Mild Hypoglycemia Research Articles

Assessing fear of hypoglycemia among adults with type 1 diabetes – psychometric properties of the Norwegian version of the Hypoglycemia Fear Survey II questionnaire

Background: Hypoglycemia is common in type 1 diabetes, but the overall frequency of both mild and severe hypoglycemia is difficult to estimate. The Hypoglycemia Fear Survey II (HFS-II) is often used to assess the fear of hypoglycemia. Material and methods: The aim of this study was to assess the psychometric properties of the Norwegian version of the HFS-II for adults, including the behavior (HFS-B) and worry (HFS-W) subscales, among 235 adults in Norway with type 1 diabetes. We assessed associations between HFS-II scores and other rating scales and demographic and clinical variables. Results: The Norwegian version of HFS-II had an acceptable factor structure in relation to HFS-W, whereas the structure within HFS-B was more questionable. The expected relationships between HFS-II subscales and measures of related constructs administered concurrently demonstrated adequate convergent and discriminant validity. Internal consistency and test-retest reliability were satisfactory. Conclusion: Access to reliable and valid self-report instruments enables the early detection of psychosocial problems. HFS-W performs well, whereas HFS-B needs to be further examined and developed.

English

Elderly are more prone to develop hypoglycemia or miss meals. Repaglinide and nateglinide are suggested to have glucose-dependent insulinotropic effect. The aim of the present work was to test the effect of both drugs on serum glucose and insulin levels in fasting elderly diabetic patients. Eight elderly diabetics underwent a fixed dose single blinded, placebo controlled, six period, cross-over study at the Department of Geriatrics and Gerontology - University hospital. Patients received either repaglinide 2 mg, nateglinide 120 mg or a placebo, both under fasting and non-fasting states. Serum glucose and insulin were measured at 30 min intervals for four hours, following drug or placebo administration. None of the eight patients developed hypoglycemia under the fasting state in response to repaglinide and only one patient developed mild hypoglycemia (3.7 mmol/L) under the fasting state in response to nateglinide. Area under the serum  insulin concentration-time curve was significantly lower (p = 0.039) in the fasting state, compared to the non-fasting state, in response to repaglinide, but not to nateglinide. The present study suggests that in case of elderly diabetic patients, who may miss meals, repaglinide is a safe alternative to other antidiabetics. As for nateglinide, further studies are required.   Key words: Repaglinide, nateglinide, hypoglycemia, fasting, elderly.

Type 1 Diabetes in Children and Adolescents

Type 1 Diabetes in Children and Adolescents

Association of Clinical Symptomatic Hypoglycemia With Cardiovascular Events and Total Mortality in Type 2 Diabetes

OBJECTIVEHypoglycemia is associated with serious health outcomes for patients treated for diabetes. However, the outcome of outpatients with type 2 diabetes who have experienced hypoglycemia episodes is largely unknown.RESEARCH DESIGN AND METHODSThe study population, derived from the National Health Insurance Research Database released by the Taiwan National Health Research Institutes during 1998–2009, comprised 77,611 patients with newly diagnosed type 2 diabetes. We designed a prospective study consisting of randomly selected hypoglycemic type 2 diabetic patients and matched type 2 diabetic patients without hypoglycemia. We investigated the relationships of hypoglycemia with total mortality and cardiovascular events, including stroke, coronary heart disease, cardiovascular diseases, and all-cause hospitalization.RESULTSThere were 1,844 hypoglycemic events (500 inpatients and 1,344 outpatients) among the 77,611 patients. Both mild (outpatient) and severe (inpatient) hypoglycemia cases had a higher percentage of comorbidities, including hypertension, renal diseases, cancer, stroke, and heart disease. In multivariate Cox regression models, including diabetes treatment adjustment, diabetic patients with hypoglycemia had a significantly higher risk of cardiovascular events during clinical treatment periods. After constructing a model adjusted with propensity scores, mild and severe hypoglycemia still demonstrated higher hazard ratios (HRs) for cardiovascular diseases (HR 2.09 [95% CI 1.63–2.67]), all-cause hospitalization (2.51 [2.00–3.16]), and total mortality (2.48 [1.41–4.38]).CONCLUSIONSSymptomatic hypoglycemia, whether clinically mild or severe, is associated with an increased risk of cardiovascular events, all-cause hospitalization, and all-cause mortality. More attention may be needed for diabetic patients with hypoglycemic episodes.

