OBJECTIVEThis study tested the hypothesis that intensive treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial disproportionately produced adverse outcomes in patients with diabetes with a high hemoglobin glycation index (HGI = observed HbA1c − predicted HbA1c).RESEARCH DESIGN AND METHODSACCORD was a randomized controlled trial of 10,251 patients with type 2 diabetes assigned to standard or intensive treatment with HbA1c goals of 7.0% to 7.9% (53 to 63 mmol/mol) and less than 6% (42 mmol/mol), respectively. In this ancillary study, a linear regression equation (HbA1c = 0.009 × fasting plasma glucose [FPG] [mg/dL] + 6.8) was derived from 1,000 randomly extracted participants at baseline. Baseline FPG values were used to calculate predicted HbA1c and HGI for the remaining 9,125 participants. Kaplan-Meier and Cox regression were used to assess the effects of intensive treatment on outcomes in patients with a low, moderate, or high HGI.RESULTSIntensive treatment was associated with improved primary outcomes (composite of cardiovascular events) in the low (hazard ratio [HR] 0.75 [95% CI 0.59–0.95]) and moderate (HR 0.77 [95% CI 0.61–0.97]) HGI subgroups but not in the high HGI subgroup (HR 1.14 [95% CI 0.93–1.40]). Higher total mortality in intensively treated patients was confined to the high HGI subgroup (HR 1.41 [95% CI 1.10–1.80]). A high HGI was associated with a greater risk for hypoglycemia in the standard and intensive treatment groups.CONCLUSIONSHGI calculated at baseline identified subpopulations in ACCORD with harms or benefits from intensive glycemic control. HbA1c is not a one-size-fits-all indicator of blood glucose control, and taking this into account when making management decisions could improve diabetes care.

Microcystins are a family of cyclic peptides that are potent inhibitors of the protein phosphatase families PP1 and PP2A. Only three human proteins are thought to be able to mediate the hepatic uptake of microcystins (the organic anion-transporting polypeptides OATP1B1, OATP1B3, and OATP1A2), and the predominant hepatic expression of these transporters accounts for the liver-specific toxicity of microcystins. A significant obstacle in the study of microcystins as anticancer drugs is the requirement of specific transport proteins for cellular uptake. We report that OATP1B3 mRNA is up-regulated in non -small cell lung cancer tumors in comparison with normal control tissues. This finding led to the exploration of microcystins as potential anticancer agents. We have developed a HeLa cell model with functional OATP1B1 and OATP1B3 activity. Transiently transfected HeLa cells are over 1,000-fold more sensitive to microcystin LR than the vector-transfected control cells, showing that transporter expression imparts marked selectivity for microcystin cytotoxicity. In addition, microcystin analogues showed variable cytotoxicities in the OATP1B1-and OATP1B3-transfected cells, including two analogues with IC 50 values <1 nmol/L. Cytotoxicity of microcystin analogues seems to correlate to the inhibition of PP2A in these cells and induces rapid cell death as seen by chromatin condensation and cell fragmentation. These studies show that microcystin-induced phosphatase inhibition results in potent cytotoxicity when microcystin compounds can gain intracellular access and are a potent novel class of therapeutic agents for tumors expressing these uptake proteins. [Mol Cancer Ther 2007;6(2):587 -98]

It has been reported that two inducible prostaglandin synthetic enzymes, cylooxygenase-2 (COX-2) and microsomal PGE synthase, are over-expressed in non-small cell lung cancer (NSCLC). Using quantitative reverse transcription-polymerase chain reaction, we analyzed RNA levels of the key prostaglandin catabolic enzyme, NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH), in 19 pairs of NSCLC tumors and adjacent non-malignant tissue from the same patient. We found that 100% of tumor-tissue pairs showed at least a 2-fold decrease and 61% showed a 10-fold decrease. This suggests that the increased expression of COX-2 and PGE synthase in tumors may work in concert with the decreased expression of 15-PGDH to amplify an increase in tissue levels of proliferative PGE2. To further explore if 15-PGDH is related to tumorigenesis, athymic nude mice were injected with control A549 cells or cells transiently over-expressing wild-type or mutant 15-PGDH (Y151F). It was found that mice injected with control A549 cells or with cells expressing mutant enzyme produced tumors normally. However, mice injected with A549 cells expressing wild-type 15-PGDH had a significant decrease in tumor growth. Examining the effects of 15-PGDH expression on cellular changes in A549 cells, we found that over-expression of 15-PGDH induced apoptosis of A549 cells as evidenced by fragmentation of DNA, activation of pro-caspase 3, cleavage of poly(ADP-ribose) polymerase and decreased expression of Bcl-2. We also found that the expression of 15-PGDH was negatively related to that of pro-adhesive and invasive CD44. Furthermore, the expression of 15-PGDH was found to be stimulated by hyaluronidase. These results suggest that 15-PGDH may decrease the level of proliferative PGE2, induce apoptosis and function like a tumor suppressor.

