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Table of
Contents
1.
Introduction – Metabolic Activation Therapy
2.
Biochemical Theory for Metabolic Activation
Therapy
3.
Studies
a.
Clinical Effects of Metabolic Activation
Therapy on Cognitive Function in People with
Diabetes Mellitus
b.
Metabolic Activation Therapy in Treatment
of Patients with Type 2
Diabetes with Nephropathy
c.
Metabolic Activation Therapy in the
Treatment of Type 2 Diabetic Patients with Heart
Disease
d.
Effects of Metabolic Activation Therapy
(MAT) on Neuropathy in Diabetic Patients
e.
Diabetes Impact Management Score in
Patients with Diabetes Mellitus Treated with
Metabolic Activation Therapy
f.
Effects of Metabolic Activation Therapy on
Progressive Retinopathy in Patients with Diabetes
Mellitus
4.
Metabolic Activation Therapy Protocol
Institutional
Review Board Documentation Introduction
Developed over 25
years of research, Metabolic Activation Therapy
(MAT) is a unique therapy for individuals with
advanced diabetes. MAT has its roots in the work
of Dr. Thomas Aoki, former Head of Research at
Joslin Diabetes Center in Boston, Massachusetts,
and a current Professor of Medicine at the
University of California, Davis.
Dr. Aoki’s
pioneering work focused on the critical role of
the liver dysfunction in diabetic metabolism. He
theorized that end organ damage in diabetes is
caused by abnormal hepatic glucose metabolism,
inadequate insulin delivery and insulin
resistance. Advanced Diabetes Treatment Centers,
in conjunction with other investigators,
universities, and foundations, is involved in
multiple studies to further delineate the clinical
benefits of MAT.
The Biochemical
Theory of MAT
Normally, insulin
is secreted in a pulsatile fashion and in various
amounts, in close relationship with meals. The
balance of available experimental evidence
suggests a more potent hypoglycemic effect of
pulsatile insulin as opposed to continuous insulin
infusion. Continuous exposure to insulin and
glucagon is known to decrease the hormones’
metabolic effectiveness on splanchnic glucose
production in man. Down-regulation at the cellular
level may partially explain the decreased action
of steady-state levels, while pulsatile hormone
secretion may allow recovery of receptor affinity
or receptor numbers. Intermittent intravenous
insulin administration with peaks of insulin
concentrations may enhance suppression of
gluconeogenesis and reduce hepatic glucose
production (HGP)
For induction and
maintenance of insulin-dependent enzymes,
essential for glucose metabolism, (e.g. hepatic
glucokinase, phosphofructokinase, and pyruvate
kinase) the hepatocytes require a defined insulin
level (200-500 µU/ml in the portal vein)
concomitant with high glucose levels (“bimolecular
signal”) In non-diabetic subjects, portal insulin
concentrations are 2-3 fold greater than those in
the peripheral circulation. During the first pass
through the liver 50% of the insulin is removed,
pointing to the liver as the principal metabolic
target organ of the gastrointestinal tract and the
pancreas. The insulin retained by the hepatocytes
may itself be essential for the long-term effects
of insulin on hepatic glucose metabolism as well
as growth and de novo enzyme synthesis.
After oral glucose intake, the liver accounts for
an equal of greater proportion of total net
glucose uptake as compared to the periphery.
Insulin exerts pivotal control of glucose levels
through its ability to regulate HGP directly or
indirectly. The traditional subcutaneous (s.c.)
insulin administration regimens used by diabetic
patients a) lack the pulsatile aspect, and b) do
not reach high enough insulin concentration at the
hepatocyte level [e.g., 10 U regular insulin
injected S.C. produce a peak systemic circulation
concentration of 30-40 µU/ml and an even lower
portal vein concentration of 15-20 µU/ml]
A relative
deficiency of insulin at the hepatocyte level
leads to impaired capacity for processing of
incoming dietary glucose. With the liver being the
target organ of the pancreas, it appears,
therefore, that the primary purpose of giving
insulin to the diabetic patient should not be to
control BG level (“control theory”), but rather
the normalization of hepatic metabolism.
