Search

Background and Aims: Insulin Degludec (IDeg) , in comparison with Insulin Glargine U100 (IGla) , reduces the risk of hypoglycemic events in people with type 1 diabetes (T1D) . The impact on CGM assessed glycemic metrics: the coefficient of variation (CV) , time in range (TIR) , time below range (TBR) , and time-above range (TAR) is less known. We present CGM results from the HypoDeg trial comparing treatment with IDeg and IGla in people with T1D and recurrent nocturnal severe hypoglycemia. Materials and Methods: This is a pre-defined optional substudy of the HypoDeg trial: a 2-year investigator-initiated, randomized, cross-over trial comparing treatment with IDeg or IGla in 149 participants with T1D and at least one nocturnal severe hypoglycemic event within the last two years. Participants underwent 2 x 6 days of blinded CGM (Medtronic iPro) in each treatment arm after 6 and 12 months of treatment. Seventy-four participants completed at least one CGM period in each treatment arm. The endpoints were CV, TIR (3.9 - 10.0 mmol/L) , TBR at level 2 (< 3.0 mmol/L) and TAR (>10.0mmol/L, >13.9mmol/L) . Time spent in, below, or above range provided as percentage of readings. Results: We collected 261 CGM traces with a mean (SD) observation period of 5.9 (0.7) days. The all-day CV was lower with IDeg than IGla, with a mean (SE) CV of 40.5% (0.9) and 42.5% (0.9) , respectively (p=0.009) . A difference in CV during the night (23:00h to 07:00h) drove this, with a mean CV of 35.7% (1.1) for IDeg versus 39.6% (1.1) for IGla (p=0.001) . The all-day level 2 TBR was lower with IDeg than IGla, with a mean TBR of 1.8% (0.4) and 3.1% (0.4) , respectively (p=0.001) . The percentages of TIR and TAR were not different between treatments. Conclusion: In people with T1D prone to nocturnal severe hypoglycemia, treatment with IDeg results in a lower mean CV, reaching the definition of stable glucose levels during the night and a lower all-day TBR than IGla. Disclosure J.M.Brøsen: None. S.Lerche: None. K.Nørgaard: Advisory Panel; Medtronic, Novo Nordisk A/S, Consultant; Novo Nordisk A/S, Research Support; Dexcom, Inc., Medtronic, Novo Nordisk A/S, Zealand Pharma A/S, Speaker's Bureau; Medtronic, Stock/Shareholder; Novo Nordisk A/S. L.Tarnow: None. B.Thorsteinsson: None. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. R.Agesen: Employee; Novo Nordisk A/S. A.Alibegovic: Employee; Novo Nordisk A/S, Novo Nordisk A/S. H.U.Andersen: Advisory Panel; Abbott Diabetes, Stock/Shareholder; Novo Nordisk A/S. P.Gustenhoff: Advisory Panel; Abbott Diagnostics. T.K.Hansen: None. C.Hedetoft: None. C.R.Stolberg: None. C.B.Juhl: None. Funding Novo Nordisk

Background and Aims: The risk of nocturnal hypoglycemia (NH) is a limiting factor for achieving good glycemic control in people with type 1 diabetes (T1D). Insulin degludec (IDeg) is proven to lower the risk of self-reported NH. As most episodes of NH are asymptomatic, we assessed differences in occurrence of NH by hourly plasma glucose (PG) measurements at treatments with IDeg or insulin glargine U100 (IGlar) in people with T1D suffering from recurrent nocturnal severe hypoglycemia. Materials and Methods: Pre-defined optional substudy of the HypoDeg trial, a 2-year investigator-initiated, randomized, cross-over trial where 149 participants with T1D were randomized to treatment with IDeg or IGlar. Fifty-one participants (mean (SD) age 58 (13) years, diabetes duration 28 (14) years and HbA1c 7.8 (1) %) were admitted for two nights for hourly blinded plasma glucose measurements for a minimum of one night (23:00h to 07:00h) during each 1-year treatment period. The primary endpoints were NH at level 1 (PG ≤ 3.9 mmol/L) and level 2 (PG < 3.0 mmol/L). Results: We collected data from 196 nights. A total of 57 nights (regardless of level) in 33 participants were hypoglycemic, including 20 nights with symptomatic hypoglycemia. The incidence of NH at level 1 was lower when treated with IDeg [17 events in 97 nights (18%)] as compared to IGlar [36 events in 99 nights (36%)], corresponding to a hazard ratio (HR) of 0.39 (95% CI: 0.22-0.71; p=0.002) during treatment with IDeg. At level 2, the incidence of NH was also lower during treatment with IDeg [8 events in 97 nights (8%)] as compared to IGlar [20 events in 99 nights (20%)], corresponding to an HR of 0.36 [95% CI: 0.16-0.80; p=0.013] during treatment with IDeg. Conclusion: In people with T1D and recurrent nocturnal severe hypoglycemia, treatment with IDeg as compared to IGlar results in a clinically significant lower rate of NH at both levels of hypoglycemia. Disclosure J. M. Brøsen: None. S. Lerche: None. K. Nørgaard: Advisory Panel; Self; Medtronic, Other Relationship; Self; Novo Nordisk Inc., Zealand Pharma A/S, Speaker’s Bureau; Self; Medtronic. H. D. Parving: None. L. Tarnow: None. B. Thorsteinsson: None. U. Pedersen-bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis, Consultant; Self; Abbott, Speaker’s Bureau; Self; Novo Nordisk A/S. R. Agesen: Employee; Self; Novo Nordisk. P. L. Kristensen: Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company. A. Alibegovic: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. H. U. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S. P. Gustenhoff: None. C. Hedetoft: None. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. C. B. Juhl: None. Funding Novo Nordisk

