Levofloxacin‐associated hypoglycaemia complicated by pontine myelinolysis and quadriplegia

Background Central pontine myelinolysis (CPM) usually presents in chronic alcoholics and in patients in whom hyponatraemia has been corrected rapidly. However, CPM may occur in other clinical circumstances, including patients with severe hypoglycaemia. We describe the occurrence of CPM and quadriplegia in a patient who experienced fluoroquinolone‐associated severe hypoglycaemia. Case report A 63‐year‐old man with Type 2 diabetes mellitus was admitted to hospital for resection of a large liposarcoma. Renal‐dose levofloxacin was utilized as part of an antimicrobial regimen to treat post‐operative peritonitis. On days 6–8 of levofloxacin therapy, the patient experienced recurrent hypoglycaemia despite total parenteral nutrition, 10% dextrose containing fluids and cessation of insulin therapy 3 days prior to the first hypoglycaemic episode. Hypoglycaemia resolved within 24 h of stopping levofloxacin. After a final and severe hypoglycaemic event, the patient developed quadriplegia and tonic left deviation of gaze. Magnetic resonance imaging revealed a high‐intensity lesion in the central pons consistent with CPM. Conclusions Fluoroquinolones should be considered as a potential cause of hypoglycaemia. Severe hypoglycaemia has the potential to cause white matter lesions in the pons. Putative mechanisms include failure of membrane ion channels, oligodendrocyte apoptosis and oxidative stress of glucose reperfusion. Fluoroquinolone‐associated hypoglycaemia and hypoglycaemia‐induced quadriplegia are both rare and we believe this is the first case report linking the two events.     

Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta‐analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion

Aims Continuous subcutaneous insulin infusion (CSII) is a recommended treatment for reducing severe hypoglycaemia in Type 1 diabetes, but the change in hypoglycaemia compared with multiple daily insulin injections (MDI) is unclear. We therefore conducted a meta‐analysis comparing severe hypoglycaemia and glycaemic control during CSII and MDI. Methods Databases and literature (1996–2006) were searched for randomized controlled trials (RCTs) and before/after studies of ≥ 6 months’ duration CSII and with severe hypoglycaemia frequency > 10 episodes/100 patient years on MDI. Results In 22 studies (21 reports), severe hypoglycaemia during MDI was related to diabetes duration (P = 0.038) and was greater in adults than children (100 vs. 36 events/100 patient years, P = 0.036). Severe hypoglycaemia was reduced during CSII compared with MDI, with a rate ratio of 2.89 (95% CI 1.45 to 5.76) for RCTs and 4.34 (2.87 to 6.56) for before/after studies [rate ratio 4.19 (2.86 to 6.13) for all studies]. The reduction was greatest in those with the highest initial severe hypoglycaemia rates on MDI (P < 0.001). The mean difference in glycated haemoglobin (HbA_1c) between treatments was less for RCTs [0.21% (0.13–0.30%)] than in before/after studies [0.72% (0.55–0.90%)] but strongly related to the initial HbA_1c on MDI (P < 0.001). Conclusions The severe hypoglycaemia rate in Type 1 diabetes was markedly less during CSII than MDI, with the greatest reduction in those with most severe hypoglycaemia on MDI and those with the longest duration of diabetes. The biggest improvement in HbA_1c was in those with the highest HbA_1c on MDI.     

