GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) is a 36-center unmasked, parallel treatment group, randomized controlled trial evaluating four diabetes medications added to metformin in people with type 2 diabetes (T2DM). We report baseline characteristics and compare GRADE participants to a National Health and Nutrition Examination Survey (NHANES) cohort. RESEARCH DESIGN AND METHODS Participants were age ‡30 years at the time of diagnosis, with duration of T2DM <10 years, HbA 1c 6.8-8.5% (51-69 mmol/mol), prescribed metformin monotherapy, and randomized to glimepiride, sitagliptin, liraglutide, or insulin glargine. RESULTS At baseline, GRADE's 5,047 randomized participants were 57.2 6 10.0 years of age, 63.6% male, with racial/ethnic breakdown of 65.7% white, 19.8% African American, 3.6% Asian, 2.7% Native American, 7.6% other or unknown, and 18.4% Hispanic/ Latino. Duration of diabetes was 4.2 6 2.8 years, with mean HbA 1c of 7.5 6 0.5% (58 6 5.3 mmol/mol), BMI of 34.3 6 6.8 kg/m 2 , and metformin dose of 1,944 6 204 mg/day. Among the cohort, 67% reported a history of hypertension, 72% a history of hyperlipidemia, and 6.5% a history of heart attack or stroke. Applying GRADE inclusion criteria to NHANES indicates enrollment of a representative cohort with T2DM on metformin monotherapy (NHANES cohort average age, 57.9 years; mean HbA 1c , 7.4% [57 mmol/mol]; BMI, 33.2 kg/m 2 ; duration, 4.2 6 2.5 years; and 7.2% with a history of cardiovascular disease). CONCLUSIONS The GRADE cohort represents patients with T2DM treated with metformin requiring a second diabetes medication. GRADE will inform decisions about the clinical effectiveness of the addition of four classes of diabetes medications to metformin. The optimal medication management of hyperglycemia in type 2 diabetes (T2DM) is not established. In addition to lifestyle intervention, metformin is the recommended initial medication in T2DM due to its glycemic effectiveness, lack of associated hypoglycemia or weight gain, low cost, and evidence of long-term benefit and safety

Background: Recruitment of participants into research studies, especially individuals from minority groups, is challenging; lack of diversity may lead to biased findings. Aim: To explore beliefs about research participation among individuals who were approached and eligible for the GRADE study. Methods: In-depth qualitative telephone interviews with randomized participants (n = 25) and eligible individuals who declined to enroll (n = 26). Results: Refusers and consenters differed in trust and perceptions of risk, benefits and burden of participation. Few participants understood how comparative effectiveness research differed from other types of trials; however, some features of comparative effectiveness research were perceived as lower risk. Conclusion: We identified facilitators and addressable barriers to participation in research studies.

Objective: Hypoglycemia due to insulin-like growth factor (IGF)-2 secretion by a tumor, referred to as nonislet cell tumor hypoglycemia, or IGF-2-oma, is a rare and serious paraneoplastic complication of malignancy. When surgical resection is not an option, studies have shown improvement of hypoglycemia with glucocorticoids. We describe the case of a patient with persistent hypoglycemia despite prolonged high-dose glucocorticoid therapy.Methods: A 22-year-old man with known metastatic hepatocellular carcinoma presented with dizziness and weakness. Initial blood glucose level was found to be 10 mg/dL. Multiple injections of 50% dextrose and continuous infusion with 25% dextrose were required to maintain normal blood glucose levels. Laboratory work-up revealed suppressed C-peptide and insulin levels with hypoglycemia and an elevated ratio of IGF-2 to IGF-1, consistent with IGF-2 secretion by the tumor.Results: Despite high-dose glucocorticoid therapy, continuous intravenous dextrose was necessary to prevent hypoglycemia. In addition, the patient's tumor progressed rapidly, and he was ultimately discharged to hospice on intravenous dextrose. Conclusion CASE REPORTA 22-year-old man presented with nausea, vomiting, dizziness, and severe weakness for 1 day. Three weeks prior, he had been diagnosed with hepatocellular carcinoma with pulmonary metastases, secondary to chronic hepatitis B infection. In the emergency room, the patient was found to have a capillary blood glucose level of 10 mg/ dL, and he received multiple intravenous doses of 50 mL of 50% dextrose (50 mg/mL). Despite these treatments, he was unable to sustain euglycemia, and continuous dextrose 25% (250 mg/mL) infusion was started. On physical examination, he appeared cachectic, with lower extremity edema, exquisite right upper-quadrant abdominal tenderness, and hepatomegaly. Initial laboratory tests were significant for serum glucose 10 mg/dL, serum calcium of 12.4 mg/dL (corrected for albumin, 13

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In women who are pregnant, the presence of thyroid autoantibodies is associated with an increased rate of miscarriage in the first trimester, with multiple reports averaging ~17% compared with ~8% in autoantibody negative women. During pregnancy immune tolerance is altered to allow implantation of the semi-allogeneic fetus and T-regulatory cells (Tregs), which play a major role in such tolerance, have been shown to increase during pregnancy, reaching a peak in the second trimester. A deficiency in this Treg response has been widely associated with spontaneous miscarriages. While it is known that the number of Tregs in patients with autoimmune thyroid disease (AITD) is decreased there are no data on pregnant women with AITD. In this study, we examined both the number and function of Tregs in pregnant women with (n=26) and without (n=41) thyroid autoantibodies (anti-Tg and/or anti-TPO) as well as healthy non pregnant women (n=25). Tregs were measured by flow cytometry of isolated CD4+, CD25+ and FoxP3+ T-cells. We found that the total number of CD4+CD25+FoxP3+ high Tregs was significantly increased in pregnancy consistent with previous reports (from 11% to 22%, p&lt;0.024). Furthermore, this increase in Tregs was less in pregnant women with thyroid autoantibodies (mean of 12%). In addition, studies of phosphorylated signal transducer and activator of transcription-5a (pStat-5a) as a marker of Treg function, showed that while Tregs were activated in pregnancy, their activity per cell was diminished in the pregnant antibody positive women with a frequency:MFI ratio of 201 compared to 316 in the negative group. These data demonstrate that pregnant women with thyroid antibodies have a reduced Treg response to pregnancy, both in number and function, and offer a likely explanation for the increased miscarriage rate in such patients.