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.     

Increased glucose-dependent insulinotropic polypeptide (GIP) secretion in acromegaly.

OBJECTIVE: Acromegaly is often associated with fasting and postprandial hyperinsulinemia, and the mechanisms involved are only partly understood. Hypersecretion of incretins such as glucose-dependent insulinotropic polypeptide (GIP) could play a role in determining hyperinsulinemia in acromegaly, but the available data are inconsistent. The aim of this study was to characterize the fasting and postprandial pattern of plasma GIP and insulin in a group of acromegalic patients. DESIGN AND METHODS: Eleven non-diabetic patients with newly diagnosed acromegaly and 11 sex- and age-matched healthy subjects were studied. Blood samples were taken at regular intervals in fasting conditions and for 3 h after a standard solid-liquid meal for growth hormone (GH), GIP and insulin measurements. RESULTS: Not only insulin, but also fasting and postprandial GIP levels were significantly higher in the patients with acromegaly than the healthy subjects (P<0.01). In the former group fasting GIP levels and the integrated GIP response to the meal correlated significantly with GH basal levels (r=0.83, P<0.01 and r=0.65, P<0.05, respectively). Moreover, multivariate linear regression analysis showed that the presence of acromegalic status was associated with higher fasting and postprandial GIP levels independently of sex, age, fasting and postprandial plasma glucose and insulin levels, and the occurrence of normal or impaired glucose tolerance. CONCLUSION: This study provides evidence that in patients with acromegaly fasting and postprandial GIP levels are abnormally high. GIP hypersecretion in turn might play a role in the pathogenesis of hyperinsulinemia that characterizes acromegaly.     

A comparison of the cellular and biological properties of DPP-IV-resistant N-glucitol analogues of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide

AIM: The two major incretin hormones--glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)--are being actively researched by the pharmaceutical industry because of their glucose-lowering and potential anti-diabetic properties. Unfortunately, the inactivation of GLP-1 and GIP in the circulation brought about by dipeptidyl-peptidase-IV (DPP-IV) degradation makes their biological actions short-lived. This study directly compares the cellular and biological properties of GLP-1, GIP and their N-terminally modified counterparts, with glucitol extension at positions His7 and Tyr1 respectively, to confer DPP-IV resistance. METHODS: Using both the glucose-responsive pancreatic beta-cell line, BRIN BD11, and the obese diabetic (ob/ob) mouse, we assessed adenosine 3',5'-cyclic monophosphate (cAMP) production and insulinotropic action in vitro as well as in vivo glucose-lowering and insulin-releasing actions. RESULTS: The results reveal that glycation of the N-terminus of GLP-1 or GIP stabilized both peptides against DPP-IV degradation. However, N-glucitol-GLP-1 displayed reduced cAMP production, insulinotropic activity and glucose-lowering potency, compared to native GLP-1. By contrast, N-glucitol-GIP exhibited substantially improved biological activities, compared to native GIP, and possessed similar or enhanced in vivo potency to GLP-1. N-terminal extension by means of glucitol addition is more beneficial to bioactivity of GIP than it is to GLP-1. CONCLUSIONS: N-terminal glycation generates a super GIP agonist, which possesses acute in vivo glucose-lowering and insulinotropic actions superior to native GLP-1. Therefore, N-glucitol-GIP is a particularly attractive potential candidate molecule for drug therapy of type 2 diabetes.     

Efficacy and safety of high-dose glucagon-like peptide-1, glucagon-like peptide-1/glucose-dependent insulinotropic peptide,and glucagon-like peptide-1/glucagon receptor agonists in type 2 diabetes