Hypoglycaemia in insulin-treated Type 2 diabetes: frequency,symptoms and impaired awareness

Aims Hypoglycaemia is considered to be less common in people with insulin-treated Type 2 diabetes than in Type 1 diabetes. A retrospective survey was made of 215 people with insulin-treated Type 2 diabetes to quantify the frequency and nature of hypoglycaemia experienced. Methods The frequencies of mild (self-treated) and severe (required assistance) hypoglycaemia during the preceding year were estimated retrospectively. The usual symptoms of hypoglycaemia and state of awareness of hypoglycaemia were scored using validated questionnaires and any history suggestive of impaired hypoglycaemia awareness was documented. Results In this cohort, 157 (73%) had experienced hypoglycaemia since commencing insulin, the frequency of which increased with duration of diabetes and of insulin therapy and was inversely related to current HbA_1c (all P < 0.05). During the preceding year, 32 individuals (15%) had experienced severe hypoglycaemia, with an estimated incidence for the entire group of 0.28 episodes/patient/year. Principal components analysis revealed two underlying symptom groups (autonomic and neuroglycopenic), similar to those reported previously by young adults with Type 1 diabetes, but the total symptom score declined with advancing age. Of the 157 with a history of hypoglycaemia, the 13 (8%) individuals who gave a history of impaired awareness of hypoglycaemia had experienced a ninefold higher incidence of severe hypoglycaemia than those with normal awareness, and reported experiencing mainly neuroglycopenic symptoms. Conclusions While the overall frequencies of mild and severe hypoglycaemia were lower in insulin-treated Type 2 diabetes than have been reported previously in Type 1 diabetes, the risk of hypoglycaemia was greater with increasing duration of diabetes and of insulin therapy. Although impaired awareness of hypoglycaemia was uncommon, it was associated with a higher incidence of severe hypoglycaemia. Diabet. Med. 20, ***–*** (2003)     

A retrospective observational study of people with Type 1 diabetes with self‐reported severe hypoglycaemia reveals high level of ambulance attendance but low levels of therapy change and specialist intervention

Aim

To evaluate the impact of severe hypoglycaemia on NHS resources and overall glycaemic control in adults with Type 1 diabetes.

Methods

An observational, retrospective study of adults (aged ≥ 18 years) with Type 1 diabetes reporting one or more episodes of severe hypoglycaemia during the preceding 24 months in 10 NHS hospital diabetes centres in England and Wales. The primary outcome was healthcare resource utilization associated with severe hypoglycaemia. Secondary outcomes included demographic and clinical characteristics, diabetes control and pathway of care.

Results

Some 140 episodes of severe hypoglycaemia were reported by 85 people during the 2‐year observation period. Ambulances were called in 99 of 140 (71%) episodes and Accident and Emergency attendance occurred in 26 of 140 (19%) episodes, whereas 29 of 140 (21%) episode required no immediate help from healthcare providers. Participants attended a median of 5 (range 0–58) diabetes clinic consultations during the observation period; 13% (70 of 552) of all consultations were severe hypoglycaemia‐related. Of the HbA_1c measurements recorded closest prior to severe hypoglycaemia (n = 119), only 7 of 119 measurements were < 48 mmol/mol (< 6.5%) and mean HbA_1c was 70 (sd 19) mmol/mol (8.5%, sd 1.7%). Some 119 changes to diabetes treatment were recorded during the observation period (median/person 0;, range 0–11), of which 52 of 119 changes (44%) followed severe hypoglycaemic events.

Conclusions

We observed a high level of ambulance service intervention but surprisingly low levels of hypoglycaemia follow‐up, therapy change and specialist intervention in people self‐reporting severe hypoglycaemia. These results suggest there may be important gaps in care pathways for people with Type 1 diabetes self‐reporting severe hypoglycaemia.     

Ketoacidosis occurs in both Type 1 and Type 2 diabetes— a population‐based study from Northern Sweden