Preliminary experience on treatment of infantile hemangioma with low-dose propranolol in China

We aimed to assess the efficacy and safety of low-dose propranolol for treatment of infantile hemangiomas (IHs) in China. Our prospective study included data from 89 patients with IH, aged 1-12 months. Plasma renin activity, angiotensin II, and aldosterone were measured before initiation of propranolol therapy. Patients were administered propranolol (0.75-1 mg/kg/day) under close observation. The volume, texture, and color of lesions were used to evaluate efficacy. Safety endpoints included heart rate, systolic and diastolic blood pressures, alanine transaminase, aspartate transaminase, thyroid function tests, and fasting blood glucose. Adverse effects were recorded. Mean plasma angiotensin II concentration in patients with IH was higher than that in age-matched healthy children, whereas mean plasma renin activity was lower. Mean aldosterone level was higher at 1-3 months but lower at 4-12 months, than values reported previously. After propranolol therapy for 6 months, IH regression was classed as grade IV in 44 patients (49.4 %), grade III in 21 patients (23.6 %), and grade II in 24 patients (27.0 %); none were grade I. Mild adverse effects, including diarrhea, restless sleep, nausea, cold extremities, and hypoglycemia, occurred in 12 patients (13.5 %). Slight decreases in heart rate and blood pressure occurred in all patients (p < 0.05). The IHs of four patients (4.5 %) relapsed after treatment cessation at 4-5 months. Low-dose propranolol is effective and safe for Chinese children with IH, and larger-scale studies are merited. Mechanisms underlying IH pathogenesis, and possible involvement of the renin-angiotensin-aldosterone system, deserve study.

Reduced capacity of heart rate regulation in response to mild hypoglycemia induced by glibenclamide and physical exercise in type 2 diabetes

ObjectiveDecreased heart rate variability (HRV) is associated with enhanced mortality due to abnormal cardiac rhythm. While hypoglycemic events are increasingly common in the treatment of type 2 diabetes, HRV is part of the counter-regulation against low blood glucose levels. We hypothesized that HRV was impaired in mild hypoglycemia in diabetic individuals. Materials/MethodsHyperinsulinemic–hypoglycemic clamps were performed in twelve type 2 diabetic patients without cardiovascular disease and in non-diabetic subjects matched for age, sex, and weight. In an additional study, hypoglycemic events, induced by either a single morning dose of glibenclamide or physical exercise, were recorded for the subsequent 24h. Blood glucose concentrations and electrocardiograms were continuously monitored. Serum hormone levels, hypoglycemic symptoms, and forearm blood flow were measured at defined time points. ResultsOccurrence of a symptomatic hypoglycemic episode (mean blood glucose 3.1±0.4mmol/l) attenuated most of the time and frequency domain measurements in both healthy and diabetic individuals. The magnitude of reduction of HRV parameters was significantly lower in diabetic compared to healthy subjects. Glibenclamide taken in the morning enhanced the daily number of mild hypoglycemic events compared with placebo or moderate exercise. Concordantly, 24-h mean HRV measurements were decreased. ConclusionHRV response to hypoglycemia is impaired in type 2 diabetic subjects resulting in a higher than expected risk for sudden arrhythmia following mild hypoglycemic episodes.

