Diabetes mellitus is diagnosed by an insulin-resistance test. Overt signs of the disease occur when the pancreas cannot secrete
enough insulin to overcome the resistance. One of the causes of altered glucose metabolism in Type 2 diabetes is the inability of tissues to communicate and adapt to new metabolic states. Glucose and its metabolites are responsible for some of this homeostatic control.Glucose and other hexoses are transported across plasma membranes by a family of transporters. The major glucose transporter is GLUT4. It is activated by insulin and expressed in skeletal and cardiac muscle as well as
adipocytes. The GLUT1 glucose transporter has a minor role in glucose homeostasis in insulin-responsive tissues but plays a larger role in other tissues. Over-expression of GLUT1 or GLUT4 in muscle or GLUT4 in adipocytes increases glucose tolerance and hypoglycemia in experimental models. However, GLUT1 overexpression in muscle is insulin-resistant and resets glycemic control, whereas GLUT4 overexpression in muscle and adipocytes is insulin-sensitive and appropriately controls insulin secretion. Glucose tolerance and insulin responsiveness is regulated more by GLUT4 in muscle rather than adipose tissue. Fasting hypoglycemia is similar in vivo between overexpression of GLUT4 in adipocytes or muscle and GLUT4 in both muscle and adipose tissue. The GLUT4 is involved in tissue-intercommunication of glucose homeostasis. Downregulation or knockout of GLUT4 in muscle or adipocytes causes insulin resistance in other target tissues. In humans insulin-resistance selectively downregulates GLUT4 in adipocytes but not muscle. Thus, adipocytes may be involved in glucose sensing if the cells respond to glucose flux. There are several ways in which tissues respond to changes in glucose concentrations. Hormones, cytokines, fatty acids and the amino acid leucine are implicated in glucose homeostasis. The best-described mechanism of glucose modulation is pancreatic insulin secretion due to closure of ATP-sensitive potassium channels. The same mechanism is used by hypothalamic neurons. These neurons are essential for centrally-mediated hypoglycemic control. The hypothalamus and other brain regions have other mechanisms to modulate glucose. In the hypothalamus for example, adenosine monophosphate-activated protein kinase responds to cellular adenosine monophosphate by phosphyrylating several enzymes and initiating gene transcription. These reactions increase cellular energy.Glucose metabolites generated by the
tricarboxylic acid (TCA) cycle contribute to glucose control. These metabolites are expelled from the TCA cycle as carriers of excess carbon that was added to the cycle by pyruvate carboxylase. This process could serve as a metabolic coupler to insulin secretion.Many TCA by-products are implicated in glucose concentration signaling. Glucose-6-phosphate itself may increase glycogen production through activation of glycogen synthase. The carbohydrate response element–binding protein increases expression of glylytic and lipolytic enzymes. Hexosamines, products of the glutamine:fructose-6-phosphate amidotransferase enzyme, are implicated in insulin sensitivity and obesity. Tissues handle glucose in a variety of ways. Glucose may be stored, use for energy or transported from tissue to tissue. The fate of intracellular glucose may depend on the pyruvate dehydrogenase enzyme complex. This complex is regulated by kinases and phosphatases. Gluconeogenic intermediates released from tissues can communicate cellular status to other tissues. For example, lactate from muscle cells could stimulate liver gluconeogenesis. Lactate production in the hypothalamus could also influence liver gluconeogenesis.Adipose tissue regulates glucose concentrations through production of cytokines and hormones such as leptin and adiponectin. In the mouse knockout of adipocyte GLUT4, the adipokine, RBP4, contributes to insulin-resistance and impairs insulin signaling in muscle. This hormone is being considered as a marker for diabetes. In the fasted state adipose tissue undergoes glyceroneogenesis. glycerol-3-phosphate is essential for fatty acid re-esterfication and fatty acid release from tissues. The release of these fatty acids could communicate the glucose deficiency to other tissues.Information on the homeostatic control of glucose concentrations is continuing to grow and it should contribute significantly to our understanding of metabolic diseases such as diabetes.