Overt Diabetes Mellitus Research Articles

Lifestyle change after gestational diabetes

Aims: Gestational diabetes mellitus (GDM) is a predictor for overt diabetes later in life. Thus, during pregnancy GDM patients are instructed to change lifestyle after pregnancy. The purpose of the present study was to assess the lifestyle changes made by these women. Methods: The study was a mailed survey with structured questions on diet, weight loss, exercise and worry about developing diabetes. One hundred and twenty-one (79%) women agreed to participate 11–42 months after pregnancy. Weight gain or loss was defined as a change ≥5 kg. Results: Among women with body mass index (BMI) >25 kg/m 2, only 18% lost weight and more than 33% gained weight. In total, more women gained than lost weight ( P<0.05). Prior to pregnancy, 90 (74%) women followed a diet rich in fat. In contrast, only 57 women (47%) did so at follow-up ( P<0.001). Further analysis showed that among these 57 women, only 7% had lost weight since pregnancy compared to 25% of women eating healthy ( P<0.05). Eighty-six percent were worried to some extent about the risk for subsequent diabetes. The exercise level did not change after pregnancy. Nineteen women (16%) had overt diabetes mellitus and 22 (18%) impaired glucose tolerance (IGT) at follow-up. Conclusions: Although the majority of the women were concerned about developing overt diabetes, only a few had changed their lifestyle and/or lost weight after pregnancy. This indicates that lifestyle instruction needs to be much more frequent and intensive in the period after pregnancy in these women.

Tumor immunity in the context of autoimmunity

As tumors develop, they escape detection by the immune system, perhaps because they differ little from “self”. In individuals with autoimmunity, tolerogenic mechanisms have broken down, resulting in activation of immune effectors against autoantigens. We postulate that immune effectors inappropriately activated in autoimmune individuals are capable of protecting against tumor expressing targeted autoantigens. To evaluate this hypothesis, we generated double transgenic mice which spontaneously develop pancreatic insulinomas and in which all CD8+ T cells recognize an autoantigen expressed by normal and transformed beta-islet cells (8.3-NOD-riptag). These mice were generated on a NOD background, which confers a propensity to develop autoimmune diabetes mellitus (DM). In mice with a normal complement of immune effectors (ie: NOD-riptag), the median time of onset of hypoglycemia (a surrogate marker for tumor) was the same as immunodeficient mice (ie: NOD-scid-riptag) (86 vs. 92 days, respectively). This suggests that the baseline immune response is insufficient to affect tumor growth. While all of these mice became hypoglycemic, not all 8.3-NOD-riptags became hypoglycemic. In 8.3-NOD-riptag mice, 13/25 became diabetic. Of diabetic 8.3-NOD-riptags, only 3 became hypoglycemic and these mice had tumor at autopsy. Even in those mice which did not develop overt DM, there was a significant delay in onset of hypoglycemia (ie: median 129 d; P = 0.0008). While these data suggest that 8.3-TCR (transgenic) CD8+ T cells inhibited tumor, the protection was incomplete. Anergy does not appear to be responsible for the failure, for transgenic CD8+ T cells in these individuals respond normally to NRP (the peptide mimotope for the antigen recognized by 8.3-TCR CD8+ T cells). Similarly, clonal deletion does not appear to be responsible for tumor outgrowth, as the number of 8.3-TCR CD8+ T cells does not decline with age or with tumor development. These data demonstrate that, in individuals with tolerogenic defects, primed CD8+ T cells capable of inducing autoimmunity are unable to completely protect against the emergence of tumor expressing the targeted autoantigens. Our initial studies suggest that this failure to confer complete protection is secondary to tumor factors rather than to acquired T cell defects. These factors will be important to define to rationally design tumor vaccines.

Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass.

Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. We have disrupted expression of the mitochondrial protein frataxin selectively in pancreatic beta cells. Mice were born healthy but subsequently developed impaired glucose tolerance progressing to overt diabetes mellitus. These observations were explained by impairment of insulin secretion due to a loss of beta cell mass in knockout animals. This phenotype was preceded by elevated levels of reactive oxygen species in knockout islets, an increased frequency of apoptosis, and a decreased number of proliferating beta cells. Hence, disruption of the frataxin gene in pancreatic beta cells causes diabetes following cellular growth arrest and apoptosis, paralleled by an increase in reactive oxygen species in islets. These observations might provide insight into the deterioration of beta cell function observed in different subtypes of diabetes in humans.

