Emptying of the gastric substitute,glucagon-like peptide-1 (GLP-1), and reactive hypoglycemia after total gastrectomy

Postprandial glucagon-like peptide-1 (GLP-1), pancreatic glucagon, and insulin were measured in 27 tumor-free patients 43 months (median) after total gastrectomy and in four controls using a⁹⁹technetium-labeled 100-g carbohydrate solid test meal. Emptying of the gastric substitute was measured by scintigraphy. Fourteen patients suffered from early dumping symptoms, and five of them also reported symptoms suggestive of reactive hypoglycemia (late dumping). The median emptying half-time (T1/2) of the gastric substitute was 480 sec. Sigstad's dumping score was 8.5±1.6 (mean±se) in patients with rapid emptying (T1/2<480 sec), and 3.0±1.5 in patients with slow emptying of the gastric substitute (P=0.02). The peak postprandial concentration of GLP-1 was 44±20 pmol/liter in controls, 172±50 in patients without reactive hypoglycemia, and 502±116 in patients whose glucose fell below 3.8 mmol/liter during the second postprandial hour. Plasma GLP-1 concentrations peaked at 15 min, and insulin concentrations at 30 min after the end of the meal. A close correlation between integrated GLP-1 responses and integrated insulin responses (r=0.68) was observed. Multiple regression revealed that three factors were significantly associated with the integrated glucose concentrations during the second hour (60–120 min): Early (first 30 min) integrated GLP-1 (inverse correlation;P=0.006), age (P=0.006), and early integrated pancreatic glucagon (P=0.005). There was a close (inverse) relationship ofT1/2 with early integrated GLP-1 and pancreatic glucagon, but not with insulin. Gel filtration of pooled postprandial plasma of gastrectomized individuals revealed that all glucagon-like immunoreactivity eluted atK _d 0.30 (K _d , coefficient of distribution), the elution position of glicentin. Almost all of the GLP-1 like immunoreactivity eluted atK _d 0.60, the elution position of gut GLP-1. The authors contend that GLP-1-induced insulin release and inhibition of pancreatic glucagon both contribute to the reactive hypoglycemia encountered in some patients following gastric surgery. Rapid emptying seems to be one causative factor for the exaggerated GLP-1 release in these subjects.     

Postprandial GLP-1, norepinephrine, and reactive hypoglycemia in dumping syndrome

Rapid gastric emptying and exaggerated plasma concentrations of the insulinotropic hormone GLP-1 precede reactive hypoglycemia after oral glucose in gastrectomy patients. We suspected that the plasma volume drop associated with rapid gastric emptying (early dumping) would be accompanied by elevated plasma concentrations of norepinephrine. In order to study any relationship between postprandial norepinephrine, the enteroinsular axis, and plasma glucose, twelve patients with dumping syndrome and nine controls were studied. The plasma concentrations of norepinephrine, GLP-1, GIP, glucagon, insulin, and glucose were measured following a 1.5 g/kg lean body mass glucose meal. The early (0–30 min) integrated norepinephrine concentration was significantly higher in dumpers (22.1 ± 3.8 nmol/ml/min) compared to controls (14.7 ± 3.1 nmol/ml/min; P < 0.001) and correlated closely with the postprandial hematocrit increment (r = 0.71; P < 0.05). Early immunoreactivities of GLP-1, GIP, and glucagon peaked 30 min after glucose ingestion and were significantly higher in dumpers. Insulin peaked after 60 min and correlated with early GLP-1. In 11 of the patients glucose fell below baseline after a median interval of 120 min. Glucose at 120 min, when most of the nadirs occurred was lowest in patients with high early GLP-1 concentrations (r = 0.78; P < 0.001). Gel filtration chromatography of the dumpers' plasma revealed that pancreatic glucagon was detectable at time 0 and after 20 min, but not after 120 min. It is concluded that in dumpers pancreatic glucagon is augmented in the early postprandial period, probably through stimulation by catecholamines. At 120 min, when most of the hypoglycemias are encountered, pancreatic glucagon is no longer detectable, probably through inhibition by GLP-1.     