Predicting Mortality of Critically Ill Patients by Blood Glucose Levels (Diabetes Metab J2013;37:385-90)

Critical illness is associated with a high risk for multiple organ failure and mortality. Hyperglycemia is common in critically ill patients and is related to adverse outcome. In the article entitled “Predicting mortality of critically ill patients by blood glucose levels,” Park et al. [1] reported that blood glucose levels upon admission to intensive care unit (ICU) predicted clinical outcomes. This article merits much attention, because its find ings remind clinicians that critically ill patients with dysglycemia upon ICU admission should be monitored and treated more closely. Although the authors did not assess the degrees of disease severity and length of stay, which could affect mortality, they clearly demonstrated that hyperglycemia (>300 mg/dL) at the time of ICU admission was associated with higher mortality rate among critically ill patients, regardless of the presence of diabetes mellitus (DM). In this study of 1,224 critically ill patients, they found that subjects whose blood glucose levels ranging between 100 and 199 mg/dL upon admission had the lowest mortality rate, revealing a J-curved relationship between glucose levels and mortality rates. This study is in line with previous reports stating that hyperglycemia during critical illness is strongly associated with increased mortality [2-5]. However, there remain a couple of intriguing queries to be addressed in this study. First, the relationship between hyperglycemia (>300 mg/dL) and mortality rate appears to be stronger in critically ill patients with DM when compared to those without. In contrast to these findings, some observational stud ies showed that mortality was much greater for hyperglycemic patients without DM in comparison to those with DM when average glucose levels during ICU stay were analyzed [5-7], suggesting that prior exposure to higher glucose levels in DM patients may weaken the association between hyperglycemia and mortality. The differences in study subjects and data col lection of glucose levels might lead to these conflicting results. Growing evidence suggests that hypoglycemia, as well as hyperglycemia, predicts morbidity and mortality in critically ill patients, although no causal relationship between glycemic statuses and mortality has been established. Egi et al. [8] have demonstrated a significant association between even mild hy poglycemia (<81 mg/dL) and mortality after adjustment for insulin therapy and other confounding factors in critically ill patients. In another study, hypoglycemia within the initial 24 hours of ICU admission has been found to be associated with an increased risk for mortality [9]. Moreover, a recent post hoc analysis of NICE-SUGAR study showed a dose-response relationship between hypoglycemia and mortality [10]. There are several plausible explanations for the association between hypoglycemia and adverse outcome in critically ill patients, while specific mechanisms remain elusive. Hypoglycemia might contribute to mortality by elevating systemic inflammatory re sponse, sympathetic stimulation, and fatal cardiac arrhythmias. Furthermore, it is possible that hypoglycemia is a biomarker for severity of disease in critical illness [6]. In this study, the authors showed that patients (group 1, n= 110) with glucose levels less than 100 mg/dL upon ICU admis

Ultrasound-aided diagnosis of an insulinoma in a cat

A 15-year old, neutered female, domestic shorthaired cat was presented for evaluation of a 3-month history of paroxysmal falling over and trembling. In laboratory work the cat displayed a mild hypoglycemia. Ultrasound revealed a nodule in the left pancreatic lobe and surgical excision was performed. The histological diagnosis was an insulinoma. To the authors knowledge this is the first ultrasound description of an insulinoma in a cat. Up to date the cat has a survival time of 32 months without recurrence of symptoms.

Fear of hypoglycaemia in patients with type 1 diabetes: Do patients and diabetologists feel the same way?

AimThis study described and compared the perception of hypoglycaemia in both patients with type 1 diabetes and diabetologists. MethodsThis was an observational cross-sectional study undertaken in France in 2011. Data for what hypoglycaemia represents and practices related to it were collected using a questionnaire completed by patients with type 1 diabetes (all>12 years of age) and their diabetologists. Agreement between patients and physicians was evaluated by the intraclass correlation coefficient (ICC) and Gwet's coefficient (GC). ResultsA total of 485 patients were enrolled by 118 diabetologists. Half the patients thought that hypoglycaemia was always symptomatic. According to both patients and diabetologists, hypoglycaemia impaired quality of life, caused anxiety and was disturbing, especially at night. Clinical symptoms of hypoglycaemia (sweating, shakiness, anxiety) were linked to patient's age and diabetes duration. Regarding hypoglycaemia frequency, agreement was good for severe hypoglycaemia (GC: 0.61 and 0.72 for diurnal and nocturnal hypoglycaemia, respectively) and poor for mild hypoglycaemia (ICC: 0.44 and 0.40, respectively). Diabetologists correctly evaluated the impact of hypoglycaemia on quality of life, but overestimated the hypoglycaemia-induced burden and anxiety. Counteractive behaviours were frequent: 23% of patients decreased their insulin dose, 20% increased their sugar intake and 12% ate extra snacks. Diabetologists were generally aware of these measures, but not of how often patients used them. ConclusionDiabetologists and patients do not share enough information about hypoglycaemia. Fear of hypoglycaemia and counteractive behaviours should be looked for by diabetologists. Systematic advice and specially adapted education should also be provided to increase patients’ awareness of hypoglycaemia.

