Young-onset type 2 diabetes and younger current age: increased susceptibility to retinopathy in contrast to other complications.

BACKGROUND: Type 2 diabetes diagnosed during youth and early adulthood is aggressive and associated with a high burden of vascular complications. The increase in complications is often attributed to long disease duration and poor metabolic control. Whether people with young-onset type 2 diabetes are inherently more susceptible to long-term complications than those diagnosed in later adulthood is unclear. METHODS: Prospective data from 3322 individuals, diagnosed between the age of 15 and 70 years and collected 10-25 years after diabetes diagnosis, were analysed. The cross-sectional associations between age at diagnosis and microvascular and macrovascular complications were analysed using logistic regression models, adjusted for duration of diabetes exposure and metabolic risk factors including blood pressure, cholesterol and updated mean HbA1c . RESULTS: The prevalence of retinopathy was highest in those with young-onset type 2 diabetes (diagnosed at age 15 to <40 years). After 10-15 years' diabetes duration, the adjusted odds ratio for retinopathy in this population was 2.8 (95% CI 1.9-4.1; reference group those diagnosed at 60 to <70 years of age). The odds of retinopathy remained higher in people with young-onset type 2 diabetes after longer durations of diabetes exposure; the odds decreased with increasing age at diagnosis. This pattern was not observed in models of other complications: after 10-15 years' diabetes exposure, the adjusted odds ratios for albuminuria, peripheral neuropathy and macrovascular disease in people with young-onset type 2 diabetes were 0.5 (95% CI 0.4-0.8), 0.7 (95% CI 0.5-1.1) and 0.2 (95% CI 0.1-0.3), respectively. CONCLUSION: After accounting for disease duration and other important confounders, people with type 2 diabetes diagnosed in youth and early adulthood (or with a younger current age) appeared to be inherently more susceptible to retinopathy. For other complications, adjusted risk appears highest in the oldest age of diagnosis group. These data have screening and treatment target implications.

Zinc transporter 8 autoantibodies: what is their clinical relevance in gestational diabetes?

AIMS: To investigate the prevalence, clinical significance and antepartum to postpartum trajectory of zinc transporter 8 autoantibodies, a novel marker of islet autoimmunity, in women with gestational diabetes mellitus. METHODS: A total of 302 consecutive women attending a multi-ethnic Australian gestational diabetes clinic were prospectively studied. Zinc transporter 8 autoantibodies were measured at gestational diabetes diagnosis and 3 months postpartum using an enzyme-linked immunosorbent assay, and were correlated with maternal phenotype, antepartum and postpartum glucose tolerance, treatment and perinatal outcomes. RESULTS: Of the 302 women, 30 (9.9%) were positive for one islet autoantibody antepartum. No participant had multiple islet autoantibodies. Zinc transporter 8 autoantibodies were the most prevalent autoantibody [zinc transporter 8 autoantibodies: 13/271 women (4.8%); glutamic acid decarboxylase 7/302 women (2.3%); insulinoma-associated antigen-2: 6/302 women (2.0%); insulin: 4/302 women (1.3%)]. Zinc transporter 8 autoantibody positivity was associated with a higher fasting glucose level on the antepartum oral glucose tolerance test, but not with BMI, insulin use, perinatal outcomes or postpartum glucose intolerance. Five of the six women who tested positive for zinc transporter 8 autoantibodies antepartum were negative for zinc transporter 8 autoantibodies postpartum, which corresponded to a significant decline in titre antepartum to postpartum (26.5 to 3.8 U/ml; P=0.03). This was in contrast to the antepartum to postpartum trajectory of the other islet autoantibodies, which remained unchanged. CONCLUSIONS: Zinc transporter 8 autoantibodies were the most common islet autoantibody in gestational diabetes. Zinc transporter 8 autoantibody positivity was associated with slightly higher fasting glucose levels and, unlike other islet autoantibodies, titres declined postpartum. Zinc transporter 8 autoantibodies may be a marker for islet autoimmunity in a proportion of women with gestational diabetes, but the clinical relevance of zinc transporter 8 autoantibodies in pregnancy and gestational diabetes requires further investigation.

