Early amygdala damage in the rat as a model for neurodevelopmental psychopathological disorders.

Neurodevelopmental disorders in medial temporal lobe structures may underlie psychopathological diseases such as schizophrenia and autism. To construct an animal model for these developmental disorders, social and non-social behavioural responses were assessed in rats with ibotenic acid lesions of the (baso-)lateral and central amygdala or ventral hippocampus, induced early in life. Lesioning the amygdala on day 7 after birth resulted in a variety of behavioural disturbances later in life, whereas after similar lesions on day 21 after birth no disturbances developed, except for deficits in social behaviours. Lesioning the hippocampus led to much less disturbances. The results show that amygdala and hippocampus damage at a specific point early in life results in enduring behavioural disturbances that become more manifest after puberty. In particular, lesions of the amygdala on day 7 of life may serve as a rat model with face and construct validity for neurodevelopmental disorders in studying psychopathology.

Lower beta-cell secretion in physically active first-degree relatives of type 2 diabetes patients.

Regular physical activity may prevent or postpone type 2 diabetes, and is thought to be related to an increase of insulin sensitivity. We studied whether physically active, glucose-tolerant first-degree relatives of type 2 diabetes patients differ in glucose tolerance (oral glucose tolerance test [OGTT]) and insulin secretion (hyperglycemic glucose clamp) from less active first-degree relatives. A group of 37 relatives was split into 2 subgroups according to the sex-specific median of the sports index, assessed by a questionnaire, as the cutoff point. Blood glucose levels during the OGTT were lower in the highly active subgroup versus the less active counterparts (multivariate ANOVA [MANOVA], P = .011), but the plasma insulin levels were similar. First-phase secretion was not different in the highly active group versus the less active group, but second-phase secretion (average plasma insulin in the third hour) was significantly lower (P = .016). As expected, the insulin sensitivity index (ISI) was higher in the highly active subgroup (P= .011). Subdivision into subgroups with high or low maximal O2 consumption (VO2max) resulted in similar differences, but these were not significant. In a group of 21 controls, the results resembled the values in the relatives but were less often statistically significant. In conclusion, regular physical activity not only is associated with increased insulin sensitivity but also downregulates the pancreatic beta cell. This downregulation may provide an extra mechanism by which physical activity diminishes the development of type 2 diabetes.

Insulin secretion in normal glucose-tolerant relatives of type 2 diabetic subjects. Assessments using hyperglycemic glucose clamps and oral glucose tolerance tests.

OBJECTIVE: To assess insulin secretion in normal glucose-tolerant Caucasian first-degree relatives of type 2 diabetes subjects and in matched normal glucose-tolerant control subjects and to compare insulin secretion as assessed using a hyperglycemic glucose clamp with insulin secretion as assessed using an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: Twenty-one first-degree relatives of type 2 diabetic subjects and 21 control subjects without a family history of type 2 diabetes, who were matched for sex, age, BMI, waist-to-hip ratio, and aerobic capacity, underwent a hyperglycemic glucose clamp (10 mmol/l, 180 min). An OGTT (75 g glucose in 300 ml water) was also performed. RESULTS: First-phase insulin release (plasma insulin, 0-10 min) was not different (multiple analysis of variance [MANOVA]: F = 2.63, P = 0.11). Second-phase insulin release was lower (MANOVA: F = 4.18, P = 0.047). Separate analyses of variance showed decreased plasma insulin levels from 120 min onward (all P < 0.05), decreasing to geometric mean (95% CI) levels of 330 (270-402) and 462 (366-582) pmol/l at 180 min in relatives and control subjects, respectively. The insulin sensitivity index (ISI) as assessed using a hyperglycemic clamp was not different between the two groups. Mean +/- SE ISI during the 3rd hour was 27.5 +/- 2.2 and 30.5 +/- 3.0 micrograms.kg-1.min-1.pmol-1.l-1 in relatives and control subjects, respectively (P > 0.20). At 90 min after the OGTT, log plasma insulin levels correlated significantly with second-phase insulin release as assessed using the hyperglycemic glucose clamp. CONCLUSIONS: Normal glucose-tolerant first-degree relatives of type 2 diabetic subjects have a decreased second-phase insulin release, compared with matched control subjects. After an OGTT, 90-min values of log plasma insulin and 90-min values of the ratio of log plasma insulin to blood glucose may be good indicators of insulin secretory properties in normal glucose-tolerant family members of type 2 diabetic subjects.