Association of low-grade inflammation with nephropathy in type 2 diabetic patients: role of elevated CRP-levels and 2 different gene-polymorphisms of proinflammatory cytokines.

BACKGROUND: Chronic inflammatory processes are thought to play a key role in the development of micro- and macrovascular complications in type 2 diabetes mellitus. An association between low -grade inflammation and type 2 diabetes has been described in some studies. We assayed the association of two frequent polymorphisms in proinflammatory cytokines: the interleukin 6 G(-174)C promoter polymorphism [IL-6G(-174)C], the exon 2 interleukin receptor antagonist insertion deletion polymorphism [IL1RA]) and serum CRP levels with the prevalence of diabetic nephropathy in patients suffering from type 2 diabetes mellitus. SUBJECTS AND METHODS: A total of 141 patients with type 2 diabetes mellitus, with and without diabetic nephropathy was genotyped for the above mentioned polymorphisms: 66 with normoalbuminuria, 31 with microalbuminuria and 44 with macroalbuminuria. CRP levels were analysed by a high sensitivity - immunnephelometric assay. RESULTS: While a significant association be-tween macroalbuminuria and CRP could be observed (p<0,015), no associations were found between IL-6G(-174)C or IL1RA genotype and any stage of nephropathy. CRP-levels were similar in the 3 different IL-6G(-174)C genotypes as well as in the 2 IL1RA genotypes. CONCLUSIONS: In type 2 diabetic subjects elevated CRP levels are associated with an increased prevalence of albuminuria. The two investigated proinflammatory polymorphisms do not seem to contribute to initiation of nephropathy in type 2 diabetic patients but we cannot exclude effects of these polymorphisms on course of nephropathy.

Long-term mortality and incidence of renal dialysis and transplantation in type 1 diabetes mellitus.

AIMS: We investigated long-term mortality and requirement of renal replacement therapy (RRT) in type 1 diabetes mellitus (T1DM) to study risk factors and late complication incidence of T1DM in a prospective cohort study at Lainz Hospital, Vienna, Austria. METHODS: In 1983-1984, T1DM patients [n = 648; 47% females, 53% males; age, 30 +/- 11 yr; T1DM duration, 15 +/- 9 yr; body mass index, 24 +/- 4 kg/m(2); glycated hemoglobin (HbA1c), 7.6 +/- 1.6%] were stratified into HbA1c quartiles [1st, 5.9 +/- 0.5% (range, 4.2-6.5%); 2nd, 6.9 +/- 0.3% (6.6-7.4%); 3rd, 7.9 +/- 0.3% (7.5-8.4%); and 4th, 9.6 +/- 1.3% (8.5-14.8%)]. Twenty years later, both endpoints (death and RRT) were investigated by record linkage with national registries. RESULTS: At baseline, creatinine clearance, blood pressure, and body mass index were comparable among the HbA1c quartiles, whereas albuminuria was more frequent in the 4th quartile (+15%; P < 0.03). After the 20-yr follow-up, 13.0% of the patients had died [rate, 708 per 100,000 person-years (95% confidence interval, 557-859)], and 5.6% had received RRT [311 per 100,000 person-years (95% confidence interval, 210-412)]. Patients with the highest HbA1c values (4th quartile) had a higher mortality rate and a greater incidence of RRT (P < 0.04). In the Cox proportional hazards analysis, age, male gender, increased HbA1c, albuminuria, and reduced creatinine clearance were predictors of mortality (P < 0.05). Predictors of RRT were albuminuria (P < 0.001), reduced creatinine clearance (P < 0.001), and belonging to the 4th HbA1c quartile (P = 0.06). In Kaplan-Meier analysis, mortality was linearly associated with poor glycemia, whereas RRT incidence appeared to rise at a HbA1c threshold of approximately 8.5%. CONCLUSION/INTERPRETATION: In the Lainz T1DM cohort, 13.0% mortality and 5.6% RRT were directly associated with and more frequently found in poor glycemia, showing that good glycemic control is essential for the longevity and quality of life in T1DM.