Dipeptidyl peptidase-4 inhibitors as a third-line oral antihyperglycaemic agent in patients with type 2 diabetes mellitus: the impact of ethnicity.

Aims. The aim of this study is to examine the efficacy of adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to patients with type 2 diabetes inadequately controlled by metformin and sulphonylurea combination treatment. The response of Asian and non-Asian patients to this regimen was also examined. Methods. The medical and computerized records of 80 patients were examined. These patients had baseline HbA1c levels ranging from 7.0 to 12.5% and had a DPP-4 inhibitor add-on therapy for a minimum period of 12 weeks. The primary endpoint was the change in HbA1c level before and after DPP-4 inhibitor treatment. Results. During oral triple therapy, there was a reduction of HbA1c from 8.3% (7.7-8.9) to 7.2% (6.8-7.6) and 26 patients (32.5%) achieved an HbA1c <7%. Poor baseline glycaemic control, lower BMI, and younger age were associated with a better response, but duration of diabetes and gender did not affect outcome. The HbA1c reduction was not different between Asians and non-Asians group [-1.00% (0.6-1.3) vs -0.90% (0.4-1.6)]. Conclusions. DPP-4 inhibitor as a third-line add-on therapy can achieve significant glycaemic improvement in patients with type 2 diabetes inadequately controlled on the combination of metformin and sulphonylurea. The improvement in HbA1c was similar between Asian and non-Asian patients.

Age of diabetes diagnosis and diabetes duration associate with glycated haemoglobin.

An earlier age of diagnosis (r=-0.28, p<0.0001) and longer duration of type 2 diabetes (r=0.26, p<0.0001) were each found to correlate with higher HbA1c level, on analysis of a diabetes centre database in people under regular shared care. When combined, these biological variables strongly associate with the current HbA1c level.

Beyond ONTARGET: angiotensin-converting enzyme inhibition and angiotensin II receptor blockade in combination, a lesser evil in some?

AIM: Following the recent Ongoing Telmistartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) finding of adverse renal outcomes, dual renin-angiotensin blockade has fallen out of favour, despite antihypertensive and antiproteinuric efficacy. However, in high-risk severe hypertension, not studied in ONTARGET, whether combination treatment should be withheld or withdrawn is not clear. We examine the renal effects of angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) monotherapy versus combination therapy in patients with type 2 diabetes and varying degrees of hypertension. METHODS: Subjects attending a hospital diabetes centre were selected as case (combination therapy, n = 120) and control (monotherapy, n = 480). Subjects were matched for age, gender, ethnicity, estimated glomerular filtration rate (eGFR), blood pressure (BP) and study duration. Patients were stratified by BP, hypertension stage 1 (BP < 160/100, n = 506) and stage 2 (≥160/100, n = 94), and by treatment group. Data were analysed for the primary renal outcome of eGFR decline ≥20 ml/min, over a median of 3.7 years. RESULTS: In keeping with the ONTARGET study, for stage 1 hypertension, combination treatment is significantly worse than monotherapy for the primary outcome of eGFR decline ≥20 ml/min (20 vs. 10.7%, p = 0.01). In contrast, for stage 2 hypertension, this endpoint was reached less often for combination versus monotherapy (12.0 vs. 23.2%, p = 0.2). Combination treatment was also not detrimental in patients with proteinuria or eGFR < 60 ml/min and was associated with fewer macrovascular events. CONCLUSION: Given that hypertension control is paramount and in the spirit of primum non nocere, these data are reassuring should clinicians choose to use ACE-I and ARB combination therapy in the very hypertensive diabetic patient.

Mitochondrial DNA content in peripheral blood monocytes: relationship with age of diabetes onsetand diabetic complications.

