Newer therapeutic options for children with diabetes mellitus: theoretical and practical considerations

Recent studies in adult patients with type 1 diabetes mellitus (T1DM) and T2DM have examined the potential utility, benefits, and side effects of agents that augment insulin secretion after oral ingestion of nutrients in comparison with intravenous nutrient delivery, the so-called incretins. Two families of incretin-like substances are now approved for use in adults. Glucagon-like peptide-1 (GLP-1) or agents that bind to its receptor (exenatide, Byetta) or agents that inhibit its destruction [dipeptidyl peptidase-IV (DPP-IV) inhibitors, Vildagliptin] improve insulin secretion, delay gastric emptying, and suppress glucagon secretion while decreasing food intake without increasing hypoglycemia. Pramlintide, a synthetic amylin analog, also decreases glucagon secretion and delays gastric emptying, improves hemoglobin A1c (HbA1C), and facilitates weight reduction without causing hypoglycemia. We review the historical discovery of these agents, their physiology [corrected] and their current applications. Remarkably, only one or two studies have been reported in children. Pediatricians caring for children with T1DM and T2DM should become familiar with these agents and investigate their applicability, as they seem likely to enhance our therapeutic armamentarium to treat children with diabetes mellitus.     

Oxygen and nonventilatory therapy of respiratory failure in copd

Administration of low concentrations of oxygen has become a widely accepted method of treating respiratory failure secondary to CORD. The immediate goal of this form of therapy is to minimize the danger of hypoxia. Supportive measures are aimed at improving oxygen delivery and reducing oxygen demands.     

Management of Type 2 diabetes: the role of incretin mimetics

Type 2 diabetes is characterised by insulin resistance and progressive β-cell dysfunction (which leads to hyperglycaemia), the risk of progressive worsening of glycaemic control and an increased risk of both macrovascular and microvascular complications. Existing treatment strategies target deficient insulin secretion and insulin resistance, but do not generally address the underlying progressive β-cell dysfunction that is common to Type 2 diabetes. Traditionally, Type 2 diabetes is first treated with medical nutrition therapy (reduced food intake and increased physical activity), followed by stepwise addition of oral antidiabetes therapies and, ultimately, exogenous insulin, as required. Unfortunately, these approaches have not been shown to delay the need for additional therapies, nor do they generally prevent or delay the inexorable decline in β-cell function. Patients with Type 2 diabetes commonly experience deterioration in glycaemic control, and may have substantial weight gain due to the diabetes therapies that contribute to worsening obesity. In addition, insulin-providing therapies, such as sulfonylureas and exogenous insulin, carry the risk of hypoglycaemia, and cannot fully address the complex hormonal irregularities that characterise Type 2 diabetes, including the role of glucagon hypersecretion. New therapeutic approaches are being developed that couple durable glycaemic control with improved control of body weight. These approaches include development of the incretin mimetics, which are a novel class of agents that share several of the glucoregulatory effects of incretin hormones, such as glucagon-like hormone-1. Deficiency of glucagon-like hormone-1 secretion is known to be present in those with abnormal glucose tolerance. Agents that manipulate the physiological actions of incretin hormones, such as glucagon-like hormone-1, may significantly benefit patients with Type 2 diabetes.     

Electronics in Medical Practice

Colon cancer is the second most common form of cancer, but survival rates could be drastically improved with early diagnosis and treatment. Among recommended routine screening methods, flexible fiberoptic sigmoidoscopy is well accepted, reliable, and relatively easy to perform. Dr Semerdjian discusses why every primary care physician should be able to perform flexible sigmoidoscopy and reports the results of its use at Scripps Clinic.     

Comparison of once-weekly with twice-daily exenatide in the treatment of type 2 diabetes (DURATION-1 trial)

The safety and efficacy of exenatide once weekly is evaluated over 52 weeks in the DURATION-1 trial in patients with type 2 diabetes. This long-acting glucagon-like peptide 1 receptor agonist given as a once weekly subcutaneous injection was found to produce better glycemic control as compared to twice daily exenatide and had a good safety profile over the trial period. Its use can help to reduce the complexity of drug regimen in patients with type 2 diabetes while maintaining a good safety and efficacy profile.     

Computer-Based Patient Interviewing

The medical history, which may well be the physician's most important diagnostic tool, has long been neglected. The computer is well suited to efficient patient interviewing. This two part article describes a computer-based technic for taking general medical and specialty histories directly from patients.     