Enhanced glucagon-like peptide-1 (GLP-1) response to oral glucose in glucose-intolerant HIV-infected patients on antiretroviral therapy

OBJECTIVES: We investigated whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are major regulators of glucose tolerance through the stimulation of insulin secretion, contribute to impaired glucose tolerance (IGT) among HIV-infected patients on highly active antiretroviral therapy (HAART). METHODS: Eighteen HIV-infected male patients (six lipodystrophic and 12 nonlipodystrophic) with normal glucose tolerance (NGT) were compared with 10 HIV-infected male patients (eight lipodystrophic and two nonlipodystrophic) with IGT. Plasma concentrations of GLP-1 and GIP were determined frequently during a 3-h, 75-g glucose tolerance test. Insulin secretion rates (ISRs) were calculated by deconvolution of C-peptide concentrations. RESULTS: The incremental area under the curve (incrAUC) for GLP-1 was increased by 250% in IGT patients compared with NGT patients (1455+/-422 vs. 409+/-254 pmol/L/180 min, respectively; P<0.05), whereas the incrAUC for GIP did not differ between the study groups (7689+/-1097 vs. 8041+/-998 pmol/L/180 min, respectively; not significant). In pooled study groups, the GIP incrAUC correlated positively with the ISR incrAUC without adjustment (r=0.38, P<0.05) and following adjustment for glucose incrAUC (r=0.49, P<0.01). CONCLUSIONS: Our data suggest: (1) that glucose-intolerant, HIV-infected male patients may display enhanced GLP-1 responses to oral glucose compared with normal glucose-tolerant HIV-infected male patients, which may represent a compensatory mechanism rather than explain the IGT; (2) that the GIP response may be associated with ISR independently of plasma glucose in nondiabetic HIV-infected males on HAART.     

Response of incretins (GIP and GLP-1) to an oral glucose load in female and male subjects with normal glucose tolerance

The aim of this study was to analyze the blood glucose profile and the response of incretins in healthy young subjects by the 75 g oral glucose tolerance test (OGTT). We first reported that plasma glucose and GIP levels were higher in males during the early phase of the OGTT.     

Overexpression of glucagon-like peptide-1 receptor in an insulin-secreting cell line enhances glucose responsiveness

Glucagon-like peptide-1 (GLP-1), secreted from intestine in response to food intake, enhances insulin secretion from pancreatic β-cells. In this study, we evaluated the effects of stably transfecting the GLP-1 receptor into an insulinoma cell line, RIN 1046-38, on basal and glucose-mediated insulin secretion and on second messenger pathways involved in insulin secretion. The GLP-1 receptor transfected cells had similar insulin mRNA levels but higher insulin content compared with parental cells. In GLP-1 receptor transfected cells, glucose (0.5 mM)-mediated insulin release was increased compared with parental cells (4.52±0.79 pmol insulin/l per mg protein·h vs. 2.21±0.36 pmol insulin/l per mg protein·h; mean±S.E., n=6, P=0.015, in transfected vs. parental cells, respectively). By hemolytic plaque assay measuring single cell insulin secretion, we observed that in the GLP-1 receptor transfected cells versus parental cells the increased insulin secretion was due to the presence of more glucose-responsive cells as well as more insulin released in response to glucose per cell. Resting intracellular cAMP was higher in the GLP-1 transfected cells (35.96±3.88 vs. 18.6±2.01 nmol/l per mg protein·h; mean±S.E., n=4, P=0.039, in transfected vs. parental cells, respectively). In response to GLP-1, both GLP-1 receptor transfected cells and parental cells showed increased cAMP levels independent of glucose. Resting intracellular calcium was the same in both parental and GLP-1 receptor transfected cells. However, more cells were responsive to glucose in the GLP-1 receptor transfected cells and the calcium transients attained in the presence of glucose developed at a faster rate and reached a higher amplitude than in parental cells. We conclude that having an excess of GLP-1 receptors renders β-cells more sensitive to glucose.     

No reactive hypoglycaemia in Type 2 diabetic patients after subcutaneous administration of GLP-1 and intravenous glucose.

