Visceral fat mass as a novel risk factor for predicting gestational diabetes in obese pregnant women.

OBJECTIVE: To develop a model to predict gestational diabetes mellitus incorporating classical and a novel risk factor, visceral fat mass. METHODS: Three hundred two obese non-diabetic pregnant women underwent body composition analysis at booking by bioimpedance analysis. Of this cohort, 72 (24%) developed gestational diabetes mellitus. Principal component analysis was initially performed to identify possible clustering of the gestational diabetes mellitus and non-GDM groups. A machine learning algorithm was then applied to develop a GDM predictive model utilising random forest and decision tree modelling. RESULTS: The predictive model was trained on 227 samples and validated using an independent testing subset of 75 samples where the model achieved a validation prediction accuracy of 77.53%. According to the decision tree developed, visceral fat mass emerged as the most important variable in determining the risk of gestational diabetes mellitus. CONCLUSIONS: We present a model incorporating visceral fat mass, which is a novel risk factor in predicting gestational diabetes mellitus in obese pregnant women.

Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study.

AIMS: To compare maternal and neonatal outcomes in women with gestational diabetes mellitus (GDM) treated with either metformin or insulin. METHODS: One hundred and twenty-seven women with GDM not adequately controlled by dietary measures received metformin 500 mg twice daily initially. The dose was titrated to achieve target blood glucose values. Pregnancy outcomes in the 100 women who remained exclusively on metformin were compared with 100 women with GDM treated with insulin matched for age, weight and ethnicity. RESULTS: There were no significant differences in baseline maternal risk factors. Women treated with insulin had significantly greater mean (sem) weight gain from enrolment to term (2.72 +/- 0.4 vs. 0.94 +/- 0.3 kg; P < 0.001). There was no difference between the metformin and insulin groups, respectively, comparing gestational hypertension (6 vs. 7%, P = 0.9), pre-eclampsia (9 vs. 2%, P = 0.06) induction of labour (26 vs. 24%, P = 0.87) or rate of Caesarean section (48 vs. 52%, P = 0.67). No perinatal loss occurred in either group. Neonatal morbidity was improved in the metformin group; prematurity (0 vs. 10%, P < 0.01), neonatal jaundice (8 vs. 30%, P < 0.01) and admission to neonatal unit (6 vs. 19%, P < 0.01). The incidence of macrosomia (birthweight centile > 90) was not significantly different [metformin (14%) vs. insulin (25%); P = 0.07]. CONCLUSIONS: Women with GDM treated with metformin and with similar baseline risk factors for adverse pregnancy outcomes had less weight gain and improved neonatal outcomes compared with those treated with insulin. Diabet. Med. 26, 798-802 (2009).

Familial medullary thyroid cancer: clinical aspects and prognosis.

OBJECTIVE: To assess clinical features and long-term results of treatment of familial medullary thyroid carcinoma (FMTC). DESIGN: Retrospective analysis of all patients with familial forms of MTC diagnosed between 1949-2000 and treated in our unit. RESULTS: Fifty five patients (25 males, 30 females) were identified with at least two first-degree relatives affected by medullary thyroid cancer; 26 were classified as MEN 2A, 1 as MEN 2B and 28 as FMTC. Median age at diagnosis was 35 years (MEN 2A), 25 (MEN 2B) and 47.5 (FMTC). Median follow-up was 9 years (range: 4-24). Total or near-total thyroidectomy was performed in all patients and 11 received adjuvant external beam radiotherapy. Cause specific survival was 89% at 10 years and 77% at 20 years for MEN patients, 51% and 32% for those with sporadic MTC, and 46% and 26% for those with FMTC. In multivariate analysis, factors predicting survival were presence of metastases, nodal status and age at diagnosis. CONCLUSIONS: Improved survival rates associated with familial types of MTC can be accounted for by the earlier stage at which disease is detected and the younger age at presentation. These observations emphasize the need for early detection in those at risk.

Medullary thyroid cancer: multivariate analysis of prognostic factors influencing survival.

AIMS: The aims of this study were to assess the long-term results of treatment of medullary thyroid carcinoma (MTC) and to define prognostic factors. METHODS: Retrospective analysis of all patients diagnosed with MTC between 1949 and 1998 and treated in our unit was carried out. RESULTS: One hundred and sixty-two patients (87 females, 75 males) were identified; 52 patients (32%) had familial disease. Median follow-up was 9 years (2-20 years). The majority of patients (90%) presented with a thyroid mass or enlarged neck nodes. Total/subtotal thyroidectomy was performed in 129/18 patients respectively; 45 patients also underwent neck dissection while 52 had simple nodal excision. External beam radiotherapy (RT) was given to 76 patients with advanced disease at presentation. Overall survival was 72% at 5 years and 56% at 10 years; case-specific survival was very similar. In multivariate analysis the factors which were significant predictors of survival were age at diagnosis, extent of nodal disease, extent of surgery and metastases at presentation. RT significantly reduced local relapse in patients with ipsilateral nodal disease. CONCLUSIONS: MTC may be associated with prolonged survival; the best prognosis occurs in young patients undergoing total thyroidectomy and neck dissection. External beam RT significantly reduces local relapse in patients with limited nodal disease.