ObjectiveThis study aimed to evaluate the association between metformin treatment and the risk of neurodegenerative disease (ND) among elderly adults with type 2 diabetes mellitus (T2DM).Design/Setting/ParticipantsThis retrospective longitudinal cohort study examined the effects of the length of metformin exposure on ND among elderly US veterans with T2DM and insulin treatment using the Veterans Affairs electronic medical record database.Primary and secondary outcome measuresThe primary clinical outcome was defined as diagnosis of ND including dementia, Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and mild cognitive impairment during the follow-up period. The secondary clinical outcomes were separately measured by AD, PD, HD, dementia and mild cognitive impairment.ResultAdjusted by propensity score weight, a total of 5528 patients (mean age, 63.2±10.9 years; male, 98%; white, 60%) with a median follow-up of 5.2 years were selected. Those with ND or other mental disorders at baseline or who were on insulin for less than two-thirds of the study period were excluded. The incidence rate of ND was 11.48 per 1000 person-years among patients with metformin treatment, compared with 25.45 per 1000 person-years for those without metformin. Compared with no metformin use, 2–4 years and >4 years of metformin exposure were significantly associated with lower risk of ND (adjusted HR (aHR)=0.62, 95% CI 0.45 to 0.85; aHR=0.19, 95% CI 0.12 to 0.31, respectively), while metformin exposure in the first 2 years showed no significant influence.ConclusionWe conclude that long-term metformin therapy (>2 years) was associated with lower incidence of ND among elderly veterans with T2DM. We need to conduct a study with more representative population and more robust method for causal inferences. Further investigation into the mechanism involved is needed along with randomised trials to confirm a potential neuroprotective effect of metformin.

The BRAVO risk engine for the US diabetes cohort provides an alternative to the UKPDS risk engine. It can be applied to assist clinical and policy decision making such as cost-effective resource allocation in USA.

HGI reflects the effects of inflammation on HbA1c in a nondiabetic population of U.S. adults and may be a marker of risk associated with inflammation independent of FPG, race, and obesity.

Purpose The use of technology to implement cost-effective health care management on a large scale may be an alternative for diabetes management but needs to be evaluated in controlled trials. This study assessed the utility and cost-effectiveness of an automated Diabetes Remote Monitoring and Management System (DRMS) in glycemic control versus usual care. Methods In this randomized, controlled study, patients with uncontrolled diabetes on insulin were randomized to use of the DRMS or usual care. Participants in both groups were followed up for 6 months and had 3 clinic visits at 0, 3, and 6 months. The DRMS used text messages or phone calls to remind patients to test their blood glucose and to report results via an automated system, with no human interaction unless a patient had severely high or low blood glucose. The DRMS made adjustments to insulin dose(s) based on validated algorithms. Participants reported medication adherence through the Morisky Medication Adherence Scale-8, and diabetes-specific quality of life through the diabetes Daily Quality of Life questionnaire. A cost-effectiveness analysis was conducted based on the estimated overall costs of DRMS and usual care. Findings A total of 98 patients were enrolled (59 [60%] female; mean age, 59 years); 87 participants (89%) completed follow-up. HbA1c was similar between the DRMS and control groups at 3 months (7.60% vs 8.10%) and at 6 months (8.10% vs 7.90%). Changes from baseline to 6 months were not statistically significant for self-reported medication adherence and diabetes-specific quality of life, with the exception of the Daily Quality of Life–Social/Vocational Concerns subscale score (P = 0.04). Implications An automated system like the DRMS may improve glycemic control to the same degree as usual clinic care and may significantly improve the social/vocational aspects of quality of life. Cost-effectiveness analysis found DRMS to be cost-effective when compared to usual care and suggests DRMS has a good scale of economy for program scale up. Further research is needed to determine how to sustain the benefits seen with the automated system over longer periods.

OBJECTIVETo evaluate the relationship between skin advanced glycation end products (sAGEs) with mean blood glucose (MBG), hemoglobin A1c (HbA1c), and MBG-independent, between-patient differences in HbA1c among children with type 1 diabetes.RESEARCH DESIGN AND METHODSChildren aged 5 to 20 years with type 1 diabetes of at least 1 year duration participated. At a clinic visit, sAGE was estimated noninvasively by measurement of skin intrinsic fluorescence (SIF). SIF data were adjusted to correct for variation in skin pigmentation. MBG-independent, between-patient differences in HbA1c were examined by statistically controlling HbA1c for MBG or alternatively by use of a hemoglobin glycation index (HGI). Results were similar whether HbA1c, MBG, and HGI were analyzed as single values from the time of the SIF examination visit or as the mean values from all available visits of the patient.RESULTSHbA1c was correlated with MBG (r = 0.5; P < 0.001; n = 110). HbA1c and HGI, but not MBG, were statistically associated with SIF after adjustment for age, duration of diabetes, race, sex, and BMI z-score. SIF increased with age and duration of diabetes and was higher in girls than boys.CONCLUSIONSsAGE levels estimated by SIF increase with age, duration of diabetes, and female sex. sAGE is correlated with MBG-independent biological variation in HbA1c, but not with MBG itself. These results suggest that factors besides MBG that influence HbA1c levels also contribute to accumulation of sAGE.