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The American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), Joint British Diabetes Societies for Inpatient Care (JBDS), American Association of Clinical Endocrinology (AACE), and Diabetes Technology Society (DTS) convened a panel of internists and diabetologists to update the ADA consensus statement on hyperglycemic crises in adults with diabetes, published in 2001 and last updated in 2009. The objective of this consensus report is to provide up-to-date knowledge about the epidemiology, pathophysiology, clinical presentation, and recommendations for the diagnosis, treatment, and prevention of diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) in adults. A systematic examination of publications since 2009 informed new recommendations. The target audience is the full spectrum of diabetes health care professionals and individuals with diabetes. [ABSTRACT FROM AUTHOR]

The Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases workshop was a 1.5-day scientific conference at the National Institutes of Health (Bethesda, MD) that engaged clinical and basic science investigators interested in diseases of the pancreas. This report provides a summary of the proceedings from the workshop. The goals of the workshop were to forge connections and identify gaps in knowledge that could guide future research directions. Presentations were segregated into six major theme areas, including 1) pancreas anatomy and physiology, 2) diabetes in the setting of exocrine disease, 3) metabolic influences on the exocrine pancreas, 4) genetic drivers of pancreatic diseases, 5) tools for integrated pancreatic analysis, and 6) implications of exocrine–endocrine cross talk. For each theme, multiple presentations were followed by panel discussions on specific topics relevant to each area of research; these are summarized here. Significantly, the discussions resulted in the identification of research gaps and opportunities for the field to address. In general, it was concluded that as a pancreas research community, we must more thoughtfully integrate our current knowledge of normal physiology as well as the disease mechanisms that underlie endocrine and exocrine disorders so that there is a better understanding of the interplay between these compartments. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3 dioxygenase-1 (IDO1) is a powerful immunoregulatory enzyme that is deficient in patients with type 1 diabetes (T1D). In this study, we present the first systematic evaluation of IDO1 expression and localization in human pancreatic tissue. Although IDO1 was constitutively expressed in β-cells from donors without diabetes, less IDO1 was expressed in insulin-containing islets from double autoantibody-positive donors and patients with recent-onset T1D, although it was virtually absent in insulin-deficient islets from donors with T1D. Scatter plot analysis suggested that IDO1 decay occurred in individuals with multiple autoantibodies, prior to β-cell demise. IDO1 impairment might therefore contribute to β-cell demise and could potentially emerge as a promising therapeutic target. [ABSTRACT FROM AUTHOR]

Microvascular and metabolic physiology are tightly linked. This Perspective reviews evidence that 1) the relationship between hyperglycemia and microvascular dysfunction (MVD) is bidirectional and constitutes a vicious cycle; 2) MVD in diabetes affects many, if not all, organs, which may play a role in diabetes-associated comorbidities such as depression and cognitive impairment; and 3) MVD precedes, and contributes to, hyperglycemia in type 2 diabetes (T2D) through impairment of insulin-mediated glucose disposal and, possibly, insulin secretion. Obesity and adverse early-life exposures are important drivers of MVD. MVD can be improved through weight loss (in obesity) and through exercise. Pharmacological interventions to improve MVD are an active area of investigation. [ABSTRACT FROM AUTHOR]

We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 × 10-16 and OR 0.84, P = 3.55 × 10-8, respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 × 10-4). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA1c level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 × 10-4). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans. [ABSTRACT FROM AUTHOR]

Gluconeogenesis is drastically increased in patients with type 2 diabetes and accounts for increased fasting plasma glucose concentrations. Circulating levels of prostaglandin (PG) F2α are also markedly elevated in diabetes; however, whether and how PGF2α regulates hepatic glucose metabolism remain unknown. Here, we demonstrated that PGF2α receptor (F-prostanoid receptor [FP]) was upregulated in the livers of mice upon fasting- and diabetic stress. Hepatic deletion of the FP receptor suppressed fasting-induced hepatic gluconeogenesis, whereas FP overexpression enhanced hepatic gluconeogenesis in mice. FP activation promoted the expression of gluconeogenic enzymes (PEPCK and glucose-6-phosphatase) in hepatocytes in a FOXO1-dependent manner. Additionally, FP coupled with Gq in hepatocytes to elicit Ca2+ release, which activated Ca2+/calmodulin-activated protein kinase IIγ (CaMKIIγ) to increase FOXO1 phosphorylation and subsequently accelerate its nuclear translocation. Blockage of p38 disrupted CaMKIIγ-induced FOXO1 nuclear translocation and abrogated FP-mediated hepatic gluconeogenesis in mice. Moreover, knockdown of hepatic FP receptor improved insulin sensitivity and glucose homeostasis in ob/ob mice. FP-mediated hepatic gluconeogenesis via the CaMKIIγ/p38/FOXO1 signaling pathway, indicating that the FP receptor might be a promising therapeutic target for type 2 diabetes. [ABSTRACT FROM AUTHOR]

There is wide variation in the age at diagnosis of diabetes in individuals with maturity-onset diabetes of the young (MODY) due to a mutation in the HNF1A gene. We hypothesized that common variants at the HNF1A locus (rs1169288 [I27L], rs1800574 [A98V]), which are associated with type 2 diabetes susceptibility, may modify age at diabetes diagnosis in individuals with HNF1A-MODY. Meta-analysis of two independent cohorts, comprising 781 individuals with HNF1A-MODY, found no significant associations between genotype and age at diagnosis. However after stratifying according to type of mutation (protein-truncating variant [PTV] or missense), we found each 27L allele to be associated with a 1.6-year decrease (95% CI -2.6, -0.7) in age at diagnosis, specifically in the subset (n = 444) of individuals with a PTV. The effect size was similar and significant across the two independent cohorts of individuals with HNF1A-MODY. We report a robust genetic modifier of HNF1A-MODY age at diagnosis that further illustrates the strong effect of genetic variation within HNF1A upon diabetes phenotype. [ABSTRACT FROM AUTHOR]

Previous studies by us and others have indicated that renal epidermal growth factor receptors (EGFR) are activated in models of diabetic nephropathy (DN) and that inhibition of EGFR activity protects against progressive DN in type 1 diabetes. In this study we examined whether inhibition of EGFR activation would affect the development of DN in a mouse model of accelerated type 2 diabetes (BKS db/db with endothelial nitric oxide knockout [eNOS-/-db/db]). eNOS-/-db/db mice received vehicle or erlotinib, an inhibitor of EGFR tyrosine kinase activity, beginning at 8 weeks of age and were sacrificed at 20 weeks of age. In addition, genetic models inhibiting EGFR activity (waved 2) and transforming growth factor-α (waved 1) were studied in this model of DN in type 2 diabetes. Compared with vehicle-treated mice, erlotinib-treated animals had less albuminuria and glomerulosclerosis, less podocyte loss, and smaller amounts of renal profibrotic and fibrotic components. Erlotinib treatment decreased renal oxidative stress, macrophage and T-lymphocyte infiltration, and the production of proinflammatory cytokines. Erlotinib treatment also preserved pancreas function, and these mice had higher blood insulin levels at 20 weeks, decreased basal blood glucose levels, increased glucose tolerance and insulin sensitivity, and increased blood levels of adiponectin compared with vehicle-treated mice. Similar to the aforementioned results, both waved 1 and waved 2 diabetic mice also had attenuated DN, preserved pancreas function, and decreased basal blood glucose levels. In this mouse model of accelerated DN, inhibition of EGFR signaling led to increased longevity. [ABSTRACT FROM AUTHOR]