Progression and distribution of plantar pressure in Type 2 diabetic patients.

The aim of this prospective 4-yr study was to analyse changes in mean plantar pressure (PP) over time and local shifts of maximal PP in Type 2 diabetic patients. One-hundred fifty-five Type 2 diabetic patients (age 58.9 +/- 7.5 yr, diabetes duration 11.0 +/- 7.6 yr, baseline HbA1c 9.6 +/- 1.6%) were examined with regard to foot abnormalities, neuropathy and measurement of PP during walking (pedobarography). They were assigned to two subgroups, namely normal PP (n=94) and elevated PP (n=57). Patients with an abnormal mean PP did not significantly differ from subjects with a normal PP with regard to sex, age, duration of diabetes and HbA1c. With the exception of the hallux, the mean PP was significantly increased in both groups at all other plantar sites. Maximum PP was located below the metatarsal heads (MTH) 2-5 and significantly increased from baseline (median, lower/upper quartile: 475, 355/715 kPa) to the end of the study (540, 435/749; p<0.0001). On the other hand, PP was normalized in 17 subjects (29.8%) who had an elevated PP at baseline. Furthermore, we observed a local shift in maximal PP towards the MTH 2-5 region. The percentage of patients who had their highest PP under MTH 2-5 was increased from 54.0% at baseline to 61.1% at the end of the study. In general, we registered an elevation of PP over time and a centralization towards sites which are generally prone to ulceration.

The value of the Rydel-Seiffer tuning fork as a predictor of diabetic polyneuropathy compared with a neurothesiometer.

AIMS: The aim of the study was to investigate the predictive value of the Rydel-Seiffer tuning fork for detecting diabetic neuropathy and to compare it with an electronic neurothesiometer. METHODS: In 2022 consecutive diabetic subjects, peripheral polyneuropathy was diagnosed by vibration perception threshold (VPT) at the tip of both great toes using a 128-Hz tuning fork and a neurothesiometer, by simple bedside tests and by the presence of neuropathic symptoms. These evaluations were further combined to diagnose peripheral nerve dysfunction (abnormal bedside tests) and symptomatic neuropathy. VPT was also measured in 175 non-diabetic control subjects to define normal values. RESULTS: VPT was normal in 1917 subjects and abnormal in 105 (5.2%) patients when measured by the tuning fork. Patients with an abnormal vibration test were significantly (P < 0.0001) older than subjects with a normal vibration sense, while diabetes duration and HbA(1c) of the former were also significantly elevated. The same was true for the percentages of an abnormal 10-g monofilament test (66.7% vs. 7.2%, P < 0.0001) and a missing Achilles' tendon reflex (68.6% vs. 24.8%, P < 0.0001). Finally, the VPT measured by the neurothesiometer was 2.5 times higher in patients with an abnormal tuning fork test (32.0 +/- 9.8 vs. 12.5 +/- 6.4 V, P < 0.0001). The plot of the difference of both methods against their mean yielded a good agreement of the two VPT measurements, and the tuning fork had a high sensitivity and positive predictive value for the diagnosis of abnormal bedside tests and for symptomatic neuropathy. CONCLUSION: The tuning fork reliably detected peripheral neuropathy in comparison with the neurothesiometer. A tuning fork is a useful screening test for diabetic neuropathy.

Evaluation of granulocyte-colony stimulating factor (Filgrastim) in infected diabetic foot ulcers.

