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1.  Hypoglycaemia-induced changes in regional brain volume and memory function 
Background
Hypoglycaemic events can be a serious complication of insulin therapy in Type 1 diabetes mellitus. Severe hypoglycaemic exposure can lead to episodic memory impairments, including anterograde amnesia. However, relatively little is known regarding the long-term impact of severe hypoglycaemia on brain structure in Type 1 diabetes mellitus. The goals of the present study were to gain a greater understanding of the long-term effects of severe hypoglycaemia exposure on brain structure and the neural correlates of memory impairments in Type 1 diabetes mellitus.
Case report
Regional grey and white matter volume and total white matter lesion volume were quantified in an individual with long-standing hypoglycaemia-induced anterograde amnesia and compared with age- and gender-matched healthy control subjects. Our patient has significant reductions in grey matter volume in the hippocampus, thalamus and pallidum, and significant reductions in white matter volume in the splenium, isthmus of the cingulate and cerebellum. He also has a significantly larger total white matter lesion volume than control subjects.
Conclusion
This case study highlights the potential of hypoglycaemia for permanent deleterious effects on brain structure and memory function. Our results suggest that subcortical grey matter, periventricular white matter and posterior white matter may be most susceptible to injury from hypoglycaemia exposure, and that structural damage to the hippocampus and isthmus of the cingulate may play a central role in hypoglycaemia-induced memory impairments.
doi:10.1111/dme.12135
PMCID: PMC3651610  PMID: 23330574
2.  Technical Editor DRH Original Article: Pathophysiology Hypoglycaemia increases aldosterone in a dose-dependent fashion 
Aims
Intensive glycaemic control increases the incidence of hypoglycaemia. We sought to define the effects of hypoglycaemia on aldosterone, a hormone involved in cardiovascular injury and baroreflex impairment.
Methods
To contrast the effects of hypoglycaemia and euglycaemia on aldosterone and plasma renin activity, in Study 1, we assessed hormone levels in 13 subjects who participated in euglycaemic (5.0 mmol/l) and hypoglycaemic (2.8 mmol/l) hyperinsulinaemic clamp protocols in random order. To determine the relationship between aldosterone and the depth of hypoglycaemia, in Study 2, we assessed hormone levels in an additional 13 subjects who participated in a 3-h stepped hypoglycaemic hyperinsulinaemic clamp protocol; blood glucose was reduced in 0.55 mmol/l steps from 5.0 to 2.2 mmol/l. Subjects were healthy and consumed controlled sodium diets.
Results
In Study 1, aldosterone increased approximately 2.5-fold during hypoglycaemic hyperinsulinaemia, P < 0.001, but did not rise with euglycaemic hyperinsulinaemia. Plasma renin activity increased during both hyperinsulinaemic clamps; however, the increase was greater during hypoglycaemia (Δ = 1.5 ± 0.2 ng ml−1 h−1) vs. euglycaemia (Δ = 0.5 ± 0.1 ng ml−1 h−1), P < 0.005. In Study 2, aldosterone increased significantly at glucose levels of 2.8 mmol/l; this increase was amplified with glucose of 2.2 mmol/l. Aldosterone increases paralleled those of ACTH.
Conclusions
Hypoglycaemia increases aldosterone in a dose-dependent fashion. This increase is likely attributable to activation of the renin-angiotensin-aldosterone system and increases in ACTH. Because aldosterone activation of the mineralocorticoid receptor is implicated in the pathophysiology of cardiovascular injury, including vascular dysfunction, inflammation, baroreflex impairment and cardiac arrhythmias, these findings may be of relevance in individuals who experience hypoglycaemia.
doi:10.1111/j.1464-5491.2010.03087.x
PMCID: PMC3957466  PMID: 20950382
aldosterone; autonomic nervous system; hypoglycaemia
3.  Longitudinal association between medication adherence and glycaemic control in Type 2 diabetes 
Aim
Despite the widespread assumption that adherence drives glycaemic control, there is little published support for this in Type 2 diabetes. The study objective was to determine whether self-reported medication adherence predicts future glycaemic control in Type 2 diabetes, after accounting for baseline control.
Methods
Medication adherence (4-item Morisky scale), glycaemic control (HbA1c %), and other variables were assessed in 287 adult primary care patients prescribed oral medication (40% also on insulin) for Type 2 diabetes. Glycaemic control was reassessed 6 months later. Regression analyses examined concurrent and future glycaemic control as a function of baseline medication adherence after adjustment for baseline glycaemia and other potential confounders.
Results
Only half of patients reported high adherence. Cross-sectional adjusted analysis replicated prior reports of an adherence—HbA1c association (P = 0.011). Even after adjusting for baseline HbA1c, each one-point increase in baseline Morisky total score was associated with a 1.8 mmol/mol (or 0.16%) increase in HbA1c measured 6 months later. Additionally, baseline endorsement of forgetting to take medication was associated with a 4.7 mmol/mol (or 0.43%) increase in 6-month HbA1c (P = 0.005). This effect persisted after adjusting for psychological distress and did not vary by key demographic and medical features.
Conclusions
Even after stringent adjustment for baseline glycaemic control, self-reported adherence to diabetes medication predicts long-term glycaemic control. The Morisky scale is an easy-to-use clinical tool to identify patients whose glycaemic control will subsequently worsen, regardless of age, gender and psychological distress.
doi:10.1111/dme.12046
PMCID: PMC3567301  PMID: 23075262
4.  The impact of blood glucose and HbA1c goals on glycaemic control in children and adolescents with Type 1 diabetes 
Aims
To evaluate parents’ goals and parents’ perceptions of physicians’ goals for blood glucose and HbA1c in children and adolescents with type 1 diabetes.