We investigated how human proislet peptide (HIP) regulates differentiation of human fetus-derived pancreatic progenitor cells (HFPPCs) and explored the potential link between HIP signaling and the menin pathway, which is key to regulating pancreatic islet differentiation. The data show that HIP promoted expression of proislet transcription factors (TFs), including PDX-1, MAFA, and NKX6.1, as well as other maturation markers of b-cells, such as insulin, GLUT2, KIR6.2, SUR1, and VDCC. Moreover, HIP increased insulin content and promoted the ability of HFPPCs to normalize blood glucose in diabetic mice. HIP inhibited the TF FOXO1 by increasing AKT-mediated phosphorylation. HIP-induced repression of FOXO1 suppressed menin expression, leading to reducing menin binding to the promoter of the three key proislet TFs, decreasing recruitment of H3K9 methyltransferase SUV39H1, and thus reducing repressive H3K9me3 at the promoter. These coordinated actions lead to increased expression of the proislet TFs, resulting in induction of HFPPC differentiation. Consistently, constitutive activation of FOXO1 blocks HIP-induced transcription of these TFs. Together, these studies unravel the crucial role of theHIP/AKT/FOXO/menin axis in epigenetically controlling expression of proislet TFs, regulating the differentiation of HFPPCs, and normalizing blood glucose in diabetic mice. [ABSTRACT FROM AUTHOR]

Very recently one of the largest type 1 diabetes prevention trials using daily administration of oral insulin or placebo was completed. After 9 years of study enrollment and follow-up, the randomized controlled trial failed to delay the onset of clinical type 1 diabetes, which was the primary end point. The unfortunate outcome follows the previous large-scale trial, the Diabetes Prevention Trial-Type 1 (DPT-1), which again failed to delay diabetes onset with oral insulin or low-dose subcutaneous insulin injections in a randomized controlled trial with relatives at risk for type 1 diabetes. These sobering results raise the important question, "Where does the type 1 diabetes prevention field move next?" In this Perspective, we advocate for a paradigm shift in which smaller mechanistic trials are conducted to define immune mechanisms and potentially identify treatment responders. The stage is set for these interventions in individuals at risk for type 1 diabetes as Type 1 Diabetes TrialNet has identified thousands of relatives with islet autoantibodies and general population screening for type 1 diabetes risk is under way. Mechanistic trials will allow for better trial design and patient selection based upon molecular markers prior to large randomized controlled trials, moving toward a personalized medicine approach for the prevention of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Although diabetes is well known to be common in prevalent heart failure (HF) and portends a poor prognosis, the role of diabetes in the development of incident HF is less well understood. We studied the role of diabetes in the transition from asymptomatic left ventricular systolic dysfunction (ALVSD) to overt HF in the prevention arm of the Studies of Left Ventricular Dysfunction (SOLVD-P).Research Design and Methods: We examined the development of symptomatic HF, HF hospitalization, and cardiovascular death according to diabetes status at baseline in patients in SOLVD-P. These outcomes were analyzed by using cumulative incidence curves and Cox regression models adjusted for age, sex, and other prognostic factors, including randomized treatment, HF severity, and comorbidity.Results: Of the 4,223 eligible participants, 647 (15%) had diabetes at baseline. Patients with diabetes were older and had a higher average weight, systolic blood pressure, and heart rate. During the median follow-up of 36 months, 861 of the 3,576 patients without diabetes (24%) developed HF compared with 214 of the 647 patients with diabetes (33%). In unadjusted analyses, patients with diabetes had a higher risk of development of HF (hazard ratio 1.53 [95% CI 1.32-1.78]; P < 0.001), HF hospitalization (2.04 [1.65-2.52]; P < 0.0001), and the composite outcome of development of HF or cardiovascular death (1.48 [1.30-1.69]; P < 0.001). The effect of enalapril on outcomes was not modified by diabetes status.Conclusions: In patients with ALVSD, diabetes is associated with an increased risk of developing HF. Development of HF is associated with an increased risk of death irrespective of diabetes status. [ABSTRACT FROM AUTHOR]

The first systems for continuous glucose monitoring (CGM) became available over 15 years ago. Many then believed CGM would revolutionize the use of intensive insulin therapy in diabetes; however, progress toward that vision has been gradual. Although increasing, the proportion of individuals using CGM rather than conventional systems for self-monitoring of blood glucose on a daily basis is still low in most parts of the world. Barriers to uptake include cost, measurement reliability (particularly with earlier-generation systems), human factors issues, lack of a standardized format for displaying results, and uncertainty on how best to use CGM data to make therapeutic decisions. This Scientific Statement makes recommendations for systemic improvements in clinical use and regulatory (pre- and postmarketing) handling of CGM devices. The aim is to improve safety and efficacy in order to support the advancement of the technology in achieving its potential to improve quality of life and health outcomes for more people with diabetes. [ABSTRACT FROM AUTHOR]

Objective: Artificial pancreas (AP) systems are best positioned for optimal treatment of type 1 diabetes (T1D) and are currently being tested in outpatient clinical trials. Our consortium developed and tested a novel adaptive AP in an outpatient, single-arm, uncontrolled multicenter clinical trial lasting 12 weeks.Research Design and Methods: Thirty adults with T1D completed a continuous glucose monitor (CGM)-augmented 1-week sensor-augmented pump (SAP) period. After the AP was started, basal insulin delivery settings used by the AP for initialization were adapted weekly, and carbohydrate ratios were adapted every 4 weeks by an algorithm running on a cloud-based server, with automatic data upload from devices. Adaptations were reviewed by expert study clinicians and patients. The primary end point was change in hemoglobin A1c (HbA1c). Outcomes are reported adhering to consensus recommendations on reporting of AP trials.Results: Twenty-nine patients completed the trial. HbA1c, 7.0 ± 0.8% at the start of AP use, improved to 6.7 ± 0.6% after 12 weeks (-0.3, 95% CI -0.5 to -0.2, P < 0.001). Compared with the SAP run-in, CGM time spent in the hypoglycemic range improved during the day from 5.0 to 1.9% (-3.1, 95% CI -4.1 to -2.1, P < 0.001) and overnight from 4.1 to 1.1% (-3.1, 95% CI -4.2 to -1.9, P < 0.001). Whereas carbohydrate ratios were adapted to a larger extent initially with minimal changes thereafter, basal insulin was adapted throughout. Approximately 10% of adaptation recommendations were manually overridden. There were no protocol-related serious adverse events.Conclusions: Use of our novel adaptive AP yielded significant reductions in HbA1c and hypoglycemia. [ABSTRACT FROM AUTHOR]

Objective: In Germany, as in many other countries, nationwide data on mortality attributable to diagnosed diabetes are not available. This study estimated the absolute number of excess deaths associated with diabetes (all types) and type 2 diabetes in Germany.Research Design and Methods: A prevalence approach that included nationwide routine data from 64.9 million people insured in the German statutory health insurance system in 2010 was used for the calculation. Because nationwide data on diabetes mortality are lacking in Germany, the mortality rate ratio from the Danish National Diabetes Register was used. The absolute number of excess deaths associated with diabetes was calculated as the number of deaths due to diabetes minus the number of deaths due to diabetes with a mortality that was as high as in the population without diabetes. Furthermore, the mortality population-attributable fraction was calculated.Results: A total of 174,627 excess deaths were due to diabetes in 2010, including 137,950 due to type 2 diabetes. Overall, 21% of all deaths in Germany were attributable to diabetes and 16% were attributable to type 2 diabetes. Most of the excess deaths (34% each) occurred in the 70- to 89-year-old age-group.Conclusions: In this first nationwide calculation of excess deaths related to diabetes in Germany, the results suggest that the official German estimates that rely on information from death certificates are grossly underestimated. Countries without national cohorts or diabetes registries could easily use this method to estimate the number of excess deaths due to diabetes. [ABSTRACT FROM AUTHOR]

