David O'Neal

Do adiponectin, TNFα, leptin and CRP relate to insulin resistance in pregnancy? Studies in women with and without gestational diabetes, during and after pregnancy

The role of adiponectin, tumour necrosis factor α (TNFα), leptin and C‐reactive protein in the insulin resistance of pregnancy is not clear. We measured their levels in women with gestational diabetes (GDM) and in controls, during and after pregnancy, and related them to insulin secretion and action.

Outcome measures for artificial pancreas clinical trials: A consensus report

Research on and commercial development of the artificial pancreas (AP) continue to progress rapidly, and the AP promises to become a part of clinical care. In this report, members of the JDRF Artificial Pancreas Project Consortium in collaboration with the wider AP community 1) advocate for the use of continuous glucose monitoring glucose metrics as outcome measures in AP trials, in addition to HbA1c, and 2) identify a short set of basic, easily interpreted outcome measures to be reported in AP studies whenever feasible. Consensus on a broader range of measures remains challenging; therefore, reporting of additional metrics is encouraged as appropriate for individual AP studies or study groups. Greater consistency in reporting of basic outcome measures may facilitate the interpretation of study results by investigators, regulatory bodies, health care providers, payers, and patients themselves, thereby accelerating the widespread adoption of AP technology to improve the lives of people with type 1 diabetes.

Increased serum pigment epithelium‐derived factor is associated with microvascular complications, vascular stiffness and inflammation in Type 1 diabetes

Aims  To determine in Type 1 diabetes patients if levels of pigment epithelium‐derived factor (PEDF), an anti‐angiogenic, anti‐inflammatory and antioxidant factor, are increased in individuals with complications and positively related to vascular and renal dysfunction, body mass index, glycated haemoglobin, lipids, inflammation and oxidative stress.

1 Growth hormone deficiency and cardiovascular risk

It is now recognized that growth hormone (GH) deficiency in adults represents a distinct clinical syndrome that encompasses reduced psychological well-being as well as specific metabolic abnormalities. The latter features, which include hypertension, central obesity, insulin resistance, dyslipidaemia and coagulopathy, closely resemble those of metabolic insulin resistance syndrome. The increased cardiovascular morbidity and mortality demonstrated in these GH-deficient (GHD) adults reinforce the close association between the two syndromes. Replacement of GH in GHD adults has resulted in a marked reduction of central obesity and significant reduction in total cholesterol but little change in other risk factors, in particular insulin resistance and dyslipidaemia. The persistent insulin resistance and dyslipidaemia, together with the elevation of plasma insulin levels and lipoprotein (a) with GH replacement in these subjects are of concern. Long-term follow-up data are required to assess the impact of GH replacement on the cardiovascular morbidity and mortality of GHD adults. Further exploration of the appropriateness of the GH dosage regimens currently being employed is also indicated.

Lipid levels and peripheral vascular disease in diabetic and non-diabetic subjects

