Filip K. Knop

Once-Weekly GLP-1 Agonists: How Do They Differ from Exenatide and Liraglutide?

Incretin mimetics offer a new modality in diabetes treatment. This modality is based on the effects of the naturally occurring glucoregulatory gut hormone glucagon-like peptide-1 (GLP-1), which counteracts several pathophysiologic traits in type 2 diabetes. GLP-1 receptor agonists with extended half-lives entailing fewer injections and presumably an improved throughout-the-day glycemic control are in clinical development. This article summarizes the physiologic effects of GLP-1; the effects of the already marketed GLP-1 analogues for daily dosing, exenatide and liraglutide; and reviews the presently published data (with emphasis on clinical pharmacokinetics, efficacy, and safety) on GLP-1 agonists, which currently are in development and intended for once-weekly dosing: albiglutide/albugon, CJC-1131, CJC-1134-PC, exenatide once weekly, and taspoglutide.

Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials

Objective To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus. Design Systematic review with meta-analyses. Data sources Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011). Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin. Data extraction Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors. Results 25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference −2.9 kg, 95% confidence interval –3.6 to –2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (–3.2 kg, –4.3 to –2.1; three trials) as well as patients with diabetes (–2.8 kg, –3.4 to –2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia. Conclusions The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.

Reduced Incretin Effect in Type 2 Diabetes Cause or Consequence of the Diabetic State

We aimed to investigate whether the reduced incretin effect observed in patients with type 2 diabetes is a primary event in the pathogenesis of type 2 diabetes or a consequence of the diabetic state. Eight patients with chronic pancreatitis and secondary diabetes (A1C mean [range] of 6.9% [6.2–8.0]), eight patients with chronic pancreatitis and normal glucose tolerance (NGT; 5.3 [4.9–5.7]), eight patients with type 2 diabetes (6.9 [6.2–8.0]); and eight healthy subjects (5.5 [5.1–5.8]) were studied. Blood was sampled over 4 h on 2 separate days after a 50-g oral glucose load and an isoglycemic intravenous glucose infusion, respectively. The incretin effect (100% × [β-cell secretory response to oral glucose tolerance test − intravenous β-cell secretory response]/β-cell secretory response to oral glucose tolerance test) was significantly (P < 0.05) reduced (means ± SE) in patients with chronic pancreatitis and secondary diabetes (31 ± 4%) compared with patients with chronic pancreatitis and NGT (68 ± 3) and healthy subjects (60 ± 4), respectively. In the type 2 diabetes group, the incretin effect amounted to 36 ± 6%, significantly (P < 0.05) lower than in chronic pancreatitis patients with NGT and in healthy subjects, respectively. These results suggest that the reduced incretin effect is not a primary event in the development of type 2 diabetes, but rather a consequence of the diabetic state.

Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity

BACKGROUND & AIMS Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in humans would affect fecal microbiota composition and subsequently bile acid and glucose metabolism. METHODS In this single blinded randomized controlled trial, 20 male obese subjects with metabolic syndrome were randomized to 7 days of amoxicillin 500 mg t.i.d. or 7 days of vancomycin 500 mg t.i.d. At baseline and after 1 week of therapy, fecal microbiota composition (Human Intestinal Tract Chip phylogenetic microarray), fecal and plasma bile acid concentrations as well as insulin sensitivity (hyperinsulinemic euglycemic clamp using [6,6-(2)H2]-glucose tracer) were measured. RESULTS Vancomycin reduced fecal microbial diversity with a decrease of gram-positive bacteria (mainly Firmicutes) and a compensatory increase in gram-negative bacteria (mainly Proteobacteria). Concomitantly, vancomycin decreased fecal secondary bile acids with a simultaneous postprandial increase in primary bile acids in plasma (p<0.05). Moreover, changes in fecal bile acid concentrations were predominantly associated with altered Firmicutes. Finally, administration of vancomycin decreased peripheral insulin sensitivity (p<0.05). Amoxicillin did not affect any of these parameters. CONCLUSIONS Oral administration of vancomycin significantly impacts host physiology by decreasing intestinal microbiota diversity, bile acid dehydroxylation and peripheral insulin sensitivity in subjects with metabolic syndrome. These data show that intestinal microbiota, particularly of the Firmicutes phylum contributes to bile acid and glucose metabolism in humans. This trial is registered at the Dutch Trial Register (NTR2566).

