S E Manley

Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study

Abstract Objective: To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Design: Prospective observational study. Setting: 23 hospital based clinics in England, Scotland, and Northern Ireland. Participants: 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. Outcome measures: Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA1c adjusted for possible confounders at diagnosis of diabetes. Results: The incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbA1c was associated with reductions in risk of 21% for any end point related to diabetes (95% confidence interval 17% to 24%, P<0.0001), 21% for deaths related to diabetes (15% to 27%, P<0.0001), 14% for myocardial infarction (8% to 21%, P<0.0001), and 37% for microvascular complications (33% to 41%, P<0.0001). No threshold of risk was observed for any end point. Conclusions: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA1c values in the normal range (<6.0%).

Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43)

Aims/hypothesis. Juvenile-onset, insulin-dependent diabetes is associated with islet cell antibodies and with specific “high-risk” HLA-DRB1 and HLA-DQB1 genotypes. Patients with Type II (non-insulin-dependent) diabetes mellitus can have islet-related antibodies, but the genotypic associations at different ages of onset have not been evaluated. Our aim was to determine (i) the prevalence of DRB1 and DQB1 genotypes in patients at diagnosis of Type II diabetes at different ages from 25 to 65 years compared with the general population, and (ii) whether the presence of islet cell antibodies (ICA) or glutamic acid decarboxylase antibodies (GADA) or both by age is associated with different DRB1 and DQB1 genotypes. Methods. The antibodies to islet cells and those to glutamic acid decarboxylase were measured in 1712 white Caucasian diabetic subjects at diagnosis of diabetes and they were genotyped for HLA DRB1*03 and DRB1*04 and the high-risk DRB1*04-DQB1* 0302 haplotype. To assess over-representation of high-risk alleles for Type I (insulin-dependent) diabetes mellitus, the prevalence of high-risk alleles in diabetic patients was expressed relative to the prevalence of low-risk alleles, non-DR3/non-DR4, that provided a reference denominator in both the diabetic patients and in 200 non-diabetic control subjects. The prevalence of ICA or GADA or both in patients with different HLA genotypes was assessed in those diagnosed in four age groups, 25–34 years, 35–44 years, 45–54 years and 55–65 years. Results. In Type II diabetic patients presenting at ages 25–34, 35–44 and 45–54 years, there was an increased prevalence of DR3/DR4 compared with the general population with approximately 6.5-fold, 2.9-fold, 2.1-fold over-representation, respectively (p < 0.0001, < 0.01, < 0.05) but this was not found in those aged 55–65 years old. In the group aged 25–34 years, 32 % of patients with ICA or GADA or both had DRB1*03/DRB1*04-DQB1*0302 compared with 10 % in those aged 55–65 years and expected 3 % prevalence. Conversely, only 14 % of those aged 25–34 years with antibodies had non-DR3/non-DR4, compared with 35 % in those aged 55–65 years. There was thus pronounced age heterogeneity in DRB1 and DQB1 predisposition to Type II diabetes. The antibodies displaced DRB1 or DQB1 genotypes in the multivariate model for requiring insulin therapy by 6 years of follow-up. Conclusion/hypothesis. The age of presentation of Type I diabetes in adulthood was in part dependent on the DRB1/DQB1 genotype. Islet cell antibodies and glutamic acid decarboxylase antibodies were strongly associated with DRB1*03/DRB1*04-DQB1*0302 in early adulthood but showed little relation with specific HLA genotypes after the age of 55 years. [Diabetologia (1999) 42: 608–616]

Validation of an algorithm combining haemoglobin A1c and fasting plasma glucose for diagnosis of diabetes mellitus in UK and Australian populations

Aim  To determine whether glycated haemoglobin (HbA1c) can be used in combination with fasting plasma glucose (FPG) for the diagnosis of diabetes in patients with impaired fasting glucose (IFG) and in a broader spectrum of patients.

Preanalytical, Analytical, and Computational Factors Affect Homeostasis Model Assessment Estimates

