Ethnicity influences cardiovascular outcomes and complications in patients with type 2 diabetes.

AIM: To determine whether cardiovascular outcomes in type 2 diabetes (T2D) differ according to ethnicity, and whether ethnicity influences the effect of gender on these outcomes in Caucasians, East-Southeast-Asians, Middle-Easterners, South-Asians and Pacific-Islanders. METHODS: We compared demographics, HbA1c, lipid profile, renal function markers, and prevalence of macrovascular and microvascular complications between ethnic groups. Cross-sectional data was prospectively collected from 204 consecutive patients at Westmead Hospital's T2D clinic from April-October 2015. Univariate analysis was performed using chi-squared test for categorical data, and Mann-Whitney-U or Kruskal-Wallis test for continuous data. RESULTS: Compared to Caucasians, South-Asians were diagnosed younger, were currently younger, had lower body-mass-index (BMI) and better renal function but higher rates of non-ST-elevation myocardial infarction (STEMI, 21.7% versus 3.5%, p<0.05). East-Southeast-Asians had lower BMI but more nephropathy than Caucasians (59% versus 39%, p<0.05). East-Southeast-Asian males had fewer CVD than Caucasians, but this protection was absent in East-Southeast-Asian females. Middle-Easterners had more non-STEMI than Caucasians (5.3% vs 3.5%, p<0.05). Middle-Eastern females were not at lower CVD risk than males. Caucasians had most PVD (20% versus 6%, p<0.05). CONCLUSIONS: Ethnicity influences rates of diabetes-related complications. Female CVD protection is altered in some groups. Ethnicity should be considered in assessing CVD and complications risk.

1,25-Dihydroxycholecalciferol (calcitriol) modifies uptake and release of 25-hydroxycholecalciferol in skeletal muscle cells in culture.

The major circulating metabolite of vitamin D3, 25-hydroxycholecalciferol [25(OH)D], has a remarkably long half-life in blood for a (seco)steroid. Data from our studies and others are consistent with the hypothesis that there is a role for skeletal muscle in the maintenance of vitamin D status. Muscle cells internalise vitamin D-binding protein (DBP) from the circulation by means of a megalin/cubilin plasma membrane transport mechanism. The internalised DBP molecules then bind to actin and thus provide an intracellular array of high affinity binding sites for its specific ligand, 25(OH)D. There is evidence that the residence time for DBP in muscle cells is short and that it undergoes proteolytic degradation, releasing bound 25(OH)D. The processes of internalisation of DBP and its intracellular residence time, bound to actin, appear to be regulated. To explore whether 1,25-dihydroxycholecalciferol (calcitriol) has any effect on this process, cell cultures of myotubes and primary skeletal muscle fibers were incubated in a medium containing 10-10M calcitriol but with no added DBP. After 3h pre-incubation with calcitriol, the net uptake of 25(OH)D by these calcitriol-treated cells over a further 4h was significantly greater than that in vehicle-treated control cells. This was accompanied by a significant increase in intracellular DBP protein. However, after 16h of pre-incubation with calcitriol, the muscle cells showed a significantly depressed ability to accumulate 25(OH)D compared to control cells over a further 4 or 16hours. These effects of pre-incubation with calcitriol were abolished in fibers from VDR-knockout mice. The effect was also abolished by the addition of 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), which inhibits chloride channel opening. Incubation of C2 myotubes with calcitriol also significantly reduced retention of previously accumulated 25(OH)D after 4 or 8h. It is concluded from these in vitro studies that calcitriol can modify the DBP-dependent uptake and release of 25(OH)D by skeletal muscle cells in a manner that suggests some inducible change in the function of these cells.

Multicenter Australian trial of islet transplantation: improving accessibility and outcomes.

Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥ 12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.

First phase insulin secretion and type 2 diabetes.

Type 2 diabetes (T2D) is a metabolic disorder characterised by the inability of ß-cells to secrete enough insulin to maintain glucose homeostasis. Pancreatic ß-cells secrete insulin in a biphasic manner, first and second phase insulin secretion, and loss of first phase insulin secretion is an independent predictor of T2D onset. Restoration of first phase insulin secretion has been shown to improve blood glucose in T2D by suppressing hepatic glucose production and priming insulin sensitive tissue to more readily take up glucose and has thus prompted numerous studies into its regulation. First phase insulin secretion is initiated primarily by the classical triggering pathway, a complex system comprised of multiple stimulatory signals. Recent studies have identified a number of novel regulatory factors that are crucial for first phase insulin secretion and glucose homeostasis. These include, among others, hypoxia inducible factor 1α, von Hippel-Lindau, factor inhibiting HIF, nicotinamide phospho-ribosyl-transferase, and the sirtuin family. This review will outline how first phase insulin secretion is initiated and detail some of the recent findings in its regulation.

