Mild Hypoglycemia Research Articles

Cystic Encephalomalacia and Infantile Spasm as a Complication of Transient and Mild Hyperinsulinemic Hypoglycemia

Cystic Encephalomalacia and Infantile Spasm as a Complication of Transient and Mild Hyperinsulinemic Hypoglycemia

Tight glycemic control in acutely ill patients: low evidence of benefit, high evidence of harm!

In 1878 Claude Bernard described hyperglycemia during hemorrhagic shock [1]. It is now well known that acute illness or injury may result in hyperglycemia, insulin resistance, and glucose intolerance, collectively termed stress hyperglycemia [2]. Stress hyperglycemia is an evolutionarily preserved adaptive response which provides the nervous and immune system with an immediate source of energy at a time of crisis. Insects, worms, and all vertebrates develop stress hyperglycemia when exposed to stress [2]. Stress hyperglycemia is a component of the stereotypic and coordinated response to stress referred to by Hans Selye as the “general adaption syndrome” which until 2001 was believed to be a beneficial host response which enhanced the host’s chances of survival [3]. On 8 November 2001, Van den Berghe and colleagues published a study entitled “Intensive insulin therapy in critically ill patients” in which they randomized 1548 surgical ICU patients (63 % who had undergone cardiac surgery) to an intensive insulin therapy (IIT) protocol targeting a blood glucose of 80–110 mg/dl or a control arm in which patients only received insulin when the blood glucose exceeded 215 mg/dl with a target of 180–200 mg/ dl (Leuven I study) [4]. Hospital mortality was 7.2 % in the IIT group as compared to 10.9 % in the control group (p = 0.01); in addition IIT reduced length of stay and patient morbidities. This study was supported by retrospective cohort studies in acutely ill patients demonstrating an association between increasing hyperglycemia and poor clinical outcomes. The findings of the Leuven study were widely embraced and endorsed by the Institute for Health Care Improvement, the American College of Endocrinology as well as other national and international organizations and soon became considered the standard of care for ICU patients around the world. In 2006, Van den Berghe and colleagues repeated their study in medical ICU patients (Leuven II study) [5]. Although failing to reproduce the improvement in survival in the entire set of patients, this study demonstrated a reduction in morbidity in the patients randomized to IIT with a reduction in mortality in the subset of patients with an ICU stay of 3 days or more. Using a similar study design these authors repeated their study in a pediatric ICU (mostly cardiac surgery patients) and demonstrated an outcome very similar to the Leuven I study [6]. Following the Leuven I study, 14 randomized controlled trials in various patient populations including mixed ICUs, neurosurgical, neurological, coronary, trauma, and pediatric ICUs have been performed (see Table 1). Without exception all of these studies demonstrated no outcome benefit (NOB) from tight glycemic control in acutely ill patients. NICE-SUGAR, the largest trial to date (n = 6022), demonstrated a 2.6 % absolute increase in 90-day mortality in patients randomized to IIT (p = 0.02) [7]. Three of these studies demonstrated harm, with almost all of the studies demonstrating a significant increase in the risk of both moderate and severe hypoglycemia. Even mild hypoglycemia in ICU patients is associated with an increased risk of death [8]. The mechanism(s) by which hypoglycemia increases the risk of death in critically ill patients has (have) not been investigated. However, it is likely that hypoglycemia increases the risk of fatal arrhythmias [9]. Furthermore, cell death *Correspondence: marikpe@evms.edu 2 Eastern Virginia Medical School, 825 Fairfax Av, Suite 410, Norfolk, VA 23507, USA Full author information is available at the end of the article

A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats.

Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose homeostasis, body weight, body composition as measured by dual-energy x-ray absorptiometry and overall safety. An intravenous glucose tolerance test (1 g/kg body weight) was conducted at week 0 and week 12. Exenatide did not change the insulin concentration, plasma glucose concentration or glucose tolerance (P>0.05 for all). Exenatide tended to reduce body weight on continued normal feeding. Median relative weight loss after 12 weeks was 5.1% (range 1.7 to 8.4%) in the exenatide group versus 3.2% (range -5.3 to 5.7%) in the placebo group (P = 0.10). Body composition and adipokine levels were unaffected by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean cats. Further investigations are required to fully elucidate the effect on insulin secretion, glucose tolerance and body weight in obese cats.

