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nutrients Article

Retrospective Evaluation of Metformin and/or Metformin Plus a New Polysaccharide Complex in Treating Severe Hyperinsulinism and Insulin Resistance in Obese Children and Adolescents with Metabolic Syndrome Stefano Stagi 1, *, Franco Ricci 1 , Martina Bianconi 1 , Maria Amina Sammarco 1 , Giovanna Municchi 2 , Sonia Toni 3 , Lorenzo Lenzi 3 , Alberto Verrotti 4 and Maurizio de Martino 1 1

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Department of Health Sciences, University of Florence, Anna Meyer Children’s University Hospital, Florence 50139, Italy; [email protected] (F.R.); [email protected] (M.B.); [email protected] (M.A.S.); [email protected] (M.d.M.) Department of Paediatrics, University of Siena, Siena 53100, Italy; [email protected] Paediatric Diabetology Unit, Anna Meyer Children's University Hospital, University of Florence, Florence 50139, Italy; [email protected] (S.T.); [email protected] (L.L.) Department of Paediatrics, University of L’Aquila, L’Aquila 67100, Italy; [email protected] Correspondence: [email protected]; Tel.: +39-055-566-2585, Fax: +39-055-566-2400

Received: 18 March 2017; Accepted: 12 May 2017; Published: 20 May 2017

Abstract: Background: Pharmacological treatment of obesity and glucose-insulin metabolism disorders in children may be more difficult than in adults. Thus, we evaluate the effects of metformin in comparison with metformin plus a polysaccharide complex (Policaptil Gel Retard® , PGR) on body weight and metabolic parameters in obese children and adolescents with metabolic syndrome (MetS). Patients and methods: We retrospectively collected 129 children and adolescents (67 girls, 62 boys; median age 12.6 years) treated for a minimum of two years with metformin and low glycemic index (LGI) diet. Of these, 71 patients were treated with metformin plus PGR after at least 12 months of metformin alone. To minimize the confounding effect of the LGI on auxological and metabolic parameters, the patients were compared with age-, sex-, and BMI-matched control group with obesity and MetS (51 subjects; 24 males, 27 females) treated only with a LGI diet. Assessments included lipids, glucose and insulin (fasting and after oral glucose tolerance test) concentrations. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Matsuda, insulinogenic and disposition indices were calculated. Results: Metformin treatment led to a significant reduction in BMI SDS (p < 0.0001), with a significant difference in ∆BMI SDS between patients and controls (p < 0.0001). Moreover, metformin treated patients showed a reduction in HOMA-IR (p < 0.0001), HbA1c levels (p < 0.0001) and a significant increase in Matsuda index (p < 0.0001) in respect to the reduction discovered in controls (p < 0.05). Moreover, in contrast to the group treated with metformin alone and controls, patients treated with metformin plus PGR showed a further reduction in BMI SDS (p < 0.0001), HOMA-IR (p < 0.0001), HbA1c (p < 0.0001), total, HDL and LDL cholesterol (p < 0.0001), as well as an increase in Matsuda (p < 0.0001), disposition (p < 0.005) and insulinogenic (respectively, p < 0.05 and p < 0.0001) indices. Conclusions: Metformin appears to show short-term efficacy in reducing BMI, adiposity and glucose and insulin parameters in obese children and adolescents with MetS. However, PGR added to metformin may be useful to potentiate weight loss and to improve glucose-insulin metabolism and adiposity parameters in these patients.

