Diagnostic pitfalls in a young adult with new diabetes.

Summary: A 20-year-old South Asian male presented with polyuria, polydipsia, HbA1c 81 mmol/mol, BMI 28.8 and family history of both type 1 and type 2 diabetes mellitus. As autoantibody testing was negative and c-peptide level demonstrated significant endogenous insulin secretion, type 1 diabetes was excluded. Given his age and family history, the differential diagnosis included maturity-onset diabetes of the young (MODY), a rare form of diabetes caused by a single-gene variant. A high probability of MODY was calculated and he was subsequently referred for genetic testing. Although a useful tool, the pre-test probability calculator for MODY is only validated in White Europeans. A heterogenous variant of unknown clinical significance of the NEUROD1 gene was detected, leading to gliclazide use with poor response. The patient responded well to metformin. Type 2 diabetes was considered the most likely diagnosis. This case highlights the diagnostic challenges in young patients of Asian ethnicity and the importance of interpreting genetic results of unknown significance within the clinical context. Ethnicity-specific BMI thresholds should be used when classifying patients as overweight or obese. Learning points: Variants of unknown significance detected by genetic sequencing should be interpreted within the context of the patient's other clinical parameters. It is important to use ethnicity-specific BMI thresholds for obesity. Diagnosis of type 2 diabetes mellitus at younger ages is becoming increasingly common. The pre-test probability calculator for MODY is only validated in White Europeans; although a useful guide, results should be interpreted with caution in patients of other ethnicities.

Practical Guide to Glucocorticoid Induced Hyperglycaemia and Diabetes.

Glucocorticoids, also known as steroids, are a class of anti-inflammatory drugs utilised widely in clinical practice for a variety of conditions. They are associated with a range of side effects including abnormalities of glucose metabolism. Multiple guidelines have been published to illustrate best management of glucocorticoid-induced hyperglycaemia and diabetes in a variety of settings. This article discusses current best clinical practice including diagnosis, investigations and ongoing management of glucocorticoid-induced dysglycaemia in both in- and outpatient settings.

Admission Glucose Number (AGN): A Point of Admission Score Associated With Inpatient Glucose Variability, Hypoglycemia, and Mortality.

AIMS: We investigated a point of admission metric of glycemia, the Admission Glucose Number (AGN), and its relationship with both high risk inpatient glucose patterns and mortality in hospital inpatients with type 2 diabetes (T2DM). METHODS: Inpatient capillary blood glucose (CBG) data for patients with T2DM in our health board were identified for a 5-year period and associated with most recent preadmission HbA1c. AGN was calculated as first CBG measured during admission (mmol/L), subtracted from most recent preadmission HbA1c (converted to estimated median glucose mmol/l) within 15 months preadmission. The association between AGN and CBG variability (interquartile range), hypoglycemia free survival (HR) and both inpatient and 100-day mortality (HR) were investigated. RESULTS: A total of 21 045 first admissions with available HbA1c data were identified. A positive correlation between AGN and glycemic variability was described (partial correlation coefficient 0.25, P < .001), which was stronger than the correlation of either of AGNs' individual components: adjusted CBG1 = 0.07 ( P < .001), eAG = 0.08 ( P < .001). The hazard ratio for time to first recorded CBG < 3 mmol/L for high AGN versus low AGN was 1.74 (95% CI 1.55-1.96), P < .001. A high AGN was associated with increased 100-day mortality (HR 1.26, P = .005), however not with in-hospital mortality (HR = 1.31, P = .08). CONCLUSION: AGN is a simple metric that combines 2 readily available measures associated with adverse outcome in T2DM. AGN may be a useful tool to stratify patients for risk of hypoglycemia and postdischarge death.

Visit-to-visit HbA1c variability and systolic blood pressure (SBP) variability are significantly and additively associated with mortality in individuals with type 1 diabetes: An observational study.