Impact of Tight Glycemic Control on Neurodevelopmental Outcomes at 1 Year of Age for Children with Congenital Heart Disease: A Randomized Controlled Trial

To assess the association of postoperative tight glycemic control and hypoglycemia in children undergoing cardiac surgery with neurodevelopmental outcomes at 1year of age. A 2-center, prospective, randomized trial of postoperative tight glycemic control vs standard care was conducted in 980 children undergoing cardiac surgery. Neurodevelopmental outcomes were assessed at nine to 18months using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), the Adaptive Behavior Assessment System, Second Edition, the Ages and Stages Questionnaire, Third Edition, and the Brief Infant Toddler Social-Emotional Assessment. Neurodevelopmental follow-up was performed on 237 patients with a mean age of 13months. No significant treatment group differences were found in the Bayley-III and Adaptive Behavior Assessment System, Second Edition composite scores or percentage at risk based on the Ages and Stages Questionnaire, Third Edition and the Brief Infant Toddler Social-Emotional Assessment. Patients who experienced moderate to severe hypoglycemia (n=8) had lower Bayley-III composite scores compared with patients with no to mild hypoglycemia, even after controlling for factors known to be associated with poorer neurodevelopmental outcomes. For infants undergoing cardiac surgery, tight glycemic control did not impact neurodevelopmental outcomes compared with standard care. These data suggest a possible association between moderate to severe hypoglycemia and poorer neurodevelopmental outcomes at 1year of age. ClinicalTrials.gov: NCT00443599.

Effects of subcutaneous, low-dose glucagon on insulin-induced mild hypoglycaemia in patients with insulin pump treated type 1 diabetes.

To investigate the dose-response relationship of subcutaneous (s.c.) glucagon administration on plasma glucose and on counter-regulatory hormone responses during s.c. insulin-induced mild hypoglycaemia in patients with type 1 diabetes treated with insulin pumps. Eight insulin pump-treated patients completed a blinded, randomized, placebo-controlled study. Hypoglycaemia was induced in the fasting state by an s.c. insulin bolus and, when plasma glucose reached 3.4 mmol/l [95% confidence interval (CI) 3.2-3.5], an s.c. bolus of either 100, 200, 300 µg glucagon or saline was administered. Plasma glucose, counter-regulatory hormones, haemodynamic variables and side effects were measured throughout each study day. Peak plasma glucose level was the primary endpoint. Plasma glucose level increased significantly by a mean (95% CI) of 2.3 (1.7-3.0), 4.2 (3.5-4.8) and 5.0 (4.3-5.6) mmol/l to 6.1 (4.9-7.4), 7.9 (6.4-9.3) and 8.7 (7.8-9.5) vs 3.6 (3.4-3.9) mmol/l (p < 0.001) after the three different glucagon doses as compared with saline, and the increase was neither correlated with weight nor insulin levels. Area under the plasma glucose curve, peak plasma glucose, time to peak plasma glucose and duration of plasma glucose level above baseline were significantly enhanced with increasing glucagon doses; however, these were not significantly different between 200 and 300 µg glucagon. Free fatty acids and heart rates were significantly lower initially after glucagon than after saline injection. Other haemodynamic variables, counter-regulatory hormones and side effects did not differ between interventions. An s.c. low-dose glucagon bolus effectively restores plasma glucose after insulin overdosing. Further research is needed to investigate whether low-dose glucagon may be an alternative treatment to oral carbohydrate intake for mild hypoglycaemia in patients with type 1 diabetes.

Nonaqueous, Mini-Dose Glucagon for Treatment of Mild Hypoglycemia in Adults With Type 1 Diabetes: A Dose-Seeking Study.

