Conventional Insulin Treatment Research Articles

The effects of exercise training versus intensive insulin treatment on skeletal muscle fibre content in type 1 diabetes mellitus rodents

BackgroundIntensive-insulin treatment (IIT) strategy for patients with type 1 diabetes mellitus (T1DM) has been associated with sedentary behaviour and the development of insulin resistance. Exercising patients with T1DM often utilize a conventional insulin treatment (CIT) strategy leading to increased insulin sensitivity through improved intramyocellular lipid (IMCL) content. It is unclear how these exercise-related metabolic adaptations in response to exercise training relate to individual fibre-type transitions, and whether these alterations are evident between different insulin strategies (CIT vs. IIT). Purpose: This study examined glycogen and fat content in skeletal muscle fibres of diabetic rats following exercise-training.MethodsMale Sprague-Dawley rats were divided into four groups: Control-Sedentary, CIT- and IIT-treated diabetic sedentary, and CIT-exercised trained (aerobic/resistance; DARE). After 12 weeks, muscle-fibre lipids and glycogen were compared through immunohistochemical analysis.ResultsThe primary findings were that both IIT and DARE led to significant increases in type I fibres when compared to CIT, while DARE led to significantly increased lipid content in type I fibres compared to IIT.ConclusionsThese findings indicate that alterations in lipid content with insulin treatment and DARE are primarily evident in type I fibres, suggesting that muscle lipotoxicity in type 1 diabetes is muscle fibre-type dependant.

Intensive Insulin Therapy (Basal-Bolus).

Intensive insulin therapy (IIT) aims at achieving near-normal glycemic control and usually uses a basal-bolus (BB) schema to mimic physiologic insulin secretion. The treatment burden of IIT should be outweighed by improved glycemic control and reduction of chronic complications, but reviews summarizing the effects of IIT in subjects with T1DM and T2DM in glycated hemoglobin, hypoglycemia, insulin doses, and weight are limited. We performed a PubMed search to identify relevant randomized control trials (RCTs) comparing IIT and conventional insulin treatment in T1DM and T2DM subjects and addressing glycated hemoglobin, hypoglycemia, insulin requirements, and weight. We have identified 11 RCTs in T1DM subjects, published years ago and very heterogenous in design. Throughout the studies there was a consistent superiority of IIT in glycated hemoglobin reduction, a higher rate of severe hypoglycemia and more weight gain in the IIT group without a clear effect on insulin doses. We have identified 2 RCTs in T2DM subjects, only one of them using a definite BB schema in the IIT group. IIT induced more hypoglycemia and better HbA1c, but not more weight gain. IIT is the best option for treatment of subjects with T1DM in HbA1c reduction with a cost in the rate of hypoglycemia and weight gain. In subjects with T2DM, IIT also yields improvement in HbA1c versus conventional treatment, also at the cost of more hypoglycemic episodes, but not of higher weight gain. RCT treatment arms did not only differ in the insulin schema, but also in treatment goals, therapeutic education, and frequency of clinical visits among other characteristics. However, most evidence was gained using a BB insulin schema in the intensive arm and it is likely that the insulin schema had a relevant contribution in the results.

Type1 diabetes management and outcomes: A multicenter study in Thailand.

Aims/IntroductionThe Thai Type 1 Diabetes and Diabetes Diagnosed Before Age 30 Years Registry, Care and Network was established in 2014 and involved 31 hospitals. The objective of the registry was to evaluate glycemic control and complications of patients with type 1 diabetes.Materials and MethodsPatients’ demographics, clinical data, frequencies of daily self‐monitoring of blood glucose (SMBG), glycemic control and complications were collected.ResultsAmong the 1,907 type 1 diabetes patients, the mean age was 21.2 ± 11.3 years. The mean glycated hemoglobin level was 9.35 ± 2.41%, with significant variations among age groups (P < 0.001). Conventional insulin treatment and intensive insulin treatment were used in 43 and 57% of patients, respectively. Mean glycated hemoglobin levels were significantly higher in patients treated with conventional insulin treatment compared to those treated with intensive insulin treatment (9.63 ± 2.34 vs 9.17 ± 2.46%, P = 0.002). Compared to the conventional insulin treatment group, significantly more patients in the intensive insulin treatment group achieved good glycemic control (P < 0.001), and fewer had diabetic retinopathy (P = 0.031). The prevalence of microvascular complications increased significantly with age (P < 0.001). Multivariate analysis showed good glycemic control to be associated with age 25 to <45 years, intensive insulin treatment with SMBG three or more times daily and diabetes duration of 1 to <5 years.ConclusionsMost Thai type 1 diabetes patients were not meeting the recommended glycemic target. As a result of this study, the national program to improve the quality of diabetes treatment and education has been implemented, and the results are ongoing.