AIM: To investigate the relationship between variability in both visit-to-visit HbA1c and SBP and mortality in individuals with type 1 diabetes. METHODS: The Scottish Care Information (SCI) Diabetes dataset was used to identify 5952 individuals with type 1 diabetes for inclusion in this observational study. The SCI-Diabetes dataset allowed access to blood pressure values, HbA1c readings, demographic information and mortality rates for all study participants. Participants were dichotomized to above and below median values for both HbA1c coefficient of variation (CV) and SBP CV, thus dividing participants into 4 cohorts for survival analysis. Survival analysis was carried out over 1430 days. A Cox proportional hazard model was used to allow comparison of mortality between the 4 cohorts. RESULTS: Of the 5952 patients, death occurred in 416. CV for both HbA1c and SBP were significantly associated with mortality. The median values for HbA1c CV and SBP CV were 8.0 and 8.1, respectively. The hazard ratio for high HbA1c CV only (P = .0015) was 1.78 ± 0.36. The hazard ratio for high SBP CV only (P = .0018) was 1.69 ± 0.33. The hazard ratio for both high HbA1c CV and high SBP CV (P < .00001) was 2.37 ± 0.32. CONCLUSIONS: Our findings demonstrate that variability of both HbA1c and SBP is significantly and additively associated with mortality in individuals with type 1 diabetes. The variability of these parameters might be useful for risk stratification and is a potential target for future interventional studies.

Hypoglycemia and Clinical Outcomes in Hospitalized Patients With Diabetes: Does Association With Adverse Outcomes Remain When Number of Glucose Tests Performed Is Accounted For?

BACKGROUND: Hypoglycemia is associated with increased length of stay in hospital patients, but previous studies have not considered the confounding effect of increased hypoglycemia detection associated with increased capillary blood glucose (CBG) measurement in prolonged admissions. We aimed to determine the effect of recorded hypoglycemia on length of stay of hospital inpatients (LOS) when this mathematical association is subtracted. METHODS: CBG data were analyzed for inpatients within our health board area (01/2009-01/2015). A simulated CBG data set was generated for each patient with an identical sampling frequency to the measured CBG data set. The mathematical component of increased LOS was determined using the simulated data set. Subtraction of this confounding mathematical association was used to provide measurement of the true clinical association between recorded hypoglycemia (CBG < 4 mmol [< 72mg/dl]) and LOS. RESULTS: A total of 196 962 admissions of 52 475 individuals with known diabetes were analyzed. 68 809 admissions of 29 551 individuals had >4 CBG measurements made and were included in analysis. After subtraction of the mathematical association of increased sample number, the clinical effect of recorded hypoglycemia is reduced-but persists-compared to previous studies. 1-2 days with recorded hypoglycemia has a relatively minor effect on LOS. LOS increases rapidly if there are ≥3 days with recorded hypoglycemia, with an increase of 0.75 days LOS per additional day with hypoglycemia. CONCLUSIONS: This technique increases accuracy of economic modeling of the impact of hypoglycemia on health care systems. This could assist study of the impact of hypoglycemia on other outcomes by factoring for bias of increased sample numbers.

A Practical Review of C-Peptide Testing in Diabetes.

C-peptide is a widely used measure of pancreatic beta cell function. It is produced in equimolar amounts to endogenous insulin but is excreted at a more constant rate over a longer time. Methods of estimation include urinary and unstimulated and stimulated serum sampling. Modern assays detect levels of c-peptide which can be used to guide diabetes diagnosis and management. We explore the evidence behind the various tests available. We recommend the glucagon stimulation c-peptide testing owing to its balance of sensitivity and practicality. C-peptide levels are associated with diabetes type and duration of disease. Specifically a c-peptide level of less than 0.2 nmol/l is associated with a diagnosis of type 1 diabetes mellitus (T1DM). C-peptide level may correlate with microvascular and macrovascular complications and future use of insulin therapy, as well as likely response to other individual therapies. We explore the potential uses of c-peptide measurement in clinical practice.

Inpatient Glycemic Variability and Long-Term Mortality in Hospitalized Patients with Type 2 Diabetes.

