Association between continued metformin use during hospital admission and hospital-acquired complications.

AIMS: The safety of continuing metformin during a hospital admission has not been robustly demonstrated. We evaluated the association of continuing metformin in hospital with the risk for a hospital-acquired complication (HAC). METHODS: This is a retrospective observational study of patients admitted to a medical or surgical ward. We considered those with diabetes who continued metformin (DM/MET group), those who discontinued metformin upon admission (DM/MET-STOP), and those with diabetes not on metformin just prior to and during admission (DM/NoMET). We prepared propensity score-matched (PSM) control groups from admitted patients without diabetes. The likelihood of a HAC was determined using a Kaplan-Meier survival analysis. A Cox proportional hazards model was employed to calculate the hazard ratio, adjusted for covariates. RESULTS: Of the 4446 (14%) patients with diabetes, 3331 (10%) were prescribed metformin on admission, and it was continued in 2557 patients. HAC occurred in 5.5% of DM/MET group and 6.4% of the PSM control group. Continuation of metformin was associated with a lower likelihood of HAC, adjusted hazard ratio 0.85 (95% CI 0.69, 1.04), p = 0.117 compared to a PSM-matched control group without diabetes. The DM/NoMET and DM/MET-STOP groups had an increased risk for HAC, adjusted HR 1.77 (1.44, 2.18), p < 0.001 and 2.57 (2.10, 3.13), p < 0.001, as compared to their respective PSM control groups. CONCLUSION: An individualized assessment to continue metformin during hospital admission was associated with a reduced likelihood of HAC, with the caveat that there was limited matching to non-diabetes controls. This finding warrants further exploration.

Decreased rates of hospital-acquired infection after introduction of an active surveillance, virtual glucose management system.

Addition of an active surveillance virtual glucose management (VGM) system to usual consultation-based diabetes inpatient care at our hospital was associated with a decrease in hospital-acquired infection from 8.7% (17/196) to 3.5% (6/172) with an adjusted odds ratio of 0.17 (95%CI: 0.05-0.61), and a reduction in hypoglycemic and hyperglycemic patient-stay days.

Significant risk of repeat adverse outcomes in recurrent gestational diabetes pregnancy: a retrospective cohort study.

BACKGROUND: The risk of adverse outcomes in recurrent GDM pregnancy has not been well documented, particularly in women who have already had an adverse outcome. The aim of this study was to compare the risk of recurrent adverse delivery outcome (ADO) or adverse neonatal outcome (ANO) between consecutive gestational diabetes (GDM) pregnancies. METHODS: In this retrospective study of 424 pairs of consecutive ("index" and "subsequent") GDM pregnancies, we compared the risk of ADO (instrumental delivery, emergency Caesarean section) and ANO (large for gestational age (LGA and small for gestational age (SGA)) in women with and without a history of adverse outcome in their index pregnancy. RESULTS: Subsequent pregnancies had higher rates of elective Caesarean (30.4% vs 17.0%, p < 0.001) and lower rates of instrumental delivery (5% vs 13.9%, p < 0.001), emergency Caesarean (7.1% vs 16.3%, p < 0.001) and vaginal delivery (62.3% vs 66.3%, p = 0.01). Index pregnancy adverse outcome was associated with a higher risk of repeat outcome: RR 3.09 (95%CI:1.30,7.34) for instrumental delivery, RR 2.20 (95%CI:1.06,4.61) for emergency Caesarean, RR 4.55 (95%CI:3.03,6.82) for LGA, and RR 5.01 (95%CI:2.73,9.22) for SGA). The greatest risk factor for subsequent LGA (RR 3.13 (95%CI:2.20,4.47)) or SGA (RR 4.71 (95%CI:2.66,8.36)) was having that outcome in the index pregnancy. CONCLUSION: A history of an adverse outcome is a powerful predictor of the same outcome in the subsequent GDM pregnancy. These high-risk women may warrant more directed management over routine GDM care such as altered glucose targets or increased frequency of ultrasound assessment.

A proinflammatory CD4+ T cell phenotype in gestational diabetes mellitus.