Non-insulin dependent diabetes (NIDDM) is associated with an increased risk of peripheral vascular disease (PVD), but within the diabetic population the relationship between lipid profile and PVD has not been clearly defined. In this study we examined the association of lipid parameters and in particular low density lipoprotein (LDL) particle size, with the presence of PVD in subjects with and without NIDDM. 41 NIDDM patients and 31 non-diabetic subjects with PVD in the absence of rest pain or ulceration, defined by ankle-brachial index measurements and duplex scanning, were compared with 41 NIDDM and 31 euglycemic control subjects of comparable age and sex, without PVD. In both groups those with PVD were found to have significantly elevated triglycerides (2.7 [2.2-3.3] versus 1.9 [1.6-2.2] mmol/l; P < 0.05 in the diabetic group and 2.0 [1.6-2.3] versus 1.4 [1.1-1.5] mmol/l; P < 0.05 in the non-diabetic group), decreased apolipoprotein A1 (124 +/- 3 versus 139 +/- 5 mg/dl; P < 0.01 in the diabetic group and 133 +/- 4 versus 147 +/- 4 mg/dl; P < 0.05 in the non-diabetic group) and decreased LDL particle size (25.4 +/- 0.1 versus 25.8 +/- 0.1 nm; P < 0.01 in the diabetic group and 26.0 +/- 0.1 versus 26.3 +/- 0.1 nm; P < 0.05 in the non diabetic group). In the non-diabetic group apolipoprotein[a] (365 [239-554] versus 184 [17-266] U/l; P < 0.01), total cholesterol (6.3 +/- 0.2 versus 5.6 +/- 0.2 mmol/l; P < 0.05), LDL cholesterol (4.1 +/- 0.2 versus 3.6 +/- 0.2 mmol/l; P < 0.05) and apolipoprotein B (146 +/- 8 versus 117 +/- 5 mg/dl; P < 0.05) were also found to be associated with PVD although these associations were not observed in the group with diabetes. In addition, 11 NIDDM subjects and 11 non-diabetic subjects with rest pain or ulceration were compared to the corresponding groups with uncomplicated PVD and had lipid profiles with significantly lower levels of total cholesterol and LDL cholesterol. We conclude that the dyslipidemic profile characterized by increased triglyceride level, decreased apolipoprotein A1 level and small dense LDL is associated with uncomplicated PVD in both NIDDM and non-diabetic subjects.

Evaluation of an Algorithm to Guide Patients With Type 1 Diabetes Treated With Continuous Subcutaneous Insulin Infusion on How to Respond to Real-Time Continuous Glucose Levels A randomized controlled trial

OBJECTIVE To evaluate an algorithm guiding responses of continuous subcutaneous insulin infusion (CSII)–treated type 1 diabetic patients using real-time continuous glucose monitoring (RT-CGM). RESEARCH DESIGN AND METHODS Sixty CSII-treated type 1 diabetic participants (aged 13–70 years, including adult and adolescent subgroups, with A1C ≤9.5%) were randomized in age-, sex-, and A1C-matched pairs. Phase 1 was an open 16-week multicenter randomized controlled trial. Group A was treated with CSII/RT-CGM with the algorithm, and group B was treated with CSII/RT-CGM without the algorithm. The primary outcome was the difference in time in target (4–10 mmol/l) glucose range on 6-day masked CGM. Secondary outcomes were differences in A1C, low (≤3.9 mmol/l) glucose CGM time, and glycemic variability. Phase 2 was the week 16–32 follow-up. Group A was returned to usual care, and group B was provided with the algorithm. Glycemia parameters were as above. Comparisons were made between baseline and 16 weeks and 32 weeks. RESULTS In phase 1, after withdrawals 29 of 30 subjects were left in group A and 28 of 30 subjects were left in group B. The change in target glucose time did not differ between groups. A1C fell (mean 7.9% [95% CI 7.7–8.2to 7.6% [7.2–8.0]; P < 0.03) in group A but not in group B (7.8% [7.5–8.1] to 7.7 [7.3–8.0]; NS) with no difference between groups. More subjects in group A achieved A1C ≤7% than those in group B (2 of 29 to 14 of 29 vs. 4 of 28 to 7 of 28; P = 0.015). In phase 2, one participant was lost from each group. In group A, A1C returned to baseline with RT-CGM discontinuation but did not change in group B, who continued RT-CGM with addition of the algorithm. CONCLUSIONS Early but not late algorithm provision to type 1 diabetic patients using CSII/RT-CGM did not increase the target glucose time but increased achievement of A1C ≤7%. Upon RT-CGM cessation, A1C returned to baseline.