Long-term glycaemic control directly correlates with glomerular filtration rate in early Type 1 diabetes mellitus before the onset of microalbuminuria.

Hyperfiltration occurs early in diabetes mellitus and has been implicated in the development of microalbuminuria. Our aim was to re-examine the controversial relationship between glycaemic control and glomerular filtration (GFR) in normoalbuminuric, normotensive, non-obese patients with short duration Type 1 diabetes mellitus (DM). We studied 75 Type 1 DM patients, 35 male, aged 18-42 years, with a duration of diabetes of 4-8 years. GFR was determined by inulin clearance; hyperfiltration was defined as above 145 ml min(-1) 1.73 m(-2) (equivalent to 2 SD above mean for a control population). Analysis was by paired Student's t-testing and linear regression. GFR correlated significantly with HbA1c (r= 0.47, p < 0.0001) and fructosamine (r= 0.24, p = 0.035). Mean HbA1c and fructosamine in the 13 patients with hyperfiltration was significantly higher than in the rest of the group (HbA1c: 9.2% (95% C.I. 7.9-10.4%) vs 7.6 % (7.2-7.9), p= 0.002; fructosamine: 479 micromol l(-1) (450-507) vs 410 micromol l(-1) (388-432), p = 0.009. This significant difference persisted even when the two highest values of HbA1c or fructosamine were removed from analysis. Effective renal plasma flow, assessed by PAH clearance, also correlated in all patients with HbA1c (r=0.31, p=0.039). We conclude that poor glycaemic control directly correlates with hyperfiltration and renal hyperperfusion in early Type 1 DM.

Rapid progression of fibrosing alveolitis and thyrotoxicosis after antithymocyte globulin therapy for aplastic anemia.

Antithymocyte globulin (ATG) therapy is an established form of treatment for aplastic anaemia and has also been used as prophylaxis against graft rejection of bone marrow and renal allografts. Administration of ATG preparations has been associated with many mild clinical reactions, as have other forms of immunomodulatory therapy. However, serious adverse effects appear to be rare. We report a case of rapidly progressive fibrosing alveolitis and thyrotoxicosis in relation to ATG therapy, highlighting its potential toxicity and emphasising that its administration should be undertaken by experienced physicians in specialised centres.

Bone mineralization after treatment of growth hormone deficiency in survivors of childhood malignancy.

Having noted symptomatic osteoporotic vertebral collapse in young adult survivors of childhood malignancy, bone mineral density (BMD) was examined at three sites by dual-energy X-ray absorptiometry in 64 patients treated in childhood for intracranial malignancy (group 1; n = 21) or acute leukaemia (group 2; n = 43). Patients in group 1 were selected for growth hormone deficiency (GHD) by auxological and biochemical criteria before the end of puberty (Tanner stage V). Seven patients (six men; mean (+/- SEM) age at study, 28.0 +/- 2.9 years; mean age at diagnosis, 8.7 +/- 1.5 years) in this group had been treated with human pituitary growth hormone (GH) for 1-12 years; and 14 patients (nine men; mean age at study, 26.8 +/- 1.0 years; mean age at diagnosis, 10.7 +/- 1.4 years) had not received GH. Bone densities in group 1 were normal in the GH-treated patients at the femoral neck (98.4 +/- 3.8% of control), lumbar spine (100.4 +/- 6.1% of control) and Ward's triangle (101.0 +/- 6.1% of control) but markedly reduced in the untreated group (femoral neck, 81.2 +/- 2.6% of control (p = 0.002); lumbar spine, 79.1 +/- 4.1% of control (p = 0.04); Ward's triangle, 80.1 +/- 3.6% of control (p = 0.01)). The majority of patients in group 2 had been treated for acute lymphoblastic leukaemia (ALL) and were in three subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone deficiency during puberty reduces adult bone mineral density.

Bone mineral density (BMD) was evaluated by dual energy x ray absorptiometry in 60 adults (33 males, 27 females; aged 50, range 23-76 years) who were growth hormone deficient from various causes for 10.4 (1-31) years. Adult patients who had acquired growth hormone deficiency before completion of puberty had significantly reduced mean (SEM) BMD compared with age matched healthy controls at the lumbar spine: 0.87 (0.09) v 1.20 (0.03) g/cm2, femoral neck: 0.81 (0.06) v 1.08 (0.04) g/cm2, and Ward's triangle: 0.68 (0.07) v 1.04 (0.05) g/cm2. These values were also reduced compared with those of patients who had received human growth hormone during puberty. Untreated growth hormone deficiency when present during puberty results in reduced adult bone density.