Aims To determine the occurrence of diabetic ketoacidosis (DKA) in adult Type 2 and Type 1 diabetic patients in Northern Sweden and to determine whether DKA presents with a different clinical picture in Type 2 compared with Type 1 diabetic subjects. Methods All adult patients from a hospital catchment area in Northern Sweden with diagnosed DKA episodes during 1997–2000 were included in a retrospective study. Medical records and laboratory reports were analysed. Results During the years 1997 to 2000, the average annual incidence rate for DKA was 5.9 per 100 000 adult inhabitants. Twenty‐five patients developed DKA, eight (32%) had Type 2 diabetes, while 17 (68%) had Type 1 diabetes. Type 2 diabetic patients with DKA were older and had higher levels of C‐peptide than Type 1 diabetic patients. On admission because of DKA, a similar degree of hyperglycaemia was present in Type 1 and Type 2 patients. Metabolic acidosis was more severe in Type 1 compared with Type 2 diabetic patients. In 50% of the Type 2 diabetic patients, diabetes was diagnosed at the episode of DKA. Conclusions DKA occurs in Caucasian Type 2 diabetic patients within a Swedish population. Although the frequency of DKA is much higher in Type 1 diabetic patients, Type 2 diabetes may account for as much as one‐third of the overall DKA cases.     

The locus of control in patients with Type 1 and Type 2 diabetes managed by individual and group care

Aims The locus of control theory distinguishes people (internals) who attribute events in life to their own control, and those (externals) who attribute events to external circumstances. It is used to assess self‐management behaviour in chronic illnesses. Group care is a model of systemic group education that improves lifestyle behaviour and quality of life in patients with Type 1 and Type 2 diabetes. This study investigated the locus of control in Type 1 and Type 2 diabetes and the possible differences between patients managed by group care and control subjects followed by traditional one‐to‐one care. Methods Cross‐sectional administration of two questionnaires (one specific for diabetes and one generic for chronic diseases) to 83 patients followed for at least 5 years by group care (27 Type 1 and 56 Type 2) and 79 control subjects (28 Type 1 and 51 Type 2) of similar sex, age and diabetes duration. Both tools explore internal control of disease, the role of chance in changing it and reliance upon others (family, friends and health professionals). Results Patients with Type 1 diabetes had lower internal control, greater fatalistic attitudes and less trust in others. Patients with either type of diabetes receiving group care had higher internal control and lower fatalism; the higher trust in others in those with Type 1 diabetes was not statistically significant. The differences associated with group care were independent of sex, age and diabetes duration. Conclusions Patients with Type 1 diabetes may have lower internal control, fatalism and reliance upon others than those with Type 2 diabetes. Receiving group care is associated with higher internal control, reduced fatalism and, in Type 1 diabetes, increased trust in others.     

A long‐term comparison of pioglitazone and gliclazide in patients with Type 2 diabetes mellitus: a randomized,double‐blind,parallel‐group comparison trial

Aims This study compared the effects of pioglitazone and gliclazide on metabolic control in drug‐naïve patients with Type 2 diabetes mellitus. Methods A total of 1270 patients with Type 2 diabetes were randomized in a parallel‐group, double‐dummy, double‐blind study. Patients with poorly controlled Type 2 diabetes (HbA_1c 7.5–11%), despite dietary advice, received either pioglitazone up to 45 mg once daily or gliclazide up to 160 mg two times daily. Primary efficacy endpoint was change in HbA_1c from baseline to the end of the study. Secondary efficacy endpoints included change in fasting plasma glucose, fasting plasma insulin and plasma lipids. At selected centres, oral glucose tolerance tests were performed and C‐peptide and pro‐insulin levels were measured. Results Mean HbA_1c values decreased by the same amount in the two treatment groups from baseline to week 52 [pioglitazone: ?1.4%; gliclazide: ?1.4%; (90% CI: ?0.18 to 0.02)]. A significantly greater mean reduction in fasting plasma glucose was observed in the pioglitazone group (2.4 mmol/l) than in the gliclazide group [2.0 mmol/l; treatment difference ?0.4 mmol/l in favour of pioglitazone; P = 0.002; (95% CI: ?0.7 to ?0.1)]. Improvements in high‐density lipoprotein cholesterol (HDL‐C) and total cholesterol/HDL‐C were greater with pioglitazone than with gliclazide (P < 0.001). The frequencies of adverse events were comparable between the two treatment groups, but more hypoglycaemic events were reported for gliclazide, whereas twice as many patients reported oedema with pioglitazone than with gliclazide. Conclusions Pioglitazone monotherapy was equivalent to gliclazide in reducing HbA_1c, with specific differences between treatments in terms of mechanism of action, plasma lipids and adverse events.     

