Pancreatic Ppy-expressing γ-cells display mixed phenotypic traits and the adaptive plasticity to engage insulin production.

The cellular identity of pancreatic polypeptide (Ppy)-expressing γ-cells, one of the rarest pancreatic islet cell-type, remains elusive. Within islets, glucagon and somatostatin, released respectively from α- and δ-cells, modulate the secretion of insulin by ß-cells. Dysregulation of insulin production raises blood glucose levels, leading to diabetes onset. Here, we present the genetic signature of human and mouse γ-cells. Using different approaches, we identified a set of genes and pathways defining their functional identity. We found that the γ-cell population is heterogeneous, with subsets of cells producing another hormone in addition to Ppy. These bihormonal cells share identity markers typical of the other islet cell-types. In mice, Ppy gene inactivation or conditional γ-cell ablation did not alter glycemia nor body weight. Interestingly, upon ß-cell injury induction, γ-cells exhibited gene expression changes and some of them engaged insulin production, like α- and δ-cells. In conclusion, we provide a comprehensive characterization of γ-cells and highlight their plasticity and therapeutic potential.

Pancreatogenic diabetes: special considerations for management.

BACKGROUND/AIMS: Pancreatogenic, or type 3c, diabetes (T3cDM) occurs due to inherited or acquired pancreatic disease or resection. Although similar to the more prevalent type 1 and type 2 diabetes, pancreatogenic diabetes has a unique pattern of hormonal and metabolic characteristics and a high incidence of pancreatic carcinoma in the majority of patients with T3cDM. Despite these differences, no guidelines for therapy have been described. METHODS: Published studies on the prevalence, pathophysiology, and cancer associations of T3cDM were reviewed. The recent studies on the protective role and mechanism of metformin therapy as both an anti-diabetic and anti-neoplastic agent were reviewed, and studies on the cancer risk of other anti-diabetic drugs were surveyed. RESULTS: T3cDM accounts for 5-10% of Western diabetic populations and is associated with mild to severe disease. Hepatic insulin resistance is characteristic of T3cDM and is caused by deficiencies of both insulin and pancreatic polypeptide. 75% of T3cDM is due to chronic pancreatitis, which carries a high risk for pancreatic carcinoma. Insulin and insulin secretagogue treatment increases the risk of malignancy, whereas metformin therapy reduces it. Pancreatic exocrine insufficiency associated with T3cDM contributes to nutritional deficiencies and the development of metabolic bone disease. CONCLUSIONS: Until consensus recommendations are reached, the glycemic treatment of T3cDM should avoid insulin and insulin secretagogues if possible. Metformin should be the first line of therapy, and continued if insulin treatment must be added for adequate glucose control. Pancreatic enzyme therapy should be added to prevent secondary nutritional and metabolic complications. and IAP.

Gastric emptying and orocecal transit time in pregnancy.

PURPOSE: To evaluate the effects of pregnancy on gastrointestinal function, we determined gastric emptying time, orocecal transit time, and fasting gastrointestinal hormone levels (cholecystokinin, gastrin, pancreatic polypeptide, neurotensin) in 11 women with mild dyspeptic symptoms during the first and third trimesters of their pregnancies, and again 4-6 months after delivery. METHODS: After the women ingested a disaccharide solution, orocecal transit time was determined by monitoring breath hydrogen concentrations at 10-min intervals, and values were compared with the postpartum value. Ultrasound examinations of gastric emptying were performed during the same intervals. RESULTS: The half-emptying time and the final gastric emptying time did not differ in the first and third trimesters and postpartum, but gastrointestinal transit time was significantly longer in the third trimester of pregnancy than postpartum (100.0 min [range, 50.5-240.0 min] vs 70.0 min [range, 40.5-240.0 min; P < 0.05]), respectively. Mean plasma pancreatic polypeptide values were lower in the third trimester of pregnancy than postpartum. and a negative correlation was observed between pancreatic polypeptide levels and transit time in the third trimester (r = -0.65; P = 0.0261). The plasma levels of other gastrointestinal hormones did not differ in the various periods studied. CONCLUSIONS: Our study shows that, despite evident dyspeptic symptoms, there were no significant alterations in gastric emptying or orocecal transit time during the first trimester of pregnancy. Conversely, in the third trimester, orocecal transit time was significantly longer.

Reversal of abnormal glucose production after pancreatic resection by pancreatic polypeptide administration in man.

Pancreatic polypeptide (PP) deficiency has been associated with impaired hepatic sensitivity to insulin and pancreatogenic diabetes in chronic pancreatitis. Since pancreatic resection might also result in PP deficiency, hepatic responses to insulin infusion (0.25 mU/kg/min) were determined by the euglycemic glucose clamp technique in 10 patients who had previously undergone pancreatic resection for trauma and in eight healthy control subjects. Six resection patients (RES-PP) demonstrated deficient PP levels, with a mean increase of plasma immunoreactive PP of 20 +/- 7 pg/ml above basal rate after a test meal compared with 232 +/- 82 pg/ml in control subjects (p less than 0.01) and 353 +/- 133 pg/ml in four other patients undergoing resection with normal levels of immunoreactive PP (RES + PP) (p less than 0.03). Three identical insulin infusion studies were performed in each subject, the second of which was performed during the final 2 hours of an 8-hour infusion of bovine PP (2.0 pmol/kg/min). Whereas hepatic glucose production (HGP) in control subjects fell 74% +/- 4% from a basal rate of 2.0 +/- 0.1 mg/kg/min to a 60- to 120-minute value of 0.5 +/- 0.1 mg/kg/min during insulin infusion, HGP was suppressed only 58% +/- 5% in RES-PP subjects, from 1.9 +/- 0.1 to 0.8 +/- 0.1 mg/kg/min (p less than 0.05 vs controls). Intravenous infusion of PP corrected the hepatic resistance to insulin seen in the PP-deficient group. During PP infusion, HGP was suppressed 74% +/- 5% in RES-PP subjects, from 2.1 +/- 0.2 to 0.5 +/- 0.1 mg/kg/min (p less than 0.04 compared with initial study). PP infusion produced no significant change in glucose metabolism in control and RES + PP subjects. Overall glucose disposal rates were not altered by PP infusion in any group. These findings support a role of PP as a glucoregulatory hormone and suggest that PP deficiency may serve as a reversible pathophysiologic factor in the abnormal glucose metabolism seen after pancreatic resection.

Reversal of abnormal glucose metabolism in chronic pancreatitis by administration of pancreatic polypeptide.

Chronic pancreatitis, induced in dogs by pancreatic duct ligation, is associated with glucose intolerance due to insulin deficiency, reduced hepatic sensitivity to insulin, and a marked deficiency of pancreatic polypeptide. Treatment with a 14 day continuous subcutaneous infusion of pancreatic polypeptide resulted in improved oral glucose tolerance and improved hepatic glucose responses to insulin in dogs with chronic pancreatitis. No effect of continuous subcutaneous infusion of pancreatic polypeptide was seen in the control dogs. The time course of the effect of continuous subcutaneous infusion on the hepatic response to insulin was relatively immediate, whereas the effects on improvement in oral glucose tolerance were prolonged. We conclude that pancreatic polypeptide may function physiologically to enhance the hepatic glucose response to insulin and that alterations in glucose metabolism seen in chronic pancreatitis may be due, in part, to a deficiency in pancreatic polypeptide. Since treatment with continuous subcutaneous infusion of pancreatic polypeptide restored the hepatic response to insulin and oral glucose tolerance to more normal levels in our animal model, administration of pancreatic polypeptide may play a therapeutic role in the treatment of certain forms of pancreatogenic diabetes.