Switch-over Study with Fast-acting Insulin Aspart Showing Lower Glycemic Variability in Type 2 Diabetics with Stage 4 Chronic Kidney Disease: A Case Series.

BackgroundDespite conventional insulin treatment being considered an effective approach for glycemic regulation during renal dysfunction, there is still a major clinical need for better insulin therapy to stabilize fluctuations in glucose levels.AimThe aim of this study was to assess the impact of mealtime fast-acting insulin aspart therapy on glycemic variability as compared to regular human insulin therapy in advanced chronic kidney disease (CKD) patients with type 2 diabetes (T2D).MethodsData from eight patients were retrospectively collected after analyzing 57 patients' data between July 2019 and October 2019. All T2D patients with stage 4 CKD were switched to mealtime fast-acting insulin aspart on account of recurrent hypoglycemic events. The continuous glucose monitoring data of the first four days were analyzed to calculate the mean amplitude of glucose excursions (MAGE) as well as five other glycemic variability indices, namely, standard deviation, mean, continuous overall net glycemic action, average daily risk range, and J index.ResultsThe primary endpoint of 24-h MAGE significantly decreased from 7.01 ± 2.59 to 4.19 ± 1.06 mg/dL (p = 0.012) when short-acting regular human insulin (RHI) therapy was replaced with mealtime fast-acting insulin aspart therapy. However, no significant change was observed in 24-h mean glucose levels and other indices of glucose variability. Significant reduction in 24-h and night-time hypoglycemic events was reported in patients after therapy switch during the four-day follow-up period.ConclusionsThe present study demonstrated an improvement in glycemic variability with the administration of fast-acting insulin aspart as compared to RHI, suggesting that modern bolus insulin replacement might prove to be a useful therapeutic strategy in type 2 diabetes patients with advanced CKD. Further clinical studies will be required to confirm the benefits of this therapeutic approach.Relevance for patientsThe safety and effectiveness of fast-acting insulin aspart in CKD patients have not yet been established. The clinical effectiveness and better safety profile of newer mealtime insulin therapy may prompt a reconsideration of its use in patients with an advanced stage of renal dysfunction, leading to better adherence and improved quality of life.

264-OR: Treatment with Human Placental Lactogen (hPL-A) Improves Glucose Homeostasis One Year after Pancreatic Islets Transplantation in Mice Anterior Eye Chamber

Type 1 diabetes (T1D) is a chronic disease characterized by destruction of insulin producing beta cells in the pancreas. In addition to conventional insulin treatment, islets transplantation represents an alternative and promising therapeutic approach to treat patients with T1D. Increasing evidences suggest that human placental lactogen (hPL), a polypeptide placental hormone, is able to promote islets survival and proliferation in vitro, however it is unknown its implication in vivo models. Therefore, in the present study, we used hPL isoform A (hPL-A) to evaluate the role of this hormone in murine engrafted islets. T1D was induced in C57BL6/J male mice by a single intraperitoneal high dose (180 mg/kg) of streptozotocin (STZ). Collagenase p and a Histopaque 1110 gradient solution were used to isolate pancreatic islets. The anterior chamber of the eye was used to inject isolated islets. The engraftment was evaluated by confocal microscopy and immunohistochemical staining on section of the right and left eye. Glucose tolerance test (GTT) was used to assess glucose tolerance in mice. First, we evaluated the engraftment of freshly isolated pancreatic islets. Iris dissections showed a positive staining for insulin and glucagon. Second, since 2 months after transplantation, STZ-treated mice injected with islets stimulated with hPL-A, showed an improvement in fed glycaemia compared to STZ-treated mice transplanted with islets alone, and non-transplanted STZ-treated mice, for a follow-up of 1 year. Furthermore, mice treated with hPL-A, showed GTT with a similar pattern to untreated control mice; islets vascularization and angiogenesis was showed using CD31. Taken together, present results provide evidence that hPL-A could have a long-term effect on islet graft function and survival through enhancing glucose homeostasis. Disclosure G. Donadel: None. R. Arriga: None. V. Marchetti: Employee; Self; STEMCELL Technologies. D. Pastore: None. A. Coppola: None. F. Pacifici: None. M. Scioli: None. A. Orlandi: None. D. Della-Morte: None. Funding Italian Ministry of Instruction University and Research; Fondazione Roma