An association between Type 2 diabetes and α1‐antitrypsin deficiency

Aims α₁‐Antitrypsin (AAT) is a serine protease inhibitor which recently has been shown to prevent Type 1 diabetes development, to prolong islet allograft survival and to inhibit pancreatic B‐cell apoptosis in vivo. It has also been reported that Type 1 diabetic patients have significantly lower plasma concentrations of AAT, suggesting the potential role of AAT in the pathogenesis of Type 1 diabetes. We have investigated whether plasma AAT levels are altered in Type 2 diabetes. Methods The study included patients with Type 2 diabetes (n = 163) and non‐diabetic control subjects matched for age, sex and smoking habits (n = 158) derived from the population‐based Malmö Diet and Cancer study. Plasma samples were analysed for AAT concentration and phenotype and serum glucose, insulin, C‐reactive protein and lipid levels were measured. Glycated haemoglobin was also measured. Results In the diabetic group, the women had higher mean plasma AAT levels than men (P < 0.05). The mean plasma AAT levels did not differ between diabetic and control subjects. However, the number of individuals with low AAT levels (< 1.0 mg/ml) was 50% higher in the diabetic group (P < 0.05) and the frequency of AAT deficiency genotypes was 50% higher (NS) in diabetic compared with control subjects. In the group of diabetic patients with AAT < 1 mg/ml, AAT directly correlated with systolic blood pressure (P = 0.048) and inversely correlated with waist–hip ratio (P = 0.031). Conclusions Our results provide evidence that deficiency of AAT may be associated with an increased risk of developing Type 2 diabetes.     

Severe prostate enlargement with severe lower urinary tract symptoms in poorly controlled acromegaly successfully treated with 5α‐reductase inhibitors: A 15‐year longitudinal case report

Acromegaly is a rare disease associated with an increased risk of prostate enlargement. Severe prostate enlargement with severe lower urinary tract symptoms (LUTS) in an acromegalic patient is even more uncommon. Herein we report on a 55‐year‐old man who was diagnosed with acromegaly and prostate enlargement at 40 years of age. Transsphenoidal surgery, postoperative radiotherapy, and octreotide medical therapy failed to control the acromegaly, and growth hormone (GH) and insulin‐like growth factor 1 (IGF‐1) levels remained elevated. When the patient was 53 years of age, severe LUTS and prostate enlargement (prostate volume = 128 mL) were noted. However, LUTS improved and prostate volume decreased markedly after 5α‐reductase inhibitors were used, despite the poorly controlled acromegaly (elevated GH and IGF‐1 levels). This is the first long‐term observation of LUTS and prostate enlargement in a poorly controlled acromegalic patient. Although the GH–IGF‐1 axis was a factor contributing to prostate enlargement, the present case suggests that androgens may still play an essential role in prostate enlargement and symptoms in active acromegalic patients >50 years of age. Indeed, we should be aware that suppressing the GH–IGF‐1 axis is not the only treatment choice for prostate enlargement in acromegalic patients, and even in poorly controlled acromegalic patients in whom suppression of the GH–IGF‐1 axis is difficult. Symptomatic prostate enlargement in cases of active acromegaly can be treated with 5α‐reductase inhibitors, as in general benign prostate hyperplasia populations.     

Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study.