Methods
In a cross-sectional observational assessment, parents (80% mothers) of 153 children/adolescents (56% female), aged 12.9 ± 2.3 years (range 8–16 years) with Type 1 diabetes for 6.3 ± 3.5 years, completed surveys regarding their goals and their perceptions of physicians’ goals for their child’s blood glucose and HbA1c levels.
Results
Children/adolescents had a mean HbA1c of 69 ± 16 mmol/mol (8.4 ± 1.4%) and blood glucose levels checked 3.8 ± 1.2 times/day; 23% received pump therapy. Almost half of parents reported a blood glucose goal of 130 (80–180) mg/dl [7.2 (4.4–10) mmol/l]; 75% of parents reported a HbA1c goal of 42–64 mmol/mol (6–8%). The HbA1c level was significantly lower when parents reported HbA1c goals ≤ 64 mmol/mol (≤ 8%) vs. > 64 mmol/mol (> 8%) [67 ± 14 mmol/mol (8.3 ± 1.2%) vs. 76 ± 20 mmol/mol (9.1 ± 1.8%), respectively, P = 0.02]. Parents’ blood glucose and HbA1c goals were tightly linked with parents’ perceptions of physicians’ blood glucose and HbA1c goals (69% concordant, P < 0.0001; 88% concordant, P < 0.0001, respectively).
Conclusions
There was a significant association between lower parent HbA1c goals and lower child/adolescent HbA1c. Further, parents appear to set glycaemic goals based upon their perceptions of physician goals. Future studies should assess the relationship between parents’ perceptions of health-care providers’ goals and health-care providers’ actual goals and the impact of unified family/provider goal-setting on glycaemic control.
doi:10.1111/dme.12083
PMCID: PMC3614346  PMID: 23190135
5.  Association of pain with HbA1c in a predominantly black population of community-dwelling adults with diabetes: a cross-sectional analysis 
Aims
To assess the relationship between pain and HbA1c levels in a predominantly black population with diabetes, and to determine whether self-management behaviours (exercise and diet) and symptoms of depression mediate this relationship.
Methods
We analysed cross-sectional data from 417 community-dwelling individuals with diabetes in rural Alabama, USA. Binary logistic regression was used to analyse the relationship between pain and HbA1c levels, defined as relatively good [≤ 64 mmol/mol (≤ 8.0%)] and relatively poor [> 64 mmol/mol (> 8.0%)], after adjusting for sociodemographics, insulin use, medication count, cigarette smoking history and body mass index (BMI). We examined the mediating roles of exercise, diet, and symptoms of depression using bootstrapping.
Results
Participants were primarily black (86.6%), female (76.1%) and reported an annual income of ≤$20,000 (52.7%). Their mean (SD) age was 59.6 (12.8) years. The majority of the participants reported moderate to extreme pain (71.5%). Participants reporting pain were more than twice as likely to have HbA1c levels > 64 mmol/mol (8.0%) in the fully adjusted model (odds ratio 2.33 [95% CI 1.28–4.24]; P < 0.05). Diet significantly mediated the relationship between pain and HbA1c control (β = 0.06; 95% CI: 0.01–0.17), but only in the unadjusted model. Exercise and symptoms of depression were not significant mediators.
Conclusions
A significant independent relationship between pain and HbA1c control was found in this mainly black population, which was not explained by self-management behaviours or symptoms of depression. Future research is needed to delineate the mechanism by which pain influences HbA1c control, especially among black people with diabetes on low incomes.
doi:10.1111/dme.12264
PMCID: PMC3935766  PMID: 23796252
6.  Intensification of diabetes medication and risk for 30-day readmission 
Aim
To examine the association of in-hospital diabetes regimen intensification with subsequent 30-day risk for unplanned readmission/emergency department admission.
Methods
We retrospectively studied 1949 adults with Type 2 diabetes receiving primary care within an academic health network admitted to the hospital between January 2007 and December 2009. Glucose therapy intensification was defined as new start of insulin or oral hypoglycaemic agents, or addition of prandial insulin or insulin mixtures. The association of glucose therapy intensification with subsequent 30-day risk for unplanned readmission/emergency department admission was examined, with focus on medicine service patients with poorly controlled glycaemia (baseline HbA1c ≥ 64 mmol/mol).
Results
One in six patients (324/1949, 17%) had early readmission/emergency department admission. Compared with patients without early readmission, readmitted patients were more often male (58 vs. 52%, P = 0.03), had higher Charlson co-morbidity score [mean (SD) 3.0 (2.0) vs. 2.8 (1.8), P = 0.02], longer length of stay [5 (4.4) vs. 3.9 (3.3) days, P < 0.01] and were more often discharged home with nursing services (38 vs. 32%, P = 0.03). Overall, glucose therapy intensification was not associated with early hospital readmission/emergency department admission (odds ratio 0.94, 95% CI 0.64–1.37, P = 0.74). However, among medicine service patients with baseline HbA1c ≥ 64 mmol/mol (8%), glucose therapy intensification was associated with a significantly decreased early readmission risk (adjusted odds ratio 0.33, 95% CI 0.12–0.88, P = 0.03) and lower post-discharge HbA1c {mean decrease (SD): 20 (26) mmol/mol [1.8 (2.4) %] vs. 7 (15) mmol/mol [0.6 (1.4) %], P < 0.01}.