Efectividad y seguridad de un modelo protocolizado de control glucémico en el medio hospitalario

ObjectiveTo evaluate the effectiveness and safety of a glucose control protocol designed to manage patients with diabetes in hospital. Material and methodsAn interventional, prospective and open study was designed for patients with diabetes admitted in a conventional hospital setting. Patients were randomized to an intervention group (glucose control protocol) or to a control group (conventional treatment for diabetes). Blood glucose was performed every 48hours. The primary endpoint was to obtain a pre-prandial blood glucose between 80 and 180mg/dl, and the secondary endpoint was the absence of hypoglycemia. ResultsThe study included a total of 104 patients (51.0% male), with a mean age of 67.8±9.2 years old, 13.7±10.2 years since onset of diabetes, and mean HbA1c of 7.8±1.5%. The patients in the intervention group showed a significant improvement in glucose control before all meals as well as in the 24hour mean compared to day 0 and with the control group. In the first week, patients achieved a mean blood glucose of 148.2±30.3mg/dl. The percentage of patients with blood glucose between 80 and 180mg/dl gradually increased, exceeding 50% of patients from day 4 for fasting blood glucose, day 5 for blood glucose before lunch, and day 7 for blood glucose before dinner. Seven patients (13.4%) had mild hypoglycemia in the intervention group, and nine (17.3%) in the control group (P=.817). ConclusionsThe use of a blood glucose control protocol in hospital settings is effective for improving metabolic control and to achieve the targets, with a low rate of associated hypoglycemia.

Blood Glucose Control in Type 1 Diabetes With a Bihormonal Bionic Endocrine Pancreas

OBJECTIVETo test whether safe and effective glycemic control could be achieved in type 1 diabetes using a bihormonal bionic endocrine pancreas driven by a continuous glucose monitor in experiments lasting more than two days and including six high-carbohydrate meals and exercise as challenges to glycemic control.RESEARCH DESIGN AND METHODSSix subjects with type 1 diabetes and no endogenous insulin secretion participated in two 51-h experiments. Blood glucose was managed with a bionic endocrine pancreas controlling subcutaneous delivery of insulin and glucagon with insulin pumps. A partial meal-priming bolus of insulin (0.035 units/kg/meal, then 0.05 units/kg/meal in repeat experiments) was administered at the beginning of each meal (on average 78 ± 12 g of carbohydrates per meal were consumed). Plasma glucose (PG) control was evaluated with a reference quality measurement on venous blood every 15 min.RESULTSThe overall mean PG was 158 mg/dL, with 68% of PG values in the range of 70–180 mg/dL. There were no significant differences in mean PG between larger and smaller meal-priming bolus experiments. Hypoglycemia (PG <70 mg/dL) was rare, with eight incidents during 576 h of closed-loop control (0.7% of total time). During 192 h of nighttime control, mean PG was 123 mg/dL, with 93% of PG values in the range of 70–180 mg/dL and only one episode of mild hypoglycemia (minimum PG 62 mg/dL).CONCLUSIONSA bihormonal bionic endocrine pancreas achieved excellent glycemic control with minimal hypoglycemia over the course of two days of continuous use despite high-carbohydrate meals and exercise. A trial testing a wearable version of the system under free-living conditions is justified.