Lipohypertrophy (LH), a common side effect of insulin therapy, is caused by repetitively injecting insulin into the same location. When insulin is injected into LH lesions, the absorption of insulin may be erratic and unpredictable, which can lead to unexpected hyperglycemia and hypoglycemia and increased blood glucose variability. To improve injection techniques and avoid LH, a new medical device, ROTO Track® which automatically guides the person with diabetes to rotate the abdominal insulin injections was tested. The hypothesis is that the device can reduce the number of insulin injections in the same subcutaneous area as compared with non-aided standard insulin injection techniques in people with T1DM. Methods: In this proof-of-concept cross-over study, baseline data about injection site in the abdominal region was collected blinded for one week with a non-guiding version of the device and compared to 12 weeks of device guidance in 35 people with T1DM. The device registered injection time and location on the abdomen. Based on this a "rotation score", the primary endpoint, was calculated. Secondary end points included number and size of LH, glycemic variability and HbA1c. LH sizes were documented by drawing on a wound care grid after palpation of the skin. Interstitial glucose was measured with a continuous glucose monitor and the coefficient of variation, CV was calculated. Results: The rotation score improved significantly from a baseline mean of 40.2% to 49.9% after one week (CI: 2.2% - 17.2%, p=0.012) and improved further after 12 weeks to 52.2% (p After 12 weeks, LH was reduced both in mean size from 11.9 (+/- 9.5) cm2 to 8.2 (+/- 9.7) cm2 (p=0.041) and numbers (p=0.039) and the CV of interstitial glucose was reduced from 38.6 to 35.1 (p=0.009). There were no changes in mean interstitial glucose, HbA1c or hypoglycemic events after 12 weeks. Conclusion: This proof-of-concept study indicates that the device is safe, improves rotation, reduces LH and reduces glycemic variability. Disclosure C.K. Klarskov: None. Y.H. Hamid: None. R.T. Tjalk-Bøggild: Board Member; Self; ROTO Health ApS. Employee; Self; ROTO Health ApS. L. Tarnow: None. P.L. Kristensen: None. Funding Innovation Fund Denmark (8063-00049B); Nordic Healthcare Technology

Background and Aims: The long-acting insulin analog degludec reduces the risk of nocturnal hypoglycemia in patients with type 1 diabetes (T1D). The HypoDeg trial compared the effect of insulin degludec to insulin glargine U100 on frequency of nocturnal hypoglycemia in T1D patients with recurrent nocturnal severe hypoglycemia and reported a significant 37% relative risk reduction (RRR) of symptomatic nocturnal hypoglycemia ≤ 3.0 mmol/L with insulin degludec. Here we report the data on severe hypoglycemia (SH). Materials and Methods: In this investigator-initiated, prospective, randomized, open-label, blinded-endpoint crossover trial conducted at 10 centers in Denmark, we recruited 149 T1D patients (>18 years) with ≥2 episodes of nocturnal SH in the preceding two year. Patients were randomly assigned (1:1) to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. Episodes of SH were reported by telephone and adjudicated blinded to treatment. Results: A total of 136 SH episodes were reported during the maintenance periods: 56 (41%) episodes during treatment with insulin degludec and 80 (59%) episodes during treatment with insulin glargine U100, resulting in a RRR of 35% (95% confidence interval [CI]: 0-60%; p=0.04). This corresponds to an absolute rate reduction of 0.3 episodes (95% CI: 0.0-0.5) per patient-year with insulin degludec. The difference was primarily due to a lower risk of nocturnal episodes (RRR 52%, 95% CI: -10-80%; p=0.08), whereas there was no difference during daytime (RRR 10%, 95% CI: -80-50%; p=0.75). Conclusion: Treatment with insulin degludec in T1D patients with recurrent nocturnal SH resulted in a clinically significant reduced rate of SH compared with insulin glargine U100. Disclosure R.M. Agesen: Employee; Self; Novo Nordisk A/S. A. Alibegovic: Employee; Self; Novo Nordisk A/S. H.U. Andersen: Advisory Panel; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. P. Gustenhoff: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi-Aventis. T.K. Hansen: None. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. C.B. Juhl: None. A.K. Jensen: None. S. Lerche: None. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk Inc. H.D. Parving: None. A.L. Sørensen: None. L. Tarnow: None. B. Thorsteinsson: None. U. Pedersen-Bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S. Funding Novo Nordisk A/S

