Pasireotide use for the treatment of endogenous hyperinsulinemic hypoglycemia refractory to conventional medical therapy: A case report and review of the literature.

Insulinomas are rare neuroendocrine pancreatic tumors that can be associated with severe episodes of hypoglycemia, leading to significant morbidity and mortality. These tumors are often difficult to localize, and hypoglycemia control can be challenging since glucose levels can be resistant to conventional therapies. Pasireotide is a novel somatostatin analog with a high affinity to multiple somatostatin receptors. It has up to 40 times higher affinity for somatostatin receptor subtype 5 in comparison with octreotide, leading to a higher inhibition of insulin release from beta cells. There are few case reports regarding the use of pasireotide in refractory hyperinsulinemic hypoglycemia. We describe a challenging case of endogenous hyperinsulinemic hypoglycemia refractory to standard medical treatment, in which pasireotide was used. In this case, imaging studies and calcium stimulation testing failed to localize an insulin-secreting tumor in an 83-year-old woman. Glucose levels remained low despite treatment with diazoxide, verapamil, and octreotide, necessitating the use of IV dextrose solutions. After starting subcutaneous (SC) pasireotide 0.9 mg twice a day, there was a significant improvement in the frequency and severity of hypoglycemic events, allowing the patient to be discharged from the hospital without needing IV glucose support.

Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device.

These preliminary data from an ongoing first-in-human phase 1/2, open-label study provide proof-of-concept that pluripotent stem cell-derived pancreatic endoderm cells (PEC-01) engrafted in type 1 diabetes patients become islet cells releasing insulin in a physiologically regulated fashion. In this study of 17 subjects aged 22-57 with type 1 diabetes, PEC-01 cells were implanted subcutaneously in VC-02 macroencapsulation devices, allowing for direct vascularization of the cells. Engraftment and insulin expression were observed in 63% of VC-02 units explanted from subjects at 3-12 months post-implant. Six of 17 subjects (35.3%) demonstrated positive C-peptide as early as 6 months post-implant. Most reported adverse events were related to surgical implant or explant procedures (27.9%) or to side-effects of immunosuppression (33.7%). Initial data suggest that pluripotent stem cells, which can be propagated to the desired biomass and differentiated into pancreatic islet-like tissue, may offer a scalable, renewable alternative to pancreatic islet transplants.

Expansion of FasL-Expressing CD5+ B Cells in Type 1 Diabetes Patients.

Fas ligand drives insulitis in the non-obese diabetic mouse model of type 1 diabetes (T1D) and negatively regulates IL-10-producing (IL-10pos) CD5+ B cells in pancreata. Relevance of these phenomena to the human disease is poorly understood. Here, using splenocytes from T1D, autoantibody (Ab+), and non-diabetic (ND) human subjects, we show that a subpopulation of CD5+ B cells that is characterized by expression of FasL (FasLhiCD5+) was significantly elevated in T1D subjects, many of whom had significantly reduced frequency of IL-10posCD5+ B cells compared to Ab+ subjects. The majority of FasLhiCD5+ B cells did not produce cytokines and were more highly resistant to activation-induced cell death than their IL-10posCD5+ counterparts. These results associate expansion of FasL-expressing CD5+ B cells with T1D and lay the groundwork for future mechanistic studies to understand specific role in disease pathogenesis.

Long-term insulin glargine therapy in type 2 diabetes mellitus: a focus on cardiovascular outcomes.