AIMS: It has previously been shown that intravenous and subcutaneous administration of glucagon-like peptide (GLP)-1 concomitant with intravenous glucose results in reactive hypoglycaemia in healthy subjects. Since GLP-1 is also effective in Type 2 diabetic patients and is presently being evaluated as a therapeutic agent in this disease, it is important to investigate whether GLP-1 can cause hypoglycaemia in such patients. METHODS: Eight Type 2 diabetic patients (age 54 (49-67) years; body mass index 31 (27-38) kg/m2; HbA1c 9.4 (7.0-12.5)%) and seven matched non-diabetic subjects (HbA1c 5.5 (5.2-5.8)%, fasting plasma glucose 5.4 (5.0-5.7) mmol/l) were given a subcutaneous injection of 1.5 nmol GLP-1/kg body weight (maximally tolerated dose), and 15 min later, plasma glucose (PG) was raised to 15 mmol/l with an intravenous glucose bolus. RESULTS: Hypoglycaemia with a PG at or below 2.5 mmol/l was seen in five of the seven healthy subjects after 60-70 min, but PG spontaneously increased again, reaching 3.7 (3.3-4.0) mmol/l at 90 min. In the patients, PG fell slowly and stabilized at 8.6 (4.2-12.1) mmol/l after 80 min. In both groups, glucagon levels initially decreased, but later increased, exceeding basal levels in healthy subjects, in spite of persistent, high concentrations of GLP-1 (P < 0.02). CONCLUSIONS: Subcutaneous GLP-1 plus intravenous glucose induced reactive hypoglycaemia in healthy subjects, but not in Type 2 diabetic patients. Therefore, a GLP-1-based therapy would not be expected to be associated with an increased risk of hypoglycaemia in Type 2 diabetes mellitus.     

Current evidence for a role of GLP-1 in Roux-en-Y gastric bypass-induced remission of type 2 diabetes

Weight-reducing surgical procedures such as Roux-en-Y gastric bypass (RYGB) have proven efficient as means of decreasing excess body weight. Furthermore, some studies report that up to 80% of patients with type 2 diabetes mellitus (T2DM) undergoing RYGB experience complete remission of their T2DM. Interestingly, the majority of remissions occur almost immediately following the operation and long before significant weight loss has taken place. Following RYGB, dramatic increases in postprandial plasma concentrations of the incretin hormone glucagon-like peptide-1 (GLP-1) have been recorded, and the known antidiabetic effects of GLP-1 are thought to be key mediators in RYGB-induced remission of T2DM. However, the published studies on the impact of RYGB on GLP-1 secretion are few, small and often not controlled properly. Furthermore, mechanistic studies delineating the role of endogenous GLP-1 secretion in RYGB-induced remission of T2DM are lacking. This article critically evaluates the current evidence for a role of GLP-1 in RYGB-induced remission of T2DM.     

Truncated and full-length glucagon-like peptide-1 (GLP-1) differentially stimulate intestinal somatostatin release

Glucagon-like peptide-1^7–36NH2 (GLP-1^7–36NH2) is a potent stimulator of insulin secretion, as well as of somatostatin-14 (SS-14) release from the pancreatic and gastric D-cells. To investigate the possible effects of this peptide on release of intestinal somatostatin (SS-28 and SS-14), rat intestinal cultures were treated with 10⁻¹²–10⁻⁶ M GLP-1^7–36NH2, as well as with the structurally related peptides, GLP-1^1–36NH2 and GLP-2. Both forms of GLP-1 stimulated dose-dependent increases in intestinal somatostatin; secretion reached 643±126% of controls (p<0.001) after treatment with 10⁻⁶ M GLP-1^7–36NH2, and 398±76% of controls (p<0.001) after 10⁻⁶ M GLP-1^1–36NH2. Thus, GLP-1^7–36NH2 was more effective than GLP-1^1–36NH2 in stimulating secretion of intestinal somatostatin-like immunoreactivity (SLI) (p<0.05). GLP-2 did not affect intestinal somatostatin release. Gel permeation analysis demonstrated that 10⁻⁶ M GLP-1^7–36NH2 stimulated SS-28 by 2.9±0.4-fold and SS-14 by 9.1±3.7-fold, whereas GLP-1^1–36NH2 exerted equivalent effects (2.8±0.9-fold) on both forms of somatostatin. These findings define a novel biological role for GLP-1^7–36NH2 in the regulation of intestinal somatostatin secretion, and demonstrate that GLP-1^1–36NH2 exerts unique biological activities in this system.     

