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.

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.

Day-long subcutaneous infusion of exenatide lowers glycemia in patients with type 2 diabetes.

Exenatide (exendin-4) is an incretin mimetic with potential antidiabetic activity. This study examined the effects of a continuous subcutaneous (SC) infusion of exenatide (0.2, 0.4, 0.6, or 0.8 microg/kg/day) or placebo (PBO) on glycemic control over 23 h intervals. Twelve subjects with type 2 diabetes treated with metformin and/or diet received 10 infusions (4 exenatide, 6 PBO) on consecutive days. Exenatide was given in a dose-increasing design with at least one placebo infusion between each exenatide infusion, and with meals and a snack provided during the first 14 h of infusion. Plasma exenatide concentrations were dose-proportional. Plasma glucose (4-23 h) was lower in all exenatide arms compared to placebo (p<0.0001). The change in insulin/glucagon ratio and amylin concentrations from pre-infusion to post-infusion was increased (p<0.005, p<0.05, respectively) in the combined exenatide arms, but remained unchanged in the placebo groups. Nausea and vomiting were the most common treatment emergent adverse events. Exenatide infusion also appeared to have positive effects on beta-cell and alpha-cell function as measured by proinsulin/insulin ratios and mean glucagon concentrations. In summary, exenatide lowered plasma glucose during both prandial and fasting states when delivered as a continuous SC infusion over twenty-three hours, suggesting that exenatide can provide day-long glycemic control in patients with type 2 diabetes.

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

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.

Ocular paintball injuries.

Paintball sport-related ocular injuries represent an increasing problem as the popularity of the sport increases and the number of participants grows. Although eye protective devices designed specifically for paintball sports are extremely effective in preventing such injuries, the failure to properly wear these devices has resulted in an alarming number of severe ocular injuries. Recent trends have indicated that an increasing percentage of paintball sport-related ocular injuries have occurred in unsupervised, noncommercial settings (i.e., backyard games) where the use of eye protective devices is not required. Paintball industry standards for eye protection have recently been developed and should be implemented for all participants.

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.

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.

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.

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.

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.

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.

Ultrasound biomicroscopy as a tool for detecting and localizing occult foreign bodies after ocular trauma.

OBJECTIVE: To show the utility of ultrasound biomicroscopy (UBM) in imaging small ocular foreign bodies of the anterior segment. DESIGN: Retrospective case series. PARTICIPANTS: Twelve eyes of 12 consecutive patients evaluated in the emergency department or referred to specialty services at 1 institution between August 1994 and November 1997 were examined. INTERVENTION: Ocular ultrasound biomicroscopy was performed. MAIN OUTCOME MEASURES: Detection and localization of an ocular foreign body were measured. RESULTS: An intraocular or superficial foreign body was detected by UBM in 9 (75%) of 12 eyes. The foreign body was classified as corneal in two eyes, subconjunctival in two, intrascleral in three, and intraocular in two eyes. The foreign body was not visible by ophthalmic physical examination in seven of the nine eyes with a confirmed ocular foreign body. In the remaining two eyes, UBM was used to determine the depth of a visible foreign body. In three of the eyes with a confirmed foreign body, computed tomography and/or contact B-scan ultrasonography was obtained and failed to show a foreign body. Six of the foreign bodies were nonmetallic. CONCLUSIONS: Clinical detection of ocular foreign bodies after trauma can be hindered by small size, haziness of the optical media, poor patient cooperation, or hidden location. Ultrasound biomicroscopy is a valuable adjunct in the evaluation of suspected ocular foreign bodies, especially in cases involving small, nonmetallic objects.

Impaired phasic insulin and amylin secretion in diabetic rats.

We have proposed that a hyperstimulated insulin secretion causing beta-cell degranulation is the basis for the impaired glucose-potentiated insulin secretion in type 2 diabetes ("overworked beta-cell"). To confirm this idea, we previously investigated tolbutamide-infused euglycemic rats. Two novel kinds of beta-cell dysfunction were observed: altered phasic glucose-potentiated insulin secretion with preferential sparing of the first phase and a raised secreted ratio of amylin to insulin. The current study tested these parameters in 90% (intact beta-cell insulin stores) and 95% (markedly lowered insulin stores) pancreatectomized (Px) diabetic rats. Rats underwent pancreas perfusion 5-6 wk postsurgery. Controls showed nonchanging insulin secretion during a 20-min perfusion of 16.7 mM glucose + 10 mM arginine. In contrast, both Px groups showed an altered phasic pattern, with the first phase being supernormal (for the beta-cell mass) but the second phase reduced in tandem with the insulin content. Amylin secretion from control and 90% Px rats paralleled the insulin output, so that the amylin-to-insulin ratio averaged 0. 12 +/- 0.03% in the controls and 0.16 +/- 0.01% in the 90% Px rats over the two secretory phases. In contrast, the amylin-to-insulin ratio in 95% Px rats equaled that of controls during the first phase (0.12 +/- 0.1%) but was twice normal during the second phase (0.32 +/- 0.4%). These results confirm the validity of the overworked beta-cell schema by showing identical beta-cell functional defects in Px rats and tolbutamide-infused normoglycemic rats.