Furthermore, these same enzymes are found in all
glucose utilizing systems of the body, suggesting
a synchronous effect by insulin and glucose.
It has been shown
that the diabetic patient’s capacity to oxidize
and store exogenous carbohydrate is markedly
impaired. In the resting post-absorptive
non-diabetic subject, the energy requirement is
net primarily by fat oxidation reflected by a
respiratory quotient (RQ) (V CO2 /V O2)
of 0.7-0.8 (indirect calorimetry) After glucose
administration, CO 2 production and
consequently the RQ increase (0.9-1.0), indicating
that glucose has become the primary source of
energy. In contrast, in the patient with diabetes
mellitus on conventional insulin therapy, no such
increase in RQ or CO2 production is
observed. The possible fate of ingested glucose
is: a) oxidation (liver, brain, muscle), b)
conversion to fat (liver, muscle, adipose tissue),
c) storage as glycogen (liver, muscle) or
transamination of intermediary metabolites to form
amino acids (e.g. alanine). Only the first two
processes generate CO2 to increase the
RQ. Liver and muscle appear to be the most active
tissues for glucose oxidation. In 1985, Meistas,
et al, showed in non-diabetic post-absorptive men
that resting muscle is not the source of the
increased CO2 production after
ingestion of a 100 gram glucose meal. An increase
in the RQ to greater than 0.9 is used as the index
of therapeutic efficacy. It was postulated that
if hepatic activation was achieved and maintained
in patients with diabetes by this treatment, the
glycohemoglobin A1c (HbA1c) blood levels and the
frequency of hypoglycemic reactions should
decrease.
Clinical Effects of
MAT in Diabetes
MAT Effect on Glycemic
Control
In a study
published in 1993, the results of long-term MAT on
20 IDDM patients indicated:
- A significant decline in
HbA1c from the baseline of 8.5% to 7.0% at the
end of the observation period (p < 0.0003)
- A decline in the frequency
of major hypoglycemic events from 3.0 to
0.1/month (p < 0.001)
- A decline in the frequency
of minor hypoglycemic events from 13.0 to 2.4 ‘
month p < 0.001)
The
exact mechanism by which MAT lowered HbA1c blood
levels and decreased the frequency of hypoglycemic
events is yet to be determined. Non-diabetic
individuals stimulate hepatic processes, by way of
high portal-vein concentrations of insulin and
glucose, with every meal. The study patients’
livers were stimulated three times during 1 day of
the week rather than three times daily as in
non-diabetic individuals. The reason for the
effectiveness of MAT may lie in the long half-life
of glucokinase. The half-life of rat glucokinase
is 3-4 days and that of the human enzyme may be
longer because of the lower rate of human
metabolism.
MAT Effect on Hypertension
Systemic
hypertension is a frequent complication found in
both IDDM and NIDDM patients and has proved to be
an important risk factor for the development of
microangiopathy and macroangiopathy. In IDDM the
prevalence of hypertension increases with the
duration of the disease and develops mainly in
connection with the clinical emergence of
nephropathy. There appears to be a positive
correlation between plasma glucose elevation and
systolic blood pressure, raising the possibility
that the metabolic disorders associated with
diabetes are acting to either cause or amplify the
concurrent BP problem. Significant reductions in
systolic and diastolic BP after improvement in
metabolic control in diabetic subjects have been
reported. Conversely, in diabetic subjects studied
during controlled insulin withdrawal, the
worsening of metabolic control was accompanied by
BP increases. These reports suggest that tight
metabolic control in diabetic subjects may provide
beneficial effects on BP levels. We have recently
assessed the effects of MAT on BP control in a
prospective, randomized, crossover clinical trial
involving 26 IDDM subjects with hypertension and
nephropathy. After a stabilization period, the
study subjects were randomly assigned to control
or treatment groups for 3 months and then crossed
over into the opposite phase for another 3 months.