Background and Aims: Nocturnal hypoglycemia is a major source of concern of people with type 1 diabetes (T1D) and may result in suboptimal glycemic control due to avoidance behavior. Optimal basal insulin therapy may reduce nocturnal hypoglycemia. Insulin degludec is associated with lower risk of nocturnal hypoglycemia in T1D. However, it has not been studied in people specifically prone to severe nocturnal hypoglycemia. We report frequencies of CGM-recorded nocturnal non-severe hypoglycemia (NSH) from the HypoDeg trial, which compared insulin degludec with insulin glargine in people with T1D and previous severe nocturnal hypoglycemia. Materials and Methods: Seventy-four people completed 4 x 6 days of blinded CGM (Medtronic iPro) during a 2-year randomized cross-over study. CGM traces were reviewed for clinically important hypoglycemic events ≤ 3.0 mmol/L according to current international consensus. Results: When defining night-time from 23-06:59 a total of 193 episodes of nocturnal NSH were found at the glucose threshold ≤ 3.0 mmol/L. A 53% (95% confidence interval [CI] 35%-64%; p Conclusion: People with T1D prone to nocturnal severe hypoglycemia have lower rates of CGM-recorded nocturnal hypoglycemia with insulin degludec as compared to insulin glargine. Disclosure J.M. Brøsen: None. R.M. Agesen: Employee; Self; Novo Nordisk A/S. A. Alibegovic: Employee; Self; Novo Nordisk A/S. H.U. Andersen: Advisory Panel; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. P. Gustenhoff: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi-Aventis. T.K. Hansen: None. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. C.B. Juhl: None. S. Lerche: None. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk Inc. H.D. Parving: None. L. Tarnow: None. B. Thorsteinsson: None. U. Pedersen-Bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S.

Introduction: Diabetic retinopathy (DR) remains the leading cause of preventable vision loss in developed countries. Adverse activation of the complement system plays an essential role in development of complications in diabetes and has been demonstrated in eyes from patients with DR. We hypothesized that complement proteins of lectin pathway can predict severe DR, defined as proliferative DR and macular edema, in newly diagnosed type 1 diabetes. Methods: In this explorative study, incidence of severe DR was monitored in a cohort of newly diagnosed type 1 diabetes patients (n=270) with median follow-up time of 18 years (range 1-22 years). Baseline complement proteins MBL, M-ficolin, H-ficolin, MASP-1, MASP-2, MASP-3, MAp44, and MAp19 were quantified using immunoassays. A cox proportional hazards regression model was applied to test for difference between quantile groups and adjusted for age and HbA1c. Results: During follow-up, 28 patients developed severe DR. A tendency arose when testing association between MAp44 levels and severe DR in an unadjusted model (HR, 4th quartile vs. the remaining, 1.3; 95% CI 0.99, 1.6), p = 0.06), which became significant in the adjusted model (HR, 1.33; 95% CI 1.0, 1.7), p = 0.04), Fig. 1. Conclusion: MAp44 was significantly associated with development of severe DR, whereas other complement factors were not. Further analysis in a larger cohort is warranted. Disclosure C.B. Holt: None. I.T. Hoffmann-Petersen: None. J.A. østergaard: None. H.D. Parving: None. S. Thiel: None. P. Hovind: None. L. Tarnow: Stock/Shareholder; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk Foundation. P. Rossing: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novartis AG, Novo Nordisk A/S. T.K. Hansen: None. Funding Aarhus University; Foundation of Skibsredder Per Henriksen