Effect of food ingestion on intestinal glucagon-like immunoreactivity (GLI) secretion in normal and gastrectomized subjects

Summary This work was undertaken to compare the intestinal GLI responses to oral glucose (1.75g/kg, 25% sol.), to a carbohydrate-rich meal (carbohydrate content about 1.75 g/kg) and to a protein meal (250–400 g grilled lean beef) in normal (n = 6) and gastrectomized (n = 6) subjects. As expected, after glucose administration the elevation of plasma GLI was more pronounced in the gastrectomy group ( 500% above baseline) than in the controls ( 75% above baseline). However, the gastrectomized patients responded to the carbohydrate meal with a very slight elevation of circulating GLI ( 45% above baseline), similar to that found in the controls ( 70% above baseline). After the protein meal, a small increase of GLI was also observed in both groups. — In conclusion, in gastrectomized subjects the ingestion of natural foodstuffs is followed by a normal elevation of plasma GLI, thereby suggesting the exclusion of this factor from involvement in the constellation of postgastrectomy syndrome. In these patients, the exaggerated rise in GLI after oral glucose is not representative of increments after physiological stimuli.Presented at the 9th Annual Meeting of the European Society for Clinical Investigation, April 24, 1975, Rotterdam, The NetherlandsSupported in part by a research grant (12-893-74) from the Instituto Nacional de Previsión, Spain, by a research contract (No. 1551/Rb) from the International Atomic Energy Agency, Vienna, Austria, and by a gift from the Alexander von Humboldt Stiftung, Bonn-Bad Godesberg, Federal Republic of Germany     

Comparison of the anti-diabetic effects of GIP- and GLP-1-receptor activation in obese diabetic (ob/ob) mice: studies with DPP IV resistant N-AcGIP and exendin(1-39)amide

BACKGROUND: The two major incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are being actively explored as anti-diabetic agents because they lower blood glucose through multiple mechanisms. The rapid inactivation of GIP and GLP-1 by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV) makes their biological actions short-lived, but stable agonists such as N-acetylated GIP (N-AcGIP) and exendin(1-39)amide have been advocated as stable and specific GIP and GLP-1 analogues. METHODS: The present study examined the sub-chronic (14 days) anti-diabetic actions of single daily doses of N-AcGIP and exendin(1-39)amide given alone or in combination to obese diabetic (ob/ob) mice over a 14-day period. RESULTS: Initial experiments confirmed the potent anti-hyperglycaemic and insulinotropic properties of N-AcGIP and exendin(1-39)amide. Sub-chronic administration of N-AcGIP alone or in combination with exendin(1-39)amide significantly decreased non-fasting plasma glucose and improved glucose tolerance compared to control ob/ob mice. This was associated with a significant enhancement of the insulin response to glucose and a notable improvement of insulin sensitivity. Combined treatment with N-AcGIP and exendin(1-39)amide also significantly decreased glycated haemoglobin. Exendin(1-39)amide alone had no significant effect on any of the metabolic parameters monitored. In addition, no significant effects were observed on body weight and food intake in any of the treatment groups. CONCLUSIONS: The results illustrate significant anti-diabetic potential of N-AcGIP alone and in combination with exendin(1-39)amide.     

