Studies have highlighted the existence of two intra-pancreatic axes of communication: one involved in the regulation of enzyme production by insulin—the insular–acinar axis; and another involved in the regulation of insulin release by pancreatic enzymes—the acini–insular axis. Previous studies by our laboratory show that pancreatic enzymes can affect blood glucose homeostasis and insulin secretion independently of their digestive functions, both from the gut lumen and probably from the blood. As a result we would like to introduce here the concept of acini–islet–acinar (AIA) axis communication (feedback), which could play an important role in the development of obesity and diabetes type 2. The AIA feedback links the endocrine and exocrine parts of the pancreas and emphasizes the essential role that the pancreas plays, as a single organ, in the regulation of glucose homeostasis by amylase most probably in gut epithelium and by insulin and glucagon in peripheral blood.

Limitations in efficacy and/or tolerance of currently available urate-lowering therapies (ULTs), such as oral xanthine oxidase inhibitors, uricosurics, and intravenous uricase agents contribute to the development of refractory gout. Renal excretion is the major route of uric acid elimination, but the intestinal tract plays an increasingly recognized role in urate homeostasis, particularly in chronic kidney disease (CKD) in which the renal elimination of urate is impaired. We targeted intestinal degradation of urate in vivo with ALLN-346, an orally administered, engineered urate oxidase, optimized for proteolytic stability, and activity in the gut. We tested ALLN-346 in uricase/urate oxidase deficient mice (URKO mice) with severe hyperuricemia, hyperuricosuria, and uric acid crystalline obstructive nephropathy. A total of 55 male and female URKO mice were used in the two consecutive studies. These seminal, proof-of-concept studies aimed to explore both short- (7-day) and long-term (19-day) effects of ALLN-346 on the reduction of plasma and urine urate. In both the 7- and 19-day studies, ALLN-346 oral therapy resulted in the normalization of urine uric acid excretion and a significant reduction of hyperuricemia by 44 and 28% when therapy was given with food over 24 h or was limited for up to 6 h, respectively. Fractional excretion of uric acid (FEUA) was normalized with ALLN-346 therapy. Oral enzyme therapy with engineered urate oxidase (ALLN-346) designed to degrade urate in the intestinal tract has the potential to reduce hyperuricemia and the renal burden of filtered urate in patients with hyperuricemia and gout with and without CKD.

Nitrogen (N₂) is an indispensable metabolite required for the synthesis of protein. In animals, gut bacteria and, to a certain extent, even hepatocytes, are able to assimilate nitrogen from ammonium (NH₄⁺), which is essentially derived from the amine group (-NH₂) and which is at the same time a very toxic metabolite. Initially, NH₄⁺ is coupled to alpha-ketoglutarate (AKG), a reaction which results in the appearance of glutamate (one amine group), and after that, in the appearance of glutamine - containing two amine groups. The surplus of NH₄⁺ which is not utilized by AKG/glutamate/glutamine is eliminated as urea in the urine, via the urea cycle in hepatocytes. Plants bacteria also assimilate nitrogen from NH₄⁺, by its fixation to ammonia (NH₃)/NH₄⁺. Previous studies have shown that AKG (also known as 2-oxo-glutaric acid or 2-oxopentanedioic acid), the primary metabolite of Rhizobium and gut bacteria, is essential for the assimilation of nitrogen. Symbiotic bacteria produce AKG, which together with glutamate dehydrogenase (GDH), 'generates' primarily amine groups from NH₄⁺. The final product is glutamate - the first amino acid. Glutamate has the capacity to be converted to glutamine, through the action of glutamine synthetase, after the assimilation of the second nitrogen from NH₄⁺. Glutamate/glutamine, derivatives of AKG metabolism, are capable of donating amine groups for the creation of other amino acids, following NH₂ transamination to certain metabolites e.g., short chain fatty acids (SCFA).

The purpose of this research is to explore the link between plasma amylase and insulin levels in growing pigs. Blood was obtained from piglets ranging in age from preterm (8 days to full gestation period), up to postnatal day 90 (2 months post-weaning) that underwent either duodenal-jejunal bariatric interposition surgery or a sham-operation. Plasma amylase activities in preterm and full-term neonates ranged between 500–600 U/L and were decreased by 50% two months post-weaning. Preprandial insulin and C-peptide levels in neonate piglets were not detectable, however they rose gradually after weaning. An increase in plasma amylase activity was observed in the young pigs that underwent duodenal-jejunum bypass (metabolic) surgery. The increase in blood pancreatic amylase activity after an intravenous amylase infusion lowered the subsequent glucose-stimulated insulin/C-peptide release. We suggest a role for blood amylase in the regulation of glucose homeostasis after observing high blood amylase levels in neonate pigs, in pigs that underwent metabolic surgery, and as a result of the reduced glucose-stimulated insulin response following intravenous amylase administration. Blood amylase level is a dynamic physiological parameter, which is not merely a consequence of exocrine pancreatic digestive enzyme production, but rather a regulated factor involved in glucose assimilation and prandial insulin regulation.

The current study was aimed at highlighting the role of blood pancreatic amylase in the regulation of glucose homeostasis and insulin secretion in a porcine model of streptozotocin- (STZ-) induced diabetes and in a rat pancreatic beta-cell line, BRIN-BD11. Blood glucose, plasma insulin, and glucagon levels were measured following a duodenal glucose tolerance test (IDGTT), in four pigs with STZ-induced type 2 diabetes (T2D pigs) and in four pigs with STZ-induced type 1 diabetes (T1D pigs). Four intact pigs were used as the control group. The effect of amylase supplementation on both acute and chronic insulin secretion was determined in a BRIN-BD11 cell line. The amylase infusion had no effect on the glucose utilization curve or glucagon levels in the healthy pigs. However, a significant lowering of insulin release was observed in healthy pigs treated with amylase. In the T2D pigs, the glucose utilization curve was significantly lowered in the presence of amylase, while the insulin response curve remained unchanged. Amylase also significantly increased glucagon release during the IDGTT in the T2D and T1D pigs, by between 2- and 4-fold. Amylase did not affect the glucose utilization curve in the T1D pigs. Amylase supplementation significantly decreased both acute and chronic insulin secretion in the BRIN-BD11 cells. These data confirm our previous observations and demonstrate the participation of pancreatic amylase in glucose absorption/utilization. Moreover, the present study clearly highlights the direct impact of pancreatic blood amylase on insulin secretion from pancreatic beta-cells and its interactions with insulin and glucagon secretion in a porcine model.

In the present review, we highlight the possible “extra-immunological” effects of maternal immunoglobulins (Ig) transferred to the blood circulation of offspring, either via the placenta before birth or via the colostrum/milk across the gut after birth in different mammalian species. Using the newborn pig as a model, since they are naturally born agammaglobulinemic, intravenously (i.v.) infused purified serum Ig rapidly improved the vitality, suckling behavior, and ensured the survival of both preterm and term piglets. In further studies, we found that proper brain development requires i.v. Ig supplementation. Studies have reported on the positive effects of i.v. Ig treatment in children with epilepsy. Moreover, feeding newborn pigs an elementary diet supplemented with Ig improved the gut structure, and recently a positive impact of enteral or parenteral Ig supplementation on the absorption of polyunsaturated fatty acids (PUFAs) was observed in the newborn pig. Summarized, our own results and those found in the literature, indicate the existence of important extra-immune effects of maternal Ig, in addition to the classical protective effects of transferred maternal passive immunity, including effects on the development of the brain, gut, and possibly other organ systems in the neonate. These additional properties of circulating Ig could have an impact on care guidelines for human neonates, especially those born prematurely with low plasma Ig levels.