Frataxin deficiency in pancreatic islets causes diabetes due to loss of β cell mass

Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing β cells. We have disrupted expression of the mitochondrial protein frataxin selectively in pancreatic β cells. Mice were born healthy but subsequently developed impaired glucose tolerance progressing to overt diabetes mellitus. These observations were explained by impairment of insulin secretion due to a loss of β cell mass in knockout animals. This phenotype was preceded by elevated levels of reactive oxygen species in knockout islets, an increased frequency of apoptosis, and a decreased number of proliferating β cells. Hence, disruption of the frataxin gene in pancreatic β cells causes diabetes following cellular growth arrest and apoptosis, paralleled by an increase in reactive oxygen species in islets. These observations might provide insight into the deterioration of β cell function observed in different subtypes of diabetes in humans.

Early effects of metformin on glucose dynamics in women with oligoamenorrhea and regular menstrual cycles who were wearing a subcutaneous glucose sensor

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder involving three generally accepted hallmarks: oligoamenorrhea, clinical evidence of androgen excess on laboratory testing, and the absence of other endocrine disturbances (1). Many oligoamenorrheic women also share the clinical features of visceral adiposity, hypertension, and dislipidemia. Recent observations indicate that insulin resistance is often present even in nonobese women (2, 3). Moreover, at least one-third of all PCOS women show impaired glucose tolerance, while 7%–10% have overt diabetes mellitus (4, 5). The initial step to improve ovulation rates in obese women with oligoamenorrhea are lifestyle modifications, such as a low-calorie diet and exercise. Recently, it has been shown that insulin-sensitizing agents improve ovulation and reduce the long-term complications of insulin resistance (6, 7). Interestingly, effective use of metformin has also been shown in lean adolescents with anovulatory hyperandrogenism (8).

Ambulatory monitoring in subjects with high-normal blood pressure

The purpose of this study was the evaluation of the predictive value of ambulatory BP monitoring (ABPM) for the development of drug-treated hypertension in subjects with high-normal BP (HNBP: ≥130/85 and <140/90 mmHg). We studied 127 subjects (69 M, 58 F, age 50±14 years): 59 subjects (26 M, 33 F, age 51±13 years) had normal BP (NBP: <130/85 mmHg; average office BP 122/77± 7/6 mmHg), 68 subjects (43 M, 25 F, age 49± 15 years) had systolic and/or diastolic HNBP (average office BP: 135/84± 4/5 mmHg). In the HNBP group there was a statistically significant (p<0.01) higher prevalence of overweight (= BMI >25 kg/m2; 66.2% vs. 33.9%) and hypercholesterolemia (= total cholesterol > 230 mg/dl; 32.3% vs. 1.7%). Prevalence of overt diabetes mellitus was not statistically different between groups. All the subjects, who had normal physical examination and ECG and no history of cardiovascular disease, underwent ABPM by means of Spacelabs 90207 recorders. All ABPM variables were statistically (at least p<0.05) higher in the HNBP group and there were 21/68 (30.9%) subjects in the HNBP group vs. 1/59 (1.7%) in the NBP group with an elevated (>135/85 mmHg) mean daytime ABP (p<0.01). Univariate analysis was performed by means of Chi-square and Student's t tests to evaluate variables which could be associated with the development of drug-treated hypertension in the follow-up. A p<0.05 was accepted as statistically significant. After an average follow-up of 103± 28 months, 27 subjects (39.7%; 17 M and 10 F) in the HNBP group and 4 subjects (6.8%; 1 M and 3 F) in the NBP group developed drug-treated hypertension (p<0.01). An elevated daytime ABP correctly predicted development of drug-treated hypertension in 17/21 subjects (81%) of the HNBP group and in the only subject of the NBP group. Development of drug-treated hypertension was associated with higher office and ambulatory BP (p<0.01) and pulse pressures (p<0.05), longer follow-up (p<0.05) and higher prevalence of hypercholesterolemia and smoking (p<0.01). We conclude that ABPM correctly predicts development of drug-treated hypertension in most subjects who were early identified as ambulatory hypertensives, i.e. having a daytime mean ABP >135/85 mmHg (following ASH and JNC VI recommmendations). ABPM appears a useful clinical tool in the early diagnosis of hypertension in subjects with metabolic risk factors and smoking.