AIMS/HYPOTHESIS: To determine the association between inpatient glycemic variability and long-term mortality in patients with type 2 diabetes mellitus. METHODS: Capillary blood glucose (CBG) of inpatients from 8 hospitals was analysed. 28,353 admissions identified were matched for age, duration of diabetes and admission and median and interquartile range of CBG. 6year mortality was investigated for (i) those with CBG IQR in the top half of all IQR measurements (matched for all except IQR), vs those in the lower half and (ii) those with the lowest quartile median glucose (matched for all except median). RESULTS: CONCLUSION: Higher inpatient glycemic variability is associated with increased mortality on long-term follow up. When matched by IQR, we have demonstrated higher median CBG is associated with lower long-term mortality. CBG variability may increase cardiovascular morbidity by increasing exposure to hypoglycaemia or to variability per se. In hospitalized patients with diabetes, glycemic variability should be minimised and when greater CBG variability is unavoidable, a less stringent CBG target considered.

How valid are wearable physical activity trackers for measuring steps?

Wearable activity trackers have become popular for tracking individual's daily physical activity, but little information is available to substantiate the validity of these devices in step counts. Thirty-five healthy individuals completed three conditions of activity tracker measurement: walking/jogging on a treadmill, walking over-ground on an indoor track, and a 24-hour free-living condition. Participants wore 10 activity trackers at the same time for both treadmill and over-ground protocol. Of these 10 activity trackers three were randomly given for 24-hour free-living condition. Correlations of steps measured to steps observed were r = 0.84 and r = 0.67 on a treadmill and over-ground protocol, respectively. The mean MAPE (mean absolute percentage error) score for all devices and speeds on a treadmill was 8.2% against manually counted steps. The MAPE value was higher for over-ground walking (9.9%) and even higher for the 24-hour free-living period (18.48%) on step counts. Equivalence testing for step count measurement resulted in a significant level within ±5% for the Fitbit Zip, Withings Pulse, and Jawbone UP24 and within ±10% for the Basis B1 band, Garmin VivoFit, and SenseWear Armband Mini. The results show that the Fitbit Zip and Withings Pulse provided the most accurate measures of step count under all three different conditions (i.e. treadmill, over-ground, and 24-hour condition), and considerable variability in accuracy across monitors and also by speeds and conditions.

Is all hypoglycaemia treated as equal? An observational study of how the type of diabetes and treatment prescribed prior to admission influences quality of treatment of inpatient hypoglycaemia.

AIMS: Inpatient hypoglycaemia is common and associated with adverse outcomes. There is often increased vigilance of hypoglycaemia in inpatients with type 1 diabetes (T1DM) compared to type 2 diabetes (T2DM). We aimed to investigate this apparent discrepancy, utilising the time to repeat (TTR) capillary blood glucose (CBG) measurement as a surrogate for engagement with guidelines stating that CBG should be rechecked following intervention within 15 min of an initial CBG of <4 mmol/L. METHODS: This is an observational study of inpatient CBG data from 8 hospitals over a 7-year period. A national diabetes registry allowed identification of individual's diagnosis and diabetes therapy. For each initial (index) CBG, the TTR for individuals with T2DM-on insulin or sulphonylurea-was compared with the TTR for individuals with T1DM, using a t test for significance performed on log(TTR). The median TTR was plotted for each group per index CBG. RESULTS: In total, 1480,335 CBG measurements were obtained. A total of 26,664 were <4 mmol/L. The TTR in T2DM individuals on sulphonylurea was significantly greater than in T1DM individuals where index CBG was ≥2.3 mmol/L (except index CBG 2.6 mmol/L). For T2DM patients receiving insulin significance exists for index CBGs of ≥3.2 mmol/L. CONCLUSIONS: This analysis suggests that quality of care of hypoglycaemia varies according to diagnosis and medication. The group with the highest TTR (T2DM sulphonylurea treated) are possibly the clinical group in whom hypoglycaemia is most concerning. These data therefore suggest a need for education and raising awareness within the inpatient nursing staff.

