After the discovery of insulin, nutrition has become central in the management of diabetes in order to limit glycemic rise after meals, optimize metabolic control, and prevent complications. Over the ...past one hundred years, international scientific societies have consecutively refined nutritional needs and optimized food intake for the treatment of diabetes. In particular, over the past century, nutrition applied with pumps for the administration of insulin and continuous glucose monitoring have allowed substantial advancement in the treatment of type 1 diabetes mellitus. The role of some substances, such as vitamin D and
-3 polyunsaturated fatty acids, have been proposed without univocal conclusions, individually or in combination, or in the diet, to improve the nutrition of type 1 and type 2 diabetes. This second condition, which is highly associated with overweight, should be prevented from childhood onwards. Personalized nutrition could bypass the problem, reaching a scientific conclusion on the individual subject. This article focuses on childhood and adolescent diabetes, aims to provide a narrative summary of nutrition over the past century, and promotes the concept of personalized nutrition to pediatricians and pediatric diabetologists as a possible tool for the treatment of type 1 diabetes and the prevention of type 2 diabetes.
Vitamin D (25OHD) effects on glycemic control are unclear in children and adolescents with type 1 diabetes. Aims of this study were to investigate 25OHD status among children with T1DM and its ...relationship with insulin sensitivity and glycemic status.
A cross sectional study was carried out between 2008-2014. A total of 141 patients had a T1DM >12 months diagnosis and were enrolled in the present study. Of these 35 (24.8%) were migrants and 106 (75.2%) Italians (T2). We retrospectively analyzed data at the onset of the disease (T0)(64 subjects) and 12-24 months before the last visit (T1,124 subjects). Fasting glucose, glycated hemoglobin (HbA1c), 25OHD levels and daily insulin requirement were evaluated and Cholecalciferol 1000 IU/day supplementation for the management of vitamin D insufficiency (<75 nmol/L) was systematically added.
A generalized 25OHD insufficiency was found at each study time, particularly in migrants. At T0, the 25OHD levels were inversely related to diabetic keto-acidosis (DKA) severity (p<0.05). At T1 and T2, subjects with 25OHD ≤25nmol/L (10 ng/mL) showed higher daily insulin requirement (p<0.05) and HbA1c values (p<0.01) than others vitamin D status. The 25OHD levels were negatively related with HbA1c (p<0.001) and daily insulin dose (p<0.05) during follow up. There was a significant difference in 25OHD (p<0.01) between subjects with different metabolic control (HbA1c <7.5%,7.5-8%,>8%), both at T1 and T2. In supplemented subjects, we found a significant increase in 25OHD levels (p<0.0001) and decrease of HbA1c (p<0.001) between T1 and T2, but this was not significant in the migrants subgroup. Multivariate regression analysis showed a link between HbA1c and 25OHD levels (p<0.001).
Children with T1DM show a generalized 25OHD deficiency that impact on metabolic status and glycemic homeostasis. Vitamin D supplementation improves glycemic control and should be considered as an additional therapy.
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After the discovery of insulin, nutrition has become central in the management of diabetes in order to limit glycemic rise after meals, optimize metabolic control, and prevent complications. Over the ...past one hundred years, international scientific societies have consecutively refined nutritional needs and optimized food intake for the treatment of diabetes. In particular, over the past century, nutrition applied with pumps for the administration of insulin and continuous glucose monitoring have allowed substantial advancement in the treatment of type 1 diabetes mellitus. The role of some substances, such as vitamin D and n-3 polyunsaturated fatty acids, have been proposed without univocal conclusions, individually or in combination, or in the diet, to improve the nutrition of type 1 and type 2 diabetes. This second condition, which is highly associated with overweight, should be prevented from childhood onwards. Personalized nutrition could bypass the problem, reaching a scientific conclusion on the individual subject. This article focuses on childhood and adolescent diabetes, aims to provide a narrative summary of nutrition over the past century, and promotes the concept of personalized nutrition to pediatricians and pediatric diabetologists as a possible tool for the treatment of type 1 diabetes and the prevention of type 2 diabetes.
Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases ...documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.
Vitamin D status during pregnancy is related to neonatal vitamin D status. Vitamin D deficiency has been associated with an increased risk of rickets in children and osteomalacia in adults. Aim of ...this study was to investigate 25OHD levels in maternal serum and in neonatal blood spots in native and migrant populations living in Novara (North Italy, 45°N latitude).
We carried out a cross sectional study from April 1st 2012 to March 30th 2013, in a tertiary Care Center. Maternal blood samples after delivery and newborns' blood spots were analyzed for 25OHD levels in 533 pairs. Maternal country of origin, skin phototype, vitamin D dietary intake and supplementation during pregnancy were recorded. Multivariate regression analysis, showed a link between neonatal and maternal 25OHD levels (R-square:0.664). Severely deficient 25OHD values (<25 nmol/L) were found in 38% of Italian and in 76.2% of migrant's newborns (p <0.0001), and in 18% of Italian and 48,4% of migrant mothers (p <0.0001) while 25OHD deficiency (≥25 and <50 nmol/L) was shown in 40.1% of Italian and 21.7% of migrant's newborns (p <0.0001), and in 43.6% of Italian and 41.3% of migrant mothers (p <0.0001). Italian newborns and mothers had higher 25OHD levels (34.4±19.2 and 44.9±21.2 nmol/L) than migrants (17.7±13.7 and 29.7±16.5 nmol/L; p<0.0001). A linear decrease of 25OHD levels was found with increasing skin pigmentation (phototype I 42.1 ±18.2 vs phototype VI 17.9±10.1 nmol/l; p<0.0001). Vitamin D supplementation resulted in higher 25OHD values both in mothers and in their newborns (p<0.0001).
Vitamin D insufficiency in pregnancy and in newborns is frequent especially among migrants. A prevention program in Piedmont should urgently be considered and people identified as being at risk should be closely monitored. Vitamin D supplementation should be taken into account when considering a preventative health care policy.
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Aims
The incidence of type 1 diabetes has increased over the last decades. The pathological pathway is not yet clear, even if genetic and environmental risk factors are known. An early diagnosis can ...avoid ketoacidosis and its complications. This work aims to discuss the determinants of both ketoacidosis at the onset and access by hospital emergency departments without a suspected diagnosis.
Methods
An observational bi-centric prospective study was conducted in Northern Italy, on a paediatric population including Italian and migrant patients at the diabetes onset. Seventy-four type 1 diabetes patients, both Italian and migrant, were included in the study. Anthropometric, socio-economic, behavioural, clinical data were collected, and microbiota analyses were performed using stool samples.
Results
Regular physical activity is associated with lower ketoacidosis incidence at onset (OR 0.33 95% CI 0.12–0.95
p
< 0.05), as is higher blood vitamin D level (OR 0.92 95% CI 0.85–0.99
p
< 0.05). Moreover, a higher weaning age (OR 0.49 95% CI 0.27–0.89
p
< 0.05), higher vitamin D level (OR 0.90 95% CI 0.83–0.98
p
< 0.05) and a higher level of
Akkermansia muciniphila
(OR 0.46 95% CI 0.25–0.87
p
< 0.05) are associated factors to lower frequency of type 1 diabetes onset without a suspected diagnosis. Diabetes migrant status is not a risk factor for severe type 1 diabetes onset; on the other hand, some protective factors are significantly more diffused among Italians, such as regular sport activity and non-critical vitamin D levels.
