Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4␣, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with earlyonset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P ؍ 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese.nuclear receptor ͉ maturity-onset diabetes of the young ͉ insulin secretion ͉ body weight ͉ hepatocyte nuclear factor H eterozygous mutations in genes encoding transcription factors in the hepatocyte nuclear factor (HNF) regulatory cascade (1) are associated with an early-onset autosomal dominant form of diabetes mellitus, maturity-onset diabetes of the young (MODY) (2). To date, diabetes-associated mutations have been found in three members of this regulatory network, HNF-1␣, -1, and -4␣ (MODY3, 5, and 1, respectively) (3-6). These forms of MODY are characterized primarily by defective insulin secretion with normal body weight (7-9). In contrast, forms of early-onset autosomal-dominant type 2 diabetes that are not linked to known MODY genes are often characterized by insulin resistance with high body weight, rather than by pure pancreatic -cell defects (10). It is not known whether obesity-associated MODY genes or other common modifying factors are responsible for these phenotypic features.The protein small heterodimer partner (SHP; also called NROB2 for nuclear receptor subfamily 0, group B, member 2), an atypical orphan nuclear receptor that lacks a conventional DNA-binding domain, interacts with a number of other nuclear receptors, including HNF-4␣, and inhibits their transcriptional activity (11)(12)(13)(14)(15)(16)(17). SHP is expressed in the liver and has recently been suggested to regulate cholesterol homeostasis by an inhibitory e...
The intraislet insulin hypothesis has been proposed to explain absent glucagon responses to hypoglycemia. Recently we directly confirmed this hypothesis by restoring glucagon secretion via provision of a pancreatic artery insulin infusion, which was switched off at the time of hypoglycemia in Wistar rats made diabetic by streptozotocin. The current study examined this hypothesis in a model of spontaneous, autoimmune diabetes, the insulin-dependent diabetic BB rat. The insulin switch-off signal restored the defective glucagon responses to hypoglycemia. However, the magnitude of the restored response was markedly less than that observed in control nondiabetic BB rats (4- to 5-month-old diabetic BB rats = 147 +/- 27; 2-month-old nondiabetic BB rats = 1038 +/- 112 pg/ml, peak delta; P < 0.0001). Because time was required for the BB rat to spontaneously develop diabetes, we asked whether the incomplete restoration of the glucagon response might be related to the animals' growth and development. This led us to compare the glucagon response to hypoglycemia in nondiabetic BB and Wistar rats at 2 and 4-5 months of age. We observed age-related deterioration of not only glucose tolerance and insulin sensitivity but also glucagon responses to hypoglycemia in both strains. There was no significant difference between the glucagon responses to hypoglycemia in age-matched nondiabetic BB rats and diabetic BB rats provided with the insulin switch-off signal. We conclude that defective glucagon responses to hypoglycemia in BB rats can be corrected by restoring regulation of alpha-cell function by insulin.
Propylthiouracil (PTU) administered to pregnant rats from day 18-21 of gestation caused a significant increase in maternal and fetal thyroid weight and plasma TSH. Fetal encephalectomy on day 18 did not significantly affect basal or PTU-stimulated pituitary-thyroid function. Destruction of the basal hypothalamus in the mother on day 13 or 16 markedly reduced maternal plasma TSH and thyroxine and prevented a PTU-induced increase in thyroid size, but did not affect fetal pituitary-thyroid function. Plasma PRL, was undetectable in both intact and encephalectomized fetuses at 21 days but was increased greater than 6-fold to approximately 2 microgram/ml in the mothers by maternal hypothalamic destruction. We conclude that fetal pituitary-thyroid function in the rat is not dependent on either fetal or maternal hypothalamic TRH.
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