Addition of weekly MAT during the treatment phase
was the only procedural difference between the
control and treatment phases. Throughout the
control and treatment phases, the BP values were
maintained at the level established in each
subject at the end of the stabilization period
through appropriate adjustment in the
antihypertensive medication (AHM) dosage. The AHM
dosage requirements decreased significantly (46%;
p < 0.0001) and linearly over time ( p < 0.0058)
during the treatment phase while remaining
essentially unchanged during the control phase.
This study indicates that MAT markedly improves BP
control in subjects with IDDM and hypertension.
Increased
vascular smooth muscle (VSM) tone is the hallmark
of the hypertensive state in both IDDM and NIDDM.
Human and animal studies suggest a role for
insulin in the regulation of VSM tone. Such
insulin regulation of VSM function may be lost in
insulinopenic states. Recent evidence suggests
that insulin causes endothelium-derived nitric
oxide-dependent vasodilation and that insulin’s
vasodilating action serves to both amplify
insulin’s overall effect to stimulate skeletal
muscle glucose uptake and modulate vascular tone.
It is possible that MAT partially normalizes the
“vascular reactivity”, thus lowering the AHM
dosage requirements.
MAT Effect of Diabetic
Nephropathy
Diabetic
Nephropathy (DN) develops in 35-40% of patients
with IDDM, and it is the most common cause of
end-stage renal disease (ESRD) in the United
States. It is generally agreed that DN is the
result of hyperglycemia, whether alone or in
combination with other factors. However, once
nephropathy is clinically overt (macroalbuminuria,
decreased glomerular filtration rate), the degree
of metabolic control is believed to have lost its
significance as a risk factor with other
mechanisms having greater influence.
The effect of MAT
on the progression of DN was evaluated in a
multicenter, retrospective, longitudinal study,
involving 31 patients with type 1 diabetes
mellitus and overt DN, on intensive subcutaneous
insulin therapy (ISIT) and weekly MAT with
aggressive BP and ACEI therapy. All studies
patients were followed weekly for at least 12
months (average: 37±4.6 months), and appropriate
adjustments were made weekly in their insulin
dosage (ISIT) and in their antihypertensive
medication with the goal of maintaining optimum
glycemic control and blood pressures at or below
140/90 mm Hg for each patient. All patients had
monthly HbA1c (HPLC) and semiannual creatinine
clearance (CrC) determinations. The HgA1c levels
declined from 8.64±o.57 to 60±0.3% (p=0.0062)
during the study. The CrC remained essentially
unchanged (from 46.1±3.9 ml/min/year (p=NS). This
study suggests that addition of MAT to ISIT in
patients with Type I DM appears to arrest or
markedly reduce the progression of overt diabetic
nephropathy. Similarly favorable (interim) results
with MAT added to ISIT were reported in a larger
multicenter, prospective, controlled clinical
trial in patients with type 1 DM and overt DN.
The mechanism by
which MAT reduces the deterioration rate of renal
function is patients with overt DN remains to be
established. A recent study showed that a high
glucose concentration inhibits mesangium
degradation and could promote the mesangium
enlargement known to occur in DN. Enlargement of
the mesangium, the most consistent morphological
finding in DN, can compress the glomerular
capillaries and thus alter intraglomerular
hemodynamics. Improved glycemic control, as
obtained in the MAT treated subjects, could
promote mesangium degradation and improve renal
hemodynamics. Indeed, we already have evidence
that MAT improves systemic hemodynamics, and it is
likely that it has a similar effect on renal
hemodynamics (e.g. decrease is glomerular efferent
arteriolar vasoconstriction) resulting in the
noted decrease in the progression of DN towards
ESRD.
MAT Effect on Diabetic
Autonomic Neuropathy
Though clinical
symptoms of diabetic autonomic neuropathy (DAN)
develop in relatively few patients, the measurable
autonomic defects are extremely common in
diabetes. DAN is known to be associated with a
higher morbidity and mortality rate, as well with
elevated HbA1c levels.
A.
