Elżbieta Kozek

Efficacy and Safety of Sulfonylurea Use in Permanent Neonatal Diabetes Due to KCNJ11 Gene Mutations: 34-Month Median Follow-Up

BACKGROUND Recently, many patients with Kir6.2-related permanent neonatal diabetes mellitus (PNDM) have been successfully transferred from insulin therapy to sulfonylurea (SU) treatment. The long-term efficacy and safety of SU treatment in PNDM patients, however, have not yet been determined. METHODS We monitored glycemic control and the occurrence of potential side effects in 14 Kir6.2-related PNDM patients from Poland (median age, 12.0 years; range, 5-50 years) who were transferred to SU therapy at least 2 years ago. Three of the 14 patients were lost to follow-up, whereas for the remaining 11 individuals the median follow-up was 34 months (range, 27-51 months). RESULTS The initial reduction of glycated hemoglobin (HbA1c) after the switch to SU (approximately 3-6 months post-transfer) was 1.68% (range, 0.3-3.7%), and good metabolic control was maintained over the entire period of observation with an average HbA1c level of 6.0% (range, 5.3-6.7%) at the last visit. This was accompanied by a substantial drop in SU dose by 0.24 mg/kg, which constituted a 38.0% decrease. A rapid progression of retinal changes was observed in one patient, a 34-year-old woman at the beginning of the observation, with preexisting proliferative diabetic retinopathy. No causal relationship between these changes and SU treatment could be proven. Neither serious side effects nor progression of diabetes complications was observed in any other patients. No detrimental effect on growth in the observed minors was recorded. CONCLUSIONS In summary, the switch from insulin therapy to SU treatment in PNDM related to KCNJ11 mutations was found to be an efficient and safe therapeutic method over a period of 34-month median follow-up. Although no serious side effects were associated with SU treatment, their use in Kir6.2 PNDM requires further attention, particularly in children, adolescents, and patients with advanced chronic diabetes complications.

Dipeptidyl Peptidase-IV Inhibitors Are Efficient Adjunct Therapy in HNF1A Maturity-Onset Diabetes of the Young Patients—Report of Two Cases

BACKGROUND In HNF1A maturity-onset diabetes of the young (MODY), sulfonylurea (SU) is the first-line treatment. Over time, such therapy fails, and additional treatment is required. Dipeptidyl peptidase IV (DPP-IV) inhibitors are new agents that lower blood glucose by prolonging the activity of circulating incretins. METHODS We applied DPP-IV inhibitors in two HNF1A MODY patients whose earlier therapeutic regimen included SU. RESULTS Case 1, a 39-year-old woman, a carrier of the ArgR171X HNF1A mutation, with a 7-year history of diabetes was on 160 mg of gliclazide and 2,000 mg of metformin. Her initial hemoglobin A1c (HbA1c) level was 7.2%, while the mean glucose level on the CGMS((R)) (Medtronic, Northridge, CA) record was 162 mg/dL. Sitagliptine, in a dose of 100 mg/day, was added to the previous treatment. Case 2, a 62-year-old woman, a carrier of the IVS7nt-6G>A mutation, with a 41-year history of diabetes was treated with 240 mg/day gliclazide and 6 IU of insulin/day. Her initial HbA1c was 8.8%, and average glycemia reached 172 mg/dL. In her case, we started the combined therapy with 50 mg of vildagliptine twice daily. Patients were reexamined after 3 months, and HbA1c fell to 6.3% in both subjects. Similarly, significant improvement in glycemic control on CGMS was observed as the average glycemia decreased to 114 mg/dL and 134 mg/dL in Case 1 and Case 2, respectively. No episodes of hypoglycemia or other side effects were recorded. As intravenous glucose tolerance tests (IVGTTs) were performed before and after DPP-IV implementation, we were able to assess their impact on insulin secretion under fasting conditions. We saw a substantial rise in insulin level increment during IVGTT (by 9.8 and13.4 mIU/L in Case 1 and Case 2, respectively). CONCLUSIONS DPP-IV inhibitors may be an effective tool of combined therapy in HNF1A MODY, and they seem to improve beta-cell function under fasting conditions.

Liraglutide therapy in Prader-Willi syndrome.

