Transcript Sellings L-Carnitine - Diabetes

L-Carnitine
Diabetes
Scientific Rationale for use of
L-carnitine in Diabetes Type II
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Insulin Resistance is a major clinical issue in diabetes.
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Glitazones such as Avandia and Actos are currently widely used.
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Insulin Resistance (IR) is defined as an impaired biological response to either exogenous
or endogenous insulin, and apply to any of the biological actions of insulin on metabolic
process (Consensus Development Conference on Insulin Resistance by the American
Diabetic Association, 1998)
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The Bruneck study shows the prevalence of IR to be 84% in NIDDM patients (Bonora,
1998)
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In diabetes, abnormalities of the carnitine system (carnitine plasmatic and tissue levels,
carnitine-dependent enzymes), are present (Peluso, 1998)
Scientific Rationale for use of
L-carnitine in Diabetes Type II
•
An impaired pyruvate dehydrogenase complex activity has been described in diabetic
patients, due to intramitochondrial accumulation of acyl-CoAs (Lopaschuk, 1992)
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In type 2 diabetic patients L-Carnitine infusion during euglycemic, hyperinsulinemic clamp
improves insulin sensitivity by determining an increase of whole body glucose uptake, of
glucose oxidation rate and of glucose storage rate (Mingrone, 1999)
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In type II diabetic patients, acute L-Carnitine administration improves insulin sensitivity,
and reduce plasma lactate concentration without affecting the antilipolytic activity of
insulin (Capaldo 1991)
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In the healthy volunteer L-Carnitine stimulates glucose disposal and oxidation (De
Gaetano, 1999)
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Experimental evidences demonstrates that L-Carnitine treatment improves glucose
oxidation by scavenging acyl moieties, and thus removing PDHC inhibition (Broderick,
1991)
Effect of L-Carnitine on Insulin Resistance
Capaldo 1991
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Capaldo Investigated the effect of L-carnitine on insulin
sensitivity - In type II (NIDDM) diabetic patients
– Small patient group – 9 patients
– Investigative technique: Euglycemic Insulinemic
clamp
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He observed
– ↑ in glucose utilization => improved insulin sensitivity
or improved glucose utilization of muscles
– ↓ in blood lactate levels => glucogen synthesis or
complete oxidation?
•
Conclusion
– L-Carnitine ↑ Insulin sensitivity in type II diabetic
patients
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Possible mechanism of action = activation of pyruvate
dehydrogenase by L-carnitine -> inc. glucose utilization.
Effect of L-Carnitine on Insulin Resistance
Mingrone 1999
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Mingrone investigated both type II diabetic patients and
healthy controls
– Larger group – 20 diabetic patients + 15 healthy
controls
– Used same investigative technique Euglycemic
Insulinemic clamp to study insulin sensitivity
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Saw / found / observed
– ↑ in glucose disposal of 8% in both patient groups
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Conclusion
– L-Carnitine ↑ Insulin sensitivity in type II diabetic
patients
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Mechanism of Action is most probably due to activation
of pyruvate dehydrogenase by L-carnitine -> inc.
glucose utilization. (dec. lactose production)
Effect of L-Carnitine on Insulin Resistance
De Gaetano 1999
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De Gaetano studied 14 healthy volunteers
– Used the IV glucose tolerance test
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Saw / found / observed
– 30% inc. in glucose uptake at 1 hr in Lcarnitine group.
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Conclusion:
– ↑ glucose uptake by tissues
– ↓ liver output
– ↓ possible reduction of C- Peptide levels
– ↑ glucose oxidation rate
Effect of L-Carnitine on Dyslipidemia
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L-Carnitine is involved in the mitochondrial metabolism of
fatty-acids
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De Rosa investigated its effect on lipid levels and in
particular on lipoprotein (a).
Derosa 2003
•
•
–
94 Type II diabetic patients
–
6 wk Double blind placebo controlled trial
–
L-carnitine 1g oral twice daily v placebo
Results:
–
Found no changes in levels of cholesterol or
triglycerides in the blood
–
But he found that in patients treated with L-Carnitine
plasma Lp(A) levels in newly diagnosed,
hypercholesterolemic NIDDM patients, were
significantly reduced after 3 and 6 months of
treatment.
Interesting to note: As hyper Lp(A) diabetic patients had not
been selected for, results may underestimate effect of LCarnitine.
Diabetes Type I – Disease Background
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Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta
cells of the islets of Langerhans of the pancreas.
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Sensitivity and responsiveness to insulin are usually normal, especially in the
early stages.
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This type comprises up to 10% of total cases in North America and Europe,
though this varies by geographical location.
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This type of diabetes can affect children or adults, but has traditionally been
termed "juvenile diabetes" because it represents a majority of cases of diabetes
affecting children.
