Daniel J. Rubin

Toll-like receptors regulate B cell cytokine production in patients with diabetes

Aims/hypothesisUnderstanding cellular and molecular events in diabetes mellitus will identify new approaches for therapy. Immune system cells are important modulators of chronic inflammation in diabetes mellitus, but the role of B cells is not adequately studied. The aim of this work was to define the function of B cells in diabetes mellitus patients through focus on B cell responses to pattern recognition receptors.MethodsWe measured expression and function of Toll-like receptors (TLRs) on peripheral blood B cells from diabetes mellitus patients by flow cytometry and multiplexed cytokine analysis. We similarly analysed B cells from non-diabetic donors and periodontal disease patients as comparative cohorts.ResultsB cells from diabetes mellitus patients secrete multiple pro-inflammatory cytokines, and IL-8 production is significantly elevated in B cells from diabetic patients compared with those from non-diabetic individuals. These data, plus modest elevation of TLR surface expression, suggest B cell IL-8 hyperproduction is a cytokine-specific outcome of altered TLR function in B cells from diabetes mellitus patients. Altered TLR function is further evidenced by demonstration of an unexpected, albeit modest ‘anti-inflammatory’ function for TLR4. Importantly, B cells from diabetes mellitus patients fail to secrete IL-10, an anti-inflammatory cytokine implicated in inflammatory disease resolution, under a variety of TLR-stimulating conditions. Comparative analyses of B cells from patients with a second chronic inflammatory disease, periodontal disease, indicated that some alterations in B cell TLR function associate specifically with diabetes mellitus.Conclusions/interpretationAltered TLR function in B cells from diabetes mellitus patients increases inflammation by two mechanisms: elevation of pro-inflammatory IL-8 and lack of anti-inflammatory/protective IL-10 production.

TLR Cross-Talk Specifically Regulates Cytokine Production by B Cells from Chronic Inflammatory Disease Patients

Chronic systemic inflammation links periodontal disease and diabetes to increased incidence of serious comorbidities. Activation of TLRs, particularly TLR2 and TLR4, promotes chronic systemic inflammation. Human B cells have been generally thought to lack these TLRs. However, recent work showed that an increased percentage of circulating B cells from inflammatory disease patients express TLR2 and TLR4, and that TLR engagement on B cells resulted in unexpected changes in gene expression. New data show that B cells from inflammatory disease patients secrete multiple cytokines in response to different classes of TLR ligands. Furthermore, the B cell response to combinations of TLR ligands is cytokine- and ligand-specific. Some cytokines (IL-1β and IL-10) are predominantly regulated by TLR4, but others (IL-8 and TNF-α) are predominantly regulated by TLR2, due in part to TLR-dictated changes in transcription factor/promoter association. TLR2 and TLR9 also regulate B cell TLR4 expression, demonstrating that TLR cross-talk controls B cell responses at multiple levels. Parallel examination of B cells from periodontal disease and diabetes patients suggested that outcomes of TLR cross-talk are influenced by disease pathology. We conclude that disease-associated alteration of B cell TLR responses specifically regulates cytokine production and may influence chronic inflammation.

Diabetes Knowledge: Are Resident Physicians and Nurses Adequately Prepared to Manage Diabetes?

OBJECTIVE To assess and compare the diabetes knowledge of nurses and residents in surgery, internal medicine, and family practice. METHODS A 21-question survey based on current diabetes standards of care was developed and administered. The results were stratified by type of participant and analyzed statistically. RESULTS A total of 52 internal medicine residents (IMR), 21 family practice residents (FPR), 42 surgery residents (SR), and 48 registered nurses (RN) participated. The survey had good overall internal consistency (Cronbach a of 0.78) and test-retest reliability (Pearson correlation coefficient of 0.71). The total mean percent correct for all participants was 61%. The total scores of IMR, FPR, and RN groups were similar (69%, 64%, and 66%) and significantly greater (P<0.001) than the SR score (44%). Collectively, all survey participants averaged less than 50% correct on several items. The IMR scored higher than the SR and FPR on several items. The nurses outscored the physicians on items regarding insulin preparations, treatment of hypoglycemia, and perioperative insulin management. A subgroup of 13 RN with additional diabetes training earned the highest total score (82%). CONCLUSION Our novel survey was shown to be a statistically valid tool for assessment of diabetes knowledge. IMR, FPR, and inpatient RN have similar but insufficient levels of knowledge about diabetes. SR may have a more profound deficit of diabetes knowledge. Previous additional diabetes training among nurses was associated with greater diabetes knowledge. Most nurses and residents require additional education in order to provide optimal care to patients with diabetes.