Lack of association between serum paraoxonase 1 activities and increased oxidized low-density lipoprotein levels in impaired glucose tolerance and newly diagnosed diabetes mellitus.

Several in vitro investigations showed that serum paraoxonase 1 (PON1) that is located on high-density lipoprotein reduces or prevents low-density lipoprotein (LDL) oxidation and therefore retards atherosclerosis. Accordingly, the well documented loss of PON1 activity in patients with overt diabetes mellitus was causally related to the development of micro- and macroangiopathy in the disease course. Because vascular complications start already in prediabetic states, e.g. impaired glucose tolerance (IGT), we investigated serum PON1 activities and circulating levels of oxidized LDL (oxLDL) in 125 IGT subjects, 75 patients with newly diagnosed diabetes mellitus type 2, and 403 individuals with normal glucose tolerance. Using three different substrates (paraoxon, phenylacetate, p-nitrophenylacetate) we found that PON1 activity is not significantly altered in IGT and diabetes mellitus subjects, respectively, when compared with normoglycemic controls. Both IGT subjects and diabetes mellitus patients had significantly increased levels of oxLDL in the circulation. However, serum PON1 activity variations and glutamine/arginine phenotype were not related to the levels of oxLDL. The data suggest that 1) PON1 activity loss is an event occurring later in the course of diabetes mellitus; and 2) PON1 does not affect oxidation of circulating LDL, at least in early diabetes mellitus.

Coronary capillary network remodeling and hypofibrinolysis in aged obese diabetic rats: implications for increased myocardial vulnerability to ischemia.

Despite the known abnormalities of cardiac function in patients with overt non-insulin dependent diabetes mellitus (NIDDM) the temporal changes of coronary capillary network remodeling leading to potential microcirculatory dysfunction have not been elucidated. To this end, left ventricular subendocardial capillary network of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, characterized by hypertension, obesity, hyperglycemia, hyperinsulinemia and mild NIDDM, and control Long-Evans Tokushima (LETO) rats were investigated. Total capillary density in OLETF was significantly higher than that in LETO at 20 weeks, suggesting compensatory improvement of O2 transport at early stages of NIDDM. The increase in capillary density in OLETF was lost at 40 and 60 weeks due to the decreases of intermediate capillary portions and venular capillary portions. Although capillary domain area (area innervated by single capillary) in OLETF was lower than that in LETO at 20 weeks, the values were similar between OLETF and LETO at 40 and 60 weeks, suggesting that adaptive improvement in the capacity for 02 transport with a high perfusion was lost in late stages of NIDDM. Activity of plasma plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of proteo(fibrino)lysis, in OLETF was higher than that in LETO at 40 and 60 weeks, suggesting that increase of PAI-1 may downregulate compensatory adaptive capillary network remodeling by inhibiting proteolysis and angiogenesis in the cardiac interstitium. Loss of adaptive myocardial microcirculation may therefore contribute to increased vulnerability in ischemic injury and to cardiac dysfunction in NIDDM.

Isolated post-challenge hyperglycemia in patients with normal fasting glucose concentration exaggerates neointimal hyperplasia after coronary stent implantation.

Postprandial hyperglycemia has been shown to increase the risk of cardiovascular disease as much as overt diabetes mellitus does. The aim of this study was to determine whether isolated post-challenge hyperglycemia during an oral glucose tolerance test (OGTT) is related to exaggerated neointimal proliferation after coronary stent implantation. Forty seven coronary lesions treated with stents in 40 patients who had normal fasting glucose levels (<110 mg/dl) were categorized into the following 2 groups according to the results of a 75-g OGTT: 29 lesions in 24 patients with normal glucose tolerance (NGT group) and 18 lesions in 16 patients with abnormal glucose tolerance (AGT group). Although there were no differences in angiographic characteristics before and immediately after stenting between the 2 groups, the minimal lumen diameter was significantly smaller (p=0.04) and the degree of stenosis and late loss were also significantly greater (p=0.01 and p=0.047) in the AGT group than in the NGT group at 6-month follow-up. Multiple regression analysis including the insulin concentrations during an OGTT revealed that the 120-min plasma glucose concentration after glucose load significantly correlated with late loss (p=0.0018) and the degree of stenosis (p=0.0100) at follow-up. It is concluded that isolated post-challenge hyperglycemia exaggerates neointimal hyperplasia after coronary stent implantation.