2-Oleoyl Glycerol Is a GPR119 Agonist and Signals GLP-1 Release in Humans

OBJECTIVE Dietary fat is thought to stimulate release of incretin hormones via activation of fatty acid receptors in the intestine. However, dietary fat (triacylglycerol) is digested to 2-monoacylglycerol and fatty acids. Activation of G protein-coupled receptor 119 (GPR119) stimulates glucagon-like peptide-1 (GLP-1) release from the intestinal L-cells. We aimed to investigate if 2-oleoyl glycerol (2OG) can activate GPR119 in vitro and stimulate GLP-1 secretion in vivo. RESEARCH DESIGN AND METHODS Agonist activity for various lipids was tested on transiently expressed human GPR119 in COS-7 cells. The effect of a jejunal bolus of 2 g 2OG on plasma levels of GLP-1 was evaluated in eight healthy human volunteers. The effect of 2OG was compared to an equimolar amount of oleic acid, a degradation product from 2OG, and the vehicle, glycerol. Digestion of 5 ml olive oil with pancreatic lipase will result in formation of approximately 2 g 2OG and 3.2 g oleic acid. RESULTS 2OG and other 2-monoacylglycerols increased intracellular concentrations of cAMP in GPR119-expressing COS-7 cells (2OG EC(50) = 2.5 μm). Administration of 2OG to humans significantly increased plasma GLP-1 (0-25 min) when compared to the two controls, oleic acid and vehicle. Plasma levels of glucose-dependent insulinotropic polypeptide also increased. CONCLUSION 2OG and other 2-monoacylglycerols formed during fat digestion can activate GPR119 and cause incretin release from the human intestine. This mechanism is likely to contribute to the known stimulatory effect of dietary fat on incretin secretion, and it indicates that GPR119 is a fat sensor.

The Glucagonostatic and Insulinotropic Effects of Glucagon-Like Peptide 1 Contribute Equally to Its Glucose-Lowering Action

OBJECTIVE Glucagon-like peptide 1 (GLP-1) exerts beneficial antidiabetic actions via effects on pancreatic β- and α-cells. Previous studies have focused on the improvements in β-cell function, while the inhibition of α-cell secretion has received less attention. The aim of this research was to quantify the glucagonostatic contribution to the glucose-lowering effect of GLP-1 infusions in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Ten male patients with well-regulated type 2 diabetes (A1C 6.9 ± 0.8%, age 56 ± 10 years, BMI 31 ± 3 kg/m2 [means ± SD]) were subjected to five 120-min glucose clamps at fasting plasma glucose (FPG) levels. On day 1, GLP-1 was infused to stimulate endogenous insulin release and suppress endogenous glucagon. On days 2–5, pancreatic endocrine clamps were performed using somatostatin infusions of somatostatin and/or selective replacement of insulin and glucagon; day 2, GLP-1 plus basal insulin and glucagon (no glucagon suppression or insulin stimulation); day 3, basal insulin only (glucagon deficiency); day 4, basal glucagon and stimulated insulin; and day 5, stimulated insulin. The basal plasma glucagon levels were chosen to simulate portal glucagon levels. RESULTS Peptide infusions produced the desired hormone levels. The amount of glucose required to clamp FPG was 24.5 ± 4.1 (day 1), 0.3 ± 0.2 (day 2), 10.6 ± 1.1 (day 3), 11.5 ± 2.7 (day 4), and 24.5 ± 2.6 g (day 5) (day 2 was lower than days 3 and 4, which were both similar and lower than days 1 and 5). CONCLUSIONS We concluded that insulin stimulation (day 4) and glucagon inhibition (day 3) contribute equally to the effect of GLP-1 on glucose turnover in patients with type 2 diabetes, and these changes explain the glucose-lowering effect of GLP-1 (day 5 vs. day 1).

Loss of Incretin Effect Is a Specific, Important, and Early Characteristic of Type 2 Diabetes

Whereas glucose-tolerant individuals are capable of adjusting their insulin secretion to their actual insulin sensitivity, people with type 2 diabetes are incapable of doing so (1). β-Cell failure is therefore the hallmark of this disease, although failure may be precipitated by the development of insulin resistance, typically as a consequence of obesity. In healthy subjects, a considerable part of the postprandial insulin response is due to the actions of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Together, the two hormones are responsible for the so-called incretin effect, i.e., the amplification of insulin secretion that is observed when glucose is taken orally as opposed to infused intravenously to provide identical plasma glucose concentrations (2). Although frequently ignored, the effect strongly depends on the dose of glucose (3). A convenient way of describing the effect is to calculate the gastrointestinally mediated glucose disposal (GIGD) (4). Here the amount of glucose required by intravenous infusion to copy the glucose excursions after the oral load is related to the oral load. Thus, if 25 g is required to copy a 75-g oral glucose load, the GIGD amounts to 100 × (75 – 25)/75 = 66%. In other words, mechanisms associated with and activated by the oral ingestion resulted in a disposal of 75 – 25 = 50 g of the ingested glucose. In healthy subjects, most of the GIGD is accounted for by the actions of the incretin hormones, but inhibition of hepatic glucose production by suppression of glucagon secretion, hepatic uptake of glucose from the portal vein, and gut-brain or liver-brain reflex activity may also play a role. GIGD is particularly useful in the study of oral glucose handling in C-peptide–negative patients with type 1 diabetes, where the classical incretin definitions have no meaning (4). In a …

Glucose-Dependent Insulinotropic Polypeptide A Bifunctional Glucose-Dependent Regulator of Glucagon and Insulin Secretion in Humans