AIMS/HYPOTHESIS: Numerous adaptations of the maternal immune system are necessary during pregnancy to maintain immunological tolerance to the semi-allogeneic fetus. Several complications of pregnancy have been associated with dysregulation of these adaptive mechanisms. While gestational diabetes mellitus (GDM) has been associated with upregulation of circulating inflammatory factors linked to innate immunity, polarisation of the adaptive immune system has not been extensively characterised in this condition. We aimed to characterise pro- and anti-inflammatory CD4+ (T helper [Th]) T cell subsets in women with GDM vs women without GDM (of similar BMI), during and after pregnancy, and examine the relationship between CD4+ subsets and severity of GDM. METHODS: This is a prospective longitudinal case-control study of 55 women with GDM (cases) and 65 women without GDM (controls) at a tertiary maternity hospital. Quantification of proinflammatory (Th17, Th17.1, Th1) and anti-inflammatory (regulatory T cell [Treg]) CD4+ T cell subsets was performed on peripheral blood at 37 weeks gestation and 7 weeks postpartum, and correlated with clinical characteristics and measures of blood glucose. RESULTS: Women with GDM had a significantly greater percentage of Th17 (median 2.49% [interquartile range 1.62-4.60] vs 1.85% [1.13-2.98], p = 0.012) and Th17.1 (3.06% [1.30-4.33] vs 1.55% [0.65-3.13], p = 0.006) cells compared with the control group of women without GDM. Women with GDM also had higher proinflammatory cell ratios (Th17:Treg, Th17.1:Treg and Th1:Treg) in pregnancy compared with the control group of women without GDM. In the control group, there was a statistically significant independent association between 1 h glucose levels in the GTT and Th17 cell percentages, and also between 2 h glucose levels and percentage of Th17 cells. The percentage of Th17 cells and the Th17:Treg ratio declined significantly after delivery in women with GDM, whereas this was not the case with the control group of women. Nevertheless, a milder inflammatory phenotype persisted after delivery (higher Th17:Treg ratio) in women with GDM vs women without. CONCLUSIONS/INTERPRETATION: Dysregulation of adaptive immunity supports a novel paradigm of GDM that extends beyond hyperglycaemia and altered innate immunity.

Maternal Diabetes, Large-for-Gestational-Age Births, and First Trimester Pregnancy-Associated Plasma Protein-A.

CONTEXT: Maternal pregnancy-associated plasma protein-A (PAPP-A) is measured at nuchal translucency scanning to assess the risk of fetal chromosomal disorders. OBJECTIVE: The aim of this study was to examine whether PAPP-A might also be a predictor of gestational diabetes (GDM), type 2 diabetes (T2D), or large-for-gestational-age (LGA) births. DESIGN: PAPP-A levels were measured in serum from 1664 women at their 10-14-week nuchal translucency scan at a tertiary referral hospital. Maternal diabetes was categorized as T2D, "early GDM" (GDM diagnosed < 22 wk), and "late GDM" (GDM diagnosed ≥ 22 wk). The relationship between PAPP-A multiples of the median (MoM), maternal diabetes, and LGA was examined with multivariate regression models. RESULTS: PAPP-A MoM was significantly lower in women with T2D and women who developed GDM than in nondiabetic women. PAPP-A MoM was 41.3% lower in T2D, 22.6% lower in early GDM, and 8.6% lower in late GDM. Women in the lowest quartile of PAPP-A MoM were 2.7 times more likely to have early GDM (odds ratio [OR], 2.74; 95% confidence interval [CI], 1.2-6.1) compared with the highest quartile. Birth weight had a positive linear association with PAPP-A MoM. Women in the highest PAPP-A MoM quartile were twice as likely to have an LGA baby (OR, 2.2; 95% CI, 1.39-3.46; P = .0007). CONCLUSIONS: Routinely tested first-trimester PAPP-A is a novel biomarker for maternal diabetes and LGA. PAPP-A decreased with increasing severity of maternal diabetes. Although this cannot infer causality, low PAPP-A may help identify women at risk of GDM, and high PAPP-A may help identify pregnancies at risk of LGA.

Increase in body mass index during pregnancy and risk of gestational diabetes.

We recorded gestational weight gain (GWG) and change in body mass index (BMI) at 28 weeks gestation in 343 vs. 339 women with and without gestational diabetes (GDM). GDM was associated with a greater increment in BMI, but not with increased GWG in kilograms.

Deletion of ARNT (Aryl hydrocarbon receptor nuclear translocator) in ß-cells causes islet transplant failure with impaired ß-cell function.

BACKGROUND: Replacing ß-cells by islet-transplantation can cure type 1 diabetes, but up to 70% of ß-cells die within 10 days of transplantation. ARNT (Aryl hydrocarbon Receptor Nuclear Translocator) regulates ß-cell function, and potentially survival. Lack of ARNT impairs the ability of ß-cells to respond to physiological stress and potentiates the onset of diabetes, but the exact role of ARNT in graft outcome is unknown. AIM: To investigate the effect of ß-cell deletion of ARNT on graft outcomes. METHODS: Islets were isolated from donor mice which had ß-cell specific ARNT-deletion (ß-ARNT) or littermate floxed controls. The islets were transplanted into diabetic SCID recipients in ratios of (a) 3 donors: 1 recipient, (b) 1 donor: 1 recipient or (c) ½ of the islets from 1 donor: 1 recipient. After 28 days, the kidney containing the graft was removed (nephrectomy) to exclude regeneration of the endogenous pancreas. RESULTS: In the supra-physiological-mass model (3:1), both groups achieved reasonable glycaemia, with slightly higher levels in ß-ARNT-recipients. In adequate-mass model (1:1), ß-ARNT recipients had poor glucose control versus floxed-control recipients and versus the ß-ARNT donors. In the low-ß-cell-mass model (½:1) ß-ARNT transplants completely failed, whereas controls had good outcomes. Unexpectedly, there was no difference in the graft insulin content or ß-cell mass between groups indicating that the defect was not due to early altered ß-cell survival. CONCLUSION: Outcomes for islet transplants lacking ß-cell ARNT were poor, unless markedly supra-physiological masses of islets were transplanted. In the 1:1 transplant model, there was no difference in ß-cell volume. This is surprising because transplants of islets lacking one of the ARNT-partners HIF-1α have increased apoptosis and decreased islet volume. ARNT also partners HIF-2α and AhR (aryl hydrocarbon receptor) to form active transcriptional complexes, and further work to understand the roles of HIF-2α and AhR in transplant outcomes is needed.

