Skin collagen pentosidine and fluorescence in diabetes were predictors of retinopathy progression and creatininemia increase already 6years after punch-biopsy.

OBJECTIVE: Advanced glycation end products (AGEs) of collagens appear to contribute to microvascular complications in diabetes. Do high concentrations of AGEs in skin collagen predict accelerated progression of these complications after 6 years and indicate the need for tighter anti-diabetic treatment? DESIGN AND METHODS: We measured two AGE parameters in collagen extracted from skin punch-biopsies: pentosidine and fluorescence at 370/440nm, as markers and predictors of microvascular complications, in 30 patients with diabetes (14 type-1, 16 type-2) without renal insufficiency, and in age- and gender-matched normoglycemic controls, followed at Hôtel-Dieu in Paris. RESULTS: At the time of biopsy, marked increases in pentosidine (p=0.0014) and fluorescence (p=0.0001) expressed per collagen hydroxyproline, were found in the patients with diabetes versus the controls. A significant effect of age was found for pentosidine, but not fluorescence, measurements in the normoglycemic controls. Therefore pentosidine but not fluorescence results were corrected for age in the patients. Pentosidine and fluorescence were correlated with diabetes duration. Fluorescence was significantly dependent on retinopathy presence and score in type-1 and type-2 diabetes, whereas pentosidine was not. Fluorescence was correlated with microalbuminuria only in type-1 diabetes. Neither fluorescence nor pentosidine were correlated with creatininemia. Already six years after biopsy, retinopathy score progression and creatininemia increase were significantly correlated with initial pentosidine and fluorescence measurements. CONCLUSIONS: These AGEs are good predictors of progression of microvascular complications and appear to be pathogenic. High skin concentrations of AGEs should induce tighter anti-diabetic treatment.

Evolution of diabetes insulin delivery devices.

The first manufactured insulin pump was introduced in the 1970s and the first insulin pens in 1985; since then, many improvements have been made to both devices. The advantages of pens over syringes have been confirmed in numerous studies and include greater accuracy, ease of use, patient satisfaction, quality of life, and adherence. United States claims database analyses indicate that the improved adherence made possible by use of an insulin pen has the potential to reduce diabetes care costs when compared with using a vial and syringe. Features of certain advanced pump models include the ability to connect wirelessly to a blood glucose meter or to a subcutaneous interstitial glucose sensor for semicontinuous glucose-driven insulin rate adjustment. A new trend in the design of insulin pumps is the tubing-free patch pump that adheres directly to the skin. The low rate of insulin pen usage in the United States compared with European countries and the fact that many patients report that they are not offered the option of an insulin pen by their physician suggest that there is a need to increase patient and provider awareness of the currently available devices for insulin administration.

Lacosamide in painful diabetic neuropathy: an 18-week double-blind placebo-controlled trial.

UNLABELLED: The efficacy and tolerability of oral lacosamide (200, 400, and 600 mg/day) was evaluated in patients with painful diabetic neuropathy in a double-blind, randomized, placebo-controlled trial. The primary target dose to be confirmed was lacosamide 400 mg/day. Efficacy was assessed by changes in pain scale scores from baseline, with changes over the last 4 weeks of the 12-week maintenance period regarded as the primary endpoint. Endpoint reductions in mean pain score were higher with all doses of lacosamide, reaching the level of significance with 400 mg/day (P = .05). Over the treatment period (titration + maintenance), pain relief was significantly higher than placebo with lacosamide 400 (P = .02) and 600 mg/day (P = .03). Lacosamide had an early-onset effect with significant reductions over placebo during the titration period. Nonparametric and mixed-model analysis approaches gave similar results, supporting significant efficacy at 400 mg/day. Secondary criteria such as Patient's Global Impression of Change, responder rates, and pain-free days provided additional support. Adverse events included dizziness, nausea, and headache. Incidence of cognitive and behavioral adverse events was low. This trial suggests that lacosamide has beneficial effects and may be a suitable treatment option for patients with diabetic neuropathic pain. PERSPECTIVE: This study presents efficacy and safety results of a phase 3, double-blind, placebo-controlled trial of the anticonvulsant drug lacosamide in patients with painful diabetic neuropathy. Lacosamide treatment at a dose of 400 mg/day reduced diabetic neuropathic pain with a favorable safety and tolerability profile that may be suitable for patients with diabetes.