Insulin Glargine in the intensive care unit: A model-based clinical trial design

IntroductionCurrent successful AGC (Accurate Glycemic Control) protocols require extra clinical effort and are impractical in less acute wards where patients are still susceptible to stress-induced hyperglycemia. Long-acting insulin Glargine has the potential to be used in a low effort controller. However, potential variability in efficacy and length of action prevent direct in-hospital use in an AGC framework for less acute wards. MethodClinically validated virtual trials based on data from stable ICU patients from the SPRINT cohort who would be transferred to such an approach are used to develop a 24-h AGC protocol robust to different Glargine potencies (1.0×, 1.5× and 2.0× regular insulin) and initial dose sizes (dose=total insulin over prior 12, 18 and 24h). Glycemic control in this period is provided only by varying nutritional inputs. Performance is assessed as %BG in the 4.0–8.0mmol/L band and safety by %BG<4.0mmol/L. ResultsThe final protocol consisted of Glargine bolus size equal to insulin over the previous 18h. Compared to SPRINT there was a 6.9–9.5% absolute decrease in mild hypoglycemia (%BG<4.0mmol/L) and up to a 6.2% increase in %BG between 4.0 and 8.0mmol/L. When the efficacy is known (1.5× assumed) there were reductions of: 27% BG measurements, 59% insulin boluses, 67% nutrition changes, and 6.3% absolute in mild hypoglycemia. ConclusionBased on current understanding of Glargine behaviour, a robust protocol for a 24–48 clinical trial has been designed to safely investigate possible differences in efficacy and kinetics of Glargine in a critically ill population. This protocol is a first step towards developing a Glargine-based protocol for less acute wards. Ensuring robustness to variability in Glargine efficacy directly affects the performance and safety that can be obtained.

Transient Liver Masses during Pregnancy: An Unusual Presentation of HELLP Syndrome

Introduction: HELLP (microangiopathic hemolytic anemia, elevated liver enzymes, low platelet count syndrome) and acute fatty liver of pregnancy (AFLP) are liver diseases unique to pregnancy primarily affecting women in their third trimester. Early diagnosis and prompt treatment is crucial for maternal and fetal survival. We present a case of HELLP syndrome with unusual focal fatty liver lesions that resolved completely after delivery. Case Report: A 37-year-old healthy female, G1P0 at 27 week gestation, was transferred from an outside hospital with a week of severe right upper quadrant abdominal pain bloating, nausea and vomiting and liver masses concerning for malignancy. Ultrasound of the abdomen performed one week prior to the transfer showed two predominantly echogenic right hepatic lesions measuring 2.9 cm and 3.5 cm. A non-contrast MRI was also performed and demonstrated two right hepatic lobe lesions measuring 3.2 cm and 3 cm in diameter. Both lesions had slightly decreased signal intensity on the T1 weighted images and slightly increased signal intensity on the T2 weighted images. Repeat RUQ ultrasound at admission demonstrated a normal gallbladder and biliary tree. There were now five echogenic areas within the liver with lobular or indistinct margins measuring between 1.2 and 7.2 cm. There was no displacement of the vasculature surrounding these echogenic areas which were suggestive for fatty infiltration or hemangiomas. Laboratory abnormalities included mild leukocytosis, low platelets, elevated LDH, hypoglycemia, elevated transaminases (AST 99 U/L, ALT 132 U/L) and normal alkaline phosphatase. Pregnancy was complicated by prolonged fetal deceleration/bradycardia despite resuscitative efforts and positional changes, resulting in an emergent cesarean section. She recovered uneventfully, and her liver transaminases normalized within 5 days after delivery. A repeat MRI 1 month post delivery, showed complete resolution of her previously seen liver lesions. Conclusion: Focal fatty infiltration of the liver may closely mimic nodular hepatic disease. Although metastatic disease is the most common cause of multiple nodular lesions of the liver, focal fatty infiltration should be considered in pregnancy. Typical MRI findings include drop out of fat on the out of phase T1 images with respect to the T1 in phase images. Common hepatic manifestations in HELLP syndrome include hemorrhage, hematoma or liver rupture. It is uncommon to have significant focal fatty infiltrates in liver during HELLP. The significant overlap between HELLP and AFLP and the focal fatty infiltrates in liver during HELLP may reflect a common pathogenic pathway between the two.