AIMS: To ascertain the frequency and identify predictors of self-reported hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes. METHODS: A random sample of 267 people with insulin-treated diabetes were recruited from a population-based diabetes register in Tayside, Scotland. Each subject prospectively recorded the number of mild and severe hypoglycaemic episodes experienced over a 1-month period. Ordinal logistic regression was performed to identify potential predictors of hypoglycaemia. RESULTS: Five hundred and seventy-two hypoglycaemic events were reported by 155 patients. The participants with Type 1 diabetes had a total of 336 hypoglycaemic events with a rate of 42.89 events per patient per year. Of these, nine were severe hypoglycaemic events, with a rate of 1.15 events per patient per year. Participants with insulin-treated Type 2 diabetes experienced a total of 236 hypoglycaemic events with a rate of 16.37 events per patient per year. Of these, five were severe hypoglycaemic events, which would be equivalent to 0.35 events per patient per year. Predictors of hypoglycaemia in Type 1 diabetes were a history of previous hypoglycaemia (P = 0.006) and co-prescribing of any oral drug (P = 0.048). In patients with insulin-treated Type 2 diabetes, a history of previous hypoglycaemia (P < 0.0001) and duration of insulin treatment (P = 0.014) were significant predictors. CONCLUSION: The incidence of self-reported severe hypoglycaemia in insulin-treated Type 2 diabetes is lower than in Type 1 diabetes but does occur more often than previously reported and with sufficient frequency to cause significant morbidity. Duration of insulin treatment is a key predictor of hypoglycaemia in insulin-treated Type 2 diabetes.     

Cardiovascular autonomic dysfunction predicts acute ischaemic stroke in patients with Type 2 diabetes mellitus: a 7‐year follow‐up study

Aims We investigated whether cardiovascular autonomic neuropathy (CAN) is associated with acute ischaemic stroke in patients with Type 2 diabetes. Methods From 1999 to 2000, cardiovascular autonomic function tests were conducted in patients with Type 2 diabetes (n = 1458). Patients were followed up between 2006 and 2007. Standard tests for CAN measured heart rate variability parameters [expiration‐to‐inspiration (E/I) ratio, responses to the Valsalva manoeuvre and standing]. Using the American Diabetes Association criteria, the CAN scores were determined from the results of each test as follows: 0 = normal, 1 = abnormal (total maximum score 3). We assessed the development of acute ischaemic stroke events. Results The prevalence of CAN at baseline was 55.7% (E/I 17.1%, Valsalva 39.4%, posture 27.3%) (n = 1126). During follow‐up, 131 patients (11.6%) developed acute ischaemic stroke. The vascular events were more frequent in older patients (P < 0.001) and in those with diabetes of longer duration (P = 0.022), hypertension (P < 0.001) or diabetic retinopathy (P = 0.03) than in patients without vascular events. Patients with ischaemic stroke had higher creatinine levels (P = 0.045) and higher urine albumin excretion (P = 0.025) than those of patients without stroke. Cox proportional hazard regression analysis revealed that the CAN score was associated with the development of acute ischaemic stroke (total score 0 vs. 3, adjusted hazard ratio 2.7, 95% CI 1.3–5.5, P = 0.006). Conclusion Cardiovascular autonomic dysfunction was significantly associated with the development of ischaemic stroke in patients with Type 2 diabetes.     

Psychological distress and risk of pre‐diabetes and Type 2 diabetes in a prospective study of Swedish middle‐aged men and women