Free-living use of artificial pancreas for children with type 1 diabetes: systematic review

BACKGRAUND: A closed-loop glucose control system or artificial pancreas consists of three components a Continuous Glucose Monitor (CGM), infusion pumps to deliver hormone(s) and a sophisticated dosing algorithm to control hormone delivery. In the past years, numerous studies with closed-loop system devices were conducted with gradual shift to out-of-hospital environment and with lengthening study duration.&#x0D; AIMS: To compare efficacy and safety of closed-loop insulin pump use in children with type 1 diabetes mellitus in compare with conventional insulin treatment (continuous subcutaneous insulin infusion (CSII) with our without CGM) based on randomized control trials data (RCT).&#x0D; METHODS: In the systematic review we have include 28 randomized controlled trials results indexed in PubMed, Medline databases published till 15 June 2017. The efficacy on metabolic control in this study evaluated by the proportion of time within target range (preferably 70 to 180 mg/dl if reported) and mean (median) glucose based on sensor measurements, and the safety evaluated by time in hypoglycemia (below 70 mg/dl if reported).&#x0D; RESULTS: Increased time in range in the night period was observed in all RCT. Only 3 RCT showed decrease of the time in range within 24 h evaluation period. In one RCT the significant positive differences have been shown in the time in range for dual hormone closed-loop glucose control system in compare with insulin-only artificial pancreas. Mean glycaemia and glucose variability changes were not in the same manner in different RCT, both in the night only and in 24 h estimation period. Night hypoglycemia duration decreased in most RCT with closed-loop control in compare with CSII, and increased only in 2 RCT. When all-day estimation period the time in hypoglycemia changed not in the same manner in different RCT. Valuable methodology differences of the glycaemic control estimation within observed RCT brought significant complications in the data analysis and made impossible the results quantitative estimation to prepare a metaanalysis.&#x0D; CONCLUSIONS: Much work has been done to develop effective and safe artificial pancreas, but not all RCTs confirmed advantages of closed-loop glucose control in compare with CSII in children and adolescents in real life. More research with prospective randomized control design required to prove benefits of closed-loop glucose control. Further RCTs should have an uniform methodology for glycemic control assessment and long duration that will allow to use cumulative measures in a closed-loop efficacy estimation (HbA1c).

Diabetes Technology Update: Use of Insulin Pumps and Continuous Glucose Monitoring in the Hospital.

The use of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) systems has gained wide acceptance in diabetes care. These devices have been demonstrated to be clinically valuable, improving glycemic control and reducing risks of hypoglycemia in ambulatory patients with type 1 diabetes and type 2 diabetes. Approximately 30–40% of patients with type 1 diabetes and an increasing number of insulin-requiring patients with type 2 diabetes are using pump and sensor technology. As the popularity of these devices increases, it becomes very likely that hospital health care providers will face the need to manage the inpatient care of patients under insulin pump therapy and CGM. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized. Health care institutions must have clear policies and procedures to allow the patient to continue to receive CSII treatment to maximize safety and to comply with existing regulations related to self-management of medication. Randomized controlled trials are needed to determine whether CSII therapy and CGM systems in the hospital are associated with improved clinical outcomes compared with intermittent monitoring and conventional insulin treatment or with a favorable cost-benefit ratio.

Intensive insulin therapy increases glutathione synthesis rate in surgical ICU patients with stress hyperglycemia.

ObjectiveThe glutathione system plays an essential role in antioxidant defense after surgery. We assessed the effects of intensive insulin treatment (IIT) on glutathione synthesis rate and redox balance in cancer patients, who had developed stress hyperglycemia after major surgery.MethodsWe evaluated 10 non-diabetic cancer patients the day after radical abdominal surgery combined with intra-operative radiation therapy. In each patient, a 24-hr period of IIT, aimed at tight euglycemic control, was preceded, or followed, by a 24-hr period of conventional insulin treatment (CIT) (control regimen). Insulin was administered for 24 hours, during total parenteral nutrition, at a dosage to maintain a moderate hyperglycemia in CIT, and normoglycemic blood glucose levels in IIT (9.3±0.5 vs 6.5±0.3 mmol/L respectively, P<0.001; coefficient of variation, 9.7±1.4 and 10.5±1.1%, P = 0.43). No hypoglycemia (i.e., blood glucose < 3.9 mmol/L) was observed in any of the patients. Insulin treatments were performed on the first and second day after surgery, in randomized order, according to a crossover experimental design. Plasma concentrations of thiobarbituric acid reactive substances (TBARS) and erythrocyte glutathione synthesis rates (EGSR), measured by primed-constant infusion of L-[2H2]cysteine, were assessed at the end of each 24-hr period of either IIT or CIT.ResultsCompared to CIT, IIT was associated with higher EGSR (2.70±0.51 versus 1.18±0.29 mmol/L/day, p = 0.01) and lower (p = 0.04) plasma TBARS concentrations (2.2±0.2 versus 2.9±0.4 nmol/L).ConclusionsIn patients developing stress hyperglycemia after major surgery, IIT, in absence of hypoglycemia, stimulates erythrocyte glutathione synthesis, while decreasing oxidative stress.

