Continuous glucose monitoring results in lower HbA1c in Malaysian women with insulin-treated gestational diabetes: a randomized controlled trial.

AIMS: To determine if therapeutic, retrospective continuous glucose monitoring (CGM) improves HbA1c with less hypoglycaemia in women with insulin-treated gestational diabetes mellitus (GDM). METHODS: This prospective, randomized controlled, open-label trial evaluated 50 women with insulin-treated GDM randomized to either retrospective CGM (6-day sensor) at 28, 32 and 36 weeks' gestation (Group 1, CGM, n = 25) or usual antenatal care without CGM (Group 2, control, n = 25). All women performed seven-point capillary blood glucose (CBG) profiles at least 3 days per week and recorded hypoglycaemic events (symptomatic and asymptomatic CBG < 3.5 mmol/l; non-fasting < 4.0 mmol/l). HbA1c was measured at 28, 33 and 37 weeks. In Group 1, both CGM and CBG data were used to manage diabetes, whereas mothers in Group 2 were managed based on CBG data alone. RESULTS: Baseline characteristics (age, pre-pregnancy BMI, HbA1c , total insulin dose) were similar between groups. There was a lower increase in HbA1c from 28 to 37 weeks' gestation in the CGM group [∆HbA1c : CGM + 1 mmol/mol (0.09%), control + 3mmol/mol (0.30%); P = 0.024]. Mean HbA1c remained unchanged throughout the trial in the CGM group, but increased significantly in controls as pregnancy advanced. Mean HbA1c in the CGM group was lower at 37 weeks compared with controls [33 ± 4 mmol/mol (5.2 ± 0.4%) vs. 38 ± 7 mmol/mol (5.6 ± 0.6%), P < 0.006]. Some 92% of the CGM group achieved an HbA1c ≤ 39 mmol/mol (≤ 5.8%) at 37 weeks compared with 68% of the control group (P = 0.012). Neither group experienced severe hypoglycaemia. CONCLUSION: CGM use may be beneficial in insulin-treated GDM because it improves HbA1c compared with usual antenatal care without increasing severe hypoglycaemia. (Clinical Trials Registry No.: NCT02204657).

HbA(1c) and birthweight in women with pre-conception type 1 and type 2 diabetes: a population-based cohort study.

AIMS/HYPOTHESIS: To investigate clinical and sociodemographic predictors of birthweight in singletons born to women with type 1 or type 2 diabetes. METHODS: Normally formed singleton live births and intrapartum stillbirths, born to women with pre-conception diabetes during 1996-2008, were identified from the population-based Northern Diabetes in Pregnancy Survey (n = 1,505). Associations between potential predictors and birthweight were analysed by multiple regression. RESULTS: Potentially modifiable independent predictors of increase in birthweight were pre-pregnancy care (adjusted regression coefficient [b] = 87.1 g; 95% CI 12.9, 161.3), increasing third-trimester HbA(1c) ≤7% (53 mmol/mol) (b = 310.5 g per 1% [11 mmol/mol]; 95% CI 246.3, 374.7) and increasing maternal BMI (b = 9.5 g per 1 kg/m(2); 95% CI 3.5, 15.5). Smoking during pregnancy (b = -145.1 g; 95% CI -231.4, -58.8), later gestation at first antenatal visit (b = -15.0 g; 95% CI -26.9, -3.0) and higher peri-conception HbA(1c) (b = -48.2 g; 95% CI -68.8, -27.6) were independently associated with birthweight reduction. Pre-pregnancy nephropathy (b = -282.7 g; 95% CI -461.8, -103.6) and retinopathy (b = -175.5 g; 95% CI -269.9, -81.0) were independent non-modifiable predictors of reduced birthweight, while greater maternal height was a non-modifiable predictor of increasing birthweight (b = 17.8 g; 95% CI 12.3, 23.2). Other predictors of birthweight increase were male sex, multiparity and increasing gestational age at delivery. Type or duration of diabetes, socioeconomic status and ethnicity were not associated with continuous birthweight. CONCLUSIONS/INTERPRETATION: Poor glycaemic control before and throughout pregnancy is associated with abnormal fetal growth, with increasing peri-conception HbA(1c) predicting weight reduction and increasing third-trimester HbA(1c) predicting increased birthweight. Women with microvascular complications of diabetes may require increased surveillance to detect fetal growth restriction.

