Frank L. Schwartz

Phenylmethimazole Decreases Toll-Like Receptor 3 and Noncanonical Wnt5a Expression in Pancreatic Cancer and Melanoma Together with Tumor Cell Growth and Migration

Purpose: To evaluate whether (a) Wnt5a expression in pancreatic cancer and malignant melanoma cells might be associated with constitutive levels of Toll-like receptor 3 (TLR3) and/or TLR3 signaling; (b) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a and TLR3 levels together with cell growth and migration; and (c) the efficacy of C10 as a potential inhibitor of pancreatic cancer and malignant melanoma cell growth in vivo. Experimental Design: We used a variety of molecular biology techniques including but not limited to PCR, Western blotting, and ELISA to evaluate the presence of constitutively activated TLR3/Wnt5a expression and signaling. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based technology and scratch assays were used to evaluate inhibition of cell growth and migration, respectively. TLR3 regulation of cell growth was confirmed using small interfering RNA technology. Nude and severe combined immunodeficient mice were implanted with human pancreatic cancer and/or melanoma cells and the effects of C10 on tumor growth were evaluated. Results: We show that constitutive TLR3 expression is associated with constitutive Wnt5a in human pancreatic cancer and malignant melanoma cell lines, that C10 can decrease constitutive TLR3/Wnt5a expression and signaling, suggesting that they are interrelated signal systems, and that C10 inhibits growth and migration in both of these cancer cell lines. We also report that C10 is effective at inhibiting human pancreatic cancer and malignant melanoma tumor growth in vivo in nude or severe combined immunodeficient mice and associate this with inhibition of signal transducers and activators of transcription 3 activation. Conclusions: C10 may have potential therapeutic applicability in pancreatic cancer and malignant melanoma.

Characterizing Blood Glucose Variability Using New Metrics with Continuous Glucose Monitoring Data

Objective: Glycemic variability contributes to oxidative stress, which has been linked to the pathogenesis of the long-term complications of diabetes. Currently, the best metric for assessing glycemic variability is mean amplitude of glycemic excursion (MAGE); however, MAGE is not in routine clinical use. A glycemic variability metric in routine clinical use could potentially be an important measure of overall glucose control and a predictor of diabetes complication risk not detected by glycosylated hemoglobin (A1C) levels. This study aimed to develop and evaluate new automated metrics of glycemic variability that could be routinely applied to continuous glucose monitoring (CGM) data to assess and enhance glucose control. Method: Individual 24 h CGM tracings from our clinical diabetes research database were scored for MAGE and two additional metrics designed to compensate for aspects of variability not captured by MAGE: (1) number of daily glucose fluctuations >75 mg/dl that leave the normal range (70–175 mg/dl), or excursion frequency, and (2) total daily fluctuation, or distance traveled. These scores were used to train machine learning algorithms to recognize excessive variability based on physician ratings of daily CGM charts, producing a third metric of glycemic variability: perceived variability. Finger stick A1C (average) and serum 1,5-anhydroglucitol (postprandial) levels were used as clinical markers of overall glucose control for comparison. Results: Mean amplitude of glycemic excursion, excursion frequency, and distance traveled did not adequately quantify the glycemic variability visualized by physicians who evaluated the daily CGM plots. A naive Bayes classifier was developed that characterizes CGM tracings based on physician interpretations of tracings. Preliminary results suggest that the number of excessively variable days, as determined by this naive Bayes classifier, may be an effective way to automatically assess glycemic variability of CGM data. This metric more closely reflects 90-day changes in serum 1,5-anhydroglucitol levels than does MAGE. Conclusion: We have developed a new automated metric to assess overall glycemic variability in people with diabetes using CGM, which could easily be incorporated into commercially available CGM software. Additional work to validate and refine this metric is underway. Future studies are planned to correlate the metric with both urinary 8-iso-prostaglandin F2 alpha excretion and serum 1,5-anhydroglucitol levels to see how well it identifies patients with high glycemic variability and increased markers of oxidative stress to assess risk for long-term complications of diabetes.

Phenylmethimazole blocks palmitate-mediated induction of inflammatory cytokine pathways in 3T3L1 adipocytes and RAW 264.7 macrophages

Visceral adipocytes and associated macrophages produce and release excessive amounts of biologically active inflammatory cytokines via the portal and systemic vascular system, which induce insulin resistance in insulin target tissues such as fat, liver, and muscle. Free fatty acids (FFAs) absorbed via the portal system or released from adipocytes also induce insulin resistance. In this report, we show that phenylmethimazole (C10) blocks basal IL6 and leptin production as well as basal Socs-3 expression in fully differentiated 3T3L1 cells (3T3L1 adipocytes) without affecting insulin-stimulated AKT signaling. In addition, C10 inhibits palmitate-induced IL6 and iNos up-regulation in both 3T3L1 adipocytes and RAW 264.7 macrophages, LPS-induced NF-κB and IFN-β activation in 3T3L1 cells, and LPS-induced iNos, Ifn-β, Il1β, Cxcl10, and Il6 expression in RAW 264.7 macrophages. C10 also blocks palmitate-induced Socs-3 up-regulation and insulin receptor substrate-1 (IRS-1) serine 307 phosphorylation in 3T3L1 adipocytes. Additionally, we show for the first time that although palmitate increases IRS-1 serine 307 phosphorylation in 3T3L1 adipocytes, AKT serine 473 phosphorylation is enhanced, not reduced, by palmitate. These results suggest that through inhibition of FFA-mediated signaling in adipocytes and associated macrophages, as well as possibly other insulin target cells/tissues (i.e. non-immune cells), C10 might be efficacious to prevent or reverse cytokine-induced insulin resistance seen in obesity-related insulin resistance and type 2 diabetes mellitus.