Glucagon-like peptide 1 (GLP-1) receptor agonists are a new class of drugs that have been recently introduced for the treatment of Type 2 diabetes mellitus [1]. Two compounds, exenatide and liraglutide, have been registered. An advantage of the use of these compounds is the reduction in body mass, which usually accompanies the improvement in glycaemic control. There have also been reports on GLP-1 agonist use in other disorders, such as obesity without diabetes or polycystic ovary syndrome [2,3]. Here, for the first time, we report short-term liraglutide use in a woman with morbid obesity and diabetes associated with Prader–Willi syndrome. At the age of 4 years, the patient, who had typical features of Prader–Willi syndrome, such as severe obesity (BMI 32.6 kg ⁄ m, BMI SDS 9.8), developmental delay, hypotonia and characteristic dysmorphic features [4], underwent genetic testing (DNA methylation analysis), which confirmed the clinical diagnosis. The patient and her family were provided with psychological support, together with dietary advice; however, the results were poor, as, at the age of 10 years, her weight was 100 kg at 140 cm in height (BMI 51.0 kg ⁄ m, BMI SDS 12.3). When the patient was 12 years old, she started receiving growth hormone therapy without any beneficial effects on her weight and height. Three years later she was diagnosed with obstructive sleep apnoea, hypertension, high myopia and Scheuermann disease. Diabetes mellitus was diagnosed when she was 17 years old. Hypoglycaemic treatment initiated by a paediatrician consisted of gliclazide modified-release 30 mg ⁄ day and acarbose 300 mg ⁄ day (metformin tablets were not tolerated because of typical gastrointestinal side effects). At the age of 18 years, she was referred to the Department of Metabolic Diseases, a diabetes centre for adults in south-eastern Poland. By then, the patient was severely obese (BMI 65.2 kg ⁄ m) and had poorly controlled diabetes [HbA1c level 7.8% (62 mmol ⁄ mol); 7-day mean fasting glucose level during self-control on glucometer 9.1 mmol ⁄ l, range 7.0–14.7 mmol ⁄ l]. She was diagnosed with asymptomatic cholelithiasis. Subsequently, the patient was scheduled for a laparoscopic cholecystectomy, and insulin therapy inamultipledaily injectionmodelwas initiatedas a result of lack of glycaemic control and the planned surgery. Over a period of 6 weeks she gained 2 kg and her HbA1c level increased to 8.5% (69 mmol ⁄ mol). Moreover, the patient did not tolerate the insulin therapy, particularly the necessity for several daily injections of insulin. After a successful cholecystectomy, we decided to switch her to liraglutide (1.8 mg ⁄ day) and powder metformin (1500 mg ⁄ day). At the follow-up, 8 weeks later, her HbA1c level had dropped to 6.7% (50 mmol ⁄ mol), her 7-day mean fasting glucose was 5.8 mmol ⁄ l (range 5.6–7.8 mmol ⁄ l), while the mean 72-h glucose level was 6.1 mmol ⁄ l, as measured on a continuous glucose monitoring system (Guardian RT; Medtronic, Minneapolis, MN, USA). No hypoglycaemic episodes were observed. The treatment was well tolerated, she lost 2 kg of weight and reported satiety. After another 6 weeks, her HbA1c level slightly decreased to 6.6% (49 mmol ⁄ mol) and her weight dropped by 1.2 kg. Thus, in total, over the entire period of 14 weeks of GLP-1 agonist therapy, we achieved a reduction of HbA1c level by 1.9% and of body mass by 3.2 kg. At the same time, her fat tissue amount decreased from 88.4 to 82.4 kg, as measured by biothesiometer, and her waist circumference decreased from 141 to 133 cm. Fasting C-peptide and insulin levels slightly increased (3.12 vs. 3.56 ng ⁄ ml and 13.2 vs. 17.9 lU ⁄ ml, respectively). In summary, we suggest that liraglutide, in this case combined with metformin, may be an effective therapy in patients with Prader–Willi syndrome who are morbidly obese and have diabetes. This is a potentially clinically important observation, particularly taking into account that the use of most anti-diabetic drugs inevitably leads to weight gain. It may be speculated that one of the mechanisms of the beneficial effect of GLP-1 agonists may be a reduction in ghrelin level, which is greatly elevated in Prader–Willi syndrome; this phenomenon has been described previously in an animal model [4,5]. However, the long-term effects of such treatment in individuals with Prader–Willi syndrome are uncertain and further studies on a larger number of patients are required.

