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.

Efficiency of fish propulsion.

The system efficiency of a self-propelled flexible body is ill-defined, hence we introduce the concept of quasi-propulsive efficiency, defined as the ratio of the power needed to tow a body in rigid-straight condition over the power it requires for self-propulsion, both measured for the same speed. Through examples we show that the quasi-propulsive efficiency is a rational non-dimensional metric of the propulsive fitness of fish and fish-like mechanisms, consistent with the goal to minimize fuel consumption under size and velocity constraints. We perform two-dimensional viscous simulations and apply the concept of quasi-propulsive efficiency to illustrate and discuss the efficiency of two-dimensional undulating foils employing first carangiform and then anguilliform kinematics. We show that low efficiency may be due to adverse body-propulsor hydrodynamic interactions, which cannot be accounted for by an increase in friction drag, as done previously, since at the Reynolds number Re = 5 000 considered in the simulations, pressure is a major contributor to both thrust and drag.

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.

The danger of using inappropriate point-of-care glucose meters in patients on icodextrin dialysis.

AIMS: Icodextrin is a glucose polymer used to maintain an osmotic gradient in peritoneal dialysis. Metabolites of icodextrin are known to cause overestimation of blood glucose in glucose meters using glucose dehydrogenase/pyrroloquinolinequinone systems. The aim of this study is to determine the extent of icodextrin interference in glucose meters using the newer glucose dehydrogenase/NAD or glucose oxidase systems. This has not been established previously. METHODS: Fasting blood samples (n = 4) were spiked with either one icodextrin metabolite (maltose, maltotriose or maltotetraose) or a combination, at various blood concentrations expected during dialysis. Samples were tested in triplicate on: five glucose-meters, a Radiometer® (glucose oxidase/hydrogen peroxide) and laboratory (hexokinase) analysers. Each meter was also tested on blood from six patients undergoing dialysis. Accuracy was evaluated as % Bias = [(meter glucose - laboratory glucose)/laboratory glucose] × 100. RESULTS: A single icodextrin metabolite affected glucose measurements and, in combination, the interferences were additive in the two Accu-Chek® and Optium® Xceed meters by > 10%. Amongst these meters, the Optium Xceed 5-s machine was less affected. Meters using glucose oxidase were least affected by interference. A similar trend in interference was observed in vivo. CONCLUSION: While meters using glucose dehydrogenase/NAD are less affected by icodextrin metabolites, interference can still be demonstrated. The degree of interference can vary in different glucose meters using this enzyme/cofactor system, as seen in the Optium Xceed machines. Icodextrin is an important source of interference that sometimes even experienced professionals are unaware of and which leads to clinically significant errors in insulin dose adjustment. Awareness of this interference and selection of the most appropriate glucose meters are crucial to minimize this hazard.

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.

Monocyte CD147 is induced by advanced glycation end products and high glucose concentration: possible role in diabetic complications.

CD147 is a highly glycosylated transmembrane protein that is known to play a role in regulation of many protein families. It has the unique ability to maintain functional activity in both the membrane bound state and in the soluble form. CD147 is known to play a role in regulation of matrix metalloproteinase (MMP) expression, but whether its expression is affected by the diabetic milieu is not known, and its role in regulation of monocyte MMPs in this environment has not been investigated. Therefore, in this study we investigated the effect of advanced glycation end products (AGEs) and high glucose (HG; 25 mM), on monocyte CD147 expression. Culture of THP-1 monocytes in the presence of AGEs or HG significantly increased CD147 at the gene and protein level. THP-1 cell results were confirmed using freshly isolated monocytes from human volunteers. The effect of AGEs and HG on CD147 expression was also mimicked by addition of proinflammatory cytokines. Addition of AGEs or HG also increased expression of monocyte MMP-1 and MMP-9 but not MMP-2. This increase in MMPs was significantly attenuated by inhibition of CD147 using either a small interfering RNA or an anti-CD147 antibody. Inhibition of NF-κB or addition of antibodies to either TNF-α or the receptor for AGE (RAGE) each significantly prevented in a dose-dependent manner the induction of CD147 gene and protein by AGE and also decreased MMP-1 and MMP-9. This novel result shows that AGEs can induce monocyte CD147 expression, an effect mediated by inflammatory pathways and RAGE. Because MMPs play a role in monocyte migration, inhibition of their regulator CD147 may assist in the prevention of diabetic complications, particularly those where monocyte infiltration is an early initiating event.

Serum MMP-7 is increased in diabetic renal disease and diabetic diastolic dysfunction.