AIMS/HYPOTHESIS: To re-evaluate the use of Granulocyte-Colony Stimulating Factor (G-CSF) in the treatment of infected diabetic foot ulcers. METHODS: Thirty-seven diabetic subjects were randomised to Granulocyte-Colony Stimulating Factor (G-CSF) (n=20) or placebo (n=17). The primary endpoint was resolution of cellulitis, which was evaluated clinically and with an infection summary score. Patients were hospitalised for 10 days and received subcutaneously either 5 microg/kg G-CSF or placebo daily. Ulcers were treated with a standard wound protocol and the patients were instructed to stay in bed. All subjects received antibiotics (clindamycin and ciprofloxacin) intravenously until the inflammation had subsided. RESULTS: Patients who received G-CSF did not have an earlier resolution of clinically defined cellulitis (p=0.57). The infection summary score declined, but comparably, in both groups (G-CSF: 29.5+/-18.4 to 6.7+/-6.3 p<0.001, placebo: 24.2+/-16.9 to 8.9+/-7.2 p<0.001). The ulcer volume, which was not greater among placebo patients, was reduced by 59% in G-CSF and by 35% in placebo patients. CONCLUSION/INTERPRETATION: We conclude that antibiotic and non weight-bearing therapy (bed rest) accelerated the resolution of cellulitis in infected foot ulcers. Additional treatment with G-CSF had no further beneficial effect.

Prospective multicentre trial comparing the efficacy of, and compliance with, glimepiride or acarbose treatment in patients with type 2 diabetes not controlled with diet alone.

AIM: To determine the efficacy of, and compliance with, glimepiride or acarbose in patients with Type 2 diabetes. METHODS: Two hundred and nineteen patients with Type 2 diabetes uncontrolled by diet alone were randomized to receive either glimepiride (1, 2, 3, 4 or 6 mg once daily, n = 111) or acarbose (50, 100, 150 or 200 mg 3 times daily, n = 108). Both drugs were titrated in a 6-week dose-finding phase to achieve a fasting blood glucose (FBG) concentration < or = 7.8 mmol/ (140 mg/dl). Patients achieving this target entered a 20-week treatment period. Efficacy was assessed by responder rate, number of patients achieving a FBG of < or = 7.8 mmol/l, HbA1c, blood glucose concentrations in response to a standard breakfast, body weight and compliance. RESULTS: Glimepiride was associated with a significantly greater responder rate than acarbose (61 vs 34%, p < 0.001), significantly greater decreases in HbA1c (2.5 +/- 2.2% vs 1.8 +/- 2.2%, p = 0.014) and FBG (2.6 +/- 2.6 mmol/l vs 1.4 +/- 2.8 mmo/l, p = 0.004), a decreased glucose response to breakfast compared with acarbose [area under curve (AUC) end: 8.9 +/- 2.7 mmol/l vs 11.3 +/- 3.9 mmol/l, p = 0.0001], and was accompanied by significantly greater compliance (91 < or = 12% vs 66 +/- 26%, p = 0.0001). Weight loss during the study was observed in both the acarbose group (1.9 +/- 3.9 kg, p = 0.001) and glimepiride group [0.4 +/- 5.2 kg, p = 0.8 (NS)]. CONCLUSIONS: Improved efficacy and greater compliance were observed in response to treatment with glimepiride compared with acarbose, in patients with Type 2 diabetes.

Limited joint mobility in selected hand and foot joints in patients with type 1 diabetes mellitus: a methodology comparison.

OBJECTIVES: First to determine the range of motion (ROM) of selected foot and hand joints with a goniometer, 2.) to determine joint limitation by prayer sign and 3.) to compare both methods used. METHODS: Maximal active ROM was measured by goniometry (Method 1) in 50 patients with Type 1 diabetes and in 44 healthy controls, respectively. The lower limits for normal ranges were defined as mean minus 2 SD. To elicit the prayer sign (Method 2) subjects were asked to put their hands together in a praying position with the fingers fanned. The number of missing joint contacts between the fingers was counted and correlated to ROM. RESULTS: The ROM of all joints measured, except that of the thumb, was significantly smaller in diabetic patients than in control subjects. The degree of the prayer sign was well correlated to the ROM of most hand joints, but was solely correlated in feet to ankle ROM. In diabetic patients the prevalence of limited joint mobility (LJM) measured by goniometry ranged from 2 to 20% in hand joints and from 10 to 14% in foot joints. By the prayer sign 33% of the diabetic patients had LJM. CONCLUSION: With both methods, diabetic patients had more limitations in joint motion than control subjects, as was their prevalence of LJM higher. Since the prayer sign was correlated to exactly measured ROMs, we would suggest using the prayer sign as a simple clinical indicator for LJM in diabetic subjects.