Weight-Based, Insulin Dose–Related Hypoglycemia in Hospitalized Patients With Diabetes

OBJECTIVE To determine the association of weight-based insulin dose with hypoglycemia in noncritically ill inpatients with diabetes. RESEARCH DESIGN AND METHODS We performed a retrospective, case-control study of 1,990 diabetic patients admitted to hospital wards. Patients with glucose levels <70 mg/dL (case subjects) were matched one to one with nonhypoglycemic control subjects on the basis of the hospital day of hypoglycemia, age, sex, and BMI. RESULTS Relative to 24-h insulin doses <0.2 units/kg, the unadjusted odds of hypoglycemia increased with increasing insulin dose. Adjusted for insulin type, sliding-scale insulin use, and albumin, creatinine, and hematocrit levels, the higher odds of hypoglycemia with increasing insulin doses remained (0.6–0.8 units/kg: odds ratio 2.10 [95% CI 1.08–4.09], P = 0.028; >0.8 units/kg: 2.95 [1.54–5.65], P = 0.001). The adjusted odds of hypoglycemia were not greater in patients who received 0.2–0.4 units/kg (1.08 [0.64–1.81], P = 0.78) or 0.4–0.6 units/kg (1.60 [0.90–2.86], P = 0.11). Although the relationship between insulin dose and hypoglycemia did not vary by insulin type, patients who received NPH trended toward greater odds of hypoglycemia compared with those given other insulins. CONCLUSIONS Higher weight-based insulin doses are associated with greater odds of hypoglycemia independent of insulin type. However, 0.6 units/kg seems to be a threshold below which the odds of hypoglycemia are relatively low. These findings may help clinicians use insulin more safely.

Hospital Readmission of Patients with Diabetes

Hospital readmission is a high-priority health care quality measure and target for cost reduction. Despite broad interest in readmission, relatively little research has focused on patients with diabetes. The burden of diabetes among hospitalized patients, however, is substantial, growing, and costly, and readmissions contribute a significant portion of this burden. Reducing readmission rates of diabetic patients has the potential to greatly reduce health care costs while simultaneously improving care. Risk factors for readmission in this population include lower socioeconomic status, racial/ethnic minority, comorbidity burden, public insurance, emergent or urgent admission, and a history of recent prior hospitalization. Hospitalized patients with diabetes may be at higher risk of readmission than those without diabetes. Potential ways to reduce readmission risk are inpatient education, specialty care, better discharge instructions, coordination of care, and post-discharge support. More studies are needed to test the effect of these interventions on the readmission rates of patients with diabetes.

Early readmission among patients with diabetes: A qualitative assessment of contributing factors

AIMS To explore causes of early readmission, i.e., hospital readmission within 30 days of discharge, among patients with diabetes. METHODS We performed thematic analysis of semi-structured interviews among 20 adults with diabetes hospitalized with an early readmission at an urban academic medical center. RESULTS Five themes emerged as contributors to readmission risk: (1) poor health literacy (lack of knowledge about diabetes and discharge instructions), (2) health system failure (of the discharge process and post-discharge support), (3) failure of expected protective factors, (e.g., following the discharge instructions, being aware of medication changes upon discharge, and having help and social support), (4) social determinants of health impeding care, and (5) loss of control over illness. A majority of patients reported needing assistance with transportation, obtaining and taking medications, and preparing food. Most patients denied an active role in exacerbating their condition prior to readmission, and many believed that being readmitted was out of their control. CONCLUSIONS Our findings suggest several interventions that may reduce the risk of early readmission for patients with diabetes, including inpatient diabetes education, improving communication of discharge instructions, and involving patients more in medication reconciliation and post-discharge planning.