Aims To determine the role of psychological distress as a predictor of pre‐diabetes and Type 2 diabetes. Methods This cohort study comprised 2127 Swedish middle‐aged men and 3100 women with baseline normal glucose tolerance measured by oral glucose tolerance test. At follow‐up 8–10 years later, 245 men and 177 women had pre‐diabetes [impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and IFG + IGT] and Type 2 diabetes was detected in 103 men and 57 women. Baseline psychological distress was measured by an index of five questions concerning anxiety, apathy, depression, fatigue and insomnia. Odds ratios (ORs) were estimated for pre‐diabetes and Type 2 diabetes in association with total psychological distress. In addition, ORs of the single‐item questions were calculated. Results In men, adjusted ORs (95% confidence interval) in the highest index group of psychological distress compared with the lowest group were 1.9 (1.2–2.8) and 2.2 (1.2–4.1) for pre‐diabetes and Type 2 diabetes, respectively. Corresponding estimates in women were 1.2 (0.7–2.1) and 0.5 (0.2–1.2). In the middle symptoms groups, adjusted ORs in men were 1.1 (0.8–1.4) for pre‐diabetes and 1.2 (0.7–2.0) for Type 2 diabetes and in women 1.8 (1.1–3.0) and 0.7 (0.3–1.4). When analysed separately, the associations with each of the five single factors were similar. Conclusions The results indicate that psychological distress, including symptoms of anxiety, apathy, depression, fatigue and insomnia, increases the risk of pre‐diabetes and Type 2 diabetes in Swedish middle‐aged men. Increased risks were not present in women, except for pre‐diabetes in the middle index group.     

Survey of glargine use in 115 pregnant women with Type 1 diabetes

Aim To examine pregnancy outcome in women with Type 1 diabetes treated with glargine. Methods Glargine use in pregnancy was surveyed over 2 years in 20 UK obstetric‐diabetes centres. Outcomes, including maternal complications, miscarriage, congenital abnormalities, perinatal morbidity and mortality, were recorded in a standardized format. Results Outcomes on 109 babies from 115 women with Type 1 diabetes were collected. Insulin glargine was used prior to pregnancy in 69% of women, started during pregnancy in 30%, and stopped at booking in one patient. Insulin aspart was the bolus insulin in 45%, lispro in 42% and human soluble in 8% of women. HbA_1c fell from 8.1 ± 0.2% at booking to 6.8 ± 0.1% during the third trimester. Background retinopathy developed in one patient, worsened in seven and laser photocoagulation was required in three women. Preeclampsia occurred in 12%, and 14% of women had more than one episode of severe hypoglycaemia. One hundred and nine babies were live born, with six miscarriages and no neonatal deaths. The mean gestational age was 37.5 weeks, and mean birth weight was 3500 g. Three babies had congenital abnormalities (malformation rate = 28/1000). Neonatal hypoglycaemia was seen in 46% and hyperbilirubinaemia in 22% of babies. No major adverse outcome was noted in a smaller subset of five Type 2 and seven gestational diabetes patients on glargine. Conclusions The use of glargine in Type 1 diabetes during pregnancy was not associated with any unexpected adverse maternal or fetal outcome in this study.     

Associations of HbA1c and educational level with risk of cardiovascular events in 32 871 drug‐treated patients with Type 2 diabetes: a cohort study in primary care

Aims

To explore the association of HbA_1c and educational level with risk of cardiovascular events and mortality in patients with Type 2 diabetes.

Methods

A cohort of 32 871 patients with Type 2 diabetes aged 35 years and older identified by extracting data from electronic patient records for all patients who had a diagnosis of Type 2 diabetes and had glucose‐lowering agents prescribed between 1999 and 2009 at 84 primary care centres in Sweden. Associations of mean HbA_1c levels and educational level with risks of cardiovascular events and all‐cause mortality were analysed.

Results

The associations of HbA_1c with risk of all‐cause and cardiovascular mortality were J‐shaped, with the lowest risk observed for cardiovascular mortality at an HbA_1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin‐treated patients. The lowest risk observed for all‐cause mortality was at an HbA_1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin‐treated patients. There was an increased risk for cardiovascular death [hazard ratio 1.6 (1.2–2.1), P = 0.0008] at the lowest HbA_1c decile for subjects in the low education category. For subjects with higher education there was no evident J curve for cardiovascular death [hazard ratio 1.2 (0.8–1.6), P = 0.3873].