To evaluate mini-dose glucagon in adults with type 1 diabetes using a stable, liquid, ready-to-use preparation. Twelve adults with type 1 diabetes receiving treatment with insulin pumps received subcutaneous doses of 75, 150, and 300 μg of nonaqueous glucagon. Plasma glucose, glucagon, and insulin concentrations were measured. At 180 min, subjects received insulin followed in ~60 min by a second identical dose of glucagon. Mean (±SE) fasting glucose concentrations (mg/dL) were 110 ± 7, 110 ± 10, and 109 ± 9 for the 75-, 150-, and 300-μg doses, respectively, increasing maximally at 60 min by 33, 64, and 95 mg/dL (all P < 0.001). The post-insulin administration glucose concentrations were 70 ± 2, 74 ± 5, and 70 ± 2 mg/dL, respectively, with maximal increases of 19, 24, and 43 mg/dL post-glucagon administration (P < 0.02) at 45-60 min. Subcutaneous, nonaqueous, ready-to-use G-Pen Mini glucagon may provide an alternative to oral carbohydrates for the management of anticipated, impending, or mild hypoglycemia in adults with type 1 diabetes.

Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD

ObjectivePeroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect...

Predictors of hypoglycemia in insulin-treated patients with type 2 diabetes mellitus in Basrah.

AIMTo measure the incidence and determinants (predictors) of hypoglycemia among patients with type 2 diabetes mellitus (T2DM) who were on insulin treatment for at least one year.METHODSThe present study is an out-patients based inquiry about the risk and predictors of hypoglycemia among patients with T2DM seeking care at the Al-Faiha Specialized Diabetes, Endocrine, and Metabolism Center, in Basrah over a period of 7 mo (from 15th of April, 2013 to 15th of October, 2013). The data used in the study were based on all detailed interview and selected laboratory investigations. A total of 336 patients could be included in the study.RESULTSThe incidence of overall hypoglycemia among the studied patients was 75.3% within the last 3 mo preceding the interview. The incidence of hypoglycemia subtypes were 10.2% for severe hypoglycemia requiring medical assistance in the hospital, 44.36% for severe hypoglycemia treated at home by family; this includes both confirmed severe hypoglycemia with an incidence rate of 14.6% and unconfirmed severe hypoglycemia for which incidence rate was 29.76%. Regarding mild self-treated hypoglycemia, the incidence of confirmed mild hypoglycemia was 21.42%, for unconfirmed mild hypoglycemia the incidence rate was 50.0% and for total mild hypoglycemia, the incidence rate was 71.42%. The most important predictors of hypoglycemia were a peripheral residence, increasing knowledge of hypoglycemia symptoms, in availability and increasing frequency of self-monitoring blood glucose, the presence of peripheral neuropathy, higher diastolic blood pressure, and lower Hemoglobin A1c.CONCLUSIONHypoglycemia is very common among insulin-treated patients with T2DM in Basrah. It was possible to identify some important predictors of hypoglycemia.

Blood levels of pro-inflammatory and anti-inflammatory cytokines during an oral glucose tolerance test in patients with symptoms suggesting reactive hypoglycemia.

We evaluated the impact of postprandial glycemia on blood levels of pro-inflammatory and anti-inflammatory cytokines during an oral glucose tolerance test in non-diabetic patients with symptoms suggesting reactive hypoglycemia. Eleven patients with clinical symptoms suggesting reactive hypoglycemia received an oral glucose solution (75 g) Blood was collected at 0 (baseline), 30, 60, 120 and 180 min after glucose ingestion and the plasma concentrations of interferon-α (IFN-α), interferon-γ (IFN-γ), interleukin-1 receptor antagonist (IL-1RA), interleukin 2 (IL-2), interleukin-2 receptor (IL-2R), interleukin 4 (IL-4), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), interleukin-12 (IL-12), interleukin 13 (IL-13), interleukin 15 (IL-15), interleukin 17 (IL-17), IFN-γ inducible protein 10 (IP-10), monocyte chemotactic protein 1 (MCP1), monokine induced by IFN-γ (MIG), macrophage inflammatory protein-1α (MIP-1α), interleukin-1β (IL-1β), colony stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), basic fibroblast growth factor (FGF-basic), eotaxin, tumor necrosis factor α (TNFα), epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), macrophage inflammatory protein-1α (MIP-1α), and 1β (MIP-1β) were evaluated. Overall, glycemic levels increased, reached its maximum at 30 min (phase 1), returned to baseline levels at 120 min (phase 2), followed by a mild hypoglycemia at 180 min (phase 3). During phase 1, cytokine blood levels were maintained. However, we observed a synchronous fall (P<0.05) in the concentrations of pro-inflammatory (IL-15, IL-17, MCP-1) and anti-inflammatory cytokines (FGF-basic, IL-13, IL-1RA) during phase 2. Furthermore, a simultaneous rise (P<0.05) of pro-inflammatory (IL-2, IL-5, IL-17) and anti-inflammatory cytokines (IL-4, IL-1RA, IL-2R, IL-13, FGF-basic) occurred during phase 3. Thus, mild acute hypoglycemia but not a physiological increase of glycemia was associated with increased blood levels of anti-inflammatory and pro-inflammatory cytokines.

