of insulin intravenously and in a pulsatile fashion. Hepatic Activation is a protocol for
intravenous insulin therapy which restores normal carbohydrate metabolism to the diabetic
patient. Responses of diabetic patients to glucose and insulin administration vary greatly, affected
in large part by their type of diabetes, their individual body habitus (thin, normal, heavy), and
11
their degree of diabetes and its duration. No matter what the particulars may be for a given
patient, PIVIT has as its ultimate goal the transition and optimization of metabolism, from one
that is predominantly lipid based, as in the diabetic, to one that is carbohydrate based that is the
normal state in those without diabetes. It appears to be able to achieve this by restoring high
amplitude insulin delivery to the liver first and secondly to the rest of the body. This potentially
important therapy began several years ago, but it has been lost as a mainstream approach of
investigation and treatment in patients with diabetes.
It is time to revisit this potentially
important method of insulin therapy, based most recently on predominantly anecdotal
observations in patients with diabetes, to determine its potential of affecting the progression of
diabetes.
The Use of PIVIT
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 (0.70.8 when the fat oxidation becomes the primary source of metabolism. While over time, the
specific treatment parameters may end up different, one patient to another, the common goal for
all is the same: to find the appropriate dosing of insulin and oral glucose that will optimize and
then maintain a more normal carbohydrate metabolism. There are two distinct phases in PIVIT
therapy: An initial induction phase during which blood sugars and RQ responses to treatment
allow the treatment to be “dialed in” for a given patient, and a maintenance phase during which
parameters tend to stay fairly constant and treatment can be appropriately “aggressive” to achieve
the most physiologic benefit during each treatment session. The treatment regimen begins with
two consecutive days of activation. The physician will determine whether these days will be done
as inpatients or outpatients. Thereafter, the patient is activated once a week (or once every two
weeks in some cases) on an outpatient basis.
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Before starting treatment, if the blood sugar level (BSL) is under 100 mg/dl, no treatment should
be commenced and the patient should review his/her diet and insulin dosages, making necessary
adjustments to ensure fasting BSL is equal or greater than 150 mg/dl the morning of treatments.
If the BSL is between 101 mg/dl and 149 mg/dl, the patient should be given 40 to 60 grams of
Glucola. If the BSL is greater than 550 mg/dl, the treatment session should not get commenced.
The goal during the maintenance phase is to administer 80 to 100 grams of glucose during each
treatment hour while administering the appropriate doses of pulsed insulin to keep blood sugar
levels in the activation range of 150 to 300 mg/dl.
Patients with type 1 diabetes and BMI below 18.5 Kg/m2 typically take up to a total of 40 units of
insulin daily. They usually have initial RQs in the 0.60 to 0.70 range and respond readily to small
doses of insulin, making them prone to hypoglycemia. They are often “brittle” diabetics. After
receiving Glucola based on a standard chart, the pulses are begun at 10 mu/Kg. BSLs are
recorded every 30 minutes if the patients are “in range” and as long as the BSL does not fall
greater than 75 mg/dl from the prior reading. Patients with BMI 18.5 to 25, are of average body
habitus and typically use 40 to 80 units of insulin a day. Initial RQs are often 0.80 to 0.90. The
starting dose is 12 mu/Kg following by the above schedule. These patients tolerate 2 mu/Kg
increases in the pulse doses and they do not normally exceed 26 mu/Kg pulsed doses. It may take
up to 4 months to achieve their optimum dosage levels. Patients with BMI 25 to 30 are “chubby”
to obese endomorphic body types, often using 40 to 120 units of total insulin daily. Initial RQs
may be from 0.60 to 0.85. Morbid obesity is not typical of Type I diabetics and these patients
almost always need higher pulsed doses than other Type I patients. While the treatment goal is to
achieve RQ levels as close to the normal range at the end of each treatment, it may take several
treatments to achieve this objective.
13
Patients with type 2 diabetes have a variable body habitus, ranging from thin to morbidly obese.