Circulating matrix metalloproteinase (MMP) levels may correlate with diabetic complications. Whether they are changed in early diabetic cardiomyopathy is not known and was examined in this study. TIMP-1 and collagen degradation products were also measured. Results from subjects with and without diastolic dysfunction were compared with those obtained for patients with varying stages of diabetic renal disease. Patients with type 2 diabetes with or without diastolic dysfunction with varying degrees of renal disease were recruited for this study. Age-matched non-diabetic subjects served as controls. MMPs (-1, -3 and -7) and TIMP-1 were measured by ELISA, MMP-2 and -9 by zymography and collagen degradation products by radioimmunoassay. Differences in the pattern of MMPs/TIMPs and collagen degradation products were observed. The most consistent change was in totalMMP-7, which was increased in those with diastolic dysfunction and those with macroalbuminuria. MMP-7 correlated with cardiac function (p<0.05 vs control, in those with diastolic dysfunction), and renal filtration function (p<0.05 vs control). In summary, we have identified novel relationships between serum MMP-7 and diabetic complications specifically in renal disease and in diastolic dysfunction. How increased circulating MMP-7 is associated with these diabetic microvascular complications and the significance of these findings will require prospective studies.

A novel primate model of delayed wound healing in diabetes: dysregulation of connective tissue growth factor.

AIMS/HYPOTHESIS: Chronic non-healing wounds are a common complication of diabetes. Prolonged inflammation and decreased matrix accumulation may contribute. Connective tissue growth factor (CTGF) is induced during normal wound healing, but its regulation in diabetic wounds is unknown. We developed a primate model for the study of in vivo wound healing in baboons with long diabetes duration. METHODS: Drum implants were placed subcutaneously into thighs of diabetic and non-diabetic control baboons. After 2 and 4 weeks the skin incision sites were removed for measurement of breaking strength and epithelial thickness. Drum implants were removed for analysis of granulation tissue and inflammatory cells, CTGF and tissue inhibitor of matrix metalloproteinase (TIMP-1). Degradation of added CTGF by wound fluid was also examined. RESULTS: Healed incision site skin was stiffer (less elastic) in diabetic baboons and epithelial remodelling was slower compared with controls. Granulation tissue from diabetic baboons was reduced at 2 and 4 weeks, with increased vessel lumen areas at 4 weeks. Macrophages were reduced while neutrophils persisted in diabetic tissue. In diabetic wound tissue at 4 weeks there was less CTGF induced, as shown by immunohistochemistry, compared with controls. In contrast, immunoreactive fragments of CTGF were significantly increased in whole tissue lysate in diabetic baboons, suggesting that CTGF is redistributed in diabetes from granulation tissue into wound fluid. When recombinant human CTGF was co-incubated with wound fluid, increased CTGF degradation products were observed in both control and diabetic samples. CONCLUSIONS/INTERPRETATION: This baboon model of wound healing reflects the abnormal microenvironment seen in human diabetic wounds and provides insights into the dysregulation of CTGF in diabetic wounds.

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.

A comparison of diabetes clinics with different emphasis on routine care, complications assessment and shared care.

OBJECTIVE: To compare clinical outcomes of patients attending diabetes clinics with different models of care. METHODS: Diabetes centres which participated in the Australian National Diabetes Information Audit and Benchmarking (ANDIAB) data collection were invited to nominate whether they provided (i) routine diabetes care only (model A), (ii) routine care and structured annual complications screening (model B) or (iii) annual review and complications screening in a system of shared care with general practitioners (model C). De-identified case data were extracted from ANDIAB and outcomes according to the three clinic models were compared. RESULTS: Data on 3052 patients from 18 diabetes centres were analysed. Centres which practised annual complications screening (models B and C) had higher rates of nephropathy and lipid screening and a higher rate of attainment of recommended blood pressure and glycated haemoglobin (HbA(1c)) targets. The implementation of appropriate treatment for patients who had not attained the targets was similar for all three clinic models. CONCLUSIONS: In our study, clinic models which incorporate a system of structured complications screening were more likely to have met screening guidelines. Patients in a shared-care model were at least as likely to have met management targets as those attending diabetes clinics for their routine care. Therefore, a system of shared care by general practitioners supported by annual review at a diabetes clinic may be an acceptable model which improves the capacity to manage large numbers of people with diabetes, without loss of quality of care.

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.

Diastolic dysfunction and abnormalities of the microcirculation in type 2 diabetes.