Diabetes Type I – Disease Background
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The most common cause of beta cell loss leading to type 1 diabetes is
autoimmune destruction, accompanied by antibodies directed against insulin
and islet cell proteins.
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The principal treatment of type 1 diabetes, even from the earliest stages, is
replacement of insulin.
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Without insulin, ketosis and diabetic ketoacidosis can develop.
Scientific / Rational for use of Carnitine in children
with Diabetes Type I
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These findings raise the questions:
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Could carnitine levels be used an indicator for the early identification of diabetes
type I and diabetes related complications?
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And ultimately could the addition of L-carnitine supplementation reduce the
progression of these diabetes related complications?
Carnitine levels in Diabetes Type I
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STUDY SHOWS that children who develop Type 1
Diabetes early in life have low levels of carnitines and
amino acids at birth and raises the question as to if
neonatal screening of carnitine levels could be used to
predict the development of Type 1 diabetes.
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HOOK : Did you know that Prof. Bottazzo (a leading
Italian endocrinologist) has identified a potential tool for
prospectively predicting the onset of type 1 diabetes in
the first few years of life?
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He found that low levels of carnitine and amino acids
could be evident from birth, before the clinical onset of
type 1 diabetes.
Bottazzo 2005
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STUDIED: He selected HLA-typed patients who had developed diabetes type I by the age of 4
and analyzed the carnitine & amino acid levels collected from birth.
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FOUND: that these HLA-typed children who developed DTI were shown to have reduced levels
of circulating carnitine and total amino acids at birth.
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CONCLUSIONS: He raises the question whether carnitine & amino acid screening at birth
could be used as early indicator for prospectively predicting the development of type 1
diabetes?
Carnitine levels in Type I Diabetes
Mamoulakis 2004
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STUDY SHOWS that children who developed type 1
diabetes early in life have reduced levels of circulating
carnitine and total amino acids at birth and that these
levels decrease over time.
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In the meantime Prof. Mamoulakis in Greece had
investigated the relationship between plasma carnitine
levels in children and adolescents with Type I diabetes.
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FOUND: He also found that children who developed
Type 1 diabetes early in life had reduced levels of
circulating carnitine and total amino acids at birth.
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In addition he found that these levels decreased over
time, with the increased duration of Type 1 Diabetes.
CONCLUSION: He concluded that as the reduction in Carnitine levels is time related, this
could have implications in the development of long-term complications observed in Type 1
Diabetes.
Carnitine levels in Diabetes Type I
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STUDY SHOWS that asymptomatic cardiomyopathy is
present in children and adolescents with type 1 diabetes
for more than 5 years and that this is associated with a
decreases in levels of free and total carnitine. No
cardiomyopathy or reduced carnitine levels were
identified in patients with diabetes type I for less than 5
years, however higher levels of acetyl-carnitine were
however found to be present.
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STUDIED: More recently Adal focused his research on
the presence of asymptomatic diabetic cardiomyopathy in
children and adolescents with Type 1 Diabetes.
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The study investigated not only the presence of key ECG
parameters, but also how these parameters varied with
the duration of diabetes mellitus and in relation to the
levels of carnitine fractions, and other metabolic
indicators.
Adal 2006
Carnitine levels in Diabetes Type I
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FOUND: He found that systolic and diastolic functions
deteriorated in patients who had suffered from diabetes for
more than 5 years.
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This deterioration was associated with decreased levels of
both free and total carnitine in the plasma. The AC / FC
carnitine ratio was also shown to be increased.
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In addition the following correlations between the metabolic
and ECG parameters were found;
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- ↓ Free and Total carnitine levels - ↑ Heart Rate
- ↓ Free Carnitine levels - ↓ Diastolic function (E/A)
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However in patients suffering from diabetes for less than 5
years no asymptomatic cardiomyopathy was identified; no
significant differences were noted in either systolic or
diastolic functions, or in the levels of Total or Free
carnitine.
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However significantly higher levels of acetyl-carnitine were
however found to be present.
Adal 2006
L-Carnitine in Insulin Resistance
HOOK
You have no doubt experience with Metformin alone
or in combination with Glitazones in the treatment of
Insulin Resistance (IR). Have you ever experienced
L-Carnitine, an endogenous substance that plays a
key role in intermediate metabolism?
MAIN PART
The team of De Gaetano utilized a pharmacokinetic
technique Minimal Modelling to evaluate the efficacy
of Carnitine on glucose metabolism in healthy
subjects.
The results showed that in the first 90 minutes,
Carnitine seems to increase overall glucose elimination
from plasma
These data open a new scenario: Carnitine, by
interfering with glucose metabolism, may have a role in
the therapy of Insulin Resistant patients.
This suggestion was confirmed by Capaldo in a small
group of IR patients with T2D on standard therapy. The
euglycemic hyperinsulinemic clamp technique showed
that …
…the acute treatment with Carnitine induced a
significant increase in whole-body glucose
utilization.