Conclusions
Diabetes medical regimen intensification during hospitalization was not associated with early readmission. Among patients with elevated HbA1c, glucose therapy intensification was associated with a decreased 30-day readmission/emergency department admission risk and lower outpatient HbA1c levels. Our findings support the safety and durable impact of diabetes regimen optimization during hospital admission.
doi:10.1111/dme.12061
PMCID: PMC3552066  PMID: 23126686
7.  The environment and the origins of islet autoimmunity and Type 1 diabetes 
Type 1 diabetes involves the specific destruction of the pancreatic islet β-cells, eventually resulting in a complete dependency of exogenous insulin. The clinical onset of diabetes is preceded by the appearance of autoantibodies against β-cell antigens. The human leukocyte antigen (HLA) region is the single most important genetic determinant of Type 1 diabetes susceptibility, yet variability in the HLA region has been estimated to explain only approximately 60% of the genetic influence of the disease. Over 50 identified non-HLA genetic polymorphisms support the notion that genetics alone cannot explain Type 1 diabetes. Several lines of evidence indicate that environmental triggers may be integral in inducing the onset of islet autoimmunity in genetically susceptible individuals. The association between environmental factors and the clinical onset is complicated by observation that the rate of progression to clinical onset may be affected by environmental determinants. Hence, the environment may be aetiological as well as pathogenic. Putative inductive mechanisms include viral, microbial, diet-related, anthropometric and psychosocial factors. Ongoing observational cohort studies such as The Environmental Determinants of Diabetes in the Young (TEDDY) study aim to ascertain environmental determinants that may trigger islet autoimmunity and either speed up or slow down the progression to clinical onset in subjects with persistent islet autoimmunity.
doi:10.1111/dme.12099
PMCID: PMC3552102  PMID: 23252770
9.  Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study 
Aims
Whether long-term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown. The aim of this study was to determine the long-term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group.
Methods
This long-term follow-up (median 10 years, interquartile range 9.0–10.5) of the three-arm Diabetes Prevention Program randomized controlled clinical trial (metformin, intensive lifestyle and placebo), performed on 2766 (88%) of the Diabetes Prevention Program participants (who originally had impaired glucose tolerance), comprised a mean of 3.2 years of randomized treatment, approximately 1-year transition (during which all participants were offered intensive lifestyle intervention) and 5 years follow-up (Diabetes Prevention Program Outcomes Study). During the study, participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting. The study determined lipoprotein profiles and blood pressure and medication use annually.
Results
After 10 years’ follow-up from Diabetes Prevention Program baseline, major reductions were seen for systolic (2–3 mmHg) and diastolic (5–6 mmHg) blood pressure, and for LDL cholesterol (0.47–0.54 mmol/l) and triglycerides (0.18–0.32 mmol/l) in all groups, with no between-group differences. HDL cholesterol also rose significantly (0.13–0.16 mmol/l) in all groups. Lipid (P < 0.012) and blood pressure (P < 0.09) medication use, however, were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study.
Conclusion
Overall, intensive lifestyle intervention achieved, with less medication, a comparable long-term effect on cardiovascular disease risk factors, to that seen in the metformin and placebo groups.
(Clinical Trials Registry No; NCT 00038727).
doi:10.1111/j.1464-5491.2012.03750.x
PMCID: PMC3524372  PMID: 22812594
blood pressure; diabetes prevention; lifestyle; lipids; metformin; statins
10.  Common variants in genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1/2), adiponectin concentrations, and diabetes incidence in the Diabetes Prevention Program 
Aims
Baseline adiponectin concentrations predict incident Type 2 diabetes mellitus in the Diabetes Prevention Program. We tested the hypothesis that common variants in the genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1, ADIPOR2) would associate with circulating adiponectin concentrations and/or with diabetes incidence in the Diabetes Prevention Program population.
Methods
Seventy-seven tagging single-nucleotide polymorphisms (SNPs) in ADIPOQ (24), ADIPOR1 (22) and ADIPOR2 (31) were genotyped. Associations of SNPs with baseline adiponectin concentrations were evaluated using linear modelling. Associations of SNPs with diabetes incidence were evaluated using Cox proportional hazards modelling.
Results
Thirteen of 24 ADIPOQ SNPs were significantly associated with baseline adiponectin concentrations. Multivariable analysis including these 13 SNPs revealed strong independent contributions from rs17366568, rs1648707, rs17373414 and rs1403696 with adiponectin concentrations. However, no ADIPOQ SNPs were directly associated with diabetes incidence. Two ADIPOR1 SNPs (rs1342387 and rs12733285) were associated with ~18% increased diabetes incidence for carriers of the minor allele without differences across treatment groups, and without any relationship with adiponectin concentrations.
Conclusions
ADIPOQ SNPs are significantly associated with adiponectin concentrations in the Diabetes Prevention Program cohort. This observation extends prior observations from unselected populations of European descent into a broader multi-ethnic population, and confirms the relevance of these variants in an obese/dysglycaemic population. Despite the robust relationship between adiponectin concentrations and diabetes risk in this cohort, variants in ADIPOQ that relate to adiponectin concentrations do not relate to diabetes risk in this population. ADIPOR1 variants exerted significant effects on diabetes risk distinct from any effect of adiponectin concentrations.
[Clinical Trials Registry Nos; NCT 00004992 (Diabetes Prevention Program) and NCT 00038727 (Diabetes Prevention Program Outcomes Study)]
doi:10.1111/j.1464-5491.2012.03662.x
PMCID: PMC3499646  PMID: 22443353
adiponectin; diabetes; genetics; polymorphism
11.  Area-under-the-A1c-Curve above the Normal Range and the Prediction of Microvascular Outcomes: An analysis of data from the Diabetes Control and Complications Trial 
Aims
In the Diabetes Control and Complications Trial (DCCT), mean updated A1c accounted for most of the differential risk of microvascular complications between intensive and conventional insulin therapy. We hypothesized, however, that a more precise measure of chronic hyperglycemic exposure may be the incremental area-under-the-A1c-curve above the DCCT-standardized normal range for A1c (iAUCA1c>norm).