Generalizability of a Nonlinear Model-based Glycemic Controller

Critically ill patients exhibit a highly complex and dynamic metabolic state, making safe, effective management of hyperglycemia difficult. Clinical practices vary significantly, thus making glycemic control (GC) protocols difficult to generalize across units. This study examines the generalizability of a nonlinear, model-based GC protocol, STAR (Stochastic TARgeted), across two different intensive care units (ICUs) with very different practices and use of GC. Patient data from the ICUs at Christchurch Hospital, New Zealand (267 Patients) and Kalman Pandy Hospital, Hungary (47 Patients) are examined. Safety and performance are examined, where complete generalizability would be indicated by similar glycemic performance distributions using non-parametric statistics as appropriate. STAR spent over 86% of time in the target BG band of 4.4-8.0 mmol/L per-episode in both Christchurch and Gyula, with the BG (blood glucose) distributions being almost identical. STAR provided safe GC with very few patients experiencing mild hypoglycemia (< 5 patients, 1.5%). The nonlinear model-based STAR GC protocol delivered equivalent high performance and safety across patient types, time, clinical practice culture, and clinical resources.

Cost-effectiveness Analysis of Insulin Detemir Compared to Neutral Protamine Hagedorn (NPH) in Patients with Type 1 and Type 2 Diabetes Mellitus in Portugal

Objectives: To estimate the short-term (1 year) cost-effectiveness of Insulin Detemir (IDet) compared with Neutral Protamine Hagedorn (NPH) insulin for Type 1 (T1DM) and Type 2 Diabetes Mellitus (T2DM) in Portugal. Methods: A short-term cost-effectiveness model was adapted to the Portuguese National Health System (NHS), to estimate the Incremental Cost-Effectiveness Ratio (ICER) of IDet vs. NPH in terms of euros per quality-adjusted life years (€/QALY) gained. Non-severe hypoglycemia (NSH) rate for both diabetes types, and weight change, only for T2DM, were the clinical benefit variables. Three scenarios were estimated in which NPH was assigned three different values corresponding to a cohort of recent insulinization and a cohort of long-run insulinization from the UK Hypoglycemia Study and from a Spanish observational study. For all scenarios, the hypoglycemia Rate Ratio (RR) for T1DM was based on the CADTH Technology Report while for T2DM it was based on the head-to-head NCT00104182 randomized clinical trial. For T2DM, weight gain was also included in the model, based on the same RCT. Disutility values to calculate quality-adjusted life years (QALYs) were associated to NSH events and to BMI unit gain. Costs (Euros 2014), estimated from the perspective of the Portuguese NHS, included only insulin treatment and mild hypoglycemia management. Results: For the three scenarios a range of 0.025 – 0.076 QALYs for T1DM and 0.014 – 0.051 QALYs for T2DM were gained for IDet vs. NPH due to NSH and weight gain avoidance, in return of an incremental cost of €159.38 - €248.98 for T1DM and €209.66 – €274.44 for T2DM. This resulted in IDet vs. NPH ICER ranging between €2,096.23 and €9,936.98/QALY for T1DM and €4,145.75 and €19,999.87/QALY for T2DM. Conclusions: IDet appears as a cost-effective alternative to NPH in Portugal for T1DM and T2DM in all considered scenarios due to lower hypoglycemic rate and less weight gain.

