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Evidence exists to support the role of dairy derived proteins whey and casein in glycemic management. The objective of the present study was to use a cell screening method to identify a suitable casein hydrolysate and to examine its ability to impact glycemia related parameters in an animal model and in humans. Following screening for the ability to stimulate insulin secretion in pancreatic beta cells, a casein hydrolysate was selected and further studied in the ob/ob mouse model. An acute postprandial study was performed in 62 overweight and obese adults. Acute and long-term supplementation with the casein hydrolysate in in vivo studies in mice revealed a glucose lowering effect and a lipid reducing effect of the hydrolysate (43% reduction in overall liver fat). The postprandial human study revealed a significant increase in insulin secretion ( p = 0.04) concomitant with a reduction in glucose ( p = 0.03). The area under the curve for the change in glucose decreased from 181.84 ± 14.6 to 153.87 ± 13.02 ( p = 0.009). Overall, the data supports further work on the hydrolysate to develop into a functional food product.

peer-reviewed The influence of different substrates and the effect of pH regulation during enzymatic hydrolysis of whey protein on glucose-stimulated insulin secretion by BRIN-BD11 pancreatic beta cells were studied. No significant differences (P >= 0.05) were detected in terms of glucose-stimulated insulin secretion by BRIN-BD11 pancreatic beta cells exposed to whey protein hydrolysates (WPH1 and WPH2) obtained with two different whey protein substrates. The whey protein hydrolysate (WPH3) obtained without pH regulation during hydrolysis, had a significantly lower insulinotropic potential in BRIN-BD11 cells than the WPH1 hydrolysate that was manufactured with pH regulation. Fractionation of WPH1 was carried out to enrich bioactive peptides. Comparing the different fractionation techniques studied (solid-phase extraction and semi-preparative reverse phase-high performance liquid chromatography), the most potent insulinotropic fraction was enriched in free amino acids and contained relatively hydrophilic peptides. This indicates that amino acids and hydrophilic peptides may be involved in the insulinotropic effect of WPH1. (C) 2013 Elsevier Ltd. All rights reserved. ACCEPTED peer-reviewed

Whey protein hydrolysates (WPHs) represent novel antidiabetic agents that affect glycemia in animals and humans, but little is known about their insulinotropic effects. The effects of a WPH were analyzed in vitro on acute glucose-induced insulin secretion in pancreatic BRIN-BD11 β cells. WPH permeability across Caco-2 cell monolayers was determined in a 2-tiered intestinal model. WPH effects on insulin resistance were studied in vivo following an 8-wk oral ingestion (100 mg/kg body weight) by ob/ob (OB-WPH) and wild-type mice (WT-WPH) compared with vehicle control (OB and WT groups) using a 2 × 2 factorial design, genotype × treatment. BRIN-BD11 cells showed a robust and reproducible dose-dependent insulinotropic effect of WPH (from 0.01 to 5.00 g/L). WPH bioactive constituents were permeable across Caco-2 cell monolayers. In the OB-WPH and WT-WPH groups, WPH administration improved glucose clearance after a glucose challenge (2 g/kg body weight), as indicated by differences in the area under curves (AUCs) (P ≤ 0.05). The basal plasma glucose concentration was not affected by WPH treatment in either genotype. The plasma insulin concentration was lower in the OB-WPH than in the OB group (P ≤ 0.005) but was similar between the WT and WT-WPH groups; the interaction genotype × treatment was significant (P ≤ 0.005). Insulin release from pancreatic islets isolated from the OB-WPH group was greater (P ≤ 0.005) than that from the OB group but did not differ between the WT-WPH and WT groups; the interaction genotype × treatment was not significant. In conclusion, an 8-wk oral administration of WPH improved blood glucose clearance, reduced hyperinsulinemia, and restored the pancreatic islet capacity to secrete insulin in response to glucose in ob/ob mice. Hence, it may be useful in diabetes management.

Whey protein hydrolysates (WPHs) represent novel antidiabetic agents that affect glycemia in animals and humans, but little is known about their insulinotropic effects. The effects of a WPH were analyzed in vitro on acute glucose-induced insulin secretion in pancreatic BRIN-BD11 β cells. WPH permeability across Caco-2 cell monolayers was determined in a 2-tiered intestinal model. WPH effects on insulin resistance were studied in vivo following an 8-wk oral ingestion (100 mg/kg body weight) by ob/ob (OB-WPH) and wild-type mice (WT-WPH) compared with vehicle control (OB and WT groups) using a 2 × 2 factorial design, genotype × treatment. BRIN-BD11 cells showed a robust and reproducible dose-dependent insulinotropic effect of WPH (from 0.01 to 5.00 g/L). WPH bioactive constituents were permeable across Caco-2 cell monolayers. In the OB-WPH and WT-WPH groups, WPH administration improved glucose clearance after a glucose challenge (2 g/kg body weight), as indicated by differences in the area under curves (AUCs) (P ≤ 0.05). The basal plasma glucose concentration was not affected by WPH treatment in either genotype. The plasma insulin concentration was lower in the OB-WPH than in the OB group (P ≤ 0.005) but was similar between the WT and WT-WPH groups; the interaction genotype × treatment was significant (P ≤ 0.005). Insulin release from pancreatic islets isolated from the OB-WPH group was greater (P ≤ 0.005) than that from the OB group but did not differ between the WT-WPH and WT groups; the interaction genotype × treatment was not significant. In conclusion, an 8-wk oral administration of WPH improved blood glucose clearance, reduced hyperinsulinemia, and restored the pancreatic islet capacity to secrete insulin in response to glucose in ob/ob mice. Hence, it may be useful in diabetes management.

