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The aim of the current study (Clinical trial reg. no. NCT02715193, clinicaltrials.gov) was to study the efficacy and safety of REMD-477, a glucagon receptor antagonist, in type 1 diabetes. This was a randomized controlled trial in which 21 patients with type 1 diabetes were enrolled. Glycaemic control and insulin use were evaluated in outpatient and inpatient settings, before and after a single 70-mg dose of REMD-477 (half-life 7-10 days) or placebo. Inpatient insulin use was 26% (95% CI, 47%, 4%) lower 1 day after dosing with REMD-477 than with placebo (P = .02). Continuous glucose monitoring during post-treatment days 6 to 12 showed that average daily glucose was 27 mg/dL lower (P.001), percent time-in-target-range (70-180 mg/dL) was ~25% greater (~3.5 h/d) (P = .001), and percent time-in-hyperglycaemic-range (180 mg/dL) was ~40% lower (~4 h/d) (P = .001) in the REMD-477 group than in the placebo group, without a difference in percent time-in-hypoglycaemic-range (70 mg/dL). No serious adverse events were reported. Glucagon receptor antagonism decreases insulin requirements and improves glycaemic control in patients with type 1 diabetes.

Pernicious anemia (PA) develops from atrophic gastritis due to autoimmune destruction of parietal cells and results in achlorhydria, vitamin B12 and iron deficiencies, anemia, neurologic deficits, and premalignant and malignant stomach lesions. We report the presentation, diagnosis and gastric complications of PA in patients from an endocrinology practice.Thirty-four patients (31 female, 3 male) with PA who underwent esophagogastroduodenoscopy (EGD) or gastrectomy were identified. Pertinent clinical, laboratory, and pathology findings were reviewed and summarized.The mean age of patients was 58.6 ± 14.2 years; the onset of PA was age 50.2 ± 15.3 years. Anemia reflected vitamin B12 and/or iron deficiencies. Parietal cell antibodies (PCA) were detected in 97% of patients, and intrinsic factor blocking antibody (IFBA) was found in 52%. Fasting gastrin and chromogranin A levels were elevated (1,518.0 ± 1,588.3 pg/mL, and 504.9.1 ± 1,524.9 ng/mL respectively). Autoimmune or immunologic diseases (AIDs) were present in 32/34 patients. Stomach pathology showed premalignant or malignant lesions in 26 patients, including gastric neuroendocrine tumors (GNETs) in 6 and adenocarcinoma in 1. One patient presented with neurologic symptoms and subacute combined degeneration of the posterior column of the spinal cord.PA should be suspected in patients with unexplained anemia or neurologic symptoms. The diagnosis of PA relies on fasting gastrin and gastric auto-antibody testing, in addition to hematologic evaluation. EGD with measurement of gastric pH and biopsies of the fundus and antrum identifies patients with achlorhydria, atrophic gastritis, and premalignant and malignant stomach lesions. EGD surveillance of patients with high-risk stomach lesions is recommended.AID = autoimmune or immunologic disease; EGD = esophagogastroduodenoscopy; GNET = gastric neuroendocrine tumor; IFBA = intrinsic factor blocking antibody; PA = pernicious anemia; PCA = parietal cell antibody; T1D = type 1 diabetes.

OBJECTIVE Type 1 diabetes (T1DM) is associated with other autoimmune diseases (AIDs), which may have serious health consequences. The epidemiology of AIDs in T1DM is not well defined in adults with T1DM. In this cross-sectional cohort study, we sought to characterize the incident ages and prevalence of AIDs in adults with T1DM across a wide age spectrum. RESEARCH DESIGN AND METHODS A total of 1,212 adults seen at the Washington University Diabetes Center from 2011 to 2018 provided informed consent for the collection of their age, sex, race, and disease onset data. We performed paired association analyses based on age at onset of T1DM. Multivariate logistic regression was used to evaluate the independent effects of sex, race, T1DM age of onset, and T1DM duration on the prevalence of an additional AID. RESULTS Mean ± SD age of T1DM onset was 21.2 ± 14.4 years. AID incidence and prevalence increased with age. Female sex strongly predicted AID risk. The most prevalent T1DM-associated AIDs were thyroid disease, collagen vascular diseases, and pernicious anemia. T1DM age of onset and T1DM duration predicted AID risk. Patients with late-onset T1DM after 30 years of age had higher risks of developing additional AIDs compared with patients with younger T1DM onset. CONCLUSIONS The prevalence of AIDs in patients with T1DM increases with age and female sex. Later onset of T1DM is an independent and significant risk factor for developing additional AIDs. Individuals who are diagnosed with T1DM at older ages, particularly women, should be monitored for other autoimmune conditions.

