Tag Archives: Homeostasis

Thyroid Hormone Coordinates Pancreatic Islet Maturation During the Zebrafish Larval-to-Juvenile Transition to Maintain Glucose Homeostasis

Thyroid hormone (TH) signaling promotes tissue maturation and adult organ formation. Developmental transitions alter an organism’s metabolic requirements, and it remains unclear how development and metabolic demands are coordinated. We used the zebrafish as a model to test whether and how TH signaling affects pancreatic islet maturation, and consequently glucose homeostasis, during the larval to juvenile transition. We found that exogenous TH precociously activates the β-cell differentiation genes pax6b and mnx1 while downregulating arxa, a master regulator of α-cell development and function. Together, these effects induced hypoglycemia, at least in part by increasing insulin and decreasing glucagon expression. We visualized TH target tissues using a novel TH-responsive reporter line and found that both α- and β-cells become targets of endogenous TH signaling during the larval-to-juvenile transition. Importantly, endogenous TH is required during this transition for the functional maturation of α- and β-cells in order to maintain glucose homeostasis. Thus, our study sheds new light on the regulation of glucose metabolism during major developmental transitions.

Diabetes Journal current issue





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How Should We Think About the Role of the Brain in Glucose Homeostasis and Diabetes?

Diabetes Journal current issue





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Roles of the Gut in Glucose Homeostasis

Jens Juul Holst
Jun 1, 2016; 39:884-892
Metabolic Surgery and the Changing Landscape for Diabetes Care
: Most-Read Full-Text Articles





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Transient Receptor Potential Canonical 3 (TRPC3) Channels Are Required for Hypothalamic Glucose Detection and Energy Homeostasis

The mediobasal hypothalamus (MBH) contains neurons capable of directly detecting metabolic signals such as glucose to control energy homeostasis. Among them, glucose-excited (GE) neurons increase their electrical activity when glucose rises. In view of previous work, we hypothesized that transient receptor potential canonical type 3 (TRPC3) channels are involved in hypothalamic glucose detection and the control of energy homeostasis. To investigate the role of TRPC3, we used constitutive and conditional TRPC3-deficient mouse models. Hypothalamic glucose detection was studied in vivo by measuring food intake and insulin secretion in response to increased brain glucose level. The role of TRPC3 in GE neuron response to glucose was studied by using in vitro calcium imaging on freshly dissociated MBH neurons. We found that whole-body and MBH TRPC3-deficient mice have increased body weight and food intake. The anorectic effect of intracerebroventricular glucose and the insulin secretory response to intracarotid glucose injection are blunted in TRPC3-deficient mice. TRPC3 loss of function or pharmacological inhibition blunts calcium responses to glucose in MBH neurons in vitro. Together, the results demonstrate that TRPC3 channels are required for the response to glucose of MBH GE neurons and the central effect of glucose on insulin secretion and food intake.

Diabetes Journal current issue





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Impact of Perturbed Pancreatic {beta}-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism

Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes.

Diabetes Journal current issue





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Roles of the Gut in Glucose Homeostasis

Jens Juul Holst, Fiona Gribble, Michael Horowitz, Chris K. Rayner
Jun 1, 2016; 39:884-892
Metabolic Surgery and the Changing Landscape for Diabetes Care
Diabetes Care: Most-Read Full-Text Articles





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