Journal Watch

Prepared for IDDT by Jim Young

February 2015

Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates
Danny Hung-Chieh Chou et al. PNAS. doi:10.1073/pnas.1424684112/-/DCSupplemental
In this paper the authors describe a strategy for the chemical modification of insulin to promote both long-lasting and glucose-responsive activity via glucose sensing. The synthetic insulin derivatives enabled rapid reversal of blood glucose in a diabetic mouse model following glucose challenge, with some derivatives responding to repeated glucose challenges over a 13 hour period. The best-performing insulin derivative provided glucose control that was superior to native insulin, with its responsiveness to glucose challenge being better than a clinically used long-acting insulin derivative. Moreover, continuous glucose monitoring revealed a responsiveness matching that of a healthy pancreas. The authors posit that this synthetic approach to insulin modification could afford both long-term and glucose-mediated insulin activity, thereby reducing the number of administrations and improving the fidelity of glycemic control for insulin therapy. They also assert that their work is the first demonstration of a glucose-binding modified insulin molecule with glucose-responsive activity verified in vivo.


An educational program for insulin self-adjustment associated with structured self-monitoring of blood glucose significantly improves glycemic control in patients with type 2 diabetes mellitus
Daniel Dutra Romualdo Silva et al. Diabetology & Metabolic Syndrome. Doi: 10.1186/1758-5996-7-2
Self-monitoring of blood glucose (SMBG) has been recommended as a useful tool for improving glycemic control, but is still an underutilized strategy and most diabetic patients are not aware of the actions that must be taken in response to its results and do not adjust their treatment. In this study twenty-three subjects with T2DM – who were poorly controlled on insulin – were randomized to two educational programs: a 2-week basic program with guidance about SMBG and types and techniques of insulin administration, and a 6-week program with additional instructions about self-titration of insulin doses according to a specific protocol. It found that training for self-titrating insulin doses combined with structured SMBG can safely improve glycemic control in patients with poorly controlled insulin-treated T2DM. The authors posit that this strategy may facilitate effective insulin therapy in routine medical practice, compensating for any reluctance on the part of physicians to optimize insulin therapy and thus to improve the achievement of recommended targets of diabetes care.


Bariatric surgery and diabetes: Implications of type 1 diabetes versus insulin-requiring type 2 diabetes
Spyridoula Maraka et al. Obesity. Doi: 10.1002/oby.20992
In this study ten subjects with type 1 diabetes (DM1) were compared with 118 subjects with insulin-requiring type 2 (IRDM2) at baseline and then at 1 and 2 years after bariatric surgery. The aspects studied were anthropometric measurements, HbA1c, and number of medications (anti-hyperglycemic, anti-hypertensive, lipid-lowering) that were prescribed. It was found that DM1 and IRDM2 groups lost similar amounts of weight 2 years post-bariatric surgery. IRDM2 subjects had significant improvements in HbA1c and decreases in number of anti-hyperglycemic, anti-hypertensive, and lipid-lowering medications. However, DM1 subjects had no improvement in HbA1c or use of anti-hypertensive medications, although their use of lipid-lowering medications improved. The authors assert that their study suggests that improved glycemic control may not be an expected outcome when considering bariatric surgery in patients with DM1, with the caveat that additional investigation is warranted.


Safety and effectiveness of dipeptidyl peptidase-4 inhibitors versus intermediate-acting insulin or placebo for patients with type 2 diabetes failing two oral antihyperglycaemic agents
Andrea C Tricco et al. BMJ Open. Doi: 10.1136/bmjopen-2014-005752
This paper reports on ten multicentre, multinational studies of 2,967 patients with T2DM that examined DPP-4 inhibitors when compared with each other, intermediate-acting insulin, no treatment or placebo. The primary outcome was HbA1c and the secondary outcomes were healthcare utilisation, body weight, fractures, quality of life, microvascular complications, macrovascular complications, all-cause mortality, harms, cost and cost-effectiveness. The findings were that DPP-4 inhibitors were superior to placebo in reducing HbA1c levels in adults with T2DM taking at least two oral agents. Compared with placebo, no safety signals were detected with DPP-4 inhibitors and there was a reduced risk of infection. There was no significant difference in HbA1c observed between NPH and placebo or NPH and DPP-4 inhibitors.


Effect comparison of metformin with insulin treatment for gestational diabetes
Genxia Li et al. Archives of Gynecology and Obstetrics. Doi: 10.1007/s00404-014-3566-0
This study identified a total of 11 studies from a literature search in PUBMED, EMBASE, Science Direct, Springer link, and Cochrane library using the search terms: “Gestational Diabetes” or “GDM”, and “insulin” and “metformin”. The overall findings were that there was no significant difference of the effect on maternal outcomes between the two treatments in HBA1c levels, fasting blood glucose, and the incidence of preeclampsia; whereas, significantly reduced results were found in the metformin group in pregnancy-induced hypertension (PIH) rate, average weight gains after enrolment, and average gestational ages at delivery. Regarding neonatal outcomes, when compared with insulin group, metformin presented significantly lower average birth weights, incidence of hypoglycemia and neonatal intensive care unit (NICU). The authors conclude that metformin can significantly reduce several adverse maternal and neonatal outcomes including PIH rate, incidence of hypoglycemia and NICU, and therefore it may be an effective and safe alternative or additional treatment to insulin for GDM women.