MAT Effect on Abnormal Circadian blood
Pressure Pattern
Several studies have demonstrated a blunted
diurnal variation in BP in patients with DAN. Insufficient BP
decline during the night might be associated with
increased target organ damage. No data is
available regarding the effects of tight glycemic
control or intensive insulin therapy on the
abnormal circadian BP pattern in patients with
IDDM. We have recently reported the results of a
randomized controlled clinical study involving 74
IDDM patients on ISIT, of which 36 (group A)
underwent, in addition, weekly MAT for three
months. Controls continued on ISIT alone. All
study patients were seen weekly by the
investigators and underwent monthly HbA1c
determinations and monthly 24-hour ambulatory BP
monitoring. The night/day systolic BP ratios
decreased from 0.97 to 0.94 and increased from
0.95 to 0.98 in the control group. Considering
that all other aspects of therapy were similar for
the two patient groups, the further improvement in
the glycemic control and the significant
improvement in the abnormal circadian BP pattern
noted in MAT patients was likely due to the
addition of weekly MAT. The cause of the abnormal
circadian BP pattern is secondary to or associated
with abnormal glucose metabolism and reduced
arterial wall distensibility as well as the
development of diabetic autonomic neuropathy. The
improvement/stability of this abnormal circadian
pattern obtained in the group A patients might be
the result of an improved metabolic milieu as
suggested by the decline in HbA1c, with possible
consequent improvement in arterial distensibility
and diabetic autonomic neuropathy. The practical
importance and clinical consequences of the
improvement in the circadian BP pattern is
conjectural at present. Insufficient BP decline
during the night might be associated with
increased target organ damage. The reversal or at
least prevention of further deterioration of the
abnormal circadian BP pattern obtained with MAT
might lesson target organ damage.
B.
MAT Effect on Orthostatic Hypotension of
Diabetes
Orthostatic hypotension (OH) of diabetes, another
likely manifestation of DAN, is defined as a decrease in
diastolic BP greater than 10 Hg or decline of
systolic BP greater than 30 mm Hg after 2 minutes
of standing, in the presence of adequate blood
volume. Diabetic patients with OH have decreased
ability to release norepinephrine, leading to low
plasma norepinephrine levels and supersensitive α
and β receptors. Diabetic OH is likely due to
impaired sympathetic vasoconstrictor activity,
leading to an impaired compensatory increase in
total peripheral resistance upon standing. The
current conventional therapy for orthostatic
hypotension of diabetes is less than satisfactory.
Even the promising newer agents such as the
somatostatin analogues, have a very limited
duration of action and require frequent
injections.
The preliminary
study was of patients with IDDM and severe
disabling postural hypotension who had previously
failed all conventional therapeutic attempts. The
patients underwent weekly MAT for 3 months while
continuing their usual regiment of four daily
subcutaneous insulin injections. Before and at the
end of this therapeutic trial the patients had
tilt-table tests, 24-hour ambulatory BP
measurements, cardiac autonomic function testing,
and HbA1c determinations. Within the first month
of MAT, a marked decrease in the intensity and
frequency of postural dizziness was noted in all
subjects, as well as the disappearance of syncopal
episodes. After 2 months of MAT, the postural
dizziness ceased entirely, and at the end of the 3rd
month of therapy, the subjects were able to resume
their customary activities. The tilt-table test
normalized in two and improved in one patient,
HbA1c levels declined, the initial abnormal
circadian BP pattern was corrected, and the score
of the cardiovascular reflex tests also improved.