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become agents of choice for people with type 2 diabetes (T2D) with established cardiovascular disease or in high-risk individuals. With currently available GLP-1 RAs, 51%-79% of subjects achieve an HbA1c target of less than 7.0% and 4%-27% lose 10% of body weight, illustrating the need for more potent agents. Three databases (PubMed, Cochrane, Web of Science) were searched using the MESH terms ‘glucagon-like peptide-1 receptor agonist’, ‘glucagon receptor agonist’, ‘glucose-dependent insulinotropic peptide’, ‘dual or co-agonist’, and ‘tirzepatide’. Quality of papers was scored using PRISMA guidelines. Risk of bias was evaluated using the Cochrane assessment tool. An HbA1c target of less than 7.0% was attained by up to 80% with high-dose GLP-1 RAs and up to 97% with tirzepatide, with even up to 62% of people with T2D reaching an HbA1c of less than 5.7%. A body weight loss of 10% or greater was obtained by up to 50% and up to 69% with high-dose GLP-1 RAs or tirzepatide, respectively. The glucose- and weight-lowering effects of the GLP-1/glucagon RA cotadutide equal those of liraglutide 1.8 mg. Gastrointestinal side effects of high-dose GLP-1 RAs and co-agonists occurred in 30%-70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient. The development of high-dose GLP-1 RAs and the dual GLP-1/glucose-dependent insulinotropic peptide RA tirzepatide resulted in increasing numbers of people reaching HbA1c and body weight targets, with up to 62% attaining normoglycaemia with 15-mg tirzepatide. Whether this will also translate to better cardiovascular outcomes and affect treatment guidelines remains to be studied.     

Ileal release of glucagon-like peptide-1 (GLP-1)

There is evidence that the distal intestine participates in the regulation of gastric motor and secretory function. It was the aim of this study to examine in greater detail the effects of ileal nutrient exposure on human gastric acid secretion and to investigate potential intermediary mechanisms. Twelve normal subjects were intubated with an oroileal multilumen tube assembly for gastric, duodenal, and ileal perfusion of marker and test solutions, aspiration, and intestinal manometry. We studied ileal effects on gastric acid output in the unstimulated, interdigestive state (during early phase II,N=6), and during endogenous stimulation by intraduodenal essential amino acid perfusion,N=6) and on release of candidate humoral mediators, peptide YY (PYY) and glucagonlike peptide-1 (GLP-1), both known inhibitors of human gastric acid secretion. Compared with ileal saline perfusion, ileal carbohydrate (total caloric load: 60 kcal) decreased interdigestive gastric acid output by 64% (P<0.01), and endogenously stimulated output by 68%, respectively (P<0.005). Under all experimental conditions, ileal carbohydrate increased plasma GLP-1 by 80–100% (allP<0.005). Ileal lipid perfusion had similar inhibitory effects on gastric acid output and stimulatory effects on GLP-1 release as had ileal carbohydrate. By contrast, ileal perfusion with peptone had no or only weak effects on either acid output or plasma GLP-1. Plasma PYY concentrations and suppression of gastric secretion in response to ileal perfusions were not correlated. In humans, both interdigestive and endogenously stimulated gastric acid output are inhibited in response to intraileal carbohydrate or lipids, but not protein, Decreased acid output is associated with release of GLP-1, but not PYY. These findings support the hypothesis that the distal small intestine may participate in the late postprandial inhibitory regulation of gastric secretory function in humans and that GLP-1 may be an intermediary factor.     

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.     

Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3-42) and GLP-1(9-36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

Glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important enteroendocrine hormones that are rapidly degraded by an ubiquitous enzyme dipeptidyl peptidase IV to yield truncated metabolites GIP(3-42) and GLP-1(9-36)amide. In this study, we investigated the effects of sub-chronic exposure to these major circulating forms of GIP and GLP-1 on blood glucose control and endocrine pancreatic function in obese diabetic (ob/ob) mice. A once daily injection of either peptide for 14 days had no effect on body weight, food intake or pancreatic insulin content or islet morphology. GLP-1(9-36)amide also had no effect on plasma glucose homeostasis or insulin secretion. Mice receiving GIP(3-42) exhibited small but significant improvements in non-fasting plasma glucose, glucose tolerance and glycaemic response to feeding. Accordingly, plasma insulin responses were unchanged suggesting that the observed enhancement of insulin sensitivity was responsible for the improvement in glycaemic control. These data indicate that sub-chronic exposure to GIP and GLP-1 metabolites does not result in physiological impairment of insulin secretion or blood glucose control. GIP(3-42) might exert an overall beneficial effect by improving insulin sensitivity through extrapancreatic action.     

