The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man.

Genetic susceptibility to type 2 diabetes involves many genes, most of which are still unknown. The lipid phosphatase SHIP2 is a potent negative regulator of insulin signaling and sensitivity in vivo and is thus a good candidate gene. Here we report the presence of SHIP2 gene mutations associated with type 2 diabetes in rats and humans. The R1142C mutation specifically identified in Goto-Kakizaki (GK) and spontaneously hypertensive rat strains disrupts a potential class II ligand for Src homology (SH)-3 domain and slightly impairs insulin signaling in cell culture. In humans, a deletion identified in the SHIP2 3' untranslated region (UTR) of type 2 diabetic subjects includes a motif implicated in the control of protein synthesis. In cell culture, the deletion results in reporter messenger RNA and protein overexpression. Finally, genotyping of a cohort of type 2 diabetic and control subjects showed a significant association between the deletion and type 2 diabetes. Altogether, our results show that mutations in the SHIP2 gene contribute to the genetic susceptibility to type 2 diabetes in rats and humans.

Reciprocal interactions between the GH axis and sleep.

For more than 30 years, growth hormone (GH) has been observed to be preferentially secreted during deep, slow-wave sleep (SWS). However, the mechanisms that underlie this robust relationship that links anabolic processes in the body with behavioral rest and decreased cerebral metabolism remain to be elucidated. Current evidence indicates that GH secretion during the beginning of sleep appears to be primarily regulated by GH-releasing hormone (GHRH) stimulation occurring during a period of relative somatostatin withdrawal, which also is associated with elevated levels of circulating ghrelin. Apparently, two populations of GHRH neurons need to be simultaneously active to stimulate, in a coordinated fashion, SWS and pituitary GH release. Pharmacological interventions that are capable of increasing the duration and/or the intensity of SWS such as oral administration of gamma-hydroxybutyrate (GHB), also increase the rate of GH release. Because the normal negative feedback exerted by GH on central GHRH is inoperative in patients with GH deficiency, it is possible that the decreased energy levels and fatigue often reported by GH-deficient adults partly reflect an alteration in sleep-wake regulation. Preliminary data from a sleep study of adults with GH deficiency using wrist actigraphy for 6 nights at home and polysomnography in the laboratory indeed show decreased total sleep time and increased sleep fragmentation in GH-deficient patients as compared with normal controls.

Impact of GH replacement therapy on sleep in adult patients with GH deficiency of pituitary origin.

OBJECTIVES: We previously reported that adult patients with GH deficiency (GHD) due to a confirmed or likely pituitary defect, compared with healthy controls individually matched for age, gender, and BMI, have more slow-wave sleep (SWS) and higher delta activity (a marker of SWS intensity). Here, we examined the impact of recombinant human GH (rhGH) therapy, compared with placebo, on objective sleep quality in a subset of patients from the same cohort. DESIGN: Single-blind, randomized, crossover design study. METHODS: Fourteen patients with untreated GHD of confirmed or likely pituitary origin, aged 22-74 years, participated in the study. Patients with associated hormonal deficiencies were on appropriate replacement therapy. Polygraphic sleep recordings, with bedtimes individually tailored to habitual sleep times, were performed after 4 months on rhGH or placebo. RESULTS: Valid data were obtained in 13 patients. At the end of the rhGH treatment period, patients had a shorter sleep period time than at the end of the placebo period (479±11 vs 431±19 min respectively; P=0.005), primarily due to an earlier wake-up time, and a decrease in the intensity of SWS (delta activity) (559±125 vs 794±219 µV(2) respectively; P=0.048). CONCLUSIONS: Four months of rhGH replacement therapy partly reversed sleep disturbances previously observed in untreated patients. The decrease in delta activity associated with rhGH treatment adds further evidence to the hypothesis that the excess of high-intensity SWS observed in untreated pituitary GHD patients is likely to result from overactivity of the hypothalamic GHRH system due to the lack of negative feedback inhibition by GH.

Sleep disturbances, daytime sleepiness, and quality of life in adults with growth hormone deficiency.

