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1.  ‘COUGH-TRIGGERED’ TUBERCULOSIS SCREENING AMONG ADULTS WITH DIABETES IN TANZANIA 
Aims
Diabetes increases the risk of tuberculosis and the prevalence of diabetes is rising in tuberculosis-endemic regions such as sub-Saharan Africa. Resource-appropriate strategies for tuberculosis case finding among African adults with diabetes are needed. The aims of this study were to determine prevalence of tuberculosis and evaluate one screening strategy among adult Tanzanians with diabetes.
Methods
In this prospective cohort study, we evaluated a “cough-triggered” strategy for tuberculosis case finding among adults with diabetes at our zonal hospital in Tanzania. All adults with diabetes and cough underwent further tuberculosis symptom assessment and those with productive cough had sputum collected for microscopy and M. tuberculosis culture.
Results
Between September 2011 and March 2012, 700 adults with diabetes attended our hospital. A total of 693 were enrolled, 121/693 (17.5%) had cough and 32/693 (4.6%) had at least 2 of the classic symptoms of tuberculosis. Of note, 87/121 (71.9%) of patients with cough could not produce sputum spontaneously. Nine patients were diagnosed with tuberculosis for a prevalence of 1299/100,000 (1.3%), 7-fold greater than the national average.
Conclusions
Tuberculosis is common among Tanzanian adults with diabetes but tuberculosis case finding is challenging due to the high prevalence of non-productive cough. This low-cost, ‘cough-triggered’ tuberculosis case-finding strategy may serve as a reasonable first step for improving tuberculosis screening among adults with diabetes in sub-Saharan Africa.
doi:10.1111/dme.12348
PMCID: PMC4049009  PMID: 24152037
2.  Association between duration and quality of sleep and the risk of pre-diabetes: evidence from NHANES 
Aims
To examine the association between duration and quality of sleep and the prevalence of undiagnosed and clinically identified diabetes mellitus and pre-diabetes in a nationally representative sample.
Methods
Cross-sectional study of 2285 participants ≥ 30 years old and without diagnosed sleep disorders from the National Health and Nutrition Examination Survey (2005–2008). The primary exposures were sleep duration and quality. Sleep quality was assessed by questionnaire using trouble initiating sleep, trouble maintaining sleep, and waking up too early. The primary outcomes were clinically identified and undiagnosed pre-diabetes and diabetes as defined by the American Diabetes Association using fasting plasma glucose (5.6–6.9 mmol/l = pre-diabetes; ≥ 7.0 mmol/l = diabetes). Multivariate logistic regression was used to test the association between sleep quality, sleep duration and glycaemic status.
Results
After adjustment for socio-demographic characteristics and health behaviors, sleeping ≤ 5 h/night was associated with clinically identified pre-diabetes (odds ratio 2.06, 95% CI 1.00–4.22 vs. 7 h). Both trouble maintaining sleep ≥ 5 times/month (odds ratio 3.50, 95% CI 1.30–9.45) and waking up too early ≥ 5 times/month (odds ratio 2.69, 95% CI 1.21–5.98) were also significantly associated with increased risk of clinically identified pre-diabetes. Trouble initiating sleep and sleeping ≥ 9 h/night were not found to be associated with having diabetes.
Conclusions
Only clinically identified pre-diabetes was associated with trouble maintaining sleep, waking up too early, and short sleep. No other relations were found to be significant. Findings suggest that poor sleep quality and short sleep duration were more strongly associated with clinically identified pre-diabetes than long sleep duration.