Background: The LeucoPatch® device uses bedside centrifugation without additional reagents to generate a disc comprising autologous platelets, fibrin and leucocytes which is applied to the surface of the wound. The aim of the study was to test the effectiveness of LeucoPatch® on the healing of hard-to-heal foot ulcers in people with diabetes. Methods: 595 people with diabetes and a foot ulcer consented to participate. After a 4 week run-in-period those with a reduction in ulcer area of < 50% were randomised to either pre-specified good standard care alone or care supplemented by weekly application of LeucoPatch®. The primary outcome was percentage of ulcers healed within 20 weeks, defined as complete epithelialisation confirmed by an observer blind to randomisation group and maintained for four weeks. Results: 269 people were randomised; mean age 62 years, 82% male, 82% type 2 diabetes. In the intervention group 34.1% (n=45/132) of ulcers healed within 20 weeks vs. 21.6% (n=29/134) of the controls (OR 1.58, 95% CI 1.06-2.35; p= 0.02) by intention-to-treat analysis. Time to healing was shorter in the intervention group (p=0.0246) (Figure). No difference in adverse events was seen between groups. Interpretation: The use of LeucoPatch® is associated with significant enhancement of healing of hard-to heal foot ulcers in people with diabetes. Disclosure F. Game: Research Support; Self; Reapplix aps. W. Jeffcoate: Research Support; Self; Reapplix Aps, Urgo, France. L. Tarnow: Stock/Shareholder; Self; Novo Nordisk A/S. J.L. Jacobsen: Consultant; Self; Reapplix. D.J. Whitham: Other Relationship; Self; Reapplix. E.F. Harrison: Research Support; Self; Reapplix. S.J. Ellender: None. M. Londahl: Speaker's Bureau; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; ReApplix AS.

Introduction: In the struggle for tight glycemic control many type 1 diabetes patients daily experience large blood glucose fluctuations. It has been demonstrated that increased glucose variability is a predictor of hypoglycemia, which is the main limiting factor for achieving the recommended HbA1c target. The relationship between glucose variability and hypoglycemia might seem intuitive, but the exact nature of the relationship is difficult to elucidate. In this study we wanted to clarify the relationship between occurrence of non-severe hypoglycemia and glycemic variability in type 1 diabetic patients at high risk of severe hypoglycemia. Material and Methods: 72 patients participated for 4 x 3 days of blinded CGM recordings during a 2-year randomized balanced cross-over study with human insulins (regular/NPH) and insulin analogs (aspart/detemir). CGM recordings were used to calculate the coefficient of variation (CV) in glucose. Results: Treatment with insulin analogs resulted in a significant lower nocturnal CV (mean 29.2%, SD 9.1) than treatment with human insulin (mean 36.9%, SD 9.1) (p Conclusion: Treatment with insulin analogs provides less glycemic variability during night-time. The coefficient of variation in patients suffering from recurrent severe hypoglycemia predicts the occurrence of especially nocturnal hypoglycemia. Disclosure R.M. Agesen: None. P.L. Kristensen: Other Relationship; Self; Eli Lilly and Company. H. Beck-Nielsen: None. K. Nørgaard: Research Support; Self; Roche Diabetes Care Health and Digital Solutions. Advisory Panel; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic, Zealand Pharma A/S, Novo Nordisk A/S. Research Support; Self; Zealand Pharma A/S. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. B. Thorsteinsson: None. L. Tarnow: Stock/Shareholder; Self; Novo Nordisk A/S. U. Pedersen-Bjergaard: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi-Aventis. Consultant; Self; Medtronic.

OBJECTIVE To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, arterial stiffness, and advanced glycation end products (AGEs). RESEARCH DESIGN AND METHODS We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of sRAGE and other biomarkers were measured at baseline. The median follow-up duration was 12.3 years (7.6–12.5). RESULTS The incidence of fatal and nonfatal CVD and all-cause mortality increased with higher baseline levels of log-transformed sRAGE (Ln-sRAGE) independently of other CVD risk factors: hazard ratio (HR) 1.90 (95% CI 1.13–3.21) and 2.12 (1.26–3.57) per 1-unit increase in Ln-sRAGE, respectively. Adjustments for estimated glomerular filtration rate (eGFRMDRD), but not or to a smaller extent for markers of endothelial dysfunction, low-grade inflammation, arterial stiffness, and AGEs, attenuated these associations to HR 1.59 (95% CI 0.91–2.77) for fatal and nonfatal CVD events and to 1.90 (1.09–3.31) for all-cause mortality. In addition, in patients with nephropathy, the rate of decline of GFR was 1.38 ml/min/1.73 m2 per year greater per 1-unit increase of Ln-sRAGE at baseline (P = 0.036). CONCLUSIONS Higher levels of sRAGE are associated with incident fatal and nonfatal CVD and all-cause mortality in individuals with type 1 diabetes. sRAGE-associated renal dysfunction may partially explain this association.