Synthesis and secretion of glucagon-like peptide-1 by fetal rat intestinal cells in culture

Secretion of the intestinal proglucagon-derived peptides (PGDPs) including the incretin glucagon-like peptide-1 (GLP-1) is regulated, at least in part, by the duodenal hormone glucose-dependent insulinotropic peptide (GIP) through a protein kinase (PK) A-dependent pathway. It has been demonstrated that the activation of PKA increases the synthesis of some intestinal PGDPs, particularly the glucagon-like immunoreactive (GLI) peptides glicentin and oxyntomodulin. However, the effects of GIP on GLI and GLP-1 synthesis are not known. Fetal rat intestinal cells in culture were therefore treated for up to 24 h with 5mm dbcAMP or 10⁻⁶ m GIP and the changes in glicentin, oxyntomodulin, GLP-1^x-37 and GLP-1^x-36NH2 secretion and synthesis were examined by RIA and HPLC. Both dbcAMP and GIP increased the acute (2 h; to 224±21 and 256±20% of controls, respectively,P<0.001) and chronic (24 h; to 230±22 and 130±6% of controls, respectively,P<0.001) secretion of intestinal PGDPs. In contrast, the total culture content of PGDPs was increased only after 24 h of incubation (to 156±15 and 125±7% of controls for dbcAMP and GIP, respectively,P<0.01). HPLC analysis confirmed that the intestinal cultures produced the GLI peptides glicentin and oxyntomodulin, as well as the biologically active forms of GLP-1, GLP-7^7–37 and GLP-1^7-36NH2. The relative proportion of these peptides was not altered by treatment with dbcAMP or GIP. Thus, in addition to its effects on GLP-1 release from the rat intestine, GIP appears to be an important regulator of the synthesis of this insulinotropic peptide.     

Emerging therapeutic potential for xenin and related peptides in obesity and diabetes

Xenin‐25 is a 25‐amino acid peptide hormone co‐secreted from the same enteroendocrine K‐cell as the incretin peptide glucose‐dependent insulinotropic polypeptide. There is no known specific receptor for xenin‐25, but studies suggest that at least some biological actions may be mediated through interaction with the neurotensin receptor. Original investigation into the physiological significance of xenin‐25 focussed on effects related to gastrointestinal transit and satiety. However, xenin‐25 has been demonstrated in pancreatic islets and recently shown to possess actions in relation to the regulation of insulin and glucagon secretion, as well as promoting beta‐cell survival. Accordingly, the beneficial impact of xenin‐25, and related analogues, has been assessed in animal models of diabetes‐obesity. In addition, studies have demonstrated that metabolically active fragment peptides of xenin‐25, particularly xenin‐8, possess independent therapeutic promise for diabetes, as well as serving as bioactive components for the generation of multi‐acting hybrid peptides with antidiabetic potential. This review focuses on continuing developments with xenin compounds in relation to new therapeutic approaches for diabetes‐obesity.     

Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM

Summary The gut hormone, glucagon-like peptide-1 (GLP-1) is a potent insulin secretogogue with potential as a therapy for non-insulin-dependent diabetes mellitus (NIDDM). GLP-1 has been shown to reduce glucose concentrations, both basally, and, independently, in response to a single meal. For it to be an effective treatment, it would need to be administered as a long-acting therapy, but this might not be feasible due to the profound delay in gastric emptying induced by GLP-1. In order to assess the feasibility and efficacy of continuous administration of GLP-1 in NIDDM, we determined the effects of continuous intravenous infusion of GLP-1 (7–36) amide, from 22.00–17.00 hours, on glucose and insulin concentrations overnight and in response to three standard meals, in eight subjects with NIDDM. These were compared with responses to 0.9 % NaCl infusion and responses in six non-diabetic control subjects who were not receiving GLP-1. Effects on beta-cell function were assessed in the basal state using homeostasis model assessment (HOMA) and in the postprandial state by dividing incremental insulin responses to breakfast by incremental glucose responses. To assess possible clinical benefit from priming of beta cells by GLP-1 given overnight only, a third study assessed the effect of GLP-1 given from 22.00–07.30 hours on subsequent glucose responses the next day. Continuous GLP-1 infusion markedly reduced overnight glucose concentrations (mean from 24.00–08.00 hours) from median (range) 7.8 (6.1–13.8) to 5.1 (4.0–9.2) mmol/l (p < 0.02), not significantly different from control subjects, 5.6 (5.0–5.8) mmol/l. Daytime glucose concentrations (mean from 08.00–17.00 hours) were reduced from 11.0 (9.3–16.4) to 7.6 (4.9–11.5) mmol/l (p < 0.02), not significantly different from control subjects, 6.7 (6.5–7.0) mmol/l. GLP-1 improved beta-cell function in the basal state from 62 (13–102) to 116 (46–180) %β (p < 0.02) and following breakfast from 57 (19–185) to 113 (31–494) pmol/mmol (p < 0.02). GLP-1 only given overnight did not improve the glucose responses to meals the next day. In conclusion, continuous infusion of GLP-1 markedly reduced diurnal glucose concentrations, suggesting that continuous GLP-1 administration may be a useful therapy in NIDDM. [Diabetologia (1997) 40: 205–211] Received: 3 July 1996 and in final revised form: 23 October 1996     