Synergistic effects of genetic beta cell dysfunction and maternal glucose intolerance on offspring metabolic phenotype in mice.

AIMS/HYPOTHESIS: Diabetes in pregnancy is linked to development of obesity in the offspring, but the mechanisms are not fully understood. Gestational diabetes mellitus (GDM) occurs when beta cells are unable to compensate for the normal insulin resistance of late pregnancy. In this study, we used a murine model of beta cell dysfunction to examine the effects of maternal GDM on phenotype in male offspring with and without an inherited predisposition for beta cell dysfunction. METHODS: Beta cell-specific aryl-hydrocarbon receptor nuclear translocator-null (ßArnt) mice develop GDM from beta cell dysfunction. ßArnt and control female mice were used to induce GDM and non-diabetic pregnancies, respectively. RESULTS: Offspring from GDM pregnancies became spontaneously obese on a normal-chow diet. They were heavier than offspring from non-diabetic pregnancies, with increased body fat. Respiratory exchange ratio (RER) was higher, indicating decreased capacity to switch to lipid oxidation. Metabolic rate in GDM offspring was decreased prior to onset of obesity. The phenotype was more pronounced in ßArnt GDM offspring than in GDM offspring of control genotype, demonstrating an interaction between genotype and pregnancy exposure. ßArnt GDM offspring had increased hypothalamic neuropeptide Y (Npy) and decreased pro-opiomelanocortin (Pomc) expression. Weight, body fat, insulin sensitivity and RER in all mice, and hypothalamic Npy in ßArnt mice were significantly correlated with AUC of maternal late pregnancy glucose tolerance tests (p < 0.01), but not with litter size, maternal weight, triacylglycerol or pre-pregnancy glycaemia. CONCLUSIONS/INTERPRETATION: In ßArnt mice, exposure to GDM and inheritance of genetic beta cell dysfunction had additive effects on male offspring obesity; severity of the offspring phenotype correlated with maternal glycaemia.

Intravenous pamidronate in the treatment and prevention of osteoporosis.

BACKGROUND: Potent oral bisphosphonates are the mainstay of therapy for osteoporosis. However, there are patients who cannot have oral bisphosphonates (e.g. because of gastrointestinal side-effects). Therefore, we wanted to examine the effects of intermittent i.v. pamidronate (APD) on bone mineral density (BMD) in patients who needed bisphosphonate therapy but could not have oral bisphosphonates. AIM: To assess BMD before and after intermittent i.v. APD in patients requiring a bisphosphonate either for the prevention of osteoporosis on concurrent steroid therapy or for the treatment of osteoporosis. METHODS: This was a retrospective audit of 84 consecutive patients at risk of fractures commencing APD between October 1997 and May 2000. Patients were treated with intermittent i.v. APD. BMD as measured by dual-energy X-ray absorptiometry before and after APD was the main outcome. RESULTS: The mean length of treatment and mean total APD dose were 16.8 +/- 7.0 months and 186.1 +/- 79.5 mg respectively. The reasons for using APD were failure to qualify for oral bisphosphonates on the pharmaceutical benefits scheme due to lack of documented minimal trauma fractures (58%), symptomatic gastro--oesophageal disease (20%), intolerance of oral bisphosphonates (18%) and lack of efficacy of calcitriol (4%). Mean baseline T-score at lumbar (L) 2-4 spine and femoral neck were -1.54 +/- 1.22 and - 2.87 +/- 1.19, respectively. From baseline to after APD treatment, there was a significant increase in L2-4 BMD (0.883 +/- 0.175 vs 0.912 +/- 0.176 g/cm(2), P < 0.001, mean increase +3.5%), in femoral neck BMD (0.667 +/- 0.137 vs 0.680 +/- 0.134 g/cm(2), P= 0.001, mean increase +2.1%) and in trochanteric BMD (0.549 +/- 0.129 vs 0.566 +/- 0.132 g/cm(2), P < 0.001, mean increase +3.1%). One-third of the patients were on oral glucocorticoids at the time of the present study and they had a similar increase in BMD compared to patients not on gluco-corticoids. Mild side-effects occurred in seven patients, none of whom discontinued treatment. CONCLUSION: Intermittent APD increases BMD and may be a suitable alternative for patients who cannot have oral bisphosphonates.