The structure and function of the glucagon-like peptide-1 receptor and its ligands

Glucagon-like peptide-1(7-36)amide (GLP-1) is a 30-residue peptide hormone released from intestinal L cells following nutrient consumption. It potentiates the glucose-induced secretion of insulin from pancreatic beta cells, increases insulin expression, inhibits beta-cell apoptosis, promotes beta-cell neogenesis, reduces glucagon secretion, delays gastric emptying, promotes satiety and increases peripheral glucose disposal. These multiple effects have generated a great deal of interest in the discovery of long-lasting agonists of the GLP-1 receptor (GLP-1R) in order to treat type 2 diabetes. This review article summarizes the literature regarding the discovery of GLP-1 and its physiological functions. The structure, function and sequence-activity relationships of the hormone and its natural analogue exendin-4 (Ex4) are reviewed in detail. The current knowledge of the structure of GLP-1R, a Family B GPCR, is summarized and discussed, before its known interactions with the principle peptide ligands are described and summarized. Finally, progress in discovering non-peptide ligands of GLP-1R is reviewed. GLP-1 is clearly an important hormone linking nutrient consumption with blood sugar control, and therefore knowledge of its structure, function and mechanism of action is of great importance.     

Safety, efficacy and tolerability of exenatide in combination with insulin in the Association of British Clinical Diabetologists nationwide exenatide audit*

Aim: To assess the extent, safety, efficacy and tolerability of reported off‐licence exenatide use through a nationwide audit. Methods: The Association of British Clinical Diabetologists hosted a password‐protected, online collection of anonymized data of exenatide use in real clinical practice. Three hundred and fifteen contributors from 126 centres across UK provided data on 6717 patients. HbA1c and weight changes, exenatide discontinuation, adverse events and treatment satisfaction were compared between non‐insulin and insulin‐treated patients. Results: Four thousand eight hundred and fifty‐seven patients had baseline and follow‐up treatment status with mean (±s.d.) baseline HbA1c 9.45 ± 1.69% and BMI 40.0 ± 8.2 kg/m². Of the 4857 patients, 1921 (39.6%) used exenatide with insulin. Comparing patients who continued insulin with exenatide with non‐insulin‐treated patients, mean (±s.e.) latest HbA1c and weight reduction (median 26 weeks) were 0.51 ± 0.06 versus 0.94 ± 0.04% (p < 0.001) and 5.8 ± 0.2 versus 5.5 ± 0.1 kg (p = 0.278). Insulin‐treated patients had higher rates of exenatide discontinuation (31.0 vs. 13.9%, p < 0.001), hypoglycaemia (8.9 vs. 6.1%, p < 0.001), gastrointestinal side effects (28.4 vs. 25.0%, p = 0.008) and treatment dissatisfaction (20.8 vs. 5.7%, p < 0.001). However, 34.2% of the patients continuing insulin still achieved HbA1c reduction ≥1%. There was significant insulin discontinuation, dose reduction and greater sulphonylurea discontinuation among insulin‐treated patients. Conclusions: Addition of exenatide to obese, insulin‐treated patients can improve glycaemia and weight. Adverse events were statistically but probably not clinically significantly higher, but combination treatment was less well tolerated. Overall, exenatide was less effective in lowering HbA1c among insulin‐treated patients, although significant number of insulin‐treated patients still achieved significant HbA1c, weight and insulin reductions. Further research into identifying obese, insulin‐treated patients who will tolerate and benefit from exenatide treatment is urgently needed.     

Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes

Aims: Most treatments for type 2 diabetes fail over time, necessitating combination therapy. We investigated the safety, tolerability and efficacy of liraglutide monotherapy compared with glimepiride monotherapy over 2 years. Methods: Participants were randomized to receive once‐daily liraglutide 1.2 mg, liraglutide 1.8 mg or glimepiride 8 mg. Participants completing the 1‐year randomized, double‐blind, double‐dummy period could continue open‐label treatment for an additional year. Safety data were evaluated for the full population exposed to treatment, and efficacy data were evaluated for the full intention‐to‐treat (ITT) and 2‐year completer populations. Outcome measures included change in glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and frequency of nausea and hypoglycaemia. Results: For patients completing 2 years of therapy, HbA1c reductions were ?0.6% with glimepiride versus ?0.9% with liraglutide 1.2 mg (difference: ?0.37, 95% CI: ?0.71 to ?0.02; p = 0.0376) and ?1.1% with liraglutide 1.8 mg (difference: ?0.55, 95% CI: ?0.88 to ?0.21; p = 0.0016). In the ITT population, HbA1c reductions were ?0.3% with glimepiride versus ?0.6% with liraglutide 1.2 mg (difference: ?0.31, 95% CI: ?0.54 to ?0.08; p = 0.0076) and ?0.9% with liraglutide 1.8 mg (difference: ?0.60, 95% CI: ?0.83 to ?0.38; p < 0.0001). For both ITT and completer populations, liraglutide was more effective in reducing HbA1c, FPG and weight. Over 2 years, rates of minor hypoglycaemia [self‐treated plasma glucose <3.1 mmol/l (<56 mg/dl)] were significantly lower with liraglutide 1.2 mg and 1.8 mg compared with glimepiride (p < 0.0001). Conclusion: Liraglutide monotherapy for 2 years provides significant and sustained improvements in glycaemic control and body weight compared with glimepiride monotherapy, at a lower risk of hypoglycaemia.