Peri-conception hyperglycaemia and nephropathy are associated with risk of congenital anomaly in women with pre-existing diabetes: a population-based cohort study.

AIMS: The aim of this study was to quantify the risk of major congenital anomaly, and to assess the influence of peri-conception HbA(1c) and other clinical and socio-demographic factors on the risk of congenital anomaly occurrence in offspring of women with type 1 and type 2 diabetes diagnosed before pregnancy. METHODS: This was a population-based cohort study using linked data from registers of congenital anomaly and diabetes in pregnancy. A total of 401,149 singleton pregnancies (1,677 in women with diabetes) between 1996 and 2008 resulting in live birth, fetal death at ≥20 weeks' gestation or termination of pregnancy for fetal anomaly were included. RESULTS: The rate of non-chromosomal major congenital anomaly in women with diabetes was 71.6 per 1,000 pregnancies (95% CI 59.6, 84.9), a relative risk of 3.8 (95% CI 3.2, 4.5) compared with women without diabetes. There was a three- to sixfold increased risk across all common anomaly groups. In a multivariate analysis, peri-conception glycaemic control (adjusted OR [aOR] 1.3 [95% CI 1.2, 1.4] per 1% [11 mmol/mol] linear increase in HbA(1c) above 6.3% [45 mmol/mol]) and pre-existing nephropathy (aOR 2.5 [95% CI 1.1, 5.3]) were significant independent predictors of congenital anomaly. Associations with gestation at booking (aOR 1.1 [95% CI 1.0, 1.1]) and parity (aOR 1.6 [95% CI 1.0, 2. 5]) were not significant. Unadjusted risk was higher for women from deprived areas or who did not take folate. Type and duration of diabetes, ethnicity, age, BMI, preconception care, smoking and fetal sex were not associated with congenital anomaly risk. CONCLUSIONS: Peri-conception glycaemia is the most important modifiable risk factor for congenital anomaly in women with diabetes. The association with nephropathy merits further study.

Prevalence and nature of anaemia in a prospective, population-based sample of people with diabetes: Teesside anaemia in diabetes (TAD) study.

AIMS: Anaemia occurs in 25% of people attending hospital diabetes clinics, but this may not be representative of all people with diabetes. We aimed to determine the prevalence of anaemia in a prospective population-based sample stratified by estimated glomerular filtration rate (eGFR) using the 4-point Modification of Diet in Renal Disease (MDRD) formula. METHODS: All 7331 patients on our district register were stratified by eGFR. Seven hundred and thirty were approached by letter on two occasions. Two hundred and thirty-four (32%) returned questionnaires and blood samples. Responders (R), non-responders (NR) and the whole cohort (C) were similar: mean +/- sd age R 61.7 +/- 12.7 years; NR 61.3 +/- 15.1 years; C 61.8 +/- 14.2 years; diabetes duration R 8.8 +/- 8.6 years; NR 8.2 +/- 7.9 years; C 7.5 +/- 7.8 years, Type 1 diabetes R 10.1%, NR 10.8%, C 9.4%. Anaemia was defined using World Health Organization criteria: haemoglobin < 13 g/dl for men, < 12 g/dl for women. RESULTS: Previously undiagnosed anaemia was present in 15% of the whole group, 36% with eGFR < 60 ml/min per 1.73 m(2) and 9% of those with eGFR > 60 ml/min per 1.73 m(2). Anaemia was as a result of erythropoietin deficiency in 34%, abnormal haematinics in 40% and was unexplained in 26% of patients. Five per cent of the patients had anaemia below the treatment threshold of 11 g/dl. CONCLUSIONS: The prevalence of unrecognized anaemia in population-based cohorts is lower than that in hospital-based studies. Current clinical surveillance in the UK is failing to detect anaemia in stage 3-5 chronic kidney disease (eGFR < 60 ml/min per 1.73 m(2)) and current guidelines will not detect 9% of diabetic patients with anaemia and an eGFR > 60 ml/min per 1.73 m(2).

Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis.

AIMS/HYPOTHESIS: Glomerular hyperfiltration is a well-established phenomenon occurring early in some patients with type 1 diabetes. However, there is no consistent answer regarding whether hyperfiltration predicts later development of nephropathy. We performed a systematic review and meta-analysis of observational studies that compared the risk of developing diabetic nephropathy in patients with and without glomerular hyperfiltration and also explored the impact of baseline GFR. METHODS: A systematic review and meta-analysis was carried out. Cohort studies in type 1 diabetic participants were included if they contained data on the development of incipient or overt nephropathy with baseline measurement of GFR and presence or absence of hyperfiltration. RESULTS: We included ten cohort studies following 780 patients. After a study median follow-up of 11.2 years, 130 patients had developed nephropathy. Using a random effects model, the pooled odds of progression to a minimum of microalbuminuria in patients with hyperfiltration was 2.71 (95% CI 1.20-6.11) times that of patients with normofiltration. There was moderate heterogeneity (heterogeneity test p = 0.05, measure of degree of inconsistency = 48%) and some evidence of funnel plot asymmetry, possibly due to publication bias. The pooled weighted mean difference in baseline GFR was 13.8 ml min(-1) 1.73 m(-2) (95% CI 5.0-22.7) greater in the group progressing to nephropathy than in those not progressing (heterogeneity test p < 0.01). CONCLUSIONS/INTERPRETATION: In published studies, individuals with glomerular hyperfiltration were at increased risk of progression to diabetic nephropathy using study level data. Further larger studies are required to explore this relationship and the role of potential confounding variables.

Are glomerular volume differences between type 1 and type 2 diabetic patients pathologically significant?

The observation that patients with type 2 diabetes tend to have larger glomeruli than patients with type 1 diabetes was first made more than 10 years ago. It has also been noted that type 2 diabetic patients with nephropathy often have more heterogeneous renal function and structure than type 1 patients. However, whether these observations are linked or have any bearing on the progression of nephropathy in the two types of diabetes remains uncertain. Here we put forward several hypotheses as to why glomerular volume in type 1 differs from that in type 2 diabetes. We suggest that although type 1 and type 2 diabetic patients appear to progress through similar stages of diabetic nephropathy, the route they take may differ. Differences in the way in which the glomeruli respond to the diabetic milieu may enable some type 2 diabetic patients to preserve their filtration surface in the face of an expanding mesangium.

Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes.

AIMS: To compare blood glucose control using insulin glargine + insulin lispro with that on NPH insulin + unmodified human insulin in adults with Type 1 diabetes managed with a multiple injection regimen. METHODS: In this 32-week, five-centre, two-way cross-over study, people with Type 1 diabetes (n = 56, baseline HbA1c 8.0 +/- 0.8%) were randomized to evening insulin glargine + mealtime insulin lispro or to NPH insulin (once- or twice-daily) + mealtime unmodified human insulin. Each 16-week period concluded with a 24-h inpatient plasma glucose profile. RESULTS: HbA1c was lower with glargine + lispro than with NPH + human insulin [7.5 vs. 8.0%, difference -0.5 (95% CI -0.7, -0.3) %, P < 0.001]. This was confirmed by an 8% lower 24-h plasma glucose area under the curve (AUC) (187 vs. 203 mmol l(-1) h(-1), P = 0.037), a 24% reduction in plasma glucose AUC > 7.0 mmol/l1 (47 vs. 62 mmol l(-1) h(-1), P = 0.017) and a 15% lower post-prandial plasma glucose AUC (75 vs. 88 mmol l(-1) h(-1), P = 0.002). There was no reduction in night-time plasma glucose AUC or increase in plasma glucose area < 3.5 mmol/l. Monthly rate of nocturnal hypoglycaemia was reduced by 44% with glargine + lispro (0.66 vs. 1.18 episodes/month, P < 0.001). CONCLUSIONS: Compared with NPH insulin + unmodified human insulin, the combination of insulin glargine with a rapid-acting insulin analogue as multiple-injection therapy for Type 1 diabetes improves overall glycaemic control as assessed by HbA1c and 24-h plasma glucose monitoring to a clinically significant degree, together with a reduction in nocturnal hypoglycaemia.

