Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes.

BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group. CONCLUSIONS: In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).

The clinical utility of free thyroxine in oral levothyroxine absorption testing.

OBJECTIVE: Original absorption studies for levothyroxine (LT4) were validated using total thyroxine (TT4) measurements. Free thyroxine (FT4) has largely supplanted TT4 in clinical practice. The objective of our study was to assess the clinical utility of FT4 in oral LT4 absorption testing. METHODS: In this retrospective electronic health record analysis, we recorded data of patients who underwent LT4 oral absorption testing between November 2010 and January 2012 because of persistent hypothyroidism despite a greater than anticipated weight-based dose of LT4. Patients included had primary hypothyroidism and an absorption test with assessment of both TT4 and FT4 measured at times 0, 30, 60, 90, 120, 180, 240, 300, and 360 minutes. The test was conducted with 1 mg (five 200-µg tablets) of Synthroid® after an overnight fast by a standard nonisotopic method. RESULTS: A total of 10 patients (3 men/7 women) underwent absorption testing. Prior to testing, the median daily LT4 dose was 250 µg (range, 150 to 350 µg). Three patients were also on liothyronine (10, 20, or 50 µg daily). Based on the calculated amount absorbed, 1 patient demonstrated subnormal absorption, and 9 patients were normal. Median body mass index was 33 kg/m2 (range, 21 to 50 kg/m2). Median calculated absorption was 105% (range, 3.7 to 195.6%). The correlation comparing FT4 and TT4 was 0.88 (95% confidence interval, 0.56 to 0.97; P<.001), a significant correlation. CONCLUSION: FT4 and TT4 correlated highly, even in patients who were severely hypothyroid; FT4 may be used interchangeably with TT4 as a qualitative assessment of suspected malabsorption using an oral LT4 absorption test.

Incidental papillary thyroid carcinoma: clinical characteristics and prognostic factors among patients with Graves' disease and euthyroid goiter, Cleveland Clinic experience.

OBJECTIVE: The prevalence and clinical significance of incidental differentiated thyroid cancer (DTC) in patients with Graves' disease (GD) remain uncertain. Thyroid stimulating antibody (TSI Ab)-titers were thought to be responsible for the potentially increased incidence or aggressiveness of PTC in that setting. The aim of this study was to compare the prevalence of incidental DTC among patients with GD and euthyroid goiter (EG), to assess the ability of TSI to predict DTC in GD and to investigate the clinical features that may predict incidental DTC in GD and EG. METHODS: Two hundred and forty eight patients with EG and 245 patients with GD patients who had undergone total thyroidectomy at our institution between 2005 and 2013 were retrospectively selected from our data base. An analysis of incidentally discovered DTC was conducted comparing GD group with EG group. RESULTS: Incidental micro-papillary thyroid cancer (MPTC) was found in 28% in EG group, as compared to 26% in GD group. PTC Patients with GD were significantly younger (44 vs 59) and less likely to have compressive symptoms than with EG before surgery (p<0.001). In GD group, patients with MPTC were also significantly older (p=0.009) than those without, were more likely to have symptomatic goiter (p<0.001), and to have a nodular disease (p<0.001). TSI ab titer did not predict MPTC in GD group (The AUC curve was 0.55 (95% CI: 0.46, 0.64). Among patients with GD and incidental MPTC, 58% of patients had at least one nodule. CONCLUSION: The prevalence of incidental DTC in GD is comparable to EG. Each is increased compared to general population. Age of presentation of PTC was significantly lower in GD suggesting an increased risk for MPTC in GD. Nodule size greater than 1cm predicted incidental DTC whereas TSI ab titers and disease duration did not.

Risk of thromboembolic events in patients with prolactinomas compared with patients with nonfunctional pituitary adenomas.

Prolactin has been proposed as a potent coactivator of platelet aggregation, possibly contributing to thromboembolic events. The objective of the study was to evaluate the relationship between prolactinoma and deep vein thrombosis (DVT), pulmonary embolism (PE), and cerebrovascular accident (CVA). Subjects were identified from a prospectively maintained pituitary database at the Cleveland Clinic. We retrospectively reviewed the charts of 544 subjects: 347 patients with prolactinomas (prolactinoma group) and 197 patients with nonfunctional pituitary adenomas (control group). Main outcome measures were DVT, PE and CVA. We found that 19 (5.5%) patients in the prolactinoma group and five (2.5%) patients in the control group had documented DVT, PE, or CVA, but this difference was not significant (p = 0.109). However, the mean initial prolactin level was higher at the time of diagnosis among prolactinoma patients than among controls (815.23 ng/ml vs. 15.90 ng/ml; p < 0.001). Among prolactinoma patients, 15 (5.5%) of 275 patients who underwent medical treatment (with cabergoline, bromocriptine, pergolide and/or other drug) and 4 (5.6%) of 72 patients who underwent transsphenoidal surgery had documented DVT, PE, or CVA, which suggests that dopaminergic therapy did not influence the risk of thromboembolic events. Hyperprolactinemia per se does not appear to predispose to a hypercoagulable state.