Conclusions

Our results lend support to the recent American Diabetes Association/ European Association for the Study of Diabetes position statement that emphasizes the importance of additional factors, including the propensity for hypoglycaemia, which should influence HbA_1c targets and treatment choices for individual patients. (Clinical Trials Registry No; NCT 01121315)     

Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels

Aims To test whether a single large dose of vitamin D2 can improve endothelial function in patients with Type 2 diabetes mellitus and low serum 25‐hydroxyvitamin D levels. Methods Double‐blind, parallel group, placebo‐controlled randomized trial. A single dose of 100 000 IU vitamin D2 or placebo was administered to patients with Type 2 diabetes over the winter, when levels of circulating 25‐hydroxyvitamin D were likely to be lowest. Patients were enrolled if their baseline 25‐hydroxyvitamin D level was < 50 nmol/l. Endothelial function and blood pressure were measured and fasting blood samples were taken at baseline and 8 weeks after administration of vitamin D. Results Forty‐nine per cent of subjects screened had 25‐hydroxyvitamin D levels < 50 nmol/l. Thirty‐four subjects completed the study, with a mean age of 64 years and a baseline 25‐hydroxyvitamin D level of 38.3 nmol/l. Vitamin D supplementation increased 25‐hydroxyvitamin D levels by 15.3 nmol/l relative to placebo and significantly improved flow mediated vasodilatation (FMD) of the brachial artery by 2.3%. The improvement in FMD remained significant after adjusting for changes in blood pressure. Vitamin D supplementation significantly decreased systolic blood pressure by 14 mmHg compared with placebo; this did not correlate with change in FMD. Conclusions Vitamin D insufficiency is common in patients with Type 2 diabetes during winter in Scotland. A single large dose of oral vitamin D2 improves endothelial function in patients with Type 2 diabetes and vitamin D insufficiency.     

Serum Th1 (CXCL10) and Th2 (CCL2) chemokine levels in children with newly diagnosed Type 1 diabetes: a longitudinal study

Aims Cell‐mediated immunity and pro‐inflammatory cytokines are implicated in the pathogenesis of Type 1 diabetes. The aim of this study was to investigate whether circulating chemokines involved in T‐helper 1 (CXCL10) and T‐helper 2 (CCL2) autoimmunity are increased in children with Type 1 diabetes at onset and follow‐up. Methods Serum CXCL10 and CCL2 were measured in 96 children with newly diagnosed Type 1 diabetes, 59 age‐matched first‐degree relatives of diabetic children and 40 age‐matched non‐diabetic children with no family history of diabetes. In the diabetic children, an additional serum sample was obtained a median of 16 months after diagnosis. Results Serum CXCL10 levels were significantly higher in Type 1 children than in relatives or control children (P < 0.001); 44.7% of patients had a serum CXCL10 level ≥ 2 standard deviation above the mean value of the control group vs. 3.4% of relatives (P < 0.0001). In contrast, serum CCL2 levels were similar in patients, relatives and control subjects. In the Type 1 diabetic patients at follow‐up, CXCL10 was significantly reduced vs. baseline (P = 0.01), while CCL2 did not change. Conclusions In children with newly diagnosed Type 1 diabetes, raised serum CXCL10 and normal CCL2 concentrations signal a predominant T‐helper 1‐driven autoimmune process, which shifts toward T‐helper 2 immunity over the first 1–2 years from diagnosis.     

Severe hypoglycaemia in type 1 diabetes mellitus: underlying drivers and potential strategies for successful prevention

