Journal Watch

Prepared for IDDT by Jim Young

September 2015

Advanced glycation end products, measured in skin, vs. HbA1c in children with type 1 diabetes mellitus
Alena Banser et al. Pediatric Diabetes. Doi: 10.1111/pedi.12311

Advanced glycation end products (AGEs) are considered major contributors to microvascular and macrovascular complications in adult patients with diabetes mellitus. AGEs can be measured non-invasively with skin autofluorescence (sAF). The primary aim of this study was to determine sAF values in children with type 1 diabetes mellitus and to study correlations between sAF values and HbA1c and mean HbA1c over the year prior to measurement. It was found that sAF values correlated strongly with single HbA1c and mean HbA1c, making the non-invasive sAF measurement an interesting alternative to provide information about cumulative hyperglycemic states. The authors advise that in order to determine the value of sAF measurement in predicting long-term microvascular and macrovascular complications, further prospective follow-up studies are needed.


Effect of 4 years subcutaneous insulin infusion treatment on albuminuria, kidney function and HbA1c compared with multiple daily injections
S. Rosenlund et al. Diabetic Medicine. Doi: 10.1111/dme.12950

The effect of insulin pump [continuous subcutaneous insulin infusion (CSII)] treatment on diabetes complications in a modern clinical setting is largely unknown. The authors of this paper investigated the effect of 4 years CSII treatment on HbA1c, albuminuria and kidney function compared with multiple daily injections (MDI) in a single-centre clinical setting. All patients with Type 1 diabetes initiating CSII treatment from 2004 to 2010 were followed for at least 4 years. 193 were matched with 386 patients treated with MDI in the same period. It was found that treatment with CSII over 4 years independently reduced HbA1c and urinary albumin/creatinine ratio (UACR) compared with MDI. [Albumin Creatinine Ratio is the preferred test for detection of small amounts of albumin (protein) in the urine]. The authors posit that the reduction in UACR may be due to less glycaemic variability because the effect of CSII on HbA1c could only partially explain the effect. They suggest that this needs confirmation in randomized controlled trials.


Bolus estimation – rethinking the effect of meal fat content
Srinivas Laxminarayan et al. Diabetes Technology and Therapeutics. Doi:10.1089/dia.2015.0118

Traditionally, insulin bolus calculations for managing postprandial glucose levels in individuals with type 1 diabetes rely solely on the carbohydrate content of a meal. However, recent studies have reported that other macronutrients in a meal can alter the insulin required for good postprandial control. Specifically, studies have shown that high-fat (HF) meals require more insulin than low-fat (LF) meals with identical carbohydrate content. This study looked at the mechanisms underlying the higher insulin requirement by comparing HF and LF dinners with identical carbohydrate content in seven subjects with type 1 diabetes. They found that during the HF meal the time of peak meal-glucose appearance was significantly delayed, and insulin sensitivity was significantly lower The authors suggest that in addition to considering the putative delay in gastric emptying associated with HF meals clinicians should consider how the fat content of these meals may alter insulin sensitivity.


Treatment intensification without improved HbA1c levels in children and adolescents with Type 1 diabetes mellitus
S. M. Sildorf et al. Diabetic Medicine. Doi: 10.1111/dme.12900

This research examined trends in diabetes treatment in Danish children and adolescents with Type 1 diabetes mellitus, and compared treatment intensity with metabolic outcomes. The observational study included 4,527 children diagnosed with Type 1 diabetes before the age of 15 years between 2000 and 2012. Self-monitored blood glucose measurements, insulin injections/boluses, treatment method and metabolic control quantifications were analysed. Treatment was intensified via an increasing number of self-monitored blood glucose measurements and injections/boluses. The study found that more than six injections/boluses and an increased number of self-monitored blood glucose measurements was significantly associated with lower metabolic control. No reduction, however, in the overall mean HbA1c concentration was observed between 2005 [66 mmol/mol (8.2%)] and 2012 [65 mmol/mol (8.1%)]. The authors conclude that intensifying treatment alone does not lead to improved metabolic control in the overall population despite the appearance of lower HbA1c in individuals with a greater number of self-monitored blood glucose measurements and injections/boluses. The contradictory results reflect difficulties in using observational studies to predict results of intervention in the individual.


Earlier intensified insulin treatment of Type 1 diabetes and its association with long-term macrovascular and renal complications
B. Rathsman et al. Diabetic Medicine. Doi: 10.1111/dme.12897

This study investigated the incidence of all-cause mortality, composite mortality and morbidity in people with Type 1 diabetes formerly randomized in the Stockholm Diabetes Intervention Study. A total of 102 people with Type 1 diabetes were randomized in the period 1982 – 1984 to intensified conventional treatment or standard treatment with insulin for a mean of 7.5 years. The investigators re-evaluated this cohort for the period until 2011 with regard to all-cause mortality and composite mortality, which consisted of myocardial infarction, stroke and end-stage renal disease as primary endpoints. Secondary endpoints were first-time hospitalization for myocardial infarction and stroke or end-stage renal disease. Data on HbA1c levels were retrospectively collected between 1996 and 2011. It was found that during the follow-up of 28 years, 22 people died: seven in the intensified conventional insulin group compared with 15 in the standard treatment group. With regard to composite mortality, six people in the intensified conventional insulin group died compared with 11 in the standard treatment group. For the secondary endpoints, 11 people in the intensified conventional insulin group developed myocardial infarction or stroke compared with 17 in the standard treatment group, and one person in the intensified conventional insulin compared with seven people in the standard treatment group developed end-stage renal disease. Mean HbA1c levels did not differ between groups during the follow-up years. Notwithstanding the differences recorded between the groups in these results, the authors concluded that all-cause mortality, cardiovascular morbidity and progression to end-stage renal disease did not differ in a statistically significant way in people with Type 1 diabetes earlier randomized to intensified insulin treatment.