Acromegaly with negative pituitary MRI and no evidence of ectopic source: the role of transphenoidal pituitary exploration?

Growth hormone (GH) producing adenomas of the pituitary gland are usually macroadenomas (>10 mm in size). Often these adenomas are locally invasive by the time of diagnosis. Acromegaly secondary to a very small pituitary microadenoma not visualized on pituitary magnetic resonance (MR) imaging is rare. We report a patient with acromegaly and an unremarkable pituitary MR imaging who had negative work up for ectopic growth hormone-releasing hormone (GHRH) or GH secreting tumors. Transsphenoidal pituitary exploration revealed a pituitary adenoma located on the left side of the sella against the medial wall of the cavernous sinus extending posteriorly along the floor of the sella all the way to the right side. The acromegaly was treated with resection of the pituitary adenoma and normalization of serum insulin-like growth factor 1 (IGF-1) and GH levels. In a patient with acromegaly and unremarkable pituitary MR imaging, with no evidence of ectopic GH and GHRH production, transsphenoidal pituitary exploration is a reasonable approach and may result in clinical improvement and biochemical cure in the hand of experienced surgeon. This approach may avoid long term medical treatment with its associated cost.

Pancreatic metastasis of tall cell variant of papillary thyroid carcinoma: diagnosis by endoscopic ultrasound-guided fine needle aspiration.

CONTEXT: The incidence of tall cell variant of papillary thyroid carcinoma that has metastasized to the pancreas is extremely rare. There has been only one previously reported case of pancreatic metastasis of the tall cell variant of papillary thyroid carcinoma. CASE REPORT: We present the case of a patient who presented with tall cell variant of papillary thyroid carcinoma with metastasis to the pancreas detected and confirmed cytologically by EUS-FNA after finding of the CT scan were equivocal. DISCUSSION: EUS-FNA is a powerful new tool that can be used for the detection and diagnosis of primary and metastatic lesions of the pancreas.

Evaluation and Referral of Diabetic Eye Disease in the Endocrinology and Primary Care Office Settings.

BACKGROUND AND OBJECTIVE: The purpose of this study was to identify whether endocrinologists and primary care physicians (PCP) adequately screen for ophthalmic symptoms/signs within office visits and provide timely ophthalmology referrals in patients with diabetes. PATIENTS AND METHODS: Patients between the ages of 18 years and 80 years with diabetes who underwent an office visit with an endocrinologist or a PCP between January 1, 2014, and December 31, 2014, were identified. Demographics, ophthalmic assessments, and referral information were collected. RESULTS: A total of 1,250 patient records were reviewed. Providers asked about ophthalmic symptoms/signs in 95.5% and 71% of endocrinology and primary care office encounters, respectively (P < .0001). Past and/or future ophthalmology appointments were verified in 86.1% and 49.7% of patients during endocrinology and PCP visits, respectively (P < .0001). CONCLUSIONS: Ophthalmic complications from diabetes are not adequately screened, especially within the primary care setting, and further quality improvement measures may improve adherence to recommended screening protocols. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:930-934.].

Multicenter retrospective assessment of thiazolidinedione monotherapy and combination therapy in patients with type 2 diabetes: comparative subgroup analyses of glycemic control and blood lipid levels.

BACKGROUND: Thiazolidinediones (TZDs) have contributed to the management of patients with type 2 diabetes mellitus as unique insulin-sensitizing agents. When used as monotherapy or in combination therapy, these drugs not only reduce glycosylated hemoglobin (HbA(1c)) levels, but also effect changes in blood lipid concentrations and have the potential to ameliorate cardiovascular disease risk. Although drugs in the TZD class are perceived to be equivalent clinically, prospective and retrospective studies have demonstrated their ability to modify blood lipid levels. OBJECTIVE: We evaluated and compared the effects of pioglitazone and rosiglitazone monotherapy and combination therapy on blood lipid levels and HbA(1c) in patients with type 2 diabetes. METHODS: We conducted a multicenter retrospective chart review of 1115 records of patients with type 2 diabetes who received pioglitazone or rosiglitazone, alone or in combination with other antidiabetic agents, between August 1, 1999, and August 31, 2000. The review was conducted to evaluate pretreatment and posttreatment levels of triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and HbA(1c). RESULTS: All observed demographic characteristics, comorbidities, and concomitant drug use were similar in both treatment cohorts. Of the patients who received pioglitazone, 83% also received >/=1 other antihyperglycemic agent and 59% received some form of antihyperlipidemic therapy. Among those who received rosiglitazone, 81% received concomitant antihyperglycemic medication and 60% received some form of antihyperlipidemic therapy. With pioglitazone, mean levels of serum triglyceride, total cholesterol, and LDL-C decreased and HDL-C increased in most patients, with or without concomitant antihyperglycemic medications; with rosiglitazone, with or without other antidiabetic agents, triglyceride and HDL-C levels decreased, whereas total cholesterol and LDL-C levels increased in most patients. Reductions in HbA(1c) levels and increases in body weight related to each study drug were comparable. CONCLUSIONS: This comparative assessment of pioglitazone and rosiglitazone, based on observational data, reveals that use of these TZDs with other antidiabetic agents was similar in 605 primary care practices in the United States. In both monotherapy and combination treatment regimens, pioglitazone was associated with greater beneficial effects on lipids than was rosiglitazone. Additional studies are needed to determine the long-term outcomes of TZD therapy with concomitant antihyperglycemic medications.

Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records.

BACKGROUND: The antihyperglycemic effects of pioglitazone hydrochloride and rosiglitazone maleate are well documented. The results of clinical trials and observational studies have suggested, however, that there are individual differences in the effects of these drugs on blood lipid levels. OBJECTIVE: The present study evaluated the effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus. METHODS: This was a retrospective review of randomly selected medical records from 605 primary care practices in the United States in which adults with type 2 diabetes received pioglitazone or rosiglitazone between August 1, 1999, and August 31, 2000. The outcome measures were mean changes in serum concentrations of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glycosylated hemoglobin (HbA1c) values. RESULTS: Treatment with pioglitazone was associated with a reduction in mean TG of 55.17 mg/dL, a reduction in TC of 8.45 mg/dL, an increase in HDL-C of 2.65 mg/dL, and a reduction in LDL-C of 5.05 mg/dL. Treatment with rosiglitazone was associated with a reduction in mean TG of 13.34 mg/dL, an increase in TC of 4.81 mg/dL, a reduction in HDL-C of 0.12 mg/dL, and an increase in LDL-C of 3.56 mg/dL. With the exception of HDL-C, the differences in mean changes in lipid parameters between treatment groups were statistically significant (P < 0.001, pioglitazone vs rosiglitazone). Reductions in HbA1c were statistically equivalent between treatments (1.04% pioglitazone, 1.18% rosiglitazone). CONCLUSIONS: Treatment with pioglitazone was associated with greater beneficial effects on blood lipid levels than treatment with rosiglitazone, whereas glycemic control was equivalent between the 2 treatments.

Advances in diabetes for the millennium: chronic microvascular complications of diabetes.

Hyperglycemia and microvascular complications of retinopathy, nephropathy, and neuropathy are shared by type 1 and type 2 diabetes. These complications seem to be uniquely associated with the diabetic state in humans and animals; they are not seen in nondiabetic humans or animals. Intervention trials aimed at achieving lower blood glucose levels as reflected in a lower HbA1c value have shown reductions in the rate of development of those complications when HbA1c is lower in one group compared with a matched group with less good control. Currently, 3 schools of thought have been championed to explain elevated blood glucose. Each is discussed here, as are interventions aimed at the various metabolic derangements rather than at correction of the hyperglycemia.

Insulin glargine use during pregnancy.

OBJECTIVE: To review the literature regarding the use of insulin glargine during pregnancy, specifically addressing the issues and concerns surrounding mitogenicity, placental transfer, and maternal and fetal safety. METHODS: We performed a systematic literature search using MEDLINE and BIOSIS Previews up to March 2011. Additional studies were identified by hand-searching reference lists from original articles. Inclusion was limited to studies and abstracts in the English language. RESULTS: A total of 23 reports with 1001 pregnancies managed with insulin glargine contained relevant information regarding the maternal and fetal safety of its use during pregnancy. Insulin glargine does not appear to have enhanced mitogenic activity when compared with the mitogenic activity of native human insulin. The transplacental transfer of insulin glargine appears to be negligible, although it is possible that antibody-bound insulin glargine may gain access to the fetal compartment. The available data suggest that there are no identifiable, consistent adverse maternal or fetal outcomes with the use of insulin glargine during pregnancy, including during the first trimester. CONCLUSIONS: Use of insulin glargine during pregnancy should be seriously considered in uncontrolled diabetes during pregnancy and in those patients taking insulin glargine before conception, because the benefits from improved glycemic control would be expected to outweigh any, as yet, unproven risks of insulin glargine exposure.

Do incretin-based therapies cause acute pancreatitis?

