GLP-1 based therapies: differential effects on fasting and postprandial glucose.

Glucagon-like peptide-1 (GLP-1), a gut-derived hormone secreted in response to nutrients, has several glucose and weight regulating actions including enhancement of glucose-stimulated insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduction in food intake. Because of these multiple effects, the GLP-1 receptor system has become an attractive target for type 2 diabetes therapies. However, GLP-1 has significant limitations as a therapeutic due to its rapid degradation (plasma half-life of 1-2 min) by dipeptidyl peptidase-4 (DPP-4). Two main classes of GLP-1-mediated therapies are now in use: DPP-4 inhibitors that reduce the degradation of GLP-1 and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists. The GLP-1R agonists can be further divided into short- and long-acting formulations which have differential effects on their mechanisms of action, ultimately resulting in differential effects on their fasting and postprandial glucose lowering potential. This review summarizes the similarities and differences among DPP-4 inhibitors, short-acting GLP-1R agonists and long-acting GLP-1R agonists. We propose that these different GLP-1-mediated therapies are all necessary tools for the treatment of type 2 diabetes and that the choice of which one to use should depend on the specific needs of the patient. This is analogous to the current use of modern insulins, as short-, intermediate- and long-acting versions are all used to optimize the 24-h plasma glucose profile as needed. Given that GLP-1-mediated therapies have advantages over insulins in terms of hypoglycaemic risk and weight gain, optimized use of these compounds could represent a significant paradigm shift for the treatment of type 2 diabetes.

GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice.

AIM: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that induces glucose-dependent insulin secretion and may have neurotrophic properties. Our aim was to identify the presence and activity of GLP-1 receptors (GLP-1Rs) in peripheral nerve and to assess the impact of GLP-1R agonists on diabetes-induced nerve disorders. METHODS: Tissues were collected from streptozotocin-diabetic rats. GLP-1R function was assessed by incubating tissues from normal and diabetic rats with GLP-1R agonists and antagonists and measuring induction of ERK1/2 phosphorylation by Western blot. Streptozotocin-diabetic mice were also treated with the GLP-1R agonist exenatide for 8 weeks to assess the impact of GLP-1R signalling on peripheral nerve function and structure. RESULTS: GLP-1R protein was detected in rat dorsal root ganglia and the neurons and Schwann cells of the sciatic nerve. Protein levels were not affected by streptozotocin-induced diabetes. GLP-1R agonists did not signal via ERK1/2 in sciatic nerve of normal rats. However, GLP-1R agonists significantly increased pERK1/2 levels in sciatic nerves from diabetic rats, indicating that GLP-1Rs are functional in this tissue. Exenatide treatment did not affect blood sugar, insulin levels or paw thermal response latencies in either control or diabetic mice. However, the reductions of motor nerve conduction velocity and paw intraepidermal fibre density seen in diabetic mice were attenuated by exenatide treatment. CONCLUSIONS: These data show that the peripheral nerve of diabetic rodents exhibits functional GLP-1R and suggest that GLP-1R-mediated ERK-signalling in sciatic nerve of diabetic rodents may protect large motor fibre function and small C fibre structure by a mechanism independent of glycaemic control.

Pharmacometrics and the transition to model-based development.

As the transition to model-based drug development continues, pharmacometric analysis will have an increasingly important role across the entire life cycle of drug discovery, development, regulatory approval, and commercialization. For this reason, pharmacometrics can--and should--have an integrating function in the transformation to model-based development. This essay describes an approach for formalizing the pharmacometrics process using the disciplines encompassed by enterprise engineering.

Exenatide effects on statin pharmacokinetics and lipid response.

