The hyperinsulinism-hyperammonemia syndrome is caused by mutations in the glutamate dehydrogenase gene that impair the control of enzyme activity.

Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man. (8-12). In contrast, abnormalities in chromosome 6q24 are the most common cause of TNDM (13), followed by mutations in the KCNJ11 and ABCC8 genes (14). Despite these advances, the etiology of neonatal diabetes is still not known in at least 30% of patients with PNDM, suggesting other genetic causes are still to be found (9).Insulin is secreted from islet beta cells of the pancreas. Insufficient secretion of insulin results in hyperglycemia and diabetes, whereas excessive secretion results in hypoglycemia. Insulin biosynthesis and secretion are therefore tightly regulated to maintain blood glucose levels within a narrow physiological range. Extensive studies have dissected an array of cis sequence elements in the INS promoter region and their cognate DNA binding factors, which together ensure the cellular specificity and rate of INS transcription (15)(16)(17)(18)(19)(20)(21)(22). In addition, insulin biosynthesis is strongly dependent on posttranscriptional regulatory mechanisms, including the modulation of translation and stability (23-25). The latter is largely mediated through sequences located in the untranslated regions of INS transcripts (26-28).

In prepubertal children, insulin lispro given before meals is safe and significantly lowers postprandial glucose levels after breakfast and dinner compared with regular human insulin, and insulin lispro given after the meal provides similar benefits as regular human insulin before the meal.

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Thyroid hormone is essential for normal brain development including structures critical for visual processing. While chick and rodent models have demonstrated abnormal visual development following prenatal thyroid hormone loss, comparable data do not exist in the human. To determine whether human infants with intrauterine and early postnatal thyroid hormone insufficiencies have compromised visual abilities, we investigated contrast sensitivity and visual acuity development in 13 infant offspring of women with hypothyroidism during pregnancy (HYPO), 16 preterm infants born between 32 and 35 weeks gestation, 12 infants with congenital hypothyroidism (CH), and 20 typically developing infants. All were assessed with the sweep visual evoked potential technique at 3, 4.5, and 6 months (corrected) age. Results showed significantly reduced contrast sensitivity but normal visual acuity in HYPO and CH groups relative to controls (p Ͻ 0.003 and p Ͻ 0.05 respectively). Stratification of the HYPO group into subgroups based on maternal TSH levels during the first half of pregnancy revealed lower contrast sensitivities for infants whose mothers' TSH values were above than below the median (p Ͻ 0.05). In the CH group, those with an absent thyroid gland and/or a newborn TSH value above 200 mIU/L had lower contrast sensitivities than did those with other etiologies or TSH levels below 100 mIU/L (p Ͻ 0.05). There were no significant effects involving the preterm group. These results indicate that thyroid hormone is important for human visual development. Thyroid hormone (TH) is essential for normal brain development (1). A lack of TH during fetal or early postnatal life is associated with specific brain damage. This includes abnormal neuronal proliferation and migration (2,3), decreased dendritic densities and synaptic profiles (4), impaired synaptic transmission (5), and reduced myelination (6). TH acts by regulating specific brain genes (7) through the formation of a nuclear receptor complex (8), which serves to up-or down-regulate specific genes (9) via a variety of signaling mechanisms (10,11). Because TH-regulated gene activity varies spatially and temporally in the brain (12), different types of deficits will follow from a loss of TH at different stages of development (13,14).In the retina, TH is needed (15-17) for the differentiation of cones versus rods (18,19), specific cone subtypes (20), and retinal oligodendrocyte precursor cells (21) and for the production of essential proteins (22,23). Animal models demonstrate that when TH is lacking at a particular time prenatally, visual development and functioning will be impaired (20

Background: Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath's four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results: Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18-20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions: Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.