Patients and physicians in the 21st century require new tools to manage the growing burden of chronic illness. For providers responsible for the care of diabetic patients, developments in information management, real-time health education and feedback, and new approaches to self-monitoring and insulin delivery hold great promise to improve the quality and safety of diabetes care. This article will briefly highlight some of the major developments in the field, and the ways these technologies can be integrated into a typical practice.

Inpatient severe hypoglycemia (SH), blood glucose (BG) This study reflects a retrospective analysis of system-wide data from 2011 to 2017. Results show BG levels post alert are higher on average (mean 92.83) than pre-alert (mean 74.43). This magnitude of difference occurs in each year (pre-post differences range from 14.7 to 19.3), suggesting that the alert system led to a sustained beneficial effect over time. A decreasing trend in SH rate over time was observed, which differed by hospital (Figure). System-wide electronic surveillance and alerts improve safety in patients with diabetes across a range of clinical settings. This study proves ongoing efficacy of the alert process and variables. Disclosure M. Elliott: None. M.C. Blackburn: None. K.M. Heard: None. P.E. Milligan: None. P. Cruz Bravo: None. G.S. Tobin: Speaker's Bureau; Self; Novo Nordisk Inc., MannKind Corporation. Advisory Panel; Self; Novo Nordisk Inc..

Hypoglycemia and severe hypoglycemia (SH) in the inpatient setting are associated with poor outcomes. This review is designed to highlight approaches to predict and prevent inpatient hypoglycemia that has been successfully implemented focusing on developing overlapping policies and procedures that allow safe glycemic management to occur at all levels of the institution. Standardizing point-of-care (POC) testing, nursing protocols, meal delivery, and formulary restriction are useful tools to prevent hypoglycemia. Informatics and real-time alert processes are highly effective tools to reduce hypoglycemia but require a significant investment in time and infrastructure as well as clear policies on how alerts are acted upon. Computerized dosing support technology and continuous glucose monitoring (CGM) technology are an emerging area of investigation showing promising results. Inpatient hypoglycemia is often predictable and preventable and requires institutional support to deliver targeted and safe diabetes care. This requires each institution to do periodic reassessment of policies and technologies. Future research needs to focus on the cost/benefits of interventions including studies of automated dosing algorithms as well as CGM in higher-risk patient populations.

BACKGROUND Severe hypoglycemia (SH), defined as a blood glucose (BG)

Summary Background: Type 2 diabetes is a progressive disease that requires stepwise additions of non-insulin and insulin therapies to meet recommended glycaemic goals. The final stage of intensification may require prandial insulin, adding complexity and increased risks of hypoglycaemia and weight gain. Aims: This review assesses the benefits and risks of adding exenatide twice daily, a glucagon-like peptide 1 receptor agonist, in patients with type 2 diabetes who are currently treated with basal insulin, but have failed to reach their glycaemic goals. Methods and Results: Based on data from published studies, exenatide has a number of actions that complement basal insulin therapy. Exenatide has been shown to increase glucose-dependent insulin production, suppress abnormal plasma glucagon production, slow gastric emptying, enhance liver uptake of glucose and promote satiety. A recently published randomised clinical trial reported that the addition of exenatide twice daily to titrated basal insulin provided greater glycaemic control than titrated basal insulin alone, and did so without an increase in hypoglycaemic events and with modest weight loss. Exenatide use was associated with gastrointestinal side effects. The recent randomised trial confirmed and extended data from a number of prior observational studies that demonstrated the efficacy and safety of insulin/exenatide combination therapy. Practical considerations for adding exenatide twice daily to ongoing basal insulin are discussed.

