Intervention fidelity assessment: A sub-study of the Norfolk Diabetes Prevention Study (NDPS).

BACKGROUND: Previous research has shown that lifestyle modification can delay or prevent the onset of type 2 diabetes in high-risk individuals. The Norfolk Diabetes Prevention Study (NDPS) was a parallel, three-arm, randomized controlled trial with up to 46 months follow-up that tested a group-delivered, theory-based lifestyle intervention to reduce the incidence of type 2 diabetes in high-risk groups. The current study aimed to evaluate if the NDPS intervention was delivered to an acceptable standard and if any part(s) of the delivery required improvement. METHODS: A sub-sample of 30, 25 for inter-rater reliability and audio-recordings of the NDPS intervention education sessions were assessed independently by two reviewers (CT, TW) using a 12-item checklist. Each item was scored on a 0-5 scale, with a score of 3 being defined as 'adequate delivery'. Inter-rater reliability was assessed. Analysis of covariance (ANCOVA) was used to assess changes in intervention fidelity as the facilitators gained experience. RESULTS: Inter-rater agreement was acceptable (86%). A mean score of 3.47 (SD = .38) was achieved across all items of the fidelity checklist and across all intervention facilitators (n = 6). There was an apparent trend for intervention fidelity scores to decrease with experience; however, this trend was non-significant (p > .05) across all domains in this small sample. CONCLUSION: The NDPS was delivered to an acceptable standard by all Diabetes Prevention Facilitators. Further research is needed to better understand how the intervention's delivery characteristics can be optimized and how they might vary over time.

Quantity and specificity of action-plans as predictors of weight loss: analysis of data from the Norfolk Diabetes Prevention Study (NDPS).

OBJECTIVE: Investigate associations between quantity, content and specificity of action-plans and weight loss in a diabetes prevention study. DESIGN: Prospective cohort study nested within a randomised controlled trial. Participants completed action-planning worksheets during intervention sessions. MAIN OUTCOME MEASURES: Action-plans were coded in terms of: number of plans set, their content, and specificity. Multivariate regression analyses assessed associations with weight loss at four-months. RESULTS: 890 planning-worksheets from 106 participants were analysed. Participants wrote a mean of 2.12 (SD = 1.20) action-plans per worksheet, using a mean of 2.20 (SD = 0.68) specificity components per action-plan. Quantity of action-plans per worksheet decreased over time (r = -0.137, p < 0.001) and increased quantity was associated with reduced specificity [r = -.215, p < 0.001]. Walking (34.9% of action-plans) and reducing high fat/sugar snacks (26.1%) were the most commonly planned lifestyle actions. In multivariate modelling, increased quantity of action-plans was associated with greater weight loss (R2 = 0.135, Unstandardised Beta = 0.144, p = 0.002). Specificity was not significantly associated with weight-loss (p = 0.096). CONCLUSION: Producing more action-plans was associated with greater weight loss. Further research should directly compare more versus less specific action-plans and explore ways to sustain engagement in action-planning. Our findings imply that participants should freely set numerous action-plans, rather than being encouraged to focus on specificity.Supplemental data for this article is available online at https://doi.org/10.1080/08870446.2022.2055026 .

A motivational peer support program for type 2 diabetes prevention delivered by people with type 2 diabetes: the UEA-IFG feasibility study.

PURPOSE: The purpose of this study was to develop a peer support program for individuals at high risk of type 2 diabetes as part of a novel Diabetes Prevention Programme (The UEA-IFG Study). Lay members of the public with existing type 2 diabetes volunteered as peer supporters (termed type 2 trainers) for participants at high risk of developing type 2 diabetes. The feasibility of type 2 trainer recruitment, training, and retention was tested. METHODS: Between January and September 2009, 1500 potential type 2 trainers with existing type 2 diabetes were contacted and 168 (11%) expressed an interest. From this group, 26 type 2 trainers were appointed to begin training. All completed 7 training seminars, covering diabetes prevention, nutrition, physical activity, listening skills, motivation, and goal planning. Motivational calls were made every 12 weeks to each study participant by each type 2 trainer in addition to health care professional-delivered education sessions. RESULTS: Twenty-six type 2 trainers were recruited to enter the program. One type 2 trainer withdrew before beginning their role. The retention rate was high, with 22 (89%) of the type 2 trainers continuing until study end (July 2010; 20 months), with a total of 240 phone calls made. CONCLUSION: The recruiting and training of lay volunteers with existing type 2 diabetes as type 2 trainers to support study participants at risk of developing the same condition was a cost-effective strategy in comparison to employing salaried health care professionals and warrants further investigation on health outcomes.