OBJECTIVE To evaluate the glucose dependency of glucose-dependent insulinotropic polypeptide (GIP) effects on insulin and glucagon release in 10 healthy male subjects ([means ± SEM] aged 23 ± 1 years, BMI 23 ± 1 kg/m2, and HbA1c 5.5 ± 0.1%). RESEARCH DESIGN AND METHODS Saline or physiological doses of GIP were administered intravenously (randomized and double blinded) during 90 min of insulin-induced hypoglycemia, euglycemia, or hyperglycemia. RESULTS During hypoglycemia, GIP infusion caused greater glucagon responses during the first 30 min compared with saline (76 ± 17 vs. 28 ± 16 pmol/L per 30 min, P < 0.008), with similar peak levels of glucagon reached after 60 min. During euglycemia, GIP infusion elicited larger glucagon responses (62 ± 18 vs. −11 ± 8 pmol/L per 90 min, P < 0.005). During hyperglycemia, comparable suppression of plasma glucagon (−461 ± 81 vs. −371 ± 50 pmol/L per 90 min, P = 0.26) was observed with GIP and saline infusions. In addition, during hyperglycemia, GIP more than doubled the insulin secretion rate (P < 0.0001). CONCLUSIONS In healthy subjects, GIP has no effect on glucagon responses during hyperglycemia while strongly potentiating insulin secretion. In contrast, GIP increases glucagon levels during fasting and hypoglycemic conditions, where it has little or no effect on insulin secretion. Thus, GIP seems to be a physiological bifunctional blood glucose stabilizer with diverging glucose-dependent effects on the two main pancreatic glucoregulatory hormones.

Self-expanding metal stents for colonic obstruction: Experiences from 104 procedures in a single center

Purpose: In the past, colonic obstruction caused by malignancy most often resulted in high-risk operations, usually involving two-step procedures or leaving the patient with a stoma in case of disseminated disease. Methods: Between May 1997 and January 2003, 104 procedures with selfexpanding metal stents have been performed in 96 patients at our institution. The goals of the procedure were either postponement of emergency operation or definitive palliative treatment. Surgeons with combined endoscopic and fluoroscopic technique performed all procedures. In most cases no analgesia or only slight sedation was used. Seven types of stents were used, CHOO stents and Wallstents accounting for the majority. Results: A total of 96 patients were included, 44 men and 52 women, with a mean age of 78 (range, 41–100) years. Technical success was achieved in 92 percent; clinical success, in 82 percent. Thirty-eight patients presented with an acute obstruction and were treated with self-expanding metal stents. Seventeen patients later underwent an elective resection, 9 patients were not decompressed, and 12 patients had disseminated disease and were not treated further. Eight patients had benign strictures. These eight patients accounted for several of the reinterventions, and only three patients truly gained benefit from stenting. In the remaining patients disseminated disease was diagnosed and the acute stenting served as the definitive palliative treatment. Procedure-related complications were few: perforation occurred in three patients during stenting and in one instance 6 to 7 hours after. Other technical problems could mainly be overcome by introducing an additional stent. Complications seen in the group treated with self-expanding metal stents and subsequent resection [mortality N = 3 (18 percent)], anastomotic leakage [N = 3 (18 percent)], do not differ from the number of complications we usually see in our patients who undergo elective colorectal resection. Conclusions: The use of self-expanding metal stents in malignant colonic obstruction is a safe and effective procedure with a low mortality and morbidity. In our experience the stenting of benign strictures is ineffective and combined with a high rate of complications.

Impaired Regulation of the Incretin Effect in Patients with Type 2 Diabetes

OBJECTIVE In healthy subjects, the incretin effect during an oral glucose tolerance test increases with the size of glucose load, resulting in similar glucose excursions independently of the glucose loads. Whether patients with type 2 diabetes mellitus (T2DM) are able to regulate their incretin effect is unknown. RESEARCH DESIGN AND METHODS Incretin effect was measured over 6 d by means of three 4-h oral glucose tolerance test with increasing glucose loads (25, 75, and 125 g) and three corresponding isoglycemic iv glucose infusions in eight patients with T2DM [fasting plasma glucose, mean 7.7 (range 7.0-8.9) mM; glycosylated hemoglobin, 7.0% (6.2-8.4%)] and eight matched healthy control subjects [fasting plasma glucose, 5.3 (4.8-5.7) mM; glycosylated hemoglobin, 5.4% (5.0-5.7%)]. RESULTS Patients with T2DM exhibited higher peak plasma glucose in response to increasing oral glucose loads, whereas no differences in peak plasma glucose values among control subjects were observed. The incretin effect was significantly (P < 0.003) lower in patients with T2DM (0 ± 7, 11 ± 9, and 36 ± 5%) as compared with control subjects (36 ± 5, 53 ± 6, and 65 ± 6%). Equal and progressively delayed gastric emptying due to the increasing loads was found in both groups. Incretin hormone responses were similar. CONCLUSIONS Up-regulation of the incretin effect in response to increasing oral glucose loads seems to be crucial for controlling glucose excursions in healthy subjects. Patients with T2DM are characterized by an impaired capability to regulate their incretin effect, which may contribute to the exaggerated glucose excursions after oral ingestion of glucose in these patients.