A Practical Approach to Glucose Abnormalities in Cystic Fibrosis.

Cystic fibrosis is a common genetic condition and abnormal glucose handling leading to cystic fibrosis-related diabetes (CFRD) is a frequent comorbidity. CFRD is mainly thought to be the result of progressive pancreatic damage resulting in beta cell dysfunction and loss of insulin secretion. Whilst Oral Glucose Tolerance Testing is still recommended for diagnosing CFRD, the relationship between glucose abnormalities and adverse outcomes in CF is complex and occurs at stages of dysglycaemia occurring prior to diagnosis of diabetes by World Health Organisation criteria. Insulin remains the mainstay of treatment of CF-related glucose abnormalities but the timing of insulin commencement, optimum insulin regime and targets of glycaemic control are not clear. These complexities are compounded by common issues with nutritional status, need for enteral feeding, steroid use and high disease burden on CF patients.

Patterns and Impact of Hypoglycemia, Hyperglycemia, and Glucose Variability on Inpatients with Insulin-Treated Cystic Fibrosis-Related Diabetes.

INTRODUCTION: Mortality in patients with cystic fibrosis-related diabetes (CFRD) is higher than that in patients with cystic fibrosis without diabetes. Hypoglycemia, hyperglycemia, and glucose variability confer excess mortality and morbidity in the general inpatient population with diabetes. METHODS: We investigated patterns of hypoglycemia and the association of hypoglycemia, hyperglycemia, and glucose variability with mortality and readmission rate in inpatients with CFRD. All capillary blood glucose (CBG) readings (measured using the Abbott Precision web system) of patients with insulin-treated CFRD measured within our health board between January 2009 and January 2015 were. Frequency and timing of hypoglycemia (<4 mmol/L) and was recorded. The effect of dysglycemia on readmission and mortality was investigated with survival analysis. RESULTS: Sixty-six patients were included. A total of 22,711 CBG results were included in the initial analysis. Hypoglycemia was common with 1433 episodes (6.3%). Hypoglycemia ascertainment was highest between 2400 and 0600 h. Hypoglycemia was associated with a significantly higher rate of readmission or death over the 3.5-year follow-up period (P = 0.03). There was no significant association between hyperglycemia or glucose variability and the rate of readmission and mortality. CONCLUSION: Among inpatients with CFRD hypoglycemia is common and is associated with an increased composite endpoint of readmission and death. As with previously reported trends in general inpatient population this group shows a peak incidence of hypoglycemic during the night.

Metformin Increases Cortisol Regeneration by 11ßHSD1 in Obese Men With and Without Type 2 Diabetes Mellitus.

CONTEXT: The mechanism of action of metformin remains unclear. Given the regulation of the cortisol-regenerating enzyme 11ßhydroxysteroid dehydrogenase 1 (11ßHSD1) by insulin and the limited efficacy of selective 11ßHSD1 inhibitors to lower blood glucose when co-prescribed with metformin, we hypothesized that metformin reduces 11ßHSD1 activity. OBJECTIVE: To determine whether metformin regulates 11ßHSD1 activity in vivo in obese men with and without type 2 diabetes mellitus. DESIGN: Double-blind, randomized, placebo-controlled, crossover study. SETTING: A hospital clinical research facility. PARTICIPANTS: Eight obese nondiabetic (OND) men and eight obese men with type 2 diabetes (ODM). INTERVENTION: Participants received 28 days of metformin (1 g twice daily), placebo, or (in the ODM group) gliclazide (80 mg twice daily) in random order. A deuterated cortisol infusion at the end of each phase measured cortisol regeneration by 11ßHSD1. Oral cortisone was given to measure hepatic 11ßHSD1 activity in the ODM group. The effect of metformin on 11ßHSD1 was also assessed in human hepatocytes and Simpson-Golabi-Behmel syndrome adipocytes. MAIN OUTCOME MEASURES: The effect of metformin on whole-body and hepatic 11ßHSD1 activity. RESULTS: Whole-body 11ßHSD1 activity was approximately 25% higher in the ODM group than the OND group. Metformin increased whole-body cortisol regeneration by 11ßHSD1 in both groups compared with placebo and gliclazide and tended to increase hepatic 11ßHSD1 activity. In vitro, metformin did not increase 11ßHSD1 activity in hepatocytes or adipocytes. CONCLUSIONS: Metformin increases whole-body cortisol generation by 11ßHSD1 probably through an indirect mechanism, potentially offsetting other metabolic benefits of metformin. Co-prescription with metformin should provide a greater target for selective 11ßHSD1 inhibitors.