Impaired tolerance for glucose in women with recurrent vaginal candidiasis

Objective: The purpose of this study was determine whether nondiabetic women with recurrent vaginal candidiasis have an impaired glucose metabolism. Study Design: A case-control study of 62 otherwise healthy women who were attending a vaginitis clinic ≥3 times a year for symptoms of Candida vaginitis, positive microscopy, and at least one positive Candida culture and of 32 Candida -negative control subjects, all of whom were undergoing standardized oral glucose tolerance testing. Results: Women with recurrent bacterial vaginal infections did not differ from women without infections, so both groups comprised the control group. Women with recurrent vaginal candidiasis had a greater mean body mass index than the control subjects (23.5 vs 21.4, P =.001). They had no more incidences of overt or preclinical diabetes mellitus than the control subjects (6/62 vs 0/32 incidents), but a greater proportion of them had at least one glucose concentration above the 95th percentile (36% vs 12%, P =.016). Glucose concentrations were higher in recurrent vaginal candidiasis cases than in control subjects at 0 (89 vs 85 mg/dL,P =.049), 30 (139 vs 126 mg/dL, P =.05), and 60 minutes (123 vs 102 mg/dL, P =.009) after the intake of 75 g of glucose. Fasting concentration of glycosylated hemoglobin was 25% higher in women with recurrent vaginal candidiasis (5 vs 4 g/dL, P =.0006), even after correction for body mass index. Compared with control subjects, ingestion of 75 g of glucose led to a 15% increase of serum glucose levels in women with recurrent vaginal candidiasis (P =.01). As expected, most of these differences were largely mediated by an increased body mass index. Conclusion: The tolerance to glucose in nondiabetic women with recurrent vaginal candidiasis is discretely impaired. Glucose tolerance testing is of value in women with recurrent vaginal candidiasis, but the interpretation of the obtained values should not be limited to the diagnosis of preclinical diabetes mellitus. (Am J Obstet Gynecol 2002;187:989-93.)

Acrochordon and impaired carbohydrate metabolism.

Acrochordons were reported to have a probable association with diabetes mellitus but detailed data about this relation has not been introduced yet. We evaluated 120 patients with acrochordon for the presence of impaired carbohydrate metabolism. Overt diabetes mellitus (DM) was found in 88 patients and glucose intolerance was detected in 6 patients; 4 patients had reactive hypoglycemia. We concluded that acrochordons may be skin markers of underlying impaired carbohydrate metabolism and the patients with acrochordon should be evaluated for the presence of diabetes mellitus.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study

Objective: The objective of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study is to clarify unanswered questions on associations of maternal glycemia, less severe than overt diabetes mellitus, with risks of adverse pregnancy outcome. This report describes the background and design of the HAPO Study. Methods: HAPO is a 5-year investigator-initiated prospective observational study that will recruit approximately 25 000 pregnant women in 10 countries. HAPO utilizes a Central Laboratory for measurement of key metabolic variables, a Clinical Coordinating Center, a Data Coordinating Center, and an independent Data Monitoring Committee. Glucose tolerance is assessed by a 75 g 2-h OGTT at 24–32 weeks’ gestation. Results are unblinded to the woman and her caregivers if: fasting plasma glucose >5.8 mmol/l, 2-h plasma glucose >11.1 mmol/l or any plasma glucose <2.5 mmol/l. Random plasma glucose measurement is performed at 34–37 weeks or if symptoms suggest hyperglycemia; results are unblinded for values ≥8.9 mmol/l. Sociodemographic and health history data are collected via questionnaire and medical record abstraction. Maternal blood is obtained for measurement of serum C-peptide and hemoglobin A1c (HbA 1C), cord blood for serum C-peptide and plasma glucose, and a capillary specimen is taken between 1 and 2 h following delivery for neonatal plasma glucose. Neonatal anthropometrics are obtained, and follow-up data are collected at 4–6 weeks post-delivery. The primary outcomes to be assessed in relation to maternal glycemia are cesarean delivery, increased fetal size (macrosomia/LGA/obesity), neonatal morbidity (hypoglycemia), and fetal hyperinsulinism.

Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus.

Pbx1 is a member of the TALE (three-amino acid loop extension) class of homeodomain transcription factors, which are components of hetero-oligomeric protein complexes thought to regulate developmental gene expression and to maintain differentiated cell states. In vitro studies have shown that Pbx1 regulates the activity of Ipf1 (also known as Pdx1), a ParaHox homeodomain transcription factor required for the development and function of the pancreas in mice and humans. To investigate in vivo roles of Pbx1 in pancreatic development and function, we examined pancreatic Pbx1 expression, and morphogenesis, cell differentiation and function in mice deficient for Pbx1. Pbx1-/- embryos had pancreatic hypoplasia and marked defects in exocrine and endocrine cell differentiation prior to death at embryonic day (E) 15 or E16. In these embryos, expression of Isl1 and Atoh5, essential regulators of pancreatic morphogenesis and differentiation, was severely reduced. Pbx1+/- adults had pancreatic islet malformations, impaired glucose tolerance and hypoinsulinemia. Thus, Pbx1 is essential for normal pancreatic development and function. Analysis of trans-heterozygous Pbx1+/- Ipf1+/- mice revealed in vivo genetic interactions between Pbx1 and Ipf1 that are essential for postnatal pancreatic function; these mice developed age-dependent overt diabetes mellitus, unlike Pbx1+/- or Ipf1+/- mice. Mutations affecting the Ipf1 protein may promote diabetes mellitus in mice and humans. This study suggests that perturbation of Pbx1 activity may also promote susceptibility to diabetes mellitus.

Fetal hyperinsulinemia increases farnesylation of p21 Ras in fetal tissues.

Even though the role of fetal hyperinsulinemia in the pathogenesis of fetal macrosomia in patients with overt diabetes and gestational diabetes mellitus seems plausible, the molecular mechanisms of action of hyperinsulinemia remain largely enigmatic. Recent indications that hyperinsulinemia "primes" various tissues to the mitogenic influence of growth factors by increasing the pool of prenylated Ras proteins prompted us to investigate the effect of fetal hyperinsulinemia on the activitiy of farnesyltransferase (FTase) and the amounts of farnesylated p21 Ras in fetal tissues in the ovine experimental model. Induction of fetal hyperinsulinemia by direct infusion of insulin into the fetus and by either fetal or maternal infusions of glucose resulted in significant increases in the activity of FTase and the amounts of farnesylated p21 Ras in fetal liver, skeletal muscle, fat, and white blood cells. An additional infusion of somatostatin into hyperglycemic fetuses blocked fetal hyperinsulinemia and completely prevented these increases, specifying insulin as the causative factor. We conclude that the ability of fetal hyperinsulinemia to increase the size of the pool of farnesylated p21 Ras may prime fetal tissues to the action of other growth factors and thereby constitute one mechanism by which fetal hyperinsulinemia could induce macrosomia in diabetic pregnancies.

Heart disease in Asian people with diabetes

AbstractType 2 diabetes is increased up to four‐fold in middle‐aged and older Indo‐Asian people, and associated with increased coronary heart disease (CHD), and premature morbidity and mortality. Seventy‐seven percent of deaths in Indo‐Asian people with diabetes were caused by cardiovascular disease compared with 46% European deaths, in the Southall Diabetes Survey. The Indo‐Asian communities have an increased inherited lipoprotein (a) level compared to white Europeans, whilst migration results in the unmasking of a cluster of cardiovascular risk factors incorporating central obesity, hyperinsulinaemia. type‐2 diabetes and dyslipidaemia. Conventional cardiovascular risk factors are important, and in India, current smoking, hypertension and overt diabetes mellitus are the strongest predictors of a first actute myocardial infarction (AMI). Hyperlipidaemia may have a less important causal role in an Indian setting, but the situation is likely to be different in a migratory Indo‐Asian population. Unfortunately there is a lamentable lack of intervention studies in Indo‐Asian diabetic people with CHD, and currently the evidence base from other populations needs to be extrapolated. The six month mortality in Indo‐Asian people post AMI is double the white European population, despite similar use of aspirin, thrombolysis and beta blockade. and is primarily due to the increase prevalence of diabetes. This stresses the importance of active treatment of all cardiovascular risk factors, including hyperglycaemia in the peri‐infarct period. Active health promotion addressing physical activity and modifying dietaary intake is crucial in the Indo‐Asian communities, and campaigns such as Project Dil in Leicestershire have incorporated both primary and secondary prevention. The extrapolated evidence base would suggest that early use of angiotensin‐converting enzyme inhibition, statin and/or fibrate therapy, and insulin therapy may all benefit Indo‐Asian diabetic people with CHD, while metformin should be the first‐line oral hypoglycaemic agent in most Indo‐Asian diabetic people without CHD. Copyright © 2001 John Wiley &amp; Sons, Ltd.