Meta-analysis of head-to-head clinical trials comparing incretin-based glucose-lowering medications and basal insulin: An update including recently developed glucagon-like peptide-1 (GLP-1) receptor agonists and the glucose-dependent insulinotropic polypeptide/GLP-1 receptor co-agonist tirzepatide

Objective

To assess comparative efficacy, safety and tolerability of injectable incretin-based glucose-lowering medications (IBGLMs) versus basal insulin treatment in patients with type 2 diabetes.

Research Design and Methods

We performed an updated meta-analysis of randomized clinical trials of head-to-head comparisons of IBGLMs (short- and long-acting glucagon-like peptide-1 [GLP-1] receptor agonists [GLP-1RAs] and glucose-dependent insulinotropic polypeptide [GIP]/GLP-1 receptor co-agonist tirzepatide) versus basal insulin using a PubMed database search (April 2022). The primary endpoint was difference in reduction of glycated haemoglobin (HbA_1c) versus baseline between pooled IBGLMs (fixed-effects meta-analysis) and their subgroups (random-effects meta-analysis) versus basal insulin treatment (mean differences). Secondary endpoints were fasting plasma glucose, body weight, HbA_1c target achievement, hypoglycaemia, blood pressure and lipids. Risk of bias assessment was performed using Jadad scores and the Risk of Bias tool 2.0.

Results

In all, 20 studies, representing 47 study arms and 11 843 patients, were eligible. Compared with basal insulin, IGBLMs lowered HbA_1c by 0.48 (0.45-0.52)% more than did basal insulin treatment. This effect was driven by pooled long-acting GLP-1RAs (ΔHbA_1c −0.25 [−0.38; −0.11]%) and the only GIP/GLP-1 receptor co-agonist, tirzepatide (pooled doses; ΔHbA_1c −0.90 [−1.06; −0.75]%), while short-acting GLP-1RAs were equally effective compared with basal insulin (P = 0.90). All IBGLM subgroups achieved significantly lower body weight versus insulin treatment (−4.6 [−4.7; −4.4] kg), in particular tirzepatide (−12.0 [−13.8; −10.1] kg). IBGLMs significantly reduced hypoglycaemia and blood pressure and improved lipid variables. Risk of bias was low. IBGLM treatment was associated with more nausea, vomiting and diarrhoea and study medication discontinuation.

Conclusions

Recently introduced, highly effective IBGLMs were superior to basal insulin treatment, reinforcing the recommendation that IBGLMs should be considered as the first injectable treatment for most patients with type 2 diabetes.     

Effect of glucagon-like peptide-1 (GLP-1) analogues on epicardial adipose tissue: A meta-analysis