Beta-cell ARNT is required for normal glucose tolerance in murine pregnancy.

AIMS: Insulin secretion increases in normal pregnancy to meet increasing demands. Inability to increase beta-cell function results in gestational diabetes mellitus (GDM). We have previously shown that the expression of the transcription factor ARNT (Aryl-hydrocarbon Receptor Nuclear Translocator) is reduced in the islets of humans with type 2 diabetes. Mice with a beta-cell specific deletion of ARNT (ß-ARNT mice) have impaired glucose tolerance secondary to defective insulin secretion. We hypothesised that ARNT is required to increase beta-cell function during pregnancy, and that ß-ARNT mice would be unable to compensate for the beta-cell stress of pregnancy. The aims of this study were to investigate the mechanisms of ARNT regulation of beta-cell function and glucose tolerance in pregnancy. METHODS: ß-ARNT females were mated with floxed control (FC) males and FC females with ß-ARNT males. RESULTS: During pregnancy, ß-ARNT mice had a marked deterioration in glucose tolerance secondary to defective insulin secretion. There was impaired beta-cell proliferation in late pregnancy, associated with decreased protein and mRNA levels of the islet cell-cycle regulator cyclinD2. There was also reduced expression of Irs2 and G6PI. In contrast, in control mice, pregnancy was associated with a 2.1-fold increase in ARNT protein and a 1.6-fold increase in cyclinD2 protein, and with increased beta-cell proliferation. CONCLUSIONS: Islet ARNT increases in normal murine pregnancy and beta-cell ARNT is required for cyclinD2 induction and increased beta-cell proliferation in pregnancy.

Hypoxia-inducible factor-1α (HIF-1α) potentiates ß-cell survival after islet transplantation of human and mouse islets.

A high proportion of ß-cells die within days of islet transplantation. Reports suggest that induction of hypoxia-inducible factor-1α (HIF-1α) predicts adverse transplant outcomes. We hypothesized that this was a compensatory response and that HIF-1α protects ß-cells during transplantation. Transplants were performed using human islets or murine ß-cell-specific HIF-1α-null (ß-HIF-1α-null) islets with or without treatment with deferoxamine (DFO) to increase HIF-1α. ß-HIF-1α-null transplants had poor outcomes, demonstrating that lack of HIF-1α impaired transplant efficiency. Increasing HIF-1α improved outcomes for mouse and human islets. No effect was seen in ß-HIF-1α-null islets. The mechanism was decreased apoptosis, resulting in increased ß-cell mass posttransplantation. These findings show that HIF-1α is a protective factor and is required for successful islet transplant outcomes. Iron chelation with DFO markedly improved transplant success in a HIF-1α-dependent manner, thus demonstrating the mechanism of action. DFO, approved for human use, may have a therapeutic role in the setting of human islet transplantation.

Hypoxia-inducible factor-1alpha regulates beta cell function in mouse and human islets.

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1alpha protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1alpha is required for normal beta cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D). Here we show that HIF-1alpha protein is present at low levels in mouse and human normoxic beta cells and islets. Decreased levels of HIF-1alpha impaired glucose-stimulated ATP generation and beta cell function. C57BL/6 mice with beta cell-specific Hif1a disruption (referred to herein as beta-Hif1a-null mice) exhibited glucose intolerance, beta cell dysfunction, and developed severe glucose intolerance on a high-fat diet. Increasing HIF-1alpha levels by inhibiting its degradation through iron chelation markedly improved insulin secretion and glucose tolerance in control mice fed a high-fat diet but not in beta-Hif1a-null mice. Increasing HIF-1alpha levels markedly increased expression of ARNT and other genes in human T2D islets and improved their function. Further analysis indicated that HIF-1alpha was bound to the Arnt promoter in a mouse beta cell line, suggesting direct regulation. Taken together, these findings suggest an important role for HIF-1alpha in beta cell reserve and regulation of ARNT expression and demonstrate that HIF-1alpha is a potential therapeutic target for the beta cell dysfunction of T2D.