OBJECTIVEWe aimed to describe the natural history of residual insulin secretion in Type 1 Diabetes TrialNet participants over 4 years from diagnosis and relate this to previously reported alternative clinical measures reflecting β-cell secretory function.RESEARCH DESIGN AND METHODSData from 407 subjects from 5 TrialNet intervention studies were analyzed. All subjects had baseline stimulated C-peptide values of ≥0.2 nmol/L from mixed-meal tolerance tests (MMTTs). During semiannual visits, C-peptide values from MMTTs, HbA1c, and insulin doses were obtained.RESULTSThe percentage of individuals with stimulated C-peptide of ≥0.2 nmol/L or detectable C-peptide of ≥0.017 nmol/L continued to diminish over 4 years; this was markedly influenced by age. At 4 years, only 5% maintained their baseline C-peptide secretion. The expected inverse relationships between C-peptide and HbA1c or insulin doses varied over time and with age. Combined clinical variables, such as insulin-dose adjusted HbA1c (IDAA1C) and the relationship of IDAA1C to C-peptide, also were influenced by age and time from diagnosis. Models using these clinical measures did not fully predict C-peptide responses. IDAA1C ≤9 underestimated the number of individuals with stimulated C-peptide ≥0.2 nmol/L, especially in children.CONCLUSIONSCurrent trials of disease-modifying therapy for type 1 diabetes should continue to use C-peptide as a primary end point of β-cell secretory function. Longer duration of follow-up is likely to provide stronger evidence of the effect of disease-modifying therapy on preservation of β-cell function.

Aims/hypothesis The long-term effects of successful immune therapies for treatment of type 1 diabetes have not been well studied. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial evaluated teplizumab, an Fc receptor non-binding humanised anti-CD3 monoclonal antibody in individuals with new-onset type 1 diabetes, and ended in 2011. Clinical drugtreated responders showed an increased frequency of 'partially exhausted' CD8 + T cells. We studied the clinical, immunological and metabolic status of participants after an average follow-up of 7 years. Methods Participants with detectable C-peptide at year 2 of AbATE returned for follow-up. C-peptide responses were assessed by 4 h mixed-meal tolerance test. Autoantibodies and HbA 1c levels were measured and average daily insulin use was obtained from patient logs. Peripheral blood mononuclear cells were analysed by flow cytometry and cytokine release. Results Fifty-six per cent of the original participants returned. Three of the original control group who did not return had lost all detectable C-peptide by the end of the 2 year trial. The C-peptide responses to a mixed-meal tolerance test were similar overall in the drug vs control group of participants but were significantly improved, with less loss of C-peptide, in drug-treated responders identified at 1 year. However, the improvements in C-peptide response were not associated with lower HbA 1c levels or insulin use. Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8 + T cells at follow-up. Conclusions/interpretation These findings suggest there is reduced decline in C-peptide and persistent immunological responses up to 7 years after diagnosis of diabetes in individuals who respond to teplizumab. Trial registration ClinicalTrials.gov NCT02067923; the protocol is available at www.immunetolerance.org (ITN027AI).

Congenital lipoid adrenal hyperplasia is the most severe form of congenital adrenal hyperplasia. Affected individuals can synthesize no steroid hormones, and hence are all phenotypic females with a severe salt-losing syndrome that is fatal if not treated in early infancy. All previous studies have suggested that the disorder is in the cholesterol side chain cleavage enzyme (P450scc), which converts cholesterol to pregnenolone. A newborn patient was diagnosed by the lack of significant concentrations of adrenal or gonadal steroids either before or after stimulation with corticotropin (ACTH) or gonadotropin (hCG). The P450scc gene in this patient and in a previously described patient were grossly intact, as evidenced by Southern blotting patterns. Enzymatic (polymerase chain reaction) amplification and sequencing of the coding regions of their P450scc genes showed these were identical to the previously cloned human P450scc cDNA and gene sequences. Undetected compound heterozygosity was ruled out in the new patient by sequencing P450scc cDNA enzymatically amplified from gonadal RNA. Northern blots of gonadal RNA from this patient contained normal sized mRNAs for P450scc and also for adrenodoxin reductase, adrenodoxin, sterol carrier protein 2, endozepine, and GRP-78 (the precursor to steroidogenesis activator peptide). These studies show that lipoid CAH is not caused by lesions in the P450scc gene, and suggest that another unidentified factor is required for the conversion of cholesterol to pregnenolone, and is disordered in congenital lipoid adrenal hyperplasia. (J. Clin. Invest. 1991.88:1955-1962

Only within the last two decades has securities regulation extended to tender offers. In 1968, Congress passed the Williams Act in an attempt to protect shareholders faced with tender offers. State legislatures have enacted regulations as well, in most cases rather similar to those of the Williams Act. All these regulations impose disclosure requirements on the offeror, substantive requirements on the terms of the offer, and general antifraud prohibitions in connection with the offer. Where the entire federal and state regulatory schemes have been brought into effect simultaneously, courts generally have held the state statutes unconstitutional under the supremacy and commerce clauses. This term, in CTS Corporation v. Dynamics Corporation of America, 1 the Supreme Court upheld an Indiana statute that severely restricted the ability of offerors to gain control of a target corporation. Under the Indiana law, any time a person acquires shares that push her total holdings over a "control share" threshold-20, 331/3, or 50 percent of outstanding shares-in a corporation subject to the statute, she must gain approval of both the target's board of directors and a majority of nonacquiring and nonmanagement shares in order to vote her shares. 2 In upholding the statute, the Court ruled that a state, through its power to regulate shareholder voting rules, may regulate takeovers of corporations that are both chartered by the state and have substantial assets in the state.$ It is likely that many states will take advantage 1 107 S.Ct. 1637 (1987). Management can delay the approval vote for up to fifty days. Ind. Code § 23-1-42-7(b) (Supp. 1986). Thus, without the requisite approval, shares acquired in a tender offer are useless for asserting control over the corporation. more than 10% of its shares owned by Indiana residents. Ind. Code § 23-1-42-4(a). 4 The noted takeover specialist, Martin Lipton, predicts that thirty to forty states eventually will eventually adopt statutes modeled after the Indiana act. Justices Back State Curbs on Takeovers, Wall St. J. 3, col. 1 (Apr. 22, 1987). 5 The Wall Street Journal reports that there probably will be a substantial fight in Delaware, the jurisdiction currently most important to corporate law, over whether to adopt a statute similar to that of Indiana. Id. at 18, col. 1. 6 See CTS, 107 S.Ct. at 1652 ("the Indiana Act applies only to corporations that have a substantial number of shareholders in Indiana"). " Even so, states may feel that they have an interest in controlling the takeover of outof-state corporations with significant local interests. For example, the North Carolina legislature approved a measure that would require out-of-state companies with major North Carolina interests to obtain the approval of 90 percent of their shares in order to go through with a takeover.