Evaluation of growth and hormonal status in patients referred to the International Fanconi Anemia Registry.

1) To determine the extent of short stature in patients with Fanconi anemia (FA); 2) to determine the extent and nature of endocrinopathy in FA; 3) to assess the impact on height of any endocrinopathies in these patients; and 4) to study the correlation, if any, between height, endocrinopathy, and FA complementation group. Fifty-four patients with FA, 30 males and 24 females from 47 unrelated families, were prospectively evaluated in a Pediatric Clinical Research Center. The patients ranged in age from 0.1-31.9 years, with the mean age at assessment 8.6 years. Endocrine abnormalities were found in 44 of the 54 FA patients tested (81%), including short stature, growth hormone (GH) insufficiency, hypothyroidism, glucose intolerance, hyperinsulinism, and/or overt diabetes mellitus. Twenty-one of 48 (44%) participants had a subnormal response to GH stimulation; 19 of 53 (36%) had overt or compensated hypothyroidism, while 8 of 40 participants had reduced thyroid-hormone binding. Two patients were diabetic at the time of study; impaired glucose tolerance was found in 8 of 40 patients (25%), but most surprisingly, hyperinsulinemia was present in 28 of 39 (72%) participants tested. Significantly, spontaneous overnight GH secretion was abnormal in all patients tested (n = 13). In addition, participants demonstrated a tendency toward primary hypothyroidism with serum tetraiodothyronine levels at the lower range of normal, while also having thyrotropin (thyroid-stimulating hormone) levels at the high end of normal. Sixteen patients were assigned to FA complementation group A, (FA-A), 12 to FA-C, and 5 to FA-G; 10 of the 12 participants in FA-C were homozygous for a mutation in the intron-4 donor splice site of the FANCC gene. Patients in groups FA-A and FA-G were relatively taller than the group as a whole (but still below the mean for the general population), whereas those in FA-C had a significantly reduced height for age. GH response to stimulation testing was most consistently normal in participants from FA-G, but this did not reach statistical significance. The tendency toward hypothyroidism was more pronounced in participants belonging to complementation groups FA-C and FA-G, whereas insulin resistance was most evident in patients in FA-G, and least evident in those in FA-C. Short stature was a very common finding among the patients with a mean height >2 standard deviations below the reference mean (standard deviation score: -2.35 +/- 0.28). Patients with subnormal GH response and those with overt or compensated hypothyroidism were shorter than the group with no endocrinopathies. The heights of those participants with glucose or insulin abnormalities were less severely affected than those of normoglycemic, normoinsulinemic participants, although all were significantly below the normal mean. The mean height standard deviation score of patients with entirely normal endocrine function was also >2 standard deviations below the normal mean, demonstrating that short stature is an inherent feature of FA. Endocrinopathies are a common feature of FA, primarily manifesting as glucose/insulin abnormalities, GH insufficiency, and hypothyroidism. Although short stature is a well-recognized feature of FA, 23 patients (43%) were within 2 standard deviations, and 5 of these (9% of the total) were actually above the mean for height for the general population. Those patients with endocrine dysfunction are more likely to have short stature. These data indicate that short stature is an integral feature of FA, but that superimposed endocrinopathies further impact on growth. The demonstration of abnormal endogenous GH secretion may demonstrate an underlying hypothalamic-pituitary dysfunction that results in poor growth.

Disease-associated autoantibodies as predictive markers of type 1 diabetes mellitus in siblings of affected children.