Nutrients 2017, 9, 524; doi:10.3390/nu9050524

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Keywords: children; adolescents; metformin; Policaptil Gel Retard® ; obesity; type 2 diabetes mellitus; haemoglobin A1c; treatment; hyperinsulinism; insulin resistance; metabolic syndrome; insulin; cholesterol; triglycerides

1. Introduction Obesity is a multifactorial disease with a rapidly increasing prevalence in children and adolescents and a significant impact on both physical and psychosocial health [1]. More than one third of children and adolescents are reportedly at risk of being overweight or obese in Italy [2] and many other European countries [3–5]. Concomitant with the global rise in pediatric obesity, there has been a significant increase in the number of children and adolescents with clinical signs of insulin resistance [6,7], the main pathophysiological event preceding metabolic syndrome abnormalities [6–9]. Furthermore, the incidence of impaired fasting glucose, impaired glucose tolerance and type 2 diabetes (T2DM) in obese children and adolescents has risen alarmingly [6–9]. Lifestyle changes such as a healthy diet and regular physical activity have been proposed as the gold standard of care in subjects with obesity, albeit with poor compliance and success [6–9]. However, given that insulin resistance is an important link between obesity and associated metabolic abnormalities and cardiovascular risk, clinicians should be aware of high risk groups and the necessary treatment approaches [6,7]. There is now a general consensus that the pharmacological treatment of T2DM or severe disorders involving insulin secretion and action may be more difficult in children than in adults [10]. The first problem is that most of the available medications have not been studied in children [10]. The American Diabetes Association and the Pediatric Endocrine Society recently prepared joint guidelines for the treatment of T2DM in children [11,12]. Metformin, a biguanide agent that decreases hepatic glucose production and increases peripheral insulin sensitivity, has been used in conjunction with a lifestyle intervention program in T2DM obese adolescents with clinical insulin resistance to achieve weight loss and improve insulin sensitivity [13]. As in adults, metformin remains the mainstay of therapy (alongside diet and exercise) in T2DM children and adolescents, even if the treatment should focus on lifestyle changes to achieve effective weight management [10]. In any case, metformin may be a useful adjuvant treatment in obese and/or insulin-resistant children and adolescents, although its role in this setting is still unclear [14–16]. Nevertheless, although lifestyle changes may produce significant weight reduction in children and adolescents, the long-term efficacy of lifestyle intervention programs on body mass index (BMI) and related complications is questionable, given the high dropout and the frequent relapse into obesity of these patients [17]. For this reason, adding a pharmacological agent to conventional treatment is often considered in clinical practice. Metformin must be taken with food. This can be a problem in children and adolescents, who often find it difficult to manage their eating, potentially leading to hypoglycemia [18]. Metformin may also be associated with gastrointestinal adverse events, commonly including abdominal pain and diarrhea [19]. Although rare, lactic acidosis may also occur [20]. Policaptil Gel Retard® (PGR) is a complex of polysaccharide macromolecules that may reduce peak blood glucose and insulin levels [21]. It may thus be able to reduce BMI, HbA1c levels, the frequency of acanthosis nigricans and glucose metabolism abnormalities in obese children and adolescents with severe hyperinsulinism, insulin resistance and a family history of T2DM and obesity [21]. The aim of this study was to retrospectively evaluate the effect of metformin and/or metformin plus PGR in treating severe hyperinsulinism and insulin resistance in a large cohort of obese children and adolescents with metabolic syndrome (MetS).

