Molecular and genetic regulation of pig pancreatic islet cell development

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Abstract

Reliance on rodents for understanding pancreatic genetics, development and islet function could limit progress in developing interventions for human diseases such as diabetes mellitus. Similarities of pancreas morphology and function suggest that porcine and human pancreas developmental biology may have useful homologies. However, little is known about pig pancreas development. To fill this knowledge gap, we investigated fetal and neonatal pig pancreas at multiple, crucial developmental stages using modern experimental approaches. Purification of islet β-, α- and δ-cells followed by transcriptome analysis (RNA-seq) and immunohistology identified cell- and stage-specific regulation, and revealed that pig and human islet cells share characteristic features that are not observed in mice. Morphometric analysis also revealed endocrine cell allocation and architectural similarities between pig and human islets. Our analysis unveiled scores of signaling pathways linked to native islet β-cell functional maturation, including evidence of fetal α-cell GLP-1 production and signaling to β-cells. Thus, the findings and resources detailed here show how pig pancreatic islet studies complement other systems for understanding the developmental programs that generate functional islet cells, and that are relevant to human pancreatic diseases. Highlighted Article: Transcriptional, signaling and cellular programs governing pig pancreatic islet development exhibit striking similarities to human islet ontogeny, providing a novel resource for advancing human islet replacement strategies.

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Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogenase in pancreatic beta-cells. Potential role in nutrient sensing.

N Sekine, V Cirulli, J.-Ll. Tamarit … (1994)

Nutrient metabolism was examined with regard to insulin secretion in purified rat islet beta- and non-beta-cells, beta-cell lines, and hepatocytes. Lactate dehydrogenase (LDH) activity (nanomoles.min-1.mg protein-1) was remarkably low in the glucose-sensitive INS-1 cell line (15.7) and in beta-cells (22.3). Thus, beta-cell LDH was respectively 8-, 122-, 17-, and 136-fold lower than in islet non-beta, liver, HIT-T15, and RINm5F cells. Plasma membrane lactate transport activity was 3-10-fold lower in beta- or INS-1 cells than in the other cell types. Conversely, mitochondrial glycerol phosphate dehydrogenase was strongly expressed only in beta- and INS-1 cells. The significance of these findings to nutrient recognition was explored using INS-1 cells as a model of native beta-cells. Glucose-stimulated lactate output and glucose utilization were, respectively, 12- and 5-fold lower in INS-1 than in RINm5F cells. Each process was entirely blocked by respiratory chain inhibitors in INS-1 cells, whereas glucose utilization was barely affected and lactate output stimulated in RINm5F cells. Glucose oxidation represented 73% of total utilization in INS-1 cells, but only 9% in RINm5F cells. Absolute rates of glucose oxidation, and the extent of mitochondrial NAD(P) reduction, were similar in the two cell types, and glucose stimulated insulin secretion 1.9-fold in INS-1 and 1.4-fold in RINm5F cells. The mitochondrial substrates, monomethyl succinate, pyruvate, and leucine, each triggered secretion in INS-1 cells. The balance of LDH, plasma membrane lactate transport, and mitochondrial glycerol phosphate dehydrogenase activities therefore appear to be important in beta- and INS-1 cell glucose recognition to ensure that mitochondrial oxidation is the principle fate of pyruvate and NADH produced by glycolysis. The resultant close coupling of glycolysis with mitochondrial oxidation explains the absence in beta-cells of Crabtree and Pasteur effects.

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Components of metabolic syndrome and coronary artery disease in female Ossabaw swine fed excess atherogenic diet.

Michael Sturek, Mouhamad Alloosh, Eric A Mokelke … (2006)

Ossabaw swine have a 'thrifty genotype' (propensity to obesity) that enables them to survive seasonal food shortages in their native environment. Consumption of excess kcal causes animals of the thrifty genotype to manifest components of the metabolic syndrome, including central (intra-abdominal) obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension. We determined whether female Ossabaw swine manifest multiple components of the metabolic syndrome by comparing lean pigs fed a normal maintenance diet (7% kcal from fat; lean, n = 9) or excess chow with 45% kcal from fat and 2% cholesterol (obese, n = 8). After 9 wk, body composition, glucose tolerance, plasma lipids, and intravascular ultrasonography and histopathology of coronary arteries were assessed. Computed tomography (CT) assessed subcutaneous and intra-abdominal fat deposition and was compared with traditional methods, including anatomical measurements, backfat ultrasonography, and proximate chemical composition analysis. Compared with lean animals, obese swine showed 2-fold greater product of the plasma insulin x glucose concentrations, 4.1-fold greater total cholesterol, 1.6-fold greater postprandial triglycerides, 4.6-fold greater low- to high-density lipoprotein cholesterol ratio, hypertension, and neointimal hyperplasia of coronary arteries. The 1.5-fold greater body weight in obese swine was largely accounted for by the 3-fold greater carcass fat mass. High correlation (0.79 to 0.95) of CT, anatomical measurements, and ultrasonography with direct chemical measures of subcutaneous, retroperitoneal, and visceral fat indicates high validity of all indirect methods. We conclude that relatively brief feeding of excess atherogenic diet produces striking features of metabolic syndrome and coronary artery disease in female Ossabaw swine.