Cardiovascular disease is the leading cause of mortality in type 2 diabetes mellitus. Hyperinsulinemia is associated with increased cardiovascular risk, but the effects of exogenous insulin on cardiovascular disease progression have been less well studied. Insulin has been shown to have both cardioprotective and atherosclerosis-promoting effects in laboratory animal studies. Long-term clinical trials using insulin to attain improved diabetes control in younger type 1 and type 2 diabetes patients have shown improved cardiovascular outcomes. Shorter trials of intensive diabetes control with high insulin use in higher risk patients with type 2 diabetes have shown either no cardiovascular benefit or increased all cause and cardiovascular mortality. Glargine insulin is a basal insulin analog widely used to treat patients with type 1 and type 2 diabetes. This review focuses on the effects of glargine on cardiovascular outcomes. Glargine lowers triglycerides, leads to a modest weight gain, causes less hypoglycemia when compared with intermediate-acting insulin, and has a neutral effect on blood pressure. The Outcome Reduction With Initial Glargine Intervention (ORIGIN trial), a 6.2 year dedicated cardiovascular outcomes trial of glargine demonstrated no increased cardiovascular risk.

Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study: results of the randomized phase III study in recent-onset human type 1 diabetes.

OBJECTIVE: Previous studies demonstrated that the anti-CD3 monoclonal antibody otelixizumab, administered at a total dose of 48-64 mg, can slow the loss of C-peptide in recent-onset type 1 diabetes patients, with frequent reactivation of Epstein Barr virus (EBV). The DEFEND-1 (Durable Response Therapy Evaluation for Early or New-Onset Type 1 Diabetes) trial was designed to test whether a lower dose of otelixizumab could preserve C-peptide secretion in new-onset type 1 diabetes patients. RESEARCH DESIGN AND METHODS: A multicenter, randomized, placebo-controlled trial was performed in sites in the U.S., Canada, and Europe. Two hundred eighty-one patients were randomized to treatment with 3.1 mg otelixizumab administered over 8 days or placebo. The primary end point of the study was the change in C-peptide area under the curve (AUC) from a 2-h mixed-meal tolerance test at month 12. RESULTS: The change in 2-h C-peptide AUC was not different between placebo-treated patients and otelixizumab-treated patients (-0.20 vs. -0.22 nmol/L, P = 0.81). Secondary end points, including HbA1c, glucose variability, and insulin dose, were also not statistically different between the two groups. More patients in the otelixizumab group than in the placebo group experienced adverse events, mostly grade 1 or grade 2. There was no EBV reactivation (viral load >10,000 copies/10(6) peripheral blood mononuclear cells) in the otelixizumab group, in contrast with previously published studies at higher doses of otelixizumab. CONCLUSIONS: Otelixizumab was well tolerated in patients with recent-onset type 1 diabetes at a total dose of 3.1 mg, but did not achieve preservation of levels of C-peptide or other markers of metabolic control.

Rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

BACKGROUND: Rosiglitazone improves glycemic control for patients with type 2 diabetes mellitus, but there remains controversy regarding an observed association with cardiovascular hazard. The cardiovascular effects of rosiglitazone for patients with coronary artery disease remain unknown. METHODS AND RESULTS: To examine any association between rosiglitazone use and cardiovascular events among patients with diabetes mellitus and coronary artery disease, we analyzed events among 2368 patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Total mortality, composite death, myocardial infarction, and stroke, and the individual incidence of death, myocardial infarction, stroke, congestive heart failure, and fractures, were compared during 4.5 years of follow-up among patients treated with rosiglitazone versus patients not receiving a thiazolidinedione by use of Cox proportional hazards and Kaplan-Meier analyses that included propensity matching. After multivariable adjustment, among patients treated with rosiglitazone, mortality was similar (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.58-1.18), whereas there was a lower incidence of composite death, myocardial infarction, and stroke (HR, 0.72; 95% CI, 0.55-0.93) and stroke (HR, 0.36; 95% CI, 0.16-0.86) and a higher incidence of fractures (HR, 1.62; 95% CI, 1.05-2.51); the incidence of myocardial infarction (HR, 0.77; 95% CI, 0.54-1.10) and congestive heart failure (HR, 1.22; 95% CI, 0.84-1.82) did not differ significantly. Among propensity-matched patients, rates of major ischemic cardiovascular events and congestive heart failure were not significantly different. CONCLUSIONS: Among patients with type 2 diabetes mellitus and coronary artery disease in the BARI 2D trial, neither on-treatment nor propensity-matched analysis supported an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Cardiovascular effects of noninsulin, glucose-lowering agents: need for more outcomes data.