OBJECTIVE: Exenatide is an adjunctive treatment for type 2 diabetes. Many patients with type 2 diabetes have dyslipidemia, which requires treatment with three hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase inhibitors (statins), hence, concurrent use of exenatide and statins is likely. Exenatide slows gastric emptying, which may alter the absorption rate of co-administered oral medications. Thus, the potential interaction between exenatide and statins was evaluated in two study settings. METHODS: In an open-label, fixed-sequence, clinical pharmacology study, the plasma pharmacokinetics of lovastatin (40 mg after breakfast) in the presence and absence of exenatide (10 microg before breakfast and dinner) was evaluated in 21 healthy subjects. In a second clinical setting, changes in lipid profiles and statin dosage over 30 weeks in patients with type 2 diabetes were retrospectively compared (n = 180 exenatide 10 microg twice daily (BID), n = 168 placebo BID) in a combined analysis of three placebo-controlled, randomized exenatide Phase 3 trials. RESULTS: In healthy subjects, exenatide decreased mean lovastatin area under the plasma concentration time curve from zero to infinity (AUC0-infinity) and maximum plasma concentration (Cmax) by 40 and 28%, respectively, and increased median time to maximum plasma concentration (tmax) by 4 hours. In the exenatide Phase 3 trials, 30-week changes from baseline for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides and statin dosage were not significantly different between the exenatide and placebo groups treated with statins. CONCLUSIONS: Despite observed changes in lovastatin bioavailability in the pharmacokinetic drug interaction study, exenatide did not negatively affect long-term lipid profiles or statin dosage in patients with concurrent statin therapy. Thus, co-administration of exenatide does not require adjustment in statin dosage.

Adjunctive therapy with pramlintide lowers HbA1c without concomitant weight gain and increased risk of severe hypoglycemia in patients with type 1 diabetes approaching glycemic targets.

AIMS: In long-term clinical trials in patients with type 1 diabetes spanning a wide range of HbA1c, addition of pramlintide to existing insulin regimens led to reductions in HbA1c that were accompanied by weight loss and no increase in overall severe hypoglycemia event rates. Given that weight gain and increased hypoglycemia risk contribute to the difficulty of attaining HbA1c targets (<7 %), the question arose whether pramlintide could benefit patients approaching, but not reaching glycemic targets with insulin alone. To address this question, we conducted a pooled analysis from 3 long-term clinical trials, including all patients with an entry HbA1c between 7.0 % and 8.5 %. METHODS: Within the subset of patients with an entry HbA1c between 7.0 % and 8.5 % (approximately 28 % of all patients enrolled in the 3 studies), 196 were treated with placebo + insulin (baseline HbA1c 7.9+/-0.4 %, body weight 76.0+/-14.3 kg [mean+/-SD]) and 281 with pramlintide+insulin (baseline HbA1c 7.9+/-0.4 %, body weight 75.4+/-13.1 kg). Endpoints included placebo-corrected changes from baseline to week 26 in HbA1c, body weight, and the event rate of severe hypoglycemia. RESULTS: Adjunctive therapy with pramlintide resulted in significant reductions in HbA1c and body weight from baseline to week 26 (0.3 % and 1.8 kg, placebo-corrected treatment differences, respectively, both p

Deficiency of total and nonglycosylated amylin in plasma characterizes subjects with impaired glucose tolerance and type 2 diabetes.

This study was undertaken to characterize first and second phase secretory profiles of total and nonglycosylated amylin and insulin and to determine whether excessive glycosylation of amylin or hyperamylinemia is a feature of abnormal glucose tolerance in humans. Plasma concentrations of total and nonglycosylated amylin and serum immunoreactive insulin were measured under identical hyperglycemic conditions using the hyperglycemic clamp technique in subjects with type 2 diabetes, impaired and normal glucose tolerance. Both amylin and insulin concentrations followed a biphasic pattern in subjects with normal and impaired glucose tolerance. In the subjects with normal and impaired glucose tolerance, the second phase amylin concentrations markedly exceeded those of the first phase, whereas the reverse was true for insulin. The first phase concentrations of both peptides were significantly lower in impaired than the normal glucose tolerance subjects. In patients with type 2 diabetes no first phase peak for either amylin or insulin could be identified, and the second phases of both amylin and insulin were significantly lower compared to subjects with normal or impaired glucose tolerance. Nonglycosylated amylin concentrations accounted for 25-45% of total amylin, regardless of glucose tolerance, and mimicked the pattern of total amylin concentrations. In summary: 1) glucose-induced increases in the magnitude of the first and second phase amylin plasma concentrations differed from those of insulin; 2) subjects with impaired glucose tolerance and more strikingly those with type 2 diabetes have impaired amylin responses; and 3) the ratio of nonglycosylated to total amylin is normal irrespective of glucose tolerance. These data imply, in view of many reports describing accumulation of amyloid in the pancreas, that circulating levels of amylin decrease as amyloid deposits accumulate and beta-cell function deteriorates and that the amount of glycosylated amylin in plasma is not increased in patients with type 2 diabetes.

