A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo

One of the hallmarks of type 2 diabetes is that pancreatic β cells fail to release sufficient amounts of insulin in the presence of elevated blood glucose levels. Insulin secretion is modulated by many hormones and neurotransmitters including acetylcholine, the major neurotransmitter of the peripheral parasympathetic nervous system. The physiological role of muscarinic acetylcholine receptors expressed by pancreatic β cells remains unclear at present. Here, we demonstrate that mutant mice selectively lacking the M₃ muscarinic acetylcholine receptor subtype in pancreatic β cells display impaired glucose tolerance and greatly reduced insulin release. In contrast, transgenic mice selectively overexpressing M₃ receptors in pancreatic β cells show a profound increase in glucose tolerance and insulin release. Moreover, these mutant mice are resistant to diet-induced glucose intolerance and hyperglycemia. These findings indicate that β cell M₃ muscarinic receptors play a key role in maintaining proper insulin release and glucose homeostasis.     

The role of peptide YY in regulating glucose homeostasis

The gut-derived hormone peptide YY (PYY) is most commonly known for its effect on satiety, decreasing food intake and body weight in animals and humans. However, PYY is also involved in a wide range of digestive functions including regulating insulin secretion and glucose homeostasis. Over the last few years, there have been several interesting clinical and animal studies investigating the role of PYY in glucose homeostasis. This review aims to present an updated summary of findings over the last few decades highlighting the role of PYY in regulating insulin output and insulin sensitivity, and the potential mechanisms involved.     

Regulation of blood glucose homeostasis during prolonged exercise

The maintenance of normal blood glucose levels at rest and during exercise is critical. The maintenance of blood glucose homeostasis depends on the coordination and integration of several physiological systems, including the sympathetic nervous system and the endocrine system. During prolonged exercise increased demand for glucose by contracting muscle causes to increase glucose uptake to working skeletal muscle. Increase in glucose uptake by working skeletal muscle during prolonged exercise is due to an increase in the translocation of insulin and contraction sensitive glucose transporter-4 (GLUT4) proteins to the plasma membrane. However, normal blood glucose level can be maintained by the augmentation of glucose production and release through the stimulation of liver glycogen breakdown, and the stimulation of the synthesis of glucose from other substances, and by the mobilization of other fuels that may serve as alternatives. Both feedback and feedforward mechanisms allow glycemia to be controlled during exercise. This review focuses on factors that control blood glucose homeostasis during prolonged exercise.     

Bile acids and signal transduction: role in glucose homeostasis

Bile acids are mainly recognized for their role in dietary lipid absorption and cholesterol homeostasis. However, recent progress in bile acid research suggests that bile acids are important signaling molecules that play a role in glucose homeostasis. Among the various supporting evidence, several reports have demonstrated an improvement of the glycemic index of type 2 diabetic patients treated with diverse bile acid binding resins. Herein, we review the diverse interactions of bile acids with various signaling/response pathways, including calcium mobilization and protein kinase activation, membrane receptor-mediated responses, and nuclear receptor responses. Some of the effects of the bile acids are direct through the activation of specific receptors, i.e., TGR5, CAR, VDR, and FXR, while others imply modulation of the hormonal, growth factor and/or neuromediator responses, i.e., glucagon, EGF, and acetylcholine. We also discuss recent evidence implicating the interaction of bile acids with glucose homeostasis mechanisms, with the integration of our understanding of how the signaling mechanisms modulated by bile acid could regulate glucose metabolism.     

A new role for myoglobin in cardiac and skeletal muscle function

For many years, myoglobin was considered as an intracellular globin involved in oxygen transport and storage in cardiac and skeletal muscles. Following the discovery of its ability to convert nitrite into nitric oxide during hypoxia, myoglobin was shown to play a new role in the hypoxic signaling pathway that regulates mitochondrial functions of the electron-transport chain. This review presents experimental evidence that supports this concept and discusses the significance of this newly reported ability for cardiac and skeletal muscle functions.     

A brain-liver circuit regulates glucose homeostasis

Increased glucose production (GP) is the major determinant of fasting hyperglycemia in diabetes mellitus. Previous studies suggested that lipid metabolism within specific hypothalamic nuclei is a biochemical sensor for nutrient availability that exerts negative feedback on GP. Here we show that central inhibition of fat oxidation leads to selective activation of brainstem neurons within the nucleus of the solitary tract and the dorsal motor nucleus of the vagus and markedly decreases liver gluconeogenesis, expression of gluconeogenic enzymes, and GP. These effects require central activation of ATP-dependent potassium channels (K(ATP)) and descending fibers within the hepatic branch of the vagus nerve. Thus, hypothalamic lipid sensing potently modulates glucose metabolism via neural circuitry that requires the activation of K(ATP) and selective brainstem neurons and intact vagal input to the liver. This crosstalk between brain and liver couples central nutrient sensing to peripheral nutrient production and its disruption may lead to hyperglycemia.     