Increased serum kallistatin levels in type 1 diabetes patients with vascular complications

BackgroundKallistatin, a serpin widely produced throughout the body, has vasodilatory, anti-angiogenic, anti-oxidant, and anti-inflammatory effects. Effects of diabetes and its vascular complications on serum kallistatin levels are unknown.MethodsSerum kallistatin was quantified by ELISA in a cross-sectional study of 116 Type 1 diabetic patients (including 50 with and 66 without complications) and 29 non-diabetic controls, and related to clinical status and measures of oxidative stress and inflammation.ResultsKallistatin levels (mean(SD)) were increased in diabetic vs. control subjects (12.6(4.2) vs. 10.3(2.8) μg/ml, p = 0.007), and differed between diabetic patients with complications (13.4(4.9) μg/ml), complication-free patients (12.1(3.7) μg/ml), and controls; ANOVA, p = 0.007. Levels were higher in diabetic patients with complications vs. controls, p = 0.01, but did not differ between complication-free diabetic patients and controls, p > 0.05. On univariate analyses, in diabetes, kallistatin correlated with renal dysfunction (cystatin C, r = 0.28, p = 0.004; urinary albumin/creatinine, r = 0.34, p = 0.001; serum creatinine, r = 0.23, p = 0.01; serum urea, r = 0.33, p = 0.001; GFR, r = -0.25, p = 0.009), total cholesterol (r = 0.28, p = 0.004); LDL-cholesterol (r = 0.21, p = 0.03); gamma-glutamyltransferase (GGT) (r = 0.27, p = 0.04), and small artery elasticity, r = -0.23, p = 0.02, but not with HbA1c, other lipids, oxidative stress or inflammation. In diabetes, geometric mean (95%CI) kallistatin levels adjusted for covariates, including renal dysfunction, were higher in those with vs. without hypertension (13.6 (12.3-14.9) vs. 11.8 (10.5-13.0) μg/ml, p = 0.03). Statistically independent determinants of kallistatin levels in diabetes were age, serum urea, total cholesterol, SAE and GGT, adjusted r2 = 0.24, p < 0.00001.ConclusionsSerum kallistatin levels are increased in Type 1 diabetic patients with microvascular complications and with hypertension, and correlate with renal and vascular dysfunction.

An Algorithm Guiding Patient Responses to Real-Time-Continuous Glucose Monitoring Improves Quality of Life

OBJECTIVE This study evaluated the impact on quality of life (QoL) of an algorithm guiding the responses of continuous subcutaneous insulin infusion (CSII)-treated type 1 diabetes (T1D) patients using real-time (RT)-continuous glucose monitoring (CGM). RESEARCH DESIGN AND METHODS Sixty CSII-treated T1D participants (13-70 years old, glycosylated hemoglobin [HbA1c] ≤ 9.5%), including adult and adolescent subgroups, were randomized in age-, gender-, and HbA1c-matched pairs. Phase 1 was an open 16-week multicenter randomized controlled trial; Group A received CSII/RT-CGM with the algorithm, and Group B received CSII/RT-CGM without algorithm. Phase 2 was the 16-32-week follow-up study; Group A returned to usual care (CSII without RT-CGM), and Group B was provided with algorithm at 16 weeks. QoL was assessed by DQOL (adults) and DQOLY (adolescents) questionnaires at baseline, 16 weeks, and 32 weeks. Higher scores (range 1-5) indicate poorer QoL. Analysis was by analysis of variance (between group for baseline-16 weeks) and paired two-tailed t tests (within group for baseline and 32 weeks) with significance at P < 0.05. RESULTS Withdrawals left 28 of 30 patients in Group A and 27 of 30 patients in Group B at 32 weeks. In Phase 1, QoL in Group A (2.16 [0.44] baseline to 1.86 [0.40] at 16 weeks) improved compared with Group B (2.03 [0.47] to 2.03 [0.50]) (P = 0.002). Change in QoL correlated with changes in HbA1c (R = 0.36; P = 0.007). In Phase 2, Group A QoL was better at 32 weeks compared with baseline (2.16 [0.44] vs. 2.02 [0.43]) (P = 0.04) but was not in Group B (2.03 [0.47] vs. 1.99 [0.51]) (P = not significant). CONCLUSIONS An algorithm guiding CSII-treated T1D responses to RT-CGM improved QoL, which persisted post-RT-CGM withdrawal. Algorithm provision at RT-CGM initiation was required to benefit QoL.