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2. Patients and Methods This was a retrospective single center study. One hundred twenty-nine Caucasian obese patients (67 females, 62 males; median age at study entry 12.6, range 8.1–14.3 years) with hyperinsulinism and insulin resistance associated with MetS were studied at the Paediatric Endocrinology Unit at the Meyer Children’s University Hospital of Florence, Italy. Inclusion criteria were the presence of severe hyperinsulinism, insulin resistance and MetS and age between 8.0 and 14.5 years at the first evaluation. Exclusion criteria were patients aged 14.5 years at the first evaluation, cognitive impairment, diagnosis of type 1 diabetes, existing syndrome disorders with or without cognitive impairment, impaired renal or hepatic function, malabsorption disorders, cancer, patients enrolled in a weight loss program at the first evaluation, endocrine causes of obesity such as hypothyroidism or Cushing disease, and use of medications for weight loss or any medication that could compromise the study evaluation such as topical or systemic glucocorticoids, anticonvulsant therapy, growth hormone, sexual steroids or gonadotropin releasing hormone analogues. This study was conducted in compliance with the Declaration of Helsinki and European Guidelines on Good Clinical Practice. Ethical approval (ethical code 122/2016) was obtained from the Meyer Children’s University Hospital Ethics Committee. Written informed assent/consent was obtained from all participants and their parents or guardians. 3. Study Design One hundred twenty-nine patients recruited for severe obesity, hyperinsulinism and insulin resistance associated with MetS were retrospectively evaluated. After the first evaluation, all patients started metformin (T0) and they were followed up after 12 months (T1; median age 13.7, range 9.1–15.4 years) and 24 months (T2; median age at study end 14.9, range 10.3–16.7 years). Because of data demonstrating improvements in adiposity and gluco-insulinemic parameters with the use of PGR in obese children and adolescents with family history of obesity and T2DM [21], we after the initial 12 months of metformin treatment we recruited 71 patients also treated with PGR (Group A), while 58 patients continued with metformin only (Group B). These patients were compared with a age-, sex-, and BMI-matched control group with obesity and MetS (51 subjects; 24 males, 27 females; median age at study entry 12.4, range 8.2–14.5 years) not taking a medication as a mean to reduce weight and treated only with a low glycemic index (LGI) diet. At the first evaluation (T0), the parents of the study participants also completed a previously tested health questionnaire and a semi-structured quality-of-life questionnaire [19,20]. Information on duration of pregnancy, birth weight, neonatal feeding and presence of diabetes gravidarum during the pregnancy of the participants’ mothers and on diseases, hospital admissions and use of medication was collected. Family history was also investigated, collecting data on hypertension, obesity, hypercholesterolemia, cardiovascular disease (myocardial infarction, stroke, transient ischemic attack, and peripheral arterial occlusions) and diabetes mellitus in first degree (parents) and second degree (grandparents, brothers, sisters) family members. Complementary information was also collected from the medical files. Nutrient diaries were logged for all subjects according to their medical charts and through standardized interviews [19,20]. At T0, T1 and T2, we collected, when available, clinical and demographic data including height, weight, BMI, waist (WC) and hip circumference (HC), waist–hip ratio (WHR), pubertal staging and the time dedicated to outdoor physical activity, using a questionnaire commonly administered at the medical evaluation in obese children in our hospital [21]. During the T0, T1 and T2 visits, an extensive physical examination was performed by the study physicians. This included auscultation of the heart, lungs and abdomen and abdominal palpation. Any abnormal findings were recorded. The skin was examined for acanthosis nigricans, striae rubra, acne and, in girls, hirsutism.