These results suggest an improvement in the
vasoconstrictor mechanisms in response to postural
changes, possibly as a result of the improvement
in diabetic autonomic neuropathy, as indicated by
the normalization of the circadian BP pattern and
by the improved cardiovascular reflex score. The
improvement in the autonomic neuropathy was likely
secondary to the improved metabolic milieu during
MAT as reflected by decreased HbA1c levels. The
vascular endothelial cell secretion of the potent
vasoconstrictor endothelium (ET1) has been shown
to be enhanced by insulin in cultured cells. And
enhancement of endothelial cells ET1 production
following exposure to the high pulsatile insulin
levels in MAT could have contributed to the
improvement of the vasoconstrictor mechanism in
our patients. The studies reviewed suggest that
MAT improves glycemic control, concomitantly with
marked decrease in the frequency of both major and
minor hypoglycemic events and improves
hypoglycemia unawareness, improves control of
hypertension in diabetes, retards progression of
overt nephropathy, reverses abnormal circadian BP
patter, and corrects postural hypotension of
diabetes. Furthermore, anecdotal clinical
experience suggests that MAT also improves
diabetic peripheral polyneuropathy, diabetic
cardiomyopathy, diabetic foot ulcer healing, and
diabetic retinopathy.
Indications for
Metabolic Activation Therapy
Patients with
Diabetes Mellitus on insulin therapy, with
severe diabetes complications which failed to
improve on intensive subcutaneous insulin therapy,
as follows:
1.
Poor glycemic control with wide blood
glucose fluctuations and hypoglycemia unawareness.
2.
Overt diabetic nephropathy and hypertension.
3.
Severe autonomic neuropathy (postural
hypotension, gastroparesis).
4.
Severe painful peripheral polyneuropathy,
unresponsive to conventional therapy.
5.
Diabetic foot ulcers, unresponsive to
conventional therapy.
6.
Severe cardiac disease (CAD, cardiomyopathy)
– unresponsive to conventional therapy.
7.
Progressive Diabetic Retinopathy.
Studies
A. Clinical Effects of
Metabolic Activation Therapy on Cognitive Function
in
Patients with Type 2 Diabetes Mellitus
Introduction
In
patients with cognitive disorders (Alzheimer’s
type) infusion of intravenous insulin over a short
interval (hours) improves cognitive function.
Patients with this type of disorder have less
insulin receptors in the affected areas of brain
and insulin resistance by measurement of insulin
and glucose levels in spinal fluid. This study is
designed to study the effects of MAT on patients
with diabetes mellitus and impaired cognitive
function.
Protocol
Patients will undergo MAT as noted in previous
protocols weekly over a period of 6-12 months.
Evaluation of MAT will include PET scan,
functional MRI and laboratory studies before and
every 3 months. The laboratory studies include
CBC, chemistry profile, TSH, B12 and folate,
HS-CRP, C peptide, hemoglobin A1C, and urine
protein studies. Serial cognitive studies using
Mindstream testing will be done before and every 3
months. Interval evaluation by endocrinologist
and neurologist, as needed, will be included.
Genetic testing for epsilon allele, a factor found
absent in certain forms of cognitive disorders,
will be done on blood drawn during the test
period. Patients must be diabetics on insulin or
oral agent who have primarily a non-traumatic
cognitive disorder without out other metabolic
causes.
Evaluation
Statistical evaluation will be performed
intermittently during the study on laboratory,
imaging and cognitive testing.
B. Metabolic Activation
Therapy in Treatment of Patients with Type 2
Diabetes with Nephropathy
Introduction
Diabetic nephropathy is a progressive complication
leading to end state kidney disease with anemia,
hypertension and eventually dialysis. A
multicenter trial of metabolic activation therapy
(MAT) in type 1 diabetics showed a slowing of the
progression over a control group using maximal
conventional therapy (Metabolism 49:1491-95,
2000). This study is to determine if the same
benefit occurs in type 2 diabetics with kidney
disease.
Background
Diabetic nephropathy develops in 20-50% of type 2
diabetics and is one of the most common causes of
dialysis requiring disease. Proteinuria occurs
early in the disease and condition continues
despite maximal treatment although the rate may
slow. The cost of treatment is significant. The
study will be a randomized controlled study done
in cooperation with the Center for Complex
Studies, Florida Atlantic University.