Macrovascular complications of type 2 diabetes mellitus (DM) are primarily driven by the combination of underlying atherosclerosis and propensity for thrombosis. Prevention of macrovascular complications in DM relies on therapies directed at multiple coexisting intermediary pathophysiologies that contribute to cardiovascular events, including hyperglycemia, lipoprotein abnormalities, hypertension, inflammation, and propensity for thrombosis. Multiple noninsulin, glucose-lowering agents have been developed that effectively lower blood glucose levels. This review explores the literature on the cardiovascular benefits and harms associated with these therapies, with an emphasis on cardiovascular outcomes when available. The lack of long-term data on cardiovascular outcomes regarding safety and efficacy of available traditional glucose-lowering agents has led to recommendations for more thorough evaluations of new therapies before approval. Furthermore, recent data suggest harm from intensive hemoglobin A(1c) reductions. Accordingly, there are multiple, large, cardiovascular-event driven phase 3-4 trials of therapies from the incretin axis currently enrolling. Recommendations for a therapeutic approach with noninsulin, glucose-lowering agents for the prevention of cardiovascular events in patients with type 2 DM are provided based on current data. Ultimately, multifactorial risk interventions, including lifestyle modifications, antihyperglycemic agents, antihypertensives, statins, and aspirin remain the primary focus to prevent macrovascular complications in patients with type 2 DM.

Intensive training of subjects with chronic hemiparesis on a motorized cycle combined with functional electrical stimulation (FES): a feasibility and safety study.

BACKGROUND AND PURPOSE: This study tested the safety and ability of subjects with chronic hemiplegia to tolerate intensive training using a motorized cycle combined with functional electrical stimulation (FES) system. METHODS: A case series of 10 subjects with chronic stroke participated in 30-minute three times per week cycling on a stationary motorized cycling system combined with FES (RT300(TM) ). The stimulation activated the dorsal and plantar flexors, the quadriceps and the hamstrings using four channels and a stimulation pattern that assisted cycling motion of the paretic lower limb. Patients were instructed to cycle as close as possible to 60 rpm and the resistance to cycling was gradually increased using a computer-based algorithm. The training lasted eight weeks. RESULTS: All 10 participants completed the training without adverse reactions to the training or the FES. The kcal utilized during the training increased significantly (p = 0.0003) between session 1 (2.2 ± 0.47), session 12 (4.3 ± 1.2) and session 24 (7.5 ± 1.8). Peak pedaling power increased from 6.5 ± 0.5 W pre-training to 18.0 ± 5.4 W post-training. Locomotion variables that improved significantly were time to complete the get up and go test (45.4 ± 54.9 seconds vs. 34.0 ± 31.8 seconds) a 24.6% improvement (p = 0.03) and gait velocity, which increased 25.0% from 0.4 ± 0.3 m/sec to 0.5 ± 0.4 m/sec (p = 0.01). CONCLUSION: Using a motorized cycle combined with FES intensive training appears safe and can be tolerated by patients with chronic stroke of wide age range, diverse severity of cardio-pulmonary deconditioning, motor loss and locomotor deficits.

Dietary supplementation with d-tagatose in subjects with type 2 diabetes leads to weight loss and raises high-density lipoprotein cholesterol.