Dose-dependent efficacy of the glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist GIP(3-30)NH2 on GIP actions in humans

The glucose-dependent insulinotropic polypeptide (GIP) fragment GIP(3-30)NH₂ is a selective, competitive GIP receptor antagonist, and doses of 800 to 1200 pmol/kg/min inhibit GIP-induced potentiation of glucose-stimulated insulin secretion by >80% in humans. We evaluated the effects of GIP(3-30)NH₂ across a wider dose range in eight healthy men undergoing six separate and randomized 10-mmol/L hyperglycaemic clamps (A–F) with concomitant intravenous infusion of GIP (1.5 pmol/kg/min; A–E) or saline (F). Clamps A to E involved double-blinded, infusions of saline (A) and GIP(3-30)NH₂ at four rates: 2 (B), 20 (C), 200 (D) and 2000 pmol/kg/min (E), respectively. Mean plasma concentrations of glucose (A–F) and GIP (A–E) were similar. GIP-induced potentiation of glucose-stimulated insulin secretion was reduced by 44 ± 10% and 84 ± 10% during clamps D and E, respectively. Correspondingly, the amounts of glucose required to maintain the clamp during D and E were not different from F. GIP-induced suppression of bone resorption and increase in heart rate were lowered by clamps D and E. In conclusion, GIP(3-30)NH₂ provides extensive, dose-dependent inhibition of the GIP receptor in humans, with most pronounced effects of the doses 200 to 2000 pmol/kg/min within the tested range.     

Normal secretion and action of the gut incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in young men with low birth weight

CONTEXT: Low birth weight (LBW) is associated with increased risk of type 2 diabetes mellitus. An impaired incretin effect was reported previously in type 2 diabetic patients. OBJECTIVE: We studied the secretion and action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in young LBW men (n = 24) and matched normal birth weight controls (NBW) (n = 25). RESULTS: LBW subjects were 5 cm shorter but had a body mass index similar to NBW. LBW subjects had significantly elevated fasting and postprandial plasma glucose, as well as postprandial (standard meal test) plasma insulin and C-peptide concentrations, suggestive of insulin resistance. Insulin secretion in response to changes in glucose concentration ("beta-cell responsiveness") during the meal test was similar in LBW and NBW but inappropriate in LBW relative to insulin sensitivity. Fasting and postprandial plasma GLP-1 and GIP levels were similar in the groups. First- and second-phase insulin responses were similar in LBW and NBW during a hyperglycemic clamp (7 mm) with infusion of GLP-1 or GIP, respectively, demonstrating normal action of these hormones on insulin secretion. CONCLUSION: Reduced secretion or action of GLP-1 or GIP does not explain a relative reduced beta-cell responsiveness to glucose or the slightly elevated plasma glucose concentrations observed in young LBW men.     

Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men

BACKGROUND: Peripheral administration of glucagon-like peptide-1 (GLP-1) for four hours, to normal weight and obese humans, decreases food intake and suppresses appetite. OBJECTIVE: The aim of this study was to assess the effect of an eight hour infusion of GLP-1 on appetite and energy intake at lunch and dinner in obese subjects. DESIGN: Randomised, blinded cross-over design with intravenous infusion of GLP-1 (0.75 pmol x kg(-1) min(-1)) or saline. SUBJECTS: Eight obese (body mass index, BMI, 45.5 +/- 2.3 kg/m2) male subjects. MEASUREMENTS: Ad libitum energy intake at lunch (12.00 h) and dinner (16.00 h) after an energy fixed breakfast (2.4 MJ) at 08.00 h. Appetite sensations using visual analogue scales, (VAS) immediately before and after meals and hourly in-between. Blood samples for the analysis of glucose, insulin, C-peptide, GLP-1 and peptide YY. Gastric emptying after breakfast and lunch using a paracetamol absorption technique. RESULTS: Hunger ratings were significantly lower with GLP-1 infusion. The summed ad libitum energy intake at lunch and dinner was reduced by 1.7 +/- 0.5 MJ (21 +/- 6%) by GLP-1 infusion (P = 0.01). Gastric emptying was delayed by GLP-1 infusion, and plasma glucose concentrations decreased (baseline: 6.6 +/- 0.35 mmol/L; nadir: 5.3 +/- 0.15 mmol/L). No nausea was recorded during GLP-1 infusion. CONCLUSIONS: Our results demonstrate that GLP-1 decreases feelings of hunger and reduces energy intake in obese humans. One possible mechanism for this finding might be an increased satiety primarily mediated by gastric vagal afferent signals.     

