Recent Advances in Immune-Based Therapies for Type 1 Diabetes.

BACKGROUND: Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by progressive destruction of the pancreatic beta cells, leading to a lifelong dependence on insulin. It is associated with an increased morbidity and mortality from diabetes-related complications and a significant treatment burden. However, there has been substantial progress in therapeutic strategies that can affect the course of the disease. SUMMARY: This review addresses advances in immunotherapy aimed at preserving residual beta-cell function in individuals with a recent onset of T1D and arresting the disease in pre-symptomatic stages. Recent and ongoing clinical trials have investigated the efficacy and safety of various immunotherapeutic strategies aimed at targeting several mechanisms of autoimmunity, which are thought to be important in disease pathogenesis, and therapies that also address beta-cell health. So far, T-cell-directed therapies that led to a favourable balance between T-effector cell depletion or modulation and preservation or expansion of regulatory T cells have shown the most success. Furthermore, regarding the timing of intervention, teplizumab was the first immunomodulatory agent to demonstrate a significant delay in disease progression in high-risk individuals before clinical onset. KEY MESSAGES: As more targeted immune interventions with potentially fewer side effects are closer to the translation into clinical practice, some new challenges may need to be addressed. The use of combination approaches that include immunotherapeutic strategies targeting different aspects of the immune system and interventions that improve beta-cell health may be required, along with the use of individualized patient-tailored approaches, a move towards early intervention, and a focus on patient-reported outcome measures.

GNRHR-related central hypogonadism with spontaneous recovery - case report.

BACKGROUND: Congenital hypogonadotropic hypogonadism (CHH) is a clinically and genetically heterogeneous disease characterized by absent or incomplete puberty and infertility. Clinical characteristics are secondary to insufficient gonadotropin secretion, caused by deficient gonadotropin-releasing hormone (GnRH) production, secretion, or action. Loss-of-function variants of the gonadotropin-releasing hormone receptor (GNRHR) are associated with CHH without anosmia. CHH was previously considered a permanent condition, but in the past two decades, cases of spontaneous recovery of CHH have been reported. The reversal of hypogonadism in CHH is currently unpredictable, and can happen unnoticed. CASE PRESENTATION: The male proband was diagnosed with CHH due to compound heterozygosity for two previously reported pathogenic missense variants in the GNRHR gene, NM_000406.2:c.416G > A (NP_000397.1:p.Arg139His) and c.785G > A (p.Arg262Gln) at 16 years of age. In addition to arrested partial puberty, he had a low testosterone level, gonadotropins in the range of early puberty, and a normal inhibin B level. A therapy with increasing doses of intramuscular testosterone undecanoate was received for 2.5 years, while there was no change in testicular volume. At the age of 19 years, testosterone supplementation was interrupted. During the next two years, he had spontaneous pubertal development to achieve a testicular volume of 20 mL, with normal adult levels of gonadotropins and testosterone. CONCLUSIONS: Genetic diagnostics can help discriminate congenital hypogonadotropic hypogonadism, deserving therapeutic intervention, from the self-limited constitutional delay of growth and puberty (CDGP). Patients with GNRHR associated hypogonadism can experience spontaneous recovery of the hypothalamic-pituitary-gonadal axis. Spontaneous testis enlargement in patients with central hypogonadism not taking gonadotropins or pulsatile GnRH therapy can indicate recovery of hypogonadism.

Impact of Temporary Glycemic Target Use in the Hybrid and Advanced Hybrid Closed-Loop Systems.

The Medtronic advanced hybrid closed-loop (AHCL) and MiniMed™ 670G hybrid closed-loop (HCL) systems provide the option to temporarily increase the glucose target to 150 mg/dL (8.3 mmol/L). This analysis investigated the efficacy of the AHCL compared with that of the HCL after the use of this setting. Data from 60 participants in the Fuzzy Logic Automated Insulin Regulation (FLAIR) study were used to compare the AHCL and HCL systems after the use of the temporary target (TT), and during analogous periods where this setting was not used. Differences in time in range 70-180 mg/dL between the systems were similar after the use of the TT setting and during analogous non-TT periods (interaction P = 0.87). Similar trends were observed for mean glucose, percentage time >180 mg/dL, and percentage time >250 mg/dL. Differences between AHCL and HCL systems were similar after the use of the TT setting compared with those of non-TT periods. ClinicalTrials.gov NCT03040414.