Longitudinal Blood Pressure Control, Long-Term Mortality, and Predictive Utility of Serum Liver Enzymes and Bilirubin in Hypertensive Patients.

There is accruing evidence from general population studies that serum bilirubin and liver enzymes affect blood pressure (BP) and cardiovascular risk, but it is unclear whether these have an impact on hypertensive patients in terms of long-term survival or BP control. We analyzed 12 000 treated hypertensive individuals attending a tertiary care clinic followed up for 35 years for association between baseline liver function tests and cause-specific mortality after adjustment for conventional cardiovascular covariates. Generalized estimating equations were used to study the association of liver tests and follow-up BP. The total time at risk was 173 806 person years with median survival 32.3 years. Follow-up systolic BP over 5 years changed by -0.4 (alanine transaminase and bilirubin), +2.1(alkaline phosphatase), +0.9(γ-glutamyl transpeptidase) mm Hg for each standard deviation increase. Serum total bilirubin and alanine transaminase showed a significant negative association with all-cause and cardiovascular mortality, whereas alkaline phosphatase and γ-glutamyl transpeptidase showed a positive association and aspartate transaminase showed a U-shapedassociation. Serum bilirubin showed an incremental improvement of continuous net reclassification improvement by 8% to 26% for 25 year and 35 year cardiovascular mortality, whereas all liver markers together improved continuous net reclassification improvement by 19% to 47% compared with reference model. In hypertensive patients, serum liver enzymes and bilirubin within 4 standard deviations of the mean show independent effects on mortality and BP control. Our findings would support further studies to elucidate the mechanisms by which liver enzymes and bilirubin may exert an effect on BP and cardiovascular risk, but there is little support for using them in risk stratification.

Long-term and ultra long-term blood pressure variability during follow-up and mortality in 14,522 patients with hypertension.

Recent evidence indicates that long-term visit-to-visit blood pressure variability (BPV) may be an independent cardiovascular risk predictor. The implication of this variability in hypertension clinical practice is unclear. BPV as average real variability (ARV) was calculated in 14,522 treated patients with hypertension in 4 time frames: year 1 (Y1), years 2 to 5 (Y2-5), years 5 to 10 (Y5-10), and years >10 (Y10+) from first clinic visit. Cox proportional hazards models for cause-specific mortality were used in each time frame separately for long-term BPV, across time frames based on ultra long-term BPV, and within each time frame stratified by mean BP. ARV in systolic blood pressure (SBP), termed ARV(SBP), was higher in Y1 (21.3±11.9 mm Hg) in contrast to Y2-5 (17.7±9.9 mm Hg), Y5-10 (17.4±9.6 mm Hg), and Y10+ (16.8±8.5 mm Hg). In all time frames, ARV(SBP) was higher in women (P<0.01) and in older age (P<0.001), chronic kidney disease (P<0.01), and prevalent cardiovascular disease (P<0.01). Higher long-term and ultra long-term BPV values were associated with increased mortality (all-cause, cardiovascular, and noncardiovascular mortality; P for trend, <0.001). This relationship was also evident in subgroups with mean SBP<140 mm Hg in all time frames. Monitoring BPV in clinical practice may facilitate risk reduction strategies by identifying treated hypertensive individuals at high risk, especially those with BP within the normal range.