A prospective study of predictors for foot ulceration in type 2 diabetes.

One hundred eighty-seven type 2 diabetic patients without a history of foot ulceration were followed for a mean period of 3.6 years to investigate the incidence of foot ulceration in a diabetes cohort and to analyze risk factors for foot ulceration by multivariate means. During the study, 10 subjects developed 18 forefoot ulcerations. In multivariate logistic regression, significant predictors for foot ulceration were an elevated vibration perception threshold (VPT) (relative risk [RR] = 25.4), an increased plantar pressure (RR = 6.3), and daily alcohol intake (RR = 5.1). This is the first prospective study to demonstrate plantar pressure and daily alcohol intake as predictors of foot ulceration among patients without previous ulceration. Further, VPT could be confirmed as the strongest predictor for foot ulceration, and it was clearly demonstrated that the more pronounced severity of complications occurred among subjects with elevated VPT.

Carbohydrate sources and glycaemic control in Type 1 diabetes mellitus. EURODIAB IDDM Complications Study Group.

AIMS: Little information is available on the relationship between glycated haemoglobin levels and the source or amount of dietary carbohydrate. The present study compares the association of carbohydrate intake with HbA1c between European individuals with Type 1 diabetes mellitus injecting insulin once or twice per day and those with > or = 3 daily injections. METHODS: The relation of carbohydrate intake (total, cereal, fruit, vegetable, milk, and potato carbohydrate assessed by a 3-day dietary record) to HbA1c was examined in 2084 patients (age 32.6 +/- 10.2 years, duration of diabetes 14.8 +/- 9.5 years) included in the EURODIAB Complications Study. RESULTS: In both insulin injection regimens, an increased intake of total carbohydrate (% of energy) and a higher consumption of potato carbohydrates (g) were associated with higher levels of HbA1c, whereas an increased intake of vegetable carbohydrate (g) was inversely related to HbA1c. These tendencies were all more pronounced in persons with one or two daily insulin injections. Consumption of cereal and fruit carbohydrates (g) was not related to HbA1c, irrespective of the insulin injection regimen. A trend of HbA1c to increase with higher intakes of milk carbohydrate was confined to those with one or two insulin injections per day (test for interaction: P = 0.01). CONCLUSIONS: In particular, subjects with only 1 or 2 daily insulin injections per day should receive specific advice to correctly consider milk and potato carbohydrates. On the other hand, people with Type 1 diabetes may profit from a higher consumption of vegetable carbohydrates for their levels of HbA1c.

Estimation of risk for plantar foot ulceration in diabetic patients with neuropathy.

The main risk factors for plantar forefoot ulcers are loss of protective sensation due to sensory neuropathy and increased mechanical stress on the sole of the foot. The aim of this study was to find a better parameter than the plantar pressure to explain the occurrence of plantar ulcers under the metatarsalheads (MTHs). Twenty diabetic patients (3 Type 1 and 17 Type 2) each with 1 plantar ulcer and 23 Type 2 diabetic patients without plantar ulceration (controls), were investigated. The parameters of plantar pressure, length of contact time and pressure-time integral (PTI) were determined by pedography at defined foot regions. PTI represents the duration of mechanical stress on the foot. Based on the distribution of ulcers, the ratio of stress on the MTHs to that on the big toe was calculated. In diabetic patients with ulcers the difference of PTI between MTHs and hallux was higher at 153% and hence 3.2 times greater than the difference in plantar pressure between MTHs and hallux of 47.3%. In the control group the ratio of difference had a factor of 2 only because the corresponding difference in PTI was 85.1% and the difference in plantar pressure was 43.1%. These results may indicate that increased stress at the MTHs is responsible for the occurrence of planar ulcers compared with other regions of the sole. Diabetic patients with elevated PTI ratio are at risk of developing foot ulcers and therefore have to be provided with orthopaedic shoes to prevent foot ulceration.

Is apolipoprotein(a) a susceptibility gene for type I diabetes mellitus and related to long-term survival?