doi:10.1111/dme.12165
PMCID: PMC3660430  PMID: 23425048
3.  Assessment of insulin action on carbohydrate metabolism: physiological and non-physiological methods 
Carbohydrate metabolism in humans is regulated by insulin secretion from pancreatic β-cells and glucose disposal by insulin-sensitive tissues. Insulin facilitates glucose utilization in peripheral tissues and suppresses hepatic glucose production. Any defects in insulin action predispose an individual to glucose intolerance and Type 2 diabetes mellitus. Early detection of defects in insulin action could provide opportunities to prevent or delay progression of the disease state. There are different approaches to assess insulin action. Initial methods, such as peripheral insulin concentration and simple indices, have several limitations. Subsequently, researchers developed methodologies using intravenous glucose infusion to determine glucose fluxes. However, these methodologies are limited by being non-physiological. Newer, innovative techniques that have been developed are more sophisticated and physiological. By modelling glucose kinetics using isotope dilution techniques, several robust parameters can be obtained that are physiologically relevant and sound. This brief review summarizes most of the non-physiological and physiological methodologies used to measure the variables of insulin action.
doi:10.1111/dme.12189
PMCID: PMC3662485  PMID: 23683103
4.  Affective symptoms and change in diabetes self-efficacy and glycaemic control 
Aims
To examine the role of baseline depression, anxiety and stress symptoms on post-intervention diabetes self-efficacy and glycaemic control (HbA1c).
Methods
The current study analysed data from patients (n = 85) with treated but uncontrolled Type 2 diabetes who participated in a comparative effectiveness study of two diabetes self-management interventions. Hierarchical linear regression was used to examine the relationships between baseline affective symptoms and post-intervention diabetes self-efficacy and the moderating effects of baseline affective symptoms on the relationship between changes in diabetes self-efficacy and post-intervention HbA1c.
Results
Baseline depression was inversely associated with post-intervention diabetes self-efficacy (P = 0.0001) after adjusting for baseline characteristics including diabetes self-efficacy. In contrast, normal–mild levels of stress were associated with higher post-intervention diabetes self-efficacy (P = 0.04). Anxiety and stress symptoms significantly and independently moderated the relationship between changes in diabetes self-efficacy and post-intervention HbA1c (P = 0.02 and P = 0.03, respectively). Further evaluation of these interactions demonstrated that changes in diabetes self-efficacy were associated with lower post-intervention HbA1c, but only among those with higher baseline affective symptoms.
Conclusions
We found a moderating effect across affective symptoms on the relationship between diabetes self-efficacy changes and post-intervention HbA1c in the context of a self-management intervention. Results suggest that patients with poorly controlled diabetes who have higher levels of depression, anxiety and stress symptoms may derive greater benefits from self-management interventions known to improve diabetes self-efficacy.
doi:10.1111/dme.12146
PMCID: PMC3628998  PMID: 23350920
5.  Characterizing the transition from paediatric to adult care among emerging adults with Type 1 diabetes 
Aims
The goals of the study were to describe the transition of youth with Type 1 diabetes from paediatric to adult healthcare services, examine the link of this transition with self care and glycaemic control, and distinguish youth who received medical treatment from different physicians in terms of demographic and parent relationship variables.
Methods
Youth with Type 1 diabetes (n = 118) were enrolled in a prospective study that examined the transition from the paediatric to adult healthcare systems and were evaluated during their senior year of high school (time 1) and 1 year later (time 2). Data on self care, glycaemic control and parent relationship were collected.
Results
The majority of youth saw a paediatric endocrinologist at both assessments (n = 64); others saw an adult care physician at both assessments (n = 26) or transitioned from a paediatric endocrinologist to an adult care physician (n = 19). Nine youth saw no physician between time 1 and time 2. There were group differences in demographic and parent relationship variables and self-care behaviour and glycaemic control related to the transition of care. Youth who remained in the paediatric healthcare system had the best self care and did not experience declines in glycaemic control over time.
Conclusions
Early transition from the paediatric healthcare system to the adult healthcare system is associated with psychosocial variables and worse glycaemic control. Future research should identify factors that determine optimal timing and strategies to avoid deterioration of care and control during this transition.
doi:10.1111/dme.12067
PMCID: PMC3628931  PMID: 23157171
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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