Once-weekly administration of dulaglutide, a glucagon-like peptide-1 receptor agonist, as monotherapy and combination therapy: review of the AWARD studies

For the purpose of exploring the development, pharmacology and clinical trial program related to dulaglutide, we conducted a nonsystematic review of dulaglutide, focusing on the AWARD (Assessment of Weekly Administration of LY2189265 [dulaglutide] in Diabetes Assessment) program of randomized, phase 3 studies. Dulaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist that causes a variety of antidiabetogenic actions by acting on the incretin system. Steady-state plasma concentrations of dulaglutide are achieved between 2 and 4 weeks following a once-weekly administration. The AWARD 16 studies were conducted in patients with different treatment needs, ranging from patients with mild diabetes who can be treated with diet management and exercise to patients for whom target glycemic control cannot be achieved with conventional insulin treatment. Changes in HbA1c from baseline to the primary endpoint assessment (primary efficacy outcome) with dulaglutide were generally dose-dependent and significantly greater than those of active comparators and placebos (AWARD 15) or non-inferior to the comparators (AWARD 6). The results of secondary outcome measures demonstrated that glycemic control attained with dulaglutide was sustained for long-term and that a greater proportion of patients treated with dulaglutide achieved a target HbA1c level of 7.0% compared with placebo and/or active comparators. Reduction in fasting serum glucose, glucagon levels and body weight after dulaglutide treatment were noted in most AWARD studies. Although treatment-emergent adverse events were common with dulaglutide, the incidence was similar to that of active comparators in most AWARD studies, and serious adverse events were generally infrequent, except in patients with more severe disease or with prolonged therapy. Hypoglycemic and immunogenic events were also infrequent.&#x0D; In patients with type 2 diabetes, dulaglutide improves glycemic control and leads to clinically useful reduction in body weight in a range of treatment settings.

Effects of Exercise on Neuropathy in Streptozotocin-Induced Diabetic Rats.

ObjectiveTo evaluate the effects of early regular exercise and to assess the electrophysiological and histopathological findings of the rat tail nerve in relation to the timing of exercise training for swimming exercise in rats with diabetic neuropathy.MethodsWe used 70 Sprague-Dawley male rats, and the experimental group comprised 60 rats, and the control group comprised 10 rats. Diabetes was induced by intraperitoneal injection of streptozotocin. Blood glucose concentrations were measured in tail vein blood samples. The experimental group was divided into 6 subgroups according to insulin treatment and swimming exercise: group 1, diabetic control; group 2, insulin treated; group 3, insulin untreated with early swimming exercise; group 4, insulin treated and early swimming exercise; group 5, insulin treated and late swimming exercise; and group 6, insulin untreated with late swimming exercise. Sensory and motor nerve conduction studies were performed weekly up to the 13th week using rat tail nerves. The effect on structural diabetic neuropathy was assessed by morphometry and ultrastructural examination of the rat tail nerve fiber at the 14th week.ResultsAn exercise effect was observed in the insulin treated groups, but it was not observed in the insulin untreated groups. The sensory nerve conduction study in the rat tail revealed significantly prolonged latency and decreased amplitude in groups 1 and 6, and a further delay was observed in group 5 when compared to group 4. Decreased thickness of myelin was found in groups 1 and 6 through morphometry.ConclusionEarly regular exercise programs in addition to conventional insulin treatment may retard the progression of diabetic peripheral neuropathy.

Efficacy of insulin analogues in diabetic patients attending primary care centers.

