Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution

We aimed to investigate how assimilation of nutrients affects the postprandial responses of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and to evaluate the effect of pancreatic enzyme substitution (PES) on insulin secretion in patients with chronic pancreatitis (CP) and pancreatic exocrine insufficiency (PEI). Eight male patients with CP and PEI were studied. Blood was sampled frequently on two separate days after ingestion of a liquid meal with and without PES, respectively. Eight healthy male subjects served as a control group. β-Cell responsiveness was estimated as changes in insulin secretion rates in response to changes in postprandial plasma glucose (PG). There was no difference in the PG incremental area under curve (AUC) for patients with and without PES [406 ± 100 vs. 425 ± 80 mM·4 h (mean ± SE), P = 0.8]. The response of total GLP-1 was higher after PES (AUC: 7.8 ± 1.2 vs. 5.3 ± 0.6 nM·4 h, P = 0.01), as was the response of total GIP (AUC: 32.7 ± 7.5 vs. 21.1 ± 8.3 nM·4 h, P = 0.01). Concurrently, both plasma insulin, plasma C-peptide, and total insulin secretion increased after PES (AUC: 17.7 ± 4.2 vs. 13.6 ± 2.9 nM·4 h, P = 0.02; 237 ± 31.4 vs. 200 ± 27.4 nM·4 h, P = 0.005; and 595 ± 82 vs. 497 ± 80 pmol·kg−1·4 h, P = 0.01, respectively). β-Cell responsiveness to glucose was not significantly different on the two study days for patients with CP. These results suggest that the secretion of GLP-1 and GIP is under influence of the digestion and absorption of nutrients in the small intestine and that PES increases insulin secretion.

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Antroduodenal motility in chronic pancreatitis: are abnormalities related to exocrine insufficiency?

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.278.3.g458 ◽

2000 ◽

Vol 278 (3) ◽

pp. G458-G466 ◽

Cited By ~ 14

Author(s):

M. K. Vu ◽

J. Vecht ◽

E. H. Eddes ◽

I. Biemond ◽

C. B. H. W. Lamers ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Pancreatic Insufficiency ◽

Motor Pattern ◽

Pancreatic Enzyme ◽

Gastrointestinal Hormone ◽

Hormone Release ◽

Exocrine Insufficiency ◽

Liquid Meal ◽

Gut Hormone ◽

Antroduodenal Motility

In patients with chronic pancreatitis (CP) the relation among exocrine pancreatic secretion, gastrointestinal hormone release, and motility is disturbed. We studied digestive and interdigestive antroduodenal motility and postprandial gut hormone release in 26 patients with CP. Fifteen of these patients had pancreatic insufficiency (PI) established by urinary para-aminobenzoic acid test and fecal fat excretion. Antroduodenal motility was recorded after ingestion of a mixed liquid meal. The effect of pancreatic enzyme supplementation was studied in 8 of the 15 CP patients with PI. The duration of the postprandial antroduodenal motor pattern was significantly ( P < 0.01) prolonged in CP patients (324 ± 20 min) compared with controls (215 ± 19 min). Antral motility indexes in the first hour after meal ingestion were significantly reduced in CP patients. The interdigestive migrating motor complex cycle length was significantly ( P < 0.01) shorter in CP patients (90 ± 8 min) compared with controls (129 ± 8 min). These abnormalities were more pronounced in CP patients with exocrine PI. After supplementation of pancreatic enzymes, these alterations in motility reverted toward normal. Digestive and interdigestive antroduodenal motility are abnormal in patients with CP but significantly different from controls only in those with exocrine PI. These abnormalities in antroduodenal motility in CP are related to maldigestion.