Non-linear associations of risk factors with mild hypoglycemia among Chinese patients with type 2 diabetes

AimsThe present study aimed to examine the nonlinear associations between risk factors and mild hypoglycemia in Chinese patients with type 2 diabetes mellitus (T2DM). MethodsFrom May 2013 to August 2013, we conducted a cross sectional survey of 6633 inpatients with T2DM and without severe hypoglycemia, aged 21–77years, from 81 top tertiary hospitals in China. Mild hypoglycemia was defined as having hypoglycemia with symptoms in one month. Binary logistic regression analysis with restricted cubic splines was used to estimate odds ratio curves of non-linear risk factors for mild hypoglycemia. ResultsIncreasing body mass index was associated with decreasing risk of mild hypoglycemia in a linear manner while age, duration of diabetes, glycated hemoglobin (HbA1c), mean artery pressure and lipids were associated with mild hypoglycemia in non-linear manners. Age ≥40years, duration ≥2years, HbA1c ≥7.0–<11.5% (≥53–<102mmol/mol), triglyceride ≥1.7–<3.6mmol/L, low-density lipoprotein cholesterol (LDL-C) ≥2.6–<4.8mmol/L, and high-density lipoprotein cholesterol (HDL-C) ≥1.2–<4.8mmol/L were associated with increased risks of mild hypoglycemia. ConclusionsChinese T2DM patients with age≥40years, duration of diabetes ≥2–<6years, HbA1c ≥7.0–<11.5% (≥53–<102mmol/mol), LDL-C ≥2.6–<4.8mmol/L, HDL-C ≥1.2–<4.8mmol/L or triglyceride ≥1.7–<3.6mmol/L were at particularly high risk for mild hypoglycemia.

Randomized clinical trial of the efficacy and safety of insulin glargine vs. NPH insulin as basal insulin for the treatment of glucocorticoid induced hyperglycemia using continuous glucose monitoring in hospitalized patients with type 2 diabetes and respiratory disease

AimsTo investigate the clinical efficacy and safety of insulin glargine compared with NPH insulin as basal insulin for the management of corticosteroid-induced hyperglycemia in hospitalized people with type 2 diabetes (T2DM) and respiratory disease. Materials and methodsRandomized, two-arm parallel group, clinical trial undertaken from February 2011 to November 2012 on the pneumology ward of the Hospital Regional Universitario de Málaga (Spain), involving 53 participants with T2DM treated with medium/high doses of intermediate-acting corticosteroids. Participants were randomly assigned to receive one single dose of insulin glargine or NPH insulin in three equally divided doses before each meal as basal insulin within a basal–bolus insulin protocol. The intervention lasted six days or until discharge if earlier. ResultsNo significant differences were seen between groups during the study in mean blood glucose (11.43±3.44mmol/l in glargine vs. 11.88±2.94mmol/l in NPH, p=0.624), and measures of glucose variability (standard deviation 3.27±1.16mmol/l vs. 3.61±0.99mmol/l, p=0.273; coefficient of variation 1.55±0.33mmol/l vs. 1.72±0.39mmol/l, p=0.200). Results from CGM were concordant with those obtained with capillary blood glucose reading. The length of hospital stay was also similar between groups (8.2±2.8 days vs. 9.8±3.4 days, p=0.166) There was a non significant trend for lower episodes of mild (4 vs. 8, p=0.351) and severe hypoglycemia (0 vs. 3, p=0.13) in the glargine group. ConclusionsThe results of this study showed that insulin glargine and NPH insulin are equally effective in a basal–bolus insulin protocol to treat glucocorticoid-induced hyperglycemia in people with T2DM on a pneumology ward.

Effects of piragliatin, a glucokinase activator, on fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus.

To assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of piragliatin, a double-blind, randomized, placebo-controlled, multiple-ascending-doses study was conducted in patients with type 2 diabetes mellitus (T2D). Fifty-nine T2D patients were given piragliatin or placebo in a dose-escalation design as a single dose on day 1 followed by multiple doses on days 3 through 8 at doses of 10, 25, 50, 100, and 200 mg twice a day (BID) as well as 200 mg every day (QD). Blood and urine samples were collected for PK analysis. PD assessments included plasma glucose, insulin, C-peptide, glucagon, and GLP-1. Piragliatin exposure was dose proportional without appreciable accumulation or food effect. Piragliatin treatment at steady state yielded dose-dependent reductions up to 32.5% and 35.5% for the highest dose in fasting and postprandial plasma glucose. Piragliatin was well tolerated. Mild or moderate hypoglycemia with rapid recovery after sugar-containing drinks or scheduled meals was the only dose-limiting adverse event. It is concluded that multiple doses of piragliatin consistently showed rapid, dose-dependent glucose reduction of fasting and postprandial plasma glucose in T2D patients.