Pathogenesis of Type 1 Diabetes: Established Facts and New Insights.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing ß-cells in pancreatic islets. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. In this review, we highlight the interplay between genetic predisposition and other non-genetic factors, such as viral infections, diet, and gut biome, which all potentially contribute to the aetiology of T1D. We also discuss a possible active role for ß-cells in initiating the pathological processes. Another component in T1D predisposition is epigenetic influences, which represent a link between genetic susceptibility and environmental factors and may account for some of the disease heterogeneity. Accordingly, a shift towards personalized therapies may improve the treatment results and, therefore, result in better outcomes for individuals in the long-run. There is also a clear need for a better understanding of the preclinical phases of T1D and finding new predictive biomarkers for earlier diagnosis and therapy, with the final goal of reverting or even preventing the development of the disease.

Sex-Related Differences in Cardiovascular Disease Risk Profile in Children and Adolescents with Type 1 Diabetes.

Cardiovascular disease (CVD) is the primary cause of higher and earlier morbidity and mortality in people with type 1 diabetes (T1D) compared to people without diabetes. In addition, women with T1D are at an even higher relative risk for CVD than men. However, the underlying pathophysiology is not well understood. Atherosclerotic changes are known to progress early in life among people with T1D, yet it is less clear when excess CVD risk begins in females with T1D. This review explores the prevalence of classical CVD risk factors (such as glycemic control, hypertension, dyslipidemia, obesity, albuminuria, smoking, diet, physical inactivity), as well as of novel biomarkers (such as chronic inflammation), in children and adolescents with T1D with particular regard to sex-related differences in risk profile. We also summarize gaps where further research and clearer clinical guidance are needed to better address this issue. Considering that girls with T1D might have a more adverse CVD risk profile than boys, the early identification of and sex-specific intervention in T1D would have the potential to reduce later CVD morbidity and excess mortality in females with T1D. To conclude, based on an extensive review of the existing literature, we found a clear difference between boys and girls with T1D in the presence of individual CVD risk factors as well as in overall CVD risk profiles; the girls were on the whole more impacted.

Central TSH Dysregulation in a Patient with Familial Non-Autoimmune Autosomal Dominant Hyperthyroidism Due to a Novel Thyroid-Stimulating Hormone Receptor Disease-Causing Variant.

Background and Objectives. Familial non-autoimmune autosomal dominant hyperthyroidism (FNAH) is a rare cause of childhood hyperthyroidism. It is caused by the thyroid-stimulating hormone receptor (TSHR) gene variants. So far, only around 40 families with FNAH have been reported. Patients with activating TSHR variants demonstrated the same classical signs and symptoms of hyperthyroidism as seen in patients with Graves' disease. Since 2012, ablative therapy is recommended to avoid relapses of hyperthyroidism and its consequences. Case Presentation. We presented a young adult male patient with a novel heterozygous TSHR disease-causing variant p.Arg418Lys (c.1253G>A) in the exon 10, who presented with a mild but progressive FNAH, with a follow-up since infancy. Discussion. Constantly suppressed TSH, including during the euthyreosis in childhood and hypothyreosis after iodine ablation therapy, suggested central dysregulation of the TSH secretion.

Dual Role of PTPN22 but Not NLRP3 Inflammasome Polymorphisms in Type 1 Diabetes and Celiac Disease in Children.