Therefore, the possibility that carnitine
could affect IR seems to be real.
Nevertheless, to complete the preliminary puzzle, we
need one more element. The team of Mingrone
evaluated the effect of Carnitine not only on glucose
disposal, but also on glucose oxidation.
With the aid of euglycemic hyperinsulinec clamp
technique associated with indirect calorimetry, the
author evidenced that acute Carnitine infusion, in
patients under antidiabetic therapy, increased not only
glucose uptake, but also glucose oxidation by more
than 8%.
We know that Carnitine not only acts ameliorating lipid
metabolism, but also controls glucolysis and
gluconeogenesis key enzymes.
Thus we can explain the IR improvement recently
confirmed by Molfino:
oral L-Carnitine (for at least 10 days) significantly reduces
the Homeostasis model assessment of insulin resistance
(HOMA-IR) and the 2 hours oral glucose tolerance test
(OGTT)
Last but not least, a large clinical study including 258
obese diabetic patients treated with L-carnitine for one
year have just been published:
not surprisingly, L-carnitine (plus orlistat) treatment
(compared to orlistat alone) significantly improves:
• glycated haemoglobin
• fasting plasma glucose
• HOMA insulin resistance index
• And also LDL-colesterol
OVERALL
CONCLUSIONS
In conclusion, oral Carnitine, by ameliorating:
• insulin resistance,
• fasting and postprandial plasma glucose
• as well as other metabolic parameters
might be worthwhile to be used for Type II
diabetes patients, don’t you think so, doctor?
HOOK
What do you think about the possibility of predicting
Type 1 Diabetes (T1D) in newborn infants with a
simple carnitine screening?
MAIN PART
The team of Gianfranco Bottazzo carried out a large
screening on more than 1,600 newborn infants with
genetic predisposition for developing T1D. Four
years later, the blood samples collected at birth of
those children who developed T1D, were analysed..
The results showed that circulating
carnitine levels at birth were significantly
lower in all children who subsequently
developed T1D.
These data offer new food for thought for the prevention
of T1D, possibly using L-Carnitine.
Interestingly enough not only newborn infants, but….
… also children and adolescents with T1D, have been
shown to have significantly lower plasma carnitine levels.
Over time, carnitine levels progressively decreased.
This might have an impact on the development of long
term diabetic complications.
I would also just like to highlight the study performed by
Adal on 35 children and adolescents with T1D.
Adal used echocardiography to monitor the development
of cardiac dysfunction, and measured metabolic
parameters like the decrease of carnitine, under and over
a 5 years time period since diagnosis.
In patients who had been diagnosed with T1D for more
than 5 years both the diastolic and systolic functions
were significantly altered ….
... metabolic parameters such as total and free carnitine
levels were also significantly reduced.
The development of cardiac complications in diabetes
was time-dependent and it is associated with low
carnitine levels.
OVERALL
CONCLUSIONS
This suggests that adding L-Carnitine to
the treatment might be an opportunity
worth while being implemented.
HOOK
Hello doctor, how are you today?
You are surely aware that Diabetes is the leading cause of
end-stage renal disease: about 30% of diabetic patients go
on to develop kidney disease, and 40% of new cases of
ESRD are attributed to diabetes.
Furthermore, in the US hospitalization accounts for about
40% of total cost of ESRD care.
What about the possibility of reducing hospital costs of the
management of long term Haemodialysis patients?
MAIN PART
Did you know that L-Carnitine, an endogenous metabolic
compound, is highly effective in doing this?
An analysis of data of almost 3000 US HD patients treated
with I.V. L-carnitine ( >1.5g / dialytic session for 2 years)
between 1998 and 2003, revealed that…
… L-carnitine reduced their hospital admissions from
2.74 times to 1.47 times / year …
…and the duration of hospital stay from 18.9 to 8.0 days
and….
The risk of future hospitalization and hospital stay were
also significantly reduced.
In a sub-group of cardiovascular patients the risk was
reduced even further.
Another study analysing a different and much larger US
database containing data on over 116,000 HD patients in
which between 4,400 to 10,500 patients had been treated
with L-carnitine (≥ 1g I.V. post dialysis) during 1998 to
2003 confirmed these results:
Two different statistical models showed that ….
…. treatment with L-carnitine resulted in a reduction of
the future risk of hospital stay in the month following
treatment.
...and this is even more remarkable: after just one
month’s treatment!
Therefore Doctor, using L-carnitine in HD patients, you
can reduce the number of hospitalizations per year and
decrease the number of days spent in hospital, both in
the month immediately after treatment and over time!
OVERALL
CONCLUSIONS
Having seen this data, would you consider using
L-carnitine treatment more routinely in your
practice?