AIMS/HYPOTHESIS: We examined whether age of type 2 diabetes onset is related to mitochondrial DNA content in peripheral blood monocytes (PBMCs). METHODS: PBMCs were isolated from 65 patients with type 2 diabetes. To minimise age as a confounder, only patients aged >or=50 years were studied. Sample mitochondrial DNA (mtDNA) content was determined by amplification of the mitochondrial gene CYT-B (also known as MT-CYB) and adjusted for single-copy nuclear control genes (36B4 [also known as RPLPO] and GAPDH). RESULTS: Age of diabetes onset ranged from 25 to 69 years. There was a significant positive relationship between age of diabetes onset in quartiles and mtDNA content for the whole group (p = 0.02 for trend). When stratified by the presence of diabetes complications, a strong positive relationship was observed between age of diagnosis and mtDNA content for participants without diabetic complications (r = 0.7; p = 0.0002), but not for those with complications (r = -0.04; p = 0.8). Multivariate analysis confirmed age of onset and complication status as independent determinants. There was co-linearity between age of onset and disease duration, with similar relationships also seen between duration and mtDNA content. CONCLUSIONS/INTERPRETATION: An earlier age of type 2 diabetes onset is associated with a lower PBMC mtDNA content, but only in patients without diabetes complications. This may reflect a differing biology of PBMC mtDNA in those with early-onset diabetes and those who are prone to complications. PBMC mtDNA depletion may accelerate diabetes onset; however the independent effect of diabetes duration remains to be evaluated.

Lipohypertrophy: does it matter in daily life? A study using a continuous glucose monitoring system.

AIMS: To use continuous glucose monitoring (CGMS) to compare glucose profiles in people with type 1 diabetes following injection of insulin into an area affected by lipohypertrophy vs. an area not affected by lipohypertrophy. METHODS: Eight patients with type 1 diabetes underwent 72 h of CGMS while following a standardized diet and injecting all insulin either into an area with or without lipohypertrophy. Patients underwent two testing periods in random order, separated by 4 days. On day 1 of each test subjects were admitted for measurement of insulin and plasma glucose levels immediately prior to, and hourly for 4 h following, a standardized lunch. RESULTS: Insulin area under the curve (AUC)(0-4 h) was similar for both test periods; 656; interquartile range (IQR): 518-1755 (normal tissue) vs. 602; IQR: 382-1436 (lipohypertrophic tissue), z = 1.7, p = 0.09. There was also no difference in the median time to maximal insulin concentration (Time(max) 2 h; IQR: 2-3 h; z = 0.6; p = 0.6). There was a 37.5% increase in mean plasma glucose levels following a standardized meal; however this was not significant between sites (AUC(0-4 h)t = -1.7; p = 0.1). Moreover, there was no difference in CGMS profiles (AUC(1-72 h)t = -0.9; p = 0.4) across the 72-h monitoring period. Overall the prevalence of hypoglycaemia (CGMS readings < 4 mmol/l) was similar between injection sites (11.6 vs. 10.6%, p = 0.1). CONCLUSION: The pharmacokinetic and pharmacodynamic effect of injecting into lipohypertrophic tissue is small in comparison to the usual clinical variation observed with insulin injections.

Hypovitaminosis D in Chinese type 2 diabetes: lack of impact on clinical metabolic status and biomarkers of cellular inflammation.

OBJECTIVE: Low vitamin D (25 OH vitamin D) is implicated in the development of diabetes and the metabolic syndrome. We examined whether hypovitaminosis D has a clinically significant impact on glycaemia, metabolic status and inflammatory markers in Chinese patients with established type 2 diabetes. METHODS: Characteristics of 109 patients aged over 50 years were stratified by 25 OH vitamin D status. Patients identified as 25 OH vitamin D deficient (or= 0.4 for all) and no association between 25OHVitD and ferritin or hsCRP (p >or= 0.3 for all). Neither BMI nor the metabolic syndrome affected the incremental rise in 25OHVitD levels during supplementation. CONCLUSION: There is no relationship between hypovitaminosis D and metabolic control or inflammatory markers in established type 2 diabetes.This suggests that at least in Chinese populations, the effect of low vitamin D is not clinically significant once diabetes is established. Future 25OHVitD intervention trials should therefore focus on prevention in pre-diabetes.

The long-term impact of ferritin level on treatment and complications of type 2 diabetes.