Typically, their insulin requirements are higher than for Type I diabetics (from 50 to over 200
units per day) and their starting and eventual PIVIT doses are higher. Except for the morbidly
obese patient, all Type II patients are treated the same as Type I diabetics, although they can
usually be started at 12 to 14 mu/Kg because of insulin resistance. Their pulsed doses may need
to be as high as 34 mu/Kg. They are less prone to hypoglycemia as the dose rate increases. These
patients lose weight, so the typical doses needed early in treatments may need to be reduced.
Because insulin and glucose needs vary greatly among patients, it may take several weeks to a
few months to find the optimal treatment regimen for a given patient. Even though metabolism is
a dynamic system, influenced by a number of factors, most patients eventually develop a steady
state “range” for insulin doses that tends to be fairly constant. Once metabolism is optimized with
PIVIT, treatment dosing schedules should begin with higher doses during the first treatment hour,
sequentially reduced or maintained for the next two treatments hours, as dictated by patient
responses. The standard activation treatment day consists of three one-hour treatment sessions
each followed by a "rest" hour for a total of six hours for a complete treatment day. The patient is
monitored with sequential blood sugar determinations at least every 30 minutes, and more often
if blood sugar levels are changing rapidly, and with hourly RQs to monitor in real time the
transition from diabetic metabolism toward normal. During the rest hour, the patient is free to
walk or move about the treatment area.
Brittle Diabetes and Hypoglycemic Unawareness
Type 1 diabetes is an intrinsically unstable condition. However, the term "brittle diabetes" is
reserved for those cases in which the instability, whatever its cause, results in disruption of life
and often recurrent and/or prolonged hospitalization. It affects 3/1000 insulin-dependent diabetic
patients, mainly young women. Its prognosis is poor with lower quality of life scores, more
14
microvascular and pregnancy complications and shortened life expectancy. Three forms have
been described: recurrent diabetic ketoacidosis, predominant hypoglycemic forms and mixed
instability. Main causes of brittleness include malabsorption, certain drugs (alcohol,
antipsychotics), defective insulin absorption or degradation, defect of hyperglycemic hormones
especially glucocorticoid and glucagon, and above all delayed gastric emptying as a result of
autonomic neuropathy. Psychosocial factors are very important and factitious brittleness may
lead to a self-perpetuating condition. Once psychogenic problems have been excluded,
therapeutic strategies require firstly, the treatment of underlying organic causes of the brittleness
whenever possible and secondly optimising standard insulin therapy using analogues, multiple
injections and consideration of Continuous Subcutaneous Insulin Infusion. Alternative
approaches may still be needed for the most severely affected patients. Islet transplantation,
which restores glucose sensing, should be considered in cases of hypoglycaemic unawareness
and/or lability especially if the body mass index is < 25, but with current immunosuppressive
protocols patients must have normal renal function and preferably no plans for pregnancy.
Implantable pumps have advantages for patients who either weigh more than 80 kgs or have
abnormalities of kidney or liver function or are highly sensitized [53]. PIVIT has also shown
advantages for the patients. There is a report on long term treatment with PIVIT on 20 type 1
diabetes with brittle diabetes. The patients received the treatment for an average of 41 months.
HbA1c significantly decreased from the baseline of 8.5% to 7.0% at the end of study. Major
hypoglycemic events significantly decreased from 3.0 to 0.1/month and minor hypoglycemic
events from 13.0 to 2.4/month at the end of the study [54]. The exact mechanism by which
PIVIT decreased HbA1c levels and the frequency of hypoglycemic events has to be determined.
Diabetic Nephropathy
15
Diabetic nephropathy has become a worldwide epidemic, accounting for approximately one third
of all cases of end-stage renal disease. With increasing prevalence of diabetes and a global
prevalence of microalbuminuria of 39%, the problem is expected to grow. Improved management
of diabetes aimed at improved glycemic control, to avoid initiation of diabetic nephropathy, and
antihypertensive treatment blocking the renin-angiotensin system, to avoid its progression, need
to be implemented, particularly in high-risk patients [55]. End-stage renal disease develops in
50% of type-1 diabetes patients with overt nephropathy within 10 years and in more than 75% by
20 years in the absence of treatment. In type-2 diabetes, a greater proportion of patients have
microalbuminuria and overt nephropathy at or shortly after diagnosis of diabetes. Treatment
interventions in diabetic nephropathy include glycemic control, treatment of hypertension,
hyperlipidemia, cessation of smoking, protein restriction, and renal replacement therapy.