Hypoglycaemia remains an over‐riding factor limiting optimal glycaemic control in type 1 diabetes. Severe hypoglycaemia is prevalent in almost half of those with long‐duration diabetes and is one of the most feared diabetes‐related complications. In this review, we present an overview of the increasing body of literature seeking to elucidate the underlying pathophysiology of severe hypoglycaemia and the limited evidence behind the strategies employed to prevent episodes. Drivers of severe hypoglycaemia including impaired counter‐regulation, hypoglycaemia‐associated autonomic failure, psychosocial and behavioural factors and neuroimaging correlates are discussed. Treatment strategies encompassing structured education, insulin analogue regimens, continuous subcutaneous insulin infusion pumps, continuous glucose sensing and beta‐cell replacement therapies have been employed, yet there is little randomized controlled trial evidence demonstrating effectiveness of new technologies in reducing severe hypoglycaemia. Optimally designed interventional trials evaluating these existing technologies and using modern methods of teaching patients flexible insulin use within structured education programmes with the specific goal of preventing severe hypoglycaemia are required. Individuals at high risk need to be monitored with meticulous collection of data on awareness, as well as frequency and severity of all hypoglycaemic episodes. Copyright © 2013 John Wiley & Sons, Ltd.     

Acute hyperglycaemia disturbs cardiac repolarization in Type 1 diabetes

Aims Patients with Type 1 diabetes have an increased risk of cardiovascular mortality. Notably, a prolonged heart rate adjusted QT interval (QTc) is a predictor of sudden cardiovascular death. Therefore, the objectives of this study were to investigate whether acute hyperglycaemia affects the QTc duration and the QTc dispersion in patients with Type 1 diabetes and in healthy volunteers. Methods Acute hyperglycaemia (15 mmol/l) for 120 min was induced in 35 males (22 men with Type 1 diabetes and 13 age‐matched non‐diabetic volunteers). All participants were non‐smokers without any diabetic complications. Electrocardiogram recordings were performed at normoglycaemia and at 0, 60 and 120 min of hyperglycaemia. Results Compared with normoglycaemia, acute hyperglycaemia increased the QTc interval in both patients with Type 1 diabetes (390 ± 6 vs. 415 ± 5 ms, P < 0.001) and in healthy volunteers (378 ± 5 vs. 412 ± 8 ms, P < 0.01). During hyperglycaemia, the QTc dispersion was prolonged in healthy volunteers (36 ± 4 ms vs. 54 ± 7 ms, P < 0.05) but not in patients with Type 1 diabetes (45 ± 3 ms at baseline vs. 48 ± 5 ms, NS). Conclusions Acute hyperglycaemia alters myocardial ventricular repolarization in patients with Type 1 diabetes and in healthy volunteers and might consequently be an additional risk factor for cardiovascular events.     

Nocturnal hypoglycaemia in Type 1 diabetic patients,assessed with continuous glucose monitoring: frequency,duration and associations

Aims We quantified the occurrence and duration of nocturnal hypoglycaemia in individuals with Type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) or multiple‐injection therapy (MIT) using a continuous subcutaneous glucose sensor. Methods A microdialysis sensor was worn at home by 24 patients on CSII (mean HbA_1c 7.8 ± 0.9%) and 33 patients on MIT (HbA_1c 8.7 ± 1.3%) for 48 h. Occurrence and duration of nocturnal hypoglycaemia were assessed and using multivariate regression analysis, the association between HbA_1c, diabetes duration, treatment type (CSII vs. MIT), fasting and bedtime blood glucose values, total daily insulin dose and mean nocturnal glucose concentrations, and hypoglycaemia occurrence and duration was investigated. Results Nocturnal hypoglycaemia ≤ 3.9 mmol/l occurred in 33.3% of both the CSII‐ (8/24) and MIT‐treated patients (11/33). Mean (± sd ; median, interquartile range) duration of hypoglycaemia ≤ 3.9 mmol/l was 78 (± 76; 57, 23–120) min per night for the CSII‐ and 98 (± 80; 81, 32–158) min per night for the MIT‐treated group. Multivariate regression analysis showed that bedtime glucose value had the strongest association with the occurrence (P = 0.026) and duration (P = 0.032) of nocturnal hypoglycaemia. Conclusions Microdialysis continuous glucose monitoring has enabled more precise quantification of nocturnal hypoglycaemia occurrence and duration in Type 1 diabetic patients. Occurrence and duration of nocturnal hypoglycaemia were mainly associated with bedtime glucose value.