Objectives:To measure the efficacy of new insulin analogues compared with the conventional types of insulin, and to compare their effects on patient satisfaction regarding their weight changes and the frequency of hypoglycemic episodes.Methods:In this retrospective cohort observational study, data was collected from the medical records of 122 eligible diabetics on insulin therapy attending government primary care centers in Jeddah, Kingdom of Saudi Arabia from June 2013 to July 2014. The data collected considered the efficacy, safety, and patient satisfaction of the types of insulin therapy used for their treatment.Results:After 12 weeks, there was a reduction in mean glycosylated hemoglobin (HbA1c) of -0.88% for the analogue type versus -0.19% for the conventional type, and at 24 weeks, the mean drop in HbA1c was -2.02% for the analogue type versus -1.12% for the conventional type, but the differences were not statistically significant. More patients (87% versus 38%) on analogue compared with conventional insulin treatment were satisfied with therapy.Conclusion:In the primary health care setting, insulin analogues showed greater efficacy improvements than conventional insulin therapy within 6 months. However, conventional insulin therapy can still be used at primary care centers with limited resources, and when patients refuse to be converted.

Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study

For patients with type 2 diabetes who do not achieve target glycaemic control with conventional insulin treatment, advancing to a basal-bolus insulin regimen is often recommended. We aimed to compare the efficacy and safety of long-acting glucagon-like peptide-1 receptor agonist dulaglutide with that of insulin glargine, both combined with prandial insulin lispro, in patients with type 2 diabetes. We did this 52 week, randomised, open-label, phase 3, non-inferiority trial at 105 study sites in 15 countries. Patients (aged ≥18 years) with type 2 diabetes inadequately controlled with conventional insulin treatment were randomly assigned (1:1:1), via a computer-generated randomisation sequence with an interactive voice-response system, to receive once-weekly dulaglutide 1·5 mg, dulaglutide 0·75 mg, or daily bedtime glargine. Randomisation was stratified by country and metformin use. Participants and study investigators were not masked to treatment allocation, but were unaware of dulaglutide dose assignment. The primary outcome was a change in glycated haemoglobin A1c (HbA1c) from baseline to week 26, with a 0·4% non-inferiority margin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01191268. Between Dec 9, 2010, and Sept 21, 2012, we randomly assigned 884 patients to receive dulaglutide 1·5 mg (n=295), dulaglutide 0·75 mg (n=293), or glargine (n=296). At 26 weeks, the adjusted mean change in HbA1c was greater in patients receiving dulaglutide 1·5 mg (-1·64% [95% CI -1·78 to -1·50], -17·93 mmol/mol [-19·44 to -16·42]) and dulaglutide 0·75 mg (-1·59% [-1·73 to -1·45], -17·38 mmol/mol [-18·89 to -15·87]) than in those receiving glargine (-1·41% [-1·55 to -1·27], -15·41 mmol/mol [-16·92 to -13·90]). The adjusted mean difference versus glargine was -0·22% (95% CI -0·38 to -0·07, -2·40 mmol/mol [-4·15 to -0·77]; p=0·005) for dulaglutide 1·5 mg and -0·17% (-0·33 to -0·02, -1·86 mmol/mol [-3·61 to -0·22]; p=0·015) for dulaglutide 0·75 mg. Five (<1%) patients died after randomisation because of septicaemia (n=1 in the dulaglutide 1·5 mg group); pneumonia (n=1 in the dulaglutide 0·75 mg group); cardiogenic shock; ventricular fibrillation; and an unknown cause (n=3 in the glargine group). We recorded serious adverse events in 27 (9%) patients in the dulaglutide 1·5 mg group, 44 (15%) patients in the dulaglutide 0·75 mg group, and 54 (18%) patients in the glargine group. The most frequent adverse events, arising more often with dulaglutide than glargine, were nausea, diarrhoea, and vomiting. Dulaglutide in combination with lispro resulted in a significantly greater improvement in glycaemic control than did glargine and represents a new treatment option for patients unable to achieve glycaemic targets with conventional insulin treatment. Eli Lilly and Company.

Soluble RAGE and the RAGE ligands HMGB1 and S100A12 in critical illness: impact of glycemic control with insulin and relation with clinical outcome.

