Autism spectrum disorder in children with Type 1 diabetes.

AIM: Links between autism spectrum disorder (ASD) and autoimmune diseases, including Type 1 diabetes have been proposed. This study assessed the frequency of ASD in children with Type 1 diabetes in the T1D Exchange (T1DX) registry and the impact of ASD on characteristics of children with Type 1 diabetes. METHODS: Analysis included 10 032 participants aged < 18 years (median Type 1 diabetes duration 6.5 years, 48% female, 77% non-Hispanic White). Diagnosis of ASD was defined as autism, Asperger's or pervasive developmental disorder. RESULTS: A diagnosis of ASD was recorded for 159 (1.58%) participants. Those with ASD were predominantly male (88% vs. 51% of those without ASD, P < 0.001) and slightly older (median 14 vs. 13 years, P = 0.022). Occurrence of diabetic ketoacidosis at Type 1 diabetes diagnosis was similar (35% vs. 41%, P = 0.161). Pump use was lower in those with ASD (51% vs. 63%, P = 0.005) but continuous glucose monitor use was similar (24% vs. 27%, P = 0.351). Median HbA1c was slightly lower in those with ASD [68 vs. 69 mmol/mol (8.4% vs. 8.5%), P = 0.006]. This difference was more pronounced after adjusting for confounders. CONCLUSIONS: The frequency of ASD in the T1DX registry was similar to that in the general population. These data show that despite deficits in communication, occurrence of diabetic ketoacidosis was similar in youth with and without ASD. Pump use was less frequent in those with ASD, possibly due to sensory issues, although CGM use did not differ. The lower HbA1c may be due to a more regimented routine with ASD. Because comorbidities such as ASD complicate care of patients with Type 1 diabetes, further research is needed to support these children.

Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation.

Glucocorticoids play a critical role in control of the cytokine response after immune challenge. Conversely, cytokines modulate glucocorticoid production by the hypothalamic-pituitary-adrenal axis. To define the potency and mechanism of interleukin-6 (IL-6) for augmentation of adrenal function, we exploited mice deficient in corticotropin-releasing hormone (CRH), IL-6, or both. Mice deficient in CRH action demonstrate severely impaired glucocorticoid production in response to psychological and metabolic challenge, but near normal responses to stressors that activate the immune system. In this paper, we demonstrate that IL-6 is essential for activation of the hypothalamic-pituitary-adrenal axis during immunological challenge in the absence of hypothalamic input from CRH. IL-6 receptors are present on pituitary corticotrophs and adrenocortical cells, consistent with the ability of IL-6 to bypass CRH in augmentation of adrenal function. Plasma corticosterone levels after bacterial lipopolysaccharide injection in mice deficient in CRH or IL-6 were significantly lower than in wild-type mice but significantly greater than in mice deficient in both CRH and IL-6. A second model of immune system activation using 2C11, an antibody to the T cell receptor, demonstrated a normal corticosterone response in mice deficient in CRH or IL-6, but a markedly decreased response in mice deficient in both CRH and IL-6. Surprisingly, the relative contribution of IL-6 for modulation of the adrenal response to stress is greater in female than in male mice. This gender-specific difference in IL-6 action in mice suggests the utility of further analysis of IL-6 in determining the female predominance seen in many human inflammatory/autoimmune diseases.

Identification of a major hepatic copper binding protein as S-adenosylhomocysteine hydrolase.

The properties of a mouse liver copper binding protein (CuBP) and human placental S-adenosylhomocysteine hydrolase (SAHH) were compared to test the hypothesis that CuBP is SAHH. CuBP and SAHH migrated identically on SDS-polyacrylamide gel electrophoresis gels, and their 48-kDa monomers both self-associate to tetramers. Human placental SAHH cross-reacted with polyclonal antibodies to mouse liver CuBP, and CuBP from mouse liver cross-reacted with two monoclonal antibodies to human placental SAHH. A third monoclonal antibody to human placenta SAHH reacted weakly with the mouse liver protein but well with CuBP from human lymphoblasts. NAD(+)-activated CuBP has high SAHH enzymatic activity. Moreover, human placental SAHH, like mouse liver CuBP, has a single high affinity copper binding site per 48-kDa subunit. Thus, the data confirm that CuBP is SAHH, and SAHH is proposed to be a bifunctional protein with roles in sulfur-amino acid metabolism and copper metabolism. The copper binding activity of SAHH is proposed to play a significant role in the intracellular distribution of copper, and SAHH enzymatic activity may influence copper metabolism through its role in cysteine biosynthesis from methionine.

Copper binding to mouse liver S-adenosylhomocysteine hydrolase and the effects of copper on its levels.

The dissociation constant and stoichiometry of copper binding to mouse liver S-adenosylhomocysteine hydrolase (SAHH) was determined as part of characterizing the possible roles of SAHH in copper metabolism. Copper (64Cu(II)) binding was measured by an ultrafiltration method in the presence of EDTA as a competing ligand. The KD was 3.9 +/- 0.7 x 10(-16) M, and the stoichiometry was one g atom of copper per 48-kDa subunit. Western blots indicated that the liver contains approximately 12 times more SAHH than the kidney, which in turn contains approximately 5 times more SAHH than the brain. The high concentration and copper affinity of SAHH in the liver may contribute to the liver's ability to preferentially accumulate copper, and the low levels of SAHH in the brain may contribute to the sensitivity of the brain to copper deficiency. The effects of genetic defects of copper metabolism and copper deficiency on SAHH were also determined. Normal SAHH levels were detected in brindled mouse liver, kidney, and brain. However, SAHH from brindled mouse liver eluted abnormally from phenyl Superose columns implying an effect of the brindled mouse defect on SAHH protein structure. Hepatic cytosols from the toxic milk mouse contained approximately 42% the amount of SAHH detected in controls, and hepatic levels of SAHH were also decreased by approximately 45% in copper-deficient mice. The binding properties of SAHH and the effects of abnormal states of copper metabolism on its levels are consistent with significant roles for SAHH in normal and abnormal copper metabolism. SAHH may have roles in regulating tissue copper levels and the distribution of intracellular copper.

Pituitary-adrenal axis regulation in CRH-deficient mice.

Corticotropin-releasing hormone (CRH)-deficient (knockout (KO)) mice demonstrate severely impaired adrenal responses to restraint, ether, and fasting, and lack the normal diurnal glucocorticoid (GC) rhythm. Here, we summarize recent studies determining the role of CRH in augmenting plasma adrenocorticotrophic hormone (ACTH) concentration after glucocorticoid withdrawal and pituitary-adrenal axis stimulation in the context of inflammation. Even though GC insufficient, basal pituitary proopiomelanocortin (POMC) mRNA, ACTH peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. POMC mRNA content in CRH KO mice increases following adrenalectomy, and this increase is reversed by GC, but not aldosterone, replacement. In marked contrast to the increase in POMC mRNA, plasma ACTH does not increase in the CRH KO mice following adrenalectomy. Administration of CRH to adrenalectomized CRH KO mice results in acute, robust ACTH secretion. Thus, loss of GC feedback can increase POMC gene expression in the pituitary, but CRH action is essential for increased secretion of ACTH into the circulation. While GC secretion is impaired in CRH KO mice after most stimuli, we have found near-normal GC responses to inflammation and systemic immune challenge. Studies in mice with CRH and IL-6 deficiency reveal that IL-6 is essential for activation of the pituitary-adrenal axis during inflammatory and other stressors in the absence of CRH.