Diabetes Research Institute’s first patient in BioHub trial no longer requires insulin therapy
This press release from the Diabetes Research Institute (DRI) announced that the first patient in its clinical trial has been free from insulin injections in record time following the implantation of islet cells within a biological scaffold. The patient underwent the minimally invasive procedure on August 18th, 2015, and is now producing her own insulin naturally for the first time since being diagnosed with type 1 diabetes at age 17. In this pilot study, DRI researchers are testing a new transplant technique for insulin-producing cells, building upon decades of progress in clinical islet transplantation. This trial is an important first step toward the development of the DRI BioHub, a bioengineered mini-organ that mimics the native pancreas to restore natural insulin production in people with type 1 diabetes. This was the first tissue engineered islet transplant using a ‘biodegradable scaffold’ implanted on the surface of the omentum.


The primary glucose-lowering effect of metformin resides in the gut, not the circulation
John B. Buse et al. Diabetes Care. Doi: 10.2337/dc15-0488

Delayed-release metformin (Met DR) is formulated to deliver drug to the lower bowel to leverage the gut-based mechanisms of metformin action with lower plasma exposure. Met DR was assessed in two studies. Study one compared the bioavailability of single daily doses of Met DR to currently available immediate-release metformin (Met IR) and extended-release metformin (Met XR) in otherwise healthy volunteers. Study two assessed glycemic control in subjects with type 2 diabetes (T2DM) over 12 weeks. In study one it was found that the bioavailability of 1,000 mg Met DR bid was approximately 50% that of Met IR and Met XR. In study two, 600, 800, and 1,000 mg Met DR produced statistically significant, clinically relevant, and sustained reductions in fasting plasma glucose (FPG) levels over 12 weeks compared with placebo, with about a 40% increase in potency compared with Met XR. All treatments were generally well tolerated. The authors conclude that dissociation of the glycemic effect from plasma exposure with gut-restricted Met DR provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action.


Who gains clinical benefit from using insulin pump therapy?
J. Lawton et al. Diabetic Medicine. Doi: 10.1111/dme.12879

This study explored health professionals’ views about insulin pump therapy [continuous subcutaneous insulin infusion (CSII)] and the types of individuals they thought would gain greatest clinical benefit from using this treatment. In-depth interviews were conducted with staff who delivered the Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial. The study showed that staff perceived insulin pumps as offering a better self-management tool to some individuals due to the drip feed of insulin, the ability to alter basal rates and other advanced features. However, staff also noted that, because of the diversity of features on offer, CSII is a more technically complex therapy to execute than multiple daily injections. For this reason, staff described how, alongside clinical criteria, they had tended to select individuals for CSII in routine clinical practice based on their perceptions about whether they possessed the personal and psychological attributes needed to make optimal use of pump technology. Staff also described how their assumptions about personal and psychological suitability had been challenged by working on the REPOSE trial and observing individuals make effective use of CSII who they would not have recommended for this type of therapy in routine clinical practice. The authors report that their findings add to those studies that highlight the difficulties of using patient characteristics and variables to predict clinical success using CSII. They suggest that to promote equitable access to CSII, attitudinal barriers and prejudicial assumptions amongst staff about who is able to make effective use of CSII may need to be addressed.


Insulin administered by needle-free jet injection corrects marked hyperglycaemia faster in overweight or obese patients with diabetes
Helena M. de Wit et al. Diabetes, Obesity and Metabolism. Doi: 10.1111/dom.12550

Because insulin administered by jet injection is more rapidly absorbed than when injected by a conventional pen, the authors tested whether jet injection resulted in faster correction of marked hyperglycaemia than when insulin is injected by a conventional pen. The study included 10 adult, overweight or obese patients with type 1 diabetes and 10 insulin-treated patients with type 2 diabetes. These were randomized, in a controlled, cross-over study. On two separate occasions, patients were instructed to reduce insulin dose(s) to achieve marked hyperglycaemia (18-23 mmol/l). Subsequently, insulin aspart was administered either by jet injection or by conventional pen. It was found that the administration of rapid-acting insulin by jet injection resulted in faster correction of marked hyperglycaemia in overweight or obese patients with insulin-requiring diabetes.


Safety, efficacy and glucose turnover of reduced prandial boluses during closed-loop therapy in adolescents with type 1 diabetes
Daniela Elleri et al. Diabetes, Obesity and Metabolism. Doi: 10.1111/dom.12549

This randomized cross-over study evaluated the safety, efficacy and glucose turnover during closed-loop with meal announcement using reduced prandial insulin boluses in adolescents with type 1 diabetes (T1D). It compared standard prandial insulin boluses versus closed-loop with prandial boluses reduced by 25%. It found that twenty five percent reduction of prandial boluses during closed-loop maintained a comparable glucose control in adolescents with T1D whilst lowering overall plasma insulin levels. The authors also state that it remains unclear whether closed-loop therapy with 25% reduction of prandial boluses will prevent postprandial hypoglycemia.