Systemic inflammation often leads to complications in critically ill patients. Activation of the receptor for advanced glycation end-products (RAGE) generates inflammatory cytokines, proteases, and oxidative stress and may link inflammation to subsequent organ damage. Furthermore, hyperglycemia-induced oxidative stress increases RAGE ligands and RAGE expression. We hypothesized that preventing hyperglycemia during critical illness reduces the risk of excessively enhanced RAGE signaling, which could relate to clinical outcomes and risk of death. In 405 long-stay surgical intensive care unit patients randomized to intensive or conventional insulin treatment, serum concentrations of soluble RAGE (decoy receptor) and the RAGE ligands high-mobility group box 1 (HMGB1) and S100A12 were measured on admission, day 7, and last day. These were compared with levels in 71 matched control subjects and with C-reactive protein (CRP) as a routinely monitored inflammation marker. On admission, soluble RAGE, HMGB1, S100A12, and CRP were higher in patients than in controls. The HMGB1, S100A12, and CRP remained elevated throughout intensive care unit stay, whereas soluble RAGE decreased to levels lower than in controls by day 7. Unexpectedly, insulin treatment did not affect the circulating levels of these markers. In univariable analysis, elevated levels of soluble RAGE on admission were associated with adverse outcome, including circulatory failure, kidney failure, liver dysfunction, and mortality. The associations with circulatory and kidney failure remained significant in multivariable logistic regression analysis corrected for baseline risk factors. Critical illness affects components of RAGE signaling, unaffected by insulin treatment. Elevated on-admission soluble RAGE was associated with adverse outcomes.

Human islet transplantation

that achieves insulin-independent, constant normoglycemic state and avoidance of hypoglycemic episodes is the replacement of a patient’s islet of Langerhans either by pancreas transplantation or by isolated islet transplantation. The cost of this benefit, however, is the need for immunosupressive treatment of the recipient with all its potential risks. Currently, only vascularized pancreas transplantation can re-establish long-term normoglycemia however this has been associate with significant morbidity and mortality. Approximately 25.000 patients worldwide underwent this procedure and it has been shown to improve quality of life and even reverse some secondary complications of diabetes.4 Simultaneous pancreas and kidney transplantation are presently considered the standard of care for selected patients with type I diabetes with end-stage renal failure.5 Diabetes is a major burden to healthcare economies despite the use of exogenous insulin injections. Type I diabetes mellitus is a chronic metabolic disorder that currently afflicts 5 million individuals in the world. It results from auto-immune mediated destruction of insulin secreting beta cells in islet of Langerhans of the pancreas.1 Long-term studies strongly suggest that tight control of blood glucose achieved by conventional or intensive insulin treatment, self blood glucose monitoring, and patient education can significantly prevent developing and retard the progression of chronic complications of this disease.2 On the other hand, the cost of this benefit was a threefold increase in the number of severe hypoglycemic episodes, a significant increase of body weight and dietary and other lifestyle restrictions affecting the quality of life.3 The only treatment for Type I diabetes mellitus Human islet transplantation

A randomised, controlled trial of self-monitoring of blood glucose in patients with type 2 diabetes receiving conventional insulin treatment

We evaluated whether self-monitoring of blood glucose (SMBG) leads to better glycaemic control (HbA(1c)) in patients with type 2 diabetes on conventional insulin regimens. Patients with type 2 diabetes on a conventional insulin regimen (basal or premixed insulin with or without additional oral glucose-lowering agents) were recruited at study centres led by members of the German Diabetes Association. In a randomised, prospective, open 2 × 2 factorial design, the once-weekly performance of four-point glucose profiles (SMBG +; n = 151 patients) was compared with no SMBG (SMBG -; n = 149), and the measuring and transmitting of HbA1c results to the study centres (HbA(1c) +; n = 158, of these 82 SMBG - and 76 SMBG +) was compared with HbA1c measurement without disclosure of results (HbA(1c) -; n = 142, of these 67 SMBG - and 75 SMBG +). Randomised allocation was carried out by a central office, using sequentially numbered, sealed envelopes. The primary endpoint was the reduction of HbA(1c) compared with baseline after 12 months. Secondary analyses were of therapy intensification in response to higher blood or urinary glucose or HbA(1c). Participants and caregivers were not blinded as to the allocation of interventions, whereas the laboratory determining HbA(1c) remained blinded. Patient characteristics were balanced across groups. A total of 56 patients dropped out. In completers, HbA(1c) was reduced in the SMBG + group from 7.3% to 7.0%, i.e. by 0.3% (0.1%, 0.5%) vs SMBG - from 7.3% to 7.0% and 0.3% (0.2%, 0.5%), respectively, the difference being 0.0% (-0.2%, 0.2%) (p = 0.93). The disclosure of HbA(1c) results had no significant influence, with a difference of 0.1% (-0.1%, 0.4%) (p = 0.28). Values above are mean (95% CI). The ORs for therapy intensification significantly rose as the following increased: proportions of urine samples testing positive for glucose, HbA1c concentrations, and fasting or postprandial glucose concentrations. No important adverse events were associated with the interventions. SMBG profiles once weekly or the disclosure of HbA(1c) results did not improve glycaemic control in patients with type 2 diabetes on conventional insulin treatment, although indicators of hyperglycaemia increased the likelihood of therapy intensification. Greater intensification may be necessary to impact on glycaemic control. www.clinicaltrials.gov (registration code NCT00688363) FUNDING: Deutsche Diabetes-Gesellschaft, Deutsche Diabetes-Stiftung, Bayer Vital GmbH.

