ARTUR CHWALBA, EWA OTTO-BUCZKOWSKA

NEW, PEDIATRIC INDICATIONS FOR METFORMIN

THERAPY SYSTEMATIC REVIEW
NOWE, PEDIATRYCZNE WSKAZANIA DO STOSOWANIA METFORMINY
SYSTEMATYCZNY PRZEGLD
Medical Speciality Centre, Gliwice

SUMMARY. Metformin is a well-established hypoglycemic agent in the treatment of adults with Type 2 diabetes mellitus and other conditions
with insulin resistance. The beneficial role of metformin in young patients with type 2 diabetes has been separately demonstrated.
Metformin is also beneficial in pediatric patients with Type 1 diabetes mellitus and insulin resistance. It may decrease HbA1c and insulin dosage
with no weight gain in youngsters with Type 1 diabetes. Also metformin is useful in the therapy of other types of diabetes mellitus in children
and adolescents.
Key-words: diabetes mellitus, insulin resistance, metformin, pediatric diabetological care.
STRESZCZENIE. Metformina, jest w penym zakresie opracowanym, lekiem przeciwcukrzycowym, stosowanym w pierwszym rzdzie w cukrzycy
typu 2 osb dorosych. Wskazania do stosowania metforminy stale si rozszerzaj. Ich podstaw jest potrzeba leczenia insulinoopornoci
mechanizmu patogenetycznego take w cukrzycy typu 1, w innych klinicznych zespoach z insulinoopornoci, take w zapobieganiu cukrzycy
typu 2. Stwierdzenie to odnosi si rwnie do klinicznych potrzeb opieki diabetologicznej dotyczcej dzieci i modziey.
Sowa kluczowe Cukrzyca, insulinooporno, metformina, opieka w cukrzycy dziecicej.

INTRODUCTORY REMARKS
Metformin is a medication with long and complicated
history. They were periods in diabetological care when it
was contraindicated as the result of side effects related
to similar compound - phenformin. Actually metformin
following the investigations of RA DeFronzo and MA
Goodman, published in 1995 (1), and many others - is recognized as the drug of multidirectional, molecular actions
with large scope of indications and practical safety. The
value of metformin in the diabetes mellitus Type 2 therapy
is incontestable, the indications now are enlarged to different diabetic types and syndromes with hyperglycemia
arising as the result of insulin resistance. They are also
clinical syndromes connected with insulin resistance without hyperglycemia, which are approached as indications
to metformin (2, 3, 4).
It is recognized also as a useful drug in pediatric diabetes care.

Description and discussion of the new indications for

metformin, expecially in pediatric care, are presented in
following separate sections I-VIII.
I. Metformin in Type 1 diabetes mellitus in children
and adolescents.
Advances in studies on the pathophysiological background of Type 1 diabetes mellitus in children and adolescents
have discovered several new, molecular pathogenic mechanisms, which are regarded now as the specific indications
to metformin in this group of patients (5, 6, 7). The most
important point of action for metformin is the decreased
insulin sensitivity mainly of the liver, skeletal muscles and
adipose tissue always present between the different mechanisms of Type 1 diabetes mellitus pathogenesis in children and adolescents (8, 9, 10, 11). The previous view that
insulin resistance is absent in children or adolescent with
Type 1 diabetes mellitus are now abandoned (9, 10). Many
studies point to the necessity of metformin administration

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as the supporting insulintherapy as adotitional drug in pediatric diabetes mellitus (11, 12, 13, 14, 15).
Positive influence of metformin for Type 1 diabetes
was largely discussed by China authors (11). Introducing metformin as the additional drug to insulin therapy
allows insulin doses reduction, facilitates body mass reduction, improves lipids metabolism, while the risk of
acute complications did not increase. In other essential
studies like published by Pang and Narendran the evidence is presented, thut metformin reduced significantly the
insulin resistance in patients with Type 1 diabetes (12).
The positive influence of metformin as supportive treatment in Type 1 diabetes was also presented by RJ Moon
et al. in a study involving group of young adults with
overweight and symptoms of insulin resistance (13). Addition of metformin to insulin decreased the requirement
for exogenous insulin and also caused lipid metabolism
normalization (14,15,16).
These observations were largely reviewed by IB Jacobsen et al. (14), They confirmed the body weight loss and
insulin dose reduction in diabetes mellitus Type 1 patients
after metformin application as supportive medication.
AS Khan et al. (17) also observed significant HbA1c
level reduction, decrease of fasting glycemia level and
statistically significant insulin dose reduction in Type 1
diabetes mellitus.
These findings were confirmed by many other authors
(16, 17, 18, 19, 20, 21, 2).
In addition our clinical experience also supports the opinion about the potential of metformin supportive treatment
of Type 1 diabetes therapy in children.
Studies conducted by T Urakami et al. (23) on metformin therapy as the supportive treatment in juvenile patients
(18.1 3.0 age) with Type 1 diabetes, overweight and high
HbA1c level additionaly confirme that metformin enhances
the metabolic compensation in adolescents.
Similar observations from USA were presented as the
results of randomized several trials in juvenile Type 1
diabetes mellitus. They confirmed that adding metformin
to insulin decreases HbA1c level in comparison to control
group receiving placebo (24). The specific, positive effect
of metformin as a supporting medication is Type 1 diabetes
patients was observed in puberty period (25).
Treatment with metformin in Type 1 diabetes mellitus
is also supported by the presently tightened criteria of metabolic compensation as well as by the several ambiguities
in defining Type 1 of diabetes mellitus (26, 27, 28).
II. Insulin resistance in Type 1 diabetes mellitus as
specific clinical problem.
Although, the recognized division between the Type
1 and Type 2 diabetes mellitus puts into discussion the
pathogenesis of insulin resistance in Type 1 diabetes they
are also views about their pathogenic proximity (29).