Lack of association of colonic epithelium telomere length and oxidative DNA damage in Type 2 diabetes under good metabolic control.

BACKGROUND: Telomeres are DNA repeat sequences necessary for DNA replication which shorten at cell division at a rate directly related to levels of oxidative stress. Critical telomere shortening predisposes to cell senescence and to epithelial malignancies. Type 2 diabetes is characterised by increased oxidative DNA damage, telomere attrition, and an increased risk of colonic malignancy. We hypothesised that the colonic mucosa in Type 2 diabetes would be characterised by increased DNA damage and telomere shortening. METHODS: We examined telomere length (by flow fluorescent in situ hybridization) and oxidative DNA damage (flow cytometry of 8 - oxoguanosine) in the colonic mucosal cells of subjects with type 2 diabetes (n = 10; mean age 62.2 years, mean HbA1c 6.9%) and 22 matched control subjects. No colonic pathology was apparent in these subjects at routine gastrointestinal investigations. RESULTS: Mean colonic epithelial telomere length in the diabetes group was not significantly different from controls (10.6 [3.6] vs. 12.1 [3.4] Molecular Equivalent of Soluble Fluorochrome Units [MESF]; P = 0.5). Levels of oxidative DNA damage were similar in both T2DM and control groups (2.6 [0.6] vs. 2.5 [0.6] Mean Fluorescent Intensity [MFI]; P = 0.7). There was no significant relationship between oxidative DNA damage and telomere length in either group (both p > 0.1). CONCLUSION: Colonic epithelium in Type 2 diabetes does not differ significantly from control colonic epithelium in oxidative DNA damage or telomere length. There is no evidence in this study for increased oxidative DNA damage or significant telomere attrition in colonic mucosa as a carcinogenic mechanism.

Low density lipoprotein from patients with Type 2 diabetes increases expression of monocyte matrix metalloproteinase and ADAM metalloproteinase genes.

AIMS: Type 2 diabetes is characterised by increased plasma concentrations of pro-inflammatory cytokines [such as tumour necrosis factor - alpha; TNF-alpha] and soluble forms of adhesion molecules involved in leukocyte - endothelial interactions. These molecules are synthesised as transmembrane proteins and the plasma soluble forms are generated by ectodomain cleavage from the cell surface by members of the ADAM [adisintegrin and metalloproteinase] proteinase family. We hypothesised that plasma low density lipoprotein [LDL] from subjects with Type 2 diabetes would influence in vitro monocytic ADAM and matrix metalloproteinase [MMP] gene expression differently compared to control LDL. METHODS: We examined relative mRNA expression by real time PCR in a monocytic cell line [THP-1] cultured for 4, 8 and 24 hrs with human plasma LDL derived from subjects with [n = 5] or without [n = 4] Type 2 diabetes. Gene expression for MMP-1 and 9, and ADAM - 8, 15, 17 and 28 was studied. RESULTS: Type 2 diabetes LDL significantly increased gene expression of MMP - 1 [p < 0.01] MMP - 9 [p < 0.001], and ADAM 17 [p < 0.05], - 28 [p < 0.01] and - 15 [p < 0.01] compared to control LDL. Type 2 diabetes LDL had disparate effects on inhibitors of MMP. CONCLUSION: These data suggest that Type 2 diabetes LDL could lead to increased adhesion molecule and TNF alpha cell surface shedding, and vascular plaque instability, by promoting increased expression of ADAM and MMP genes.

Pro-oxidant effect of alpha-tocopherol in patients with type 2 diabetes after an oral glucose tolerance test--a randomised controlled trial.

BACKGROUND: As a part of a larger study investigating the effects of alpha-tocopherol on gene expression in type 2 diabetics we observed a pro-oxidant effect of alpha-tocopherol which we believe may be useful in interpreting outcomes of large intervention trials of alpha-tocopherol. METHODS: 19 type 2 diabetes subjects were randomised into two groups taking either 1200 IU/day of alpha-tocopherol or a matched placebo for 4 weeks. On day 0 and 29 of this study oxidative DNA damage was assessed in mononuclear cells from fasted blood samples and following a 2 h glucose tolerance test (GTT). RESULTS: On day 0 there was no significant difference in oxidative DNA damage between the two groups or following a GTT. On day 29 there was no significant difference in oxidative DNA damage in fasted blood samples, however following a GTT there was a significant increase in oxidative DNA damage in the alpha-tocopherol treatment group. CONCLUSION: High dose supplementation with alpha-tocopherol primes mononuclear cells from patients with type 2 diabetes for a potentially damaging response to acute hyperglycaemia.