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Chronic pancreatitis

Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0336 ◽

2020 ◽

pp. 3218-3227

Author(s):

Marco J. Bruno ◽

Djuna L. Cahen

Keyword(s):

Diabetes Mellitus ◽

Chronic Pancreatitis ◽

Pancreatic Enzyme ◽

Exocrine Insufficiency ◽

Endocrine Insufficiency ◽

Diabetes Mellitus Diagnosis ◽

Permanent Loss ◽

Stimulation Tests ◽

Enteric Coated ◽

Pancreatic Duct Stricture

Chronic pancreatitis is a major source of morbidity, loss in quality of life, and healthcare expenditure. It is most commonly caused by chronic alcoholism in adults and cystic fibrosis in children, but there are many other causes. Patients typically present with severe abdominal pain, but this may vary and even be absent. Exo- and endocrine insufficiency usually occur late in the disease course and reflect permanent loss of pancreatic parenchyma due to ongoing inflammation and fibrosis, exocrine insufficiency manifesting as steatorrhea and weight loss due to fat maldigestion and endocrine insufficiency as diabetes mellitus. Diagnosis is confirmed by imaging investigations such as CT, MRI, and endoscopic ultrasonography. Endoscopic retrograde cholangiopancreatography to diagnose chronic pancreatitis is obsolete. Hormone stimulation tests (e.g. secretin–cholecystokinin stimulation test) to diagnose exocrine insufficiency are largely abandoned because of their complexity and burden to patients. They are replaced by faecal elastase testing, even though this test is less sensitive. Management focuses on the treatment of pain using a stepwise approach. Initially, nonopioid analgesics are prescribed. Next, when feasible, endoscopic therapy is initiated, including pancreatic stone fragmentation by extracorporeal shock-wave lithotripsy, endotherapy to remove stone fragments, and placement of plastic stents to dilate any concomitant pancreatic duct stricture. If that fails or when, for example, the pancreatic head is enlarged, surgical intervention is indicated. Medical management includes enteric-coated pancreatic enzyme preparations and treatment of diabetes mellitus, usually by means of insulin. Abstinence from alcohol and smoking cessation are important predictors of disease and treatment outcome.

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CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00318.2012 ◽

2013 ◽

Vol 304 (8) ◽

pp. G700-G707 ◽

Cited By ~ 7

Author(s):

Yuji Nakamura ◽

Takanori Kanai ◽

Keita Saeki ◽

Miho Takabe ◽

Junichiro Irie ◽

...

Keyword(s):

Cell Migration ◽

Insulin Secretion ◽

Chronic Pancreatitis ◽

Immune Cells ◽

Receptor Expression ◽

Wild Type ◽

Multiple Series ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

The Relationship

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b+Gr-1low macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b+/Gr-1− and CD11b+/Gr-1high cells, but not CD11b+/Gr-1low cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b+-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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Pancreatic exocrine insufficiency (PEI) and need for pancreatic enzyme replacement therapy (PERT) in patients with chronic pancreatitis (CP) is predicted by the degree of pancreatic fibrosis as measured by endoscopic ultrasound (EUS)-guided elastography

Pancreatology ◽

10.1016/j.pan.2013.07.060 ◽

2013 ◽

Vol 13 (4) ◽

pp. e17

Author(s):

J.E. Domínguez-Muñoz ◽

M. Castiñeiras ◽

M. Luaces ◽

J. Lariño-Noia ◽

L. Nieto ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Endoscopic Ultrasound ◽

Pancreatic Enzyme ◽

Pancreatic Exocrine Insufficiency ◽

Exocrine Insufficiency ◽

Enzyme Replacement ◽

Pancreatic Enzyme Replacement Therapy ◽

Pancreatic Exocrine

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488 The Degree of Pancreatic Fibrosis As Measured by Endoscopic Ultrasound (EUS)-Guided Elastography Predicts Pancreatic Exocrine Insufficiency (PEI) and Need for Pancreatic Enzyme Replacement Therapy (PERT) in Patients With Chronic Pancreatitis (CP)

Gastroenterology ◽

10.1016/s0016-5085(13)60332-7 ◽

2013 ◽

Vol 144 (5) ◽

pp. S-90 ◽

Cited By ~ 1

Author(s):

Enrique Dominguez-Munoz ◽

Margarita Castineira ◽

Maria Luaces-Regueira ◽

Jose Larino-Noia ◽

Laura Nieto ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Endoscopic Ultrasound ◽