Methods
Using the Principal DCCT Dataset, we compared the following 3 measures of chronic glycemic exposure for their capacity to predict retinopathy, nephropathy, and neuropathy during the DCCT: mean updated A1c, iAUCA1c>norm, and total area-under-the-A1c-curve (tAUCA1c). For each outcome, models using each of these 3 glycemic measures were compared in the following 3 ways: hazard or odds ratio, chi-square statistic, and Akaike information criterion.
Results
The 3 glycemic measures did not differ in their prediction of neuropathy. iAUCA1c>norm was modestly superior to mean updated A1c for predicting nephropathy (chi-square p=0.017, Akaike p=0.032). In contrast, for predicting retinopathy, both iAUCA1c>norm (chi-square p=0.0005, Akaike p=0.0005) and tAUCA1c (chi-square p=0.004, Akaike p=0.0004) were significantly better than mean updated A1c. Varying its A1c threshold incrementally between 37 and 53 mmol/mol (5.5% - 7.0%) inclusive did not improve the prediction of retinopathy by iAUCA1c>threshold beyond that of tAUCA1c, consistent with the concept of a continuous relationship between glycemia and retinopathy with no glycemic threshold.
Conclusions
Both iAUCA1c>norm and tAUCA1c were superior to mean updated A1c for predicting retinopathy. Optimal assessment of chronic glycemic exposure as a determinant of retinopathic risk may require consideration of both the degree of hyperglycemia and its duration.
doi:10.1111/dme.12004
PMCID: PMC3843010  PMID: 22937915
A1c; glycated hemoglobin; glycemic exposure; retinopathy; DCCT; Diabetes Control and Complications Trial
12.  Functional analyses of the mutation nt-128 T→G in the hepatocyte nuclear factor-1α promoter region in Chinese diabetes pedigrees 
Aims
Hepatocyte nuclear factor-1α (HNF-1α) regulates the expression of genes encoding proteins involved in glucose metabolism and insulin secretion. Mutations in the HNF-1α gene cause maturity-onset diabetes of the young Type 3. However, the mechanism leading to this disease has not been completely ascertained. Previously, we found a novel mutation in the regulatory element of the human HNF-1α gene in two Chinese diabetes pedigrees. The nucleotide at position -128 T was substituted by G (nt-128 T→G). In this study, we analysed the functional defect of nt-128 T→G in HNF-1α transcription activity.
Methods
Luciferase reporter gene assays were carried out to examine the functional characteristics of this mutant. Electrophoretic mobility shift assays and chromatin immunoprecipitation were performed to confirm the binding of nuclear proteins to oligonucleotides.
Results
The variant construct (nt-128 T→G) had a 1.65-fold increase in promoter activity compared with that of the wild-type construct in HepG2 cells and a 1.33-fold increase in MIN6 cells, respectively. The variant resided at a FOXA/ HNF-3 binding site identified by a series of competitive electrophoretic mobility shift assays and antibody supershift analyses. The assays showed a differential binding affinity in the wild-type and the nt-128 T→G mutant fragments by FOXA/ HNF-3. Chromatin immunoprecipitation indicated that FOXA/ HNF-3 bound to this region in vivo. One nucleotide substitution in the FOXA/ HNF-3 site in the human HNF-1α regulatory element caused an increase of HNF-1α transcriptional activity.
Conclusions
Our data suggested that this substitution in the promoter region affects DNA–protein interaction and HNF-1α gene transcription. The mutant may contribute to the development of diabetes in these two nt-128 T→G pedigrees of Chinese.
doi:10.1111/j.1464-5491.2012.03626.x
PMCID: PMC3570122  PMID: 22413961
13.  Effect of screening for Type 2 diabetes on population-level self-rated health outcomes and measures of cardiovascular risk: 13-year follow-up of the Ely cohort 
Diabetic Medicine  2012;29(7):886-892.
Aims
There is continuing uncertainty regarding the overall net benefits of population-based screening for Type 2 diabetes. We compared clinical measures, prescribed medication, cardiovascular morbidity and self-rated health in individuals without diabetes in a screened vs. an unscreened population.
Methods
A parallel-group, cohort study of people aged 40–65 years, free of known diabetes, identified from the population register of a general practice in Ely, Cambridgeshire (n = 4936). In 1990–1992, one third (n = 1705), selected randomly, received an invitation for screening for diabetes and cardiovascular risk factors at 5-yearly intervals (screened population). From the remainder of the sampling frame, 1705 randomly selected individuals were invited to diabetes screening 10 years later (unscreened population). Patients without known diabetes from both populations were invited for a health assessment.
Results
Of 3390 eligible individuals without diabetes, 1442 (43%) attended for health assessment, with no significant difference in attendance between groups. Thirteen years after the commencement of screening, self-rated functional health status and health utility were identical between the screened and unscreened populations. Clinical measures, self-reported medication and cardiovascular morbidity were similar between the two groups.