Background and aimsGlucagon-like peptide-1 (GLP-1) analogues reduce body fat and cardiovascular events in patients with type 2 diabetes. Accumulation of epicardial adipose tissue (EAT) is associated with increased cardio-metabolic risks and coronary events in type 2 diabetes.MethodsA systematic review and meta-analysis were performed from Glucagon-like peptide-1 analogues therapy on type 2 diabetes patients, reporting data from changes in EAT, after searching the PubMed/MEDLINE, Embase, Science Direct, Scopus, Google Scholar, and Cochrane databases.ResultsIt has been found a limited number of studies, a total of 4 studies (n = 160 patients with GLP-1 analogues therapy) were included in the final analysis. Pooled analysis revealed that GLP-1 analogues reduce EAT (MD: 1.83 mm [-2.50; ?1.10]; P < 0.01). Compared with the patients before the treatment, the patients after the treatment had a smaller HbA1c (MD -1.10%[-1.80; ?0.30]; p = 0.0143) and body mass index was reduced (MD -2.20 kg/m²[-3.70; ?0.60]; p = 0.0058), GLP-1 therapy reduced low-density lipoprotein levels (MD-13.53 mg/dL [-21.74; ?5.31]; p = 0.001) and reduced triglycerides levels significantly (MD -18.32 -28.20 mg/dL; ?8.50); p = 0.0003).ConclusionsThis meta-analysis suggests that the amount of EAT is significantly reduced in T2D patients with Glucagon-like peptide-1 analogues.     

Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7–36 amide]) in patients with NIDDM

Summary Intravenous glucagon-like peptide (GLP)-1 [7–36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 ± 7, 61 ± 9, 50 ± 11 years; BMI 29.5 ± 2.5, 26.1 ± 2.3, 28.0 ± 4.2 kg/m²; HbA_{1 c} 11.3 ± 1.5, 9.9 ± 1.0, 10.6 ± 0.7 %) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7–36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8 %, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30–60 min, then return to basal levels after 90–120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p < 0.0001, respectively) and inhibited glucagon secretion (p < 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 ± 0.4 mmol/l after 240 min vs 8.2 ± 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30–45 min (p < 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40 % (p = 0.051). In conclusion, subcutaneous GLP-1 [7–36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7–36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia. [Diabetologia (1996) 39: 1546–1553]     

The novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long-acting GLP-1 receptor agonists

The effect of dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide on gastric emptying (GE) was compared to that of GLP-1RAs in non-clinical and clinical studies. GE was assessed following acute and chronic treatment with tirzepatide in diet-induced obese mice versus semaglutide or long-acting GIP analogue alone. Participants [with and without type 2 diabetes (T2DM)] from a phase 1, 4-week multiple dose study received tirzepatide, dulaglutide or placebo. GE was assessed by acetaminophen absorption. In mice, tirzepatide delayed GE to a similar degree to that achieved with semaglutide; however, these acute inhibitory effects were abolished after 2 weeks of treatment. GIP analogue alone had no effect on GE or on GLP-1's effect on GE. In participants with and without T2DM, once-weekly tirzepatide (≥5 and ≥4.5 mg, respectively) delayed GE after a single dose. This effect diminished after multiple doses of tirzepatide or dulaglutide in healthy participants. In participants with T2DM treated with an escalation schedule of tirzepatide 5/5/10/10 or 5/5/10/15 mg, a residual GE delay was still observed after multiple doses. These data suggest that tirzepatide's activity on GE is comparable to that of selective GLP-1RAs.     

Glucagon-like peptide 1(GLP-1) in biology and pathology

Post-translational proteolytic processing of the preproglucagon gene in the gut results in the formation of glucagon-like peptide 1 (GLP-1). Owing to its glucose-dependent insulinotropic effect, this hormone was postulated to primarily act as an incretin, i.e. to augment insulin secretion after oral glucose or meal ingestion. In addition, GLP-1 decelerates gastric emptying and suppresses glucagon secretion. Under physiological conditions, GLP-1 acts as a part of the 'ileal brake', meaning that is slows the transition of nutrients into the distal gut. Animal studies suggest a role for GLP-1 in the development and growth of the endocrine pancreas. In light of its multiple actions throughout the body, different therapeutic applications of GLP-1 are possible. Promising results have been obtained with GLP-1 in the treatment of type 2 diabetes, but its potential to reduce appetite and food intake may also allow its use for the treatment of obesity. While rapid in vivo degradation of GLP-1 has yet prevented its broad clinical use, different pharmacological approaches aiming to extend the in vivo half-life of GLP-1 or to inhibit its inactivation are currently being evaluated. Therefore, antidiabetic treatment based on GLP-1 may become available within the next years. This review will summarize the biological effects of GLP-1, characterize its role in human biology and pathology, and discuss potential clinical applications as well as current clinical studies.