Journal Watch

Prepared for IDDT by Jim Young

September 2016

Beta cell function and ongoing autoimmunity in long-standing, childhood onset type 1 diabetes
Georgina M. Williams et al. Diabetologia. Doi: 10.1007/s00125-016-4087-0

In this study two-hour post-meal urine C-peptide:creatinine ratio (UCPCR) and islet autoantibodies were measured in samples collected from 144 participants: at diagnosis (median age 11.7 years), and following on from diagnosis at a median of 23 years. Autoantibodies against GAD (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) were also measured.
[C-peptide is a protein that connects insulin’s A-chain to its B-chain in the proinsulin molecule. Measuring C-peptide can help to determine how much of a patient’s own natural insulin is being produced as C-peptide is secreted in equimolar amounts to insulin] [Serum creatinine is an important indicator of renal health because it is an easily measured by-product of muscle metabolism. Creatinine levels in blood and urine may be used to calculate the creatinine clearance, which correlates with the glomerular filtration rate]

Endogenous C-peptide secretion was detectable in 51 participants (35.4%), including residual secretion in seven individuals (4.9%) and minimal secretion in 14 individuals (9.7%). In the 132 samples collected more than 10 years after diagnosis, 86 participants (65.2%) had at least one islet autoantibody: 42 (31.8%) were positive for GADA, 69 (52.3%) for IA-2A and 14 of 104 tested were positive for ZnT8A (13.5%). The level of UCPCR was related to age at diagnosis and was independent of diabetes duration, and baseline or current islet autoantibody status. The authors conclude from their findings that there was evidence of ongoing autoimmunity in the majority of individuals with longstanding diabetes. Endogenous insulin secretion continued for many years after diagnosis in individuals diagnosed with autoimmune-mediated type 1 diabetes above age 5. They posit that their findings suggest that some beta cells are protected from continued autoimmune attack in longstanding type 1 diabetes.

Examining factors that impact inpatient management of diabetes and the role of insulin pen devices
Chelsea Smallwood et al. Canadian Journal of Diabetes. Doi:

In this open access paper, the investigators evaluated the impact of insulin pen implementation in the acute care setting on patients, healthcare workers and health resource utilisation. They conducted a review of published literature, including guidelines, to identify how insulin pen devices in the acute care setting may impact inpatient diabetes management. They report that a multitude of published studies and unpublished pilot studies have demonstrated the value of implementing pen devices and a safety pen needle in hospitals. The benefits include reducing the risk for adverse events, such as needlestick injuries and medication errors, and achieving tighter glycemic control as a result of shorter needle length availability (i.e. reduction in intramuscular injections and improved adherence). Insulin pen devices in the acute care setting may also decrease waste and inefficiencies, such as insulin waste and nursing time.

Dipeptidyl peptidase −4 activity is associated with urine albumin excretion in type 1 diabetes
Lea Duvnjak et al. Journal of Diabetes and Its Complications. Doi:

This study investigated whether serum DPP-4 activity was associated with urine albumin excretion (UAE) in patients with type 1 diabetes (type 1 DM).
[Dipeptidyl peptidase-4 (DPP4) plays a major role in glucose metabolism. It is responsible for the degradation of incretins such as GLP-1].
[Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating] The inability of kidneys to prevent urinary protein leakage represents the earliest sign of renal damage in diabetic kidney disease (DKD), and recent data suggests a possible nephroprotective role for dipeptidyl peptidase-4 (DPP-4) inhibitors. The study measured DPP-4 activity and UAE in 113 patients with type 1 DM and with glomerular filtration rate (GFR) within normal range. It discovered that the worse lipid profile and higher waist circumference were observed in the group with highest DPP-4 activity. Patients within lowest UAE had lowest DPP-4 activity value compared to groups within second and third levels of UAE. DPP-4 activity also correlated with systolic blood pressure, HbA1c and UAE. UAE increased as DPP-4 increased. Because the results indicate that serum DPP-4 activity is associated with albuminuria in type 1 diabetes. The authors speculate that the use of DPP-4 inhibitors might serve as an additional therapeutic strategy to prevent proteinuria in patients with DKD.

Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study
Fahad W. Ahmed et al. Cardiovascular Diabetology. Doi: 10.1186/s12933-016-0413-6

This study set out to determine if the cardioprotective effect of metformin is mediated by increasing circulating endothelial progenitor cells (cEPCs), pro-angiogenic cells (PACs) and decreasing circulating endothelial cells (cECs) count whilst maintaining unchanged glycemic control.
[Endothelial cells line the interior surface of blood vessels]
In the study twenty-three patients with type 1 diabetes, but without overt cardiovascular disease (CVD), were treated with metformin for 8 weeks (treatment group-TG). They were matched with nine patients with type 1 diabetes on standard treatment (SG) and 23 healthy volunteers (HC). Insulin dose was adjusted to keep glycaemic control unchanged. It found that Metformin had a potential cardio-protective effect through improving cEPCs, cECs, PACs counts and this function was independent of an hypoglycaemic effect. The authors offer the caveat that their finding need to be confirmed by long term cardiovascular outcome studies.

Diabetes distress in males and females with type 1 diabetes in adolescence and emerging adulthood
Lina Lašaitė et al. Journal of Diabetes and Its Complications. DOI:

This study explored the gender and age differences in diabetes distress between 255 adolescents and 283 emerging adults with type 1 diabetes (T1D). It found high diabetes distress levels in 22.8% of participants.

Lack of confidence in self-care, negative emotional consequences, and overall score were higher in adult than in adolescent males, when adjusted for age at T1D onset. Negative emotional consequences and overall score were higher in adult compared to adolescent females, when adjusted for age at T1D onset.