Effects of ethnicity on glucose tolerance, insulin resistance and beta cell function in 223 women with an abnormal glucose challenge test during pregnancy.

This study was conducted to investigate body-mass-index (BMI), insulin resistance and beta cell function in a group of pregnant women. Two hundred and twenty-three consecutive women with an abnormal 50 g glucose challenge test in the third trimester were studied. All underwent oral glucose tolerance testing; 97 had a 100 g test and 126 a 75 g test. Fasting insulin was measured. Insulin resistance and beta cell function were calculated using the homeostasis model. Among the 136 Caucasian, 60 Asian, 11 Indian and 16 Arabic women studied, there were no age differences. Arabic women had higher parity (p < 0.05). Asian women had lower BMI than Caucasian (p < 0.001), Indian (p < 0.01), and Arabic women (p < 0.01). Women with gestational diabetes had higher insulin resistance than women with normal glucose tolerance (2.9+/-4.0 vs. 2.3 +/- 2.5 p = 0.025). Women with gestational diabetes tended to have lower beta cell function 199 +/- 203 vs. 247 +/-380 p = 0.08). Asian women had higher glucose levels than Caucasian women after 50 g challenge (8.9 +/- 2.1 mmol/1 vs. 8.6 +/- 1.6; p = 0.034). Asian women were more likely to have gestational diabetes than Caucasian women (31.7% vs. 14%; p = 0.02). Fasting glucose and insulin were comparable in Asian and Caucasian women. Mean insulin resistance and beta cell function in Asian and Caucasian women were not significantly different. We concluded that Asian women had lower BMI than Caucasian women. Women with gestational diabetes were more insulin resistant. Insulin resistance and beta cell function in Asian and Caucasian women are similar. Gestational diabetes in Asian women is of similar aetiology to that seen in Caucasian women, but occurs at a lower BMI.

Serum chromium does not predict glucose tolerance in late pregnancy.

BACKGROUND: Chromium is an essential element in human nutrition. Serum concentrations of chromium are not well characterized during pregnancy or in gestational diabetes mellitus. OBJECTIVE: The objective of this study was to determine whether low plasma chromium concentrations (< or =3 nmol/L) are associated with altered glucose, insulin, or lipid concentrations during pregnancy. DESIGN: The study was conducted prospectively and took place at the medical obstetric clinic of a tertiary referral hospital. Seventy-nine women with abnormal results of a 50-g glucose challenge test in the third trimester of pregnancy were studied. All women had a formal 75-g oral-glucose-tolerance test, and fasting insulin, lipid, and chromium concentrations were determined. Chromium was measured by graphite furnace atomic absorption spectrometry. RESULTS: The median chromium concentration was 2 nmol/L (95% CI: 0, 12). There were no significant differences in age, plasma glucose, insulin, lipids, calculated insulin resistance, or calculated ss cell function between women with normal and those with abnormal (< or =3 nmol/L) chromium concentrations. CONCLUSIONS: Plasma chromium during pregnancy does not correlate with glucose intolerance, insulin resistance, or serum lipids. Plasma chromium concentrations may not accurately reflect tissue stores of chromium. Several trials showed a beneficial effect of chromium supplementation on glucose tolerance, insulin, and lipids. A method for assessing body chromium stores is required to allow further study.

Outcome of pregnancies complicated by pre-gestational diabetes mellitus.

Pregestational diabetes mellitus (DM) is associated with adverse fetal and maternal outcomes. Studies suggest that optimal control of diabetes before and during pregnancy minimises these risks. There are few recent reviews of outcomes of pregnancies complicated by DM in Australia. Ninety-three pregnancies in women with DM at our hospital since 1989 were identified. We collected data for maternal age, type of diabetes, duration of therapy, complications of diabetes, maternal complications of pregnancy and fetal outcomes including malformations. The rate of pregnancy planning with optimal glycaemic control at conception was low in our population, particularly in patients with Type 1 diabetes. Women who smoked had worse glycaemic control, and a higher rate of miscarriage. There was a high rate of Caesarean section, particularly in those women with Type 1 diabetes (77.4%). The rate of Caesarean section was lower in planned pregnancies. There were no perinatal deaths. The number of neonates with major congenital anomalies was high (13%) in the Type 1 population. It is important to increase the rates of prepregnancy planning and to optimise glycaemic control before pregnancy. In many cases there has been a long interval between diagnosis and pregnancy, so all women with diabetes should receive counselling at frequent intervals about pregnancy and the importance of planning. Women who planned their pregnancies had improved outcomes, with decreased rate of Caesarean section, better glycaemic control and better neonatal Apgar scores. Women with diabetes should not smoke during pregnancy because of the increased risk of miscarriage and poorer glycaemic control.