An economic evaluation of the Irbesartan in Diabetic Nephropathy Trial (IDNT) in a UK setting.

There are substantial healthcare costs associated with the provision of renal replacement therapy. Patients with diabetes mellitus are the largest and fastest growing group developing end-stage renal disease (ESRD) in the United Kingdom (UK). Treatment leading to a slowing of progression to ESRD in diabetic patients could lead to considerable cost savings. Using treatment-specific probabilities derived from the Irbesartan in Diabetic Nephropathy Trial (IDNT), the cost effectiveness of treating patients with hypertension, type II diabetes and nephropathy with irbesartan, amlodipine or control was calculated using a Markov model. UK-specific ESRD-related data were retrieved from published sources to reflect local management practices, ESRD outcomes and costs. Mean 10-year costs and changes in life expectancy due to ESRD delayed or avoided were calculated. Future costs and clinical benefits were discounted at 6.0 and 1.5% per annum and extensive sensitivity analyses were performed. Delay in the onset of ESRD with irbesartan led to cost savings of pound sterling 5125 and pound sterling 2919/patient and improvements in projected discounted life expectancy of 0.07 and 0.21 years over 10 years vs amlodipine and control, respectively. The costs of treatment of ESRD were the main contributor to the total costs. The cost of trial medications had only a minor impact. These results were robust in a wide range of plausible assumptions. Given that the IDNT efficacy results could be translated to a UK setting, treating patients with hypertension, type II diabetes and overt nephropathy with irbesartan was cost saving over a 10-year period compared to amlodipine and control.

Does ACE inhibition slow progression of glomerulopathy in patients with Type 2 diabetes mellitus?

AIMS: To examine the effect of ACE inhibition on glomerular structure in Type 2 diabetic patients with nephropathy. METHODS: Twenty-two patients were randomized to receive either perindopril (PE) or placebo (PO) and biopsied at baseline and after 2 years. Nineteen patients completed the study and data on interstitial changes, examined by light microscopy, have already been published. Only 11 patients (five PE, six PO) had sufficient tissue at baseline and follow-up to provide material for detailed electron microscopic examination. RESULTS: At baseline, mean +/- sd age (PE vs. PO) was 48 +/- 12 vs. 45 +/- 7 years; creatinine clearance 116 +/- 24 vs. 128 +/- 68 ml/min; median (range) proteinuria 0.7 (0.1-1.0) vs. 0.5 (0.07-3.9) g/24 h (P = NS for all). This cohort of 11 patients showed the same interstitial changes as the whole group. Between-group analysis showed that the change in interstitial volume fraction was significantly greater in the PO compared with PE group (0.10 +/- 0.07 vs. -0.001 +/- 0.04, P = 0.020). There were no significant changes in proteinuria or glomerular structural parameters (mesangial volume fraction PO 0.40 +/- 0.17 to 0.42 +/- 0.21; PE 0.29 +/- 0.08 to 0.28 +/- 0.14) in either treatment group. CONCLUSIONS: Interstitial changes appear to be more sensitive to ACE inhibition than glomerulopathy. Larger patient groups and longer treatment periods are necessary in order to detect any possible impact of ACE inhibition on the glomerular changes in Type 2 diabetes mellitus.

Audit of influenza and pneumococcal vaccination uptake in diabetic patients attending secondary care in the Northern Region.