Visceral obesity and hemostatic profile in patients with type 2 diabetes: the effect of gender and metabolic compensation.

BACKGROUND Type 2 diabetes (T2DM) patients are characterized by a very high risk of cardiovascular diseases. Among the factors that are responsible for this phenomenon are abdominal obesity and hemostatic abnormalities. AIM OF THE STUDY To examine the association of the markers of coagulation and fibrinolysis with the parameters of abdominal obesity and metabolic compensation in T2DM patients. METHODS 46 T2DM patients participated in the study: 24 men (mean age 61.1 +/- 7.9 years) and 22 postmenopausal women (mean age 62.6 +/- 8.7 years). In each patient the content and distribution of fatty tissue was measured by a dual energy X-ray absorptiometry method (DEXA). The central abdominal fat/gynoid hip fat (CAF/GF) ratio was calculated. The following hemostatic parameters were measured: fibrinogen (Fb), factor VII (fVII), antithrombin III (ATIII), C protein (pC), tissue plasminogen activator inhibitor (PAI-1) and alpha 2 antiplasmin (alpha2 AP). In addition, the biochemical indices of metabolic compensation were measured: HbA1c, glucose levels and lipids. RESULTS Patients of both genders were divided according to median CAF/GF ratio. The activity of PAI-1 was significantly higher in women with CAF/GF ratio >or= 0.88 as compared to those with CAF/GF < 0.88 (2.64 +/- 1.28 vs. 1.61 +/- 0.27 U/ml, p < 0.05). The activity of ATIII was significantly lower in men with CAF/GF ratio >or= 1.17, as compared to those with CAF/GF < 1.17 (105.10 +/- 10.02 vs. 113.42 +/- 10.72 %, p < 0.05). There was a significant correlation between the CAF/GF ratio and the activity of PAI-1 in women (r = 0.30, p < 0.05). In addition, in men the CAF/GF ratio was negatively correlated with ATIII activity (r = -0.44, p < 0.05). Multiple stepwise regression analysis demonstrated independent association between the CAF/ GF ratio and the activity of PAI-1 (p < 0.001), and between the CAF/GF ratio and the activity of alpha2 AP (p < 0.01). There was an independent association between the concentration of HbA1c and the concentration of Fb (p < 0.001) and between triglycerides and the activity of fVII (p < 0.01). CONCLUSIONS The results of our study show that the patients with T2DM and with higher markers of abdominal obesity measured by DEXA show fibrinolysis impairment and thrombinogenesis elevation compared to those with lower abdominal obesity markers. Independent factors determining hypercoagulation also include metabolic control and lipids. Hemostatic disorders place subjects with diabetes and abdominal obesity at risk of developing vascular complications.

Diabetic retinopathy in permanent neonatal diabetes due to Kir6.2 gene mutations: the results of a minimum 2‐year follow‐up after the transfer from insulin to sulphonylurea