Objective: Diabetes is known to be associated with increased arterial stiffness. However, the temporal association between increased carotid-femoral pulse wave velocity (c-f PWV) and diabetes is unclear. The aim of this study is to explore the relationship between arterial stiffness, as determined by c-f PWV, and incidence of diabetes.Research Design and Methods: The study population included participants from the Malmö Diet and Cancer cardiovascular cohort, using measurements from the 2007-2012 reexamination as baseline. Arterial stiffness was evaluated by measuring c-f PWV (SphygmoCor). After excluding participants with prevalent diabetes (according to measurements of fasting glucose, oral glucose tolerance tests, and physician's diagnoses), the final study population consisted of 2,450 individuals (mean age = 71.9 ± 5.6 years). Incidence of diabetes was followed by linkage to local and national diabetes registers. Cox proportional hazards regression was used to assess the incidence of diabetes in relation to the tertiles of c-f PWV, adjusted for potential confounders.Results: During a mean follow-up of 4.43 ± 1.40 years, 68 (2.8%) participants developed diabetes. Crude incidence of diabetes (per 1,000 person-years) was 3.5, 5.7, and 9.5, respectively, for subjects in the first, second, and third tertiles of c-f PWV. After adjustment for potential confounders, the hazard ratio of diabetes was 1.00 (reference), 1.83 (95% CI 0.88-3.8), and 3.24 (95% CI 1.51-6.97), respectively, for the tertiles of c-f PWV (P for trend = 0.002).Conclusions: Increased c-f PWV is associated with increased incidence of diabetes, independent of other risk factors. These results suggest that increased arterial stiffness is an early risk marker for developing diabetes. [ABSTRACT FROM AUTHOR]

Objective: Intense exercise is a major challenge to the management of type 1 diabetes (T1D). Closed-loop control (CLC) systems (artificial pancreas) improve glycemic control during limited intensity and short duration of physical activity (PA). However, CLC has not been tested during extended vigorous outdoor exercise common among adolescents.Research Design and Methods: Skiing presents unique metabolic challenges: intense prolonged PA, cold, altitude, and stress/fear/excitement. In a randomized controlled trial, 32 adolescents with T1D (ages 10-16 years) participated in a 5-day ski camp (∼5 h skiing/day) at two sites: Wintergreen, VA, and Breckenridge, CO. Participants were randomized to the University of Virginia CLC system or remotely monitored sensor-augmented pump (RM-SAP). The CLC and RM-SAP groups were coarsely paired by age and hemoglobin A1c (HbA1c). All subjects were remotely monitored 24 h per day by the study physicians and clinical team.Results: Compared with physician-monitored open loop, percent time in range (70-180 mg/dL) improved using CLC: 71.3 vs. 64.7% (+6.6% [95% CI 1-12]; P = 0.005), with maximum effect late at night. Hypoglycemia exposure and carbohydrate treatments were improved overall (P = 0.001 and P = 0.007) and during the daytime with strong ski level effects (P = 0.0001 and P = 0.006); ski/snowboard proficiency was balanced between groups but with a very strong site effect: naive in Virginia and experienced in Colorado. There was no adverse event associated with CLC; the participants' feedback was overwhelmingly positive.Conclusions: CLC in adolescents with T1D improved glycemic control and reduced exposure to hypoglycemia during prolonged intensive winter sport activities, despite the added challenges of cold and altitude. [ABSTRACT FROM AUTHOR]

Objective: The increasing importance of peers in adolescence and emerging adulthood has been widely acknowledged. However, longitudinal research linking the peer context to diabetes management and outcomes is scarce. The present longitudinal study in a large sample of youths with type 1 diabetes related both positive and negative peer variables to diabetes outcomes over a time interval of 1 year.Research Design and Methods: Our sample consisted of 467 adolescents (14-17 years of age) and emerging adults (18-25 years of age) with type 1 diabetes who participated in a two-wave longitudinal study. Questionnaires tapped into peer support, extreme peer orientation, parental responsiveness, diabetes-related distress, and treatment adherence. HbA1c values were obtained from the treating physicians of patients. Cross-lagged analysis from a structural equation modeling approach was performed to assess the directionality of effects.Results: Peer support negatively predicted diabetes-related distress over time. Extreme peer orientation positively predicted treatment distress over time. Parental responsiveness negatively predicted food distress over time. Treatment adherence negatively predicted extreme peer orientation, treatment distress, and HbA1c values over time. For emerging adults specifically, there was a reciprocal relationship between HbA1c values and extreme peer orientation because they positively predicted each other.Conclusions: This study highlights the importance of peers in predicting the functioning of youths with type 1 diabetes. Additionally, treatment adherence at baseline was found to negatively predict extreme peer orientation, treatment distress, and worse glycemic control over time. In sum, the current study underscores the importance of the peer context for adolescents and emerging adults with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objective: To determine trends in hospitalization for hypoglycemia in adults with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in England.Research Design and Methods: Adults with T1DM or T2DM were identified from 398 of the 684 practices within the Clinical Practice Research Datalink, for which linkage to the Hospital Episode Statistics was possible. Hypoglycemia as the primary reason for hospitalization between 1998 and 2013 was extracted. Trends were estimated using joinpoint regression models for adults with T1DM, young and middle-aged adults with T2DM (18-64 years), and elderly adults with T2DM (≥65 years), respectively.Results: Among 23,246 adults with T1DM, 1,591 hypoglycemia hospitalizations occurred during 121,262 person-years. Among 241,441 adults with T2DM, 3,738 hypoglycemia hospitalizations occurred during 1,344,818 person-years. In adults with T1DM, the incidence increased 3.74% (95% CI 1.70-5.83) annually from 1998 to 2013. In young and middle-aged adults with T2DM, the annual incidence increase was 4.12% (0.61-7.75) from 1998 to 2013. In elderly adults with T2DM, the incidence increased 8.59% (5.76-11.50) annually from 1998 to 2009, and decreased 8.05% (-14.48 to -1.13) annually from 2009 to 2013, but the incidence was still higher in 2013 than 1998 (adjusted rate ratio 3.01 [1.76-5.14]). Trends in HbA1c level did not parallel trends of hypoglycemia hospitalization for both diabetes types. A possible reason for declined hypoglycemia trend in 2009-2013 in elderly adults with T2DM may be continuously decreased sulfonylurea use after 2009, which was not seen in young and middle-aged adults with T2DM.Conclusions: Hypoglycemia requiring hospitalization has been an increasing burden in adults with T1DM and T2DM in England in the previous two decades, with the exception of the decline in elderly adults with T2DM starting in 2009. [ABSTRACT FROM AUTHOR]

The Edwin Bierman Award Lecture is presented in honor of the memory of Edwin L. Bierman, MD, an exemplary scientist, mentor, and leader in the field of diabetes, obesity, hyperlipidemia, and atherosclerosis. The award and lecture recognizes a leading scientist in the field of macrovascular complications and contributing risk factors in diabetes. Clay F. Semenkovich, MD, the Irene E. and Michael M. Karl Professor and Chief of the Division of Endocrinology, Metabolism and Lipid Research at Washington University School of Medicine in St. Louis, St. Louis, MO, received the prestigious award at the American Diabetes Association's 76th Scientific Sessions, 10-14 June 2016, in New Orleans, LA. He presented the Edwin Bierman Award Lecture, "We Know More Than We Can Tell About Diabetes and Vascular Disease," on Sunday, 12 June 2016.Diabetes is a disorder of abnormal lipid metabolism, a notion strongly supported by the work of Edwin Bierman, for whom this eponymous lecture is named. This abnormal lipid environment continues to be associated with devastating vascular complications in diabetes despite current therapies, suggesting that our understanding of the pathophysiology of blood vessel disease in diabetes is limited. In this review, potential new insights into the nature of diabetic vasculopathy will be discussed. Recent observations suggest that while the concept of distinct macrovascular and microvascular complications of diabetes has been useful, vascular diseases in diabetes may be more interrelated than previously appreciated. Moreover, the intermediary metabolic pathway of de novo lipogenesis, which synthesizes lipids from simple precursors, is robustly sensitive to insulin and may contribute to these complications. De novo lipogenesis requires fatty acid synthase, and recent studies of this enzyme suggest that endogenously produced lipids are channeled to specific intracellular sites to affect physiology. These findings raise the possibility that novel approaches to treating diabetes and its complications could be based on altering the intracellular lipid milieu. [ABSTRACT FROM AUTHOR]

The article presents insights on the role of the brain in glucose homeostasis and diabetes. Topics discussed include the evidence of the brain's capacity to influence biologically defended level of circulating glucose through rapid and highly coordinated adjustments of both insulin sensitivity and insulin secretion, the possible influence of brain dysfunction on the pathogenesis of type 2 diabetes, and the implications of the concepts for the future of diabetes treatment.