AIM: To investigate if high-serum ferritin has long-term impact on response to treatment and the development of diabetic complications in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We analysed the record of 90 consecutive type 2 diabetic subjects who had serum ferritin level determined soon after diagnosis of diabetes and who also had long-term follow-up data. RESULTS: Patients with higher serum ferritin level had slightly worse triglyceride, blood pressure and liver enzyme levels at the end of follow up. However, ferritin level had no impact on the initial or final requirements for diabetic medication and the development of diabetic complications. CONCLUSIONS: Although elevated serum ferritin is a marker of insulin resistance and chronic inflammation, it is not necessarily a bad prognostic indicator that should affect the clinician's approach to management.

The metabolic syndrome in type 2 diabetes: When does it matter?

AIMS: Young adults with type 2 diabetes (T2Dm) present the clinician with the problem of when to start therapies for the primary prevention of vascular disease and how to identify those at most vascular risk. We examine whether the metabolic syndrome (MetS) can be a useful clinical tool to stratify vascular risk in this context. METHODS: Data were collected from 5928 subjects with T2Dm, and subjects were categorized as having MetS by World Health Organization criteria (body mass index criteria modified for Asians using >23 kg/m2). The prevalence of macrovascular disease was examined by MetS status and age. RESULTS: The overall MetS prevalence was 72.3%. MetS was associated with an increased prevalence of ischaemic heart disease (IHD) (17.2% MetS vs. 11.6% no MetS, p < 0.0001), coronary artery bypass graft (7.6 vs. 4.7%, p < 0.0003), peripheral vascular disease (PVD) (4.7 vs. 3.7%, p = 0.08) and stroke (6 vs. 3.9%, p = 0.002) across all age groups. MetS subjects had an IHD prevalence equivalent to that seen in subjects who were one decade older without MetS. The most significant impact of MetS was for the age group of 40-49 years with much lesser impact seen with progressively increasing age [odds ratio (OR) = 2.1 for IHD in MetS compared with no MetS at age 40-50 years, p < 0.05; falling progressively to OR = 1.5 at age >70 years, p > 0.05]. Similar trends were seen for coronary artery by-pass graft (CABG) and PVD. There was a strong relationship between the number of MetS risk factors and IHD prevalence (r = 0.99, p = 0.0001). CONCLUSIONS: These data suggest that MetS is particularly useful in stratifying vascular risk in younger T2Dm patients and in those with a high number of MetS components. For patients with MetS, especially those with a full house of MetS risk factors, commencing risk-lowering interventions 10 years earlier than their MetS-free counterparts could be considered.

Which diabetic patients should receive podiatry care? An objective analysis.

INTRODUCTION: Diabetes is the leading cause of lower limb amputation in Australia. However, due to limited resources, it is not feasible for everyone with diabetes to access podiatry care, and some objective guidelines of who should receive podiatry is required. METHODS: A total of 250 patients with neuropathy (Biothesiometer; Biomedical Instruments, Newbury, Ohio, USA) ( > 30, age < 65)) but no active foot lesion, and 222 without neuropathy matched for age, type of diabetes, gender and duration, was followed prospectively for 2 years. Sensation was also tested using a 10 g Semmes Weinstein monofilament (Royal Prince Alfred Hospital Diabetes Centre). After the baseline examination, patients were contacted at 6 months and thereafter yearly to determine ulcer status. Incidence of foot ulceration across different risk categories was calculated using Kaplan-Meier survival curve. Log-rank test and Cox's proportional model were used to compare groups. The Number Needed to Treat (NNT) to prevent one ulcer per year was calculated using the standard formulae. RESULTS: During the follow-up period, 34 new ulcers occurred in the neuropathy group and three ulcers in the control group (chi2 (1df) = 21.3; P < 0.0001), equating to an annual incidence of 6.3% and 0.5%, respectively. Fifty-four per cent of the ulcers were due to trauma from footwear. Further stratification of the neuropathy group showed annual incidence of ulceration to be 4% for those with abnormal biothesiometer reading, but who could still feel the monofilament, 10% for those who cannot feel the monofilament and 26% for those with previous ulceration or amputation. Predictors of ulceration were past history of ulceration/amputation (chi2 = 27.8; P < 0.0001) and the presence of neuropathy (chi2 = 4.7; P = 0.03). Assuming a 55% relative risk reduction in ulceration from podiatry care (mean of estimates from 10 reports), the NNT to prevent one foot ulcer per year was: no neuropathy (vibration perception threshold (VPT) < 30)), NNT = 367; neuropathy (VPT > 30) alone, NNT = 45; +cannot feel monofilament, NNT = 18; +previous ulcer/amputation, NNT = 7. CONCLUSION: Provision of podiatry care to diabetic patients should not be only economically based, but should also be directed to those with reduced sensation, especially where there is a previous history of ulceration or amputation.

