Giuseppe d'Annunzio

A telemedicine support for diabetes management: the T-IDDM project

In the context of the EU funded Telematic Management of Insulin-Dependent Diabetes Mellitus (T-IDDM) project, we have designed, developed and evaluated a telemedicine system for insulin dependent diabetic patients management. The system relies on the integration of two modules, a Patient Unit (PU) and a Medical Unit (MU), able to communicate over the Internet and the Public Switched Telephone Network. Using the PU, patients are allowed to automatically download their monitoring data from the blood glucose monitoring device, and to send them to the hospital data-base; moreover, they are supported in their every day self monitoring activity. The MU provides physicians with a set of tools for data visualization, data analysis and decision support, and allows them to send messages and/or therapeutic advice to the patients. The T-IDDM service has been evaluated through the application of a formal methodology, and has been used by European patients and physicians for about 18 months. The results obtained during the project demonstration, even if obtained on a pilot study of 12 subjects, show the feasibility of the T-IDDM telemedicine service, and seem to substantiate the hypothesis that the use of the system could present an advantage in the management of insulin dependent diabetic patients, by improving communications and, potentially, clinical outcomes.

Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young.

Glucokinase (GCK) serves as the pancreatic glucose sensor. Heterozygous inactivating GCK mutations cause hyperglycemia, whereas activating mutations cause hypoglycemia. We studied the GCK V62M mutation identified in two families and co-segregating with hyperglycemia to understand how this mutation resulted in reduced function. Structural modeling locates the mutation close to five naturally occurring activating mutations in the allosteric activator site of the enzyme. Recombinant glutathionyl S-transferase-V62M GCK is paradoxically activated rather than inactivated due to a decreased S0.5 for glucose compared with wild type (4.88 versus 7.55 mm). The recently described pharmacological activator (RO0281675) interacts with GCK at this site. V62M GCK does not respond to RO0281675, nor does it respond to the hepatic glucokinase regulatory protein (GKRP). The enzyme is also thermally unstable, but this lability is apparently less pronounced than in the proven instability mutant E300K. Functional and structural analysis of seven amino acid substitutions at residue Val62 has identified a non-linear relationship between activation by the pharmacological activator and the van der Waals interactions energies. Smaller energies allow a hydrophobic interaction between the activator and glucokinase, whereas larger energies prohibit the ligand from fitting into the binding pocket. We conclude that V62M may cause hyperglycemia by a complex defect of GCK regulation involving instability in combination with loss of control by a putative endogenous activator and/or GKRP. This study illustrates that mutations that cause hyperglycemia are not necessarily kinetically inactivating but may exert their effects by other complex mechanisms. Elucidating such mechanisms leads to a deeper understanding of the GCK glucose sensor and the biochemistry of β-cells and hepatocytes.

Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families

OBJECTIVE To investigate the prevalence of maturity-onset diabetes of the young (MODY) in Italian children with incidental hyperglycemia. RESEARCH DESIGN AND METHODS Among 748 subjects age 1–18 years with incidental hyperglycemia, minimal diagnostic criteria for MODY were met by 172 families. Mutational analyses of the glucokinase (GCK) and hepatocyte nuclear factor 1α (HNF1Α) genes were performed. RESULTS We identified 85 GCK gene mutations in 109 probands and 10 HNF1Α mutations in 12 probands. In GCK patients, the median neonatal weight and age at the first evaluation were lower than those found in patients with HNF1A mutations. Median fasting plasma glucose and impaired fasting glucose/impaired glucose tolerance frequency after oral glucose tolerance testing were higher in GCK patients, who also showed a lower frequency of diabetes than HNF1A patients. CONCLUSIONS GCK mutations are the prevailing cause of MODY (63.4%) when the index case is recruited in Italian children with incidental hyperglycemia.

Meta-Analysis of the Effect of the Use of Computer-Based Systems on the Metabolic Control of Patients with Diabetes Mellitus

The purpose of this study was to evaluate, through a meta-analysis study, whether the use of computer-based systems reported in the literature improves the metabolic control of diabetic patients. On the retrieved papers, a set of meta-analysis studies were performed: first the difference of HbA1c between cases and controls at follow-up was evaluated (sign test); then the difference between cases and controls in the total variation of HbA1c from the beginning to the end of the trial was considered (method of effect sizes). The latter methodology was reapplied also on three more homogeneous article subgroups. The sign test was performed on 16 papers: in two of them, the HbA1c level was higher in the intervention group than in the control group at follow-up: it is unlikely that this is a random occurrence (p < 0.01). The method of effect sizes was first applied to 13 papers, as in the others some needed data were missing: the results obtained showed a statistically significant amelioration of metabolic control in the intervention group in comparison to the control group (p < 0.01). A progressive reinforcement of this outcome was obtained on the trial subgroups. Our study supports the hypothesis that the use of computer-based systems can be an effective means of improving metabolic control. The differential benefit obtained in the amelioration of HbA1c does not justify, by itself, the applicability of such systems into clinical practice; additional investigations should be carried out to evaluate the enhancement of other clinical and organizational indicators.