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Objective  The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Methods  Eight obese patients with type 2 diabetes with poor glycaemic control (HbA_1c 8.6 ± 1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4 ± 1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Results  Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0–10 min). The late phase C-peptide response (10–120 min) increased during GIP infusion from 33.0 ± 8.5 to 103.9 ± 24.2 (nmol/l) × (110 min)⁻¹ (p < 0.05) and during GLP-1 infusion from 48.7 ± 11.8 to 126.6 ± 32.5 (nmol/l) × (110 min)⁻¹ (p < 0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2 ± 11.2 vs 46.5 ± 12.7 [nmol/l] × [110 min]⁻¹). Conclusions  Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone. ClinicalTrials.gov ID no.: NCT 00612950 Funding: This study was supported by The Novo Nordisk Foundation, The Medical Science Research Foundation for Copenhagen.     

Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia

Summary The plasma concentrations of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1) are abnormally high after oral glucose in partially gastrectomised subjects with reactive hypoglycaemia, suggesting a causal relationship. Because of the glucose-dependency of its effects, it is impossible to induce hypoglycaemia in normal subjects in the basal state by exogenous GLP-1, regardless of dose. To further assess the role of the incretin hormones in reactive hypoglycaemia, we reproduced the glucose and hormone profiles of the patients with reactive hypoglycaemia in 8 healthy volunteers in 4 separate protocols: 1) i. v. infusion of glucose (25 g) alone, 2) glucose together with i. v. GLP-1 infusion, and 3) and 4) glucose together with i. v. infusion of the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), at two different infusion rates. The plasma glucose, GLP-1 and GIP concentrations (low dose) obtained were comparable with those of the patients. With GLP-1, infusion of a total of 33.4 ± 1.3 g glucose was required to obtain plasma glucose concentrations similar to those obtained by glucose infusion alone; with low GIP, 28.0 ± 1.2 g and with high GIP 38.4 ± 3.5 g. Insulin concentrations increased 10-fold with GLP-1 compared with i. v. glucose alone, but less with high and low GIP. In contrast, C-peptide concentrations were similar after GLP-1 and high GIP. After termination of i. v. glucose the lowest glucose concentrations were 4.5 (3.7–4.9) (median, range) for glucose alone; 2.4 (1.9–2.8) mmol/l with GLP-1; 3.7 (2.6–4.0) with low GIP and 3.3 (2.1–4.2 ) with high GIP. Thus, the exaggerated GLP-1 response to nutrients in patients with accelerated gastric emptying could be responsible for their high incidence of postprandial reactive hypoglycaemia. [Diabetologia (1998) 41: 1180–1186] Received: 23 February 1998 and in revised form: 18 May 1998     

High-fat feeding stimulates endocrine, glucose-dependent insulinotropic polypeptide (GIP)-expressing cell hyperplasia in the duodenum of Wistar rats

Aims/hypothesis  

Incretins are hormones released by enteroendocrine cells in response to meals, depending upon absorption of nutrients. The present study aimed to elucidate the mechanisms through which a high-fat diet (HFD) induces insulin resistance and insulin hypersecretion by focusing on the effects on enteroendocrine cells, especially those secreting glucose-dependent insulinotropic polypeptide (GIP).     

Dipeptidylpeptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) receptor agonists: yes

The pharmacological treatment of type 2 diabetes (T2DM) is becoming increasingly complex, especially since the availability of incretin-based therapies. Compared with other glucose-lowering strategies, these novel drugs offer some advantages such as an absence of weight gain and a negligible risk of hypoglycaemia and, possibly, better cardiovascular and β-cell protection. The physician has now multiple choices to manage his/her patient after secondary failure of metformin, and the question whether it is preferable to add an oral dipeptidylpeptidase-4 (DPP-4) inhibitor (gliptin) or an injectable glucagon-like peptide-1 (GLP-1) receptor agonist will emerge. Obviously, DPP-4 inhibitors offer several advantages compared with GLP-1 receptor agonists, especially regarding easiness of use, tolerance profile and cost. However, because they can only increase endogenous GLP-1 concentrations to physiological (rather than pharmacological) levels, they are less potent to improve glucose control, promote weight reduction ("weight neutrality") and reduce blood pressure compared to GLP-1 receptor agonists. Of note, none of the two classes have proven long-term safety and positive impact on diabetic complications yet. The role of DPP-4 inhibitors and GLP-1 receptor agonists in the therapeutic armamentarium of T2DM is rapidly evolving, but their respective potential strengths and weaknesses should be better defined in long-term head-to-head comparative controlled trials. Instead of trying to answer the question whether DPP-4 inhibitors are favourable to GLP-1 receptor agonists (or vice versa), it is probably more clinically relevant to look at which T2DM patient will benefit more from one or the other therapy considering all his/her individual clinical characteristics ("personalized medicine").     

Dipeptidyl peptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) agonists: no

Incretin-based therapies, which include the GLP-1 receptor agonists and DPP-4 inhibitors, use the antidiabetic properties of potentiating the GLP-1 receptor signalling via the regulation of insulin and glucagon secretion, inhibition of gastric emptying and suppression of appetite. Most physicians will start antidiabetic treatment with metformin, but adding a GLP-1 receptor agonist as the second drug seems to be optimal since more patients will reach an HbA1c below 7% than with a DPP-4 inhibitor or another oral antidiabetic agents and with minimal risk of hypoglycaemia. The GLP-1 receptor agonists are also more effective in weight and systolic blood pressure control than DPP-4 inhibitors. The side effects of the GLP-1 receptor agonists are primarily nausea and vomiting, which is less pronounced with the long acting agonists and often transient. A GLP-1 receptor agonist can be recommended before a DPP-4 inhibitor in obese type 2 diabetic patients, who want to lose weight. Furthermore, the GLP-1 receptor agonists cover the whole spectrum of treatment from time of diagnosis with lifestyle treatment to combination treatment with basal insulin.     

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.     

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.     

Commercially available preparations of porcine glucose-dependent insulinotropic polypeptide (GIP) contain a biologically inactive GIP-fragment and cholecystokinin-33/-39

Commercially available preparations of natural porcine glucose-dependent insulinotropic polypeptide (GIP) were subjected to reverse phase HPLC. The material was found to give rise to 4 peaks which were characterized by HPLC-retention time and N-terminal sequence analysis. They represented: intact porcine GIP(1-42), 58% (wt/wt); the GIP-fragment des-tyr-ala-GIP(3-42), 32% (wt/wt); cholecystokinin (CCK)-33 2% (wt/wt); CCK-39 2% (wt/wt). HPLC-pure GIP(1-42) stimulated insulin release in rat isolated pre-cultured pancreatic islets in the presence of 16.7 mM glucose up to 240% vs. control, whereas the fragment des-tyr-ala-GIP(3-42) did neither increase insulin release nor exhibit antagonistic activity to GIP(1-42) at 100 ng/ml. These results indicate that commercially available porcine GIP-preparations may contain the biologically inactive des-tyr-ala-GIP(3-42) in high amounts, and in addition may be contaminated by CCK-peptides. HPLC-characterization of these peptide preparations prior to any biological study is crucial.