Conventional insulin vs insulin infusion therapy in acute coronary syndrome diabetic patients.

To evaluate the impact on glucose variability (GLUCV) of an nurse-implemented insulin infusion protocol when compared with a conventional insulin treatment during the day-to-day clinical activity. We enrolled 44 type 2 diabetic patients (n = 32 males; n = 12 females) with acute coronary syndrome (ACS) and randomy assigned to standard a subcutaneous insulin treatment (n = 23) or a nurse-implemented continuous intravenous insulin infusion protocol (n = 21). We utilized some parameters of GLUCV representing well-known surrogate markers of prognosis, i.e., glucose standard deviation (SD), the mean daily δ glucose (mean of daily difference between maximum and minimum glucose), and the coefficient of variation (CV) of glucose, expressed as percent glucose (SD)/glucose (mean). At the admission, first fasting blood glucose, pharmacological treatments (insulin and/or anti-diabetic drugs) prior to entering the study and basal glycated hemoglobin (HbA1c) were observed in the two groups treated with subcutaneous or intravenous insulin infusion, respectively. When compared with patients submitted to standard therapy, insulin-infused patients showed both increased first 24-h (median 6.9 mmol/L vs 5.7 mmol/L P < 0.045) and overall hospitalization δ glucose (median 10.9 mmol/L vs 9.3 mmol/L, P < 0.028), with a tendency to a significant increase in first 24-h glycaemic CV (23.1% vs 19.6%, P < 0.053). Severe hypoglycaemia was rare (14.3%), and it was observed only in 3 patients receiving insulin infusion therapy. HbA1c values measured during hospitalization and 3 mo after discharge did not differ in the two groups of treatment. Our pilot data suggest that no real benefit in terms of GLUCV is observed when routinely managing blood glucose by insulin infusion therapy in type 2 diabetic ACS hospitalized patients in respect to conventional insulin treatment.

S‐allyl cysteine restores erectile function through inhibition of reactive oxygen species generation in diabetic rats

Excessive production of reactive oxygen species (ROS) by an overactive nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system in penile tissue is an important mechanism of erectile dysfunction (ED). S-allyl cysteine (SAC), a bioactive component derived from garlic, was recently reported to exert versatile antioxidant properties. We hypothesized that SAC would be able to resolve diabetes-related ED by reducing ROS generation, and designed this study to investigate this possibility as well as to determine the related underlying mechanisms. A streptozotocin-induced diabetes rat model was established and used for comparative analysis of 4-week treatment regimens with insulin or SAC. The ratio of maximal intracavernous pressure (ICP) to mean arterial blood pressure (MAP) was measured to determine erectile function. Differential levels of ROS, NADPH oxidase subunits, nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signalling pathway, and apoptosis were evaluated in cavernous tissues. Max ICP/MAP was found to be markedly decreased in untreated diabetic rats; SAC, but not insulin, treatment restored the ratio to baseline (in non-diabetic untreated controls). The corpus cavernosum of untreated diabetic rats showed increased p47(phox) and p67(phox) expression, ROS production and penile apoptotic index, and decreased phospho-endothelial nitric oxide synthase (phospho-eNOS, Ser1177) expression, cGMP concentration, B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio and smooth muscle cell number. SAC treatment normalized all the diabetes-induced effects, whereas insulin treatment partially normalized the alterations, but produced no effects on P47(phox) expression, penile ROS level, apoptotic index, Bcl-2/Bax ratio and smooth muscle cell number. Collectively, these data indicate that SAC treatment can restore erectile function in diabetic rats by preventing ROS formation through modulation of NADPH oxidase subunit expression. Furthermore, the poor efficacy of conventional insulin treatment for diabetic ED may be associated with an elevated level of ROS in penile tissue.