Macular blood flow response to acute reduction of plasma glucose in diabetic patients measured by the blue light entoptic technique.

The response of retinal blood flow to acute reduction in plasma glucose levels was studied in 20 poorly controlled type I diabetic patients. Perifoveal flow velocity was determined, using the blue-light entoptoscope, and arterial calibers measured, using a computer-aided digitizing system. Mean plasma glucose level was lowered from 17.7 +/- 4 to 7.0 +/- 1 mmol/l after a subcutaneous insulin infusion and measurements taken at both glucose levels. The autoregulatory change induced by breathing 60% oxygen at the two plasma glucose levels also was compared. Mean flow velocities were 0.54 +/- 0.28 mm/sec at a high plasma glucose level compared with 0.55 +/- 0.32 mm/sec at a low plasma glucose level, whereas hyperoxia reduced these by 16.58 and 16.71%, respectively. No significant difference in the responses of arterial diameters to hyperoxia between the two glucose levels was found. The authors conclude that acute reduction in plasma glucose level in this group of patients is not associated with significant changes in macular blood flow or in alteration in autoregulation.

Aspects of growth hormone control in diabetes.

Growth Hormone (GH) has been implicated in the development of retinal new vessels that characterise diabetic proliferative retinopathy. Formerly, pituitary ablation was successful in causing such new vessels to regress but this approach has been largely superseded by panretinal photocoagulation. A clearer understanding of the GH abnormalities in diabetes might not only shed light on the process of retinal new vessel formation but could also provide a means for pharmacological suppression of GH in those patients not fully responding to laser photocoagulation. In this review, GH control in diabetes is considered with particular reference to studies in patients with diabetic retinopathy.

A two-year follow-up study of serum insulinlike growth factor-I in diabetics with retinopathy.

Serum insulinlike growth factor-I (IGF-I) concentration was evaluated prospectively over two years in 35 diabetic patients with severe background or preproliferative retinopathy (group 1) and 24 diabetics with mild background retinopathy matched for age, sex, and glycemic control (group 2). In addition, 12 normal subjects were also studied to assess the variability of individual serum IGF-I levels over two years. Mean serum IGF-I (+/- SD) micrograms/l at entry, one year, and two years was not significantly different in the patient groups (157 +/- 71 v 168 +/- 77; 166 +/- 78 v 159 +/- 87; 143 +/- 58 v 159 +/- 67) or when compared with the normal subjects (181 +/- 47, 188 +/- 30; 221 +/- 56). Eight patients in the preproliferative group and none in the mild background group developed proliferative retinopathy. In this subgroup developing retinal neovascularization, serum IGF-I at the time of the first appearance of retinal new vessels was significantly higher than 3 months (1 to 4 months) before the onset of proliferation (271 +/- 94 v 196 +/- 58; P = .036). Values at the time of proliferation were not, however, significantly different from the mean serum IGF-I value of all patients in group 1 and by 4 months (3 to 6 m) had returned to their previous values. Although a transient elevation of IGF-I occurs at the time of retinal new vessel formation, the rise in serum concentration is not sufficiently great or early enough to be of clinical value as a predictor of retinal neovascularization.

Continuous subcutaneous octreotide infusion markedly suppresses IGF-I levels whilst only partially suppressing GH secretion in diabetics with retinopathy.

The response to GH releasing hormone (GHRH 1-29) and 24-h serum GH and IGF-I levels were measured in 9 insulin-dependent diabetics with retinopathy and 6 normal volunteers before and after different treatment regimens with octreotide, a long-acting somatostatin analogue. Octreotide, 50 micrograms by sc injection, completely suppressed GHRH-stimulated GH release in both groups. Thrice daily sc injections for up to 20 weeks were associated with variable plasma octreotide levels and failed completely to suppress GH secretion in either the patients or the normal controls. Three days of continuous sc pump infusion (500 micrograms/24-h) resulted in consistently high plasma octreotide levels and completely suppressed 24-h GH in 4 normal subjects, whilst treatment for up to 16 weeks only partially suppressed GH levels in 6 patients (AUC mU.l-1.h-1; 209 +/- 81 vs 121 +/- 82; P = 0.01). Mean +/- SD IGF-I levels (micrograms/l) in the patients (but not controls) were suppressed into the hypopituitary range by median 6 weeks (range 2-16) pump administration (203 +/- 62 vs 60 +/- 25; P = 0.02). Pump treatment achieved total GH suppression in normal subjects; diabetics with retinopathy seem more resistant to the GH suppressing effects of the drug. However, the reduction of serum IGF-I with prolonged treatment may be of clinical value in arresting the progress of diabetic retinopathy.

