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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.
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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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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.
REFERENCES,
1. DeFronzo RA, Goodman AM, Efficacy of metformin
in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl
J Med 1995, 333, 541-549.
2. Czupryniak L, Guidelines for the management of type
2 diabetes, is ADA and EASD consensus more clinically relevant than the IDF recommendations? Diabetes Res Clin Pract. 2009,86 Suppl 1,S22-25.
3. Inzucchi SE, Bergenstal RM, Buse JB. et al, American
Diabetes Association (ADA), European Association
for the Study of Diabetes (EASD). Management of
hyperglycemia in type 2 diabetes, a patient-centered
approach, position statement of the American Diabe-
75
76
31. Fourlanos S, Harrison LC, Colman PG, The accelerator hypothesis and increasing incidence of type 1
diabetes. Curr Opin Endocrinol Diabetes Obes 2008,
15, 321-325.
32. uczyski W, Szypowska A, Gowiska-Olszewska
B, Bossowski A, Overweight, obesity and features of
metabolic syndrome in children with diabetes treated
with insulin pump therapy. Eur J Pediatr 2011, 170,
891-898.
33. Szadkowska A, Pietrzak I, Szlawska J et al., Abdominal obesity, metabolic syndrome in type 1 diabetic
children and adolescents. Pediatr Endocrinol Diabetes
Metab 2009, 15, 233-239.
34. Verbeeten KC, Elks CE, Daneman D, Ong KK, Association between childhood obesity and subsequent
Type 1 diabetes, a systematic review and meta-analysis. Diabet Med 2011, 28, 10-18.
35. Diabetes Prevention Program Research Group, Long-term safety, tolerability, and Wright loss associated
with metformin In the Diabetes Program Research
Group. Diabetes Care 2012, 35, 731-737.
36. TODAY Study Group, Zeitler P, Hirst K et al., Collaborators (213), A clinical trial to maintain glycemic
control in youth with type 2 diabetes. N Engl J Med
2012, 366, 2247-2256.
37. Bouza C, Lpez-Cuadrado T, Gutierrez-Torres LF,
Amate J, Efficacy and safety of metformin for treatment of overweight and obesity in adolescents, an
updated systematic review and meta-analysis. Obes
Facts. 2012, 5, 753-765.
38. Daz M, Bassols J, Lpez-Bermejo A, de Zegher F,
Ibez L, Metformin treatment to reduce central
adiposity after prenatal growth restraint, a placebo-controlled pilot study in prepubertal children. Pediatr
Diabetes. 2015, 16, 538-545.
39. Gray L, Lee JH, Nashelsky J, Metformin use in adolescents. Am Fam Physician. 2013, 87, od4.See comment in PubMed Commons below
40. Kendall DL, Amin R, Clayton PE, Metformin in the
treatment of obese children and adolescents at risk of
type 2 diabetes. Paediatr Drugs. 2014, 16, 13-20.
41. Brufani C, Crin A, Fintini D, Patera PI, Cappa M,
Manco M, Systematic review of metformin use in
obese nondiabetic children and adolescents. Horm
Res Paediatr. 2013, 80, 78-85.
42. McDonagh MS, Selph S, Ozpinar A, Foley C, Systematic review of the benefits and risks of metformin in
treating obesity in children aged 18 years and younger.
JAMA Pediatr. 2014, 168, 178-184
43. Metformin in obesity, Arch Dis Child. 2014,99,231.
44. Ibez L, Lopez-Bermejo A, Diaz M et al., Pubertal
metformin therapy to reduce total, visceral, and hepatic adiposity. J Pediatr 2010, 156, 98-102.e1.
45. Otto-Buczkowska E, Pathogenetic influence of obesity associated with insulin resistance on the induction
of the several clinical complications in children and
adolescents. Med Metabol 2012, 16, 59-65.
46. Park MH, Kinra S, Ward KJ et al., Metformin for obesity in children and adolescents, a systematic review.
Diabetes Care 2009, 32, 1743-1745.
47. Wilson DM, Abrams SH, Aye T et al., Glaser Pediatric
Research Network Obesity Study Group. Metformin
extended release treatment of adolescent obesity, a 48week randomized, double-blind, placebo-controlled
trial with 48-week follow-up. Arch Pediatr Adolesc
Med 2010, 164, 116-123.
48. Yanovski JA, Krakoff J, Salaita CG et al., Effects of
metformin on body weight and body composition in
obese insulin-resistant children, a randomized clinical
trial. Diabetes 2011, 60, 477-485.
49. Crk DA, Dilbaz B, What do we know about metabolic syndrome in adolescents with PCOS? J Turk Ger
Gynecol Assoc. 2014, 15, 49-55.
50. Nicandri KF, Hoeger K, Diagnosis and treatment of
polycystic ovarian syndrome in adolescents. Curr
Opin Endocrinol Diabetes Obes. 2012, 19, 497-504.
See comment in PubMed Commons below
51. Williams RM, Ong KK, Dunger DB, Polycystic ovarian syndrome during puberty and adolescence. Mol
Cell Endocrinol. 2013, 373, 61-67.
52. Spritzer PM, Motta AB, Adolescence and polycystic
ovary syndrome, current concepts on diagnosis and
treatment. Int J Clin Pract. 2015, 69, 1236-1246.
53. Ibez L, Lopez-Bermejo A, Diaz M et al., Early metformin therapy to delay menarche and augment height
in girls with precocious pubarche. Fertil Steril 2011,
95, 727-730.
54. Ibez L, Lpez-Bermejo A, Daz M et al., Early metformin therapy (age 8-12 years) in girls with precocious pubarche to reduce hirsutism, androgen excess,
and oligomenorrhea in adolescence. J Clin Endocrinol
Metab 2011, 96, E1262-1267.
55. Paisey RB, Smith J, Carey C, Barrett T, Campbell F,
Maffei P, Marshall JD, Paisey C, Steeds RP, Edwards
NC, Bunce S, Geberhiwot T, Duration of diabetes predicts aortic pulse wave velocity and vascular events in
Alstrm Syndrome. J Clin Endocrinol Metab. 2015,
100, E1116-24.
56. Casteels K, Fieuws S, van Helvoirt M et al., Metformin therapy to reduce weight gain and visceral adiposity in children and adolescents with neurogenic or
myogenic motor deficit. Pediatr Diabetes 2010, 11,
61-69.
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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