Conclusions
Screening for diabetes is not associated with long-term harms at the population level. However, screening has limited long-term impact on those testing negative; benefits may largely be restricted to those whose diabetes is detected early through screening.
doi:10.1111/j.1464-5491.2012.03570.x
PMCID: PMC3814419  PMID: 22283392
diabetes; Ely; mortality; population; screening
14.  Telomere length in blood and skeletal muscle in relation to measures of glycaemia and insulinaemia 
Summary
Aims
Skeletal muscle is a major metabolic organ and plays important roles in glucose metabolism, insulin sensitivity, and insulin action. Muscle telomere length reflects the myocyte's exposure to harmful environmental factors. Leukocyte telomere length is considered a marker of muscle telomere length and is used in epidemiologic studies to assess associations with ageing-related diseases where muscle physiology is important. However, the extent to which leucocyte telomere length and muscle telomere length are correlated is unknown, as are their relative correlations with glucose and insulin concentrations. The purpose of this study was to determine the extent of these relationships.
Methods
Leucocyte telomere length and muscle telomere length were measured by quantitative real-time PCR in participants from the Malmö Exercise Intervention (MEI; n=27) and the PPP-Botnia studies (n=31). Participants in both studies were free from type 2 diabetes. We assessed the association between leucocyte telomere length, muscle telomere length and metabolic traits using Spearmen correlations and multivariate linear regression. Bland-Altman analysis was used to assess agreement between leucocyte telomere length and muscle telomere length.
Results
In age-, study-, diabetes family history- and sex-adjusted models, leucocyte telomere length and muscle telomere length were positively correlated (r=0.39, 95% CI: 0.15, 0.59). Leucocyte telomere length was inversely associated with 2hr glucose concentrations (r= -0.58, 95% CI: -1.0, -0.16), but there was no correlation between muscle telomere length and 2 hr glucose concentrations (r=0.05, 95% CI: -0.35, 0.46) or between leucocyte telomere length or muscle telomere length with other metabolic traits.
Conclusions
In summary, the current study supports the use of leucocyte telomere length as a proxy for muscle telomere length in epidemiological studies of type 2 diabetes aetiology.
doi:10.1111/j.1464-5491.2012.03737.x
PMCID: PMC3698879  PMID: 22747879
Leukocyte telomere length; muscle telomere length; cardiometabolic; type 2 diabetes; skeletal muscle physiology
15.  Sex ratio variations among the offspring of women with diabetes in pregnancy 
Aims
It has long been hypothesized that natural selection would favour a reproductive strategy biased towards females under adverse circumstances in order to maximize the number of surviving grandchildren. An excess of daughters in women with Type 1 diabetes and a greater likelihood of gestational diabetes in women carrying male fetuses have also been reported. This study aims to compare the sex ratio across categories of maternal glycaemia.
Methods
Among 288 009 mother–infant pairs delivering at Kaiser Permanente Northern California in 1996–2008, sex ratios were calculated for the following categories: pregravid diabetes, gestational diabetes, mild pregnancy hyperglycaemia (defined as an abnormal screening but normal diagnostic test for gestational diabetes) and normoglycaemia. Odds ratios for delivering a male were estimated with logistic regression; normoglycaemic pregnancies comprised the reference.
Results
Women with pregravid diabetes delivered the fewest males (ratio male/female = 1.01), followed by women with normoglycaemic pregnancies and those with an abnormal screening only (both sex ratios = 1.05); women with gestational diabetes delivered the most males (sex ratio = 1.07). Odds ratio estimates suggested the same pattern, but none attained statistical significance.
Conclusions
The crude sex ratios in this cohort suggest a possible gradient by category of maternal glycaemia. Women with gestational diabetes, a condition characterized by excessive fuel substrates, appear to deliver more males. Women with pregravid diabetes delivered the fewest males, possibly reflecting the unfavourable state of chronic disease.
doi:10.1111/j.1464-5491.2012.03663.x
PMCID: PMC3392463  PMID: 22443388
diabetes; gestational diabetes; sex ratio
16.  Development of associations among central adiposity, adiponectin and insulin sensitivity from adolescence to young adulthood 
Objective
To examine associations of central adiposity, serum adiponectin and clamp-derived insulin sensitivity in a single longitudinal cohort from early adolescence to young adulthood.
Methods
The cohort was examined three times at mean ages 15 years (n = 308), 19 years (n = 218) and 22 years (n = 163). Insulin sensitivity was measured with the euglycaemic hyperinsulinaemic clamp. Circulating adiponectin was measured by enzyme-linked immunosorbent assay. Computed tomography scans were used at mean age 22 years to compute subcutaneous and visceral abdominal fat volume. Partial Pearson correlations and linear regression were used to examine cross-sectional associations at each examination.
Results
The moderate negative correlation between waist circumference and adiponectin was significant and essentially unchanged from mean age 15 years (−0.32, P < 0.0001) to mean age 22 years (−0.29, P < 0.002), whereas the negative correlation between waist circumference and insulin sensitivity and the positive correlation between adiponectin and insulin sensitivity increased steadily in magnitude to mean age 22 years (−0.29, P = 0.0002; and 0.32, P < 0.0001, respectively). In regression models including both visceral and subcutaneous fat, only visceral fat was significantly associated with insulin sensitivity, while only subcutaneous fat was nearly significantly associated with adiponectin.
Conclusions
This study shows that the significant negative relationship between waist circumference and adiponectin predated the development of significant relationships between insulin sensitivity and both waist circumference and adiponectin. It also shows that adiponectin is more closely related to subcutaneous fat and insulin sensitivity is more closely related to visceral fat in young adults.
doi:10.1111/j.1464-5491.2012.03726.x
PMCID: PMC3418404  PMID: 22672197
adiponectin; adolescence; euglycaemic clamp; insulin sensitivity; visceral fat
17.  Insulin secretion based on the late oral glucose tolerance test period and incident diabetes: the San Antonio Heart Study 
Diabetic Medicine  2012;29(8):e151-e158.
