Adiponectin more than conventional CV risk factors and inflammation status may be related to early atherosclerosis in obese children.

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In these cohorts, the majority of deaths (76%) were caused by accidents or suicides. Importantly, none of the patients died from cancer or from a cardiovascular disease.

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Maturity-onset diabetes of the young (MODY) is a subtype of Type II (non-insulin dependent) diabetes mellitus characterised by early onset, usually before 25 years of age, an autosomal dominant mode of inheritance with high penetrance, and a primary defect of insulin secretion [1,2]. MODY is not an uncommon disorder and could account for about 2 to 5 % of all cases of Type II diabetes [3]. MODY is genetically heterogeneous and to date five MODY genes have been identified on chromosomes 20q12-q13.1 (MODY1) [4,5], 7p15-p13 (MODY2) [6,7], 12q24.2 (MODY3) [8,9], 13q12.1 (MODY4) [10,11] and 17cen-q21.3 (MODY5) [12]. The MODY2 gene encodes the glycolytic enzyme glucokinase which plays a major role in the regulation and integration of glucose metabolism in pancreatic beta cells and liver [13]. Recent studies have shown that mutations in three transcription factors, hepatocyte nuclear factor-4a (HNF-4a) [5] (gene symbol TCF14), hepatocyte nuclear factor-1a (HNF-1a) [9, 14] (TCF1) and insulin promoter factor-1 (IPF1) [10], are responsible for the MODY1, MODY3 and MODY4 subtypes, re- Diabetologia (1998) Summary Maturity-onset diabetes of the young (MODY) is a heterogeneous subtype of non-insulindependent diabetes mellitus characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date five MODY genes have been identified: hepatocyte nuclear factor-4 alpha (HNF-4a/MODY1/TCF14) on chromosome 20 q, glucokinase (GCK/MODY2) on chromosome 7 p, hepatocyte nuclear factor-1 alpha (HNF-1a/ MODY3/TCF1) on chromosome 12 q, insulin promoter factor-1 (IPF1/MODY4) on chromosome 13 q and hepatocyte nuclear factor-1 beta (HNF-1b/MODY5/ TCF2) on chromosome 17cen-q. We have screened the HNF-4a, HNF-1a and HNF-1b genes in members of 18 MODY kindreds who tested negative for glucokinase mutations. Five missense (G31D, R159W, A161T, R200W, R271W), one substitution at the splice donor site of intron 5 (IVS5nt + 2T®A) and one deletion mutation (P379fsdelT) were found in the HNF-1a gene, but no MODY-associated mutations were found in the HNF-4a and HNF-1b genes.

Circulating levels of somatomedins in man and rats are reduced by fasting and restored by refeeding. To determine the mechanisms for these alterations in somatomedin levels, the affinities and binding capacities of 125I-labelled bovine GH (somatogenic binding sites) and of 125I-labelled ovine prolactin (lactogenic binding sites) were assessed in liver homogenates from fasted and refed rats. Correlations were made with plasma immunoreactive somatomedin-C (Sm-C) and plasma insulin.During fasting and refeeding there was a close temporal relationship between the fall and the rise of plasma levels of Sm-C and insulin, and the number of hepatic GH binding sites. After fasting for 1 day, plasma Sm-C dropped by 68% and plasma insulin by 76% when compared with values before fasting. At the same time, GH binding capacity was significantly reduced (7\m=.\3\ m=+-\ 2\ m=. \ 8(s.e.m.) pmol/liver v. controls, 20\m=.\3 \ m=+-\ 2\ m=. \ 1 pmol/liver; P < 0\ m=. \ 01) . Refeeding for 24h normalized plasma insulin levels and restored GH binding capacity to values before fasting (13\m=.\2 \ m=+-\2\m=.\4v. 20\m=.\3\ m=+-\ 2\m=.\1 pmol/liver; P > 0\ m=. \ 05) . Plasma Sm-C rose significantly with refeeding and returned to initial values at day 4 of refeeding (0\m=.\82 \ m=+-\ 0\m=.\10v. 0\m=.\77\ m=+-\ 0\m=.\07 units/ml; P > 0\ m=. \ 05) .In contrast, changes in prolactin binding sites correlated poorly with changes in plasma Sm-C. There was a modest decline with fasting significant only after 72 h (6\m=.\8 \ m=+-\ 0\ m=. \ 6v.13\m=.\9 \ m=+-\ 3\m=.\2 pmol/liver; P < 0\ m=. \ 05), and refeeding for 24 h did not restore prolactin binding (5\m=.\7 \ m = + -\1\m=.\2 pmol/liver).Since a number of reports suggest that fasting induces a state of tissue insensitivity to GH, our findings suggest that the reduction in hepatic GH binding capacity might be a mechanism for the fasting-induced reduction in Sm-C. The reduction in plasma insulin, which accompanies fasting, might play a permissive role in the intracellular metabolic events involved in Sm-C and GH receptor regulation.

To determine if the pattern of GH delivery is important for the regulation of serum somatomedin-C/insulinlike growth factor I (Sm-C/IGF-I) and liver somatogenic receptors, we have measured serum Sm-C/IGF-I concentrations and free (H 2 O-treated homogenates) and total (MgCl 2 -treated homogenates) liver GH-binding sites in hypophysectomized rats treated for 7 days with rat GH (rGH), given either continuously by osmotic minipumps (50 and 250 /ig/day) or intermittently (four sc injections of 12.5 /ig/day). At a daily dose of 50 jig, intermittent rGH produced greater weight gain [+29.7 ± 0.8 g (mean ± SE)] than continuous GH infusion (23.3 ± 2.0 g; P < 0.01). Likewise, the serum Sm-C/IGF-I concentration rose more with intermittent (0.33 ±0.1 U/ml) than with continuous delivery (0.17 ± 0.01 U/ml; P < 0.01). The serum Sm-C/IGF-I level achieved with repeated GH injections was even greater than that after continuous delivery of a 5-fold higher GH dose (250 fig/ day; 0.27 ± 0.02 U/ml; P < 0.05). Continuous infusions of 50 and 250 fig rGH/day increased the number of liver total GH receptors by 2.5-fold over that of controls. In contrast, frequent GH injections did not affect GH binding, and the serum Sm-C/ IGF-I concentration did not correlate with liver GH-binding sites in the GH-injected rats (r = 0.189; P = NS). Induction of hepatic PRL receptors was 10-fold higher when GH was given continuously than when it was given intermittently. The close correlation observed between GH-and PRL-binding sites in all GH-treated rats (r = 0.955; P < 0.001) suggests that their regulation may be linked.These data suggest that the regulatory mechanism controlling Sm-C/IGF-I production and growth might be different from those that regulate GH receptor concentrations, with GH pulses being crucial for the maximal stimulation of Sm-C/IGF and growth, but continuous exposure to GH being required for upregulation of liver GH receptors. {Endocrinology 123: [1053][1054][1055][1056][1057][1058][1059]1988)