Evaluation of an Algorithm to Guide Patients with Type I Diabetes Treated with Continuous Subcutaneous Insulin Infusion (CSII) on How to Respond to Real-Time Continuous Glucose Levels- A Randomised Control Trial.

OBJECTIVE To evaluate an algorithm guiding responses of continuous subcutaneous insulin infusion (CSII)–treated type 1 diabetic patients using real-time continuous glucose monitoring (RT-CGM). RESEARCH DESIGN AND METHODS Sixty CSII-treated type 1 diabetic participants (aged 13–70 years, including adult and adolescent subgroups, with A1C ≤9.5%) were randomized in age-, sex-, and A1C-matched pairs. Phase 1 was an open 16-week multicenter randomized controlled trial. Group A was treated with CSII/RT-CGM with the algorithm, and group B was treated with CSII/RT-CGM without the algorithm. The primary outcome was the difference in time in target (4–10 mmol/l) glucose range on 6-day masked CGM. Secondary outcomes were differences in A1C, low (≤3.9 mmol/l) glucose CGM time, and glycemic variability. Phase 2 was the week 16–32 follow-up. Group A was returned to usual care, and group B was provided with the algorithm. Glycemia parameters were as above. Comparisons were made between baseline and 16 weeks and 32 weeks. RESULTS In phase 1, after withdrawals 29 of 30 subjects were left in group A and 28 of 30 subjects were left in group B. The change in target glucose time did not differ between groups. A1C fell (mean 7.9% [95% CI 7.7–8.2to 7.6% [7.2–8.0]; P < 0.03) in group A but not in group B (7.8% [7.5–8.1] to 7.7 [7.3–8.0]; NS) with no difference between groups. More subjects in group A achieved A1C ≤7% than those in group B (2 of 29 to 14 of 29 vs. 4 of 28 to 7 of 28; P = 0.015). In phase 2, one participant was lost from each group. In group A, A1C returned to baseline with RT-CGM discontinuation but did not change in group B, who continued RT-CGM with addition of the algorithm. CONCLUSIONS Early but not late algorithm provision to type 1 diabetic patients using CSII/RT-CGM did not increase the target glucose time but increased achievement of A1C ≤7%. Upon RT-CGM cessation, A1C returned to baseline.

Plasma Low‐Molecular Weight Fluorescence in Type 1 Diabetes Mellitus

Abstract: Characteristic tissue fluorescence is associated with advanced glycation end product (AGE) accumulation in experimental diabetes models, but its utility in patients with type 1 diabetes remains to be established. We studied 148 patients with type 1 diabetes and 77 healthy age‐matched control subjects. Low‐molecular weight (LMW) fluorophore levels were estimated in plasma samples obtained after an overnight fast. Intra‐ and interassay coefficients of variation were 4.7% and 6.4%, respectively. LMW fluorophore levels were significantly higher in patients with diabetes than in control subjects (6.3 ± 0.6 AU/mL vs. 4.1 ± 0.3; P= 0.007). However, all of this difference came from patients with microvascular complications (n= 67, 7.5 ± 1.3). There was no significant difference in LMW fluorescence between complication‐free patients (4.4 ± 0.2) and control subjects (P > 0.05). On multivariate analysis, LMW fluorophores correlated with measures of renal function (P < 0.05) but not with diabetes per se. In addition, there was no correlation between LMW fluorophores and the markers of oxidative stress or systemic inflammation. Longitudinal and interventional studies are required to determine whether the association between LMW fluorophores and nephropathy is cause or effect.