Prevalence of positive anti-neutrophil cytoplasmic antibody (ANCA) in patients receiving anti-thyroid medication.

OBJECTIVE: Vasculitis is a rare complication of anti-thyroid medications. There are 32 cases of anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis in association with anti-thyroid medication reported in the English literature. The objectives of this study were to assess the frequency of positive ANCA in patients on long-term anti-thyroid medication, and to follow patients prospectively from commencement of medication to determine whether they became ANCA-positive after therapy. DESIGN: Prospectively collected cross-sectional study of two groups of patients: (i) who had received long-term (>18 months) anti-thyroid medication, and (ii) newly diagnosed thyrotoxicosis before commencement of anti-thyroid medication attending clinic between 28 April 1998 and 30 September 1998. Data were collected for age, sex, ethnicity, underlying thyroid disease, medication and duration, and symptomatology. RESULTS: Eight of 30 patients on long-term anti-thyroid medication (26.7%) were ANCA-positive. All ANCA-positive patients were female, seven were taking propylthiouracil (PTU) at the time of testing. ANCA-positive patients had taken PTU for a mean +/- s.d. of 7.9+/-10.2 years, compared with 0.8+/-2.2 years in ANCA-negative patients (Mann-Whitney, P<0.0001). The ten patients with newly diagnosed thyrotoxicosis were ANCA-negative before commencement of carbimazole. One (10%) became ANCA-positive within 8 months of therapy. CONCLUSIONS: In our population, ANCA-positivity in association with long-term anti-thyroid medication is common (26.7%). One patient who was ANCA-negative prior to anti-thyroid therapy has become ANCA-positive. ANCA should be tested in patients receiving long-term anti-thyroid medications, and in patients with adverse reactions. As PTU is more commonly associated with vasculitis and positive ANCA, carbimazole may be the preferred medication for long-term use. Patients with positive ANCA should be followed, and considered for definitive anti-thyroid therapy, to allow cessation of medication. ANCA-positivity may resolve after cessation of anti-thyroid medication.

Iodine deficiency in ambulatory participants at a Sydney teaching hospital: is Australia truly iodine replete?

OBJECTIVE: To assess iodine status in four separate groups--pregnant women, postpartum women, patients with diabetes mellitus and volunteers. DESIGN AND SETTING: Prospective cross-sectional study at a tertiary referral hospital in Sydney. PARTICIPANTS: 81 pregnant women attending a "high risk" obstetric clinic; 26 of these same women who attended three months postpartum; 135 consecutive patients with diabetes mellitus attending the diabetes clinic for an annual complications screen; and 19 volunteers. There were no exclusion criteria. METHODS: Spot urine samples were obtained, and urinary iodine was measured by inductively coupled plasma mass spectrometer. OUTCOME MEASURES: Iodine status based on urinary iodine concentration categorised as normal (> 100 micrograms/L), mild deficiency (51-100 micrograms/L) and moderate to severe deficiency (< 50 micrograms/L). RESULTS: Moderate to severe iodine deficiency was found in 16 pregnant women (19.8%), five postpartum women (19.2%), 46 patients with diabetes (34.1%) and five volunteers (26.3%). Mild iodine deficiency was found in an additional 24 pregnant women (29.6%), nine postpartum women (34.6%), 51 patients with diabetes (37.8%) and 9 normal volunteers (47.4%). Median urinary iodine concentration was 104 micrograms/L in pregnant women, 79 micrograms/L in postpartum women, 65 micrograms/L in patients with diabetes mellitus and 64 micrograms/L in volunteers. CONCLUSIONS: The high frequency of iodine deficiency found in our participants suggests that dietary sources of iodine in this country may no longer be sufficient. Further population studies are required.