CONTEXT: Low energy and fatigue are frequent complaints in subjects with GH deficiency (GHD). Because interrelations between sleep and GH regulation are well documented, these complaints could partly reflect alterations of sleep quality. OBJECTIVE: The objective of the study was to determine objective and subjective sleep quality and daytime sleepiness in adult GHD patients. SUBJECTS: Thirty patients, aged 19-74 yr, with untreated GHD (primary pituitary defects confirmed or likely in 26 patients, hypothalamic origin in four patients), and 30 healthy controls individually matched for gender, age, and body mass index participated in the study. Patients with associated pituitary deficiencies (n = 28) were on hormonal replacement therapy. METHODS: Polygraphic sleep recordings, assessment of Pittsburgh Sleep Quality Index, and Quality of Life Assessment for GHD in Adults were measured. RESULTS: Irrespective of etiology, GHD patients had a Pittsburgh Sleep Quality Index score above the clinical cutoff for poor sleep and lower Quality of Life Assessment for GHD in Adults scores than controls, with tiredness being the most affected domain. Patients with pituitary GHD spent more time in slow-wave sleep (SWS) and had a higher intensity of SWS than their controls. Among these patients, older individuals obtained less total sleep than controls, and their late sleep was more fragmented. Contrasting with pituitary GHD, the four patients with hypothalamic GHD had lower intensity of SWS than their controls. CONCLUSIONS: GHD is associated with sleep disorders that may be caused by specific hormonal alterations as well as with poor subjective sleep quality and daytime sleepiness. Disturbed sleep is likely to be partly responsible for increased tiredness, a major component of quality of life in GHD.

AcroBel--the Belgian registry on acromegaly: a survey of the 'real-life' outcome in 418 acromegalic subjects.

OBJECTIVES: To constitute a registry on acromegaly, AcroBel, to evaluate the epidemiology and quality of care of acromegaly in Belgium and Luxembourg. DESIGN: A nationwide survey from June 2003 till September 2004 aiming to collect data from all patients with acromegaly who had visited the participating endocrine clinics after 1 January 2000. METHODS: Retrospective data collection coupled to a visit within the survey period, allowing sampling of metabolic parameters and centralised determination of GH and IGF-I. RESULTS: Four hundred and eighteen patients (51% men) were included, of which 96 were new cases, giving a mean incidence of 1.9 cases per million (c.p.m.) per year. The global prevalence was 41 c.p.m. but varied between 21 and 61 among different areas. Twenty-eight deaths were reported at a median age of 68 years in men and 74 years in women. The standardised mortality rate was significantly increased only in irradiated patients (2.70; confidence interval 1.60-4.55). Central measurements were available in 316 (75%) patients. Mean GH was < or = 2 microg/l in 65% and IGF-I was normal for age in 56%, while both criteria were fulfilled in 49%. Multimodal treatment was more effective than primary medical therapy, since 56.5% were controlled versus 24.3% (P < 0.0001). CONCLUSIONS: AcroBel provides an excellent tool to analyse the prevalence, incidence, treatment modalities and outcome of acromegaly in Belgium. This real-life survey reveals that only half of acromegalic patients received an adequate therapy resulting in cure or disease control when stringent biochemical criteria are used.

Relative adrenal insufficiency in patients with septic shock: comparison of low-dose and conventional corticotropin tests.

OBJECTIVE: To compare a low-dose (1 microg) corticotropin stimulation test with the more standard (250 microg) test for the diagnosis of relative adrenal insufficiency. DESIGN: Diagnostic study. SETTING: Thirty-one-bed mixed medico-surgical department of intensive care. PATIENTS: Forty-six consecutive patients with septic shock. INTERVENTIONS: Corticotropin stimulation tests (low-dose test, 1 microg, and standard 250-microg test), performed consecutively at an interval >4 hrs. MEASUREMENTS AND MAIN RESULTS: In each test, serum cortisol levels were measured before (T0) and 30 (T30), 60 (T60), and 90 (T90) mins after corticotropin injection. The maximal increase in cortisol (Deltamax) was calculated as the difference between T0 and the highest cortisol value at T30, T60, or T90 and considered as adequate if >9 microg/dL (250 nmol/L). Nonresponders to the low-dose test had a lower survival rate than responders to both tests (27 vs. 47%, p = .06; Kaplan Meier curves). Interestingly, nonresponders to high-dose test received hydrocortisone treatment and had a similar survival to responders. Multivariable logistic regression disclosed that the response to the combined low-dose test and high-dose test was an independent predictor of survival (odds ratio 28.91, 95% confidence interval 1.81-462.70, p = .017), whereas basal or maximal cortisol levels in both tests were not. CONCLUSIONS: The low-dose test identified a subgroup of patients in septic shock with inadequate adrenal reserve who had a worse outcome and would have been missed by the high-dose test. These patients may also benefit from glucocorticoid replacement therapy.