Strong family history predicts a younger age of onset for subjects diagnosed with type 2 diabetes.

AIMS: Age of onset of type 2 diabetes is becoming earlier and with it there is an increase in the development of chronic complications. This study examined the relationship between the strength of family history of diabetes on (i) age of diabetes onset and (ii) prevalence of diabetic complications. RESEARCH DESIGN AND METHODS: Data on family history of diabetes and age of diabetes onset were prospectively collected on 5193 subjects. Family members were deemed to include grandparents, parents, siblings, aunts/uncles and children. To adjust for family size and to assess effects of pathway to diagnosis, we also contacted a subset of 180 patients selected on the basis of the strength of family histories of diabetes. A full assessment for diabetic complications including retinopathy, neuropathy and renal and macrovascular status was performed for the total cohort. RESULTS: The more cases of diabetes found in a family, the younger the age of onset of type 2 diabetes. This phenomenon does not appear to be due to patients with strong family history of diabetes being more concerned about the possibility of having diabetes. The effect of strong family history is also evident in many ethnic groups when examined individually, although they differ from each other in their characteristic age of onset of diabetes. Once adjusted for duration of diabetes, strength of family history does not appear to affect metabolic profiles or prevalence of chronic complications. CONCLUSIONS: There is a strong relationship between the number of affected family members with diabetes and age of developing diabetes. The genetic and environmental factors underlying this phenomenon remain to be elucidated. However, it may be one of the reasons explaining why type 2 diabetes is affecting younger people worldwide.

Retinopathy in a Chinese population with type 2 diabetes: factors affecting the presence of this complication at diagnosis of diabetes.

This study examined the prevalence of retinopathy in 2131 patients with type 2 diabetes attending a Beijing hospital for the first time. The median age of patients was 58 years (IQR 50-65). The overall prevalence of retinopathy was 27.3% (95% CI: 25.4-29.2) and for proliferative retinopathy 7.8% (95% CI: 6.7-8.9). When all patients were considered together, duration of diabetes (OR=1.8; P=0.001) and albumin excretion rate (OR=1.5; P=0.019) were independent risk factors for retinopathy. Blue-collar occupation (OR=1.5; P=0.047) and blood pressure (OR=1.2; P=0.021) were additional risk factors for non-proliferative and proliferative retinopathy respectively. Amongst the 773 newly diagnosed patients, 21% (95% CI: 17.8-23.6) already had retinopathy. The median age of those patients with retinopathy at diagnosis of diabetes was 3 years higher that those without retinopathy, and blue-collar workers (OR=2.2; P=0.012) as well as female gender were particularly at risk (OR=2.0; P=0.033). There was a strong correlation between duration of diabetes with the presence of retinopathy (r=0.95; P=0.01). By extrapolation, it could be estimated that some degree of hyperglycaemia might have been present for more than 20 years before diabetes was diagnosed. These findings emphasise the importance of earlier diagnosis of diabetes and its complications, especially in socially disadvantaged groups.

TBI or not TBI: that is the question. Is it better to measure toe pressure than ankle pressure in diabetic patients?