Genetic polymorphisms in genes coding for inflammasome components nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) and caspase recruitment domain-containing protein 8 (CARD8) have been associated with autoinflammatory and autoimmune diseases. On the other hand several studies suggested that NLRP3 inflammasome contributes to maintenance of gastrointestinal immune homeostasis and that activation of NLRP3 is regulated by protein tyrosine phosphatase non-receptor 22 (PTPN22). PTPN22 polymorphism was implicated in the risk for various autoimmune diseases including type 1 diabetes (T1D) but not for celiac disease (CD). The aim of our study was to evaluate the role of inflammasome related polymorphisms in subjects with either T1D or CD as well as in subjects affected by both diseases. We examined PTPN22 rs2476601 (p.Arg620Trp), NLRP3 rs35829419 (p.Gln705Lys), and CARD8 rs2043211 (p.Cys10Ter) in 66 subjects with coexisting T1D and CD, 65 subjects with T1D who did not develop CD, 67 subjects diagnosed only with CD and 127 healthy unrelated Slovenian individuals. All results were adjusted for clinical characteristic and human leukocyte antigen (HLA) risk. PTPN22 rs2476601 allele was significantly more frequent among subjects with T1D (Padj = 0.001) and less frequent in subjects with CD (Padj = 0.039) when compared to controls. In patients with coexisting T1D and CD this variant was significantly less frequent compared to T1D group (Padj = 0.010). Protective effect on CD development in individuals with T1D was observed only within the low risk HLA group. On the other hand, we found no association of NLRP3 rs35829419 and CARD8 rs2043211 with the development of T1D, CD or both diseases together. In conclusion PTPN22 rs2476601polymorphism was significantly associated with the risk of developing T1D in Slovenian population, while no associations of proinflammatory NLRP3 and CARD8 polymorphisms with T1D and CD were observed. Interestingly, the same PTPN22 variant protected from CD. We hypothesize that this effect may be mediated through the NLRP3 inflammasome activation.

High-risk genotypes HLA-DR3-DQ2/DR3-DQ2 and DR3-DQ2/DR4-DQ8 in co-occurrence of type 1 diabetes and celiac disease.

Shared susceptibility alleles in the HLA region contribute to the co-existence of type 1 diabetes (T1D) and celiac disease (CD). The aim of our study was to identify HLA genotype variations that influence co-occurrence of T1D and CD (T1D + CD) and the order of their onset. Totally 244 patients, 67 with T1D, 68 with CD and 69 with T1D + CD, (split into "T1D first" and "CD first"), were analyzed. Control group consisted of 130 healthy unrelated individuals. Two-tailed Fisher's exact test was used for statistical analysis. The genetic background of Slovenian CD patients resembled more northern than southern European populations with DR3-DQ2/DR3-DQ2 (odds ratio [OR] = 19.68) conferring the highest risk. The T1D + CD was associated with DR3-DQ2/DR3-DQ2 (OR = 45.53) and even more with DR3-DQ2/DR4-DQ8 (OR = 93.76). DR3-DQ2/DR7-DQ2 played a neutral role in susceptibility for T1D + CD. The order of the onset of T1D or CD in patients with co-occurring diseases was not influenced by HLA risk genotype profile. DR3-DQ2/DR3-DQ2 was associated with an increased risk for developing CD in patients with T1D, whereas patients with CD carrying DR3-DQ2/DR4-DQ8 were at higher risk for developing T1D. In addition to other genetic factors including HLA class I alleles present on DR3-DQ2 extended haplotype, the second extended haplotype may moderate the risk for T1D + CD conferred by DR3-DQ2. Our results suggested that individuals carrying high-risk genotypes DR3-DQ2/DR3-DQ2 or DR3-DQ2/DR4-DQ8 would more likely develop both T1D and CD than either disease alone.

Cytogenetic and Molecular Genetic Characterization of Children with Short Stature.

BACKGROUND: The deficiency of SHOX gene (short stature homeobox-containing gene) has been recognized as the most frequent monogenetic cause of short stature. SHOX gene has been associated with short stature in Turner syndrome and Leri Weill dyschondrosteosis as well with non-syndromic idiopathic short stature. The aim of this study was to determine the frequency of SHOX deletions and mutations in a cohort of Slovenian children with short stature, and to delineate indications for routine SHOX gene mutation screening. METHODS AND RESULTS: 40 selected subjects with idiopathic short stature were screened for entire SHOX gene deletion and for mutations in the SHOX gene coding region (exon 2 to 6), together with sequences flanking the exon-intron boundaries. FISH analysis on metaphase and interphase spreads revealed no entire gene deletion. Additionally, no pathogenic point mutations or smaller deletion/duplications were identified in this study group. CONCLUSIONS: SHOX gene deletions and point mutations are not a common cause of idiopathic short stature in a cohort of Slovenian children with short stature. Therefore, the frequency of SHOX mutations must be much lower as expected based on the reported data.