OBJECTIVE Experimental and clinical studies have suggested that uric acid may contribute to the development of hypertension and kidney disease. Whether uric acid has a causal role in the development of diabetic nephropathy is not known. The objective of the present study is to evaluate uric acid as a predictor of persistent micro- and macroalbuminuria. RESEARCH DESIGN AND METHODS This prospective observational follow-up study consisted of an inception cohort of 277 patients followed from onset of type 1 diabetes. Of these, 270 patients had blood samples taken at baseline. In seven cases, uric acid could not be determined; therefore, 263 patients (156 men) were available for analysis. Uric acid was measured 3 years after onset of diabetes and before any patient developed microalbuminuria. RESULTS During a median follow-up of 18.1 years (range 1.0–21.8), 23 of 263 patients developed persistent macroalbuminuria (urinary albumin excretion rate >300 mg/24 h in at least two of three consecutive samples). In patients with uric acid levels in the highest quartile (>249 μmol/l), the cumulative incidence of persistent macroalbumnuria was 22.3% (95% CI 10.3–34.3) compared with 9.5% (3.8–15.2) in patients with uric acid in the three lower quartiles (log-rank test, P = 0.006). In a Cox proportional hazards model with sex and age as fixed covariates, uric acid was associated with subsequent development of persistent macroalbuminuria (hazard ratio 2.37 [95% CI 1.04–5.37] per 100 μmol/l increase in uric acid level; P = 0.04). Adjustment for confounders did not change the estimate significantly. CONCLUSIONS Uric acid level soon after onset of type 1 diabetes is independently associated with risk for later development of diabetic nephropathy.

The impact of irbesartan treatment on biomarkers of low-grade inflammation, endothelial dysfunction, growth factors, and advanced glycation end products (AGEs) during the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study was evaluated. IRMA 2 was a 2-year multicenter, randomized, double-blind trial in patients comparing irbesartan (150 or 300 mg once daily) versus placebo. The primary end point was onset of overt nephropathy. A subgroup (n = 269, 68%) was analyzed for biomarkers at baseline and after 1 and 2 years. High-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, fibrinogen, adhesion molecules, transforming growth factor-β, and AGE peptides were assessed. Irbesartan treatment yielded significant changes in hs-CRP (based on generalized estimating equation regression coefficient) with a 5.4% decrease per year versus a 10% increase per year in the placebo group (P < 0.001). Fibrinogen decreased 0.059 g/l per year from baseline versus placebo’s 0.059 g/l increase per year (P = 0.027). IL-6 showed a 1.8% increase per year compared with placebo’s 6.5% increase per year (P = 0.005). Changes in IL-6 were associated with changes in albumin excretion (P = 0.04). There was no treatment effect on the other biomarkers. Irbesartan (300 mg once daily) reduces low-grade inflammation in this high-risk population, and this may reduce the risk of micro- and macrovascular disease.

Linkage studies have mapped loci for diabetic nephropathy and associated phenotypes on chromosome 3q. We studied 14 plausible candidate genes in the linkage region because of their potential role in vascular complications. In a large-scale study of patients from Denmark, Finland, and France who have type 1 diabetes, 1,057 case and 1,127 control subjects, as well as 532 trios, were investigated for association with diabetic nephropathy. We analyzed 69 haplotype-tagging single nucleotide polymorphisms and nonsynonymous variants that were identified by sequencing. Polymorphisms in three genes, glucose transporter 2 (SLC2A2), kininogen (KNG1), and adiponectin (ADIPOQ), showed nominal association with diabetic nephropathy in single-point analysis. The T-allele of SLC2A2_16459CT was associated with a decreased risk of diabetic nephropathy (odds ratio 0.79 [95% CI 0.66–0.96], P = 0.016), whereas the T-allele of KNG_7965CT and the A-allele of ADIPOQ_prom2GA were associated with increased risk of nephropathy (1.17 [1.03–1.32], P = 0.016; 1.46 [1.11–1.93], P = 0.006, respectively). Analyses of the transmission disequilibrium test showed similar trends only for ADIPOQ_prom2GA with the overtransmission of the A-allele to patients with diabetic nephropathy (1.52 [0.86–2.66], P = NS) and of the G-allele to patients without diabetic nephropathy (0.50 [0.27–0.92], P = 0.026). The overall significance for this variant (nominal P = 0.011) suggests that ADIPOQ might be involved in the development of diabetic nephropathy.

Inflammation and complement activation via the mannose-binding lectin (MBL) pathway have been suggested to play a role in the pathogenesis of diabetic microvascular complications. The association between the complement-activating protein MBL and the development of persistent microalbuminuria was evaluated in an inception cohort of 286 newly diagnosed type 1 diabetic patients consecutively admitted to the Steno Diabetes Center between 1 September 1979 and 31 August 1984. Serum MBL was measured with an immunofluorometric assay in 270 of the patients (159 men) after 3 years of diabetes duration. During the median (range) follow-up period of 18.0 (1.0–21.8) years, 75 patients subsequently progressed to persistent micro- or macroalbuminuria (urinary albumin excretion rate >30 mg/24 h). In patients with MBL levels above the median (1,597 μg/l), the cumulative incidence of persistent micro- or macroalbuminuria was 41% (CI 31–50) as compared with 26% (CI 17–34) in patients with MBL levels below the median (log-rank test, P = 0.003). In a Cox proportional hazard model with sex and age as fixed covariates, MBL was independently associated with later development of persistent micro- or macroalbuminuria (hazard ratio 1.21 [CI 1.02–1.42] per 1,000 μg/l increase in MBL; P = 0.03) after adjusting for possible confounders. In our study, high levels of MBL early in the course of type 1 diabetes was significantly associated with later development of persistent micro- or macroalbuminuria, suggesting that complement activation initiated by MBL may be involved in the pathogenesis of diabetic microvascular complications.