Management of Hyperglycemia, Dyslipidemia, and Albuminuria in Patients With Diabetes and CKD: A Systematic Review for a KDOQI Clinical Practice Guideline

In 2007, the National Kidney Foundation (NKF) published clinical practice guidelines and recommendations for treating patients with diabetes and kidney diseases. Given recent studies that may enhance our understanding of the benefits and harms of glycemic, lipid, and albuminuria management in patients with diabetes and chronic kidney disease (CKD), the NKF commissioned a systematic review to evaluate data on the management of these patients. Systematic review and evidence synthesis. Patients with type 1 or 2 diabetes with or without CKD. English-language publications indexed in the MEDLINE database from January 2003 to October 2010, as well as cited references in these publications and publications identified after consultation with the NKF Diabetes Work Group were screened. Randomized controlled trials providing evidence for the management of hyperglycemia, dyslipidemia, and albuminuria in individuals with diabetes were included. (1) Intensive glycemic control; (2) lipid management; (3) interventions aimed at prevention of incident albuminuria and/or progression of albuminuria in normotensive patients. For all interventions, all-cause mortality was the primary outcome and secondary clinical outcomes included death from cardiovascular causes, incident kidney failure, and nonfatal cardiovascular events. Intermediate outcomes included changes in albuminuria and measures of kidney function. For intensive glycemic control only, severe and mild hypoglycemia were secondary and intermediate outcomes, respectively. 5 studies (n=27,159) assessed the impact of intensive versus conventional glycemic control strategies on clinical outcomes in type 2 diabetes. Intensive glycemic control reduced the development of micro- and macroalbuminuria, but did not reduce the incidence of primary or secondary clinical outcomes and was associated with a 2.5-fold increase in severe hypoglycemia. 11 studies (n=7,539) assessed lipid management. Statins did not reduce all-cause mortality or stroke compared to placebo in adults with diabetes and CKD. Fenofibrate increased regression of microalbuminuria to normoalbuminuria compared to placebo. 3 studies reported inconsistent effects of different angiotensin II receptor blockers on the incidence of microalbuminuria, and one study reported that telmisartan reduced macroalbuminuria in normotensive participants. No study demonstrated a benefit on primary or secondary clinical outcomes. Patients with CKD constituted a subgroup in most studies. Substantial heterogeneity with respect to population, interventions, outcome measures, and duration of follow-up. Intensive glycemic control and lipid interventions did not improve clinical outcomes in patients with type 2 diabetes. Although interventions typically improved albuminuria, evidence was insufficient to determine whether treatment of albuminuria in normotensive patients provides beneficial effects on clinical outcomes. More intensive clinical management of patients with diabetes and CKD has inherent risks, including severe hypoglycemia, which should be considered when formulating treatment strategies.

Meconium-Stained Amniotic Fluid and Hypoglycemia Among Term Newborn Infants

To evaluate whether meconium-stained amniotic fluid (MSAF) is a risk factor for neonatal hypoglycemia. Retrospective recording of medical charts of full-term infants born following observation of meconium-stained amniotic fluid to examine glucose levels in the first hours of life. Out of 803 infants of the study group, 68 (8.5%) had glucose levels lower than 47 mg/dl. Most (6.7%) had mild hypoglycemia, and 14 (1.8%) had moderate or severe hypoglycemia (1.4% and 0.4% respectively). No infant developed clinical signs clearly related to hypoglycemia. Low-risk infants born following meconium-stained amniotic fluid are not at increased risk for neonatal hypoglycemia.

