Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus characterized by an, early age of onset, usually before 25 years of age, and an autosomal dominant mode of inheritance. The largest and best-studied MODY pedigree is the RW family. The majority of the diabetic subjects in this pedigree has a reduced and delayed insulin-secretory response to glucose, and it has been proposed that this abnormal response is the manifestation of the basic genetic defect that leads to diabetes. Using DNA from members of the'RW family, we tested more than 75 DNA markers for linkage with MODY. A DNA polymorphism in the adenosine deam.ase gene (ADA) on the long arm of chromosome 20 was found to cosegregate with MODY. The maximum logarithm of odds (lod score) for linkage between MODY and ADA was 5.25 at a recombination fraction of0.00. These results indicate that the odds are >178,000:1 that the gene responsible for MODY in this family is tightly linked to the ADA gene on chromosome 20q.Non-insulin-dependent or type 2 diabetes mellitus (NIDDM) is a common disorder of glucose homeostasis affecting -5% of the general population. The causes of the fasting hyperglycemia and/or glucose intolerance associated with this form of diabetes are not well understood. The contribution of heredity to the development of NIDDM has been recognized for many years (1), and the high degree of concordance of NIDDM in monozygotic twin pairs (2) indicates that genetic factors play an important role in its development. Since an understanding of the molecular basis of NIDDM would elucidate the mechanisms controlling glucose homeostasis and facilitate the development of more rational therapeutic strategies, we have undertaken a linkage study of NIDDM to identify diabetes-susceptibility genes. The use of linkage strategies to identify DNA markers for NIDDM has been difficult because this disorder does not exhibit simple Mendelian recessive or dominant inheritance. In addition, because of its late age of onset, it is difficult to obtain large multigenerational families suitable for genetic studies.

Pancreatic b cells adapt to pregnancy-induced insulin resistance by unclear mechanisms. This study sought to identify genes involved in b cell adaptation during pregnancy. To examine changes in global RNA expression during pregnancy, murine islets were isolated at a time point of increased b cell proliferation (E13 . 5), and RNA levels were determined by two different assays (global gene expression array and G-protein-coupled receptor (GPCR) array). Follow-up studies confirmed the findings for select genes. Differential expression of 110 genes was identified and follow-up studies confirmed the changes in select genes at both the RNA and protein level. Surfactant protein D (SP-D) mRNA and protein levels exhibited large increases, which were confirmed in murine islets. Cytokine-induced expression of SP-D in islets was also demonstrated, suggesting a possible role as an anti-inflammatory molecule. Complementing these studies, an expression array was performed to define pregnancy-induced changes in expression of GPCRs that are known to impact islet cell function and proliferation. This assay, the results of which were confirmed using realtime reverse transcription-PCR assays, demonstrated that free fatty acid receptor 2 and cholecystokinin receptor A mRNA levels were increased at E13 . 5. This study has identified multiple novel targets that may be important for the adaptation of islets to pregnancy.

Misalignment of feeding rhythms with the light-dark cycle leads to disrupted peripheral circadian clocks and obesity. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. We found that genetic enhancement of adipocyte thermogenesis through ablation of the zinc finger protein 423 (ZFP423) attenuated obesity caused by consumption of a high-fat diet during the inactive (light) period by increasing futile creatine cycling in mice. Circadian control of adipocyte creatine metabolism underlies the timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator brain and muscle Arnt-like protein-1 (BMAL1) ameliorated metabolic complications during diet-induced obesity. These findings uncover rhythmic creatine-mediated thermogenesis as an essential mechanism that drives metabolic benefits during time-restricted feeding.

DNA at the end point of the gene deletion associated with one form of hereditary persistence of fetal hemoglobin (HPFH) was cloned and used as a probe in gene mapping experiments to analyze the extent and approximate 3' end points of various deletions associated with HPFH and 8P-thalassemia.The deletions in the two known forms of deletion-type HPFH were shown to be considerably more extensive than in the two cases of 6P-thalassemia studied. The overall extents of the deletions in the two types of HPFH were quite similar in both cases and the 3' end points were located at a minimum distance of =52 and 57 kilobases from the 3' extremity of the (3-globin gene. In contrast, the 3' end points of the deletions in the two forms of 8P-thalassemia were located ==5 and 10 kilobases to the 3' side of the P-globin gene. The extent of these deletions and the nature of the DNA brought into the vicinity of the y-globin genes by the deletions may therefore be a more important influence on the phenotype of the deletions than the specific nature of the DNA sequences that are deleted within the non-a-globin gene cluster as a result of the mutations.In an effort to understand the molecular mechanisms that may be associated with the control of human globin gene expression, we studied the disorder hereditary persistence of fetal hemoglobin (HPFH), which provides an especially interesting system for study. In individuals with HPFH, expression of the 'y-globin genes of fetal hemoglobin persists at a high level into adult life, instead of being suppressed, as in normal individuals, to < 1% of the total globin gene output after the first 6 months of life (for review, see ref. 1). A common type of HPFH found in Blacks is associated with an extensive deletion involving the entire adult 8-and f3-globin genes (2-5). The deletions of the 8-and ,B-globin genes, however, do not seem to constitute the basis for the persistent y-globin gene expression in HPFH, because, in other disorders, such as 3,&thalassemia, the Hb Lepore syndrome, and one form of f30-thalassemia, the & and P3-globin genes are totally or partially deleted (3-14), but the y-globin genes are not expressed at the same high or uniform levels as in HPFH.Initial attention focused on the different 5' end points of the deletions in HPFH and 583-thalassemia (3,(13)(14)(15)(16)(17)(18) and provided some support for the original hypothesis proposed by Huisman et al. (19) that the inter-y5-globin gene DNA might contain regulatory sequences, the deletion of which would result in persistent y-globin gene expression into adult life. However, in certain forms of 583-thalassemia, the entire inter-yS-globin gene DNA is deleted (3,11,14), but the deletions do not result in the HPFH phenotype. Thus it has not been possible to elaborate a single model, consistent with all of the known deletion mutants, that adequately explains the persistent 'y-globin gene expression in HPFH on the basis of differential deletion of inter-y8-globin gene DNA sequences. Alternatively, differences in the siz...