Can Lifestyle Interventions Do More Than Reduce Diabetes Risk? Treating Depression in Adults With Type 2 Diabetes With Exercise and Cognitive Behavioral Therapy

The epidemic of metabolic syndrome, prediabetes, and type 2 diabetes is global in scope and comprehensive in its impact on individuals, health care systems, and societies. One in four patients with diabetes will experience depression in their lifetime. Comorbid depression is associated with poorer outcomes, greater functional disability, and early mortality. Prior studies have demonstrated beneficial effects of exercise as an efficacious form of treatment for depression in the general population. Few studies have evaluated this strategy in patients with prediabetes or type 2 diabetes. Program ACTIVE (Appalachians Coming Together to Increase Vital Exercise) was designed to treat depression among adults with type 2 diabetes by pairing aerobic activity with individual cognitive behavioral therapy. This combination treatment approach has been shown to be feasible to implement in a rural environment and promising in terms of depression, diabetes, and cardiovascular outcomes. Data from this study suggest that exercise can be used to achieve multiple benefits for adults with type 2 diabetes. Future work to compare this approach to singular treatment strategies for adults at risk for type 2 diabetes is needed.

Case-Based Decision Support for Patients with Type 1 Diabetes on Insulin Pump Therapy

This paper presents a case-based approach to decision support for diabetes management in patients with Type 1 diabetes on insulin pump therapy. To avoid serious disease complications, including heart attack, blindness and stroke, these patients must continuously monitor their blood glucose levels and keep them as close to normal as possible. Achieving and maintaining good blood glucose control is a difficult task for these patients and their health care providers. A prototypical case-based decision support system was built to assist with this task. A clinical research study, involving 20 patients, yielded 50 cases of actual problems in blood glucose control, with their associated therapeutic adjustments and clinical outcomes, for the prototypes case base. The prototype operates by: (1) detecting problems in blood glucose control in large quantities of patient blood glucose and life event data; (2) finding similar past problems in the case base; and (3) offering the associated therapeutic adjustments stored in the case base to the physician as decision support. Results from structured evaluation sessions and a patient feedback survey encourage continued research and work towards a practical tool for diabetes management.

Depression Among Adults With Diabetes: Prevalence, Impact, and Treatment Options.

In Brief Patients with type 1 or type 2 diabetes are two times more likely to experience depression than their peers without diabetes. Comorbid depression results in deleterious effects on glycemic control, worsened diabetes complications, functional disability, and premature mortality. Once identified, depression can be effectively treated with antidepressant medications, psychotherapy, or a combination of both. Patients and providers should monitor depressive symptoms to identify their recurrence and work collaboratively to address barriers to care that exist in both urban and rural areas.

Hypoglycemia in Type 2 Diabetes - More Common Than You Think A Continuous Glucose Monitoring Study

Background: Hypoglycemia is often the limiting factor for intensive glucose control in diabetes management, however its actual prevalence in type 2 diabetes (T2DM) is not well documented. Methodology: A total of 108 patients with T2DM wore a continuous glucose monitoring system (CGMS) for 5 days. Rates and patterns of hypoglycemia and glycemic variability (GV) were calculated. Patient and medication factors were correlated with rates, timing, and severity of hypoglycemia. Results: Of the patients, 49.1% had at least 1 hypoglycemic episode (mean 1.74 episodes/patient/ 5 days of CGMS) and 75% of those patients experienced at least 1 asymptomatic hypoglycemic episode. There was no significant difference in the frequency of daytime versus nocturnal hypoglycemia. Hypoglycemia was more frequent in individuals on insulin (alone or in combination) (P = .02) and those on oral hypoglycemic agents (P < .001) compared to noninsulin secretagogues. CGMS analysis resulted in treatment modifications in 64% of the patients. T2DM patients on insulin exhibited higher glycemic variability (GV) scores (2.3 ± 0.6) as compared to those on oral medications (1.8 ± 0.7, P = .017). Conclusions: CGMS can provide rich data that show glucose excursions in diabetes patients throughout the day. Consequently, unwarranted onset of hypo- and hyperglycemic events can be detected, intervened, and prevented by using CGMS. Hypoglycemia was frequently unrecognized by the patients in this study (75%), which increases their potential risk of significant adverse events. Incorporation of CGMS into the routine management of T2DM would increase the detection and self-awareness of hypoglycemia resulting in safer and potentially better overall control.