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TJ Wilkin in his accelerator hypothesis even states, that

both types of diabetes mellitus are the similar disease,
which vary only in the tempo of -cells loss caused by
responsible functional accelerators - one of them is insulin
resistance) (30).
One of such another accelerator is adipose tissue mass
(31). The overweight may play a role in insulin resistance arising in Type 1 diabetes. It is observed now more
frequently in patients with Type 1 diabetes mellitus, who
improve the hyperglycaemic levels rather by increasing
insulin doses instead of dietary restrictions and physical
activity (32,33,34).
III. Metabolic syndrome and Type 2 diabetes mellitus.
Metformin plays significant role in Type 2 diabetes prevention in people with abdominal obesity. Investigations
conducted as a part of DPPOS programme underlined that
metformin improves tolerance to glucose and also impaired glucose tolerance transformation into Type 2 diabetes
(35, 36).
In 2000, ADA recommendations for Type 2 diabetes
mellitus treatment in children and youth point to similar
conclusions. The metabolic syndrome is diagnosed in juvenile patients more and more frequently. Hence, if there
is no improvement after behavior changes (diet, physical
activity), they are indications for metformin treatment.
Metformin application in juvenile patients with abdominal
obesity is also the preventive measure for Type 2 diabetes
mellitus (6,7,37,38,39,40). This questions requires further
investigations (41,42,43).
IV. The obesity as a cause of insulin resistance in juvenile patients without diabetes mellitus and indication to
metformin use.
Metformin could be applied in other metabolic homeostatic disorders, like insulin resistance without diabetes
mellitus. One of such condition is obesity associated with
insulin resistance (44). Contemporary increase in obesity
incidence in children and adolescents underlines the significance of metformin use as a supportive therapy of young
patients with insulin resistance (45 - 48).
V. Polycystic ovary syndrome PCOS and metformin.
One of the disturbances, that is associated with significant insulin resistance is polycystic ovary syndrome
(PCOS) diagnosed in girls and also young women (49 51). In PCOS the insulin resistance is accompanied by
hyperinsulinemia. Studies on medications decreasing insulinemia and increasing insulin sensitivity, revealed that
normalizing the hyperinsulinemia and insulin resistance
reduces hyperandrogenism. Therefore the insulin resistance treatment in PCOS is essential.
PCOS is also the risk factor for disorders of glucose
tolerance as well as of Type 2 diabetes. The PCOS insulin

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resistance acts as important risk factor for cardiovascular disorders and arterial hypertension. Due to these circumstances PCOS has to be regarded as the indication to
metformin (13, 52).
VI. Girls with low birth weight and accelerated puberty.
The attempts of metformin application in girls with low
birth weight and accelerated puberty are already well described. The metformin in these clinical conditions reduces
hyperinsulinemia, hirsutism, hyperandrogenism and additionally improves lipid profile (53). It is achived, because
metformin increases of circulating sex-hormone-binding
globulin (SHBG), reduces the level of androgens in plasma
and decreases 17-hydroxyprogesterone (17OHP). Activity
of ovarian P450c17 is inhibited. Metformin extends also
the puberty period which enables to increase the height
close to the normal and to maintain the slim silhouette (54).
VII. Genetic syndromes with concomitant insulin
resistance.
There is a group of young patients where insulin resistance accompanies different genetic syndromes. One
of such syndrome is Alstrm syndrome, that is associated
with ALMS1, locus 2p13 gene mutation and is characterized by diabetes mellitus, pigmentary retinopathy, deafness,
obesity and hypogonadism (55). It was documented, that
metformin is useful in this syndrome.
VIII. Use of metformin in pediatric patients with neurological disorders.
The positive influence of metformin was confirmed also
in pediatric patients with reduced insulin sensitivity and
excessive body mass increase due to several psychoactive
medications (56). Metformin prevents such side-effects.
Bibliography on the new metformin indications in pediatric care is continously increasing and interesting. The
enclosed list of publications confirms this opinion.