Multifactorial approach includes combined therapy targeting hyperglycemia, hypertension,
microalbuminuria, and dyslipidemia [56]. PIVIT has shown positive effects on glycemic control
[54] in DM, as well as on BP control in Type 1 DM with nephropathy, [57] possibly through
improvement in endothelial function. Medications required to control hypertension were reduced
46% after 3 months on PIVIT when compared to intensive conventional insulin therapy. The
exact mechanism by which PIVIT slows the progression of overt diabetic nephropathy remains to
be determined and requires additional study. This effect could also favorably influence the
intraglomerular hemodynamics and delay the progression of diabetic renal disease. However,
PIVIT’s antinephropathic effects may not arise directly from glycemic or BP control. One
hypothesis is that the restoration of nondiabetic physiologic insulin concentrations in the portal
system may directly trigger unknown mechanisms that protect renal function to a significant
degree. Another possibility is that various mechanisms crucial to protecting the glomerulus may
have a higher sensitivity to pulsatile, as opposed to continuous, administration of exogenous
16
insulin. Experiments in animals have indicated that glomerular expression of transforming
growth factor b, the key mediator between hyperglycemic and mesangial cell stimulation toward
overproduction of extracellular matrix, is stimulated by hyperglycemia, hypoinsulinemia, or both
[58], and PIVIT tends to reverse both hyperglycemia and hypoinsulinemia. The study of the
mechanisms of improvement observed by PIVIT need to be elucidated.
Diabetic Neuropathy
Diabetic polyneuropathy (DPN) is the most common late diabetic complication, and is more
frequent and severe in the type 1 diabetic population. Currently, no effective therapy exists to
prevent or treat this complication. Management and control of hyperglycemia remains
a major therapeutic goal when dealing with DPN in both Type 1 and Type 2 diabetes, and should
be supplemented by aldose reductase inhibition and antioxidant treatment. However, in the past
few years, preclinical and clinical data have indicated that factors other than hyperglycemia
contribute to DPN, and these factors account for the disproportionality of prevalence of DPN
between the two types of diabetes. Insulin and C-peptide deficiencies have emerged as important
pathogenetic factors and underlie the acute metabolic abnormalities, as well as serious chronic
perturbations of gene regulatory mechanisms, impaired neurotrophism, protein-protein
interactions and specific degenerative disorders that characterize Type 1 DPN. It has become
apparent that in insulin-deficient conditions, such as Type 1 diabetes and advanced Type 2
diabetes, both insulin and C-peptide must be replaced in order to gain hyperglycemic control and
to combat complications. As with any chronic ailment, emphasis should be on the prevention of
DPN; as the disease progresses, metabolic interventions, either directed against hyperglycemia
and its consequences or against insulin/C-peptide deficiencies, are likely to be increasingly
ineffective [59]. There is evidence showing that replacement of C-peptide in type 1 diabetes
prevents and even improves DPN [60]. The sequential abnormalities in the molecular regulation
17
of normal nerve fiber regeneration in the insulinopenic BB/Wor-rat, compared to the near normal
situation in the hyperinsulinemic BB/Z-rat, are primarily due to impaired insulin action rather
than hyperglycemia [61]. The normal nocturnal fall in blood pressure is associated with glucose
metabolism and arterial wall distensibility [62].
Abnormal circadian blood pressure rhythm has been reported to be associated with the
development of diabetic autonomic neuropathy [63]. The result of a randomized controlled
clinical study has shown an improvement of abnormal circadian blood pressure rhythm in IDDM
patients who received weekly PIVIT for 3 months besides their intensive insulin therapy [64].
Orthostatic hypotension is another manifestation of diabetic autonomic neuropathy. It’s defined
as as a decrease in diastolic blood pressure greater than 10 mmHG or decrease in systolic blood
pressure greater than 30 mmHg after 2 min of standing. Patients treated with weekly PIVIT
reported complete relief from dizziness and fainting when they stood up and blood pressure no
longer dropped precipitously with upright posture [65].