Total and excess bed occupancy by age, specialty and insulin use for nearly one million diabetes patients discharged from all English Acute Hospitals.

To investigate total diabetes bed occupancy and prolonged inpatient length of stay (LOS) in all English Acute Hospitals, we analysed hospital episode statistics (HES) discharge data for all English Acute Hospitals over 4 years for ICD10 discharge codes of E10 ('insulin-dependent diabetes') or E11 ('non-insulin dependent diabetes') by age-band (18-60, 61-75 and >75 years) and specialties. We matched these data to control discharges without these codes. There were 943,613 diabetes discharges (6,508,668 bed days) and 10,724,414 matched controls. Mean diabetes LOS increased with age for each specialty and both E10 and E11 codes, but excess diabetes LOS decreased with age. Excess diabetes LOS was <1.0 days in most groups and highest (1.2 days) in insulin-dependent surgical patients under 60 years old, where 19.7% of bed days were excess. A similar pattern was seen for 76,570 diabetes inpatients with key cardiac or surgical conditions. Excess bed occupancy due to prolonged mean LOS accounted for 325,033 bed days under general medical and surgical codes. There were 25,525 discharges with diabetic ketoacidosis (126,495 bed days) in these 4 years. Excess diabetes LOS is concentrated in younger age groups. Excess bed occupancy due to prolonged LOS in medical and surgical inpatients is three times greater than bed occupancy due to diabetic ketoacidosis. Strategies to reduce excess diabetes bed occupancy should emphasize reducing inpatient LOS in younger inpatients.

Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes.

OBJECTIVE: Telomeres are DNA sequences necessary for DNA replication, which shorten at cell division at a rate related to levels of oxidative stress. Once shortened to a critical length, cells are triggered into replicative senescence. Type 2 diabetes is associated with oxidative DNA damage, and we hypothesized that telomere shortening would characterize type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 21 male type 2 diabetic subjects (mean age 61.2 years, mean HbA(1c) 7.9%) selected to limit confounding effects on telomere length and 29 matched control subjects. Telomere length was measured in peripheral venous monocyte and T-cells (naïve and memory) by fluorescent in situ hybridization and oxidative DNA damage by flow cytometry of oxidized DNA bases. Peripheral insulin resistance (homeostasis model assessment) and high-sensitivity C-reactive protein (hsCRP) were measured. RESULTS: Mean monocyte telomere length in the diabetic group was highly significantly lower than in control subjects (4.0 [1.1] vs. 5.5 [1.1]; P < 0.0001), without significant differences in lymphocyte telomere length. There was a trend toward increased oxidative DNA damage in all diabetes cell types examined and a significant inverse relationship between oxidative DNA damage and telomere length (r = -0.55; P = 0.018) in the diabetic group. Telomere length was unrelated to plasma CRP concentration or insulin resistance. CONCLUSIONS: Monocyte telomere shortening in type 2 diabetes could be due to increased oxidative DNA damage to monocyte precursors during cell division. This data suggests that monocytes adhering to vascular endothelium and entering the vessel wall in type 2 diabetes are from a population with shorter telomeres and at increased risk of replicative senescence within vascular plaque.

Paraoxonase-1 (PON-1) genotype and activity and in vivo oxidized plasma low-density lipoprotein in Type II diabetes.

The HDL (high-density lipoprotein)-associated enzyme PON (paraoxonase)-1 protects LDL (low-density lipoprotein) from oxidative modification in vitro, although it is unknown if this anti-atherogenic action occurs in vivo. In a cross-sectional study of 58 Type II diabetic subjects and 50 controls, we examined the fasting plasma LDL basal conjugated diene concentration [a direct measurement of circulating oxLDL (oxidatively modified LDL)], lipoprotein particle size by NMR spectroscopy, PON-1 polymorphisms (coding region polymorphisms Q192R and L55M, and gene promoter polymorphisms -108C/T and -162G/A), PON activity (with paraoxon or phenyl acetate as the substrates) and dietary antioxidant intake. Plasma oxLDL concentrations were higher in Type II diabetic patients (males, P = 0.048; females, P = 0.009) and unrelated to NMR lipoprotein size, PON-1 polymorphisms or PON activity (with paraoxon as the substrate) in any group. In men with Type II diabetes, however, there was a direct relationship between oxLDL concentrations and PON activity (with phenyl acetate as the substrate; r = 0.611, P = 0.0001) and an atherogenic NMR lipid profile in those who were PON-1 55LL homozygotes. Circulating oxLDL concentrations in vivo were unrelated to PON-1 genotypes or activity, except in male Type II diabetics where there was a direct association between PON activity (with phenyl acetate as the substrate) and oxLDL levels. These in vivo data contrast with in vitro data, and may be due to confounding by dietary fat intake. Male Type II diabetic subjects with PON-1 55LL homozygosity have an atherogenic NMR lipid profile independent of LDL oxidation. These data do not support an in vivo action of PON on LDL oxidation.