OBJECTIVE—We investigated how β-cell function and insulin sensitivity or resistance are affected by the type of blood sample collected or choice of insulin assay and homeostatis model assessment (HOMA) calculator (http://www.dtu.ox.ac.uk). RESEARCH DESIGN AND METHODS—Insulin was measured using 11 different assays in serum and 1 assay in heparinized plasma. Fasting subjects with normoglycemia (n = 12), pre-diabetes, i.e., impaired fasting glucose or impaired glucose tolerance (n = 18), or type 2 diabetes (n = 67) were recruited. Patients treated with insulin or those who were insulin antibody–positive were excluded. HOMA estimates were calculated using specific insulin (SI) or radioimmunoassay (RIA) calculators (version 2.2). RESULTS—All glucose values were within model (HOMA) limits but not all insulin results, as 4.3% were <20 pmol/l and 1% were >300 pmol/l. β-Cell function derived from different insulin assays ranged from 67 to 122% (median) for those with normoglycemia (P = 0.026), from 89 to 138% for those with pre-diabetes (P = 0.990), and from 50 to 81% for those with type 2 diabetes (P < 0.0001). Furthermore, insulin resistance ranged from 0.8 to 2.0 (P = 0.0007), from 1.9 to 3.2 (P = 0.842), and from 1.5 to 2.9 (P < 0.0001), respectively. This twofold variation in HOMA estimates from the various insulin assays studied in serum may be significant metabolically. Insulin was 15% lower in heparinized plasma (used in the original HOMA study) compared with serum, which is now more commonly used. β-Cell function differed by 11% and insulin resistance by 15% when estimates derived from specific insulin were calculated using the RIA rather than the SI calculator. CONCLUSIONS—To enable comparison of HOMA estimates among individuals and different research studies, preanalytical factors and calculator selection should be standardized with insulin assays traceable to an insulin reference method procedure.

Hypertension in Diabetes Study IV. Therapeutic requirements to maintain tight blood pressure control Hypertension in Diabetes Study Group

Summary We report the efficacy of therapy over 5 years follow-up in 758 non-insulin-dependent diabetic patients in a prospective, randomised controlled study of therapy of mild hypertension. Patients were recruited who on antihypertensive therapy had systolic blood pressure over 150 mmHg or diastolic over 85 mmHg, or if not on therapy had systolic blood pressure over 160 mmHg or diastolic over 90 mmHg. Their mean blood pressure at entry to the study was 160/94 mmHg at a mean age of 57 years. They were allocated to tight control (aiming for systolic < 150/diastolic < 85 mmHg) or to less tight control (aiming for systolic < 180/ diastolic < 105 mmHg). The tight control group were allocated to primary therapy either with a beta blocker (atenolol) or with an antiotensin converting enzyme inhibitor (captopril), with addition of other agents as required. Over 5 years, the mean blood pressure in the tight control group was significantly lower (143/82 vs 154/88 mmHg, p < 0.001). No difference was seen between those allocated to atenolol or captopril. The proportion of patients requiring three or more antihypertensive therapies to maintain tight control in those allocated to atenolol or captopril increased from 16 and 15 %, respectively at 2 years to 25 and 26 %, respectively at 5 years, whereas in the less tight control group at 2 and 5 years only 5 and 7 %, respectively required three or more therapies. There was no difference in the incidence of side effects or hypoglycaemic episodes between those allocated to atenolol or captopril, but those allocated to atenolol increased their body weight by a mean of 2.3 kg compared with 0.5 kg in those allocated to captopril (p < 0.01). Allocation to atenolol was also associated with small increases in triglyceride, and decreases in LDL and HDL cholesterol, which are of uncertain clinical relevance. The study is continuing to determine whether the improved blood pressure control, which was obtained, will be beneficial in maintaining the health of patients by decreasing the incidence of major clinical complications, principally myocardial infarction and strokes, and microvascular complications, such as severe retinopathy requiring photocoagulation and deterioration of renal function. [Diabetologia (1996) 39: 1554–1561]

Parallel changes of proinsulin and islet amyloid polypeptide in glucose intolerance

Elevated proinsulin secretion and islet amyloid deposition are both features of Type 2 diabetes but their relationship to beta-cell dysfunction is unknown. To determine if islet amyloid polypeptide (IAPP) secretion is disproportionate with other beta-cell products at any stage of glucose intolerance, 116 subjects were studied. Non-diabetic subjects with equivalent body mass index (BMI) were assigned to three groups, (i) normal fasting glucose, fpg<5.5 mmol l(-1); (ii) intermediate fasting glucose, fpg> or =5.5<6.15 mmol l(-1); (iii) impaired fasting glucose (IFG), fpg> or =6.1<7.0 mmol l(-1). Diabetic subjects were divided according to therapy (9 diet, 19 tablet, and 11 insulin). IAPP, C-peptide and proinsulin were measured fasting and at the end of a 1-h glucose infusion. Fasting C-peptide, IAPP and proinsulin were significantly elevated in the IFG group compared with the other non-diabetic groups (P<0.02); fasting IAPP/C-peptide and proinsulin/C-peptide were 1-2% in all non-diabetic groups. Fasting and 1-h proinsulin and proinsulin/C-peptide were higher in diabetic compared with non-diabetic subjects (P<0.01). IAPP and IAPP/C-peptide in diabetic groups were similar to that in non-diabetic subjects but reduced in the insulin-treated group (P<0.01). Proinsulin was disproportionately increased compared with C-peptide and IAPP in Type 2 diabetes particularly in severe beta-cell failure implying more than one concurrent beta-cell pathology.

