Stephen L. Atkin

A1C Variability and the Risk of Microvascular Complications in Type 1 Diabetes: Data from the Diabetes Control and Complications Trial

OBJECTIVE—Debate remains as to whether short- or long-term glycemic instability confers a risk of microvascular complications in addition to that predicted by mean glycemia alone. In this study, we analyzed data from the Diabetes Control and Complications Trial (DCCT) to assess the effect of A1C variability on the risk of retinopathy and nephropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS—A1C was collected quarterly during the DCCT in 1,441 individuals. The mean A1C and the SD of A1C variability after stabilization of glycemia (from 6 months onwards) were compared with the risk of retinopathy and nephropathy with adjustments for age, sex, disease duration, treatment group, and baseline A1C. RESULTS—Multivariate Cox regression showed that the variability in A1C added to mean A1C in predicting the risk of development or progression of both retinopathy (hazard ratio 2.26 for every 1% increase in A1C SD [95% CI 1.63–3.14], P < 0.0001) and nephropathy (1.80 [1.37–2.42], P < 0.0001), with the relationship a feature in conventionally treated patients in particular. CONCLUSIONS—This study has shown that variability in A1C adds to the mean value in predicting microvascular complications in type 1 diabetes. Thus, in contrast to analyses of DCCT data investigating the effect of short-term glucose instability on complication risk, longer-term fluctuations in glycemia seem to contribute to the development of retinopathy and nephropathy in type 1 diabetes.

Insulin Resistance, the Metabolic Syndrome, and Complication Risk in Type 1 Diabetes: “Double diabetes” in the Diabetes Control and Complications Trial

OBJECTIVE—The presence of insulin resistance and the metabolic syndrome are known risk markers for macrovascular disease in patients with and without type 2 diabetes. This study has examined whether these also were predictors of micro- and macrovascular complications in type 1 diabetic patients participating in the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS—International Diabetes Federation (IDF) criteria were used to identify the metabolic syndrome in 1,337 Caucasian DCCT patients at baseline. Insulin resistance was calculated using their estimated glucose disposal rate (eGDR). Insulin dose (units/kg) was also used as a separate marker of insulin resistance. RESULTS—The eGDR (but not insulin dose or metabolic syndrome) at baseline strongly predicted the development of retinopathy, nephropathy, and cardiovascular disease (hazard ratios 0.75, 0.88, and 0.70, respectively, per mg · kg−1 · min−1 change; P < 0.001, P = 0.005, and P = 0.002, respectively). Through mainly weight gain, the prevalence of the metabolic syndrome increased steadily from baseline to year 9 in conventionally treated (from 15.5 to 27.2%) and especially in the intensively treated (from 13.7 to 45.4%) patients. CONCLUSIONS—Higher insulin resistance at baseline in the DCCT (as estimated by eGDR) was associated with increased subsequent risk of both micro- and macrovascular complications. Insulin dose and the presence of IDF-defined metabolic syndrome were poor predictors by comparison. Although intensive treatment was associated with a higher subsequent prevalence of metabolic syndrome, the benefits of improved glycemia appear to outweigh the risks related to development of the metabolic syndrome.

HbA1c variability and the risk of microvascular complications in type 1 diabetes: data from the DCCT

OBJECTIVE—Debate remains as to whether short- or long-term glycemic instability confers a risk of microvascular complications in addition to that predicted by mean glycemia alone. In this study, we analyzed data from the Diabetes Control and Complications Trial (DCCT) to assess the effect of A1C variability on the risk of retinopathy and nephropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS—A1C was collected quarterly during the DCCT in 1,441 individuals. The mean A1C and the SD of A1C variability after stabilization of glycemia (from 6 months onwards) were compared with the risk of retinopathy and nephropathy with adjustments for age, sex, disease duration, treatment group, and baseline A1C. RESULTS—Multivariate Cox regression showed that the variability in A1C added to mean A1C in predicting the risk of development or progression of both retinopathy (hazard ratio 2.26 for every 1% increase in A1C SD [95% CI 1.63–3.14], P < 0.0001) and nephropathy (1.80 [1.37–2.42], P < 0.0001), with the relationship a feature in conventionally treated patients in particular. CONCLUSIONS—This study has shown that variability in A1C adds to the mean value in predicting microvascular complications in type 1 diabetes. Thus, in contrast to analyses of DCCT data investigating the effect of short-term glucose instability on complication risk, longer-term fluctuations in glycemia seem to contribute to the development of retinopathy and nephropathy in type 1 diabetes.

