incretins and Pancreatitis--Chronic

Incretin-based therapies like glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors help maintain the glycaemic control in patients with type 2 diabetes mellitus with additional systemic benefits and little risk of hypoglycaemia. These medications are associated with low-grade chronic pancreatitis in animal models inconsistently. The incidence of acute pancreatitis was also reported in some human studies. This inflammation provides fertile ground for developing pancreatic carcinoma (PC). Although the data from clinical trials and population-based studies have established safety regarding PC, the pathophysiological possibility that low-grade chronic pancreatitis leads to PC remains. We review the existing literature and describe the relationship between incretin-based therapies and PC.

Topics: Acute Disease; Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Pancreatic Neoplasms; Pancreatitis, Chronic

Type 2 diabetes mellitus (T2DM) has been shown to be characterised by an almost abolished incretin effect. The incretin effect refers to the phenomenon of oral glucose eliciting a higher insulin response than intravenous glucose at identical plasma glucose profiles. It is conveyed by the two insulinotropic incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are secreted from the small intestines in response to ingestion of nutrients. The incretin defect of T2DM has been characterised by a virtually lost insulinotropic effect of GIP. It is unknown whether the incretin defect is a primary event leading to T2DM or arises as a consequence of the diabetic state. To investigate this we studied patients with chronic pancreatitis (CP). Over time, CP leads to secondary diabetes mellitus (DM). If patients with CP and secondary DM exhibit the characteristic type 2 diabetic incretin deficiencies and patients with CP and normal glucose tolerance are normal in that regard, it is more likely that these deficiencies are consequences of the diabetic state rather than primary events leading to T2DM. On the other hand, if incretin physiology is preserved independently of the endocrine status of patients with CP, the incretin defect could represent a primary pathogenetic defect. Three protocols have been employed to investigate this. In a study investigating postprandial incretin responses in 8 patients with CP and exocrine pancreatic insufficiency, with and without pancreatic enzyme supplementation (PES), we observed preserved incretin responses as compared to matched healthy subjects; and, further, that PES increased postprandial incretin responses in these patients. This suggests not only that the secretion of incretin hormones is regulated by the mere presence of nutrients in the small intestine, but also that the assimilation of such nutrients is involved, as well. Furthermore, we gauged the incretin effect in 8 patients with CP and normal glucose tolerance and in 8 patients with CP and secondary DM. Eight healthy subjects and 8 patients with T2DM were studied for comparison. The incretin effect was shown to be preserved in normal glucose tolerant patients with CP, whereas it was strongly reduced in patients with CP and secondary DM, suggesting the incretin defect to be a consequence of the diabetic state. Lastly, we investigated the insulinotropic effect of the incretin hormones in 8 patients with CP

Topics: Diabetes Mellitus, Type 2; Humans; Incretins; Insulin-Secreting Cells; Pancreatitis, Chronic