Study Design
Entry criteria are patients with type 2 diabetes
with serum creatinine over 1.4 mg/dl, mild to
severe proteinuria, and no evidence of other
kidney disease who will be compared to age matched
diabetic controls. Treatment groups will undergo
MAT weekly for 12 months with self renewing 12
month periods. MAT will be done as follows;
Intravenous insulin will be given in a
predetermined pulsatile manner along with oral
glucose over a one hour period with monitoring of
frequent capillary glucoses and respiratory
quotients (RQ) before and after the infusion.
After the one hour MAT, a one hour rest is given
and glucose are monitored. The MAT is repeated
again for one hour with a one hour rest two more
times in sequence, again with the monitoring of
capillary glucoses and RQ's. These measurements
are used to determine the doses of insulin and the
glucose loads required on subsequent MATs.
Study Parameters
In
addition to weight, and blood pressure, laboratory
studies will be done before as well as at 3, 6,
and 12 months of study. These will include CBC,
Chemistry profile, HbA1C, TSH, lipid profile, C-
peptide, aldosterone, brain natiuretic protein,
HS-CRP, IgF-1, homocysteine, and urine protein
studies.
End points
The
study will be evaluated every 3 months
statistically and compared with the control group
by the study parameters noted.
C. Metabolic Activation
Therapy in the Treatment of Type 2 Diabetics with
Heart Disease
Introduction
Infusion intravenously of glucose and insulin work
at the cellular level in cardiac muscle as oubain
(digitalis). Altered glucose metabolism in the
heart makes fatty acids a primary energy source.
Fatty acids require increased oxygen utilization
for energy production while producing decreased
contractility. Glucose metabolism is preferred by
heart muscle but impaired in diabetics by insulin
resistance and decreased post-prandial glucose
uptake. This study is designed to test the effect
of MAT on cardiac function in Type 2 diabetics
with significant cardiac disease.
Protocol
Patients selected will undergo MAT for 6-12 months
weekly with cardiac PET scans, functional MRI,
echocardiography, nuclear stress tests, and
questionnaires before and every 3 months.
Laboratory studies to be done before and every 3
months include CBC, chemistry profile, TSH, C
peptide, hemoglobin A1C, aldosterone, HS-CRP, B-natiuretic
protein, IgF-1, lipids, and urine protein
studies. Patients will have class 2-3 NYHA cardiac
disease non-valvular in nature which is on
appropriate maximal therapy. Interval evaluation
by cardiologist and endocrinologist will be
included.
End Point
Statistical evaluation will be preformed
intermittently during the study.
D. Effects of Metabolic
Activation Therapy (MAT) on Neuropathy in
Diabetic Patients
(Joint study of FAU and
Strelitz Diabetes Institute of Eastern Virginia
Medical School)
Introduction
Diabetic Neuropathy is a progressive complication
causing serious problems in 25-40% of diabetics.
It is especially common in producing peripheral
dysthesias and gastroparesis. MAT has been shown
in non controlled studies to improve both of these
types of neuropathy. This study is being done is
a controlled manner to evaluate the effectiveness
of MAT. Patients to be selected may have type 1
or 2 diabetes on oral agents or insulin and
neuropathy primarily related to diabetes,
preferably age 50-80, and the study will be 6-12
months in duration.
Protocol
Selected patients will have weekly MAT therapy
done as follows:
Intravenous access is
obtained and routine Blood pressure and glucose
levels are done. Initial respiratory quotient (RQ)
is obtained by breathing into a mouthpiece
attached to a metabolic cart. Then insulin is
infused at a protocol ration in a pulsatile manner
while the patient takes in oral glucose solutions
in palatable forms. Capillary glucoses are
measured intermittently to prevent hypoglycemia.
The infusion lasts one hour and a second hour of
rest completes the first 2 hour protocol. This is
repeated 2 more times in succession on the
treatment day. RQ measurements are done
intermittently to determine the effectiveness of
the treatment. RQ goes from lower levels of
0.7-0.8 which shows primarily fat metabolism to
>0.9 which is primarily carbohydrate metabolism
during MAT. The MAT is repeated weekly for the
duration of the protocol which is 6-12 months.