New lessons from gastric bypass: Impact of glucose‐independent islet function

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Post-partum hypoglycaemia in lactating women with type 1 diabetes: a pilot study using continuous glucose monitoring

Aims: To observe glucose profiles in post-partum women with type 1 diabetes with a particular focus on hypoglycaemia.Methods: Post-partum women with type 1 diabetes were studied for 4 weeks using home blood glucose monitoring (HBGM) and continuous glucose monitoring (CGM). Episodes of hypoglycaemia were documented using self-reported questionnaires.Results: Of 15 consenting participants, only six women completed the study, four of whom breastfed their baby. HBGM was performed a median of 7 times per day. No severe hypoglycaemia (requiring third party assistance) occurred, but a median of 17 (range 10–23) episodes of mild hypoglycaemia occurred. In all participants, CGM revealed several episodes of hypoglycaemia that were not detected by capillary blood glucose testing. Conclusions: Asymptomatic hypoglycaemia is common during breastfeeding. Recruitment and retention difficulties illustrate the challenge of studying glycaemia and intensive interventions in the post-partum period. Education programmes may help to reduce post-partum hypoglycaemia in women with type 1 diabetes.

Randomized controlled study in pregnancy on treatment of marked hyperglycemia that is short of overt diabetes.

A randomized multicenter study was conducted in the Stockholm-Örebro areas in Sweden to evaluate how treatment aiming at normoglycemia affects fetal growth, pregnancy and neonatal outcome in pregnant women with severe hyperglycemia. Pregnant women with hyperglycemia defined as fasting capillary plasma glucose <7.0 mmol/L and a two-hour plasma glucose value ≥10.0 and <12.2 mmol/L following a 75-g oral glucose tolerance test (OGTT) diagnosed before 34 weeks of gestation were randomized to treatment (n = 33) or controls (n = 36). Women assigned to the control group were blinded for the OGTT results and received routine care. The therapeutic goal was fasting plasma glucose 4-5 mmol/L, and <6.5 mmol/L after a meal. Primary outcomes were size at birth and number of large-for-gestational age (>90th percentile) neonates. Secondary outcomes were pregnancy complications, neonatal morbidity and glycemic control. The planned number of participating women was not reached. There was a significantly reduced rate of large-for-gestational age neonates, 21 vs. 47%, P < 0.05. Group differences in pregnancy complications and neonatal morbidity were not detected because of limited statistical power. In total, 66.7% of the women in the intervention group received insulin. Of all measured plasma glucose values, 64.1% were in the target range, 7.2% in the hypoglycemic range and 28.7% above target values. There were no cases of severe hypoglycemia. Aiming for normalized glycemia in a pregnancy complicated by severe hyperglycemia reduces fetal growth but is associated with an increased rate of mild hypoglycemia.

Hypoglycemia and risk of vascular events and mortality: a systematic review and meta-analysis.

Hypoglycemia has been associated with adverse outcomes in patients with diabetes and critical illness. However, such associations in these populations have not been systematically examined. We conducted a systematic review and meta-analysis of longitudinal follow-up cohort studies to investigate the associations between hypoglycemia and various adverse outcomes. After removing duplicates and critically appraising all screened citations, a total of 19 eligible studies were included. As demonstrated by random-effects meta-analysis, hypoglycemia was strongly associated with a higher risk of adverse events (HR 1.90, 95% CI 1.63-2.20; P<0.001). Comparable risk ratios were shown in prespecified stratified analyses investigating above association for different study endpoints, in patients with or without critical illness, in patients with and without diabetes (from 1.47 to 3.31; p for interaction or heterogeneity >0.1). Additionally, a dose-dependent relationship between the severity of hypoglycemia and adverse vascular events and mortality (HR for mild hypoglycemia: 1.68, 95% CI 1.25-2.26; P<0.001 and HR for severe hypoglycemia: 2.33, 95% CI 2.07-2.61; P<0.001; p for trend 0.02) was observed. Suggested by a bias analysis, the above observations were unlikely to have resulted from unmeasured confounding parameters. This is the first study demonstrating that hypoglycemia was associated with comparable risk ratios in different study populations and various study endpoints, and a trend of a dose-dependent relationship between hypoglycemia severity and adverse events. The findings of this systematic review support the speculation that hypoglycemia is a risk factor for adverse vascular events and mortality.