Conclusion
Behavioural and nutritional data, such as microbiota bio-indicators, seem to be useful to identify an at-risk population to prevent ketoacidosis and its severe complications.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Variations of the Perforin Gene in Patients With Type 1 Diabetes
Elisabetta Orilieri 1 ,
Giuseppe Cappellano 1 ,
Rita Clementi 1 ,
Angela Cometa 2 ,
Massimo Ferretti 1 ,
Elisa Cerutti 1 ,
Francesco ...Cadario 1 ,
Miryam Martinetti 3 ,
Daniela Larizza 4 ,
Valeria Calcaterra 4 ,
Giuseppe D’Annunzio 5 ,
Renata Lorini 5 ,
Franco Cerutti 6 ,
Graziella Bruno 7 ,
Annalisa Chiocchetti 1 and
Umberto Dianzani 1
1 Interdisciplinary Research Center of Autoimmune Diseases and Department of Medical Sciences, A. Avogadro University of Eastern
Piedmont, Novara, Italy
2 Pediatric Haematology-Oncology, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
3 Immunohaematology and Transfusion Center, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
4 Department of Pediatric Sciences University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
5 Department of Pediatric Sciences, Gaslini Institute-IRCCS, University of Genoa, Genoa, Italy
6 Department of Pediatrics, University of Turin, Turin, Italy
7 Department of Internal Medicine, University of Turin, Turin, Italy
Address correspondence and reprint requests to Umberto Dianzani, IRCAD-Department of Medical Sciences, Via Solaroli, 17, I-28100,
Novara, Italy. E-mail: umberto.dianzani{at}med.unipmn.it
Abstract
OBJECTIVE— Perforin plays a key role in cell-mediated cytotoxicity. Mutations of its gene, PRF1 , cause familial hemophagocytic lymphohistiocytosis but have also been associated with lymphomas and the autoimmune/lymphoproliferative
syndrome. The aim of this work was to investigate the role of PRF1 variations in type 1 diabetes.
RESEARCH DESIGN AND METHODS— We typed for the N252S and A91V variations in an initial population of 352 type 1 diabetic patients and 816 control subjects
and a second population of 365 patients and 964 control subjects. Moreover, we sequenced the coding sequence and intron-exons
boundaries in 200 patients and 300 control subjects.
RESULTS— In both cohorts, allelic frequency of N252S was significantly higher in patients than in control subjects (combined cohorts:
1.5 vs. 0.4%; odds ratio 6.68 95% CI 1.83–7.48). Sequencing of the entire coding region detected one novel mutation in one
patient, causing a P477A amino acid change not detected in 199 patients and 300 control subjects. Typing for HLA-DQA1 and
DQB1 alleles showed that type 1 diabetes–predisposing DQα/DQβ heterodimers were less frequent in patients carrying N252S or
P477A than in those carrying wild-type PRF1 . We previously found that natural killer (NK) activity is not decreased in most N252S heterozygotes, but we detected one
whose NK activity was normal at the age of 12 but strikingly low in early childhood. Here, we discovered that NK function
was low in three heterozygotes in early childhood, one homozygous adult, and in the subject carrying P477A.
CONCLUSIONS— These data suggest that N252S and possibly other PRF1 variations are susceptibility factors for type 1 diabetes development.
ALPS, autoimmune lymphoproliferative syndrome
HLH, hemophagocytic lymphohistiocytosis
NK, natural killer
PBMC, peripheral blood mononuclear cells
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 15 January 2008. DOI: 10.2337/db07-0947.
E.O. and G.C. contributed equally to this work.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted January 9, 2008.
Received July 10, 2007.
DIABETES
Abstract
Objectives
Vitamin D plays an immunoregulatory activity. The aim of this study was to assess the correlation between blood serum 25(OH)D levels and Th17 and Treg circulating subsets, mainly ...Treg/inducible costimulatory-positive (ICOS+), which seems to have a protective role in autoimmunity, in children with type 1 diabetes mellitus (T1D) and their healthy siblings (S). The secondary aim was to evaluate the impact of vitamin D supplementation on these subsets.