The article presents the position statement of the American Diabetes Association on psychosocial care for people with diabetes. Topics discussed include the general considerations in psychosocial care, situations that warrant referral of a person with diabetes to a mental health provide for evaluation and treatment, and selected measures for the evaluation of psychosocial constructs in the clinical setting.

Objective: To assess the frequency of adverse outcomes for women who are diagnosed with gestational diabetes mellitus (GDM) by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria using data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study.Research Design and Methods: This is a secondary analysis from the North American HAPO study centers. Glucose measurements from a 75-g oral glucose tolerance test were used to group participants into three nonoverlapping categories: GDM based on Carpenter-Coustan (CC) criteria (also GDM based on IADPSG criteria), GDM diagnosed based on IADPSG criteria but not CC criteria, and no GDM. Newborn outcomes included birth weight, cord C-peptide, and newborn percentage fat above the 90th percentile; maternal outcomes included primary cesarean delivery and preeclampsia. Outcome frequencies were compared using multiple logistic regression, adjusting for predefined covariates.Results: Among 25,505 HAPO study participants, 6,159 blinded participants from North American centers were included. Of these, 81% had normal glucose testing, 4.2% had GDM based on CC criteria, and 14.3% had GDM based on IADPSG criteria but not CC criteria. Compared with women with no GDM, those diagnosed with GDM based on IADPSG criteria had adjusted odds ratios (95% CIs) for birth weight, cord C-peptide, and newborn percentage fat above the 90th percentile, as well as primary cesarean delivery and preeclampsia, of 1.87 (1.50-2.34), 2.00 (1.54-2.58), 1.73 (1.35-2.23), 1.31 (1.07-1.60), and 1.73 (1.32-2.27), respectively.Conclusions: Women diagnosed with GDM based on IADPSG criteria had higher adverse outcome frequencies compared with women with no GDM. These data underscore the need for research to assess the effect of treatment to improve outcomes in such women. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the effects of severe hypoglycemia on risks of all-cause mortality and cardiovascular disease (CVD) incidence in patients with type 1 diabetes mellitus (T1DM).Research Design and Methods: Two nested case-control studies with age- and sex-matched control subjects and using the time-density sampling method were performed separately within a cohort of 10,411 patients with T1DM in Taiwan. The study enrolled 564 nonsurvivors and 1,615 control subjects as well as 743 CVD case subjects and 1,439 control subjects between 1997 and 2011. History of severe hypoglycemia was identified during 1 year, 1-3 years, and 3-5 years before the occurrence of the study outcomes. Conditional logistic regression analyses were performed to estimate the odds ratio (OR) and 95% CI of the study outcomes.Results: Prior severe hypoglycemic events within 1 year were associated with higher risks of all-cause mortality and CVD (adjusted OR 2.74 [95% CI 1.96-3.85] and 2.02 [1.35-3.01], respectively). Events occurring within 1-3 years and 3-5 years before death were also associated with adjusted ORs of 1.94 (95% CI 1.39-2.71) and 1.68 (1.15-2.44), respectively. Significant dose-gradient effects of severe hypoglycemia frequency on mortality and CVD were observed within 5 years.Conclusions: Although the CVD incidence may be associated with severe hypoglycemic events occurring in the previous year, the risk of all-cause mortality was associated with severe hypoglycemic events occurring in the preceding 5 years. Exposure to repeated severe hypoglycemic events can lead to higher risks of mortality and CVD. [ABSTRACT FROM AUTHOR]

Objective: Historically, mortality in type 1 diabetes has exceeded that in the general population. We compared mortality in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study cohort to that of the current general U.S.Research Design and Methods: The DCCT (1983-1993) compared intensive versus conventional therapy, with HbA1c levels of ∼7 vs. 9%, respectively, over an average of 6.5 years of treatment. EDIC is the observational follow-up study of the DCCT (1994 to the present). Vital status was ascertained for 97.5% of the original DCCT cohort (n = 1,441) after a mean of 27 years follow-up. Expected mortality during DCCT/EDIC was estimated using the current age-, sex-, and race-specific risks in the general U.S. population, and the observed versus expected mortality compared using standardized mortality ratios (SMRs) and Poisson regression models.Results: Mortality in the DCCT intensive therapy group was nonsignificantly lower than that in the general U.S. population (SMR = 0.88 [95% CI 0.67, 1.16]), whereas mortality in the DCCT conventional therapy group was significantly greater than that in the general population (SMR = 1.31 [95% CI 1.05, 1.65]). The SMR increased with increasing mean HbA1c, and above an HbA1c of 9%, the rate of increase in SMR among females was greater than that among males.Conclusions: Overall mortality in the combined DCCT/EDIC cohort was similar to that of the general population but was higher in the DCCT conventional therapy group. Mortality increased significantly with increasing mean HbA1c, more so among females than males, especially for HbA1c >9%. [ABSTRACT FROM AUTHOR]

Objective: Studies indicate that off-loading adherence is low in patients with diabetic foot ulcers (DFUs), which may subsequently delay healing. However, there is little empirical evidence for this relationship or the factors that influence adherence.Research Design and Methods: This prospective, multicenter, international study of 79 (46 from the U.K. and 33 the U.S.) persons with type 2 diabetes and plantar DFUs assessed the association between off-loading adherence and DFU healing over a 6-week period. Additionally, potential demographic, disease, and psychological determinants of adherence were examined. DFUs were off-loaded with a removable device (77% a removable cast walker). Off-loading adherence was assessed objectively by activity monitors. Patient-reported measures included Hospital Anxiety and Depression Scale (HADS), Neuropathy and Foot Ulcer Quality of Life (NeuroQoL) instrument, and Revised Illness Perception Questionnaire (IPQ-R).Results: Off-loading adherence was monitored for 35 ± 10 days, and devices were used during 59 ± 22% of subjects' activity. In multivariate analyses, smaller baseline DFU size, U.K. study site, and better off-loading adherence predicted smaller DFU size at 6 weeks (P < 0.05). Better off-loading adherence was, in turn, predicted by larger and more severe baseline DFUs, more severe neuropathy, and NeuroQoL foot pain (P < 0.05). In contrast, greater NeuroQoL postural instability predicted worse off-loading adherence (P < 0.001). HADS and IPQ-R measures were not significantly associated with off-loading adherence.Conclusions: Off-loading adherence is associated with the amount of DFU healing that occurs, while postural instability is a powerful predictor of nonadherence. Clinicians should take this neuropathic symptom into consideration when selecting an off-loading device, as off-loading-induced postural instability may further contribute to nonadherence. [ABSTRACT FROM AUTHOR]

Objective: To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study.Research Design and Methods: Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement <54 mg/dL) or major hypoglycemia (requiring extended assistance) and patient characteristics overall and by treatment allocation were studied.Results: At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia.Conclusions: The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy. [ABSTRACT FROM AUTHOR]

A mechanistic cause for Mauriac syndrome, a syndrome of growth failure and delayed puberty associated with massive liver enlargement from glycogen deposition in children with poorly controlled type 1 diabetes, is unknown. We discovered a mutation in the catalytic subunit of liver glycogen phosphorylase kinase in a patient with Mauriac syndrome whose liver extended into his pelvis. Glycogen phosphorylase kinase activates glycogen phosphorylase, the enzyme that catalyzes the first step in glycogen breakdown. We show that the mutant subunit acts in a dominant manner to completely inhibit glycogen phosphorylase kinase enzyme activity and that this interferes with glycogenolysis causing increased levels of glycogen in human liver cells. It is known that even normal blood glucose levels physiologically inhibit glycogen phosphorylase to diminish glucose release from the liver when glycogenolysis is not needed. The patient's mother possessed the same mutant glycogen phosphorylase kinase subunit, but did not have diabetes or hepatomegaly. His father had childhood type 1 diabetes in poor glycemic control, but lacked the mutation and had neither hepatomegaly nor growth failure. This case proves that the effect of a mutant enzyme of glycogen metabolism can combine with hyperglycemia to directly hyperinhibit glycogen phosphorylase, in turn blocking glycogenolysis causing the massive liver in Mauriac disease. [ABSTRACT FROM AUTHOR]