AIMS: Measurement of ankle blood pressure is a simple method of assessing lower limb arterial blood supply. However, its use in diabetes has been questioned due to the presence of medial artery calcification. Measurement of toe blood pressure has been advocated as an alternative but it is technically more difficult. The aim of this study was to obtain information to guide clinicians as to when pressure measurements should be taken at the toe. METHODS: Ankle brachial index (ABI) and toe brachial index (TBI) were measured by Doppler ultrasound, or photoplethysmography on 174 subjects with diabetes and 53 control subjects. The Bland and Altman method, and the Cohen's method of measuring agreement between two tests were used to compare ABI with TBI. RESULTS: The mean differences between ABI and TBI in control and diabetic subjects are 0.40 +/- 0.13 and 0.37 +/- 0.15, respectively. Nearly all diabetic patients with an ABI < 1.3 have an ABI-TBI gradient falling within the normal range established from the non-diabetic cohort. In contrast, the majority of diabetic subjects with an ABI > or = 1.3 have ABI-TBI differences outside this range. When patients are categorized according to ABI and TBI, there is also good agreement between the tests when ABI is low or normal (84% and 78% agreement, respectively), but not when ABI is elevated. CONCLUSION: In the majority of patients with diabetes, assessment of TBI conveys no advantage over ABI in determining perfusion pressure of the lower limbs. Only in those patients with overt calcification, which gives an ABI > or = 1.3, are toe pressure measurements superior. This guideline should simplify assessment and treatment of diabetic patients with disease of the lower limbs. Diabet. Med. 18, 528-532 (2001)

Augmentation of central arterial pressure in Type 2 diabetes.

AIMS: Aortic systolic blood pressure has been shown to be augmented in Type 1 diabetes, indicative of more rapid pulse wave reflection due to increased arterial stiffness. This abnormality is more pronounced in diabetic males. The aim of this study was to examine the effects of diabetes on augmentation of aortic systolic pressure in subjects with Type 2 diabetes. METHODS: Radial artery pressure waveforms were obtained non-invasively by applanation tonometry. A central aortic waveform can be derived using a transfer function obtained from previous studies during cardiac catheterization. A total of 88 subjects with Type 2 diabetes (51 men and 37 women, aged 55.8 years (interquartile range (IR) 49.7-64.1), duration of diabetes 7.5 years (IR 2.4-12.4), HbA1c 7.6% (IR 6.6-8.7)) and 85 controls subjects (40 men and 45 women, aged 55.3 years (IR 44.2-66.4)) were studied. The central aortic waveform allowed determination of the: (i) aortic augmentation index and (ii) subendocardial viability ratio. RESULTS: Similar to Type 1 diabetic subjects, patients with Type 2 diabetes had a significantly higher aortic augmentation index (136.1 +/- 18.0% vs. 128.3 +/- 19.2%, t = 2.8, P = 0.006) and lower subendocardial viability ratio (137.4 +/- 25.0% vs. 155.1 +/- 25.9%; t = 4.6, P = 0.0001) compared with controls. Multivariate analysis identified diabetes as an important determinant of aortic augmentation index (t = 4.0, P = 0.0001). The higher aortic augmentation index was due mainly to the male cohort (t = 2.6; P = 0.01) and was not apparent for females with diabetes (P = 0.2). CONCLUSIONS: Type 2 diabetes is characterized by higher augmentation of aortic systolic pressure and unfavourable ratio of myocardial perfusion to cardiac workload. These results are consistent with increased arterial stiffness. The age-related progression of arterial stiffness is similar in Type 1 and Type 2 diabetes. Anti-hypertensive agents that reduce wave reflection and augmentation may help to prevent systolic hypertension and cardiac hypertrophy in diabetes.

Clustering of cardiovascular risk factors with diabetes in Chinese patients: the effects of sex and hyperinsulinaemia.

OBJECTIVE: This study was designed to investigate factors which affect the clustering of cardiovascular risk factors with diabetes in Chinese patients. RESEARCH DESIGN AND METHODS: Six hundred and fifty-four patients with diabetes were assessed comprehensively for diabetes complications and cardiovascular risk factors in a metropolitan hospital in Beijing, China. Insulin resistance and secretion were also evaluated by measurement of glucose and insulin levels before and after a meal tolerance test. Results were analysed according to patient groups stratified by the number of cardiovascular risk factors coexisting with diabetes. RESULTS: Cardiovascular risk factors were common in Chinese diabetic patients. The clustering of three or more of these factors with diabetes occurred more often than by chance alone and was associated with postprandial hyperinsulinaemia. Patients with a high number of risk factors were more prone to macrovascular events but did not have higher albuminuria. Using the commonly adopted lower threshold for diagnosing obesity and central obesity in women, there were more women with multiple risk factors. However, this disappeared if the same criteria were used for men and women. Even in the presence of diabetes, cardiovascular risk factors were inadequately controlled in most patients. CONCLUSIONS: The concurrence of diabetes and other cardiovascular risk factors which constitute the metabolic syndrome is a common phenomenon in urban Chinese diabetic patients. It is associated with hyperinsulinaemia and possibly the female sex. This study emphasises the importance of public health measures to control cardiovascular risk factors in patients with diabetes.