Protocol-based reasoning in diabetic patient management

We propose a system for teleconsultation in Insulin Dependent Diabetes Mellitus (IDDM) management, accessible through the use of the net. The system is able to collect monitoring data, to analyze them through a set of tools, and to suggest a therapy adjustment in order to tackle the identified metabolic problems and to fit the patients needs. The therapy revision has been implemented through the Episodic Skeletal Planning Methodi, it generates an advice and employs it to modify the current therapeutic protocol, presenting to the physician a set of feasible solutions, among which she can choose the new one.

Wolfram Syndrome (Diabetes Insipidus, Diabetes, Optic Atrophy, and Deafness): Clinical and genetic study

OBJECTIVE—Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by diabetes insipidus, diabetes (nonautoimmune), optic atrophy, and deafness (a set of conditions referred to as DIDMOAD). The WFS1 gene is located on the short arm of chromosome 4. Wolfram syndrome prevalence is 1 in 770,000 live births, with a 1 in 354 carrier frequency. RESEARCH DESIGN AND METHODS—We evaluated six Italian children from five unrelated families. Genetic analysis for Wolfram syndrome was performed by PCR amplification and direct sequencing. RESULTS—Mutation screening revealed five distinct variants, one novel mutation (c.1346C>T; p.T449I) and four previously described, all located in exon 8. CONCLUSIONS—Phenotype-genotype correlation is difficult, and the same mutation gives very different phenotypes. Severely inactivating mutations result in a more severe phenotype than mildly inactivating ones. Clinical follow-up showed the progressive syndromes seriousness.

Variations of the Perforin Gene in Patients With Type 1 Diabetes

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.

Genetic investigation in an Italian child with an unusual association of atrial septal defect, attributable to a new familial GATA4 gene mutation, and neonatal diabetes due to pancreatic agenesis

Diabet. Med. 27, 1195–1200 (2010)

Association of alleles at polymorphic sites in the osteopontin encoding gene in young type 1 diabetic patients

The Osteopontin (OPN) encoding gene, SPP1, can be considered as a candidate for genetic susceptibility to type 1 diabetes (T1D) because of its known function in immune response and inflammation. This work aimed to evaluate the role of SPP1 gene in susceptibility to T1D. Patients (238: 130 male, 108 female) and unaffected adult control individuals (137: 68 males and 69 females) have been genotyped for three variants in the SPP1 gene: -156 (G/GG) and -66 (T/G) in the promoter and a biallelic ins/del variant (TG/TGTG) at +245 in the first intron. The G allele at the -66 SNP had significantly higher frequency in controls than T1D patients. Interestingly, case-control comparison in males showed no significant association, whereas the association was confirmed in females. These results suggest that SPP1 can play a role as susceptibility gene, possibly by a sex-specific mechanism acting in the autoimmune process.

Evaluation of insulin resistance in a cohort of HIV-infected youth

OBJECTIVE Metabolic abnormalities, including impairment of glucose homeostasis, have been well characterized in HIV-infected patients. In contrast to adults, insulin resistance and diabetes mellitus appear to be relatively uncommon finding in youth. DESIGN We assessed insulin resistance, and associated risk factors, in a population of vertically HIV-infected children and young adults, when compared with a control population of healthy children. METHODS At the time of enrolment, weeks of pregnancy, birth weight, sex, age, weight, height, body mass index (BMI), pubertal stages, CDC classification, blood pressure, clinical lipodystrophy, hepatitis B or C co-infection, antiretroviral therapy, CD4 T lymphocyte counts, and HIV-RNA levels were recorded. Fasting plasma glucose and insulin levels and homeostatic model assessment-insulin resistance (HOMA-IR) were determined. These parameters were compared between HIV patients and healthy controls with multivariate analyses. RESULTS Fasting insulin levels (OR=1.21, P<0.001) and glycemia (OR=0.89, P<0.001) were significantly different between HIV-infected patients and controls. Antiretroviral therapy duration (r=0.281, P<0.05), triglyceride levels (r=0.286, P<0.05), age (r=0.299, P<0.05), and BMI SDS (r=0.485, P<0.001) were significant predictor variables of insulin resistance, expressed as HOMA-IR. Moreover, clinical lipodystrophy seems to be strongly correlated to glycemia (P<0.05), triglyceride levels (P<0.05), serum insulin levels (P<0.001), HOMA-IR (P<0.05), and also with therapy duration (P<0.05). CONCLUSIONS Both HIV infection and antiretroviral therapy demonstrate differential effects on glucose metabolism in HIV-infected children. Targeted prevention of insulin resistance and diabetes mellitus in HIV-infected children and young adults is needed in order to avoid the associated long-term complications that would otherwise occur, given the improvement in life expectancy of HIV-infected individuals.