Transcription factor expression fluctuates during β-cell ontogeny, and disruptions in this pattern can affect the development or function of those cells. Here we uncovered that murine endocrine pancreatic progenitors express high levels of the homeodomain transcription factor Prox1, whereas both immature and mature β-cells scarcely express this protein. We also investigated if sustained Prox1 expression is incompatible with β-cell development or maintenance using transgenic mouse approaches. We discovered that Prox1 upregulation in mature β-cells has no functional consequences; in contrast, Prox1 overexpression in immature β-cells promotes acute fasting hyperglycemia. Using a combination of immunostaining and quantitative and comparative gene expression analyses, we determined that Prox1 upregulation reduces proliferation, impairs maturation, and enables apoptosis in postnatal β-cells. Also, we uncovered substantial deficiency in β-cells that overexpress Prox1 of the key regulator of β-cell maturation MafA, several MafA downstream targets required for glucose-stimulated insulin secretion, and genes encoding important components of FGF signaling. Moreover, knocking down PROX1 in human EndoC-βH1 β-cells caused increased expression of many of these same gene products. These and other results in our study indicate that reducing the expression of Prox1 is beneficial for the expansion and maturation of postnatal β-cells. [ABSTRACT FROM AUTHOR]

The authors reflect on the advantage of the availability of the advances for the continuous glocuse monitoring (CGM) and glycemic measurements in patients with diabetes. They explore how such devices can help provide opportunity to develop measures of glycemic control an treatments. However, the authors also emphasize that instruction, advice and support provided by physicians in intensive diabetes management remains critical when applying CGM data.

The view that a hemoglobin A1c (A1C) level <7% (55 mmol/mol) is the accepted glycemic goal for most people with diabetes sometimes conflicts with the view that glycemic goals should be individualized and, thus, that somewhat higher A1C levels are appropriate for some, particularly many at risk for iatrogenic hypoglycemia because of treatment with insulin, a sulfonylurea, or a glinide. The relationship between A1C and chronic complications of diabetes is curvilinear, A1C is a relatively weak predictor of cardiovascular disease, and minor elevations of A1C above 7% have not been found to be associated with increased mortality. Iatrogenic hypoglycemia causes recurrent morbidity in diabetes and is sometimes fatal. In those at risk for hypoglycemia, a reasonable individualized glycemic goal is the lowest A1C that does not cause severe hypoglycemia and preserves awareness of hypoglycemia, preferably with little or no symptomatic or even asymptomatic hypoglycemia, at a given stage in the evolution of the individual's diabetes. A somewhat higher A1C level is appropriate in those who have previously experienced hypoglycemia or have potential high risk for hypoglycemia, have a long duration of diabetes, and have a short life expectancy, among other traits. Given the importance of severe hypoglycemia in selecting glycemic goals, it is proposed to expand the classification of severe hypoglycemia beyond a hypoglycemic event requiring assistance from another person to include a measured glucose concentration <50 mg/dL (2.8 mmol/L), a level associated with sudden death. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the effects of single and repeated episodes of clamped hypoglycemia on fibrinolytic balance, pro-inflammatory biomarkers, pro-atherothrombotic mechanisms and endothelial function. Twenty healthy individuals (12M/8F) were studied during separate 2 day randomized protocols. Day 1 consisted of either two 2hr hyperinsulinemic (812±50 pmol/L) euglycemic (5±0.1 mmol/L) or hypoglycemic (2.9±0.1 mmol/L) clamps. Day 2 consisted of a single 2 hr hypoglycemic clamp. Two D Doppler ultrasound was used to determine brachial arterial endothelial function. PAI-1, VCAM-1, ICAM-1, E-selectin, P-selectin, TAT (thrombin/anti-thrombin complex), TNF-α and IL-6 responses were increased (p<0.05) during single or repeated hypoglycemia as compared to euglycemia. Endogenous and exogenous NO mediated vasodilation were both impaired by repeated hypoglycemia. Neuroendocrine and autonomic nervous system (ANS) responses were also blunted by repeated hypoglycemia (p<0.05). In summary, acute moderate hypoglycemia impairs fibrinolytic balance, increases pro-inflammatory responses, platelet activation and coagulation biomarkers and reduces NO mediated endothelial function in healthy individuals. Repeated episodes of hypoglycemia further impair vascular function by additionally reducing exogenously NO mediated endothelial function and increasing coagulation biomarkers. We conclude that despite reduced neuroendocrine and ANS responses, antecedent hypoglycemia results in greater endothelial dysfunction and an increased pro-atherothrombotic state as compared to a single acute episode of hypoglycemia. [ABSTRACT FROM AUTHOR]

OBJECTIVE Adults with diabetes typically take multiple medications for hyperglycemia, diabetes-associated conditions, and other comorbidities. Medication adherence is associated with improved outcomes, including reduced health care costs, hospitalization, and mortality. We conducted a retrospective analysis of a large pharmacy claims database to examine patient, medication, and prescriber factors associated with adherence to antidiabetic medications. RESEARCH DESIGN AND METHODS We extracted data on a cohort of >200,000 patients who were treated for diabetes with noninsulin medications in the second half of 2010 and had continuous prescription benefits eligibility through 2011. Adherence was defined as a medication possession ratio ‡0.8. We used a modified adherence measure that accounted for switching therapies. Logistic regression analysis was performed to determine factors independently associated with adherence. RESULTS Sixty-nine percent of patients were adherent. Adherence was independently associated with older age, male sex, higher education, higher income, use of mail order versus retail pharmacies, primary care versus nonendocrinology specialist prescribers, higher daily total pill burden, and lower out-of-pocket costs. Patients who were new to diabetes therapy were significantly less likely to be adherent. CONCLUSIONS Several demographic, clinical, and potentially modifiable system-level factors were associated with adherence to antidiabetic medications. Patients typically perceived to be healthy (those who are younger, new to diabetes, and on few other medications) may be at risk for nonadherence. For all patients, efforts to reduce out-of-pocket costs and encourage use of mail order pharmacies may result in higher adherence. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate racial and ethnic differences in the association between a dietary diabetes risk reduction score and incidence of type 2 diabetes in U.S. white and minority women. RESEARCH DESIGN AND METHODS We followed 156,030 non-Hispanic white (NHW), 2,026 Asian, 2,053 Hispanic, and 2,307 black women in the Nurses' Health Study (NHS) (1980-2008) and NHS II (1991-2009). A time-updated dietary diabetes risk reduction score (range 8-32) was created by adding points corresponding with each quartile of intake of eight dietary factors (1 = highest risk; 4 = lowest risk). A higher score indicates a healthier overall diet. RESULTS We documented 10,922 incident type 2 diabetes cases in NHW, 157 in Asian, 193 in Hispanic, and 307 in black women. Multivariable-adjusted pooled hazard ratio across two cohorts for a 10th-90th percentile range difference in dietary diabetes risk reduction score was 0.49 (95% CI 0.46, 0.52) for NHW, 0.53 (0.31, 0.92) for Asian, 0.45 (0.29, 0.70) for Hispanic, 0.68 (0.47, 0.98) for black, and 0.58 (0.46, 0.74) for overall minority women (P for interaction between minority race/ethnicity and dietary score = 0.08). The absolute risk difference (cases per 1,000 person- years) for the same contrast in dietary score was -5.3 (-7.8,- 2.7) for NHW, -7.2 (-22.9, 8.4) for Asian, -11.6 (-26.7, 3.5) for Hispanic, -6.8 (-19.5, 5.9) for black, and -8.0 (-15.6, -0.5) for overall minority women (P for interaction = 0.04). CONCLUSIONS A higher dietary diabetes risk reduction score was inversely associated with risk of type 2 diabetes in all racial and ethnic groups, but the absolute risk difference was greater in minority women. [ABSTRACT FROM AUTHOR]