Continuous glucose monitoring system in a rural intensive care unit: a pilot study evaluating accuracy and acceptance.

Background: Glucose management in an intensive care unit (ICU) is labor-intensive. A continuous glucose monitoring system (CGMS) has the potential to improve efficiency and safety in this setting. The goal of this study was to determine if the Medtronic Guardian® REAL-Time CGMS was accurate and tolerated by patients in a rural hospital ICU unit. Method: Differences between individual finger stick blood glucose (FSBG) and CGMS values were compared to American Diabetes Association (ADA) and International Organization for Standardization (ISO) standards. Continuous glucose monitoring system accuracy was evaluated over four ranges: <75, 75–140, 140–200, and >200 mg/dl. Other accuracy measures [mean absolute deviation (MAD), mean absolute relative difference (MARD), and coefficient of linear regression of CGMS on FSBG] were calculated. Nursing staff and patients were surveyed regarding use of the CGMS in the ICU. Results: Twenty-nine participants had 320 FSBG and corresponding CGMS readings. Sixty-two percent of participants were admitted with diabetic ketoacidosis (DKA). Two hundred and thirteen (66.6%) were accurate within the ISO standard, whereas only 70 out of 320 (21.9%) were within the 5% ADA standard. The CGMS was most accurate in euglycemia. Technical difficulties, such as adequate time for “wetting” and calibration of electrodes, arose with the sensors. The MAD was 28.3 mg/dl, the MRAD was 17.4%, and the linear regression coefficient of CGMS on FSBG was 0.834 (p < 0.001). Conclusions: The CGMS is well tolerated by ICU patients but, at present, is not sufficiently accurate to be used for therapeutic decisions in the acute setting, particularly in patients with diabetic ketoacidosis. There is a need to find resolution to the technical issues regarding electrode “wetting” and calibration if CGMS use in the ICU setting is to provide an effective means of diabetes care and management.

Diabetes Care in Extended-Care Facilities: Appropriate intensity of care?

OBJECTIVE—The American Diabetes Association (ADA) does not recognize different treatment goals for the institutionalized adult compared with the outpatient adult with diabetes, nor has it outlined specific recommendations for this population. The purpose of this study was to examine physician management of patients with type 1 and type 2 diabetes residing in extended-care facilities and to compare this management with ADA standards of care for the outpatient adult. RESEARCH DESIGN AND METHODS—This retrospective chart review included data from 108 residents with type 1 or type 2 diabetes at 11 extended health care facilities in the Midwestern U.S. and included a review of the medical problem list, medication list, laboratory reports, and all physician and consultation notes during the study period. RESULTS—Blood glucose was monitored in 98% of the subjects, and 38% met glucose goals. A1C goal was achieved in 67% of patients. Blood pressure was monitored in 94% of patients, with 55% meeting goal. Thirty-one percent of patients had yearly lipids checked, 37% had annual electrocardiograms, 7% had urine analyzed for microalbuminuria, 42% were on aspirin, 87% received foot exams, 42% received dilated eye exams, 89% received influenza vaccinations, and 46% received pneumoccocal vaccinations. CONCLUSIONS—Care of the institutionalized elderly with diabetes fails to meet ADA standards of care for the outpatient adult. Separate practice guidelines are needed for people with diabetes who reside in extended care facilities in order to improve quality and consistency of care.

Diabetes, depressive symptoms, and inflammation in older adults: Results from the Health, Aging, and Body Composition Study

OBJECTIVE Up-regulated levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) are common to both type 2 diabetes mellitus (T2DM) and elevated depressive symptoms, yet little attention has been given to the biological mechanisms associated with these co-morbidities. This study examined the association between inflammation and both T2DM and elevated depressive symptoms. METHODS Baseline data were analyzed from 3009 adults, aged 70-79, participating in the Health, Aging, and Body Composition Study. Diabetes was assessed per self-report, medication use, fasting glucose and/or glucose tolerance tests. Elevated depressive symptoms were categorized using the Center for Epidemiologic Studies Depression scale (cut-score≥20). Log-transformed IL-6, TNF-α, and CRP were analyzed using ANCOVA. RESULTS Participants with T2DM and elevated depressive symptoms (T2DM+DEP n=14) demonstrated significantly (p<.05) higher IL-6 compared to (T2DM Only n=628), (DEP Only n=49), and (No T2DM or DEP n=2067) groups following covariate adjustment. Similarly, participants with T2DM+DEP (n=14) had significantly (p<.05) higher CRP, after covariate adjustment, compared to DEP Only (n=50) and No T2DM or DEP groups (n=2153). No association was observed for TNF-α. CONCLUSIONS These findings provide evidence that inflammation is associated with T2DM and elevated depressive symptoms. Participants with T2DM+DEP demonstrated the highest IL-6 levels compared to all other groups. Greater CRP levels were also observed in T2DM, but not elevated depressive symptoms, which may suggest that differential associations between T2DM and depressive symptoms exist for various inflammatory markers. Further investigation into these associations could aid in understanding the biological pathways underlying both T2DM and depressive symptoms.