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Adress do korespondencji,
Otto-Buczkowska Ewa, MD, PhD, Professor
Jasnogorska 16/21 44-100 Gliwice Poland
em.buczkowski@pro.onet.pl

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LEKI ZMNIEJSZAJCE INSULINOOPORNO

WCUKRZYCY TYPU 2
Metformina
Mechanizm dziaania. Zwizek ten zmienia powierzchniowy potencja elektrostatyczny bony mitochondrialnej
wwielu komrkach. Moe to powodowa zmniejszenie wytwarzania ATP. Komrkowy niedobr ATP ma zkolei rnorakie skutki, jak:
hamowanie glukoneogenezy wwtrobie;
zwikszenie glikozy beztlenowej wtkankach obwodowych (zwaszcza wminiach szkieletowych);
zmniejszenie nadmiernego wydzielania insuliny wdiabetogennej otyoci;
hamowanie lipogenezy ipobudzenie lipolizy wadypocytach;
aktywacja fibrynolizy;
hamowanie wchaniania jelitowego glukozy iinnych heksoz, aminokwasw, witamin, kwasw ciowych, elaza.
Wskazania:
Metformin naley stosowa wniepowikanej cukrzycy ostabilnym przebiegu.
Przed podaniem naley zawsze dokona prby wyrwnania cukrzycy za pomoc diety izmniejszenia nadmiaru
masy ciaa.
Przeciwwskazania:
Uczulenie.
Objawy ostrych powika cukrzycy ketoza, odwodnienie.
Cukrzyca przebiegajca zwyniszczeniem, ketoza godowa.
Spoywanie alkoholu.
Zaburzenia czynnoci nerek iwtroby.
Wszystkie kliniczne zaburzenia przebiegajce ze wstrzsem lub upoledzeniem przepywu krwi przez wiksze
obszary tkanek.
Wszystkie kliniczne zaburzenia przebiegajce zhipoksemi lub predyspozycj do niej, np. przewleka obturacyjna
choroba puc, astma oskrzelowa, niewydolno krenia.
Ostre choroby zakane (np. posocznica).
Okres okoooperacyjny, zastosowanie znieczulenia oglnego.
Niedobr witaminy B12, niedobr elaza.
Cia.
Stosowanie lekw zmniejszajcych potencja oksydoredukcyjny komrek, np. pochodnych fenotiazyn, barbituranw.
Choroby lub zaburzenia, ktre stwarzaj ryzyko kwasicy mleczanowej.
Niepodane dziaanie metforminy:
Dolegliwoci ze strony przewodu pokarmowego. 9095% powika polega na przejciowych dolegliwociach
odkowo-jelitowych. Nale do nich: sucho wjamie ustnej, uczucie metalicznego smaku, brak aknienia,
nudnoci, wzdcia lub ble wnadbrzuszu, zaparcie. Prawdopodobnie przyczyn tych zaburze jest fakt, e wenterocytach wybirczo stenie metforminy jest okoo 200 razy wiksze ni winnych tkankach.
Niedokrwisto. Zmniejszenie stenia kwasu foliowego iwitaminy B12 we krwi jest drugim pod wzgldem
czstoci wystpowania niepodanym objawem stosowania metforminy. Jest ono przyczyn niedokrwistoci,
szczeglnie atwo powstajcej uosb wpodeszym wieku.
Kwasica mleczanowa. Przyczyn rozwoju kwasicy mleczanowej uchorych na cukrzyc leczonych metformin jest
jej wpyw na rdkomrkow przemian materii, awic zmniejszenie wytwarzania ATP inasilenie glikolizy beztlenowej (zjawisko Pasteura), atake zmniejszenie potencjau oksydoredukcyjnego cytoplazmy. Wpywy te mog
by nasilane przez rne czynniki, np. spoycie alkoholu, hipoksj. Uosb zupoledzeniem czynnoci wtroby lub
nerek wskutek zmniejszenia wychwytywania przez narzdy mleczanu zkrwi take atwiej dochodzi do kwasicy.
Tiazolidinediony - pioglitazon
Do celw lecznictwa wwielu krajach zarejestrowano pioglitazon. Lek ten zwiksza komrkowe dziaanie insuliny, nie
wpywajc na jej sekrecj. Ztego powodu (podobnie jak metformina) okrela si go mianem uwraliwiacza insulinowego. Tiazolidinediony przede wszystkim pobudzaj receptory zlokalizowane na powierzchni jdra komrkowego, ate
zkolei dziaaj jako czynniki zwikszajce transkrypcj (stenie) wielu enzymw korzystnie regulujcych przemian
glukozy ilipidw. Pioglitazon stosuje si jako lek do terapii skojarzonej zinnymi rodzajami lekw doustnych lub insulin.

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