Glucagon-like peptide 1 (GLP-1) is potentially a very attractive agent for treating type 2 diabetes. We explored the effect of short-term (1 week) treatment with a GLP-1 derivative, liraglutide (NN2211), on 24-h dynamics in glycemia and circulating free fatty acids, islet cell hormone profiles, and gastric emptying during meals using acetaminophen. Furthermore, fasting endogenous glucose release and gluconeogenesis (3-3 Hglucose infusion and 2 H 2 O ingestion, respectively) were determined, and aspects of pancreatic islet cell function were elucidated on the subsequent day using homeostasis model assessment and first-and second-phase insulin response during a hyperglycemic clamp (plasma glucose ϳ16 mmol/l), and, finally, on top of hyperglycemia, an arginine stimulation test was performed. For accomplishing this, 13 patients with type 2 diabetes were examined in a double-blind, placebo-controlled crossover design. Liraglutide (6 g/kg) was administered subcutaneously once daily. Liraglutide significantly reduced the 24-h area under the curve for glucose (P ‫؍‬ 0.01) and glucagon (P ‫؍‬ 0.04), whereas the area under the curve for circulating free fatty acids was unaltered. Twenty-four-hour insulin secretion rates as assessed by deconvolution of serum C-peptide concentrations were unchanged, indicating a relative increase. Gastric emptying was not influenced at the dose of liraglutide used. Fasting endogenous glucose release was decreased (P ‫؍‬ 0.04) as a result of a reduced glycogenolysis (P ‫؍‬ 0.01), whereas gluconeogenesis was unaltered. First-phase insulin response and the insulin response to an arginine stimulation test with the presence of hyperglycemia were markedly increased (P < 0.001), whereas the proinsulin/insulin ratio fell (P ‫؍‬ 0.001). The disposition index (peak insulin concentration after intravenous bolus of glucose multiplied by insulin sensitivity as assessed by homeostasis model assessment) almost doubled during liraglutide treatment (P < 0.01). Both during hyperglycemia per se and after arginine exposure, the glucagon responses were reduced during liraglutide administration (P < 0.01 and P ‫؍‬ 0.01). Thus, 1 week's treatment with a single daily dose of the GLP-1 derivative liraglutide, operating through several different mechanisms including an ameliorated pancreatic islet cell function in individuals with type 2 diabetes, improves glycemic control throughout 24 h of daily living, i.e., prandial and nocturnal periods. This study further emphasizes GLP-1 and its derivatives as a promising novel concept for treatment of type 2 diabetes.

Glucagon-like peptide 1 (GLP-1) is a potent glucoselowering agent of potential interest for the treatment of type 2 diabetes. To evaluate actions of NN2211, a long-acting GLP-1 derivative, we examined 11 patients with type 2 diabetes, age 59 ؎ 7 years (mean ؎ SD), BMI 28.9 ؎ 3.0 kg/m 2 , HbA 1c 6.5 ؎ 0.6%, in a double-blind, placebo-controlled, crossover design. A single injection (10 g/kg) of NN2211 was administered at 2300 h, and profiles of circulating insulin, C-peptide, glucose, and glucagon were monitored during the next 16.5 h. A standardized mixed meal was served at 1130 h. Efficacy analyses were performed for the fasting (7-8 h) and mealtime (1130 -1530 h) periods. Insulin secretory rates (ISR) were estimated by C-peptide deconvolution analysis. Glucose pulse entrainment (6 mg ⅐ kg ؊1 ⅐ min P atients with type 2 diabetes experience relative insulin deficiency as well as delayed and blunted meal-related insulin response (1). Glucagon excess contributes to the elevated fasting and postprandial glycemia (2). Because of a marked and glucosedependent insulinotropic action and a restraining effect on glucagon release, glucagon like peptide-1 (GLP-1) is an obvious candidate for the treatment of type 2 diabetes (3). In addition, GLP-1 delays gastric emptying and reduces appetite in patients with type 2 diabetes also in nonemetic doses (4). Continuous intravenous infusion and repeated subcutaneous injections of GLP-1 (7-36 amide) effectively reduce fasting plasma glucose as well as meal-related glycemia (3,5). Even in patients with type 2 diabetes and secondary failure of sulfonylurea treatment, GLP-1 has been demonstrated to reduce glycemia effectively (6).Increased ␤-cell function has been reported after overnight GLP-1 infusion, as measured by homeostasis model assessment (HOMA) and by first-and second-phase insulin secretion (7). The secretagogue effect is achieved by a concomitant increase of basal (nonpulsatile) and highfrequency pulsatile insulin release in patients with type 2 diabetes (8). In a study of ultradian insulin pulsatility, GLP-1 was reported to restore glucose entrainment in individuals with impaired glucose tolerance (9), indicating preferential effects on the coordination of insulin release.GLP-1 is rapidly cleaved by dipeptidyl-peptidase IV after both intravenous and subcutaneous injections, and the development of long-acting derivatives is needed for clinical use. NN2211 is an acylated GLP-1 derivative with prolonged action due to a combination of albumin binding, metabolic stability, and slow release from the injection site. NN2211 has shown a favorable pharmacokinetic