HypoAware-a brief and partly web-based psycho-educational group intervention for adults with type 1 and insulin-treated type 2 diabetes and problematic hypoglycaemia: design of a cost-effectiveness randomised controlled trial.

BackgroundProblematic hypoglycaemia is a significant problem among people with insulin-treated type 1 and 2 diabetes mellitus, which adversely affects quality of life and leads to high societal costs. Blood glucose awareness training (BGAT) is a psycho-educational group intervention that has shown to be effective but difficult to implement in clinical practice, due to its demanding nature. The aim of this study is to evaluate the cost-effectiveness of the HypoAware intervention that has its roots in BGAT and helps patients to effectively recognize, treat and prevent hypoglycaemia, while also focussing on the psychosocial consequences of living with the constant risk of hypoglycaemia, both for patients and their significant others.Methods/designAn economic evaluation will be conducted alongside a cluster-randomised controlled trial in eight hospitals in the Netherlands. We aim to include 154 participants who will either receive HypoAware or care as usual. HypoAware consists of three group sessions and is combined with two online modules. The primary clinical outcome is severe hypoglycaemia. Secondary outcomes include mild hypoglycaemia, hypoglycaemia awareness, fear of hypoglycaemia, diabetes distress, anxiety and depression, health-related quality of life, diabetes-specific self-efficacy and HbA1c. Utilities will be measured using the EQ-5D-5 L questionnaire. Costs will be measured from a societal perspective and include health care utilization, medication and lost productivity costs. Measurements will be performed at baseline, 2, 4, and 6 months to compare both groups, and an additional 12 months for the intervention group only. Process outcomes will be gathered after every group meeting via telephone/email contact with health care professionals and via the online environment.DiscussionHypoAware is expected to significantly reduce episodes of severe hypoglycaemia, with subsequent beneficial effects on psychosocial outcomes and health care costs. When proven cost-effective, HypoAware will be incorporated in the clinical guidelines of Dutch diabetes care.Trial registrationDutch Trial Register NTR4538

Low levels of C-peptide have clinical significance for established Type 1 diabetes.

To determine whether the low C-peptide levels (<50pmol/l) produced by the pancreas for decades after onset of Type 1 diabetes have clinical significance. We evaluated fasting C-peptide levels, duration of disease and age of onset in a large cross-sectional series (n=1272) of people with Type 1 diabetes. We then expanded the scope of the study to include the relationship between C-peptide and HbA1c control (n=1273), as well as diabetic complications (n=324) and presence of hypoglycaemia (n=323). The full range of C-peptide levels was also compared with 1,5-Anhydroglucitol, a glucose responsive marker. C-peptide levels declined for decades after diagnosis, and the rate of decline was significantly related to age of onset (P<0.0001), after adjusting for disease duration. C-peptide levels >10pmol/l were associated with protection from complications (e.g. nephropathy, neuropathy, foot ulcers and retinopathy; P=0.03). Low C-peptide levels were associated with poor metabolic control measured by HbA1c (P<0.0001). Severe hypoglycaemia was associated with the lowest C-peptide levels compared with mild (P=0.049) or moderate (P=0.04) hypoglycaemia. All levels of measurable C-peptide were responsive to acute fluctuations in blood glucose levels as assessed by 1,5-Anhydroglucitol (P<0.0001). Low C-peptide levels have clinical significance and appear helpful in characterizing groups at-risk for faster C-peptide decline, complications, poorer metabolic control and severe hypoglycaemia. Low C-peptide levels may be a biomarker for characterizing at-risk patients with Type 1 diabetes.