Studies evaluating endocrine and exocrine functions in fibrocalculous pancreatic diabetes (FCPD) are scarce.. Insulin, C-peptide, glucagon, incretin hormones (glucagon-like peptide 1 [GLP-1] and gastric inhibitory peptide [GIP]), and dipeptidyl peptidase IV (DPP-IV) were estimated in patients with FCPD (n = 20), type 2 diabetes mellitus (T2DM) (n = 20), and controls (n = 20) in fasting and 60 minutes after 75 g glucose.. Fasting and post-glucose C-peptide and insulin in FCPD were lower than that of T2DM and controls. Plasma glucagon decreased after glucose load in controls (3.72, 2.29), but increased in T2DM (4.01, 5.73), and remained unchanged in FCPD (3.44, 3.44). Active GLP-1 (pmol/L) after glucose load increased in FCPD (6.14 to 9.72, P = <.001), in T2DM (2.87 to 4.62, P < .001), and in controls (3.91 to 6.13, P < .001). Median active GLP-1 in FCPD, both in fasting and post-glucose state (6.14, 9.72), was twice that of T2DM (2.87, 4.62) and 1.5 times that of controls (3.91, 6.13) (P < .001 for all). Post-glucose GIP (pmol/L) increased in all: FCPD (15.83 to 94.14), T2DM (21.85 to 88.29), and control (13.00 to 74.65) (P < .001 for all). GIP was not different between groups. DPP-IV concentration (ng/mL) increased in controls (1578.54, 3012.00) and FCPD (1609.95, 1995.42), but not in T2DM (1204.50, 1939.50) (P = .131). DPP-IV between the three groups was not different. Fecal elastase was low in FCPD compared with T2DM controls.. In FCPD, basal C-peptide and glucagon are low, and glucagon does not increase after glucose load. GLP-1, but not GIP, in FCPD increases 1.5 to 2 times as compared with T2DM and controls (fasting and post glucose) without differences in DPP-IV.. 背景: 评价纤维结石性胰腺糖尿病(FCPD)内分泌和外分泌功能的研究很少。 方法: 测定FCPD组(n=20)、2型糖尿病(T2 DM)组(n=20)和对照组(n=20)空腹和75g葡萄糖后60min的胰岛素、C肽、胰高血糖素、肠泌素(胰高血糖素样肽1[GLP-1]和胃抑制肽[GIP])、二肽基肽酶IV(DPP-IV)水平。 结果: FCPD组空腹和糖负荷后C肽、胰岛素水平均低于T2 DM组和对照组。对照组糖负荷后胰高血糖素(pmol/L)降低(3.72; 2.29); T2 DM组升高(4.01; 5.73); FCPD组(3.44; 3.44)无明显变化。FCPD组(6.14~9.72; P=<0.001)、T2 DM组(2.87~4.62; P<0.001)和对照组(3.91~6.13; P<0.001)糖负荷后活性GLP-1(pmol/L)升高。FCPD组空腹和糖负荷后GLP-1(pmol/L)活性中位数(6.14; 9.72)是T2 DM组(2.87; 4.62)的两倍; 是对照组(3.91; 6.13)的1.5倍(P<0.001)。糖负荷后GIP(pmol/L)在所有组别中都升高:FCPD(15.83~94.14)、T2DM(21.85~88.29)、对照组(13.00~74.65), P<0.01。不同组间GIP差异无统计学意义。对照组(1578.54,3012.00)和FCPD组(1609.95,1995.42)的DPP-IV浓度(ng/mL)升高; 而T2 DM组(1204.50,1939.50)的DPP-IV浓度无明显变化(P=0.131)。DPP-IV于三组间差异无统计学意义。FCPD组中粪弹性蛋白酶低于T2 DM组对照组。 结论: FCPD患者糖负荷后基础C肽和胰高血糖素降低; 在糖负荷后胰高血糖素不升高。FCPD的GLP-1; 而不是GIP; 与T2 DM和对照组(空腹和糖负荷后)相比升高了1.5-2倍; 而DPP-IV没有差异.

Topics: Adolescent; Adult; Biomarkers; Blood Glucose; C-Peptide; Calcinosis; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Female; Fibrosis; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Pancreatitis, Chronic; Time Factors; Young Adult

To determine the association between the use of incretin agents (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) for the treatment of type 2 diabetes mellitus (T2DM) and the risk of any, acute and chronic pancreatitis.. A population-based cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD 2007-2012). A total of 182 428 adult patients with ≥1 non-insulin antidiabetic drug (NIAD) prescription were matched to control subjects without diabetes. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of pancreatitis in incretin-users (N = 28 370) compared with controls and with other NIAD users. Adjustments were made for lifestyle, disease and drug history. In a sensitivity analysis, a new-user design was used.. Current incretin users had a 1.5-fold increased risk of any pancreatitis compared with NIAD users (adjusted HR 1.47, 95% CI 1.06-2.04). In incident current incretin users the risk of any and acute pancreatitis was increased 2.1- and 2.0-fold compared with NIAD users (adjusted HR 2.12, 95% CI 1.31-3.43 and adjusted HR 1.96, 95% CI 1.13-3.41), whereas there was no increased risk found for chronic pancreatitis.. Incretin use was associated with an increased risk of any pancreatitis. Moreover, risk of any and acute pancreatitis was higher when applying a new-user design. We were not able to detect an association with chronic pancreatitis, but the number in this subgroup was small.