Permanent neonatal diabetes mellitus (PNDM) is a monogenic form of disease usually diagnosed within the first 6 months of life. Its most common form is associated with KCNJ11 gene mutations. This gene encodes the pore-forming Kir6.2 subunit of the pancreatic B-cell KATP-dependent potassium channel. Most children and adults with Kir6.2 mutations can be successfully transferred from insulin to sulphonylureas (SU) [1]. This transfer usually results in rapid and profound improvement in glycaemic control as measured by glucose and HbA1c. However, there are scant data on the influence of this change in therapy on the occurrence and progression of diabetic complications, e.g. diabetic retinopathy (DR). This could be a concern, particularly as transientprogressionof DRwas previously reported in various patients directly after intensification of glucose-lowering therapy [2,3]. The aim of this study was to assess the long-term effect of the switch from insulin to SU in diabetic patients with Kir6.2 mutations on the occurrence and progression of DR. We examined 11 Kir6.2 mutation carriers who after genetic testing wereswitchedfrominsulin toSUandinwhomthisnewtreatment was continued for at least 2 years (median 34 months, range 27– 51). The subjects underwent ophthalmological examinations at the time when diabetic therapy was changed and at least every 12 months during the follow-up period of a minimum of 2 years. The age of the 11 patients included ranged from 5 to 34 years. The mean HbA1c at baseline was 7.4% (range 6.6–10.2). Based on measurement before the transfer to SU and the first one after transfer (3–6 months), the initial dropinHbA1c was1.2%(range 0.3–3.7%). Excellent glycaemic control was maintained over the follow-up, and the mean HbA1c at the end of the observation was 6.0% (range 5.3–6.7%). Nine subjects were free of DR when SU treatment was started and no evidence of DR was found during follow-up. During the initial examination, one patient, a 21-year-old woman, showed evidence of mild non-proliferative DR. On follow-upevery12 months for the three subsequentyears, noDR progression was observed and there was no indication for laser treatment. However, in one 34-year-old female PNDM patient, a carrier of the R201H mutation, proliferative DR was present at the time when genetic testing was performed. She had undergone four episodes of laser photocoagulation during the 10 years prior to treatment intensification. Fundus eye examination and fluorescein angiography revealed the presence of proliferative DR. In addition, she also had microalbuminuria, moderate peripheral polyneuropathy, cardiovascular autonomic neuropathy and hypertension. This woman was diagnosed with diabetes at the age of 6 weeks and insulin therapy was startedat that time.Herdiabetes controlwasunsatisfactory,with most documented HbA1c measurements around 12.0–13.0%. She was transferred to an intensive insulin regimen (multiple daily injections) just 3 months before PNDM was diagnosed on genetic testing. This intensified insulin therapy resulted in a rapid and profound fall of HbA1c from 13.0 to 7.2%. Following identification of the R201H Kir6.2 mutation, she was, as previously described [4], transferred to glipizide gastrointestinal therapeutic system. Shortly thereafter, this patient became completely insulin independent. Six months later, her HbA1c level dropped further from to 7.2 to 5.9%. Over 28 months’ follow-up, progression of DR was observed with new areas of macular, iridal and optic disc neovascularization. After the switch the patient underwent laser therapy on 17 occasions (Fig. 1). During the most recent 10 months, however, stabilization in eye status was observed and further laser treatment was not required. At the same time, no other chronic complications of diabetes emerged or progressed. Thirty-four months after SU treatment was introduced she required 30 mg of glipizide daily. Glycaemic control was satisfactory (HbA1c 5.9%) and Continuous Glucose Monitoring System revealed normal glucose levels except for some rare episodes of moderate postprandial hyperglycaemia. The clinical characteristics of this patient in whom DR progressed are different from the other individuals. First, she had pre-existing proliferative DR at the switch from insulin to SU. In addition, she was the oldest of our patients and thus diabetes duration in her case was the longest. This patient not only had the highest recorded HbA1c values (> 13.0%), but had been exposed to those high values for many years. She also experienced the greatest initial drop in HbA1c (by 5.8% following intensification of insulin therapy and by another 1.3% following the start of SU), which could put the patient at higher risk of early development ⁄ progression of diabetic complications [2,3]. Finally, unlike the other patients, she had hypertension, a well-established risk factor for the development of DR [5]. In summary, the switch from insulin to SU in PNDM related to Kir6.2 mutations seems not to carry a risk of DR development andprogression in most patients. Nevertheless, subjects withpreexisting advanced DR and initial poor glycaemic control require special ophthalmological attention. DIABETICMedicine Letters

Risk of macrosomia remains glucose-dependent in a cohort of women with pregestational type 1 diabetes and good glycemic control

Macrosomia risk remains high in type 1 diabetes (T1DM) complicated pregnancies. A linear relationship between macrosomia risk and glycated hemoglobin A1c (HbA1c) was described; however, low range of HbA1c has not been studied. We aimed to identify risk factors and examine the impact of HbA1c on the occurrence of macrosomia in newborns of T1DM women from a cohort with good glycemic control. In this observational retrospective one-center study we analyzed records of 510 consecutive T1DM pregnancies (1998–2012). The analyzed group consisted of 375 term singleton pregnancies. We used multiple regression models to examine the impact of HbA1c and self-monitored glucose in each trimester on the risk of macrosomia and birth weight. The median age of T1DM women was 28 years, median T1DM duration—11 years, median pregestational BMI—23.3 kg/m2. Median birth weight reached 3520 g (1st and 3rd quartiles 3150 and 3960, respectively) at median 39 weeks of gestation. There were 85 (22.7 %) macrosomic (>4000 g) newborns. Median HbA1c levels in the 1st, 2nd, and 3rd trimester were 6.4, 5.7, and 5.6 %. Third trimester HbA1c, mean fasting self-monitored glucose and maternal age were independent predictors of birth weight and macrosomia. There was a linear relationship between 3rd trimester HbA1c and macrosomia risk in HbA1c range from 4.5 to 7.0 %. Macrosomia in children of T1DM mothers was common despite excellent metabolic control. Glycemia during the 3rd trimester was predominantly responsible for this condition.