Pancreatic Enzyme ◽

Pancreatic Exocrine Insufficiency ◽

Exocrine Insufficiency ◽

Enzyme Replacement ◽

Pancreatic Enzyme Replacement Therapy ◽

Pancreatic Exocrine

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Effects of Liraglutide on β-Cell-Specific Glucokinase-Deficient Neonatal Mice

Endocrinology ◽

10.1210/en.2012-1165 ◽

2012 ◽

Vol 153 (7) ◽

pp. 3066-3075 ◽

Cited By ~ 16

Author(s):

Jun Shirakawa ◽

Ritsuko Tanami ◽

Yu Togashi ◽

Kazuki Tajima ◽

Kazuki Orime ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Sensor ◽

Liver Steatosis ◽

Survival Rates ◽

Glycolytic Enzyme ◽

Β Cells ◽

Β Cell ◽

Newborn Mice ◽

Glucose Levels ◽

Glucagon Like Peptide 1

The glucagon-like peptide-1 receptor agonist liraglutide is used to treat diabetes. A hallmark of liraglutide is the glucose-dependent facilitation of insulin secretion from pancreatic β-cells. In β-cells, the glycolytic enzyme glucokinase plays a pivotal role as a glucose sensor. However, the role of glucokinase in the glucose-dependent action of liraglutide remains unknown. We first examined the effects of liraglutide on glucokinase haploinsufficient (Gck+/−) mice. Single administration of liraglutide significantly improved glucose tolerance in Gck+/− mice without increase of insulin secretion. We also assessed the effects of liraglutide on the survival rates, metabolic parameters, and histology of liver or pancreas of β-cell-specific glucokinase-deficient (Gck−/−) newborn mice. Liraglutide reduced the blood glucose levels in Gck−/− neonates but failed to prolong survival, and all the mice died within 1 wk. Furthermore, liraglutide did not improve glucose-induced insulin secretion in isolated islets from Gck−/− neonates. Liraglutide initially prevented increases in alanine aminotransferase, free fatty acids, and triglycerides in Gck−/− neonates but not at 4 d after birth. Liraglutide transiently prevented liver steatosis, with reduced triglyceride contents and elevated glycogen contents in Gck−/− neonate livers at 2 d after birth. Liraglutide also protected against reductions in β-cells in Gck−/− neonates at 4 d after birth. Taken together, β-cell glucokinase appears to be essential for liraglutide-mediated insulin secretion, but liraglutide may improve glycemic control, steatosis, and β-cell death in a glucokinase-independent fashion.

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Emerging role of testosterone in pancreatic β cell function and insulin secretion

Journal of Endocrinology ◽

10.1530/joe-18-0573 ◽

2019 ◽

Vol 240 (3) ◽

pp. R97-R105 ◽

Cited By ~ 10

Author(s):

Weiwei Xu ◽

Jamie Morford ◽

Franck Mauvais-Jarvis

Keyword(s):

Insulin Secretion ◽

Metabolic Regulation ◽

Cell Function ◽

Visceral Obesity ◽

Β Cells ◽

Β Cell ◽

Β Cell Function ◽

Glucagon Like Peptide 1 ◽

Glucose Stimulated Insulin Secretion

One of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose homeostasis by testosterone in male and females. Severe testosterone deficiency predisposes men to type 2 diabetes (T2D), while in contrast, androgen excess predisposes women to hyperglycemia. The role of androgen deficiency and excess in promoting visceral obesity and insulin resistance in men and women respectively is well established. However, although it is established that hyperglycemia requires β cell dysfunction to develop, the role of testosterone in β cell function is less understood. This review discusses recent evidence that the androgen receptor (AR) is present in male and female β cells. In males, testosterone action on AR in β cells enhances glucose-stimulated insulin secretion by potentiating the insulinotropic action of glucagon-like peptide-1. In females, excess testosterone action via AR in β cells promotes insulin hypersecretion leading to oxidative injury, which in turn predisposes to T2D.