AIMS: To document uptake of influenza and pneumococcal vaccination in diabetic patients attending secondary care in the Northern Region, and to explore influencing factors. METHODS: Diabetic patients attending out-patients in Middlesbrough, Gateshead and Newcastle were questioned from October 1999 to March 2000. Physicians inquired about influenza and pneumococcal vaccination status using a standardized questionnaire. Data collected included age, year of diagnosis, duration of diabetes, type of diabetes, and the presence of other recognized indications for vaccination. RESULTS: Two hundred and sixty-eight diabetic patients, 42% (113/268) with Type 1 diabetes, 34% (91/268) with ischaemic heart disease, 10% (26/268) with chronic pulmonary disease (CPD) and 10% (27/268) with chronic renal disease, were questioned. Thirty-five percent (93/268) of patients received both influenza and pneumococcal vaccines, 24% (64/268) received only influenza vaccine, and none received pneumococcus vaccine alone. Most vaccinees received advice about influenza and pneumococcal vaccination from their general practitioner (90% (142/157) and 87% (81/93), respectively). A large number of non-vaccinees were unaware of the need for influenza and pneumococcal vaccination (69% (76/111) and 91% (159/175), respectively). Using multiple logistic regression co-existing CPD increased the odds of receiving influenza (odds ratio (OR) (95% confidence interval (CI)) = 1.99 (1.07-14.12)) or pneumococcal (OR = 3.77 (1.69-21.76)) vaccination. Furthermore, each 1-year increase in age increased the chance of receiving influenza or pneumococcal vaccination by 22% (OR = 1.22 (1.09-1.67) and 29% (OR = 1.29 (1.07-1.72)), respectively. CONCLUSIONS: Vaccination rates in these diabetic patients are unsatisfactory. Secondary care health professionals might increase rates by raising the topic in consultations. Diabet. Med. 18, 599-603 (2001)

HOPE for patients with Type 2 diabetes: an application of the findings of the MICRO-HOPE substudy in a British hospital diabetes clinic.

AIMS: The MICRO-HOPE substudy demonstrated that when ramipril treatment was added to people with Type 2 diabetes and additional cardiovascular risk factors cardiovascular events were reduced by 25% in 4.5 years. We wished to determine the proportion of people with Type 2 diabetes and additional cardiovascular risk factors registered with a hospital diabetes service. METHODS: Non-proteinuric people (n = 1370) with Type 2 diabetes identified on our diabetes register were subject to analysis. Anticipated reductions in cardiovascular events due to ramipril treatment were based on reductions observed in the MICRO-HOPE substudy. RESULTS: Non-proteinuric people (n = 1075 (78%)) with Type 2 diabetes had at least one additional cardiovascular risk factor. Twenty-nine percent were already taking an angiotensin-converting enzyme inhibitor. The remaining 764 patients were similar to ramipril-treated participants in the MICRO-HOPE substudy. Treatment with ramipril for 4.5 years would be anticipated to reduce cardiovascular deaths by 26, revascularization procedures by 19 and admissions for myocardial infarction and stroke by 18 and 26, respectively. CONCLUSIONS: Of non-proteinuric people with Type 2 diabetes, 78% have additional cardiovascular risk factors. Only a small proportion currently receive treatment with an angiotensin-converting enzyme inhibitor. The incidence of cardiovascular events could be reduced if more patients were treated with ramipril and other cardiovascular risk factors were addressed.

Intra-uterine environment influences glomerular number and the acute renal adaptation to experimental diabetes.

AIMS/HYPOTHESIS: We sought to test the hypothesis of whether low birth weight rats would have reduced glomerular number, higher systolic blood pressure and an altered acute response to streptozotocin diabetes compared to normal birth weight rats. METHODS: Female offspring of Wistar rats fed an isocaloric diet containing either 6% casein (LPD) or 18% casein (NPD) in utero were studied. Birth weight, body weight, systolic blood pressure and urine albumin excretion were measured before and after streptozotocin diabetes. Glomerular number and volume were estimated after one week of diabetes. RESULTS: The LPD rats were of low birth weight (5.4 +/- 0.5 g vs 6.4 +/- 0.8 g, p < 0.0001) with higher systolic blood pressure (137 +/- 9mmHg vs 120 +/- 7 mmHg, p < 0.0001) and reduced glomerular number (17,435 +/- 2,074 vs 24,846 +/- 1,864, p < 0.0001). The LPD rats had smaller kidneys (0.925 +/- 0.009 g vs 1.200 +/- 0.173 g, p = 0.041) but similar glomerular volume to NPD control rats (1.11 +/- 0.15 x 10(6) microm3 vs 1.08 +/- 0.17 x 10(6) microm3). After 1 week of diabetes LPD rats had a greater proportional increase in renal size (diabetes 50 +/- 12 % vs control 20 +/- 4%, p = 0.003). Insulin suppressed renal hypertrophy in both LPD and NPD rats but failed to suppress glomerular hypertrophy in LPD rats (1.48 +/- 0.21 x 10(6) microm3 vs 1.03 +/- 0.23 x 10(6) microm3 p = 0.015). CONCLUSION/INTERPRETATION: Abnormal intra-uterine environment reduces both renal size and glomerular number and influences the acute renal adaptation to experimental diabetes.