Influence of active muscle mass on glucose homeostasis during exercise in humans

To study the effect of increasing amounts of exercising muscle mass on the relationship between glucose mobilization and peripheral glucose uptake, seven young men (23-28 yr) bicycled for 70 min at a work load of 55-60% VO2max. From minute 30 to 50, arm cranking was added and total work load increased to 82 +/- 4% VO2max. During leg exercise, hepatic glucose production (Ra) increased in parallel with peripheral glucose uptake (Rd) and euglycemia was maintained. During arm + leg exercise, Ra increased more than Rd and accordingly plasma glucose increased from 5.11 +/- 0.22 to 8.00 +/- 0.66 mmol/l (P less than 0.05). Plasma catecholamines increased three- to four-fold more during arm + leg exercise than during leg exercise. Leg glucose uptake increased with time regardless of arm cranking. Net leg lactate release during leg exercise was reverted to a net leg lactate uptake during arm + leg exercise. The rate of glycogen breakdown in exercising leg muscle was not altered by addition of arm cranking. In conclusion, when large amounts of muscle mass are active, plasma catecholamines increase sharply and mobilization of glucose exceeds peripheral glucose uptake. This indicates that mechanisms other than feedback regulation to maintain euglycemia are involved in hormonal and substrate mobilization during intense exercise in humans.     

A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle

Eukaryotic cells possess systems for sensing nutritional stress and inducing compensatory mechanisms that minimize the consumption of ATP while utilizing alternative energy sources. Such stress can also be imposed by increased energy needs, such as in skeletal muscle of exercising animals. In these studies, we consider the role of the metabolic sensor, AMP-activated protein kinase (AMPK), in the regulation of glucose transport in skeletal muscle. Expression in mouse muscle of a dominant inhibitory mutant of AMPK completely blocked the ability of hypoxia or AICAR to activate hexose uptake, while only partially reducing contraction-stimulated hexose uptake. These data indicate that AMPK transmits a portion of the signal by which muscle contraction increases glucose uptake, but other AMPK-independent pathways also contribute to the response.     

Menstrual cycle phase dissociation of blood glucose homeostasis during exercise

The purpose of this investigation was to evaluate the effects of 24-h carbohydrate-poor diet on metabolic and hormonal responses induced by prolonged exercise in both follicular (FP) and luteal (LP) phases of the menstrual cycle. At mid-FP and at mid-LP, seven eumenorrheic young women [means +/- SE; chronological age, 21.1 +/- 0.6 yr; O2 uptake (VO2) peak, 43.7 +/- 2.0 ml X kg-1 X min-1; body fat, 19.2 +/- 2.0%] were subjected to a 90-min bicycle exercise period at an intensity representing 63% of their measured VO2 peak. Venous blood samples obtained before and during exercise were analyzed for levels of substrates (glucose, lactate, free fatty acids, glycerol) and hormones (luteinizing hormone, progesterone, estradiol, insulin, glucagon, cortisol, catecholamines). Contrary to FP, a significant (P less than 0.01) decrease in blood glucose concentration was observed after 70 and 90 min of exercise during LP. Significant phase differences were also observed for blood lactate (highest in FP), cortisol (highest in LP), and progesterone (highest in LP). Although not significantly different, tendencies for menstrual phase dissociations were noticed for some of the other measured variables. Hence, a menstrual phase dissociation in circulating glucose level, unmasked by a prolonged exercise performed after a 24-h carbohydrate-poor diet, suggests to the authors a specific metabolic involvement for gonadotrophic and/or gonadal hormones.     

The activation of hepatic and muscle polyamine catabolism improves glucose homeostasis

The mitochondrial biogenesis and energy expenditure regulator, PGC-1α, has been previously reported to be induced in the white adipose tissue (WAT) and liver of mice overexpressing spermidine/spermine N (1)-acetyltransferase (SSAT). The activation of PGC-1α in these mouse lines leads to increased number of mitochondria, improved glucose homeostasis, reduced WAT mass and elevated basal metabolic rate. The constant activation of polyamine catabolism produces a futile cycle that greatly reduces the ATP pools and induces 5'-AMP-activated protein kinase (AMPK), which in turn activates PGC-1α in WAT. In this study, we have investigated the effects of activated polyamine catabolism on the glucose and energy metabolisms when targeted to specific tissues. For that we used a mouse line overexpressing SSAT under the endogenous SSAT promoter, an inducible SSAT overexpressing mouse model using the metallothionein I promoter (MT-SSAT), and a mouse model with WAT-specific SSAT overexpression (aP2-SSAT). The results demonstrated that WAT-specific SSAT overexpression was sufficient to increase the number of mitochondria, reduce WAT mass and protect the mice from high-fat diet-induced obesity. However, the improvement in the glucose homeostasis is achieved only when polyamine catabolism is enhanced at the same time in the liver and skeletal muscle. Our results suggest that the tissue-specific targeting of activated polyamine catabolism may reveal new possibilities for the development of drugs boosting mitochondrial metabolism and eventually for treatment of obesity and type 2 diabetes.