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At T0 blood was taken for glycosylated hemoglobin (HbA1c), oral glucose tolerance test (OGTT), renal profile, lipid profile (including total, HDL LDL cholesterol and triglycerides), full blood count, IgA anti-tissue transglutaminase antibody (tTG) and total IgA levels. HbA1c, OGTT, renal profile, lipid profile and full blood count were also repeated at T1 and T2. Finally, in addition to the data obtained from telephone interviews, a questionnaire was completed at T1 and T2 to assess any side effects that had occurred during the study. However, as per clinical practice, all patients underwent a telephone interview every three months to monitor BMI changes and any adverse events of treatments. As for clinical practice in our Unit, because of research demonstrating improvements in adiposity and gluco-insulinemic parameters [21], all patients with obesity and MetS were treated with a LGI diet. Subjects were visited or interviewed every three months by a dietician (M.A.S.), for nine sessions during the 24-month intervention period, to receive standardized instructions for healthy eating and exercising. Counseling sessions included the child and at least one parent, when possible, according the established practice. Each session lasted approximately 30 min and was based on a strategy of increasing energy expenditure and modifying the dietary food intake using lifestyle behavioral change to achieve long-lasting impact. The dietician completed a tracking form and progress note after each counseling session to document patterns of dietary intake. Regarding the physical exercise, we encourage children to do aerobic exercise, such as swimming, cycling, running, and dancing, 2–3 times per week. 3.1. Metformin Treatment After the T0 evaluation results, in the daily practice, subject’s study medication dose was progressively increased according to a prespecified algorithm: in Weeks 1 and 2, participants took one tablet (500 mg) daily; thereafter, the dosage was increased by 500 mg/day every seven days to a maximum dose of 1500 mg/day (three tablets). Treatment was administered during meals (to minimize gastrointestinal side effects and the risk of hypoglycemia). In the event that the participant developed gastrointestinal symptoms, the dosage was reduced to the last well-tolerated dosage. For example, we decreased the dose by 250 mg/dose for one week when participants reported difficulty tolerating study medication and then attempted to increase it. 3.2. Policaptil Gel Retard® (PGR) Treatment As previously reported [21], PGR is the active pharmaceutical ingredient (API) of the medical device Libramed tablets (Aboca Spa Company, Sansepolcro, Arezzo, Italy). This complex contains polysaccharide macromolecules (cellulose, hemicellulose, pectin, and mucilage) and is derived from the following high-fiber raw materials: glucomannan (Amorphophallus konjac), cellulose, Opuntia pulp stem (Opuntia ficus indica), chicory root (Cichorium intybus), freeze-dried mallow root mucilage (Althaea officinalis), freeze-dried flaxseed mucilage (Linum usitatissimum L) and freeze-dried linden flower mucilage (Tilia platyphyllos Scop). PGR slows the rate of carbohydrate absorption, hence potentially reducing peak blood glucose and insulin concentrations. The exact composition and production process of the API are covered by a European patent (no. 1679009). All patients took three tablets (2175 mg) before their two main meals. 3.3. Adherence to Study Protocol Adherence to therapy was evaluated by means of written instructions provided at T0 and at clinical controls through a written questionnaire completed by the parents. As per clinical practice, adherence was also verified by e-mails and telephone interviews and by the bottle count on number of tablets consumed performed at the programmed visits. Furthermore, adherence to the diet was measured through the food record and 24-h recall of all food and drink intake and was revealed on the individual consultation, when specific questioned were asked about the food record.

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3.4. Control Group Patients with obesity and MetS, who chose not to take a medication as a mean to reduce weight and treated only with a LGI served as a control group (51 subjects; 24 males, 27 females; median age at study entry 12.4, range 8.2–14.5 years). For minimize the confounding effect of the LGI on auxological and metabolic parameters, this control group was age-, sex-, and BMI-matched and had no statistical different auxological and metabolic parameters at T0 in respect to the study group. Inclusion and exclusion criteria and the study protocol of the control group were the same as previously seen for patients. 3.5. Study Protocol As reported above, at T0, T1 and T2, the habitual food intake of the patients in the six months prior to and during the study was assessed using a validated quantitative food frequency questionnaire [21,22]. Standardized pictures of small, medium and large food portions were used to increase the accuracy of estimated food consumption [21]. The glycemic index (GI) of the diet of each patient was estimated from the sum of the GI values of each food consumed daily (GIA, GIB, GIC, etc. according to the amount (in grams) of available carbohydrate in each food (gA, gB, gC, etc.) divided by the total amount of available carbohydrate (g), as described by Wolever et al. [23]. The GI of each food was obtained from the values published in the International Table of Glycemic Index, considering glucose as reference [24]. For foods not listed in this table, the GI of foods with a similar nutritional composition and preparation method was used. GI values of the edible products were assumed as following: GI < 55 low, GI = 56–70 medium, GI > 70 high [23]. As per clinical practice, the study’s dietician provided to ask a complete a three-day food record (including two weekdays and two weekend days) at baseline and again three months. These four-day food diaries provided information on dietary composition and served as the basis of individualized dietary counseling. A 24-h recall of all food and drink intake was conducted during each session to assess compliance. In the case of noncompliance, suitable alternative LGI foods were encouraged. Food sample baskets containing key foods for the assigned diet were provided to promote product recognition and dietary adherence. LGI have a target GI ≤ 55. Our eating guideline encouraged the addition of fiber (exchanging white bread to whole meal bread) and legumes (lentil, peas, and beans), and focused on designing meals using low-GI carbohydrate foods. Examples of LGI foods used in this study: legumes (beans, chick pea, and lentils), whole grains (oat, barley, bulgur wheat, cracked wheat, semolina, basmati rice, and all bran), temperate fruits (apples, berries, pears, apricot, peach, plums, etc.), citrus fruits (oranges, grapefruit, tangerine, and pineapple), “above the ground” vegetables (squash, mixed vegetables, green beans, broccoli, tomato juice, tomato sauce, vegetable soups, asparagus, cauliflower, spinach, cabbage and onions, leafy greens, all above ground growing vegetables, and carrots), breads (pumpernickel and whole grain), and cereals (muesli with whole grain flakes, raw bran, etc). The age of pubertal onset was defined as the age at durable Tanner B2 stage for females or a testicular volume of 14 mL for males (G2). The age at which this occurred was taken as mid-age between the previous clinic visit when the child was still prepubertal and the clinic visit when the child was G2/B2. Duration of puberty was taken as time from G2/B2 to G4/B4. Age at G4/B4 was assessed similarly by taking mid-age between the previous clinic visit when the child was G3/B3 and the clinic visit when the child was G4/B4 [25]. Obesity was defined according to the reference values in growth charts as shown in the study by Cacciari et al. [26]. Children with a BMI greater than the 95th percentile for their age and gender were classified as obese. The variables for insulin resistance and β-cell function were evaluated in all patients by OGTT, carried out at T0, T1 and T2. OGTT was performed at four time points after an overnight fast of 12 h. After insertion of a venous cannula and collection of the baseline blood sample (T0), participants