Response of Charcot's arthropathy to contact casting: assessment by quantitative techniques.

AIMS/HYPOTHESIS: This study used two different methods of quantitative bone scanning to study the relation between activity of Charcot's arthropathy and clinical variables over 12 months. METHODS: Skin temperature of affected and unaffected feet was measured at baseline and every 3 months for 12 months in 17 subjects. Eight subjects underwent a three-phase quantitative bone scan at baseline and 3 monthly for 12 months. Bone isotope uptake in a standard rectangular area over the foot and tibia was analysed by the bilateral scan method (the ratio of isotope uptake of affected and unaffected feet) and the unilateral scan method (the ratio of isotope uptake of affected foot and ipsilateral tibia). The affected foot was placed in a contact cast for an average of 8 months. RESULTS: At presentation the affected foot was hotter than the unaffected foot but the temperature became progressively cooler over 12 months. Median isotope uptake in the affected foot was 2.1% of the injected dose (interquartile range, IQR 1.9-3.0). In both scanning methods the ratio of uptake decreased after casting but at 12 months the affected foot still had more isotope uptake. There was a strong correlation between temperature difference and the ratio of uptake in the bilateral scan method (r = 0.90; p < 0.0001) but when using the unilateral scan method this relation was not significant (r = 0.1;p = 0.6). A strong relation existed between perfusion of the affected foot in the dynamic phase and isotope uptake in the delayed phase of the scans (r = 0.92; p < 0.0001). CONCLUSION/INTERPRETATION: Bone activity and skin temperature of Charcot's arthropathy can be measured quantitatively and both improve over 12 months with contact casting. There is a strong relation between perfusion and disease activity in this condition.

Augmentation of central arterial pressure in type 1 diabetes.

OBJECTIVE: Atherosclerosis is more severe in individuals with diabetes. Whether diabetic subjects have accelerated arterial hardening (i.e., arteriosclerosis) is less clear. Arteriosclerosis increases pulse-wave velocity and can augment central arterial pressure due to early wave reflection. The aim of this study was to determine whether subjects with type 1 diabetes had evidence of increased arterial stiffness by using pulse-wave analysis. RESEARCH DESIGN AND METHODS: Radial artery pressure waveforms were obtained noninvasively by applanation tonometry (PWV Medical Blood Pressure Analysis System, Sydney). A central aortic waveform can be derived by using a transfer function used in previous studies during cardiac catheterization. A total of 89 subjects with type 1 diabetes (46 men and 43 women, aged 34.0 +/- 11.0 years, duration of diabetes 13.1 years [interquartile range 5.8-24.3], HbA1c 8.2 +/- 1.7%) and 95 control subjects (44 men and 51 women, aged 36.1 +/- 12.0 years) were studied. The central aortic waveform allowed the determination of 1) the aortic augmentation index (AAI), a parameter that reflects the degree to which central arterial pressure is augmented by wave reflection, and 2) the subendocardial viability ratio (SEVR), which is a measure of myocardial perfusion relative to cardiac workload. RESULTS: In multivariate analysis, diabetes was an important determinant of AAI (P = 0.001). The higher AAI was mainly evident in the men, for whom diabetes was a highly significant covariate (P = 0.006); this was not the case for diabetic women (P = 0.2). Nondiabetic men had a lower AAI than nondiabetic women (103.7 +/- 18.6 vs. 117.0 +/- 22.3%, respectively, P = 0.002), but this difference was abolished by diabetes (110.7 +/- 18.5 vs. 116.1 +/- 18.7%, respectively, P = 0.2). Subjects with type 1 diabetes had a significantly lower mean SEVR compared with control subjects (139.2 +/- 28.3 vs. 163.6 +/- 27.4%, respectively, P < 0.0001). In multivariate analysis, diabetes was an important determinant of SEVR (P = 0.001). A significant interaction between diabetes and age was evident (P = 0.0001), which suggests that the effect of age is modified by diabetes. CONCLUSIONS: These findings suggest that central systolic blood pressure is increased in relatively young individuals with type 1 diabetes, although myocardial perfusion related to cardiac workload is decreased. These changes can be explained by more rapid pulse-wave velocity resulting from arterial stiffening.

