Therapeutic Inertia in the Management of Type 2 Diabetes: A Narrative Review.

Adequate glycemic control is key to prevent morbi-mortality from type 2 diabetes (T2D). Despite the increasing availability of novel, effective, and safe medications for the treatment of T2D, and periodically updated guidelines on its management, the overall rate of glycemic goal attainment remains low (around 50%) and has not improved in the past decade. Therapeutic inertia (TI), defined as the failure to advance or de-intensify medical therapy when appropriate to do so, has been identified as a central contributor to the lack of progress in the rates of HbA1c goal attainment. The time to treatment intensification in patients not meeting glycemic goals has been estimated to be between 1 and 7 years from the time HbA1c exceeded 7%, and often, even when an intervention is carried out, it proves insufficient to achieve glycemic goals, which led to the concept of intensification inertia. Therefore, finding strategies to overcome all forms of TI in the management of T2D is a fundamental initiative, likely to have an enormous impact in health outcomes for people with T2D. There are several factors that have been described in the literature leading to TI, including clinician-related, patient-related, and healthcare system-related factors, which are discussed in this review. Likewise, several interventions addressing TI had been tested, most of them proving limited efficacy. Within the most effective interventions, there appear to be two common factors. First, they involve a team-based effort, including nurses, pharmacists, and diabetes educators. Second, they were built upon a framework based on results of qualitative studies conducted in the same context where they were later implemented, as will be discussed in this article. Given the complex nature of TI, it is crucial to use a research method that allows for an in-depth understanding of the phenomenon. Most of the literature on TI is focused on quantitatively describing its consequences; unfortunately, however, not many study groups have undertaken qualitative studies to deeply investigate the drivers of TI in their diverse contexts. This is particularly true in the United States, where there is an abundance of publications exploring the effects of different strategies to overcome TI in type 2 diabetes, but a severe shortage of qualitative studies aiming to truly understand the phenomenon.

Follow-Up of Patients After Total Pancreatectomy and Islet Cell Autotransplantation at Off-Site Islet Isolation Facility.

CONTEXT: Total pancreatectomy with islet autotransplantation (TPIAT) is a definitive management for intractable pain in patients with chronic pancreatitis (CP). Islet autotransplantation (IAT) allows for the preservation of beta cells to prevent complications of long-term diabetes. OBJECTIVE: Our study follows TPIAT recipients for up to 12 years to determine the efficacy of the procedure completed with an off-site islet isolation facility. METHODS: Patient demographics, mixed meal tolerance test measures, glycosylated hemoglobin, insulin requirements, and homeostatic model assessment for insulin resistance values were collected prior to surgery and at the most recent follow-up assessment. RESULTS: Forty-four patients (median age, 46.0 years; range, 20-78 years) underwent TPIAT for CP. At an overall median follow-up time of 845.5 days (range, 195-4470 days) 8 patients were insulin independent and 36 patients were insulin dependent. At the most recent follow-up time point, islet yield per kilogram was the strongest indicator of insulin independence. Homeostatic model assessment for insulin resistance values were comparable between insulin independent and dependent cohorts. CONCLUSIONS: Our long-term follow-up data suggest that IAT can effectively reduce insulin requirements and improve postoperative glycemic control.

Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation.

The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating donor/recipients with chronic pancreatitis undergoing total pancreatectomy and autologous islet transplantation (TPAIT) to test the hypothesis that peri-transplant treatment with the FDA-approved anti-inflammatory hydroxychloroquine (HCQ) improves graft function. In this randomized placebo-controlled pilot clinical study, patients (n = 6) were treated with oral HCQ for 30 days prior to and 90 days after TPAIT. In vivo islet function was assessed via Mixed Meal Tolerance Testing before HCQ treatment, 6- and 12-months after surgery. In vitro islet bioenergetics were assessed at the time of transplantation via extracellular flux analysis of islet preparation samples from the clinical trial cohort and six additional patients (n = 12). Our study shows that HCQ did not alter clinical endpoints, but HCQ-treated patients showed greater spare respiratory capacity (SRC) compared to samples from control patients (P=0.028). Glycolytic metabolism of islet preparations directly correlated with stimulated C-peptide secretion both before and after TPAIT (P=0.01, R2=0.489 and P=0.03, R2=0.674, respectively), and predicted in vivo islet function better than mitochondrial metabolism of islet preps or islet equivalents infused. Overnight culture of islet preparations altered bioenergetic function, significantly decreasing SRC and maximal respiration (P<0.001). In conclusion, while HCQ did not alter clinical outcomes, it was associated with significantly increased SRC in islet preparations. Bioenergetic analyses of islet preparations suggests that culture should be avoided and that glycolysis may be a more sensitive indicator of in vivo islet function than current metrics, including islet oxygen consumption and islet equivalents infused.

Real-world Comparison of Afirma GEC and GSC for the Assessment of Cytologically Indeterminate Thyroid Nodules.