Aims
The Insulinogenic Index from 0 to 30 min (ΔI 0-30/ΔG0-30), a measure of insulin secretion derived from the early period of the oral glucose tolerance test, predicts future diabetes. However, there are few data on secretory measures from the late oral glucose tolerance test period. We therefore investigated the association of the ratio of the area under the insulin curve to the area under the glucose curve from 60 to 120 min (I/GAUC 60-120) with incident diabetes.
Methods
Participants were 1540 Mexican Americans and non-Hispanic whites in the San Antonio Heart Study who were free of diabetes at baseline. We analysed indices of sensitivity (Matsuda index) and secretion from the early (ΔI0-30/ΔG0-30) and late oral glucose tolerance test periods (I/GAUC 60-120).
Results
A total of 179 participants developed diabetes after 7.5 years. I/GAUC60-120 was an independent predictor of diabetes [odds ratio × 1 SD unit increase, 0.37 (0.26–0.54)] in a model that also included age, sex, ethnicity, body mass index, family history of diabetes, Matsuda index and (ΔI 0-30/ΔG0-30) as covariates. I/GAUC 60–120 increased the C statistic (a test of discrimination) of the model (0.882 vs. 0.875, P = 0.044). I/GAUC 60–120 correctly reclassified one-fifth of individuals with moderate and strong risks of future diabetes. The net reclassification improvement was 0.13 (P < 0.001) and the integrated discrimination improvement was 0.033 (P < 0.001).
Conclusions
An insulin secretory measure derived from the late oral glucose tolerance test period is useful for classifying individuals at risk of future diabetes independently of other risk factors, including insulin sensitivity and a secretory measure from the early oral glucose tolerance test period.
doi:10.1111/j.1464-5491.2012.03660.x
PMCID: PMC3391351  PMID: 22435928
epidemiology; insulin resistance; insulin secretion; oral glucose tolerance test; prediction of Type 2 diabetes mellitus
18.  The effect of rising vs. falling glucose level on amperometric glucose sensor lag and accuracy in Type 1 diabetes 
Background
Because declining glucose levels should be detected quickly in persons with Type 1 diabetes, a lag between blood glucose and subcutaneous sensor glucose can be problematic. It is unclear whether the magnitude of sensor lag is lower during falling glucose than during rising glucose.
Methods
Initially, we analysed 95 data segments during which glucose changed and during which very frequent reference blood glucose monitoring was performed. However, to minimize confounding effects of noise and calibration error, we excluded data segments in which there was substantial sensor error. After these exclusions, and combination of data from duplicate sensors, there were 72 analysable data segments (36 for rising glucose, 36 for falling). We measured lag in two ways: (1) the time delay at the vertical mid-point of the glucose change (regression delay); and (2) determination of the optimal time shift required to minimize the difference between glucose sensor signals and blood glucose values drawn concurrently.
Results
Using the regression delay method, the mean sensor lag for rising vs. falling glucose segments was 8.9 min (95% CI 6.1–11.6) vs. 1.5 min (95% CI −2.6 to 5.5, P < 0.005). Using the time shift optimization method, results were similar, with a lag that was higher for rising than for falling segments [8.3 (95% CI 5.8–10.7) vs. 1.5 min (95% CI −2.2 to 5.2), P < 0.001]. Commensurate with the lag results, sensor accuracy was greater during falling than during rising glucose segments.
Conclusions
In Type 1 diabetes, when noise and calibration error are minimized to reduce effects that confound delay measurement, subcutaneous glucose sensors demonstrate a shorter lag duration and greater accuracy when glucose is falling than when rising.
doi:10.1111/j.1464-5491.2011.03545.x
PMCID: PMC3697744  PMID: 22150642
biotechnology; continuous blood glucose monitoring; Type 1 diabetes
19.  Contemporary Rates of Severe Hypoglycaemia in Youth with Type 1 Diabetes: Variability by Insulin Regimen 
Aims
To determine incidence rates of severe hypoglycaemia and compare incidence rates by insulin regimen in a diverse sample of youth with type 1 diabetes from two sites.
Methods
In this observational study, 255 youth (51% female) aged 9–15 years receiving varied insulin regimens provided data prospectively for a median of 1.2 years. Reported episodes of severe hypoglycaemia, defined as episodes requiring help from another person for oral treatment or episodes resulting in seizure/coma, and current insulin regimens were collected systematically. Incidence rates were calculated and compared according to insulin regimen in bivariate and multivariate analyses.
Results
At first encounter, participants had a median age of 12.2 years (range 9.0–15.0), median diabetes duration of 4.4 years (range 1.0–13.0) and mean A1C of 67±12 mmol/mol (8.3±1.1%). The incidence rate was 37.6/100-patient-years for all severe hypoglycaemia and 9.6/100-patient-years for seizure/coma. The incidence rate for severe hypoglycaemia was 31.8/100-patient-years on continuous subcutaneous insulin infusion (CSII), 34.4/100-patient-years on basal-bolus injections (B-B) and 46.1/100-patient-years on NPH (NPH vs. CSII: p=.04). The incidence rate for seizure/coma was 4.5/100-patient-years on CSII, 11.1/100-patient-years on B-B, and 14.4/100-patient-years on NPH (NPH vs. CSII: p=.004). In the multivariate analysis, the rate of seizure/coma was significantly higher for those on NPH vs. CSII (rate ratio 2.9, p=.03).