AIMS/HYPOTHESIS: High lipoprotein(a) [Lp(a)] plasma concentrations are a genetically determined risk factor for atherosclerotic complications. In healthy subjects Lp(a) concentrations are mostly controlled by the apolipoprotein(a) [apo(a)] gene locus which determines a size polymorphism with more than 30 alleles. Subjects with low molecular weight apo(a) phenotypes on average have higher Lp(a) concentrations than those with high molecular weight apo(a) phenotypes. There are many opinions about whether and why Lp(a) is raised in patients with Type I diabetes (insulin-dependent) mellitus. METHODS: We investigated Lp(a) plasma concentrations and apo(a) phenotypes in 327 patients with Type I diabetes mellitus (disease duration 1-61 years) and in 200 control subjects matched for age and sex. RESULTS: Patients with a disease duration of up to 15 years had significantly higher Lp(a) concentrations (24.3 +/- 34.0 mg/dl vs 16.7 +/- 22.6 mg/dl, p = 0.014) compared with control subjects. This increase can be explained by a considerably higher frequency of low molecular weight apo(a) phenotypes (38.9% vs 23.5%, p < 0.005). The frequency of low molecular weight apo(a) phenotypes decreased continuously with disease duration from 41.7% in those with disease duration of up to 5 years to 18.2% in those with the disease lasting more than 35 years. CONCLUSIONS/INTERPRETATION: Our data show that an increase of Lp(a) in Type I diabetic patients can only be observed in groups with short diabetes duration and that this elevation is genetically determined. Therefore, the apo(a) gene, located at 6q26-27, might be a susceptibility gene for Type I diabetes mellitus which is supported by recently published studies reporting evidence for linkage of this region (6q27) with Type I diabetes mellitus. Furthermore, the decreasing frequency of low molecular weight apo(a) phenotypes with disease duration suggests a survivor effect.

ACE gene polymorphism and proliferative retinopathy in type 1 diabetes: results of a case-control study.

OBJECTIVE: To evaluate the relationship between the ACE insertion/deletion polymorphism and proliferative diabetic retinopathy in patients with type 1 diabetes of long duration. Based on epidemiological and pathophysiological findings, risk factors apart from glycemic control and duration of disease are likely to be involved in the development of proliferative retinopathy. RESEARCH DESIGN AND METHODS: In this case-control study, we compared 81 patients with longstanding (> or =20 years) type 1 diabetes who had nonproliferative (mild or moderate background) retinopathy with 95 patients with diabetes of similar duration and HbA1c who had proliferative retinopathy. To avoid the confounding effect of nephropathy, patients with overt nephropathy were excluded, and microalbuminuria was introduced into the multiple logistical regression model. The polymorphic region in intron 16 of the ACE gene (17q23) was analyzed using the polymerase chain reaction. RESULTS: The ACE genotype distribution in patients with proliferative retinopathy (DD 39.4%, ID 48.9%, II 11.7%) was significantly different (P < 0.001) from that of patients with nonproliferative retinopathy (DD 17.3%, ID 54.3%, II 28.4%). In a multiple logistical regression analysis, the adjusted relative risk for proliferative retinopathy in a patient with a DD genotype compared with a patient with an II genotype was 6.6 (95% CI 2.2-19.5), P = 0.0026. In addition to genotype, systolic blood pressure (odds ratio 1.027 [95% CI 1.0-1.1], P = 0.0093) but not microalbuminuria (< or =20 vs. > or =20 microg/min) reached statistical significance in the multiple regression model. Because subjects were matched regarding diabetes duration and HbA1c, we did not interpret the respective parameter estimates. CONCLUSIONS: These data provide evidence that deletion in the ACE gene is associated with the prevalence of proliferative retinopathy in type 1 diabetes and suggest that the DD genotype confers susceptibility to proliferative retinopathy independent of diabetic nephropathy

Previous episodes of hypoglycemic coma are not associated with permanent cognitive brain dysfunction in IDDM patients on intensive insulin treatment.