Association between Perioperative Glucose Levels and Adverse Outcomes in Infants Receiving Open-Heart Surgery with Cardiopulmonary Bypass for Congenital Heart Disease

There is no consensus that hyperglycaemia is an independent predictor of morbidity-mortality in children. This retrospective observational study aimed to assess the association between abnormal perioperative glucose levels and adverse outcomes in infants receiving open-heart surgery with cardiopulmonary bypass. The records of a total of 233 infants who underwent cardiopulmonary bypass for a variety of congenital cardiac procedures between January and December 2010 were reviewed. The blood glucose levels, demographic and perioperative information were recorded. Patients who experienced complications (n=91) were compared with those who did not (n=142). We found both intraoperative and postoperative glucose levels increased compared to the preoperative values (P<0.001). Thirty patients (12.8%) experienced hyperglycaemia and 15 patients (6.4%) experienced at least one episode of hypoglycaemia during surgery. Within the first two days after surgery, 12 (5.2%) patients experienced hyperglycaemia and 32 (13.7%) became hypoglycaemic in the paediatric intensive care unit. However, the abnormal perioperative glucose levels were not associated with increased adverse outcomes. After adjusting for other potential variables, lower weight at surgery, longer surgery time and hospital length-of-stay are the independent predictors of morbidity-mortality. Our findings suggest that perioperative hyperglycaemia and mild transient hypoglycaemia do not appear to be detrimental to infants with congenital heart disease, although we did not assess neurological outcomes. Nevertheless, due to the limitations of the retrospective design of this study and its limited power, more thorough clinical randomised controlled trials are needed.

Risk Factors for Inpatient Hypoglycemia during Subcutaneous Insulin Therapy in Non-Critically Ill Patients with Type 2 Diabetes

We aimed to determine risk factors associated with hypoglycemia during subcutaneous insulin therapy in non-critically ill patients with type 2 diabetes. We conducted an analysis of three randomized control trials using basal/bolus regimen and regular sliding scale insulin (SSI) in patients with diabetes admitted to medical and surgical settings. We analyzed medical records of 261 general medicine and 211 noncardiac surgery patients treated with basal/bolus regimen with glargine/glulisine (n = 169), detemir/aspart (n = 67), neutral protamine Hagedorn/regular (n = 63), or with SSI (n = 173). The overall frequency of mild and severe hypoglycemia (<70 and <40 mg/dl) was 19% and 2%, respectively. During treatment, medical patients experienced a higher number of hypoglycemia than surgical patients (23% versus 13%; p = .005), but the rate of severe hypoglycemia was similar between groups (1.9% versus 1.9%; p = not significant). Increasing age, impaired kidney function (glomerular filtration rate < 60 ml/min), total daily insulin dose, and type of insulin regimen (basal/bolus versus SSI) during hospitalization were important contributors for hypoglycemia in both medical and surgical patients. Among these variables, increasing age and type of insulin regimen (basal/bolus versus SSI) were found to be independent predictors of hypoglycemic events. Mild hypoglycemic events are common during subcutaneous insulin therapy in medical and surgical patients with type 2 diabetes. Increasing age, impaired renal function, daily insulin dose, and insulin regimen (basal/bolus versus SSI) are important predictors of hypoglycemia during insulin therapy in patients with type 2 diabetes mellitus.

STAR Development and Protocol Comparison

Accurate glycemic control (AGC) is difficult due to excessive hypoglycemia risk. Stochastic TARgeted (STAR) glycemic control forecasts changes in insulin sensitivity to calculate a range of glycemic outcomes for an insulin intervention, creating a risk framework to improve safety and performance. An improved, simplified STAR framework was developed to reduce light hypoglycemia and clinical effort, while improving nutrition rates and performance. Blood glucose (BG) levels are targeted to 80-145mg/dL, using insulin and nutrition control for 1-3h interventions. Insulin changes are limited to +3U/h and nutrition to ±30% of goal rate (minimum 30%). All targets and rate change limits are clinically specified and generalizable. Clinically validated virtual trials were run on using clinical data from 371 patients (39841h) from the Specialized Relative Insulin and Nutrition Tables (SPRINT) cohort. Cohort and per-patient results are compared to clinical SPRINT data, and virtual trials of three published protocols. Performance was measured as time within glycemic bands, and safety by patients with severe (BG < 40mg/dL) and mild (%BG < 72mg/dL) hypoglycemia. Pilot trial results from the first ten patients (1486h) are included to support the in-silico findings. In both virtual and clinical trials, mild hypoglycemia was below 2% versus 4% for SPRINT. Severe hypoglycemia was reduced from 14 (SPRINT) to 6 (STAR), and 0 in the pilot trial. AGC was tighter than both SPRINT clinical data and in-silico comparison protocols, with 91% BG within the specified target (80-145mg/dL) in virtual trials and 89.4% in pilot trials. Clinical effort (measurements) was reduced from 16.2/day to 11.8/day (13.5/day in pilot trials). This STAR framework provides safe AGC with significant reductions in hypoglycemia and clinical effort due to stochastic forecasting of patient variation-a unique risk-based approach. Initial pilot trials validate the in-silico design methods and resulting protocol, all of which can be generalized to suit any given clinical environment.