Conclusions
Rates of severe hypoglycaemia in youth with type 1 diabetes remain high. CSII was associated with lower rates of all severe hypoglycaemia and seizure/coma in comparison to NPH.
doi:10.1111/j.1464-5491.2012.03646.x
PMCID: PMC3597100  PMID: 22417321
Hypoglycaemia; type 1 diabetes; paediatrics; insulin therapy
20.  Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in Type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications 
Aims
The Michigan Neuropathy Screening Instrument (MNSI) is used to assess distal symmetrical peripheral neuropathy in diabetes. It includes two separate assessments: a 15-item self-administered questionnaire and a lower extremity examination that includes inspection and assessment of vibratory sensation and ankle reflexes. The purpose of this study was to evaluate the performance of the MNSI in detecting distal symmetrical peripheral neuropathy in patients with Type 1 diabetes and to develop new scoring algorithms.
Methods
The MNSI was performed by trained personnel at each of the 28 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications clinical sites. Neurologic examinations and nerve conduction studies were performed during the same year. Confirmed clinical neuropathy was defined by symptoms and signs of distal symmetrical peripheral neuropathy based on the examination of a neurologist and abnormal nerve conduction findings in ≥ 2 anatomically distinct nerves among the sural, peroneal and median nerves.
Results
We studied 1184 subjects with Type 1 diabetes. Mean age was 47 years and duration of diabetes was 26 years. Thirty per cent of participants had confirmed clinical neuropathy, 18% had ≥ 4 and 5% had ≥ 7 abnormal responses on the MNSI questionnaire, and 33% had abnormal scores (≥ 2.5) on the MNSI examination. New scoring algorithms were developed and cut points defined to improve the performance of the MNSI questionnaire, examination and the combination of the two.
Conclusions
Altering the cut point to define an abnormal test from ≥ 7 abnormal to ≥ 4 abnormal items improves the performance of the MNSI questionnaire. The MNSI is a simple, non-invasive and valid measure of distal symmetrical peripheral neuropathy in Type 1 diabetes.
doi:10.1111/j.1464-5491.2012.03644.x
PMCID: PMC3641573  PMID: 22417277
measurement; peripheral neuropathy
21.  TRAIT ANXIETY AND GLUCOSE METABOLISM IN PEOPLE WITHOUT DIABETES: VULNERABILITIES AMONG BLACK WOMEN 
Diabetic Medicine  2012;29(6):803-806.
Aims
We examined whether the relationship between anxiety and indicators of glucose metabolism in people without diabetes varies by race and gender.
Methods
Participants were 914 adults (777 white, 137 black) without diabetes in the MIDUS II study. Glucose metabolism was characterized by fasting glucose, insulin, HOMA-IR, and HbA1c. Hierarchical linear regressions stratified by race and gender examined whether anxiety was associated with glucose metabolism.
Results
After adjustment for potential confounders, positive relationships between anxiety and fasting glucose (p=.04), insulin (p=.01), and HOMA-IR (p=.02) but not HbA1c, were observed in black women only.
Conclusions
Our findings extend prior evidence about the links between psychosocial vulnerabilities and impaired glucose metabolism in black women, by documenting significant associations between anxiety and clinical indicators of glycemic control among black women without diabetes. Thus, anxiety might constitute an intervention target in black women, a subgroup disproportionately affected by type 2 diabetes, its complications, and premature mortality.
doi:10.1111/j.1464-5491.2011.3534.x
PMCID: PMC3395206  PMID: 22587407
22.  Pioglitazone Initiation and Subsequent Hospitalisation for Congestive Heart Failure 
Aims
Thiazolidinediones (TZD) have been associated with an expansion in plasma volume and the development of peripheral oedema. A recent study reported an association between the use of TZDs and development of congestive heart failure (CHF). The objective of this study was to determine if short-term use of pioglitazone, a TZD, is associated with increased risk of CHF hospitalisation in a well-characterised, community-based cohort of type 2 diabetic patients without prevalent CHF.
Methods
A cohort study of all patients in the Kaiser Permanente Medical Care Program with type 2 diabetes (Kaiser Permanente Northern California Diabetes Registry) who initiated any diabetes pharmacotherapy (n=23,440) between October, 1999 and November, 2001. Only patients initiating single new therapies (“new users”) were included to reduce confounding and create mutually-exclusive exposure groups. We constructed Cox proportional hazards models (with sulfonylureas initiators specified as the reference group) to evaluate the impact of initiating new diabetes therapies on time to incident CHF hospitalisation, defined by primary hospital discharge diagnosis.
Results
Patients initiated pioglitazone (15.2%), sulfonylureas (25.3%), metformin (50.9%), and insulin (8.6%) alone or as additions to pre-existing or maintained therapies. Three hundred and twenty CHF hospitalisations were observed during the follow-up (10.2 months on average) after initiation. Relative to sulfonylurea initiators, there were no significant increases in the incidence of CHF hospitalisation among those initiating pioglitazone (hazard ratio (HR) = 1.28; 95% confidence interval (CI): 0.85 – 1.92) after adjusting for demographic, behavioural, and clinical factors. There was a significantly higher incidence among those initiating insulin (HR = 1.56; 95% CI: 1.00 – 2.45) and lower incidence among those initiating metformin, (HR = 0.70; 95% CI: 0.49 – 0.99).
Conclusions
This study of patients with type 2 diabetes failed to find evidence that short-term pioglitazone use was associated with an elevated risk of CHF hospitalisation relative to the standard, first line diabetes therapy.
doi:10.1111/j.1464-5491.2005.01704.x
PMCID: PMC3557913  PMID: 16026362
diabetes mellitus; congestive heart failure; thiazolidinediones; pioglitazone; hypoglycaemic agents; pharmacoepidemiology; new user design
23.  Is the Physical Functioning of Older Adults with Diabetes Associated with the Processes and Outcomes of Care? Evidence from Translating Research Into Action for Diabetes (TRIAD) 
Aims
To examine the relationship between physical function limitations and diabetes self-management, processes of care, and intermediate outcomes in adults ≥65 years of age with type 2 diabetes.