Oral d-tagatose (d-tag) attenuates the rise in plasma glucose during an oral glucose tolerance test in subjects with type 2 diabetes mellitus (DM) and reduces food intake in healthy human subjects. A reduction in food consumption and less weight gain occur in rats fed tagatose. This pilot study explored the metabolic effects of d-tag given daily to 8 human subjects with type 2 DM for 1 year. We hypothesized that this treatment period would lead to weight loss and improvements in glycated hemoglobin and the lipid profile. A 2-month run-in period was followed by a 12-month treatment period when 15 g of oral d-tag was taken 3 times daily with food. No serious adverse effects were seen during the 12-month treatment period. Ten of the initially 12 recruited subjects experienced gastrointestinal side effects that tended to be mild and transient. When 3 subjects were excluded who had oral diabetes, medications added and/or dosages increased during the study and mean (SD) body weight declined from 108.4 (9.0) to 103.3 (7.3) kg (P = .001). Glycated hemoglobin fell nonsignificantly from 10.6% ± 1.9% to 9.6% ± 2.3% (P = .08). High-density lipoprotein cholesterol progressively rose from a baseline level of 30.5 ± 15.8 to 41.7 ± 12.1 mg/dL at month 12 in the 6 subjects who did not have lipid-modifying medications added during the study (P < .001). Significant improvements in body weight and high-density lipoprotein cholesterol in this pilot study suggest that d-tag may be a potentially useful adjunct in the management of patients with type 2 DM.

US trends in glycemic control, treatment, and comorbidity burden in patients with diabetes.

This study explored trends over time in diabetes prevalence, glycemic control, and antidiabetic therapy choices among adults (18-64 years) and older adults (≥ 65 years). Factors that predict diabetes outcomes were explored. The study was cross-sectional, with data from the 1999 to 2004 National Health and Nutrition Examination Survey. The study group consisted of 1211 persons with self-reported diabetes. Other information obtained from the study included self-reported medication for diabetes, hypertension, stroke, heart failure, and health status. The survey also provided examination or laboratory tests of obesity, nephropathy, and glycosylated hemoglobin level. Descriptive and logistic regression analyses were used in the study. The study showed that the proportion of diabetics with good glycemic control increased during the period from 1999 to 2004. However, nearly half of the adults and one third of older adults with diabetes did not reach glycemic control in 2003-2004. Overall, 59% of adults and 46% of older adults were obese. There was a high prevalence of hypertension, heart failure, stroke, and nephropathy among patients with diabetes, especially in older adults. The results indicate a high percentage of poor glycemic control among persons with diabetes. There were also a substantial number of comorbid conditions associated with diabetes.

Diabetes management in the hospital.

Hyperglycemia is an increasingly common and often complex condition to manage in the inpatient setting. Numerous clinical trials have demonstrated associations between uncontrolled diabetes and poor clinical outcomes in a number of inpatient settings. Insulin remains the treatment of choice for the majority of hyperglycemic hospitalized patients and should be prescribed in a physiologic manner, employing basal and bolus insulin. Intravenous insulin should be used liberally in the ICU setting where randomized studies have demonstrated improved outcomes. Recommendations for insulin use in the inpatient setting are provided.

A comparison of type 2 diabetes outcomes among persons with and without severe mental illnesses.

OBJECTIVE: Type 2 diabetes is an important comorbid medical condition associated with schizophrenia. The objective of this study was to compare glycosylated hemoglobin (HbA(1c)) levels of patients who had type 2 diabetes and schizophrenia with those of patients who had type 2 diabetes and major mood disorders and those who had type 2 diabetes but who did not have severe mental illness. METHODS: A sample of 300 patients with type 2 diabetes was recruited from community mental health centers in the greater Baltimore region and nearby primary care clinics. Of these, 100 had schizophrenia, 101 had a major mood disorder, and 99 had no identified severe mental illness. HbA(1c), the main outcome measure, was compared between the group with schizophrenia and the other two groups. RESULTS: All three groups had HbA(1c) values above recommended levels. HbA(1c) levels were significantly lower among patients with schizophrenia than among patients who did not have severe mental illness but were not significantly different from those of patients who had major mood disorders. Patients for whom olanzapine was prescribed had higher HbA(1c) levels than those for whom other antipsychotic agents were prescribed. CONCLUSIONS: All three groups of patients require improved diabetes treatment to achieve acceptable HbA(1c) levels. There may be previously unrecognized benefits for diabetes management among persons with severe mental illnesses who are receiving regular mental heath care, but these individuals may also have risk factors that can influence diabetes outcomes and HbA(1c) levels.