Circulating levels of incretin hormones and amylin in the fasting state and after oral glucose in GH-deficient patients before and after GH replacement: a placebo-controlled study.

OBJECTIVE: Hyperinsulinemia in association with GH excess is considered a compensatory response to insulin resistance, but the possibility of alternative insulinotropic mechanisms has not been investigated in vivo. It is also unknown how GH influences the secretion from pancreatic beta-cells of amylin, a peptide which regulates prandial glucose homeostasis and may be linked to development of beta-cell dysfunction. We therefore measured plasma concentrations of two gut insulinotropic hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulin-releasing peptide (GIP), and total as well as non-glycosylated amylin, in 24 GH-deficient adults before and after 4 months of GH replacement (daily evening injections of 2 IU GH/m). DESIGN: Double-blind, placebo-controlled, parallel study. METHODS: All participants underwent an oral glucose tolerance test (OGTT) at 0 and 4 months. RESULTS: A 33% suppression of fasting GLP-1 concentrations was measured in the GH group at 4 months (P=0.02), whereas a non-significant increase occurred in the placebo group (P=0.08). Fasting levels of GIP and amylin did not change significantly after 4 months in either group. The incremental response in GLP-1 during the OGTT was significantly lower after GH treatment as compared with both baseline (P=0.02) and the response in the placebo group (P=0. 03). The stimulation of GIP secretion following OGTT was similar on all occasions. The OGTT-induced incremental response in non-glycosylated amylin was moderately elevated after GH treatment as compared with placebo (P=0.05). Plasma concentrations of glucose and insulin, both in the fasting state and after the OGTT, were higher after GH treatment, but the ratio between amylin and insulin remained unchanged. CONCLUSIONS: GH-induced hyperinsulinemia is accompanied by proportionate elevations in amylin concentrations and a blunting of gut GLP-1 secretion. The mechanisms underlying the suppression of GLP-1 remain to be elucidated.

Changing trends in paintball sport-related ocular injuries.

OBJECTIVES: To describe the type and severity of ocular injuries caused by paintballs, to summarize the outcomes, to determine if the injury occurred in a commercial or noncommercial setting, to compare the number of injuries in each setting as a function of time, and to ascertain whether eye-protective devices were worn and why they were removed. DESIGN: Retrospective analysis of 35 patients who sustained ocular injuries caused by paintballs and underwent evaluation and treatment at an eye hospital from January 1, 1985, to September 30, 1998. Thirty-five eyes of 35 patients underwent a complete ocular examination, diagnostic testing, and surgical intervention when indicated. RESULTS: All patients were male (average age, 22 years). Twenty-six patients (74%) had an initial visual acuity of 20/200 or worse, and visual acuity in 16 (46%) remained 20/200 or worse on follow-up (range, 2 weeks to 22 months). Traumatic hyphema was seen in 21 patients (60%). Twenty-two patients (63%) had access to goggles, 7 (33%) of whom removed them due to fogging before the injury. Injuries sustained after 1995 were 5.8 times (relative risk, 5.8; 95% confidence interval, 1.5-22.4) more likely to occur during a noncommercial war game than those occurring in 1995 or before. CONCLUSIONS: As the popularity of war games increases, so does the potential for serious ocular injury caused by paint pellet guns. Most injuries seen after 1995 occurred in noncommercial war game settings, where the use of eye-protective devices is not required. Industry standards for eye protection have been developed recently and should be implemented.

Safety of indocyanine green angiography during pregnancy: a survey of the retina, macula, and vitreous societies.