Increased Mortality of Patients With Diabetes Reporting Severe Hypoglycemia

OBJECTIVEHypoglycemia is a cause of significant morbidity among patients with diabetes and may be associated with greater risk of death. We conducted a retrospective study to determine whether patient self-report of severe hypoglycemia is associated with increased mortality.RESEARCH DESIGN AND METHODSAdult patients (N = 1,020) seen in a specialty diabetes clinic between August 2005 and July 2006 were questioned about frequency of hypoglycemia during a preencounter interview; 7 were lost to follow-up and excluded from analysis. Mild hypoglycemia was defined as symptoms managed without assistance, and severe hypoglycemia was defined as symptoms requiring external assistance. Mortality data, demographics, clinical characteristics, and Charlson comorbidity index (CCI) were obtained from the electronic medical record after 5 years. Patients were stratified by self-report of hypoglycemia at baseline, demographics were compared using the two-sample t test, and risk of death was expressed as odds ratio (95% CI). Associations were controlled for age, sex, diabetes type and duration, CCI, HbA1c, and report of severe hypoglycemia.RESULTSIn total, 1,013 patients with type 1 (21.3%) and type 2 (78.7%) diabetes were questioned about hypoglycemia. Among these, 625 (61.7%) reported any hypoglycemia, and 76 (7.5%) reported severe hypoglycemia. After 5 years, patients who reported severe hypoglycemia had 3.4-fold higher mortality (95% CI 1.5–7.4; P = 0.005) compared with those who reported mild/no hypoglycemia.CONCLUSIONSSelf-report of severe hypoglycemia is associated with 3.4-fold increased risk of death. Patient-reported outcomes, including patient-reported hypoglycemia, may therefore augment risk stratification and disease management of patients with diabetes.

Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats

BackgroundRecurrent/moderate (R/M) hypoglycemia is common in type 1 diabetes. Although mild or moderate hypoglycemia is not life-threatening, if recurrent, it may cause cognitive impairment. In the present study, we sought to determine whether R/M hypoglycemia leads to neuronal death, dendritic injury, or cognitive impairment.MethodsThe experiments were conducted in normal and in diabetic rats. Rats were subjected to moderate hypoglycemia by insulin without anesthesia. Oxidative stress was evaluated by 4-Hydroxy-2-nonenal immunostaining and neuronal death was determined by Fluoro-Jade B staining 7 days after R/M hypoglycemia. To test whether oxidative injury caused by NADPH oxidase activation, an NADPH oxidase inhibitor, apocynin, was used. Cognitive function was assessed by Barnes maze and open field tests at 6 weeks after R/M hypoglycemia.ResultsThe present study found that oxidative injury was detected in the dendritic area of the hippocampus after R/M hypoglycemia. Sparse neuronal death was found in the cortex, but no neuronal death was detected in the hippocampus. Significant cognitive impairment and thinning of the CA1 dendritic region was detected 6 weeks after hypoglycemia. Oxidative injury, cognitive impairment, and hippocampal thinning after R/M hypoglycemia were more severe in diabetic rats than in non-diabetic rats. Oxidative damage in the hippocampal CA1 dendritic area and microglial activation were reduced by the NADPH oxidase inhibitor, apocynin.ConclusionThe present study suggests that oxidative injury of the hippocampal CA1 dendritic region by R/M hypoglycemia is associated with chronic cognitive impairment in diabetic patients. The present study further suggests that NADPH oxidase inhibition may prevent R/M hypoglycemia-induced hippocampal dendritic injury.