OBJECTIVE Women with preexisting (type 1 or type 2) diabetes experience an increased risk of serious adverse pregnancy outcomes. It is not known, however, how these risks change between the first and second pregnancy and whether there is an increased risk of recurrence. This study describes the absolute risks and recurrence of serious adverse pregnancy outcomes in 220 women with preexisting diabetes. RESEARCH DESIGN AND METHODS A total of 440 pregnancies occurring in 220 women with preexisting diabetes who delivered successive singleton pregnancies in the North of England during 1996-2008 were identified from the Northern Diabetes in Pregnancy Survey (NorDIP). Predictors of serious adverse outcome were estimated by competing-risks regression. RESULTS Sixty-seven first pregnancies (30.5%) ended in serious adverse outcome, including 14 (6.4%) with congenital anomalies and 53 (24.1%) additional fetal or infant deaths. Thirty-seven second pregnancies (16.8%) ended in serious adverse outcome half the rate among first pregnancies (P = 0.0004) -- including 21 (9.5%) with congenital anomalies and 16 (7.3%) additional fetal or infant deaths. Serious adverse outcomes in the second pregnancy occurred twice as frequently in women who experienced a previous adverse outcome than in those who did not (26.9% vs. 12.4%, P = 0.004), but previous adverse outcome was not associated with preparation for the following pregnancy. CONCLUSIONS Serious adverse outcomes are less common in the second pregnancies of women with preexisting diabetes, although the risk is comparable in those whose first pregnancy ends in adverse outcome. Reducing the risk of recurrence may require more support in the immediate period after an adverse pregnancy outcome. [ABSTRACT FROM AUTHOR]

OBJECTIVE Diabetes care has changed substantially in the past 2 decades. We examined the change in medical spending and use related to diabetes between 1987 and 2011. RESEARCH DESIGN AND METHODS Using the 1987 National Medical Expenditure Survey and the Medical Expenditure Panel Surveys in 2000-2001 and 2010-2011, we compared per person medical expenditures and uses among adults ≥18 years of age with or without diabetes at the three time points. Types of medical services included inpatient care, emergency room (ER) visits, outpatient visits, prescription drugs, and others. We also examined the changes in unit cost, defined by the expenditure per encounter for medical services. RESULTS The excess medical spending attributed to diabetes was $2,588 (95% CI, $2,265 to $3,104), $4,205 ($3,746 to $4,920), and $5,378 ($5,129 to $5,688) per person, respectively, in 1987, 2000-2001, and 2010-2011. Of the $2,790 increase, prescription medication accounted for 55%; inpatient visits accounted for 24%; outpatient visits accounted for 15%; and ER visits and other medical spending accounted for 6%. The growth in prescription medication spending was due to the increase in both the volume of use and unit cost, whereas the increase in outpatient expenditure was almost entirely driven by more visits. In contrast, the increase in inpatient and ER expenditures was caused by the rise of unit costs. CONCLUSIONS In the past 2 decades, managing diabetes has become more expensive, mostly due to the higher spending on drugs. Further studies are needed to assess the cost-effectiveness of increased spending on drugs. [ABSTRACT FROM AUTHOR]

OBJECTIVE To compare usual diabetes care (UDC) to a comprehensive diabetes care intervention condition (IC) involving an Internet-based "diabetes dashboard" management tool used by clinicians. RESEARCH DESIGN AND METHODS We used a parallel-group randomized design. Diabetes nurses, diabetes dietitians, and providers used the diabetes dashboard as a clinical decision support system to deliver a five-visit, 6-month intervention to 199 poorly controlled (HbA1c >7.5% [58 mmol/mol]) Latino type 2 diabetic (T2D) patients (mean age 55 years, 60% female) at urban community health centers. We compared this intervention to an established, in-house UDC program (n = 200) for its impact on blood glucose control and psychosocial outcomes. RESULTS Recruitment and retention rates were 79.0 and 88.5%, respectively. Compared with UDC, more IC patients reached HbA1c targets of <7% (53 mmol/mol; 15.8 vs. 7.0%, respectively, P < 0.01) and <8% (64 mmol/mol; 45.2 vs. 25.3%, respectively, P < 0.001). In multiple linear regression adjusting for baseline HbA1c, adjusted mean ± SE HbA± at follow-up was significantly lower in the IC compared with the UDC group (P< 0.001; IC8.4 ± 0.10%; UDC 9.2 ± 0.10%). The results showed lower diabetes distress at follow-up for IC patients (40.4 ± 2.1) as compared with UDC patients (48.3 ± 2.0) (P< 0.01), and also lower social distress (32.2 ± 1.3 vs. 27.2 ± 1.4, P < 0.01). There was a similar, statistically significant (P < 0.01) improvement for both groups in the proportion of patients moving from depressed status at baseline to nondepressed at follow-up (41.8 vs. 40%; no significance between groups). CONCLUSIONS The diabetes dashboard intervention significantly improved diabetes-related outcomes among Latinos with poorly controlled T2D compared with a similar diabetes team condition without access to the diabetes dashboard. [ABSTRACT FROM AUTHOR]

Objective Pancreatic Scintigraphy With Interleukin-2 Radiolabeled With 99MTc (99MTc-Il-2) Is A Technique Used To Image Chronic Inflammatory-Mediated Disorders. We Used This Method To Detect A Signal Consistent With The Presence Of Insulitis In Patients With Autoimmune Diabetes. Positive And Negative Controls (Patients With Pancreatic Carcinoma And Type 2 Diabetes, Respectively) Also Were Studied. Research Design And Methods We Examined 25 Patients With Autoimmune Diabetes (16 With Recently Diagnosed Type 1 Diabetes, 9 With Latent Autoimmune Diabetes In Adults [Lada]), 6 With Type 2 Diabetes, And 7 With Pancreatic Carcinoma (The Latter Two Groups Were Used As Negative And Positive Controls, Respectively). All Patients Underwent 99MTc-Il-2 Scintigraphy And Contrast-Enhanced Mri Of The Pancreas. To Validate Positive Controls, Samples Were Taken From Patients With Pancreatic Carcinoma During Surgery For Histological And Immunohistochemical Investigations. Results Pancreatic Accumulation Of 99MTc-Il-2 Was Detected In Patients With Autoimmune Diabetes (61% Positive) And, Notably, In 6 Of 9 Patients With Lada; Semiquantita-Tive Evaluation Of Pancreatic Uptake Of 99MTc-Il-2 Showed Higher Values In Patients With Autoimmune Diabetes (Both Childhood And Lada) And Pancreatic Carcinoma Than In Those With Type 2 Diabetes (4.45 ± 1.99, ± 4.79 1.1, And 4.54 ± 1.62 Vs. 2.81 ± 0.63; P = 0.06, P = 0.01, And P = 0.04, Respectively). In Patients With Pancreatic Carcinoma, Pancreatic Interleukin-2 Receptor Expression Correlated With Pancreatic ±Tc-Il-2 Uptake (R = 0.8; P = 0.01). In Patients With Lada, ±Tc-Il-2 Uptake Inversely Correlated With Duration Of Disease (R = 0.7; P = 0.03). Conclusions Autoimmune Diabetes In Adults Is Associated With Increased Pancreatic ±Tc-Il-2 Uptake, Indicating The Presence Of Insulitis, Particularly Within 1 Year Of The Beginning Of Insulin Therapy, Similar To Type 1 Diabetes At Diagnosis. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcer (DFU) caused by impaired wound healing is a common vascular complication of diabetes. The current study revealed that plasma levels of pigment epithelium--derived factor (PEDF) were elevated in type 2 diabetic patients with DFU and in db/db mice. To test whether elevated PEDF levels contribute to skin wound-healing delay in diabetes, endogenous PEDF was neutralized with an anti-PEDF antibody in db/db mice. Our results showed that neutralization of PEDF accelerated wound healing, increased angiogenesis in the wound skin, and improved the functions and numbers of endothelial progenitor cells (EPCs) in the diabetic mice. Further, PEDF-deficient mice showed higher baseline blood flow in the skin, higher density of cutaneous microvessels, increased skin thickness, improved numbers and functions of circulating EPCs, and accelerated wound healing compared with wild-type mice. Overexpression of PEDF suppressed the Wnt signaling pathway in the wound skin. Lithium chloride--induced Wnt signaling activation downstream of the PEDF interaction site attenuated the inhibitory effect of PEDF on EPCs and rescued the wound-healing deficiency in diabetic mice. Taken together, these results suggest that elevated circulating PEDF levels contribute to impaired wound healing in the process of angiogenesis and vasculogenesis through the inhibition of Wnt/β-catenin signaling. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is characterized by the destruction of the insulin-producing β-cells of pancreatic islets. Genetic and environmental factors both contribute to T1D development. Viral infection with enteroviruses is a suspected trigger for T1D, but a causal role remains unproven and controversial. Studies in animals are problematic because of species-specific differences in host cell susceptibility and immune responses to candidate viral pathogens such as coxsackievirus B (CVB). In order to resolve the controversial role of viruses in human T1D, we developed a viral infection model in immunodeficient mice bearing human islet grafts. Hyperglycemia was induced in mice by specific ablation of native β-cells. Human islets, which are naturally susceptible to CVB infection, were transplanted to restore normoglycemia. Transplanted mice were infected with CVB4 and monitored for hyperglycemia. Forty-seven percent of CVB4-infected mice developed hyperglycemia. Human islet grafts from infected mice contained viral RNA, expressed viral protein, and had reduced insulin levels compared with grafts from uninfected mice. Human-specific gene expression profiles in grafts from infected mice revealed the induction of multiple interferon-stimulated genes. Thus, human islets can become severely dysfunctional with diminished insulin production after CVB infection of β-cells, resulting in diabetes. [ABSTRACT FROM AUTHOR]