Advanced glycation end-products (AGEs) may play an important role in the pathogenesis and progression of cardiovascular and renal complications of diabetes. Four putative AGE receptors (RAGEs), AGE-R1, AGE-R2, and AGE-R3 have been described. In this study, we scanned the sequence of the genes encoding these AGE receptors in 48 patients with type 1 diabetes and investigated the identified polymorphisms (n = 19) in 199 type 1 diabetic patients with nephropathy and 193 type 1 diabetic patients without nephropathy. Overall, none of the polymorphisms was strongly associated with nephropathy. The minor allele of a polymorphism located in the promoter region of the RAGE gene (C-1152A) conferred a weak protective effect (P < 0.05) and was associated with a longer duration of nephropathy-free diabetes (P = 0.08).

Genotypic abnormalities of the renin-angiotensin system have been suggested as a risk factor for the development of diabetic nephropathy and proliferative retinopathy. We studied the relationship between an insertion(I)/deletion (D) polymorphism in the angiotensin-converting enzyme (ACE) gene in insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy (121 men and 77 women, age 40.9 ± 10 years, diabetes duration 27 ± 8 years) and in IDDM patients with normoalbuminuria (118 men and 74 women, age 42.7 ± 10 years, diabetes duration 26 ± 8 years). A total of 155 patients (40%) had proliferative retinopathy, and 67 patients (17%) had no diabetic retinopathy. There was no difference in genotype distribution between IDDM patients with diabetic nephropathy and those with normoalbuminuria: 63 (32%)/95 (48%)/40 (20%) vs. 67 (35%)/77 (41%)/46 (24%) had DD/ID/II genotypes, respectively. Patients with nephropathy had higher plasma ACE levels (609 [151–1,504] ³g/l) compared with patients with normoalbuminuria (428 [55–1,630] ³g/l) (P < 0.001). Multiple linear regression analysis revealed that the plasma ACE level in patients with nephropathy is partially determined by ACE/ID polymorphism, mean arterial blood pressure, and glomerular filtration rate (r2 = 0.30, P < 0.001). There was no difference in genotype distribution between IDDM patients with proliferative retinopathy and those without diabetic retinopathy: 52 (34%)/74 (48%)/29 (19%) vs. 26 (39%)/25 (37%)/16 (24%) had DD/ID/II genotypes, respectively. There was also no difference in plasma ACE concentration detected among patients with no, simplex, or proliferative retinopathy. We conclude that the ACE/ID polymorphism does not contribute to the genetic susceptibility to diabetic nephropathy and proliferative retinopathy, whereas the raised plasma ACE concentration may play a role in the initiation and progression of diabetic nephropathy in Caucasian IDDM patients.

OBJECTIVE Hyperglycemia plays a pivotal role in the development and progression of vascular complications, which are the major sources of morbidity and mortality in diabetes. Furthermore, these vascular complications often persist and progress despite improved glucose control, possibly as a result of prior episodes of hyperglycemia. Epigenetic modifications mediated by histone methyltransferases are associated with gene-activating events that promote enhanced expression of key proinflammatory molecules implicated in vascular injury. In this study, we investigated genetic polymorphisms of the SETD7, SUV39H1, and SUV39H2 methyltransferases as predictors of risk for micro- and macrovascular complications in type 1 diabetes. RESEARCH DESIGN AND METHODS In the Finnish Diabetic Nephropathy Study (FinnDiane) cohort, 37 tagging single nucleotide polymorphisms (SNPs) were genotyped in 2,991 individuals with type 1 diabetes and diabetic retinopathy, diabetic nephropathy, and cardiovascular disease. Seven SNPs were genotyped in the replication cohorts from the Steno Diabetes Center and All Ireland/Warren 3/Genetics of Kidneys in Diabetes (GoKinD) U.K. study. RESULTS In a meta-analysis, the minor T allele of the exonic SNP rs17353856 in the SUV39H2 was associated with diabetic retinopathy (genotypic odds ratio 0.75, P = 1.2 × 10−4). The same SNP showed a trend toward an association with diabetic nephropathy as well as cardiovascular disease in the FinnDiane cohort. CONCLUSIONS Our findings propose that a genetic variation in a gene coding for a histone methyltransferase is protective for a diabetic microvascular complication. The pathophysiological implications of this polymorphism or other genetic variation nearby for the vascular complications of type 1 diabetes remain to be investigated.