Efficacy of sitagliptin for the hospital management of general medicine and surgery patients with type 2 diabetes (Sita-Hospital): a multicentre, prospective, open-label, non-inferiority randomised trial

BACKGROUND The role of incretin-based drugs in the treatment of patients with type 2 diabetes admitted to hospital has not been extensively assessed. In this study, we compared the safety and efficacy of a dipeptidyl peptidase-4 inhibitor (sitagliptin) plus basal insulin with a basal-bolus insulin regimen for the management of patients with type 2 diabetes in general medicine and surgery in hospitals. METHODS We did a multicentre, prospective, open-label, non-inferiority randomised clinical trial (Sita-Hospital) in five hospitals in the USA, enrolling patients aged 18-80 years with type 2 diabetes and a random blood glucose concentration of 7·8-22·2 mmol/L who were being treated with diet or oral antidiabetic drugs or had a total daily insulin dose of 0·6 units per kg or less, admitted to general medicine and surgery services. We randomly assigned patients (1:1) to receive either sitagliptin plus basal glargine once daily (the sitagliptin-basal group) or a basal-bolus regimen with glargine once daily and rapid-acting insulin lispro or aspart before meals (the basal-bolus group) during the hospital stay. All other antidiabetic drugs were discontinued on admission. The randomisation was achieved by computer-generated tables with block stratification according to randomisation blood glucose concentrations (ie, higher or lower than 11·1 mmol/L). The primary endpoint of the trial was non-inferiority in mean differences between groups in their daily blood glucose concentrations during the first 10 days of therapy (point-of-care measurements; non-inferiority was deemed a difference <1 mmol/L). The safety endpoints included hypoglycaemia and uncontrolled hyperglycaemia leading to treatment failure. All participants who received at least one dose of study drug were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT01845831. FINDINGS Between Aug 23, 2013, and July 27, 2015, we recruited 279 patients, and randomly assigned 277 to treatment; 138 to sitagliptin-basal and 139 to basal-bolus. The length of stay in hospital was similar for both groups (median 4 days [IQR 3-8] vs 4 [3-8] days, p=0·54). The mean daily blood glucose concentration in the sitagliptin-basal group (9·5 mmol/L [SD 2·7]) was not inferior to that in the basal-bolus group 9·4 mmol/L [2·7]) with a mean blood glucose difference of 0·1 mmol/L (95% CI -0·6 to 0·7). No deaths occurred in this trial. Treatment failure occurred in 22 patients (16%) in the sitagliptin-basal group versus 26 (19%) in the basal-bolus group (p=0·54). Hypoglycaemia occurred in 13 patients (9%) in the sitagliptin-basal group and in 17 (12%) in the basal-bolus group (p=0·45). No differences in hospital complications were noted between groups. Seven patients (5%) developed acute kidney injury in the sitagliptin-basal group and six (4%) in the basal-bolus group. One patient (0·7%) developed acute pancreatitis (in the basal-bolus group). INTERPRETATION The trial met the non-inferiority threshold for the primary endpoint, because there was no significant difference between groups in mean daily blood glucose concentrations. Treatment with sitagliptin plus basal insulin is as effective and safe as, and a convenient alternative to, the labour-intensive basal-bolus insulin regimen for the management of hyperglycaemia in patients with type 2 diabetes admitted to general medicine and surgery services in hospital in the non-intensive-care setting. FUNDING Merck.