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Ghrelin Impairs Prandial Glucose Tolerance and Insulin Secretion in Healthy Humans Despite Increasing GLP-1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-4154 ◽

2016 ◽

Vol 101 (6) ◽

pp. 2405-2414 ◽

Cited By ~ 23

Author(s):

Jenny Tong ◽

Harold W. Davis ◽

Amalia Gastaldelli ◽

David D'Alessio

Keyword(s):

Insulin Secretion ◽

Steady State ◽

Glucose Tolerance ◽

Healthy Subjects ◽

Tolerance Test ◽

Β Cell ◽

Meal Tolerance Test ◽

Healthy Humans ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract Objectives: Administration of ghrelin inhibits the acute insulin response to glucose and worsens IV glucose tolerance in healthy subjects. Evidence from preclinical studies suggests that ghrelin may have differential effects on glucose metabolism during fasting and feeding. Our objective was to test the effects of ghrelin on glucose and insulin responses during a meal tolerance test. Design: Acyl ghrelin (0.26 and 2.0 μg/kg/h) or saline was infused in 13 healthy subjects on three separate occasions in randomized order. Ghrelin was infused for 45 minutes to achieve steady-state levels and continued for 240 minutes after ingestion of a liquid test meal. Primary outcomes were area under the curve for glucose and insulin secretion. Results: We found that ghrelin infusions of 0.26 and 2.0 μg/kg/h raised steady-state plasma total ghrelin levels to 1.7- and 4.8-fold above fasting concentrations, but did not alter fasting plasma glucose or insulin levels. During the meal tolerance test, ghrelin decreased insulin sensitivity, impaired β-cell function, and induced glucose intolerance. The high-dose ghrelin infusion also raised postprandial glucagon like peptide 1 secretion without affecting glucose dependent insulinotropic polypeptide, glucagon, or peptide YY concentrations. Conclusions: We conclude that both physiologic and pharmacologic doses of ghrelin worsen the glucose and β-cell responses to meal ingestion in healthy humans. The increase in postprandial glucagon like peptide 1 secretion by ghrelin suggests a novel enteroendocrine connection, but does not mitigate the glucose intolerance.

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Chronic pancreatitis: review and update of etiology, risk factors, and management

F1000Research ◽

10.12688/f1000research.12852.1 ◽

2018 ◽

Vol 7 ◽

pp. 607 ◽

Cited By ~ 24

Author(s):

Angela Pham ◽

Christopher Forsmark

Keyword(s):

Chronic Pancreatitis ◽

Islet Cells ◽

Pancreatic Insufficiency ◽

Pancreatic Enzyme ◽

Exocrine Insufficiency ◽

Disease Etiology ◽

Enzyme Replacement ◽

Endocrine Insufficiency ◽

Pancreatic Enzyme Replacement Therapy ◽

Pancreatic Exocrine

Chronic pancreatitis is a syndrome involving inflammation, fibrosis, and loss of acinar and islet cells which can manifest in unrelenting abdominal pain, malnutrition, and exocrine and endocrine insufficiency. The Toxic-Metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and Severe Acute Pancreatitis, Obstructive (TIGAR-O) classification system categorizes known causes and factors that contribute to chronic pancreatitis. Although determining disease etiology provides a framework for focused and specific treatments, chronic pancreatitis remains a challenging condition to treat owing to the often refractory, centrally mediated pain and the lack of consensus regarding when endoscopic therapy and surgery are indicated. Further complications incurred include both exocrine and endocrine pancreatic insufficiency, pseudocyst formation, bile duct obstruction, and pancreatic cancer. Medical treatment of chronic pancreatitis involves controlling pain, addressing malnutrition via the treatment of vitamin and mineral deficiencies and recognizing the risk of osteoporosis, and administering appropriate pancreatic enzyme supplementation and diabetic agents. Cornerstones in treatment include the recognition of pancreatic exocrine insufficiency and administration of pancreatic enzyme replacement therapy, support to cease smoking and alcohol consumption, consultation with a dietitian, and a systematic follow-up to assure optimal treatment effect.

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