A new variant of Carney's triad: phaeochromocytoma and chondrosarcoma.

A 61 year old hypertensive woman presented in 1986 with a right scapular chondrosarcoma. She developed type 1 diabetes mellitus in 1991 and suffered a stroke in 1991. Chest radiography showed pulmonary metastases in 1997. Further radiological staging detected a right sided phaeochromocytoma, which was subsequently removed in 1998. Before this, repeated urine estimations of vanillylmandelic acid had been normal. Her diabetes was cured by adrenalectomy. It is believed that the combination of phaeochromocytoma and extrapulmonary chondrosarcoma represents a new variant of Carney's triad.

Excess mortality in a population with diabetes and the impact of material deprivation: longitudinal, population based study.

OBJECTIVES: To establish the age and sex specific mortality for people with diabetes in comparison with local and national background populations; to investigate the relationship between mortality and material deprivation in an unselected population with diabetes. DESIGN: Longitudinal study, using a population based district diabetes register. SETTING: South Tees, United Kingdom. PARTICIPANTS: All people known to have diabetes living in Middlesbrough and Redcar and Cleveland local authorities on 1 January 1994. MAIN OUTCOME MEASURE: Death, from any cause, between 1 January 1994 and 31 December 1999. RESULTS: Over the six years of the study 1205 (24.9%) of 4842 participants died. All cause standardised mortality ratios for type 1 diabetes were 641 (95% confidence interval 406 to 962) in women and 294 (200 to 418) in men, and those for type 2 diabetes were 160 (147 to 174) in women and 141 (130 to 152) in men. Cause specific standardised mortality ratios were increased for ischaemic heart disease, cerebrovascular disease, and renal disease; no reductions in mortality from other causes were seen. The risk of premature death increased significantly with increasing material deprivation (P<0.001). CONCLUSIONS: Diabetes is associated with excess mortality, even in an area with high background death rates from cardiovascular disease. This excess mortality is evident in all age groups, most pronounced in young people with type 1 diabetes, and exacerbated by material deprivation. Aggressive approaches to the management of cardiovascular risk factors could reduce the excess mortality in people with diabetes.

Birth weight has no influence on glomerular number and volume.

It has been proposed that low birth weight (LBW) results in a reduction in glomerular number that may, in turn, predispose an individual to develop hypertension in adulthood. Glomerular number is reduced in animal models of intra-uterine malnutrition using a variety of techniques. However, the relevance of such extreme models to man is uncertain. The purpose of this study was to evaluate whether animals with naturally occurring LBW, which have not received any manipulation in utero, have a reduction in glomerular number, altered glomerular volume and abnormal urine albumin excretion. Litters from female rats delivering at term on the same day were weighed and sexed at birth. From each litter 2 males with the lowest birth weight (LBW n = 18) and 2 males with a birth weight closest to the litter mean [normal birth weight (NBW) n = 18] were selected and cross-fostered onto periparturient lactating dams. LBW rats weighted 6.7 +/- 0.6 g compared with 7.2 +/- 0.6 g for NBW rats (P = 0.03). After weaning all rats were weighed weekly and underwent metabolic studies at 4, 8, 12 and 16 weeks. Following perfusion fixation, glomerular number and mean glomerular volume were estimated using standard stereological techniques. There was no significant difference between LBW and NBW rats with respect to glomerular number (24,499 +/- 2,078 vs. 24,825 +/- 1,818), mean glomerular volume and urine albumin excretion, and no rats had a glomerular number outside the normal range. This study suggests that naturally occurring LBW has little influence on renal development, glomerular number and volume.