Polish Forum for Prevention Guidelines on Diabetes: update 2017

1Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland 21st Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences, Poznan, Poland 3Department of Cardiac and Vascular Diseases, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland 4Department of Haemodynamics and Angiocardiography, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland 5Chair of Epidemiology and Population Studies, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland 6Department of Preventive Medicine and Medical Education, Medical University in Gdansk, Gdansk, Poland 71st Department of Cardiology, Interventional Electrocardiology, and Hypertension, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland 8Department of Pharmacogenomics, Division of Biochemistry and Clinical Chemistry, Medical University of Warsaw, Warsaw, Poland 9Department of Family Medicine, Jagiellonian University Medical College, Krakow, Poland 10Department of Paediatric Cardiology and Rheumatology, Medical University of Lodz, Lodz, Poland 11Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland 122nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland 13Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland

Wytyczne Polskiego Forum Profilaktyki Chorób Układu Krążenia dotyczące farmakoterapii prewencyjnej: aktualizacja 2017

1Department of Cardiac and Vascular Diseases, Institute of Cardiology, Jagiellonian University Medical College at John Paul II Hospital, Krakow, Poland 21st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland 3Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland 4Chair of Epidemiology and Population Studies, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland 5Centre for Family and Community Medicine, Faculty of Health Sciences, Medical University of Lodz, Lodz, Poland 6Department of Epidemiology, CVD Prevention, and Health Promotion, Institute of Cardiology, Warsaw, Poland 7Department of Preventive Medicine and Medical Education, Medical University in Gdansk, Gdansk, Poland 81st Department of Cardiology, Interventional Electrocardiology and Hypertension, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland 9Department of Haemodynamics and Angiocardiography, John Paul II Hospital, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland 10Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland 11Department of Pharmacogenomics, Division of Biochemistry and Clinical Chemistry, Medical University of Warsaw, Warsaw, Poland 122nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland 13Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland 14Department of Paediatric Cardiology and Rheumatology, Medical University of Lodz, Lodz, Poland 15Department of Family Medicine, Jagiellonian University Medical College, Krakow, Poland 16Department of Internal Diseases and Rural Medicine, Jagiellonian University Medical College, Krakow, Poland

The association of maternal gestational diabetes mellitus with autism spectrum disorders in the offspring

Introduction. Some evidence exists for the association between exposure to pregestational maternal diabetes and risk of autism spectrum disorders (ASD) in offspring. Less information is available on the association of exposure to maternal gestational diabetes mellitus (GDM) with risk of ASD. We aimed to examine the prevalence of ASD disorders in offspring of mothers diagnosed with GDM. Material and methods. We analyzed data gathered from GDM patients (947 women; 1007 children aged 4–16 years) treated at the Department of Metabolic Diseases, University Hospital in Krakow from 1999 to 2011. We conducted a telephone survey to collect clinical information and biochemical parameters. We performed significance test based on the exact binomial probability to assess if the prevalence rate of ASD in offspring of mothers with GDM was different from available epidemiological data for children aged 0–18 years in Poland. We also checked whether there are any significant factors discriminating the mothers and offspring with and without ASD. Results. The prevalence of ASD in the offspring of mothers with GDM in our study (8/1007) was higher than in children aged 0–18 years in Poland (17.6/ /10 000; p = 0.0004). The mothers of children with ASD had median pre-pregnancy BMI (20.862 vs . 23.529), SBP (110 mm Hg vs . 120 mm Hg) and DBP (70 mm Hg vs . 80 mm Hg) lower vs. group without ASD (p = 0.0349; p = 0.0149 and p = 0.0306 respectively). Birth weight of ASD children was significantly higher vs group without ASD (3695 g vs . 3320 g, p = 0.0482). Conclusions. The prevalence of ASD seems to be higher in offspring of mothers with GDM than in the general population. Studying the potential risk factors is crucial for better understanding of this phenomenon and it may be helpful to preventi it.