AIM: Diabetic cardiomyopathy is an increasingly recognized entity. The pathogenic factors that may contribute to its development, especially the earliest changes of diastolic dysfunction (DD), have not been clearly defined. Microvessel dysfunction and upregulation of profibrotic growth factors have been described as possible causes. The aim of this study was therefore to determine whether microvascular dysfunction and/or upregulation of the profibrotic connective tissue growth factor (CTGF) are associated with subclinical DD in subjects with type 2 diabetes. METHODS: Forty subjects with type 2 diabetes and 20 age-matched non-diabetic controls, all of whom had no clinical evidence of ischaemic heart disease, cardiac failure or echo evidence of systolic ventricular dysfunction, were recruited. Microvascular function was measured by laser Doppler velocimetry, with examination of endothelium-dependent increase in blood flow following iontophoresis of acetylcholine (ACh) and endothelium-independent increase in blood flow in response to the nitric oxide donor sodium nitroprusside (SNP). CTGF levels were determined by Western immunoblotting. RESULTS: DD determined on the basis of traditional echocardiographic criteria was similar in diabetic subjects compared with controls (28 vs. 20%, p = 0.5). Using left ventricular myocardial tissue Doppler-based indices for DD, the E/E' and the E'/A' ratios (where E is the flow related to early ventricular filling and E' and A' are early and late diastolic velocities, respectively) in diabetic subjects revealed evidence of more DD than controls (p = 0.046 and p = 0.007 respectively) . Comparing controls with no DD by conventional echocardiographic criteria (Group I), diabetes and no DD (Group II) and diabetes with DD (Group III), there was a significant trend in reduction of both endothelium-dependent (ACh fold change; p = 0.04) and endothelium-independent (SNP fold change; p = 0.0004) blood flow across the groups. The ACh and SNP responses, however, were not correlated significantly with quartiles of the E/E' ratio or the E'/A' ratio. CTGF plasma levels did not differ across the groups and CTGF did not correlate with parameters of microvascular function. CONCLUSIONS: This study indicates that while there is a significant association between DD and measures of microvascular function, the relationship between endothelial dysfunction, CTGF and subtle measures of DD is not strong. Other factors are therefore likely to play an important role in the early pathogenesis of subclinical cardiac DD in type 2 diabetes.

Advanced glycation end products decrease mesangial cell MMP-7: a role in matrix accumulation in diabetic nephropathy?

Increased extracellular matrix material is a pathological hallmark of diabetic nephropathy. In addition to collagens, a variety of non-collagenous glycoproteins such as fibronectin also accumulate in the kidney of diabetics. The effect of diabetes on degradative pathways, in particular those involving non-collagenous proteins, are relatively unexplored. In this study, we determined the expression of the major matrix metalloproteinase (MMP) responsible for degrading the non-collagenous matrix glycoprotein fibronectin. Furthermore, the modulation of these MMPs by advanced glycation end products (AGE), a key factor in the diabetic milieu, was explored. Exposure of mesangial cells to AGEs led to a significant reduction in MMP-7, but not MMP-3 or -10. MMP-7 expression was normalized by both aminoguanidine, an inhibitor of glycation product formation, or by a neutralizing anti-transforming growth factor-beta (TGF-beta) antibody. In streptozotocin-induced diabetic rats, the diminution in MMP-7 expression and excessive fibronectin accumulation were attenuated by aminoguanidine. Humans with type 2 diabetes and nephropathy displayed similar alterations in MMP-7 to their rodent counterparts. Our findings suggest that diminished expression of the glycoprotein-degrading enzyme, MMP-7, may play a role in fibronectin accumulation in the diabetic kidney in response to AGEs and/or TGF-beta.

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.

Glargine is superior to neutral protamine Hagedorn for improving glycated haemoglobin and fasting blood glucose levels during intensive insulin therapy.

AIM: To compare glycaemic control and symptomatic hypoglycaemia rates with glargine versus neutral protamine Hagedorn (NPH) in poorly controlled type 1 diabetes patients. METHODS: Patients (n = 125) received preprandial insulin lispro and either glargine (n = 62) or NPH (n = 63) at bedtime for 30 weeks in a multicentre, randomized, single-blind (a blinded investigator made titration decisions) study. Basal insulin dosage was titrated to achieve fasting blood glucose (FBG) values < 5.5 mmol/L. RESULTS: Baseline characteristics were similar for the two groups (mean diabetes duration 17.5 +/- 10.1 years) except mean glycated haemoglobin (HbA(1c)), which was lower in the glargine versus NPH group (9.2 +/- 1.1% vs 9.7 +/- 1.3%; P < 0.02). At end-point, mean HbA(1c) was 8.3 versus 9.1% for the glargine versus NPH groups. Adjusted least-squares mean (LSM) change from baseline was -1.04 versus -0.51%, a significant treatment benefit of 0.53% for HbA(1c) in favour of glargine (P < 0.01). Mean baseline FBG were similar for the glargine and NPH groups (11.2 vs 11.4 mmol/L). The means for end-point FBG were 7.9 versus 9.0 mmol/L. Adjusted LSM change from baseline was -3.46 versus -2.34 mmol/L, with a significant difference of 1.12 mmol/L in favour of glargine (P < 0.05). There were similar total numbers of daytime mild, moderate or severe hypoglycaemia episodes in the two treatment arms. However, significantly fewer moderate or severe nocturnal hypoglycaemic episodes were observed in the glargine group (P = 0.04 and P = 0.02). CONCLUSION: Glargine is superior to NPH for improving HbA(1c) and FBG levels during intensive insulin therapy in patients with type 1 diabetes, and is associated with less severe nocturnal hypoglycaemia.