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ingested 1.75 g of glucose per kilogram of body weight (maximum dose 75 g), dissolved in 200–300 mL of water. Glucose and insulin levels were determined at baseline and 30, 60, 90 and 120 min after ingestion of the glucose solution [22]. The glycemic status was defined based on 2010 American Diabetes Association criteria [27]. Impaired fasting glucose (IFG) was defined as fasting plasma glucose (FPG) 100–125 mg/dL (5.6–6.9 mmol/L). Impaired glucose tolerance (IGT) was defined as OGTT 2-h value 140–199 mg/dL (7.8–11.0 mmol/L). Finally, diabetes was defined as FPG ≥ 126 mg/dL (≥ 7.0 mmol/L) and OGTT 2-h plasma glucose ≥ 200 mg/dL (≥ 11.1 mmol/L). The HOMA-IR and the Matsuda index of insulin sensitivity [28–30] were calculated for all patients. A low HOMA-IR index indicates high insulin sensitivity, whereas a high HOMA-IR index indicates low insulin sensitivity (insulin resistance). HOMA-IR > 4.4 was considered as consistent with insulin resistance [30,31]. The Matsuda index [29] also provides a measure of insulin sensitivity and is calculated using the following equation: Matsuda index = 10,000/(square-root (FPG x FPI) × (meanPG x meanPI) Where FPG is fasting plasma glucose, FPI is fasting plasma insulin, PG is plasma glucose and PI is plasma insulin. The Matsuda index is consistent with direct measurements using an insulin clamp [29]. The glucose and insulin area under the curve (AUC) during the OGTT were calculated using the trapezoidal rule [32]. Delta glucose (∆G30–0) and delta insulin (∆I30–0) were evaluated as the changes in glucose and insulin concentrations from 0 min to 30 min. The insulinogenic index, calculated as (Ins30-Ins0)/(Glu30-Glu0), was used to estimate insulin secretion [33]. The β-cell compensatory capacity was evaluated using the disposition index (DI), defined as the product of the Matsuda and insulinogenic indices [33]. MetS was diagnosed applying the International Diabetes Federation (IDF) 2007 definition according to different age groups: 6 to