In 2007 a question was raised about the causal relationship between the first of the glucagon-like peptide 1 receptor agonists, exenatide, and pancreatitis, as postmarketing reports of pancreatitis in patients treated with this agent had been received by the Food and Drug Administration (FDA). There had been six reports of hemorrhagic pancreatitis, with two of the cases resulting in death. An update of the package insert for Byetta was mandated. Sitagliptin entered the market about a year and a half later, and now there are similar reports of acute pancreatitis. As the number of patients treated with these agents increases, is it uncovering a risk not appreciated in the premarket phase or just what should be expected from the population treated with these agents? To date, 88 cases of acute pancreatitis have been reported to the FDA in patients taking sitagliptin (Januvia/Janumet). Of these, two cases have been hemorrhagic or necrotizing pancreatitis. A revision of the package insert for sitagliptin has been made recently. An examination of available data should help shed light on whether the relation is likely causal or merely incidental.

Cleveland Clinic cardiovascular intensive care unit insulin conversion protocol.

BACKGROUND: The importance of near-normal blood glucose in the immediate postoperative period is generally accepted and is best achieved in the perioperative period with a constant intravenous (IV) infusion of insulin. This requires intensive nursing only achievable in an intensive care unit (ICU) setting. Glucose management after transfer to a regular nursing floor (RNF) has not been studied systematically. In August 2006, the Cleveland Clinic began using long-acting insulin glargine as the insulin infusion was terminated in the ICU. METHODS: This prospective analysis examined all patients receiving IV insulin infusion after cardiothoracic surgery in a 1 month period. The analyses evaluated the safety and efficacy of a protocol using a transition to subcutaneous insulin glargine of 50% of the calculated 24 h requirement at the end of the ICU insulin infusion protocol in preparation for transfer to the RNF. RESULTS: Only 1 patient in 99 developed hypoglycemia, and no patient suffered severe hypoglycemia (glucose < 40 mg/dl), while the majority (70%) had euglycemia (glucose between 70 and 150 mg/dl). CONCLUSIONS: This approach was both safe-as there was very little hypoglycemia (1 patient in 99)-and effective, as blood sugar was well controlled in most subjects. Efficacy for achieving euglycemia was 70%. Efficacy was likely reduced because of the upper limit of insulin glargine dosage imposed by some providers as a safety consideration. Although there was a physician option to override, the maximum protocol dose of 30 U was rarely exceeded, leading to inadequate dosing in some subjects who required high insulin infusion rates in the ICU.

Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies.

Myocarditis, often initiated by viral infection, may progress to autoimmune inflammatory heart disease, dilated cardiomyopathy and heart failure. Although cardiac myosin is a dominant autoantigen in animal models of myocarditis and is released from the heart during viral myocarditis, the characterization, role and significance of anti-cardiac myosin autoantibodies is poorly defined. In our study, we define the human cardiac myosin epitopes in human myocarditis and cardiomyopathies and establish a mechanism to explain how anti-cardiac myosin autoantibodies may contribute to heart disease. We show that autoantibodies to cardiac myosin in sera from myocarditis and dilated cardiomyopathies in humans targeted primarily epitopes in the S2 hinge region of cardiac myosin. In addition, anti-cardiac myosin antibodies in sera or purified IgG from myocarditis and cardiomyopathy targeted the beta-adrenergic receptor and induced antibody-mediated cAMP-dependent protein kinase A (PKA) cell signaling activity in heart cells. Antibody-mediated PKA activity in sera was abrogated by absorption with anti-human IgG. Antibody-mediated cell signaling of PKA was blocked by antigen-specific inhibition by human cardiac myosin or the beta-adrenergic receptor but not the alpha adrenergic receptor or bovine serum albumin. Propranolol, a beta blocker and inhibitor of the beta-adrenergic receptor pathway also blocked the antibody-mediated signaling of the beta-adrenergic receptor and PKA. The data suggest that IgG antibody against human cardiac myosin reacts with the beta-adrenergic receptor and triggers PKA signaling in heart cells. In summary, we have identified a new class of crossreactive autoantibodies against human cardiac myosin and the beta-adrenergic receptor in the heart. In addition, we have defined disease specific peptide epitopes in the human cardiac myosin rod S2 region in human myocarditis and cardiomyopathy as well as a mechanistic role of autoantibody in the pathogenesis of disease.

Coated-platelet levels in patients with Type 1 and with Type 2 diabetes mellitus.

Coated-platelet levels were quantified in 58 people with Type 1 diabetes, 90 with Type 2 diabetes, and 54 non-diabetic controls. In diabetes high coated-platelet levels were related to smoking and glucose control drugs, but not to glycaemia or other drugs. Prospective studies should evaluate coated-platelets and complications and drug effects.