Comparison of a multiple daily insulin injection regimen (basal once-daily glargine plus mealtime lispro) and continuous subcutaneous insulin infusion (lispro) in type 1 diabetes: a randomized open parallel multicenter study.

OBJECTIVE: Insulin pump therapy (continuous subcutaneous insulin infusion [CSII]) and multiple daily injections (MDIs) with insulin glargine as basal insulin and mealtime insulin lispro have not been prospectively compared in people naïve to either regimen in a multicenter study. We aimed to help close that deficiency. RESEARCH DESIGN AND METHODS: People with type 1 diabetes on NPH-based insulin therapy were randomized to CSII or glargine-based MDI (both otherwise using lispro) and followed for 24 weeks in an equivalence design. Fifty people were correctly randomized, and 43 completed the study. RESULTS: Total insulin requirement (mean +/- SD) at end point was 36.2 +/- 11.5 units/day on CSII and 42.6 +/- 15.5 units/day on MDI. Mean A1C fell similarly in the two groups (CSII -0.7 +/- 0.7%; MDI -0.6 +/- 0.8%) with a baseline-adjusted difference of -0.1% (95% CI -0.5 to 0.3). Similarly, fasting blood glucose and other preprandial, postprandial, and nighttime self-monitored plasma glucose levels did not differ between the regimens, nor did measures of plasma glucose variability. On CSII, 1,152 hypoglycemia events were recorded by 23 of 28 participants (82%) and 1,022 in the MDI group by 27 of 29 patients (93%) (all hypoglycemia differences were nonsignificant). Treatment satisfaction score increased more with CSII; however, the change in score was similar for the groups. Costs were approximately 3.9 times higher for CSII. CONCLUSIONS: In unselected people with type 1 diabetes naïve to CSII or insulin glargine, glycemic control is no better with the more expensive CSII therapy compared with glargine-based MDI therapy.

Basal-bolus therapy with insulin detemir using the 303 algorithm in the US PREDICTIVE 303 trial.

INTRODUCTION: The aim of this study was to compare a simplified patient-driven algorithm (303 Algorithm) to physician-driven adjustments in a subset of 193 patients with type 2 diabetes from the PREDICTIVE 303 study who were using basal-bolus insulin therapy. METHODS: PREDICTIVE 303 was a 26-week, randomized, phase 4 study, in which subjects were either instructed to adjust their insulin detemir dose every 3 days by +/-3 units if mean fasting plasma glucose (FPG) values were above 110 mg/dL or below 80 mg/dL (303 Algorithm), or had physicians adjust the insulin detemir dose according to usual practice (Standard-of-care). RESULTS: Patients in both groups achieved similar reductions in glycated hemoglobin (-0.2% and -0.3% for 303 Algorithm and Standard-of care groups, respectively; between groups P=0.60). 303 Algorithm group patients achieved a greater reduction in FPG (-21.3 mg/dL vs. 0.2 mg/dL; between groups P=0.03). Both 303 Algorithm and Standard-of care groups experienced a similar rate of overall hypoglycemia, and similar weight reduction (-1.7 kg and -0.4 kg, respectively; between groups P=0.07). Over 82% of patients in both groups used insulin detemir once daily. CONCLUSIONS: Adjustments of a once-daily detemir dose by patients using the 303 Algorithm in a basal-bolus setting is equally effective in improving glycemic control in patients with type 2 diabetes compared with physician-directed basal dose adjustments.

Inhaled insulin: promises and concerns.

Since the introduction of Pfizer Exubera in the early 1990s, a number of other inhaled insulin solutions have been developed. This article provides an overview of inhaled insulin systems developed by Pfizer, Novo Nordisk, MannKind, and Lilly, three of which are currently in phase 3 trials. The strengths and weaknesses of each product, as well as the general technologies (liquid vs dry powder), are evaluated. Results of clinical studies conducted by Pfizer and corroborated by other studies are summarized. Although inhaled insulin promises much, a greater body of controlled studies is necessary to draw firm conclusions about its safety and efficacy.

Improving glycemic control with insulin detemir using the 303 Algorithm in insulin naïve patients with type 2 diabetes: a subgroup analysis of the US PREDICTIVE 303 study.