CONTEXT: Molecular tests have improved the accuracy of preoperative diagnosis of indeterminate thyroid nodules. The Afirma Gene Sequencing Classifier (GSC) was developed to improve the specificity of the Gene Expression Classifier (GEC). Independent studies are needed to assess the performance of GSC. OBJECTIVE: The aim was to compare the performance of GEC and GSC in the assessment of indeterminate nodules. DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective analysis of Bethesda III and IV nodules tested with GEC or GSC in an academic center between December 2011 and September 2018. Benign call rates (BCRs) and surgical outcomes were compared. Histopathologic data were collected on nodules that were surgically resected to calculate measures of test performance. RESULTS: The BCR was 41% (73/178) for GEC and 67.8% (82/121) for GSC (P < .001). Among specimens with dominant Hürthle cell cytology, the BCR was 22% (6/27) for GEC and 63.2% (12/19) for GSC (P = .005). The overall surgery rate decreased from 47.8% in the GEC group to 34.7% in the GSC group (P = .025). One GEC-benign and 3 GSC-benign nodules proved to be malignant on surgical excision. GSC had a statistically significant higher specificity (94% vs 60%, P < .001) and positive predictive value (PPV) (85.3% vs 40%, P < .001) than GEC. While sensitivity and negative predictive value (NPV) dropped with GSC (97.0% vs 90.6% and 98.6% vs 96.3%, respectively), these differences were not significant. CONCLUSIONS: GSC reclassified more indeterminate nodules as benign and improved the specificity and PPV of the test. These enhancements appear to be resulting in fewer diagnostic surgeries.

Change in Functional Beta Cell Capacity With Time Following Autologous Islet Transplantation.

OBJECTIVES: Autologous islet transplantation (AIT) is performed to preserve insulin secretory function in chronic pancreatitis patients undergoing total pancreatectomy (TP). No data exist on the effect of time lapse on beta cell function post TP-AIT. We aimed to investigate the factor of time lapse on beta cell function following TP-AIT. METHODS: Retrospectively, we identified 31 adult patients with chronic pancreatitis who underwent TP-AIT between 2008 and 2016. Changes in beta cell function were assessed using (1) BETA-2 scores and (2) analysis of posttransplant mixed-meal tolerance testing. RESULTS: Significant decrease in functional beta cell capacity expressed by BETA-2 scores was seen in the first 2 years following TP-AIT, with an annual decrease of 6.3 points in median BETA-2 score (interquartile range, 4.6-11.6; P = 0.002). In the mixed-meal tolerance testing analysis, nonsignificant trends toward higher glucose, lower insulin, and lower C-peptide were seen with time lapse. Additionally, higher hemoglobin A1c values (P = 0.033) and higher insulin requirements (P = 0.04) were seen with longer follow-up after AIT. CONCLUSIONS: A steady drop in functional beta cell capacity was observed in the 2 years following TP and AIT. To our knowledge, to date this is the first report of the BETA-2 score applicability in the AIT setting.

Beta Cell Stress in Insulin Independent Subjects Following Total Pancreatectomy and Autologous Islet Transplantation.

In patients with chronic pancreatitis (CP), autologous islet transplantation (AIT) is often coupled with total pancreatectomy (TP) in aims to preserve patients' insulin secretory function. Despite a third of patients achieving insulin independence post-total pancreatectomy and autologous islet transplantation (TPAIT), many will require the addition of insulin therapy for maintenance of glycemic control overtime. We aimed through this study to investigate the early metabolic profile signature of insulin independent subjects post-TPAIT, specifically exploring markers of beta cell stress in this cohort. In a prospective study design, we identified 37 subjects who underwent TPAIT between 2008 and 2017. Metabolic parameters were assessed using mixed meal tolerance test data (MMTT), and the insulin-to-proinsulin index ratio, a marker of beta cell stress. Assessments between metabolic variables were evaluated using the Wilcoxon signed rank test. A significance level of 0.05 was assumed for all comparisons. At a mean (±standard deviation) follow up duration of 37.7±17 months post-TPAIT, 11 patients (30%) were insulin independent with a mean HbA1C of 5.85±0.42%. Despite adequate glycemic control in the latter cohort, we observed significantly higher median peak glucose (180.5 versus 115.0 mg/dL; p=0.031), and lower median fasting C-peptide (0.95 versus 1.5 ng/mL; p=0.008) on post-TPAIT MMTT compared to pre-TPAIT MMTT. Additionally, significantly lower insulin-to-proinsulin index AUC ratio was seen post-TPAIT compared to pre-TPAIT (p=0.022). A decline in the proinsulin processing capacity, expressed by a lower insulin-to-proinsulin index ratio was seen in insulin independent subjects post-TPAIT. Further studies exploring the pathophysiology underlying these findings should be attained.

Autoimmunity in Autologous Islet Transplantation.

Total pancreatectomy (TP) is increasingly being utilized for definitive treatment in patients with debilitating chronic pancreatitis (CP). In an effort to prevent surgical diabetes, the procedure can be performed in conjunction with transplantation of islets of Langerhans recovered from the patients' own resected pancreas (autologous islet transplantation, AIT). Given that patients undergoing TP and AIT are traditionally assumed not to be at risk for the development of beta-cell autoimmunity, it is possible that the presence of autoimmune islet graft failure has been overlooked and underreported in this patient population. Herein, we describe two cases who underwent TP and AIT and later developed new-onset beta-cell autoimmunity (as evidenced by de novo glutamic acid decarboxylase antibody positivity), accompanied by complete insulin-dependent states. These cases emphasize the need for considering a possible autoimmune phenomenon in the workup of TP and AIT patients who manifest with unexpected and rapid deterioration in their glycemic control.