Insulin Dose and Cardiovascular Mortality in the ACCORD Trial

OBJECTIVE In the ACCORD trial, intensive treatment of patients with type 2 diabetes and high cardiovascular (CV) risk was associated with higher all-cause and CV mortality. Post hoc analyses have failed to implicate rapid reduction of glucose, hypoglycemia, or specific drugs as the causes of this finding. We hypothesized that exposure to injected insulin was quantitatively associated with increased CV mortality. RESEARCH DESIGN AND METHODS We examined insulin exposure data from 10,163 participants with a mean follow-up of 5 years. Using Cox proportional hazards models, we explored associations between CV mortality and total, basal, and prandial insulin dose over time, adjusting for both baseline and on-treatment covariates including randomized intervention assignment. RESULTS More participants allocated to intensive treatment (79%) than standard treatment (62%) were ever prescribed insulin in ACCORD, with a higher mean updated total daily dose (0.41 vs. 0.30 units/kg) (P < 0.001). Before adjustment for covariates, higher insulin dose was associated with increased risk of CV death (hazard ratios [HRs] per 1 unit/kg/day 1.83 [1.45, 2.31], 2.29 [1.62, 3.23], and 3.36 [2.00, 5.66] for total, basal, and prandial insulin, respectively). However, after adjustment for baseline covariates, no significant association of insulin dose with CV death remained. Moreover, further adjustment for severe hypoglycemia, weight change, attained A1C, and randomized treatment assignment did not materially alter this observation. CONCLUSIONS These analyses provide no support for the hypothesis that insulin dose contributed to CV mortality in ACCORD.

Round Table Discussion on Inpatient Use of Continuous Glucose Monitoring at the International Hospital Diabetes Meeting

In May 2015 the Diabetes Technology Society convened a panel of 27 experts in hospital medicine and endocrinology to discuss the current and potential future roles of continuous glucose monitoring (CGM) in delivering optimum health care to hospitalized patients in the United States. The panel focused on 3 potential settings for CGM in the hospital, including (1) the intensive care unit (ICU), (2) non-ICU, and (3) continuation of use of home CGM in the hospital. The group reviewed barriers to use and solutions to overcome the barriers. They concluded that CGM has the potential to improve the quality of patient care and can provide useful information to help health care providers learn more about glucose management. Widespread adoption of CGM by hospitals, however, has been limited by added costs and insufficient outcome data.In May 2015 the Diabetes Technology Society convened a panel of 27 experts in hospital medicine and endocrinology to discuss the current and potential future roles of continuous glucose monitoring (CGM) in delivering optimum health care to hospitalized patients in the United States. The panel focused on 3 potential settings for CGM in the hospital, including (1) the intensive care unit (ICU), (2) non-ICU, and (3) continuation of use of home CGM in the hospital. The group reviewed barriers to use and solutions to overcome the barriers. They concluded that CGM has the potential to improve the quality of patient care and can provide useful information to help health care providers learn more about glucose management. Widespread adoption of CGM by hospitals, however, has been limited by added costs and insufficient outcome data.

Hypoglycemia in non-critically ill, hospitalized patients with diabetes: evaluation, prevention, and management.

Abstract Hypoglycemia among hospitalized patients with diabetes is a common problem. Of the > 8 million patients admitted to US hospitals annually with a diagnosis of diabetes, up to 25% may have a low blood glucose level during hospitalization. As a widely recognized cause of acute, potentially fatal events, hypoglycemia remains a significant barrier to optimal inpatient glycemic control. Although iatrogenic hypoglycemia is associated with adverse outcomes, it may be a marker for illness rather than causal in itself. Several factors, such as administration of exogenous insulin, mismatch of insulin administration with nutrition, and the loss of normal counterregulatory responses, place patients with diabetes at higher risk for hypoglycemia than patients without diabetes. Causes and predictors of hypoglycemia in hospitalized patients with diabetes are discussed. Careful attention to contributing factors, responsiveness to changes in clinical status, and specific institutional protocols and policies can reduce the risk of hypoglycemia. Use of subcutaneous basal-bolus insulin dosing consistent with national guidelines and correction rather than sliding-scale insulin may minimize both hyper- and hypoglycemia. A majority of the literature on inpatient hypoglycemia has been limited to the critical-care setting. This review therefore focuses on hypoglycemia among non-critically ill inpatients with diabetes.