Topics: Acute Disease; Adolescent; Adult; Aged; Case-Control Studies; Cohort Studies; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Pancreatitis; Pancreatitis, Chronic; Proportional Hazards Models; Risk Factors; United Kingdom; Young Adult

Incretin-based therapies have been associated with an increased risk of pancreatitis. Recently, various histological abnormalities have been reported in human pancreatic tissue from brain-dead organ donors who had been exposed to incretin-based drugs. In the present study we examined pancreatic tissue collected at surgery.. Human pancreatic tissue from 7 type 2-diabetic patients treated with incretin-based drugs (type 2-I), 6 diabetic patients without incretin treatment (type 2-NI), 11 patients without diabetes (no diabetes group) and 9 brain-dead organ donors (BDOD group) was examined.. Fractional beta-cell area was reduced in the type 2-NI group compared to the group without diabetes (P < .05), but there was no difference compared to the type 2-I patients. Alpha-cell area (P = .30), beta-cell replication (P = .17) and alpha-cell replication (P = .91) were not different. There were also no differences in acinar cell (P = .13) and duct cell replication (P = .099). Insulin-positive duct cells were more frequent in the type 2-I and the BDOD groups (P = .034). No co-expression of insulin and glucagon was detected. Pancreatic intraepithelial neoplasia (PanIN) lesions were very rare, all low-grade (PanIN 1a and 1b) and tended to occur more frequently in the type 2-I group (P = .084).. The present results did not reveal marked histological abnormalities in the pancreas of incretin-treated patients with type 2 diabetes. Low numbers of specimens available and a large inter-individual variability of the findings warrant caution regarding the interpretation of histological data concerning drug effects on the human pancreas.

Topics: Acinar Cells; Adamantane; Adenocarcinoma; Adult; Aged; Carcinoma in Situ; Case-Control Studies; Cystadenoma; Diabetes Mellitus, Type 2; Digestive System Surgical Procedures; Dipeptides; Exenatide; Female; Glucagon; Glucagon-Secreting Cells; Humans; Incretins; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Middle Aged; Neuroendocrine Tumors; Nitriles; Organ Size; Pancreas; Pancreas, Exocrine; Pancreatic Neoplasms; Pancreatitis, Chronic; Peptides; Pyrrolidines; Sitagliptin Phosphate; Tissue Donors; Venoms; Vildagliptin

The incretin effect is reduced and the insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is abolished in patients with type 2 diabetes mellitus (T2DM).. To evaluate the causality of this deficiency we investigated 8 patients with chronic pancreatitis (CP) and normal glucose tolerance (NGT) (fasting plasma glucose (FPG): 5.5 (4.5-6.0) mM (mean (range); HbA(1c): 5.8 (5.4-6.3) %) and 8 patients with CP and secondary diabetes not requiring insulin (FPG: 7.1 (6.0-8.8) mM; HbA(1c): 7.0 (5.8-10.0) %) during three 15-mM hyperglycaemic clamps with continuous iv infusion of saline, glucagon-like peptide-1 (GLP-1) or GIP.. The initial (0-20 min) insulin and C-peptide responses were enhanced significantly in both groups by GLP-1 and GIP, respectively, compared to saline (P<0.05). In both groups GLP-1 infusion resulted in significantly greater insulin and C-peptide responses from 20-120 min compared with saline infusion. During GIP infusion the late-phase insulin response (20-120 min) was 3.1+/-1.0 fold greater than during saline infusion in the group of patients with CP and NGT (P<0.05), whereas there was no significant differences in patients with CP and DM.. The lack of GIP amplification of the late insulin response to iv glucose develops alongside the deterioration of glucose tolerance in patients with CP, suggesting that the same may be true for the loss of the GIP effect in patients with T2DM.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Male; Middle Aged; Pancreatitis, Chronic