The long latent preclinical period of type 1 diabetes mellitus (DM) makes it possible to identify individuals at increased risk for clinical DM before the beta-cell destructive process has reached the point of no return. A series of reports on the predictive value of DM-associated autoantibodies are available in first-degree relatives of patients with type 1 DM, but only a few of these studies target exclusively siblings and young siblings of affected children. When planning screening of siblings for DM risk, their age needs to be considered, as predictive characteristics of autoantibodies seem to vary in different age groups. Autoimmunity may be initiated early in life and therefore early screening for signs of beta-cell autoimmunity is crucial to avoid missing young children en route to overt DM and to be able to start intervention, when clinically applicable preventive modalities become available, before the disease process has advanced too far. Young age, positivity for at least two autoantibodies, high levels of autoantibodies and low first phase insulin response are highly predictive for progression to clinical disease in initially unaffected siblings of children with type 1 DM.

Prevalence of diabetes in acromegaly and Cushing syndrome

In a retrospective study glucose metabolism was investigated in 206 patients with acromegaly and 131 patients with Cushing's disease. 40.5% of the patients with hypersomatotropism and 32.0% of the patients with hypercortisolism suffered from overt diabetes mellitus. Impaired glucose tolerance was present prior to therapy in 28.2% and 30.6% of the patients, respectively. In acromegaly the incidence of overt diabetes mellitus was higher in women than in men, but no difference existed in the distribution of impaired glucose tolerance between both sexes. No correlation was found between growth hormone levels and occurrence of diabetes. In acromegaly and Cushing's disease overt diabetes increased with advanced age. Diabetes mellitus occurred independently from the etiology of hypercortisolism.

Lipoproteins, diabeto-genicity, age and risk of diabetes mellitus death

ObjectiveTo examine the clinical significance of a specific relationship between very low density lipoprotein (VLDL) and high density lipoprotein (HDL), namely their differential, in relation to Type 2 non-insulin dependent diabetes mellitus (NIDDM). MethodsThe study subjects were 300 female and 300 male patients of doctors in city and rural New South Wales referred for lipid studies. Their clinical notes suggested a relationship of VLDL-HDL to diabetes mellitus (DM) and it was therefore hypothesised that this expression is a functional measure of diabeto-genicity. ResultsBy incorporation of age, a calculated measure of risk of overt DM and consequent death can be derived. This is confirmed by comparing the age incidence of this risk function with the age incidence of death attributed to DM in the Australian population to give a simple linear correlation. The principal conclusion is drawn from a mathematical model of the population incidence of DM in terms of VLDL, HDL and age. ConclusionFrom this model springs the inference that NIDDM is a cumulative dyslipidaemia-over-time process. If this inference is correct, NIDDM can properly be viewed as a societal disease of which all run a measurable risk that increases with age and from which all will die in the long term who do not die sooner from another cause. ImplicationsThe implications for public health are the ability to identify the individuals at raised risk before DM becomes symptomatic by lipoprotein screening, and the ability to lower risk of DM over the whole population by preventive measures with increased longevity for all.

Effect of Growth Hormone and Oxandrolone Treatment on Glucose Metabolism in Turner Syndrome

In 18 girls with Turner syndrome, glucose tolerance was studied before treatment and after 6 and 24 months of growth-promoting treatment with recombinant human growth hormone (24 IU/m²/week; 8 mg/m²/week) and oxandrolone (0.06 mg/kg/day), as well as after termination of the treatment. One girl developed an overt non-ketotic diabetes mellitus 50 months after termination of treatment. The results of the remaining 17 girls in whom the effect of treatment on glucose metabolism was reversible are presented as a group. Their median age at the beginning of the treatment was 10.4 years (range 6.9–15.9), and 15.0 years (range 12.1–19.9) at the final assessment. There was a moderate, but not significant rise in fasting glucose throughout the course of the longitudinal study. At oral glucose tolerance testing (oGTT), the area under the curve for glucose rose significantly (p = 0.013) during the period of treatment and returned to the basic value thereafter. Fasting insulin and especially the integrated insulin values (AUCi; area under the curve for insulin) during oGTT increased continuously during treatment, declined after termination of treatment but were still significantly (p = 0.04) higher than before treatment. Considering the fact that in untreated girls with Turner syndrome the fasting insulin and the AUCi increase with age, one can conclude that the insulinaemia returned to age-specific norm after termination of treatment. Thus the effect of a combined growth hormone and oxandrolone growth-promoting treatment on glucose metabolism was fully reversible in these 17 girls with Turner syndrome.