**3. Glucose homeostasis: insulin-glucagon interplay**

Alpha and β cells work together to maintain glucose homeostasis under feeding and fasting conditions through the periodic release of insulin and glucagon respectively [4, 25, 48]. Feeding results in increased plasma glucose levels. Rising plasma glucose levels demand immediate systemic activation of glucose metabolism by insulin. A delayed or deficient activation of glucose metabolism will result in abnormally high plasma and cellular glucose levels, a medical condition known as hyperglycemia. Glucose at higher-than-normal concentrations induces glucotoxic effects inside the cells. Rising postprandial glucose levels will trigger β cells to synthesize and secrete insulin. The postprandial rise in insulin levels activates glucokinase and hexokinase activity resulting in glucose phosphorylation in hepatocytes and muscle cells. Conversion of glucose into glucose-6-phosphate will result in the decline of plasma glucose levels over time. Physiologically because of GSIS the postprandial rise in the insulin secretion from β cells declines over time as the blood glucose level decline [15]. Thus, the rising plasma glucose levels provide positive feedback to enhance insulin secretion and the declining plasma glucose levels act as a negative feedback loop to lower insulin levels. Insulin negatively impacts glucagon secretion [49–52]. Plasma glucose levels decline under fasting conditions. As glucose is the primary cellular source to generate ATP, a minimum threshold of plasma glucose levels must be maintained to avoid hypoglycemia.

Hypoglycemia is a serious medical condition characterized by very low plasma glucose levels. Fasting induced a decline in plasma glucose levels and subsequent diminished insulin levels initiate glucagon synthesis and secretion from alpha cells. To avoid hypoglycemia during fasting, glucagon enhances plasma glucose levels by activating hepatic gluconeogenesis/glucogenolysis thus forming glucose molecules from non-carbohydrate sources [10, 53–57]. Glucagon secretion from alpha cells and insulin secretion from β cells are also regulated by incretin hormones secreted from the intestines [58]. Incretin hormones are gut peptides secreted from the L and K cells of the small intestine and include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP*-*1) [59, 60]. GIP and GLP-1 functional receptors are present on both alpha and β cells. In normal physiological conditions, the GIP induces glucagon secretion from alpha cells during fasting or hypoglycemic state whereas GLP-1 induces insulin secretion from β cells and inhibits glucagon secretion from alpha cells [59, 61].