Effect of subcutaneous insulin detemir on glucose flux and lipolysis during hyperglycaemia in people with type 1 diabetes
R. A. Herring et al. Diabetes, Obesity and Metabolism. Doi: 10.1111/dom.12434
This study investigated the differential effects of subcutaneous (sc) detemir and NPH insulin on glucose flux and lipid metabolism after insulin withdrawal. After a period of insulin withdrawal resulting in whole-blood glucose concentration of 7 mmol/l, the 11 participants with type 1 diabetes received 0.5 units per kg body weight s.c. insulin detemir or NPH insulin in random order. Stable isotopes of glucose and glycerol were infused intravenously throughout the study protocol. The results showed that glucose concentration decreased after insulin treatment as a result of suppression of endogenous glucose production, which occurred to a similar extent with both detemir and NPH insulin. The rate of glucose disappearance (Rd) was not increased significantly with either type of insulin. When the effect of detemir and NPH insulin on glucose flux at glucose concentrations between 9 and 6 mmol/l was examined, glucose rate of appearance (Ra) was similar with the two insulins; however, glucose Rd was greater with NPH insulin than with detemir at glucose concentrations of 8.0, 8.5, 7.0 and 6.0 mmol/l.  The percentage change in glycerol Ra, a measure of lipolysis, was greater in the NPH group than in the detemir group. The authors suggest that the results of their study are consistent with the hypothesis that detemir has a lesser effect on the periphery, as evidenced by a lesser effect on peripheral glucose uptake at specific glucose concentrations.


Treating hypertension in patients with diabetes when to start and how low to go?
Bryan Williams. JAMA. Doi:10.1001/jama.2015.89
This editorial discusses the association between hypertension and type 2 diabetes.
It reminds us that hypertension and type 2 diabetes are inextricably linked. Indeed, the epidemiological and pathophysiological link between hypertension and diabetes dates back to 1929, when an increased likelihood of high blood pressure (BP) in people with diabetes was first recognized. The perspective for this editorial is illustrated by the observations that subsequent studies have demonstrated that high BP is at least twice as common in individuals with type 2 diabetes, when compared to age-matched individuals without diabetes. Moreover, hypertension greatly increases the risk of developing macrovascular (myocardial infarction, stroke, peripheral vascular disease, and congestive heart failure) and microvascular (retinopathy and nephropathy) complications of diabetes and risk of premature death. The editorial recommends lowering the target thresholds for blood pressure.


Glomerular haemodynamic profile of patients with Type 1 diabetes compared with healthy control subjects
M. Škrtić et al. Diabetic Medicine. Doi: 10.1111/dme.1271
This study evaluated the glomerular haemodynamic profile of patients with Type 1 diabetes with either renal hyperfiltration or renal normofiltration during euglycaemic and hyperglycaemic conditions, and compared this profile with that of a similar group of healthy control subjects. It found that hyperfiltration in Type 1 diabetes is primarily driven by alterations in afferent arteriolar resistance rather than efferent arteriolar resistance. It suggests that renal protective therapies should focus on afferent renal arteriolar mechanisms through the use of pharmacological agents that target tubuloglomerular feedback, including sodium-glucose cotransporter 2 inhibitors and incretins.


Sanofi and MannKind announce Afrezza®, the only inhaled insulin, now available in the U.S.
This press release from Sanofi and MannKind described the medication Afrezza as a drug-device combination that consists of a dry formulation of human insulin delivered from a small and portable inhaler to help patients achieve blood sugar control. It states that Afrezza could help control high blood sugar as part of a diabetes management plan that may include diet, exercise and other diabetes medications.


How do people with diabetes describe their experiences in primary care?
Charlotte A.M. Paddison et al. Diabetes Care. Doi: 10.2337/dc14-1095
This paper described the experiences of people with diabetes in primary care and examined how these experiences vary with increasing comorbidity. It used data from 906,578 responders to the 2012 General Practice Patient Survey (England), including 85,760 with self-reported diabetes. It was controlled for age, sex, ethnicity, and socioeconomic status and analyzed patient experience using seven items covering three domains of primary care: access, continuity, and communication. It found that people with diabetes were significantly more likely to report better experience on six out of seven primary care items than people without diabetes, however those with diabetes and additional comorbid long-term conditions were more likely to report worse experiences, particularly for access to primary care appointments. The conclusion was that people with diabetes in England report primary care experiences that are at least as good as those without diabetes for most domains of care. However, improvements in primary care are needed for diabetes patients with comorbid long-term conditions, including better access to appointments and improved communication.