Patients and Methods
22 T1D and 33 S were enrolled. Glucose, hemoglobin A1c, 25 OH vitamin D (25OHD), T helper type 17 (Th17; CD4+CCR6+), regulatory T cells (Treg; CD4+CD25+Foxp3+), and Treg/ICOS+ cells were evaluated. According to human leukocyte antigen (HLA) haplotypes, subjects were classified as “at risk” (HLA+), “protective haplotypes” (HLA−; “nested controls”), and “undetermined” (HLAUND). T1D and S subjects were supplemented with cholecalciferol 1000 IU/die and evaluated after 6 months.
Results
Vitamin D insufficiency (74.4%) and deficiency (43%) were frequent. S subjects with 25(OH)D levels <25 nmol/L had Th17, Treg (p < 0.01), and Treg/ICOS+ (P < 0.05) percentages higher than subjects with 25(OH)D >75 nmol/L. Treg/ICOS+ percentages (P < 0.05) were higher in HLA− S subjects compared to percentages observed in S with T1D. At baseline, in S subjects, a decreasing trend in Th17 and Treg/ICOS+ values (P < 0.05) from vitamin D deficiency to sufficiency was observed; 25(OH)D levels were negative predictors of Treg/ICOS+ (R2 = 0.301) and Th17 percentages (R2 = 0.138). After 6 months, supplemented S subjects showed higher 25(OH)D levels (P < 0.0001), and lower Th17 (P < 0.0001) and Treg/ICOS+ (P < 0.05) percentages than at baseline; supplemented T1D patients only had a decrease in Th17 levels (P < 0.05).
Conclusion
Serum 25(OH)D levels seem to affect Th17 and Treg cell subsets in S subjects, consistent with its immunomodulating role. HLA role should be investigated in a larger population.
Type 1 diabetes (T1D) is a common autoimmune disease that is characterized by insufficient insulin production. The onset of T1D is the result of gene-environment interactions. Sociodemographic and ...behavioural factors may contribute to T1D, and the gut microbiota is proposed to be a driving factor of T1D. An integrated preventive strategy for T1D is not available at present. This case-control study attempted to estimate the exposure linked to T1D to identify significant risk factors for healthy children. Forty children with T1D and 56 healthy controls were included in this study. Anthropometric, socio-economic, nutritional, behavioural, and clinical data were collected. Faecal bacteria were investigated by molecular methods. The findings showed, in multivariable model, that the risk factors for T1D include higher Firmicutes levels (OR 7.30; IC 2.26-23.54) and higher carbohydrate intake (OR 1.03; IC 1.01-1.05), whereas having a greater amount of Bifidobacterium in the gut (OR 0.13; IC 0.05 - 0.34) was a protective factor for T1D. These findings may facilitate the development of preventive strategies for T1D, such as performing genetic screening, characterizing the gut microbiota, and managing nutritional and social factors.
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KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with ...excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.
In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.
90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer for HbA1c, year 1, and most recent follow-up; n=64)—median HbA1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol 55·2–77·1) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol 35·5–47·5; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9–7·3; 46·4 mmol/mol 41·0–56·3; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years IQR 9·2–10·9). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14–0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12–0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years IQR 10·5–24·0 vs 4·1 years 1·3–10·2; p=0·0005). Initial improvement was noted following transfer to sulfonylureas in 18 (47%) of 38 patients with CNS features. After long-term therapy with sulfonylureas, CNS features were seen in 52 (64%) of 81 patients.
High-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years.
Wellcome Trust, Diabetes UK, Royal Society, European Research Council, Norwegian Research Council, Kristian Gerhard Jebsen Foundation, Western Norway Regional Health Authority, Southern and Eastern Norway Regional Health Authority, Italian Ministry of Health, Aide aux Jeunes Diabetiques, Societe Francophone du Diabete, Ipsen, Slovak Research and Development Agency, and Research and Development Operational Programme funded by the European Regional Development Fund.
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