Hematocrit predicts long-term mortality in a nonlinear and sex-specific manner in hypertensive adults.

Hematocrit has been inconsistently reported to be a risk marker of cardiovascular morbidity and mortality. The Glasgow Blood Pressure Clinic Study cohort included 10951 hypertensive patients, who had hematocrit measured at their initial clinic visit and followed for ≤35 years. Cox proportional hazards models were used to estimate hazard ratios for all-cause, cardiovascular, ischemic heart disease, stroke, and noncardiovascular mortality. There were 3484 deaths over a follow-up period of 173245 person-years. Hematocrit was higher in men (median, 0.44; interquartile range, 0.42-0.47) than in women (median, 0.41; interquartile range, 0.38-0.43). The lowest risk for all-cause mortality was seen in quartile 2 for men (range, 0.421-0.440) and women (range, 0.381-0.400). Compared with quartile 2, the adjusted hazard ratios for quartiles 1, 3, and 4 were, respectively, 1.11 (range, 0.97-1.28), 1.19 (range, 1.04-1.37), and 1.22 (range, 1.06-1.39) in men and 1.17 (range, 1.01-1.36), 0.97 (range, 0.83-1.13), and 1.19 (range, 1.04-1.37) in women. Men showed a J-shaped pattern for cardiovascular mortality and a linear pattern for noncardiovascular mortality in cause-specific analysis, whereas in women a U-shaped pattern was observed for noncardiovascular mortality only. Higher baseline hematocrit was associated with higher on-treatment blood pressure during follow-up. Baseline hematocrit did not affect the time to reach target blood pressure. The increased risk of death attributed to higher hematocrit was seen in men and women irrespective of their achievement of target blood pressure, indicating that the risk is independent of the effect of hematocrit on blood pressure. Hypertensive patients with hematocrit levels outside of the sex-specific reference ranges identified in this study should be targeted for more aggressive blood pressure and cardiovascular risk reduction treatment.

Distinguishing the activities of 11beta-hydroxysteroid dehydrogenases in vivo using isotopically labeled cortisol.

The isozymes of 11beta-hydroxysteroid dehydrogenase (11betaHSDs) catalyze the interconversion of cortisol and cortisone. The type 2 dehydrogenase inactivates cortisol to cortisone, whereas the type 1 catalyzes predominantly the reverse reductive reaction. These reactions take place in different tissues, where they are subject to distinct regulation, and may be important in common pathologies. Current methods to determine the activities of these enzymes in vivo rely only on the balance between cortisol and cortisone, do not measure turnover, and cannot distinguish between the two reactions. We have investigated the use of [9,11,12,12-2H4]cortisol (d4F) to distinguish the dehydrogenase and reductase activities. On metabolism by dehydrogenation, d4F loses 11alpha- deuterium, forming trideuterated cortisone (d3E) and is regenerated by reduction to trideuterated cortisol (d3F). Healthy men (n = 6) participated in a randomized, double blind, cross-over study comparing oral placebo and the 11betaHSD inhibitor, carbenoxolone (100 mg every 8 h for 7 d). d4F and its metabolites were measured in plasma and urine during a steady state infusion. Inhibition of 11betaHSDs by carbenoxolone was measured by increased steady state concentrations of d4F (41 +/- 5.1 vs. 48 +/- 7.7 nM; P < 0.05) and a fall in the rate of appearance of d3F (P < 0.05). 11betaHSD1 reductase activity could be measured specifically as conversion of d3E to d3F (28 +/- 4.2 vs. 17 +/- 3.1 nM; P < 0.05), whereas 11betaHSD2 could be measured by initial rates of appearance of d3E or from urinary ratios of d4F/(d3E + d3F) (0.73 +/- 0.06 vs. 1.02 +/- 0.03; P < 0.05). This technique offers a significant advance in the methods available to measure turnover in 11betaHSDs and isozymes of 11betaHSDs in vivo in human studies, and this study confirms that carbenoxolone inhibits both isozymes of 11betaHSD.