Laboratory Studies
The
studies to be done initially and then at 3, 6, and
12 months include CBC, Chemistry profile, TSH,
Hemoglobin A1C, C-peptide, HS-CRP and B12 and
folate levels. Further research laboratory
studies will be done at Strelitz Diabetes
Institute on blood samples drawn. Questionnaire on
the neuropathy is done every 3 months.
End Point
Analysis of data is to be reviewed every 3 months
for changes.
E. Diabetic Impact
Management Score (DIMS) in Patients with Diabetes
Mellitus Treated with
Metabolic Activation Therapy
Introduction
Well
being is evaluated by a 44 question study protocol
to evaluate the overall change in subjective
patient feelings during MAT. All patients
selected for MAT will undergo the DIMS protocol
intermittently during the course of their
treatment.
Protocol
MAT
will be performed weekly as per physician’s orders
for the appropriate complication requiring
therapy. Routine laboratory studies done before
and every 3-6 months during therapy include CBC,
chemistry profile, TSH, hemoglobin A1C ,
C-peptide, HS-CRP, B12 and folate and urine
protein studies.
End point
Statistical evaluation will be preformed
intermittently during the study.
F. Effects of Metabolic
Activation Therapy on Progressive Retinopathy with Diabetes Mellitus
Introduction
MAT
has been shown to reduce the rate of diabetic
nephropathy progression in type 1 diabetic
patients. The blood vessels in the glomeruli and
retina share similar developmental
characteristics. Diabetic retina and renal
diseases are both accelerated by hypertension, and
hyperglycemia. This study is to evaluate the
effect of MAT on progressive diabetic retinopathy.
Protocol
MAT
therapy will be performed by standard weekly
protocols over 6-12 months in patients selected
because of progressive eye disease. Patients must
be under glycemic and hypertensive control.
Retinal evaluation will be done before and
intermittently by a retinal specialist. Those
unable to see a retina specialist will have non
dilated retinal photography which will be
evaluated by a retina specialist. Routine
laboratory studies to be done before and during
therapy every 3-6 months include CBC, chemistry
profile, IgF-1, TSH, hemoglobin A1C, C peptide,
lipids and urine protein studies. Serial
evaluation by an endocrinologist is also included.
End Point
Evaluation will be by a retinal specialist to
determine effectiveness of MAT.
MAT Protocol
Metabolic
Activation Therapy (MAT) is a process which
encourages the glucose metabolism in diabetics to
normalize in multiple organs, especially muscle,
retina, liver, kidney and nerve endings. The
process fundamentally requires the administration
of high dose insulin pulses similar to those found
in normal humans by their pancreas into the
surrounding portal circulation. Oral carbohydrates
are given simultaneously to augment to process and
prevent hypoglycemia. The process is monitored by
frequent glucose levels and respiratory quotients
(RQ). The glucose levels are monitored to keep
glucose levels appropriate and the RQ determine
the need to readjust the infusion protocol in each
patient. MAT is done over 1-hour periods with a
1-hour rest period between each session for three
courses each day of activation. Specifically, in
most centers, the day’s activation session is as
follows:
Patient clinical assessment,
vital signs and initial glucose level.
MAT
activation session – 1 Hour:
10-50
µU / kg of Insulin, pulsed at 10 pulses/hour, over
1 hour RQ or
metabolic measurement performed at the beginning
and the end of the hour to measure activation.
Glucose levels taken every 30 minutes of more
frequently as medically indicated in
patients with a tendency for a quick drop in blood sugar Rest period – 1
Hour. This 2-hour cycle
is repeated twice more. Patient is evaluated post
session and discharged
Frequent monitoring of RQ is
necessary as these levels change rapidly,
depending on the fuel being utilized by the body.
When RQ is low (0.7-0.8) fat is the primary fuel
and at RQ > 0.9, glucose is the primary fuel.
MAT drives the RQ from 0.7 –
0.8 > 0.9. the success of the treatment depends on
this fact. However during rest periods the RQ may
fall back to lower levels. Therefore RQ’s are done
at the beginning and at the end of each insulin
infusion session of 1 hour.
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