Comparison of IFCC-calibrated HbA1c from laboratory and point of care testing systems

OBJECTIVE WHO, IDF and ADA recommend HbA(1c) ≥6.5% (48 mmol/mol) for diagnosis of diabetes with pre-diabetes 6.0% (42 mmol/mol) [WHO] or 5.7% (39 mmol/mol) [ADA] to 6.4% (47 mmol/mol). We have compared HbA(1c) from several methods for research relating glycaemic markers. RESEARCH DESIGN AND METHODS HbA1c was measured in EDTA blood from 128 patients with diabetes on IE HPLC analysers (Bio-Rad Variant II NU, Menarini HA8160 and Tosoh G8), point of care systems, POCT, (A1cNow+ disposable cartridges and DCA 2000(®)+ analyser), affinity chromatography (Primus Ultra2) and the IFCC secondary reference method (Menarini HA8160 calibrated using IFCC SRM protocol). RESULTS Median (IQ range) on IFCC SRM was 7.5% (6.8-8.4) (58(51-68) mmol/mol) HbA(1c) with minimum 5.3%(34 mmol/mol)/maximum 11.9%(107 mmol/mol). There were positive offsets between IFCC SRM and Bio-Rad Variant II NU, mean difference (1SD), +0.33%(0.17) (+3.6(1.9) mmol/mol), r(2)=0.984, p<0.001 and Tosoh G8, +0.22%(0.20) (2.4(2.2) mmol/mol), r(2)=0.976, p<0.001 with a very small negative difference -0.04%(0.11) (-0.4(1.2) mmol/mol), r(2)=0.992, p<0.001 for Menarini HA8160. POCT methods were less precise with negative offsets for DCA 2000(®)+ analyser -0.13%(0.28) (-1.4(3.1) mmol/mol), r(2)=0.955, p<0.001 and A1cNow+ cartridges -0.70%(0.67) (-7.7(7.3) mmol/mol), r(2)=0.699, p<0.001 (n=113). Positive biases for Tosoh and Bio-Rad (compared with IFCC SRM) have been eliminated by subsequent revision of calibration. CONCLUSIONS Small differences observed between IFCC-calibrated and NGSP certified methods across a wide HbA(1c) range were confirmed by quality control and external quality assurance. As these offsets affect estimates of diabetes prevalence, the analyser (and calibrator) employed should be considered when evaluating diagnostic data.

Can HbA1c detect undiagnosed diabetes in acute medical hospital admissions

OBJECTIVE To study hyperglycaemia in acute medical admissions to Irish regional hospital. RESEARCH DESIGN AND METHODS From 2005 to 2007, 2061 white Caucasians, aged >18 years, were admitted by 1/7 physicians. Those with diabetes symptoms/complications but no previous record of hyperglycaemia (n=390), underwent OGTT with concurrent HbA1c in representative subgroup (n=148). Comparable data were obtained for 108 primary care patients at risk of diabetes. RESULTS Diabetes was diagnosed immediately by routine practice in 1% (22/2061) [aged 36 (26-61) years (median IQ range)/55% (12/22) male] with pre-existing diabetes/dysglycaemia present in 19% (390/2061) [69 (58-80) years/60% (235/390) male]. Possible diabetes symptoms/complications were identified in 19% [70 (59-79) years/57% (223/390) male] with their HbA1c similar to primary care patients [54 (46-61) years], 5.7 (5.3-6.0)%/39 (34-42)mmol/mol (n=148) vs 5.7 (5.4-6.1)%/39 (36-43)mmol/mol, p=0.35, but lower than those diagnosed on admission, 10.2 (7.4-13.3)%/88 (57-122)mmol/mol, p<0.001. Their fasting plasma glucose (FPG) was similar to primary care patients, 5.2 (4.8-5.7) vs 5.2 (4.8-5.9) mmol/L, p=0.65, but 2hPG higher, 9.0 (7.3-11.4) vs 5.5 (4.4-7.5), p<0.001. HbA1c identified diabetes in 10% (15/148) with 14 confirmed on OGTT but overall 32% (48/148) were in diabetic range on OGTT. The specificity of HbA1c in 2061 admissions was similar to primary care, 99% vs 96%, p=0.20, but sensitivity lower, 38% vs 93%, p<0.001 (63% on FPG/23% on 2hPG, p=0.037, in those with possible symptoms/complications). CONCLUSION HbA1c can play a diagnostic role in acute medicine as it diagnosed another 2% of admissions with diabetes but the discrepancy in sensitivity shows that it does not reflect transient/acute hyperglycaemia resulting from the acute medical event.

Algorithm combining HbA1c and fasting plasma glucose for screening subjects for OGTT: Authors' response

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