PURPOSE: The aim of this study was to assess the incidence of hypoglycemia in hospitalized patients following acute treatment of hyperkalemia with insulin. A characterization of the affected patients and the administered insulin/dextrose regimens was also performed. METHODS: A retrospective search of the electronic records of a large university-based tertiary care hospital was conducted, from June 1, 2009 to December 1, 2009, to identify patients who developed hypoglycemia following acute stabilization of hyperkalemia treatment with regular insulin. RESULTS: Of 219 hyperkalemic patients who met the criteria of the study, 19 patients (8.7%) were identified as hypoglycemic (blood glucose

BACKGROUND: In-hospital insulin administration is associated with many medication errors, but the frequency and reasons for insulin administration errors are poorly described. To document types and frequency of errors related to insulin administration, an examination of 4 units was conducted. METHODS: Using snapshot methodology, 4 non-intensive care unit (ICU) areas (medicine, cardiology, transplant, and surgery) were examined in an observational, prospective manner for 4 weeks. Each patient on insulin on the first day was followed for 7 days. Definitions and error categories were defined prior to data collection. Error types and numbers were collected and quantified on per-day or per-patient basis. RESULTS: A total of 116 patient audit periods covering a total of 378 inpatient hospital days were examined. Inpatient insulin regimens on day 1 included correctional insulin only (51.7% of cases), neutral protamine Hagedorn ([NPH] 12%), and glargine (28.4%). A total of 199 administration errors occurred at a rate of 1.72 errors/patient-period and 0.53 errors/patient day. Missing documentation of doses (15.5% of all patients) and insulin being held without an order (25% of patients) were the most frequently occurring events. Other errors include transcription (7.5%), timing errors (22.7%), and lack of documentation of physician notification of hypoglycemia (12.6%). CONCLUSIONS: Errors associated with insulin in the hospital are common and reveal a number of system errors that should be addressed. These data provide a foundation for future performance improvement. Journal of Hospital Medicine 2011;. © 2011 Society of Hospital Medicine

Hyperkalemia treatment with intravenous insulin has been associated with hypoglycemia. This single-center, retrospective study compared the effects on hypoglycemia between weight-based insulin dosing (0.1 U/kg of body weight up to a maximum of 10 U) compared to standard flat doses of 10 U among patients weighing less than 95 kg. Of the 132 charts randomly selected for review, hypoglycemic events (blood glucose

Severe hypoglycemia (SH), defined as a blood glucose (BG)40 mg/dL, is associated with an increased risk of adverse clinical outcomes in inpatients.To determine whether a predictive informatics hypoglycemia risk-alert supported by trained nurse responders would reduce the incidence of SH in our hospital.A 5-month prospective cohort intervention study.Acute care medical floors in a tertiary care academic hospital in St. Louis, Missouri.From 655 inpatients on designated medical floors with a BG of90 mg/dL, 390 were identified as high risk for hypoglycemia by the alert system.The primary outcome was the incidence of SH occurring in high-risk intervention versus high-risk control patients. Secondary outcomes included: number of episodes of SH in all study patients, incidence of BG 60 mg/dL and severe hyperglycemia with a BG299 mg/dL, length of stay, transfer to a higher level of care, the frequency that high-risk patient's orders were changed in response to the alert-intervention process, and mortality.The alert process, when augmented by nurse-physician collaboration, resulted in a significant decrease by 68% in the rate of SH in alerted high-risk patients versus nonalerted high-risk patients (3.1% vs 9.7%, P = 0.012). Rates of hyperglycemia were similar on intervention and control floors at 28% each. There was no difference in mortality, length of stay, or patients requiring transfer to a higher level of care.A real-time predictive informatics-generated alert, when supported by trained nurse responders, significantly reduced inpatient SH.

To describe a case of severe neuropathy associated with hypertriglyceridemia.We describe the clinical and laboratory findings of the study patient and review the relevant literature.A 45-year-old woman presented to the emergency department with recurrent abdominal pain and severe peripheral neuropathy. Her laboratory data revealed elevated lipase and a very high triglyceride concentration (10,000 mg/dL), consistent with a diagnosis of recurrent hypertriglyceridemia-induced pancreatitis. Workup for peripheral neuropathy showed normal concentrations of thyrotropin, fasting blood glucose, vitamin B(12), and creatinine, as well as a normal hemoglobin A(1c) level, serum protein electrophoresis, and urine protein electrophoresis. Rapid plasma reagin antibodies, antinuclear antibodies, and lyme antibodies were not detected. In the absence of other identifiable causes, hypertriglyceridemia was deemed the likely etiology of severe neuropathy in this patient.Peripheral nerve conduction abnormalities can be identified in patients with mild hypertriglyceridemia in the absence of symptoms. Early recognition and aggressive management of hypertriglyceridemia may prevent the complications of severe peripheral neuropathy.