Progression of diabetic retinopathy and changes in serum insulin-like growth factor I (IGF I) during continuous subcutaneous insulin infusion (CSII).

The rise in serum IGF I concentration during continuous subcutaneous insulin infusion (CSII) may be a contributory factor in the deterioration of diabetic retinopathy that sometimes occurs during this treatment but the relation of serum levels to the severity of retinopathy has not been previously studied. In twelve non-obese insulin dependent diabetics (age range: 22-41 yrs) with mean +/- SD duration of diabetes: 14.8 +/- 4.7 yrs, serum IGF I concentration, HbA1 and retinopathy score were estimated prospectively over twelve months following the institution of CSII therapy. After four months of treatment, eight patients showed deterioration of retinopathy by at least one level of severity. Serum IGF I concentration rose from a mean +/- SEM of 155 +/- 17.7 micrograms/l at entry to 199 +/- 23.1 micrograms/l at four months and by twelve months had returned to near initial values 163 +/- 17.4 micrograms/l. There was however, no significant correlation between retinopathy score and serum IGF I level by analysis of variance for the whole group, or in the group of diabetics whose retinopathy deteriorated. The rise in IGF I concentration over the first four months and subsequent decline in IGF I values over the next eight months was inversely related to HbA1 concentration (r = -0.58; P less than 0.05). One patient with early ischaemic retinopathy on entry, experienced a marked rise in serum IGF I corresponding to a rapid tightening of glycaemic control. At four months she developed florid proliferative changes requiring panretinal laser therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure to suppress GH secretion after 2 weeks treatment with atropine or propanthelene in diabetics with proliferative retinopathy.

Complete suppression of GH secretion may halt the development of retinal new vessels in patients with diabetic proliferative retinopathy. We have investigated the effectiveness of two cholinergic antagonists, atropine and propanthelene given orally for 2 weeks, in suppressing 24-h GH and IGF-I levels. Seven insulin-dependent diabetics (3 males, 4 females; aged 22-34 years) with active proliferative retinopathy and 6 matched non-diabetic normal subjects were studied in random order with at least 2 weeks between treatments. Suppression of GHRH-induced GH release was demonstrated in both groups of subjects. Twenty-four hour GH secretion was not, however, suppressed in either the patient group (mean area under the GH curve mU.l-1.h-1 +/- SD; baseline: 251 +/- 108.7; after atropine: 174 +/- 106.9; after propanthelene: 180 +/- 72.4; P greater than 0.05) or in the control group (baseline: 103 +/- 53.1; after atropine: 73 +/- 83.6; after propanthelene: 122 +/- 71.6; P greater than 0.05). GH release at times of hypoglycemia was not suppressed. Mean IGF-I concentration was not significantly reduced. Two subjects (one patient and one control) could not tolerate atropine for more than one week. We conclude that repeated doses of atropine and propanthelene do not achieve complete 24-h GH suppression and are associated with a high incidence of unpleasant adverse reactions.

Serum IGF-1 concentration in diabetic retinopathy.

Growth factors such as growth hormone and insulin-like growth factor 1 (IGF-1) may be important in the pathogenesis of diabetic retinopathy. We measured serum IGF-1 in 371 diabetic patients attending a diabetic retinopathy clinic and in 73 non-diabetic control subjects. No significant difference was observed in IGF-1 level between the diabetic and control groups (168 +/- 3.9 vs 177 +/- 7.4 micrograms/l [mean +/- SE]). Within the diabetic group, there was no difference between patients with no retinopathy and those with proliferative change (198.7 +/- 8.8 vs 190.5 +/- 11 micrograms/l). After adjusting for differences in age, duration of diabetes, and presence of proteinuria, only the inactive previously proliferative group showed any significant difference from the other patient subgroups (151.8 +/- 11.5 micrograms/l; p less than 0.05). Serum IGF-1 correlated with age in the control group (r = 0.49; p less than 0.001) and to a lesser extent in the diabetic group (r = -0.23; p less than 0.05). IGF-1 levels were higher in patients with proteinuria than in those without proteinuria (196.8 +/- 10.3 vs 138.8 +/- 4.4 micrograms/l; p less than 0.001).

The effects of propranolol and metoprolol on skin blood flow in diabetic patients.

The effect of 2 weeks treatment with propranolol or metoprolol on skin blood flow (SBF) at rest was examined in 12 diabetic patients with essential hypertension in whom gross large vessel disease had been excluded. Neither drug significantly altered resting skin blood flow. However we cannot exclude an important difference between the two beta-adrenoceptor blockers because of the great variability of SBF within subjects. A larger study and/or more accurate methods of measuring SBF are needed to determine if beta 1-selective adrenoceptor antagonists differ from non-selective beta-adrenoceptor blockers with respect to skin blood flow.