Lack of confidence in self-care negative emotional consequences and overall score were higher in adolescent females compared to males, when adjusted for age at T1D onset. Negative emotional consequences score was higher in adult females compared to males when adjusted for age at T1D onset.

The authors conclude that patients with T1D have greater burden of diabetes distress in emerging adulthood than in adolescence, and the importance of addressing diabetes distress in clinical care.

Type 1 diabetes: a disease of developmental origins
Jessica E. Phillips et al. Pediatric Diabetes. DOI: 10.1111/pedi.12425

This abstract is worth noting because it refers to the world’s first pregnancy to early childhood cohort study in at-risk children. The rational for the study is reviewed in the abstract:

The incidence of type 1 diabetes globally has increased dramatically over the last 50 years. Proposed environmental reasons for this increase mirror the modern lifestyle. Type 1 diabetes can be viewed as part of the non-communicable disease epidemic in our modern society. Meanwhile rapidly evolving new technologies are advancing our understanding of how human microbial communities interface with the immune system and metabolism, and how the modern pro-inflammatory environment is changing these communities and contributing to the rapid rise of non-communicable disease. The majority of children who present with clinical type 1 diabetes are of school age; however, 80% of children who develop type 1 diabetes by 18 years of age will have detectable islet autoantibodies by 3 years of age. The evolving concept that type 1 diabetes in many children has developmental origins has directed research questions in search of prevention back to pregnancy and early life.

Anti-Inflammatory effects of metformin irrespective of diabetes status
Amy R. Cameron et al. Circulation Research. Doi: 10.1161/CIRCRESAHA.116.308445

The diabetes drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood. This study looked at the anti-inflammatory effects of metformin and their relationship to antihyperglycemic properties. In a large treatment naive diabetes mellitus population cohort, the investigators observed differences in the systemic inflammation marker, neutrophil to lymphocyte ratio, after incident treatment with either metformin or sulfonylurea monotherapy. Compared with sulfonylurea exposure, metformin reduced the neutrophil to lymphocyte ratio after 8 to 16 months and increased the likelihood that neutrophil to lymphocyte ratio would be lower than baseline after 8 to 16 months. The investigators concluded that the anti-inflammatory properties of metformin are exerted irrespective of diabetes mellitus status. They posit that this may accelerate investigation of drug utility in nondiabetic cardiovascular disease groups.

Efficacy of Internet-based self-monitoring interventions on maternal and neonatal outcomes in perinatal diabetic women
Ying Lau et al. Journal of Medical Internet Research. Doi: 10.2196/jmir.6153
Self-monitoring using the Internet offers new opportunities to engage perinatal diabetic women in self-management to reduce maternal and neonatal complications. This review set out to synthesize the best available evidence to evaluate the efficacy of Internet-based self-monitoring interventions in improving maternal and neonatal outcomes among perinatal diabetic women. The review was conducted using Cochrane Central Register of Controlled Trials, PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature, PsyINFO, Scopus, and ProQuest Dissertations and Theses to search for English-language research studies without any year limitation. It found that half of the selected studies showed low risk of bias and comprised 852 perinatal diabetic women in six countries. The analysis revealed that Internet-based self-monitoring interventions significantly decreased the level of maternal glycated hemoglobin compared to usual care among perinatal diabetic women at post-intervention. Moreover, Internet-based self-monitoring interventions significantly decreased the cesarean delivery rate compared to usual care among the mixed group at post-intervention. The authors offer the caveat that the long-term effects of the intervention must be confirmed in future studies using randomized controlled trials and follow-up data.

β-Cell death is decreased in women with gestational diabetes mellitus
Lauren A. Kenna et al. Diabetology & Metabolic Syndrome. Doi: 10.1186/s13098-016-0175-z

Gestational diabetes mellitus (GDM) affects approximately 7–17 % of all pregnancies and has been recognised as a significant risk factor to neonatal and maternal health. Postpartum, GDM significantly increases the likelihood of developing type 2 diabetes (T2D). While it is well established that insulin resistance and impaired β-cell function contribute to GDM development, the role of active β-cell loss remains unknown. This study examined the levels of β-cell death in women with GDM. It found that β-cell death was reduced in women with GDM. This reduction is associated with impaired insulin production and hyperglycemia, suggesting that β-cell death does not contribute to GDM during the 2nd and 3rd trimester of pregnancy.

Closed-loop insulin delivery during pregnancy in women with type 1 diabetes
Zoe A. Stewart et al. NEJM. Doi: 10.1056/NEJMoa1602494

In patients with type 1 diabetes who are not pregnant, closed-loop (automated) insulin delivery can provide better glycemic control than sensor-augmented pump therapy, but data are lacking on the efficacy, safety, and feasibility of closed-loop therapy during pregnancy. This study compared overnight closed-loop therapy with sensor-augmented pump therapy, followed by a continuation phase in which the closed-loop system was used day and night. It found that the percentage of time that overnight glucose levels were in the target range was higher during closed-loop therapy than during control therapy. The overnight mean glucose level was lower during closed-loop therapy than during control therapy. There were no significant differences between closed-loop and control therapy in the percentage of time in which glucose levels were below the target range, in insulin doses, or in adverse-event rates. During the continuation phase (up to 14.6 additional weeks, including antenatal hospitalizations, labour, and delivery), glucose levels were in the target range 68.7% of the time. No episodes of severe hypoglycemia requiring third-party assistance occurred during either phase. The investigators assert that their findings demonstrate that overnight closed-loop therapy resulted in better glucose control than sensor-augmented pump therapy in pregnant women with type 1 diabetes. Women receiving day-and-night closed-loop therapy maintained glycemic control during a high proportion of the time in a period that encompassed antenatal hospital admission, labour, and delivery