Prolonged severe hypoglycemia (SH) in hospitalized patients is associated with increased morbidity and mortality. This study was undertaken to identify risk factors for SH, to apply that knowledge to the development of a prediction algorithm, and to institute a prevention program at a tertiary medical center.We analyzed SH events for 172 patients and developed computer algorithms to predict SH that were tested on a population of 3028 inpatients who were found to have blood glucose (BG)90 mg/dl during their hospital stay. Variables with significant bivariate associations were entered into partition analyses to identify interactions. Logistic regression was performed by calculating parameters related to the odds of hypoglycemia below each cut point. Sensitivity and specificity were determined at various cut points. The cut points resulting in 50% sensitivity for each hypoglycemia level were determined. These algorithms were tested against the initial 172 adjudicated patients.Variables related to the BG40 mg/dl cut off point were basal and adjustment scale insulin doses, weight, and creatinine clearance, while variables related to the 60 mg/dl and 70 mg/dl cut points were basal, prandial, and adjustment scale insulin doses, weight, creatinine clearance, and sulfonylurea use. The 50% sensitivity cut point developed using the70 mg/dl algorithm correctly identified 71% of the adjudicated cases, while the60 mg/dl and40 mg/dl algorithms identified 70% and 55% respectively.A validated prediction algorithm for SH can aid in the identification of patients at risk for SH and may be useful in the development of prevention strategies.

Diabetes is increasing at an alarming rate. Treatment-associated hypoglycemia is a major limitation to achieving glycemic control in diabetes. Appropriate use of new technology and flexible treatment regimens, especially in those with defined risk factors, may decrease the frequency of hypoglycemia.

Serious hyperglycemia, defined as blood glucose (BG) greater than 300 mg/dL, is a common occurrence in hospitalized patients, and can be challenging to manage. Subcutaneous insulin may provide less desirable pharmacokinetics in these urgent situations and intravenous continuous infusions present a significant safety concern in areas with less nursing coverage. Regular insulin given intravenously as a bolus dose offers a unique advantage in treating these urgent elevations in BG due to its quick onset of action and short duration of action. Based on these characteristics, we developed a Hyperglycemia Urgency Order Set that was implemented into our electronic order entry system at Barnes-Jewish Hospital. The intent of this order set was to provide an option for the treatment of serious hyperglycemia that was not associated clinical deterioration or any of the following: potassium < 4 mEq/L, bicarbonate < 15 mEq/L, or severe symptoms such as coma, metabolic compromise, or hypotension. Secondarily, the hyperglycemia order set was designed to prevent the need for higher levels of care, such as transfer to an ICU. Components of the order set include narrative on the intent of the order set, description of patients in need of higher level of care, instructions to hold dextrose fluids or tube feeds, an order for nothing by mouth (NPO) status, an order for a basic metabolic panel, an order for a 1-time bolus dose of intravenous regular insulin along with dosing recommendations (see Table 1), and follow-up BG monitoring. Table 1. Recommended IV Push Doses of Insulin for Hyperglycemia Urgency. Following the implementation of this order set, we reviewed the use of this protocol during the first 6 months using a retrospective chart review. The order set was used to provide 31 doses of insulin in 24 patients (median weight 82 kg). The order set was used by internal medicine (n = 9), neurology (n = 6), surgery (n = 5), and oncology (n = 4) services. The reasons for hyperglycemia were due to corticosteroid use (n = 13), inadequate dose titration (n = 7), missed doses of insulin (n = 3), and unknown (n = 8). The median glucose value immediately prior to order set use was 439 mg/dL (range 215-549 mg/dL). Doses of insulin (range 2-15 units) were in line with the recommended doses in 23 of 31 cases. No orders for IV regular insulin were completed among patients outside of the intent of the Hyperglycemia Urgency Order Set. The median glucose value 4 hours following administration of IV push bolus insulin was 238 mg/dL (range 138-478 mg/dL). No patients experienced hypoglycemia, but 4 patients required repeat doses of IV insulin. Only 1 patient treated with IV regular insulin, but who received less than recommended dose of IV push insulin, subsequently required escalation of care including transfer to an intensive care unit for continuous intravenous infusion of insulin. Two patients had glucose values >350mg/dL at 9 and 12 hours after the original order set was utilized. Overall, this approach to managing hyperglycemia urgency in non–critically ill patients seems safe and effective in this cohort. We would suggest this approach for other institutions wishing to reduce the use of intravenous insulin by continuous infusion in this patient population.