Weighty Matters

Type 1 diabetes mellitus, characterized by a deficiency of insulin production owing to damaged pancreatic β-cells, is associated with a 10-fold increase in the risk of cardiovascular disease in comparison with the general population.1,2 Intensive insulin therapy, whether administered by multiple daily injections or continuous infusion via a pump, is the cornerstone of glycemic control in the patient with type 1 diabetes mellitus.3 Much of what we know regarding the benefits of intensive insulin therapy is derived from the Diabetes Control and Complications Trial (DCCT), a trial of patients with type 1 diabetes mellitus who were randomly assigned to either intensive or conventional insulin treatment. Article see p 180 The DCCT enrolled a total of 1441 patients with type 1 diabetes mellitus, beginning in 1983, with final closeout in 1993, for a total of 6.5 years of follow-up. Conventional therapy consisted of 1 or 2 daily injections of insulin with daily self-monitoring and examinations every 3 months, whereas intensive insulin therapy consisted of at least 3 insulin injections per day or external pump therapy with target blood glucose concentrations of 70 to 120 mg/dL fasting, postprandial glucose values of <180 mg/dL, and a target hemoglobin A1c goal in the normal range (<6.05%). The primary trial results showed that intensive therapy achieved a statistically significant lower hemoglobin A1c, evident by the first 3 months of the study, with a closeout A1c of 7.0% in the intensive therapy arm in comparison with 9.0% in the conventional arm. Importantly, those in the intensive insulin therapy arm experienced delayed progression of nephropathy, retinopathy, and neuropathy.4 In the primary trial, the risk of major cardiovascular events trended to significance, although the young age of the participants (mean age, 27 years at enrollment) rendered it difficult to detect a statistically significant …

Multiple complications and frequent severe hypoglycaemia in ‘elderly’ and ‘old’ patients with Type 1 diabetes

Elderly and old patients with Type 1 diabetes represent a growing population that requires thorough diabetes care. The increasing relevance of this subgroup, however, plays only a minor role in the literature. Here, we describe elderly patients with Type 1 diabetes on the basis of a large multi-centre database in order to point out special features of this population. Data of 64609 patients with Type 1 diabetes treated by 350 qualified diabetes treatment centres were assessed and analysed by age group. Compared with the age group ≤ 60 years, patients aged >60 years (n=3610 61-80 years and n=377 >80 years old) were characterized by a longer diabetes duration (27.7 vs. 7.7 years), an almost double risk for severe hypoglycaemia (40.1 vs. 24.3/100 patient-years), a lower level of HbA(1c) [60 vs. 67 mmol/mol (7.6 vs. 8.3%)] and higher percentages of microalbuminuria (34.5 vs. 15.6%), diabetic retinopathy (45.2 vs. 8.3%), myocardial infarction (9.0 vs. 0.4%) or stroke (6.8 vs. 0.3%). Elderly patients used insulin pumps less frequently (12.2 vs. 23.8%), but more often used conventional premixed insulin treatment (10.8 vs. 3.8%). Differences between elderly and younger patient groups were significant, respectively. Diabetes care of elderly patients with Type 1 diabetes involves individualized treatment concepts. Increased hypoglycaemia risk and functional impairment attributable to diabetes-associated and/or age-related disorders must be taken into account.

Timely Bolus Insulin for Glucose Control during Cardiopulmonary Bypass

Hyperglycemia during cardiopulmonary bypass (CPB) with glucose containing cardioplegia is common; normoglycemia is difficult to maintain and failure to do so may result in worse outcomes. The purpose of this quality improvement initiative was to show that a simple timely insulin bolus is more effective for glucose control during CPB with glucose containing cardioplegia than conventional (not standardized) glucose management in historical case-matched controls. A single bolus of insulin (.2 international units per kilogram; iu/kg) was administered, at the time of aortic cannulation, to 211 consecutive patients undergoing cardiac surgery with CPB and glucose containing cardioplegia. A further .1 iu/kg bolus of insulin was given for blood glucose (BG) measurements greater than 10.0 mmol/L (180 mg/dL) during CPB. The control group of 211 historical case-matched patients had glucose management according to anesthesiologist preference (insulin as a bolus, bolus plus infusion, infusion only, or no insulin). The frequency of hyperglycemia (BG &gt; 11.0 mmol/L; 198 mg/dL) during CPB was significantly less in the study group (22; 10.5%) than in the control group (117; 55.5%) (p &lt; .0001). Hyperglycemia in the first 6 hours in the intensive care unit was also significantly less frequent in the study group (5; 2.4%) than in the control group (14; 6.6%) (p = .03). Severe hypoglycemia (BG &lt; 2.8 mmol/L; 50.4 mg/dL) occurred in one patient (.47%) in the timely bolus insulin group and five patients (2.3%) in the control group (p = .09). The timely bolus insulin method is more efficacious, but equally safe, in preventing hyperglycemia during CPB with glucose containing cardioplegia, compared with conventional (not standardized) insulin treatment in historical case-matched controls.