Association studies of insulin receptor substrate 1 gene (IRS1) variants in type 2 diabetes samples enriched for family history and early age of onset.

The gene encoding insulin receptor substrate-1 (IRS1) represents a strong biological candidate for a contributory role in type 2 diabetes susceptibility. Indeed, functional studies have implicated the G971R variant, and a recent meta-analysis of 27 association studies suggested that carriage of 971R was associated with a 25% increase in disease risk. However, this association has not been evaluated in large samples. The present study genotyped the P512A and G971R IRS1 variants in 971 U.K. type 2 diabetic subjects ascertained for strong family history and/or early onset, as well as 1,257 control subjects matched by ethnicity. There was no evidence for association with type 2 diabetes for either variant. (For example, the odds ratio [OR] for carriage of 971R was 1.11 [95% CI 0.86-1.44, P = 0.44]) An updated meta-analysis (31 studies: 5,104 case and 7,418 control subjects) remained significant for the G971R association (P = 0.025), albeit with a diminished OR (1.15 [95% CI 1.02-1.31]). Additional studies of IRS1 variation will be required to obtain a robust estimate of the overall contribution of IRS1 variation to type 2 diabetes susceptibility, but the current study suggests that previous studies have overestimated the magnitude of this effect.

Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and 9-cis-retinoic acid.

The PPAR gamma agonists, thiazolidinediones (TZDs), have anti-inflammatory properties as well as increasing insulin sensitivity. This has widened their therapeutic scope to treat inflammatory diseases such as atherosclerosis in addition to Type 2 Diabetes. TZDs are known to reduce monocyte/macrophage expression of Matrix metalloproteinase (MMP)-9, which is implicated in atherosclerotic plaque destabilization. This study aims to identify other metalloproteinase genes of the ADAM (A Disintegin And Metalloproteinase) and ADAMTS families that are regulated by PPAR gamma or RXR agonists, which are potentially important in type 2 diabetes and/or related atherosclerosis. The synthetic PPAR gamma agonist, GW7845, and the natural agonist 15d-PGJ2, suppressed PMA stimulated MMP-9 in human monocyte-like cells (THP-1) only in the presence of 9-cis-retinoic acid. Quantitative Real-Time PCR showed that this reduction was regulated at the mRNA level. Expression of ADAMs 8, 9, and 17 were increased, and ADAM15 was decreased by stimulation of THP-1 with PMA, although these ADAMs were not regulated by PPAR gamma or RXR agonists. PMA-induced ADAM28 expression was further enhanced by the addition of 9-cis-retinoic acid. ADAMTS4, implicated in rheumatoid arthritis, was expressed in THP-1 cells, and significantly increased after 24 h of PMA stimulation. ADAMTS4 expression was suppressed by both PPAR gamma and RXR agonists and was undetectable when the agonists were combined. Pretreatment of THP-1 cells with the PPAR gamma antagonist, GW9662, suggests that PPAR gamma plays subtly different roles in the regulation of MMP-9, ADAMTS4 and ADAM28 gene expression. These results indicate that PPAR gamma and RXR agonists have complex effects on monocyte metalloproteinase expression, which may have implications for therapeutic strategies.

Monocyte matrix metalloproteinase production in Type 2 diabetes and controls--a cross sectional study.

BACKGROUND: Coronary plaque rupture may result from localised over expression of matrix metalloproteinases (MMPs) within the plaque by infiltrating monocyte-macrophages. As MMP expression can be promoted by the modified lipoproteins, oxidative stress and hyperglycaemia that characterises Type 2 diabetes, we hypothesised that peripheral monocytes in these patients, exposed to these factors in vivo, would demonstrate increased MMP production compared to controls. METHODS: We examined peripheral venous monocyte expression of MMP and tissue inhibitor of metalloproteinase-1 (TIMP-1) in 18 controls and 22 subjects with Type 2 diabetes and no previous cardiovascular complications. RESULTS: No significant difference in MMP-1, 3 or 9 or TIMP-1 production was observed between control and diabetes groups. CONCLUSIONS: Monocyte MMP-1, 3, and 9, and TIMP-1, production are not abnormal in Type 2 diabetes. This data cannot be extrapolated to monocyte-macrophage behaviour in the vessel wall, but it does suggest MMP and TIMP-1 expression prior to monocyte infiltration and transformation are not abnormal in Type 2 diabetes.