OBJECTIVE: PREDICTIVE 303 was a 26-week, prospective, randomized, open-label, multi-center study in patients with type 2 diabetes that investigated whether patient-driven adjustments of insulin detemir doses using the 303 Algorithm achieved similar glycemic control compared to standard-of-care, physician-driven adjustments in doses. This post hoc sub-analysis evaluates insulin naïve patients on oral anti-diabetic drugs (OADs) who were directed to start on once-daily insulin detemir as add-on therapy to any other glucose-lowering regimens. METHODS: Patients in the 303 Algorithm group were instructed to adjust their detemir dose every 3 days based on mean fasting plasma glucose (FPG) values using a simple algorithm: mean FPG < 80 mg/dL, reduce dose by 3 units; between 80-110mg/dL, no change; > 110mg/dL, increase by 3 units. Physicians adjusted the detemir dose for patients in the Standard-of-care group according to their usual practice. No control insulin was used for comparison to insulin detemir. RESULTS: Reductions in glycosylated hemoglobin (HbA(1c)) from baseline were similar between those patients in the 303 Algorithm and Standard-of-care groups (-1.1 and -1.0%, respectively; between group p = 0.0933); patients in the 303 Algorithm group achieved a greater reduction in FPG. Patients in both groups experienced a similar, low rate of hypoglycemia. Over 95% and 92% of patients, respectively, used detemir once daily. CONCLUSION: These data indicate that patients with type 2 diabetes naïve to insulin can effectively implement the 303 Algorithm to initiate and adjust a once-daily dose of insulin detemir to achieve improvements in glycemic control.

Association between a protein polymorphism in the start codon of the vitamin D receptor gene and severe diabetic retinopathy in C-peptide-negative type 1 diabetes.

CONTEXT: The vitamin D (VD) receptor (VDR) is extensively expressed in retina. The plasma concentration of 1,25-dihydroxyvitamin D3 has been inversely correlated with the severity of diabetic retinopathy (DR), which raises the possibility that VD, through its antiinflammatory, antioxidant, antiproliferative, and antiangiogenic properties, may protect diabetic retina. The TaqI VDR polymorphism has been associated with severe DR. The FokI VDR polymorphism is a T-to-C substitution in the first codon (f allele), abolishing the first translation initiation site and resulting in a peptide lacking three amino acids (F allele), which increases the transcriptional activity of VDR. OBJECTIVE AND DESIGN: To examine whether FokI polymorphism is involved in severe DR, 254 Caucasians with longstanding C-peptide-negative type 1 diabetes, 128 patients with absent/mild DR (control group), and 126 patients with preproliferative/proliferative DR (study group) were genotyped using PCR-restriction fragment length polymorphism analysis. RESULTS: The genotype distribution was in Hardy-Weinberg equilibrium and was different between groups (P = 0.046). The frequency of F allele was significantly higher in the control (66.4%) than in the study group (56%, odds ratio = 0.64, 95% confidence interval 0.44-0.92, P = 0.016). In subjects with fewer than 25 yr of diabetes duration (median value, n = 134), this association was strongly increased (P = 0.0008). CONCLUSIONS: In conclusion, we observed, in a cohort of Caucasians with C-peptide-negative type 1 diabetes, a novel association between the functional FokI VDR polymorphism and severe DR, especially among subjects with fewer than 25 yr of diabetes duration.

The T-786C and C774T endothelial nitric oxide synthase gene polymorphisms independently affect the onset pattern of severe diabetic retinopathy.

Genetic factors could be implicated in the pathogenesis of severe diabetic retinopathy (DR). Recently, we reported a strong association between the eNOS4b/a endothelial nitric oxide synthase (eNOS) polymorphism and severe DR. To examine whether T-786C and C774T eNOS polymorphisms are involved in severe DR, 254 Caucasians with longstanding C-peptide-negative type 1 diabetes, 128 patients with absent/mild DR (control group), and 126 patients with preproliferative/proliferative DR (study group) were genotyped. The distribution of T-786C and C774T eNOS polymorphisms was in Hardy-Weinberg equilibrium and did not differ between the study and control groups. However, in case patients (n=126), T-786C and C774T polymorphisms influenced the onset pattern of severe DR (P=0.0169 and P=0.0257, respectively). The C-786C genotype was associated with early-onset severe DR (duration of diabetes: 15.2+/-5.9 vs. 19.4+/-6.3 years, P=0.0105), and the homozygous T774T genotype was associated with late-onset severe DR (24.3+/-7.0 vs. 18.4+/-6.2 years, P=0.0067). In the case of patients with high glycosylated hemoglobin levels (HbA1c >8%, n=88), the association between the T-786C polymorphism and early-onset severe DR was stronger (P=0.0068). Case patients carrying the C-786C genotype had higher HbA1c values (9.61+/-1.89%) than those carrying the T-786T genotype (8.93+/-1.47%, P=0.0173). Multivariate analysis showed that T-786C polymorphism was the best independent factor for onset pattern of severe DR (P<0.001). These findings, supported by previous associations between eNOS4b/a polymorphism and DR, suggest that T-786C and C774T eNOS polymorphisms affect the onset pattern of severe DR.

