Journal Watch

Prepared for IDDT by Jim Young

January 2015

Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century
J. A. McKnight. et al. Diabetic Medicine. Doi: 10.1111/dme.12676

This study compared glycaemic control among 324,501 people with Type 1 diabetes using data gathered in regional and national registries. Data were obtained for children and/or adults from the following countries or regions: Western Australia, Austria, Denmark, England, Champagne-Ardenne (France), Germany, Epirus, Thessaly and Thessaloniki (Greece), Galway (Ireland), several Italian regions, Latvia, Rotterdam (The Netherlands), Otago (New Zealand), Norway, Northern Ireland, Scotland, Sweden, Volyn (Ukraine), USA and Wales . The results suggested that there were substantial variations in glycaemic control among people with Type 1 diabetes and that there is room for improvement in all populations, especially in young adults.


Pharmacokinetics and pharmacodynamics of insulin glargine given evening as compared with morning in type 2 diabetes mellitus
Francesca Porcellati et al. Diabetes Care. Doi: 10.2337/dc14-0649

This paper compared the pharmacokinetics (PK) and pharmacodynamics (PD) of insulin glargine in type 2 diabetes mellitus (T2DM) after evening versus morning administration. The results showed that the PD of insulin glargine differs depending on time of administration. With morning administration insulin activity is greater in the first 0–12 h, while with evening administration the activity is greater in the 12–24 h period following dosing. However, glargine PK and plasma C-peptide levels were similar, as well as glargine PD when analyzed by 24-h clock time independent of the time of administration. Thus, the results reflect the impact of circadian changes in insulin sensitivity in T2DM.
[Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body][Pharmacokinetics looks at the fate of drugs administered to a patient] [Circadian rhythm is a biological process that displays oscillation of about 24 hours driven by a circadian clock coordinating biology and behavior with daily and seasonal changes]


Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors
Richard A. Oram et al. Diabetes Care. Doi: 10.2337/dc14-0871

This study recruited 924 patients from primary and secondary care in two UK centers who had a clinical diagnosis of T1D, were under 30 years of age when they received a diagnosis, and had diabetes of duration greater than 5 years. It was discovered that 80% of patients (740 of 924 patients) had detectable endogenous C-peptide levels; however most (52%) had historically very low or undetectable levels. Interestingly, 8% of patients (70 of 924 patients) had results that were equivalent to the serum levels associated with reduced complications and hypoglycemia. The conclusions of the study were that the majority of long-duration T1D patients had detectable urine C-peptide levels. While the majority of patients are insulin microsecretors, some maintain clinically relevant endogenous insulin secretion for many years after the diagnosis of diabetes.
[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].


Impact of HbA1c, followed from onset of type 1 diabetes, on the development of severe retinopathy and nephropathy
Maria Nordwall et al. Diabetes Care. Doi: 10.2337/dc14-1203

 Although HbA1c is strongly related to the development of diabetes complications, it is still controversial which HbA1c level to strive for in the treatment of type 1 diabetes. The aim of this longitudinal observation study was to evaluate HbA1c, followed from diagnosis, as a predictor of severe microvascular complications and to formulate HbA1c target levels for treatment. The study followed 451 patients diagnosed with type 1 diabetes during 1983 to 1987 before the age of 35 years in a region of Southeast Sweden. It found that the incidence of proliferative retinopathy and persistent macroalbuminuria increased sharply and occurred earlier with increasing long-term mean HbA1c. None of the 451 patients developed proliferative retinopathy or persistent macroalbuminuria below long-term weighted mean HbA1c 7.6% (60 mmol/mol); 51% of the patients with long-term mean HbA1c above 9.5% (80 mmol/mol) developed proliferative retinopathy and 23% persistent macroalbuminuria. The authors posit that keeping HbA1c below 7.6% (60 mmol/mol) as a treatment target seems to prevent proliferative retinopathy and persistent macroalbuminuria for up to 20 years.


Low within- and between-day variability in exposure to new insulin glargine 300 U.mL-1
R. H. A. Becker et al. Diabetes, Obesity and Metabolism. Doi: 10.1111/dom.12416

In this double-blind, randomized, two-treatment, two-period, crossover study a total of 50 participants with T1DM were randomized to receive Gla-300 as a standard cartridge formulation in the first treatment period, and as a formulation with enhanced stability through polysorbate-20 addition in the second treatment period, or vice versa. The methodology was designed to assess the bioequivalence between formulations and, subsequently, within- and between-day variability. It was found that Gla-300 provided predictable, evenly distributed 24-h coverage as a result of low fluctuation and high reproducibility in insulin exposure, and appears suitable for effective basal insulin use.


Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes
Lars Krogvold et al. Diabetes. Doi: 10.2337/db14-1370

The Diabetes Virus Detection study (DiViD) was the first to examine fresh pancreatic tissue at the diagnosis of type 1 diabetes for the presence of viruses. Minimal pancreatic tail resection was performed 3-9 weeks after onset of type 1 diabetes in 6 adult patients (age 24-35 years). The presence of enteroviral capsid protein 1 (VP1) and the expression of class I HLA were investigated. Non-diabetic organ donors served as controls. [Enteroviral capsid protein is the shell of a virus. Enteroviruses are associated with several human diseases]. [HLAs serve as the sole link between the immune system and what happens inside cells]. VP1 was detected in the islets of all type 1 diabetes patients (2 of 9 controls). Hyperexpression of class I HLA molecules was found in the islets of all patients (1 of 9 controls). Enterovirus specific RNA sequences were detected in 4 of 6 cases (0 of 6 controls). The results were confirmed in different laboratories. The authors assert that the results provide evidence for the presence of enterovirus in pancreatic islets of type 1 diabetic patients, being consistent with the possibility that a low grade enteroviral infection in the pancreatic islets contribute to disease progression in humans.


Unsupervised home use of overnight closed-loop system over 3 to 4 weeks in adults and adolescents with type 1 diabetes
H. Thabit et al. Diabetes, Obesity and Metabolism. Doi: 10.1111/dom.12427
A total of 40 participants with type 1 diabetes took part in this study. 24 were adults with HbA1c 8.0 (± 0.9%) and 16 were adolescents with HbA1c 8.1 (± 0.8%). All participants underwent two periods of sensor-augmented pump therapy in the home setting, in combination with or without an overnight closed-loop insulin delivery system that used a model predictive control algorithm to direct insulin delivery. The order of the two interventions was random, and each period lasted 4 weeks in adults and 3 weeks in adolescents. The primary outcome was the time during which sensor glucose readings were in the target range of 3.9 to 8.0 mmol/l. It was found that the proportion of time when sensor glucose was in the target range overnight was 18.5% greater during closed-loop insulin delivery than during sensor-augmented therapy. Closed-loop therapy significantly reduced mean overnight glucose levels by 0.9 mmol/l with no difference in glycaemic variability. Also, the time spent above the target range was reduced, as was time spent in hypoglycaemia during closed-loop therapy. The conclusions were that overnight closed-loop insulin therapy at home in adults and adolescents with type 1 diabetes was feasible and showed improvements in glucose control and reduced the risk of nocturnal hypoglycaemia.


Effects of high vs low glycemic index of dietary carbohydrate on cardiovascular disease risk factors and insulin sensitivity
Frank M. Sacks et al. JAMA. doi:10.1001/jama.2014.16658

This trial was conducted in research units in academic medical centers, in which 163 overweight adults (systolic blood pressure, 120-159 mm Hg) were given 4 complete diets that contained all of their meals, snacks, and calorie-containing beverages, each for 5 weeks.

The categories were:  

(1) A high–glycemic index (65% on the glucose scale), high-carbohydrate diet (58% energy)
(2) A low–glycemic index (40%), high-carbohydrate diet
(3) A high–glycemic index, low-carbohydrate diet (40% energy)
(4) A low–glycemic index, low-carbohydrate diet.
Each diet was based on a healthful DASH-type diet

The 5 primary outcomes were insulin sensitivity; levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides; and systolic blood pressure. It was found that diets with low glycemic index of dietary carbohydrate, compared with high glycemic index of dietary carbohydrate, did not result in improvements in insulin sensitivity, lipid levels, or systolic blood pressure. In the context of an overall DASH-type diet, using glycemic index to select specific foods may not improve cardiovascular risk factors or insulin resistance.
[The DASH diet (Dietary Approaches to Stop Hypertension) is a dietary pattern promoted by the U.S. based National Heart, Lung, and Blood Institute to prevent and control hypertension]


Metformin use reduction in mild to moderate renal impairment
James H. Flory and Sean Hennessy.  JAMA Internal Medicine. Doi:10.1001/jamainternmed.2014.6936

This interesting update from America does illustrate the ongoing debate about medication s for diabetes, even such established drugs such as Metformin. Metformin hydrochloride is the first-line drug for type 2 diabetes mellitus (T2DM) and is the only oral diabetes drug with evidence for improved cardiovascular outcomes. Despite this, half of the patients with T2DM do not take Metformin. Even in patients who are taking other oral T2DM drugs, only about 70% use Metformin. One likely explanation for this shortfall is the avoidance of Metformin use in renal insufficiency. This contraindication has been widely criticized as overly conservative. Because this contraindication may inappropriately discourage Metformin use in patients with mild renal impairment, US Food and Drug Administration (FDA) citizen petitions were filed in 2012 and 2013, respectively, requesting that the contraindication be relaxed and reframed in terms of the more modern eGFR measure, although the FDA has provided no substantive response.


Management of hyperglycemia in type 2 diabetes, 2015
Silvio E. Inzucchi et al. Diabetes Care. Doi: 10.2337/dc14-2441

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have recently requested an update to the position statement incorporating new data from recent clinical trials. This open access paper discusses glycemic targets, therapeutic options, and implementation strategies. Although there are now more head-to-head trials that show slight variance between agents with regard to glucose-lowering effects, these differences are often small and would be unlikely to reflect any definite differential effect in an individual patient. The document promises that more long-term data regarding the cardiovascular impact of glucose-lowering therapies will be available over the next 1 to3 years, with a large comparative effectiveness study in the U.S. now being assessed about long-term outcomes with multiple agents after metformin monotherapy, but results are not anticipated until at least 2020. So this position statement will obviously need to be updated in future years in order to provide the best and most evidence-based recommendations for patients with type 2 diabetes.