OBJECTIVES: To establish current practice patterns and assess the general knowledge among vitreoretinal-trained physicians regarding the use of indocyanine green (ICG) angiography during pregnancy, and to review the literature regarding the established safety of ICG angiography in pregnant women. METHODS: A survey was mailed to 1101 members of the Retina, Macula, and Vitreous Societies. RESULTS: Of the 520 respondents, 434 (83%) had seen at least 1 pregnant woman who required ICG angiography or fluorescein angiography. Of these, 385 (89%) withheld fluorescein angiography and 105 (24%) withheld ICG angiography, largely because of fear of teratogenicity or lawsuit. Diabetic retinopathy and choroidal neovascular membrane were the most common indications for fluorescein angiography, and choroidal neovascular membrane and choroidal tumor were the most common indications for ICG angiography. Only 24% thought that it was safe to use ICG angiography in a pregnant patient, and only 5% thought it was safer than fluorescein angiography. CONCLUSIONS: Despite the documented safety of ICG when used for retinal angiography and the extensive experience with the use of intravenous ICG to measure hepatic blood flow in pregnant women, the results of this survey suggest widespread hesitation to use ICG for retinal angiography in pregnant women. Current practice patterns regarding the use of ICG angiography in pregnant patients may be unnecessarily restrictive.

The human amylin analog, pramlintide, corrects postprandial hyperglucagonemia in patients with type 1 diabetes.

Mealtime amylin replacement with the human amylin analog pramlintide as an adjunct to insulin therapy improves postprandial glycemia and long-term glycemic control in type 1 diabetes. Preclinical animal studies indicate that these complementary effects may result from at least 2 independent mechanisms: a slowing of nutrient delivery to the small intestine and a suppression of nutrient-stimulated glucagon secretion. The former effect of pramlintide has previously been demonstrated in patients with type 1 diabetes. The present studies characterize the effect of pramlintide on postprandial glucagon secretion in this patient population. Plasma glucagon and glucose concentrations were measured before and after a standardized liquid meal in 2 separate randomized, double-blind, placebo-controlled studies of pramlintide administration to patients with type 1 diabetes. In a 2-day crossover study, 18 patients received a 5-hour intravenous infusion of pramlintide (25 microg/h or 50 microg/h) or placebo in addition to subcutaneous (SC) insulin injections. In a 14-day parallel-group study, 84 patients received SC injections of 30, 100, or 300 microg of pramlintide or placebo 3 times daily in addition to SC injections of insulin. In both studies plasma glucagon concentrations increased in response to the meal in the placebo-plus-insulin group but not in any of the pramlintide-treated groups (all pramlintide treatment arms v placebo, P <.05). We conclude that mealtime amylin replacement with pramlintide prevents the abnormal meal-related rise in glucagonemia in insulin-treated patients with type 1 diabetes, an effect that likely contributes to its ability to improve postprandial glucose homeostasis and long-term glycemic control.

Glucoregulatory endocrine responses to intermittent exercise of different intensities: plasma changes in a pancreatic beta-cell peptide, amylin.

Amylin, a peptide hormone released from the beta cells of the pancreas and cosecreted with insulin, is reported to inhibit the release of postprandial glucagon and insulin and to modulate gastric emptying. Changes in insulin and glucagon are important for controlling blood glucose levels under conditions in which metabolic rate is elevated, such as during and following exercise. Amylin may participate in the regulation of blood glucose levels in response to exercise, although the role of amylin has not been investigated. The purpose of the study was to determine the effects of a progressive, intermittent exercise protocol on amylin concentrations and to compare its response to circulating levels of insulin, glucagon, cortisol, and glucose. Seven well-trained males completed an intermittent exercise trial on a treadmill at four progressive exercise intensities: 60%, 75%, 90%, and 100% of maximum oxygen consumption (.VO(2)max). Blood samples were collected before exercise, after each exercise intensity, and for 1 hour following the exercise protocol. Subjects also completed a control trial with no exercise. Amylin and insulin rose from baseline (5.79 +/-.78 pmol/L and 4.76 +/-.88 microIU/mL) to peak after 100% .VO(2)max (9.16 +/- 1.35 pmol/L and 14.37 +/- microIU/ml), respectively and remained elevated during much of recovery. Thus, a progressive intermittent exercise protocol of moderate to maximum exercise intensities stimulates increases in amylin levels in well-trained individuals in a similar fashion to that of insulin, whereas glucagon concentrations only increase after the greatest exercise intensity, then quickly decline. Future studies should examine the effects of higher amylin concentrations in exercise recovery on glucoregulation.