Methods
We studied 1,796 participants 65 years of age and older in managed care health plans enrolled in Translating Research into Action for Diabetes (TRIAD). Physical functioning was assessed at baseline with the Physical Component Summary of the Short Form-12 (SF-12) Health Survey. Diabetes self-management was assessed with follow-up surveys, and processes of care (eye exams, urine microalbumin testing, foot exams, etc.) and intermediate health outcomes (HbA1c, blood pressure, LDL-c) were assessed with medical chart reviews. Multivariate regression models were constructed to examine the associations between physical function limitations and outcomes.
Results
Frequency of eye exams (OR 0.69, 95% CI 0.49 - 0.99) was the only process of care that was worse for participants with physical function limitations (n=573) compared to those without limitations (n=618). Neither self-management nor intermediate outcomes differed by whether patients had or did not have physical function limitations.
Conclusion
Limitations in physical functioning as assessed by the SF-12 were not associated with substantial difference in diabetes care in adults ≥65 years of age enrolled in managed care health plans.
doi:10.1111/j.1464-5491.2012.03584.x
PMCID: PMC3557946  PMID: 22268866
physical function; quality of care; geriatrics
24.  Association between vitamin D and diabetic neuropathy in a nationally representative sample: results from 2001–2004 NHANES 
Aims
To evaluate the association between vitamin D insufficiency and peripheral neuropathy in a nationally representative sample of adults with diagnosed diabetes.
Methods
Vitamin D concentrations, medical examination variables and questionnaire results from the 2001–2004 National Health and Nutrition Examination Survey were analysed for adults ≥ 40 years old with diagnosed diabetes (unweighted n = 591, weighted n = 8.82 million). Neuropathy was defined as self report of peripheral neuropathy symptoms of painful sensation, tingling, numbness or loss of feeling in hands or feet. Additionally, Semmes–Weinstein monofilament test results were used as an indicator of neuropathy. Insufficient vitamin D was characterized as < 30 ng/ml.
Results
In the weighted population, 81% of adults with diabetes had vitamin D insufficiency. Vitamin D insufficiency was more common among Hispanics (92%) and non-Hispanic black people (98%) than among non-Hispanic white people (76%). Within the 3 months preceding the questionnaire, 50% reported experiencing pain or numbness (paresthesia) in their hands or feet; 37% reported pain or tingling in hands or feet; and 38% reported numbness or loss of feeling in hands or feet. Eight per cent had 4–6 insensate areas on their feet as determined by the Semmes– Weinstein monofilament test. Logistic regressions demonstrate vitamin D insufficiency is associated with the adjusted composite paresthesia measure (odds ratio 2.12; 95% CI 1.17–3.85) and the adjusted numbness measure (odds ratio 2.04; 95% CI 1.18–3.52).
Conclusions
Vitamin D insufficiency is associated with self-reported peripheral neuropathy symptoms even after adjusting for demographic factors, obesity, co-morbidities, use of medications for neuropathy and diabetes duration and control.
doi:10.1111/j.1464-5491.2011.03379.x
PMCID: PMC3461835  PMID: 21726279
diabetes mellitus; peripheral neuropathy; vitamin D
25.  Comparison of longitudinal point-of-care and high-performance liquid chromatography HbA1c measurements in a multi-centre trial 
Aims
Point-of-care HbA1c is routine in clinical practice. Comparison of point-of-care HbA1c against laboratory measurements across sites and over time is warranted.
Methods
One hundred and twenty-one young persons with Type 1 diabetes from four centres provided 450 paired samples collected over 10 months for point-of-care HbA1c and central laboratory-based high-performance liquid chromatography (HPLC) HbA1c determinations. Change in HbA1c over time was assessed by difference from initial to final HbA1c and by growth modelling with annualized slope calculation. Change in HbA1c was categorized as improved (decrease of ≥ 0.5% or negative slope), no change (± 0.4% of initial HbA1c or slope = 0) or worsened (increase of ≥ 0.5% or positive slope).
Results
The 450 paired samples (median of four pairs/patient) were highly correlated (r = 0.97, P < 0.0001), as were time-specific and site-specific pairs (r = 0.94 to 0.98, P < 0.0001). Initial-to-final point-of-care HbA1c and HPLC HbA1c changes were 0.3 ± 1.1% (range −2.7 to 4.1) and 0.4 ± 1.2% (–3.9 to 4.5), respectively, with 21% of patients (n = 26) discordant for change categories. ΔHbA1c by point-of-care HbA1c vs. HPLC HbA1c differed across the HbA1c range and by ≥ 0.5% absolute difference in ΔHbA1c in 14 (54%) of the 26 patients discordant for HbA1c change categories. Mean annual HbA1c slope was 0.4 ± 1.5% (−5.4 to 4.8) for point-of-care HbA1c and 0.4 ± 1.6% (−6.9 to 5.2) for HPLC HbA1c, with 18% (n = 22 pairs) discordant for change categories.
Conclusions
Assessment of absolute HbA1c change may not be different for point-of-care HbA1c compared with HPLC HbA1c; however, misclassification of patients by discrete cut-off values may occur with point-of-care HbA1c compared with HPLC HbA1c determinations.
doi:10.1111/j.1464-5491.2011.03404.x
PMCID: PMC3220776  PMID: 21824185
children; HbA1c; point-of-care; Type 1 diabetes

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