Inhaled insulin for the treatment of diabetes: projects and devices.

A non-invasive alternative to insulin injections would represent a major improvement for Type 1 and 2 insulin-treated patients. The lung is the only route which allows bio-availability of insulin, approaching 10% without absorption enhancers. However, the reproducibility of the plasma response to the pulmonary insulin is similar to subcutaneous insulin analogues, that is to say, relatively poor. In the Exubera Project, the device is a dry powder inhaler. The insulin powder (Aventis) is packaged into a single dose blister containing 1 or 3 mg; the 1 mg blister corresponding to approximately 3 U of insulin. Phase II studies have shown similar efficacy than regular insulin. Data are available on 328 Type 1 and 309 Type 2 patients after 6 months of Phase III trials. The inhaled insulin group developed increased insulin antibodies. A total of 25% of the patients experienced cough after inhalation. The number of overall and severe hypoglycaemic episodes were similar in the two groups. Pulmonary function tests remained stable and normal except for minor reductions of carbon monoxide diffusion capacity. The AERx IDMS system is a microprocessor-controlled, aqeous mist inhaler. The insulin (regular 100 U/ml, Novo Nordisk) is delivered by 1 U increments. The clinical experience reported with this system so far is limited to 107 Type 2 insulin-treated patients. The results are similar to those obtained in the Exubera trials. In the Alkermes project, large, porous, regular insulin of low-mass density have been developed by the Advanced Inhalation Project. Results from human studies in normal subjects show similar pharmacokinetics as the two other devices above. Other projects seem less advanced than the projects cited above e.g., Aerodos and Oralin. Current clinical experience with inhaled insulin seems promising. It represents currently the only viable non-invasive alternative to insulin injections. However, long-term local tolerance of the pulmonary tissue is a crucial issue.

Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart.

OBJECTIVE: Insulin detemir is a soluble basal insulin analog with a unique mechanism of protracted action designed to reduce the variability associated with conventional basal insulins. This trial compared the glycemic control, risk of hypoglycemia, and effect on body weight of insulin detemir and NPH insulin in patients with type 1 diabetes treated with rapid-acting insulin aspart at meals. RESEARCH DESIGN AND METHODS: This study was a 6-month multinational open parallel-group comparison conducted at 46 centers in five countries and included 448 patients with type 1 diabetes randomized 2:1 to insulin detemir or NPH insulin, respectively. RESULTS: After 6 months, comparable HbA(1c) levels were found between the two treatment groups. Fasting plasma glucose tended to be lower in patients treated with insulin detemir, but this difference was not statistically significant (-0.76 mmol/l, P = 0.097). Within-subject variation in self-measured fasting blood glucose was lower with insulin detemir than with NPH insulin (SD 3.37 vs. 3.78 mmol/l, P < 0.001). Risk of hypoglycemia was 22% lower with insulin detemir than with NPH insulin (P < 0.05) and 34% lower for nocturnal (2300-0600) hypoglycemia (P < 0.005). Nightly plasma glucose profiles were smoother and more stable with insulin detemir (P = 0.05). Body weight was significantly lower with insulin detemir at the end of the trial (P < 0.001). CONCLUSIONS: Treatment with insulin detemir resulted in more predictable glycemic control, with smoother plasma glucose profiles than NPH insulin and a significant reduction in the risk of hypoglycemia. The reduction in body weight with insulin detemir is a potential additional advantage. Regimens optimized for insulin detemir may be able to improve glycemic control beyond that possible with NPH insulin.