Endogenous pancreatic multipotent progenitors (PMPs) are ideal candidates for regenerative approaches to compensate for β-cell loss since their β-cell--producing capacities as well as strategic location would eliminate unnecessary invasive manipulations. However, little is known about the status and potentials of PMPs under diabetic conditions. Here we show that β-cell metabolic stress and hyperglycemia enhance the proliferation capacities of adult PMP cells and bias their production of progeny toward β-cells in mouse and human. These effects are dynamic and correlate with functional β-cell regeneration when conditions allow. [ABSTRACT FROM AUTHOR]

Hypoplastic coronary artery disease is a congenital coronary artery malformation associated with a high risk of sudden cardiac death. However, the etiology and pathogenesis of hypoplastic coronary artery disease remain undefined. Pregestational diabetes increases reactive oxygen species (ROS) levels and the risk of congenital heart defects. We show that pregestational diabetes in mice induced by streptozotocin significantly increased 4-hydroxynonenal production and decreased coronary artery volume in fetal hearts. Pregestational diabetes also impaired epicardial epithelialto- mesenchymal transition (EMT) as shown by analyses of the epicardium, epicardial-derived cells, and fate mapping. Additionally, the expression of hypoxia-inducible factor 1a (Hif-1a), Snail1, Slug, basic fibroblast growth factor (bFgf), and retinaldehyde dehydrogenase (Aldh1a2) was decreased and E-cadherin expression was increased in the hearts of fetuses of diabetic mothers. Of note, these abnormalities were all rescued by treatment with N-acetylcysteine (NAC) in diabetic females during gestation. Ex vivo analysis showed that high glucose levels inhibited epicardial EMT, which was reversed by NAC treatment. We conclude that pregestational diabetes in mice can cause coronary artery malformation through ROS signaling. This study may provide a rationale for further clinical studies to investigate whether pregestational diabetes could cause hypoplastic coronary artery disease in humans. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether treatment of mild gestational diabetes mellitus (GDM) confers sustained offspring health benefits, including a lower frequency of obesity. Research Design and Methods: Follow-up study of children (ages 5-10) of women enrolled in a multicenter trial of treatment versus no treatment of mild GDM. Height, weight, blood pressure, waist circumference, fasting glucose, fasting insulin, triglycerides, and HDL cholesterol were measured. Results: Five hundred of 905 eligible offspring (55%) were enrolled. Maternal baseline characteristics were similar between the follow-up treated and untreated groups. The frequencies of BMI ≥95th (20.8% and 22.9%) and 85th (32.6% and 38.6%) percentiles were not significantly different in treated versus untreated offspring (P = 0.69 and P = 0.26). No associations were observed for BMI z score, log waist circumference, log triglycerides, HDL cholesterol, blood pressure, or log HOMA-estimated insulin resistance (HOMA-IR). The effect of treatment was different by sex for fasting glucose and log HOMA-IR (P for interaction = 0.002 and 0.02, respectively) but not by age-group (5-6 and 7-10 years) for any outcomes. Female offspring of treated women had significantly lower fasting glucose levels. Conclusions: Although treatment for mild GDM has been associated with neonatal benefits, no reduction in childhood obesity or metabolic dysfunction in the offspring of treated women was found. However, only female offspring of women treated for mild GDM had lower fasting glucose. [ABSTRACT FROM AUTHOR]

The dipeptidyl peptidase-4 inhibitor sitagliptin, an antidiabetic agent, which lowers blood glucose levels, also reduces postprandial lipid excursion after a mixed meal. The underlying mechanism of this effect, however, is not clear. This study examined the production and clearance of triglyceride-rich lipoprotein particles from the liver and intestine in healthy volunteers in response to a single oral dose of sitagliptin. Using stable isotope tracer techniques and with control of pancreatic hormone levels, the kinetics of lipoprotein particles of intestinal and hepatic origin were measured. Compared with placebo, sitagliptin decreased intestinal lipoprotein concentration by inhibiting particle production, independent of changes in pancreatic hormones, and circulating levels of glucose and free fatty acids. Fractional clearance of particles of both intestinal and hepatic origin, and production of particles of hepatic origin, were not affected. This pleiotropic effect of sitagliptin may explain the reduction in postprandial lipemia seen in clinical trials of this agent and may provide metabolic benefits beyond lowering of glucose levels. [ABSTRACT FROM AUTHOR]

Shortened leukocyte telomere length (LTL) and diagnosis of periodontitis are associated with an increased risk of complications and mortality in diabetes. This study investigated the association between LTL, endotoxemia, and severity of periodontitis in a large cohort of people with diabetes. RESEARCH DESIGN AND METHODS Six hundred thirty individuals (371 with type 2 and 259 with type 1 diabetes) were recruited from the University College Hospital in London, U.K. During a baseline visit, blood was collected for standard biochemical tests and DNA extraction, while a dental examination was performed to determine diagnosis and extent of periodontitis. LTLwas measured by real-time PCR, and endotoxemia was assessed by the limulus amoebocyte lysate method. RESULTS Two hundred fifty-five individuals were diagnosed with gingivitis, 327 with periodontitis (114 with moderate and 213 with severe disease), and 48 with edentulous. Diagnosis of periodontitis was associated with shorter LTL (P = 0.04). A negative association between LTL and endotoxemia was found in the severe periodontitis and type 2 diabetes groups (P = 0.01 for both). Shorter LTL was associated with increased extent of periodontitis (P = 0.01) and increased insulin resistance (homeostatic model assessment). Multiple adjustments for biochemical, anthropometric, and medication-use variables did not affect the results. CONCLUSIONS LTL is associated with endotoxemia and diagnosis of periodontitis in people with diabetes. LTL shortening might represent a novel biological pathway accounting for previous epidemiological data that documented higher prevalence of diabetes and its complications in people with periodontitis and vice versa. [ABSTRACT FROM AUTHOR]

OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of b-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Of 112 subjects (ages 6-36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years showed higher d C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months. RESULTS C-peptide AUC means, adjusted for age and baseline C-peptide, at 36monthswere 0.217 nmol/L (95% CI 0.168-0.268) and 0.141 nmol/L (95% CI 0.071-0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months' delay with abatacept. Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years. CONCLUSIONS Costimulation modulation with abatacept slowed decline of β-cell function and improved HbA1c in recent-onset T1D. The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE Apolipoprotein (apo)C1 is a potent physiological inhibitor of cholesteryl ester transfer protein (CETP). ApoC1 operates through its ability to modify the electrostatic charge at the lipoprotein surface. We aimed to determine whether the inhibitory ability of apoC1 is still effective in vivo in patients with diabetes and whether in vitro glycation of apoC1 influences its electrostatic charge and its CETP inhibitory effect. RESEARCH DESIGN AND METHODS ApoC1 concentrations and CETP activity were measured in 70 type 1 diabetic (T1D) patients, 113 patients with type 2 diabetes, and 83 control subjects. The consequences of in vitro glycation by methylglyoxal on the electrostatic properties of apoC1 and on its inhibitory effect on CETP activity were studied. An isoelectric analysis of apoC1 was performed in patients with T1D and in normolipidemic-normoglycemic subjects. RESULTS An independent negative correlation was found between CETP activity and apoC1 in control subjects but not in patients with diabetes. HbA1c was independently associated with CETP activity in T1D patients. In vitro glycation of apoC1 modified its electrostatic charge and abrogated its ability to inhibit CETP activity in a concentration-dependent manner. The isoelectric point of apoC1 in T1D patients was significantly lower than that in control subjects. CONCLUSIONS The ability of apoC1 to inhibit CETP activity is impaired in patients with diabetes. Glycation of apoC1 leads to a change in its electrostatic properties that might account, at least in part, for a loss of constitutive CETP inhibition and an increase in plasma CETP activity in patients with diabetes. [ABSTRACT FROM AUTHOR]

Increased glycemic variability has been reported to be associated with the risk of hypoglycemia and possibly diabetes complications and is believed to be due to β -cell dysfunction. However, it is not known whether improvement in β-cell function can reduce glycemic variability. Because short-term intensive insulin therapy (IIT) can improve β-cell function in early type 2 diabetes (T2DM), our objectivewas to determine whether the β-cell functional recovery induced by this therapy is associated with decreased glycemic variability. RESEARCH DESIGN AND METHODS Sixty-one patients with T2DM of 3.0 years mean duration underwent 4 weeks of IIT, which consisted of basal insulin detemir and premeal insulin aspart. Glucose variability was assessed in both the first and the last week by the coefficient of variation of capillary glucose on daily 6-point self-monitoring profiles. β-cell function before and after IIT was assessed with the Insulin Secretion-Sensitivity Index-2 (ISSI-2). RESULTS Between the first and the last week on IIT, 55.7% of patients had a reduction in glucose variability. Change in glucose variability was negatively correlated with the change in β-cell function (ISSI-2) (r = -0.34, P = 0.008). On multiple linear regression analyses, percentage change in ISSI-2 emerged as the only factor independently associated with the change in glucose variability (standardized b = -0.42, P = 0.03).Moreover, patients with an increase in ISSI-2 ≥ 25%experienced a reduction in glucose variability compared with their peers who had almost no change (-0.041 ± 0.06 vs. -0.0002 ± 0.04, respectively; P = 0.006). CONCLUSIONS In early T2DM, glycemic variability is a modifiable parameter that can be reduced by improving β-cell function with short-term IIT. [ABSTRACT FROM AUTHOR]

Salsalate is a nonacetylated salicylate that lowers glucose levels in people with type 2 diabetes (T2D). Here we examined whether salsalate also lowered serum-protein-bound levels of early and advanced glycation end products (AGEs) that have been implicated in diabetic vascular complications. RESEARCH DESIGN AND METHODS Participants were from the Targeting Inflammation Using Salsalate for Type 2 Diabetes (TINSAL-T2D) study, which examined the impact of salsalate treatment on hemoglobin A1c (HbA1c) and a wide variety of other parameters. One hundred eighteen participants received salsalate, 3.5 g/day for 48 weeks, and 109 received placebo. Early glycation product levels (HbA1c and fructoselysine [measured as furosine]) and AGE levels (glyoxal and methylglyoxal hydroimidazolones [G-¹H, MG- H], carboxymethyllysine [CML], carboxyethyllysine [CEL], pentosidine) were measured in patient serum samples. RESULTS Forty-eight weeks of salsalate treatment lowered levels of HbA1cc and serum furosine (P < 0.001) and CML compared with placebo. The AGEs CEL and G-¹H and MG-¹H levels were unchanged, whereas pentosidine levels increased more than twofold (P < 0.001). Among salsalate users, increases in adiponectin levels were associated with lower HbA1c levels during follow-up (P < 0.001). Changes in renal and inflammation factor levels were not associated with changes in levels of early or late glycation factors. Pentosidine level changes were unrelated to changes in levels of renal function, inflammation, or cytokines. CONCLUSIONS Salsalate therapy was associated with a reduction in early but not late glycation end products. There was a paradoxical increase in serum pentosidine levels suggestive of an increase in oxidative stress or decreased clearance of pentosidine precursor. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated aberrant glucagon physiology in the setting of type 1 diabetes (T1D) but have not addressed the potential impact of ambient glycemia on this glucagon response. Thus, our objective was to evaluate the impact of euglycemia versus hyperglycemia on the glucagon response to an oral glucose challenge in T1D. RESEARCH DESIGN AND METHODS Ten adults with T1D (mean age 56.6 ± 9.0 years, duration of diabetes 26.4 ± 7.5 years, HbA1c 7.5% 6 0.77, and BMI 24.1 kg/m² [22.6-25.4]) underwent 3-h 50-g oral glucose tolerance tests (OGTTs) on two separate days at least 24 h apart in random order under conditions of pretest euglycemia (plasma glucose [PG] between 4 and 6 mmol/L) and hyperglycemia (PG between 9 and 11 mmol/L), respectively. RESULTS Glycemic excursion on the OGTT was similar between the euglycemic and hyperglycemic tests (P = 0.72 for interaction between time postchallenge and glycemic setting). Interestingly, glucagon levels increased in response to the OGTT under both glycemic conditions (P < 0.001) and there were no differences in glucagon response between the euglycemic and hyperglycemic days (P =0.40 for interaction between time postchallenge and glycemic setting). In addition, the incretin responses to the OGTT (glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon-like peptide-2) were also not different between the euglycemic and hyperglycemic settings. CONCLUSIONS In patients with T1D, there is a paradoxical increase in glucagon in response to oral glucose that is not reversed when euglycemia is achieved prior to the test. This abnormal glucagon response likely contributes to the postprandial hyperglycemia in T1D irrespective of ambient glycemia. [ABSTRACT FROM AUTHOR]

We prospectively evaluated the association between autoimmunity to autonomic nervous structures and autonomic neuropathy in type 1 diabetes in relation to clinical variables. RESEARCH DESIGN AND METHODS A cohort of 112 patients with type 1 diabetes was prospectively followed from adolescence (T0) to approximately 4 (T4) and 16 (T16) years later. Standard cardiovascular (CV) tests and neurological examination were performed and related to the presence of circulating antibodies (Ab) to autonomic nervous structures detected at T0 and T4. Quality of life was assessed by a diabetes-specific questionnaire. RESULTS Sixty-six patients (59% of the cohort) were reexamined at T16 (age 31.4±2 years; disease duration 23.4±3.7 years). Nineteen had circulating Ab to autonomic structures. Prevalence of abnormal tests and autonomic symptoms were higher in Ab-positive (68 and 26%, respectively) than Ab-negative (32 and 4%) patients (P < 0.05). Among Ab-positive patients, the relative risk (RR) of having at least one altered CV test was 5.77 (95% CI 1.56-21.33), and an altered deep breathing (DB) test (<15 bpm) was 14.65 (2.48-86.46). Previous glycemic control was the only other predictor (RR 1.06 [1.002-1.13]/mmol/mol HbA1c increase). Presence of Ab carried over a 68% probability of developing an altered CV test; absence of Ab carried a 91% probability of not having an altered DB test and an 89% probability of not having an altered Valsalva ratio. Autonomic neuropathy was independently associated with worse quality of life. CONCLUSIONS Circulating Ab to autonomic structures are associated with the development of autonomic dysfunction in young diabetic patients independent of glycemic control. [ABSTRACT FROM AUTHOR]