Angiotensin converting enzyme inhibition and arterial endothelial function in adults with Type 1 diabetes mellitus.

AIMS: Arterial endothelial dysfunction is a key early event in atherogenesis, and occurs in asymptomatic adults with Type 1 diabetes mellitus (DM). As angiotensin converting enzyme (ACE) inhibitors have been reported to reverse microvascular endothelial dysfunction acutely, we assessed the longer term effect of ACE inhibition on large vessel endothelial physiology in a randomized, crossover double-blind controlled clinical trial. METHODS: Flow-mediated arterial dilatation (FMD), which is largely due to endothelial release of nitric oxide, was assessed by vascular ultrasound in 20 Type 1 DM subjects with known endothelial dysfunction. These subjects, aged 28+/-5 years, were studied before and after 12 weeks oral therapy with either the ACE inhibitor perindopril 4 mg daily or the diuretic hydrene (triamterene 50 mg with hydrochlorothiazide 25 mg) daily. RESULTS: Although perindopril lowered both systolic and diastolic blood pressure by 2.7/3.2 mmHg, respectively (F3,78 = 4.7, P= 0.006; F3,78 = 3.2, P = 0.03), there was no significant effect of either perindopril or hydrene on FMD (baseline FMD before perindopril 4.6+/-2.5%, after 4.1+/-3.4%, baseline FMD before hydrene 5.4+/-3.6%, after 6.0+/-3.3%; F3,78= 1.9, P=0.1). Glycaemic control deteriorated slightly on hydrene whilst lipid levels, heart rate, resting blood flow and the arterial responses to nitroglycerine, a smooth muscle dilator, were unaffected by the treatment given. CONCLUSION: ACE inhibitor therapy for 3 months did not improve arterial endothelial function in Type 1 DM subjects.

Possible sources of discrepancies in the use of the Semmes-Weinstein monofilament. Impact on prevalence of insensate foot and workload requirements.

OBJECTIVE: The purpose of this study was to evaluate the effects of different testing sites and buckling strengths on the sensitivity and specificity of using the Semmes-Weinstein monofilament to detect patients with insensate foot. The impact on workload required to educate and follow up these high-risk individuals was estimated by modeling in our patient population with a documented status of neuropathy. RESEARCH DESIGN AND METHODS: Using the 5.07/10-g monofilament, one observer tested 132 randomly selected subjects with diabetes at five sites on the right foot. The sensitivity and specificity of each site and combinations of sites in detecting vibration perception threshold > 40 was calculated. In addition, two monofilaments, one with a buckling force of 5 g and the other with a force of 15 g, were compared by testing 200 randomly selected patients. An estimate of the prevalence of insensate foot and workload was made by modeling the findings to the 5,270 patients with neuropathy status registered on our computerized database. RESULTS: Specificity of the 5.07/10-g monofilament to detect insensate foot at each of the five sites is high, at approximately 90%, but there is considerably more variation and lower sensitivity, ranging from 44-71%. Data derived from the use of different combinations of sites showed that more stringent criteria are associated with lower sensitivity but higher specificity. If the foot is considered insensate when either of sites 3 and 4 (plantar aspect of the first and fifth metatarsal heads, respectively) cannot feel the monofilament, there is reasonable sensitivity and specificity (80-86%, respectively). By modeling on our diabetes center population, it can be demonstrated that the choice of different methodologies leads to different conclusions about the prevalence of severe neuropathy, ranging from 3.4 to 29.3%. CONCLUSIONS: Using a combination of sites 3 and 4 for monofilament testing gives a reasonable compromise for time, sensitivity, and specificity. Minor changes in sensitivity and specificity can lead to major changes in the prevalence of neuropathy, with implications for workload.