OBJECTIVE— Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy. RESEARCH DESIGN AND METHODS— Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria ≥300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations. RESULTS— Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29–2.19) (P = 1.0 × 10−4). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR of 1.63 [95% CI 1.30–2.05], P = 2.3 × 10−5). CONCLUSIONS— We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy.

The impact of irbesartan treatment on biomarkers of low-grade inflammation, endothelial dysfunction, growth factors, and advanced glycation end products (AGEs) during the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study was evaluated. IRMA 2 was a 2-year multicenter, randomized, double-blind trial in patients comparing irbesartan (150 or 300 mg once daily) versus placebo. The primary end point was onset of overt nephropathy. A subgroup (n = 269, 68%) was analyzed for biomarkers at baseline and after 1 and 2 years. High-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, fibrinogen, adhesion molecules, transforming growth factor-beta, and AGE peptides were assessed. Irbesartan treatment yielded significant changes in hs-CRP (based on generalized estimating equation regression coefficient) with a 5.4% decrease per year versus a 10% increase per year in the placebo group (P0.001). Fibrinogen decreased 0.059 g/l per year from baseline versus placebo's 0.059 g/l increase per year (P = 0.027). IL-6 showed a 1.8% increase per year compared with placebo's 6.5% increase per year (P = 0.005). Changes in IL-6 were associated with changes in albumin excretion (P = 0.04). There was no treatment effect on the other biomarkers. Irbesartan (300 mg once daily) reduces low-grade inflammation in this high-risk population, and this may reduce the risk of micro- and macrovascular disease.

Linkage studies have mapped loci for diabetic nephropathy and associated phenotypes on chromosome 3q. We studied 14 plausible candidate genes in the linkage region because of their potential role in vascular complications. In a large-scale study of patients from Denmark, Finland, and France who have type 1 diabetes, 1,057 case and 1,127 control subjects, as well as 532 trios, were investigated for association with diabetic nephropathy. We analyzed 69 haplotype-tagging single nucleotide polymorphisms and nonsynonymous variants that were identified by sequencing. Polymorphisms in three genes, glucose transporter 2 (SLC2A2), kininogen (KNG1), and adiponectin (ADIPOQ), showed nominal association with diabetic nephropathy in single-point analysis. The T-allele of SLC2A2_16459CT was associated with a decreased risk of diabetic nephropathy (odds ratio 0.79 [95% CI 0.66-0.96], P = 0.016), whereas the T-allele of KNG_7965CT and the A-allele of ADIPOQ_prom2GA were associated with increased risk of nephropathy (1.17 [1.03-1.32], P = 0.016; 1.46 [1.11-1.93], P = 0.006, respectively). Analyses of the transmission disequilibrium test showed similar trends only for ADIPOQ_prom2GA with the overtransmission of the A-allele to patients with diabetic nephropathy (1.52 [0.86-2.66], P = NS) and of the G-allele to patients without diabetic nephropathy (0.50 [0.27-0.92], P = 0.026). The overall significance for this variant (nominal P = 0.011) suggests that ADIPOQ might be involved in the development of diabetic nephropathy.

Inflammation and complement activation via the mannose-binding lectin (MBL) pathway have been suggested to play a role in the pathogenesis of diabetic microvascular complications. The association between the complement-activating protein MBL and the development of persistent microalbuminuria was evaluated in an inception cohort of 286 newly diagnosed type 1 diabetic patients consecutively admitted to the Steno Diabetes Center between 1 September 1979 and 31 August 1984. Serum MBL was measured with an immunofluorometric assay in 270 of the patients (159 men) after 3 years of diabetes duration. During the median (range) follow-up period of 18.0 (1.0-21.8) years, 75 patients subsequently progressed to persistent micro- or macroalbuminuria (urinary albumin excretion rate30 mg/24 h). In patients with MBL levels above the median (1,597 microg/l), the cumulative incidence of persistent micro- or macroalbuminuria was 41% (CI 31-50) as compared with 26% (CI 17-34) in patients with MBL levels below the median (log-rank test, P = 0.003). In a Cox proportional hazard model with sex and age as fixed covariates, MBL was independently associated with later development of persistent micro- or macroalbuminuria (hazard ratio 1.21 [CI 1.02-1.42] per 1,000 microg/l increase in MBL; P = 0.03) after adjusting for possible confounders. In our study, high levels of MBL early in the course of type 1 diabetes was significantly associated with later development of persistent micro- or macroalbuminuria, suggesting that complement activation initiated by MBL may be involved in the pathogenesis of diabetic microvascular complications.