The Efficacy and Safety of Insulin Degludec Given in Variable Once-Daily Dosing Intervals Compared With Insulin Glargine and Insulin Degludec Dosed at the Same Time Daily: A 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes

OBJECTIVE The requirement to inject current basal insulin analogs at a fixed time each day may complicate adherence and compromise glycemic control. This trial evaluated the efficacy and safety of varying the daily injection time of insulin degludec (IDeg), an ultra-long-acting basal insulin. RESEARCH DESIGN AND METHODS This 26-week, open-label, treat-to-target trial enrolled adults (≥18 years) with type 2 diabetes who were either insulin naïve and receiving oral antidiabetic drugs (OADs) (HbA1c = 7–11%) or previously on basal insulin ± OAD(s) (HbA1c = 7–10%). Participants were randomized to 1) once-daily (OD) IDeg in a prespecified dosing schedule, creating 8–40-h intervals between injections (IDeg OD Flex; n = 229); 2) once-daily IDeg at the main evening meal (IDeg OD; n = 228); or 3) once-daily insulin glargine at the same time each day (IGlar OD; n = 230). The primary outcome was noninferiority of IDeg OD Flex to IGlar OD in HbA1c reduction after 26 weeks. RESULTS After 26 weeks, IDeg OD Flex, IDeg OD, and IGlar OD improved HbA1c by 1.28, 1.07, and 1.26% points, respectively (estimated treatment difference [IDeg OD Flex − IGlar OD]: 0.04% points [–0.12 to 0.20], confirming noninferiority). No statistically significant differences in overall or nocturnal hypoglycemia were found between IDeg OD Flex and IGlar OD. Comparable glycemic control and rates of hypoglycemia were seen with IDeg OD Flex and IDeg OD. Adverse event profiles were similar across groups. CONCLUSIONS The use of extreme dosing intervals of 8–40 h demonstrates that the daily injection time of IDeg can be varied without compromising glycemic control or safety.

High-cocoa polyphenol-rich chocolate improves HDL cholesterol in Type 2 diabetes patients

Diabet. Med. 27, 1318–1321 (2010)

Effect of Glucose Variability on the Long-Term Risk of Microvascular Complications in Type 1 Diabetes

OBJECTIVE This study analyzed data from the Epidemiology of Diabetes Interventions and Complications (EDIC) study to see whether longer-term follow-up of Diabetes Control and Complications Trial (DCCT) patients reveals a role for glycemic instability in the development of microvascular complications. RESEARCH DESIGN AND METHODS The mean area under the curve glucose and the within-day glucose variability (SD and mean amplitude of glycemic excursions [MAGE]) during the DCCT were assessed to see whether they contributed to the risk of retinopathy and nephropathy by year 4 of the EDIC. RESULTS Logistic regression analysis showed that mean glucose during the DCCT and mean A1C during EDIC were independently predictive of retinopathy (each P < 0.001) as well as A1C during EDIC of nephropathy (P = 0.001) development by EDIC year 4. Glucose variability did not add to this (all P > 0.25 using SD or MAGE). CONCLUSIONS Glucose variability in the DCCT did not predict the development of retinopathy or nephropathy by EDIC year 4.

The Effect of Atorvastatin in Patients with Polycystic Ovary Syndrome: A Randomized Double-Blind Placebo-Controlled Study

CONTEXT Polycystic ovary syndrome (PCOS) is associated with increased risk of cardiovascular morbidity, whereas statins are proven to reduce cardiovascular mortality and morbidity through lipid-lowering and perhaps through their pleiotropic effects. Statins can also reduce testosterone in vitro by inhibiting ovarian theca-interstitial cell proliferation and steroidogenesis and reducing inflammation in vivo. OBJECTIVE Our objective was to assess the effect of atorvastatin on inflammatory markers, insulin resistance, and biochemical hyperandrogenemia in patients with PCOS. DESIGN AND SETTING We conducted a randomized, double-blind, placebo-controlled study at a tertiary care setting in United Kingdom. PATIENTS Patients included 40 medication-naive patients with PCOS and biochemical hyperandrogenemia. METHODS Patients were randomized to either atorvastatin 20 mg daily or placebo. MAIN OUTCOME MEASURES The primary endpoint of the study was a change in the inflammatory marker high-sensitivity C-reactive protein. The secondary endpoints were a change in insulin resistance and total testosterone. RESULTS After 12 wk atorvastatin, there was a significant reduction (mean +/- sem) in total cholesterol (4.6 +/- 0.2 vs. 3.4 +/- 0.2 mmol/liter, P < 0.01), low-density lipoprotein cholesterol (2.9 +/- 0.2 vs. 1.8 +/- 0.2 mmol/liter, P < 0.01), triglycerides (1.34 +/- 0.08 vs. 1.08 +/- 0.13 mmol/liter, P <0.01), high-sensitivity C-reactive protein (4.9 +/- 1.4 vs. 3.4 +/- 1.1 mg/liter, P = 0.04), free androgen index (13.4 +/- 0.6 vs. 8.7 +/- 0.4, P < 0.01), testosterone (4.1 +/- 0.2 vs. 2.9 +/- 0.1 nmol/liter, P < 0.01) and insulin resistance as measured by homeostasis model assessment for insulin resistance (HOMA-IR) (3.3 +/- 0.4 vs. 2.7 +/- 0.4). There was a significant increase in SHBG (31.1 +/- 1.0 vs. 35.3 +/- 1.2 nmol/liter, P < 0.01). There was a positive correlation between the reduction in HOMA-IR in the atorvastatin group with the reduction in triglycerides and the reduction of free androgen index. There was a significant deterioration of HOMA-IR in the placebo group (3.0 +/- 0.4 vs. 3.8 +/- 0.5). CONCLUSIONS This study suggests that atorvastatin is effective in reducing inflammation, biochemical hyperandrogenemia, and metabolic parameters in patients with PCOS after a 12-wk period.