This study assessed whether glucose-dependent insulin secretion and overall counterregulatory response are preserved during hypoglycemia in the presence of exenatide. Twelve healthy fasted volunteers were randomized in a triple-blind crossover study to receive either intravenous exenatide (0.066 pmol ⅐ kg ؊1 ⅐ min ؊1 ) or placebo during a 270-min stepwise hyperinsulinemichypoglycemic clamp (insulin infusion 0.8 mU ⅐ kg ؊1 ⅐ min ؊1 ). Plasma glucose was clamped sequentially at 5.0 (0 -120 min), 4.0 (120 -180 min), 3.2 (180 -240 min), and 2.7 mmol/l (240 -270 min). At 270 min, insulin infusion was terminated and plasma glucose increased to ϳ3.2 mmol/l. The time to achieve plasma glucose >4 mmol/l thereafter was recorded. Insulin secretory rates (ISRs) and counterregulatory hormones were measured throughout. Glucose profiles were superimposable between the exenatide and placebo arms. In the presence of euglycemic hyperinsulinemia, ISRs in the exenatide arm were ϳ3.5-fold higher than in the placebo arm (353 ؎ 29 vs. 100 ؎ 29 pmol/min [least-square means ؎ SE]). However, ISRs declined similarly and rapidly at all hypoglycemic steps (<4 mmol/l) in both groups. Glucagon was suppressed in the exenatide arm during euglycemia and higher than placebo during hypoglycemia. Plasma glucose recovery time was equivalent for both treatments. The areas under the concentration-time curve from 270 to 360 min for cortisol, epinephrine, norepinephrine, and growth hormone were similar between treatment arms. There were no differences in adverse events. In the presence of exenatide, there was a preserved, glucose-dependent insulin secretory response and counterregulatory response during hypoglycemia. Diabetes 53:2397-2403, 2004 T he pathogenesis of type 2 diabetes is characterized by peripheral insulin resistance and progressive failure of pancreatic ␤-cell function, ultimately resulting in deficient insulin secretion. Furthermore, an excessive glucagon secretion and an impaired incretin response to meals contribute to the metabolic derangement of the disease (1-4). Control of circulating glucose levels is rarely optimal, and many currently available therapies also have unfavorable side effects and restrictions, limiting the extent of their use (5-8). This emphasizes the need for novel antidiabetic agents.Glucagon-like peptide (GLP)-1 is an incretin hormone secreted from the intestinal mucosa in response to meal ingestion. Physiological GLP-1 exhibits several glucoregulatory functions, such as glucose-dependent enhancement of insulin secretion, suppression of glucagon secretion, delayed gastric emptying, and reduction of food intake. It may even promote ␤-cell preservation and improved neogenesis (9). GLP-1 has an extremely short half-life in plasma.Exenatide (synthetic exendin-4) is a 39 -amino acid peptide incretin mimetic that demonstrates the above glucoregulatory actions of GLP-1 (10,11), and it has been shown to be a potent agonist to the GLP-1 receptor in vitro (12). Clinical studies in humans have demonstrated markedly improved ...

Insulin concentrations oscillate at a periodicity of 5-15 min per oscillation. These oscillations are due to coordinate insulin secretory bursts, from millions of islets. The generation of common secretory bursts requires strong within-islet and within-pancreas coordination to synchronize the secretory activity from the ␤-cell population. The overall contribution of this pulsatile mechanism dominates and accounts for the majority of insulin release. This review discusses the methods involved in the detection and quantification of periodicities and individual secretory bursts. The mechanism by which overall insulin secretion is regulated through changes in the pulsatile component is discussed for nerves, metabolites, hormones, and drugs. The impaired pulsatile secretion of insulin in type 2 diabetes has resulted in much focus on the impact of the insulin delivery pattern on insulin action, and improved action from oscillatory insulin exposure is demonstrated on liver, muscle, and adipose tissues. Therefore, not only is the dominant regulation of insulin through changes in secretory burst mass and amplitude, but the changes may affect insulin action. Finally, the role of impaired pulsatile release in early type 2 diabetes suggests a predictive value of studies on insulin pulsatility in the development of this disease. Diabetes 51 (Suppl. 1): S245-S254, 2002

Physical training following RYGB improves weight loss and cardiovascular health.

RYGB improves HRQoL, but does not increase PA. Supervised physical training intervention improves general health 24 months after RYGB and tends to improve certain domains of PA right after the intervention period, but fails to increase the patients' overall PA level over time. Clinical Trial Registration Registered at ClinicalTrials.gov-no. NCT01690728.

No abstract

Acute severe pain decreases insulin sensitivity, primarily by affecting nonoxidative glucose metabolism. It is conceivable that the counterregulatory hormonal response plays an important role. This may indicate that pain relief in stress states is important for maintenance of normal glucose metabolism.