Conclusion
The plasma insulin pattern in diabetes could be explained by a lack of co-ordination between the
secretory activities of the beta cells. Loss of co-ordination could exist both between the b-cells in
the islet and between the islets in the pancreas [66].When hepatocytes were either perfused with a
constant or an oscillatory insulin concentration, the receptor expression was significantly higher
in hepatocytes exposed to the oscillatory insulin concentration [67]. The pulsatile level may act as
the enzyme production trigger to allow the liver to function in a more normal way. Intrahepatic
islet transplantation is the only existent treatment coordinated to secrete insulin in a pulsatile
manner albeit with detectable impairment of rapid release and deliver insulin directly to the liver
sinusoids. Hence, chronically implanted intrahepatic islets are capable of restoring a pattern of
insulin secretion and clearance that closely reproduces that of the native pancreas, however, it can
18
accomplish insulin independence just for 3–5 years and exposure of the liver sinusoids to high
local concentrations of insulin secreted from intraportal islet grafts may have other metabolic
consequences such as lipid deposition.
PIVIT has shown advantages for diabetic patients when added to routine insulin regimen. PIVIT
appears to markedly reduce the progression of diabetic nephropathy, neuropathy. While insulin
concentrations with PIVIT have not been confirmed to reach amplitudes in the portal vein equal
to normal endogenous pulses, peripheral venous administrations following intravenous
administration and following transit of the systemic circulation approximate that seen in the
portal vein in normals. PIVIT has not been adequately studied to date in animal models of
diabetes nor in the clinical trials under way. Upon examination, it is clear that the anecdotal, but
consistent responses being observed in patients receiving PIVIT are quite remarkable to those
experiencing these treatments and those delivering it. It is time to perform more rigorous study
in animals and in patients with diabetes to understand the mechanisms of how these changes are
being accomplished. It is time to determine how increasing the amplitude of oscillating insulin
delivery affects the liver and other cells and tissues in patients with diabetes to result in these
observed improvements.
Table 1: Comparison of PIVIT and Conventional Insulin Therapy
Insulin injection site
Insulin reaches the liver
Level of insulin available
to the liver.
Pattern of insulin delivery
PIVIT
Conventional Insulin Therapy
Directly into a vein
Subcutaneous tissue
Rapidly
Slowly
Very High
Very Low
(200-1000 microU/ml)*
(15-20 microU/ml)*
Sharp spikes
Gradual rise and fall
to the liver Pulses
19
* microU /ml = one millionth of a Unit of insulin per milliliter.
Table 2: PIVIT protocol
Pre-assessment
Treatment
(3 treatment courses
per day)
Goal
To collect the basal data
To make the decision of starting the
treatment
Protocol
BSL< 100: No treatment commenced on that day
100≤BSL<150: Administration of 40-60 g Glucola and
reassess in an hour. If it’s not over 150, No treatment
commenced on that day
150≤BSL<550: Start the treatment if the RQ<.90
BSL≥550: No treatment commenced on that day
Urine ketones: No treatment commenced on that day
To increase RQ to over 0.90
To keep 150≤BSL<300
Before starting insulin:
150≤BSL<200: 40 g Glucola
200≤BSL<300: 30 g Glucola
300≤BSL<350: 20 g Glucola
350≤BSL<400: 15 g Glucola
400≤BSL<550: 10 g Glucola
BMI< 18.5
18.5≤BMI<25
25≤BMI<30
BMI≥30
Starting insulin: 10 mu/Kg
Starting insulin: 12 mu/Kg
Starting insulin: 14 mu/Kg
Starting insulin: 14 mu/Kg
Max. insulin: 40 mu/Kg
Max. insulin: 80 mu/Kg
Max. insulin: 120 mu/Kg
Max. insulin: 200 mu/Kg
Rest
Rest
1 hour rest period between each treatment course
Monitoring
BSL: To prevent hypoglycemia
RQ: To evaluate the patient’s
response
BSL: Every 30 minutes
RQ: After each treatment course
20
Legend to figure
Fig 1. Oscillations, intercellular coupling, and insulin secretion in pancreatic beta cells.
Reference: MacDonald PE, Rorsman P. PLoS Biol. 2006 Feb;4(2):e49.
21
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