Mitochondria play a key role in energy metabolism and ATP production in many tissues, including skeletal muscle, cardiac muscle, brain and liver. Inherent disorders of mitochondria such as mDNA deletions cause major disruption of metabolism and can result in severe disease phenotypes. However, the incidence of such mDNA based disorders is extremely rare and cannot account for the dramatic rise in human metabolic diseases, which are characterised by defects in energy metabolism. Mitochondrial dysfunction characterized by reduced ATP generation and reduced mitochondrial number in skeletal muscle or reduced ATP generation and mitochondrial stimulus-secretion coupling in the pancreatic beta cell has been implicated in the pathology of chronic metabolic disease associated with type 2 diabetes mellitus and also with aging. Additionally the generation of ROS from mitochondria and other cellular sources may interfere in insulin signaling in muscle, contributing to insulin resistance. Reduced mitochondrial oxidative capacity coupled with increased ROS generation underlies the accumulation of intramuscular fat, insulin resistance and muscle dysfunction in aging. We will review the molecular basis for optimal mitochondrial function or mechanisms of dysfunction and correlate with pathology of identified diseases and aging.

Mitochondria play a key role in energy metabolism and ATP production in many tissues, including skeletal muscle, cardiac muscle, brain and liver. Inherent disorders of mitochondria such as mDNA deletions cause major disruption of metabolism and can result in severe disease phenotypes. However, the incidence of such mDNA based disorders is extremely rare and cannot account for the dramatic rise in human metabolic diseases, which are characterised by defects in energy metabolism. Mitochondrial dysfunction characterized by reduced ATP generation and reduced mitochondrial number in skeletal muscle or reduced ATP generation and mitochondrial stimulus-secretion coupling in the pancreatic beta cell has been implicated in the pathology of chronic metabolic disease associated with type 2 diabetes mellitus and also with aging. Additionally the generation of ROS from mitochondria and other cellular sources may interfere in insulin signaling in muscle, contributing to insulin resistance. Reduced mitochondrial oxidative capacity coupled with increased ROS generation underlies the accumulation of intramuscular fat, insulin resistance and muscle dysfunction in aging. We will review the molecular basis for optimal mitochondrial function or mechanisms of dysfunction and correlate with pathology of identified diseases and aging.

Pancreatic beta-cells are often referred to as "fuel sensors" as they continually monitor and respond to dietary nutrients, under the modulation of additional neurohormonal signals, in order to secrete insulin to best meet the needs of the organism. beta-cell nutrient sensing requires metabolic activation, resulting in production of stimulus-secretion coupling signals that promote insulin biosynthesis and release. The primary stimulus for insulin secretion is glucose, and islet beta-cells are particularly responsive to this important nutrient secretagogue, It is important to consider individual effects of different classes of nutrient or other physiological or pharmacological agents on metabolism and insulin secretion. However, given that beta-cells are continually exposed to a complex milieu of nutrients and other circulating factors, it is important to also acknowledge and examine the interplay between glucose metabolism and that of the two other primary nutrient classes, the amino acids and fatty acids. It is the mixed nutrient sensing and outputs of glucose, amino and fatty acid metabolism that generate the metabolic coupling factors (MCFs) involved in signaling for insulin exocytosis. Primary MCFs in the beta-cell include ATP, NADPH, glutamate, long chain acyl-CoA and diacylglycerol and are discussed in detail in this article.

Pancreatic β-cells are often referred to as “fuel sensors” as they continually monitor and respond to dietary nutrients, under the modulation of additional neurohormonal signals, in order to secrete insulin to best meet the needs of the organism. β-cell nutrient sensing requires metabolic activation, resulting in production of stimulus-secretion coupling signals that promote insulin biosynthesis and release. The primary stimulus for insulin secretion is glucose, and islet β-cells are particularly responsive to this important nutrient secretagogue, It is important to consider individual effects of different classes of nutrient or other physiological or pharmacological agents on metabolism and insulin secretion. However, given that β-cells are continually exposed to a complex milieu of nutrients and other circulating factors, it is important to also acknowledge and examine the interplay between glucose metabolism and that of the two other primary nutrient classes, the amino acids and fatty acids. It is the mixed nutrient sensing and outputs of glucose, amino and fatty acid metabolism that generate the metabolic coupling factors (MCFs) involved in signaling for insulin exocytosis. Primary MCFs in the β-cell include ATP, NADPH, glutamate, long chain acyl-CoA and diacylglycerol and are discussed in detail in this article.