Glucose-lowering therapies in type 2 diabetes: Opportunities and challenges for peptides

This overview considers the opportunities and challenges that face the use of gluco-regulatory peptides to treat type 2 diabetes. New insulin analogues and formulations are being developed with pharmacokinetic properties to speed-up or prolong transfer from a subcutaneous injection site to the target tissues, or to selectively favour effects on the liver. Alternative routes of insulin administration continue to attract attention, and advances in the integration of glucose monitoring with insulin pump devices are improving miniaturised ‘closed loop’ artificial pancreas systems. Proof of concept has been established for non-cellular glucose-responsive insulin delivery (‘smart insulins’) to release insulin from implants or circulating depots in proportion to circulating glucose. The many peptides involved in blood glucose control offer diverse therapeutic opportunities. Exploitation of multiple selected receptor targets using constructs of hybrid and chimeric peptides, especially those based on glucagon and gastrointestinal hormones, has gained much credence from initial preclinical studies. Peptide templates identified from comparative endocrine studies have also provided valuable insights in this respect and indicated novel approaches to address associated conditions such as obesity and infections at the same time. Nevertheless, there are many challenges to the use of therapeutic peptides that impose on every step in the complex pathway from design and testing through to making a fully characterised therapeutic product, and optimising administration, tissue targeting and degradation. Stability of peptides and immunological uncertainties of novel structures require particular consideration as well as the need to avoid over-reduction of blood glucose into hypoglycaemia

Childhood Obesity

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community

Insulin Patch Pumps: Their Development and Future in Closed-Loop Systems

Steady progress is being made toward the development of a so-called “artificial pancreas,” which may ultimately be a fully automated, closed-loop, glucose control system comprising a continuous glucose monitor, an insulin pump, and a controller. The controller will use individualized algorithms to direct delivery of insulin without user input. A major factor propelling artificial pancreas development is the substantial incidence of—and attendant patient, parental, and physician concerns about—hypoglycemia and extreme hyperglycemia associated with current means of insulin delivery for type 1 diabetes mellitus (T1DM). A successful fully automated artificial pancreas would likely reduce the frequency of and anxiety about hypoglycemia and marked hyperglycemia. Patch-pump systems (“patch pumps”) are likely to be used increasingly in the control of T1DM and may be incorporated into the artificial pancreas systems of tomorrow. Patch pumps are free of tubing, small, lightweight, and unobtrusive. This article describes features of patch pumps that have been approved for U.S. marketing or are under development. Included in the review is an introduction to control algorithms driving insulin delivery, particularly the two major types: proportional integrative derivative and model predictive control. The use of advanced algorithms in the clinical development of closed-loop systems is reviewed along with projected next steps in artificial pancreas development

Continuous Glucose Monitoring: A Consensus Conference Of The American Association Of Clinical Endocrinologists And American College Of Endocrinology

Objective/Methods: Barriers to continuous glucose monitoring (CGM) use continue to hamper adoption of this valuable technology for the management of diabetes. The American Association of Clinical Endocrinologists and the American College of Endocrinology convened a public consensus conference February 20, 2016, to review available CGM data and propose strategies for expanding CGM access. Results: Conference participants agreed that evidence supports the benefits of CGM in type 1 diabetes and that these benefits are likely to apply whenever intensive insulin therapy is used, regardless of diabetes type. CGM is likely to reduce healthcare resource utilization for acute and chronic complications, although real-world analyses are needed to confirm potential cost savings and quality of life improvements. Ongoing technological advances have improved CGM accuracy and usability, but more innovations in human factors, data delivery, reporting, and interpretation are needed to foster expanded use. The development of a standardized data report using similar metrics across all devices would facilitate clinician and patient understanding and utilization of CGM. Expanded CGM coverage by government and private payers is an urgent need. Conclusion: CGM improves glycemic control, reduces hypoglycemia, and may reduce overall costs of diabetes management. Expanding CGM coverage and utilization is likely to improve the health outcomes of people with diabetes

Rebranding asymptomatic type 1 diabetes: the case for autoimmune beta cell disorder as a pathological and diagnostic entity

The asymptomatic phase of type 1 diabetes is recognised by the presence of beta cell autoantibodies in the absence of hyperglycaemia. We propose that an accurate description of this stage is provided by the name 'Autoimmune Beta Cell Disorder' (ABCD). Specifically, we suggest that this nomenclature and diagnosis will, in a proactive manner, shift the paradigm towards type 1 diabetes being first and foremost an immune-mediated disease and only later a metabolic disease, presaging more active therapeutic intervention in the asymptomatic stage of disease, before end-stage beta cell failure. Furthermore, we argue that accepting ABCD as a diagnosis will be critical in order to accelerate pharmaceutical, academic and public activities leading to clinical trials that could reverse beta cell autoimmunity and halt progression to symptomatic insulin-requiring type 1 diabetes. We recognize that there are both opportunities and challenges in the implementation of the ABCD concept but hope that the notion of 'asymptomatic autoimmune disease' as a disorder will be widely discussed and eventually accepted.status: publishe

Achieve control: a pragmatic clinical trial of insulin glargine 300 U/mL versus other basal insulins in insulin-naïve patients with type 2 diabetes

<p><b>Objective</b>: This study aims to compare the effectiveness of insulin glargine 300 U/mL (Gla-300) with its accompanying patient support program with that of other basal insulin and available patient support programs in patients with type 2 diabetes (T2D) in a real-world setting in terms of achieving HEDIS (Healthcare Effectiveness Data and Information Set) individualized glycemic targets without documented symptomatic hypoglycemia.</p> <p><b>Methods</b>: Achieve Control is a US-based, multicenter, randomized, open-label, active-controlled, parallel group pragmatic Phase IV trial in insulin-naïve patients with T2D uncontrolled on ≥2 oral antidiabetes drugs (OAD) and/or glucagon-like peptide-1 receptor antagonists (GLP-1 RA). Inclusion criteria include a diagnosis of T2D, age ≥18 years, and glycated hemoglobin (HbA1c) between 8.0% and 11.0%. Patients will be assigned to either the Gla-300 or other basal insulin group. The primary end point is the proportion of patients achieving HEDIS HbA1c targets (<8.0% [64 mmol/mol] in patients with comorbidities or aged ≥65 years; <7.0% [58 mmol/mol] in all other patients) without occurrence of symptomatic hypoglycemia (blood glucose ≤70 mg/dL) from baseline to 6 months. Secondary end points include rates of documented symptomatic nocturnal hypoglycemia and severe hypoglycemia; change from baseline in HbA1c, fasting glucose, and body weight; treatment persistence; patient-reported outcomes; and healthcare resource utilization. Planned enrollment is 3270 patients across approximately 400 clinical sites.</p> <p><b>Conclusion</b>: Pragmatic clinical trials offer the potential to assess comparative effectiveness in broadly based patient populations receiving care (with or without a corresponding educational support program) in real-world clinical settings. The results of Achieve Control should elucidate the benefits of management of T2D with Gla-300 versus other basal insulins in terms of patient outcomes, experiences, and perceptions, and its impact on healthcare resource utilization and cost.</p> <p><b>Clinical trial registration</b>: <a href="http://www.clinicaltrials.gov" target="_blank">www.clinicaltrials.gov</a> identifier is NCT02451137.</p