It has been demonstrated that intrauterine growth retardation, defined as birth weight below the 10th percentile, gives rise to a reduction in nephron number. Oligonephropathy has been suggested to increase the risk for systemic and glomerular hypertension in adult life as well as enhance risk for expression of renal disease after exposure to potentially injurious renal stimuli. The aimof this study was to determine if low birth weight is a risk factor for development of diabetic nephropathy. In a case-control study, we investigated 184 (110 men) insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy (persistent albuminuria >300 mg/24 h)(age [mean ± SD] 41.0 ± 9.3 years, duration of diabetes 26.9 ± 8.2 years) and 182 (111 men) normoalbuminuric (

Conflicting results have been reported on the relationship between familial predisposition to hypertension and development of diabetic nephropathy in IDDM. In our case-control study, we assessed the prevalence of hypertension among parents of 73 IDDM patients with diabetic nephropathy (DN+; persistent albuminuria > 200 microg/min or > 300 mg/24 h) and 73 IDDM patients without diabetic nephropathy (DN-; urinary albumin excretion < 20 microg/min or < 30 mg/24 h). Arterial hypertension, defined as antihypertensive therapy or a 24-h ambulatory blood pressure (SpaceLabs 90207) > or = 135/85 mmHg, was present in 57% of parents of DN+ patients compared with 41% of parents of DN- patients (P = 0.034; difference 16% [95% CI 1.3-29.6%]). In addition, the cumulative incidence of hypertension was higher among parents of DN+ patients (log-rank test P < 0.001), with a shift toward younger age at onset of hypertension in this group. However, the difference in prevalence of parental hypertension was not evident using office blood pressure measurements (64 vs. 57%; NS; difference 7% [-5.8-20%). Furthermore, patients with DN+ and with antihypertensive therapy in both parents were themselves more frequently treated for hypertension than were patients with DN+ and without parental treatment for hypertension (100 vs. 61%; P = 0.034; difference 39% [21-57%]). In conclusion, familial predisposition to essential hypertension increases the risk of diabetic nephropathy and may also contribute to the development of systemic hypertension in patients with IDDM and diabetic nephropathy.

Our objective was to compare the effect of a long-acting calcium antagonist (nisoldipine) versus an ACE inhibitor (lisinopril) on albuminuria, arterial blood pressure, and glomerular filtration rate (GFR) in hypertensive IDDM patients with diabetic nephropathy. We performed a 1-year, double-blind, doubledummy, randomized, controlled study comparing nisoldipine (20–40 mg once daily) with lisinopril (10–20 mg once daily) in 52 hypertensive IDDM subjects with diabetic nephropathy. Three patients dropped out, and results for the remaining 49 (25 nisoldipine, 24 lisinopril) are presented. Diuretics were required in 10 nisoldipineand 8 lisinopril-treated patients. Every 3 months, 24-h ambulatory blood pressure (TM2420, A&D, Tokyo, Japan) and albuminuria in three 24-h samples (enzyme immunoassay) were measured; GFR (51Cr-EDTA plasma clearance) was recorded every 6 months. Mean arterial blood pressure (24 h) was reduced from (mean ± SE) 108 ± 3 mmHg at baseline to 101 ± 2 in average during treatment in the lisinopril group and from 105 ± 2 to 103 ± 2 in the nisoldipine group (P = 0.06 comparing changes in the two groups). Albuminuria was reduced 47% (95% CI 21–65) in the lisinopril group versus an increase of 11% (−3 to 27) in the nisoldipine group (P = 0.001). Fractional albumin clearance was reduced 37% (95% CI 4–59%) in the lisinopril versus an increase of 35% (8–69%) in the nisoldipine group (P < 0.01). GFR decreased from 85 ± 5 ml · min−1 · 1.73 m−2 to 73 ± 5 in the lisinopril group and from 84 ± 6 to 80 ± 7 in the nisoldipine group (P < 0.05). The effect of study medication on albuminuria and GFR was independent of changes in systemic blood pressure and baseline variables in multiple regression analyses. In summary, lisinopril reduced albuminuria, but also GFR, to a greater extent than did nisoldipine in hypertensive IDDM patients with diabetic nephropathy during the 1st year of treatment. Longer follow-up is required to clarify whether these drugs have different renoprotective effects.

We read with interest the article by Wanic et al. (1) in which they present the first prospective data on polymorphisms in carnosinase genes and progression of diabetic nephropathy in diabetic patients. Prior studies, in which a polymorphism in carnosinase gene CNDP1 was identified and confirmed as a risk factor, were cross-sectional and mostly in patients with type 2 diabetes (2–4). At variance with …