Low dose cabergoline for hyperprolactinaemia is not associated with clinically significant valvular heart disease

OBJECTIVE Recent trials suggest that using ergot-derived dopamine agonists such as cabergoline in the treatment of Parkinsons disease is associated with an increased risk of valvular heart disease. However, the dose of cabergoline used to treat hyperprolactinaemia is considerably less than that used in Parkinsons disease. DESIGN AND METHODS A cross-sectional comparative assessment. Forty-four patients treated with cabergoline for hyperprolactinaemia underwent transthoracic echocardiography and were compared with 566 sequential subjects complaining of palpitations, taken from a contemporary echocardiography database. RESULTS The mean cumulative dose of cabergoline in the cases was 311 mg. There was no significant, severe or moderate, right- or left-sided valvular regurgitation in either group. Left heart: in the mitral and aortic valves, the rate of mild and trivial valvular regurgitation was not different between the two groups. Right heart: mild tricuspid and pulmonary regurgitation on colour Doppler alone was increased significantly in the cabergoline group, odds ratios of 3.1 and 7.8 respectively (95% confidence interval 1.0-9.6 and 0.8-78.4, P=0.04 and P<0.0001 respectively). CONCLUSION Cabergoline at doses sufficient to suppress hyperprolactinaemia for a period of 3-4 years is not associated with an increased risk of clinically significant valvular regurgitation.

Short-term primary culture of epithelial cells derived from human breast tumours.

As experimental models for breast cancer, most studies rely on established human breast cancer cell lines. However, many of these lines were established over 20 years ago, many from pleural effusions rather than the primary tumour, so the validity of using them as representative models is questionable. This paper describes our experiences, over a 3-year period, in establishing short-term epithelial-cell-enriched preparations from primary breast tumours based on differential centrifugation followed by culture in selective media. Epithelial cells were successfully cultured from 55% of samples, but culture success did not appear to be correlated with tumour histology, stage, grade or node status. Epithelial cell-enriched cultures were immunopositive for broad-spectrum cytokeratin and epithelial membrane antigen (EMA). Positivity for keratin 19 confirmed that the cultures contained tumour-derived cells, which additionally showed significantly higher activity of the reductive pathway of the steroid-converting enzyme 17beta-hydroxysteroid dehydrogenase type I. That the cultures contained tumour and not normal epithelial cells was further substantiated by the complete absence of the calmodulin-like gene NB-1 in tumour-derived cultures; this is only associated with normal breast epithelia. Eighty-five per cent of cultures established from oestrogen receptor (ER)-positive tumours expressed ER in vitro; this was functional in 66% of cultures, although ER-positive phenotype was gradually lost over time. In conclusion, epithelial cells can be isolated and maintained as short-term cultures from primary breast tumours irrespective of histopathological or clinical details, providing a model system with a greater biological and clinical relevance than breast cancer cell lines.

Somatostatin receptors 2 and 5 are preferentially expressed in proliferating endothelium.

Angiogenesis is characterised by activation, migration and proliferation of endothelial cells and is central to the pathology of cancer, cardiovascular disease and chronic inflammation. Somatostatin is an inhibitory polypeptide that acts through five receptors (sst 1, 2, 3, 4, 5). Sst has previously been reported in endothelium, but their role remains obscure. Here, we report the expression of sst in human umbilical vein endothelial cells (HUVECs) in vitro, during proliferation and quiescence. A protocol for culturing proliferating and quiescent HUVECs was established, and verified by analysing cell cycle distribution in propidium-iodide-stained samples using flow cytometry. Sst mRNA was then quantified in nine proliferating and quiescent HUVEC lines using quantitative reverse transcriptase–polymerase chain reaction. Sst 2 and 5 were preferentially expressed in proliferating HUVECs. All samples were negative for sst 4. Sst 1 and 3 expression and cell cycle progression were unrelated. Immunostaining for sst 2 and 5 showed positivity in proliferating but not quiescent cells, confirming sst 2 and 5 protein expression. Inhibition of proliferating cells with somatostatin analogues Octreotide and SOM230, which have sst 5 activity, was found (Octreotide 10−10–10−6 M: 48.5–70.2% inhibition; SOM230 10−9–10−6 M: 44.9–65.4% inhibition) in a dose-dependent manner, suggesting that sst 5 may have functional activity in proliferation. Dynamic changes in sst 2 and 5 expression during the cell cycle and the inhibition of proliferation with specific analogues suggest that these receptors may have a role in angiogenesis.