Intensive insulin treatment of IDDM is associated with increased frequency of hypoglycemic coma. The extent of possible cerebral sequelae after recovery is still unknown. We studied the impact of previous hypoglycemic coma on neurophysiological measures of cognitive brain function in 108 patients with adult-onset IDDM receiving intensive insulin treatment. In the study, 55 IDDM patients (age 38 +/- 14 years, mean +/- SD) who had a history of > or =1 (median 3, range 1-35) comatose hypoglycemic event were compared with 53 IDDM patients (age 34 +/- 12 years) with no history of hypoglycemic events using P300 event-related potentials and psychometric tests (the Mini-Mental State Exam and trailmaking test, part A). Findings on these patients were compared with those from 108 matched healthy control subjects. No difference was observed in P300 latencies and psychometric tests between patients with and without a history of hypoglycemic coma (P300 latency, 346 vs. 342 ms; trailmaking test, 31 vs. 30 s; Mini-Mental State Exam, 29.5 vs. 29.6; NS). In diabetic patients, however, P300 latencies were delayed compared with those of healthy control subjects (344 vs. 332 ms; P < 0.001) and were correlated to diabetes duration but not to total hypoglycemic episodes. Scores on the Mini-Mental State Exam (29.5 vs. 29.6; P = 0.59) and trailmaking test (31 vs. 28 s; P = 0.10) were not different between patients and control subjects. In conclusion, previous episodes of hypoglycemic coma are not associated with permanent impairment of cognitive brain function in patients with adult-onset IDDM receiving intensive insulin treatment compared with patients without such episodes. Cognitive brain function, however, is subclinically impaired in relation to duration of diabetes.

Running shoes for relief of plantar pressure in diabetic patients.

There is a causal relationship between diabetic foot ulceration, elevated plantar pressure, and severe sensory neuropathy. Cushioned footwear intended to relieve plantar pressure is well established for prevention and healing of plantar ulcers. The aim of the present study was to investigate whether pressure relief by means of a running shoe with optimized forefoot pressure damping is comparable to that of a custom-made soft insole placed into an in-depth shoe. The in-shoe pressures were compared to an in-depth shoe with the original cork insole and with a leather-soled Oxford shoe. The maximum reduction of plantar pressure in the running shoe was 47% under the 2nd and 3rd metatarsal heads, 29% at the first metatarsal head, and 32% at the great toe in comparison to the Oxford shoe. This was surpassed only by the custom-made insole, which reduced pressures at the metatarsal heads by 50%. The specially designed running shoe yielded the same pressure relief at the central metatarsal heads as the custom-made insole. Such shoes are likely to be very useful in preventing diabetic foot ulceration in high-risk patients as a comparatively affordable and immediately available device.

Evaluation of risk factors for the development of nephropathy in patients with IDDM: insertion/deletion angiotensin converting enzyme gene polymorphism, hypertension and metabolic control.

Diabetic nephropathy represents a major complication in patients with insulin-dependent diabetes mellitus (IDDM). Intervention trials using angiotensin-converting enzyme (ACE) inhibitors have pointed towards the important pathogenetic role of the renin-angiotensin system. Recently an insertion/ deletion (I/D) polymorphism for the gene encoding the ACE has been described, the deletion type being associated with higher plasma ACE levels. As the intrarenal renin-angiotensin system might also be activated in this setting, we determined the ACE genotype together with other risk factors for the development of diabetic nephropathy in 122 patients with IDDM from a single centre with (n = 63) and without (n = 59) nephropathy. Long-term glycaemic control was evaluated using mean HbA1c values from the last 10 years. The two patient group were comparable with regard to duration of diabetes and glycaemic control as assessed by current HbA1c values. However, mean long-term HbA1c values were significantly higher in patients with diabetic nephropathy as was systemic blood pressure. The DD genotype was more prevalent in patients with renal disease. In the subgroup of patients who had had diabetes for more than 20 years (n = 90), the DD genotype was even more frequent in patients with nephropathy, and blood pressure and long-term HbA1c values were also higher in patients with renal disease. Logistic regression analysis revealed long-term glycaemic control, blood pressure and the ACE genotype to be independent risk factors for the prevalence of diabetic nephropathy.