A new approach to an old problem.

A patient with progressive visual loss was found to have an optic nerve sheath meningioma. The patient was treated with stereotactic radiotherapy, a computer-guided stereotactic technique that minimizes the risk of radiation-induced optic neuropathy. Six months after treatment, the patient was doing well and showed no signs of radiation-induced optic neuropathy.

Branch retinal artery occlusion as the initial sign of giant cell arteritis.

PURPOSE: To describe a patient whose initial sign of giant cell arteritis was a branch retinal artery occlusion. METHODS: We examined a 77-year-old woman who developed arteritic anterior ischemic optic neuropathy three weeks after an isolated non-embolic branch retinal artery occlusion occurred in the same eye. RESULTS: The diagnosis of giant cell arteritis was confirmed by temporal artery biopsy after the patient was treated with intravenous corticosteroids. CONCLUSIONS: Although a rare cause of branch retinal vascular occlusion, giant cell arteritis should be considered in the differential diagnosis of a non-embolic branch retinal artery occlusion in elderly patients.

Arteriovenous adventitial sheathotomy for the treatment of macular edema associated with branch retinal vein occlusion.

PURPOSE: To report arteriovenous adventitial sheathotomy for treatment of macular edema associated with branch retinal vein occlusion. METHODS: Case reports with review. Five eyes of five patients with best-corrected visual acuity of less than 20/200 secondary to branch retinal vein occlusion had pars plana vitrectomy and arteriovenous adventitial sheathotomy and were followed postoperatively for a mean of 6.5 years (range, 5 to 7 years). RESULTS: In four of five eyes, the best-corrected visual acuity improved to 20/30 to 20/70. In the remaining eye, visual acuity remained at finger counting secondary to macular ischemia. CONCLUSION: Arteriovenous adventitial sheathotomy may be beneficial for select patients with poor vision secondary to branch retinal vein occlusion.

The role of ultrasound biomicroscopy in ocular trauma.

PURPOSE: To demonstrate the usefulness of ultrasound biomicroscopy (UBM) in detecting and localizing small ocular foreign bodies. METHODS: This is a retrospective study of the records of 555 consecutive patients evaluated by UBM by the Visual Physiology Unit of the Wills Eye Hospital from August 1994 to November 1997. RESULTS: In 9 patients, a foreign body was identified. In 6 patients, the history suggested the presence of a foreign body, but one could not be detected by clinical examination. In 2 patients, the referring physicians requested UBM to determine whether or how deep a known foreign body had penetrated the globe. In 1 patient, the foreign body was not suspected clinically. In regard to other diagnostic techniques, CT failed to identify the foreign body in 1 patient. In another, contact B-scan ultrasonography failed. In a third, both CT and contact B-scan ultrasonography failed. The foreign body was intracorneal in 2 eyes, subconjunctival in 2, intrascleral in 3, and intraocular in 2. Six were nonmetallic. Two were metallic. In one case, the foreign body was lost and its composition is unknown. In 5 cases, the UBM findings altered the patient's management. CONCLUSIONS: UBM is a valuable adjunct in the evaluation of small, anteriorly located foreign body that may not be detectable by other methods. UBM may be especially useful for finding nonmetallic foreign bodies.

Complexity of context and orientation of figure in the corridor illusion.

12 subjects judged the magnitude of the corridor illusion as two independent variables were manipulated, complexity of context and orientation of the target figures. The contexts included a complete corridor, one with vertical elements deleted, and one having but two converging lines. Figures embedded within these contexts were thin black lines oriented either vertically or horizontally. Although the context had a significant effect upon the magnitude of the illusion, orientation of the judged lines did not. These results suggest that it is legitimate to use the corridor illusion to illustrate size-distance relationships.