Insulin-like growth factor I (IGF-I) mediates many of the systemic growth-promoting effects of growth hormone and also functions as a locally acting growth stimulator. In mammals, IGF-I gene expression is complicated, as the gene is transcribed and processed into multiple mRNAs (ranging in length from less than 1 to nearly 7.5 kb) that encode at least two protein precursors. As a step toward understanding the regulation of IGF-I, we report the complete organization of the rat IGF-I gene, including identification of the structural determinants for all IGF-I mRNA species, and an initial functional analysis of its promoters. The gene is composed of 6 exons distributed over nearly 80 kb of chromosomal DNA and is structurally heterogeneous. Several transcription start sites were identified within IGF-I exons 1 and 2, adjacent to presumptive promoters 1 and 2, respectively, and at least three polyadenylation sites were mapped to exon 6. To test promoter function, fusion genes were constructed linking fragments of IGF-I DNA to a reporter plasmid. Chimeric genes containing at least 395 bp of DNA from the 5'-flanking region of exon 1 enhanced luciferase activity after transfection into the IGF-I-producing SK-N-MC cell line, while fusion plasmids containing up to 1,300 bp of DNA from the 5'-flanking region of exon 2 were inactive. Relative levels of IGF-I mRNAs containing exons 1 or 2 varied among different rat tissues, although in response to acute or chronic growth hormone treatment both classes of transcripts were induced coordinately in rat liver. These observations represent the first thorough characterization of a mammalian IGF-I gene, and provide a starting point for defining the mechanisms by which growth hormone and other trophic factors regulate IGF-I gene expression.

Objective To describe a structured inpatient insulin management protocol and order set for glycemic control on a vascular surgery service. Methods Patients admitted to the vascular surgery service with underlying diabetes were enrolled in a study of use of a preprinted basal-bolus insulin order set based on a total daily dose of 0.5 U/kg (0.25 U/kg of insulin glargine and 0.25 U/kg of insulin aspart divided into 3 equal mealtime doses). Outcomes included the mean glycemic control at each of 5 established time intervals, the percentage of blood glucose measurements within the target range of 70 to 180 mg/dL, the incidence of hypoglycemia, and the insulin dosages. Historical control patients with diabetes from the same hospital service were used for comparison. Results Both the study group and the control group consisted of 26 patients. The number of finger-stick blood glucose measurements performed was 871 in the control group and 896 in the intervention group. The mean blood glucose level (± SD) for the intervention group was 149.4 ± 50.7 mg/dL, in comparison with 165.2 ± 64.4 mg/dL for the control group. The incidence of hypoglycemia decreased 50% in the intervention group—from 32 (4% of the finger-stick assessments in the control group) to 19 (2% of the finger-stick blood glucose measurements in the study group). The blood glucose target range of 70 to 180 mg/dL was achieved in 75% of the measurements in the study group versus 61% in the control group. The basal insulin dose was unchanged in 65% of the patients, and of the 9 patients requiring a change in the dose, 5 had the dose decreased by 10% and 4 had the dose increased by 10%. Conclusion The use of a standardized basal-bolus weight-based insulin regimen was successful at achieving improved glycemic control as well as reducing the incidence of hypoglycemia in an inpatient population with diabetes. (Endocr Pract. 2008;14:185-192)

We have identified and characterized a novel human insulin-like growth factor I (IGF-I) precursor from the transplantable T61 human breast cancer xenograft and from normal liver. The mRNA encoding this precursor contains a 5'-untranslated region that is 83% identical to the corresponding region of a previously described variant rat IGF-I. The nucleotide sequence of the cloned cDNA predicts an IGF-IA protein precursor of 137 amino acids, including a 32 residue signal peptide, 70 amino acid IGF-I, and a 35 residue COOH-terminal extension or E peptide. The exon encoding this variant maps in the genome between IGF-I exons 1 and 2, in a similar location to the homologous rat exon 1a. The rat and human exons 1a are 59% identical over 1443 nucleotides, with DNA sequence conservation occurring in a mosaic pattern. Human IGF-I mRNAs encoding this novel exon are expressed in liver, T61 tumor cells, and in an ovarian carcinoma cell line, NIH OVCAR3. These studies demonstrate that as in the rat, the human IGF-I gene contains six exons that are variably processed into multiple IGF-I mRNAs. The mechanisms responsible for generating different IGF-I mRNAs thus appear to be conserved among mammalian species.