Gluconeogenesis is the process of synthesizing glucose from noncarbohydrate precursors. The major substrates are the glucogenic amino acids , lactate, glycerol, and propionate. Liver and kidney are the major gluconeogenic tissues. The liver is the primary gluconeogenic organ. While the renal cortex of the kidney may contribute about 10% of whole-body gluconeogenesis after a short-term fast (18-24 h), the kidney is not a net source of glucose. This is because the renal medulla is a consumer of glucose. It is only with long-term fasting (~7 days) that the kidney can supply net glucose carbon to contribute to glucose homeostasis. The key gluconeogenic enzymes are expressed in the small intestine. Propionate arising from intestinal bacterial fermentation of carbohydrates is a substrate for gluconeogenesis in enterocytes. The intestine is not a net consumer of lactate and alanine or glycerol, the major substrates for gluconeogenesis. It is a consumer of glucose in the fasting state. Thus, any glucose synthesis that occurs locally is likely metabolized locally.

The rate of hepatic gluconeogenesis is determined by four factors: (1) the availability of gluconeogenic substrates, (2) the capacity of the liver to take up gluconeogenic substrates, (3) the quantity and activity of the gluconeogenic enzymes, and (4) the oxidative capacity of the liver to not only supply the energy to support the energy requiring process of gluconeogenesis but metabolize the nitrogen from the glucogenic amino acids (Ureagenesis).

Throughout the 24-hour feeding fasting cycle gluconeogenic precursors are available. In the fasting state adipose tissue lipolysis releases glycerol. Skeletal muscle releases lactate and gluconeogenic amino acids. As the fast is extended glycerol and amino acids provide an increasing role in sup plying carbon for gluconeogenesis. One might think that as a fast progresses gluconeogenesis increases even more. In fact, it does not. This is because the glucose demands of peripheral tissues decrease including the brain. This preserves the vital protein stores. In the fed state gluconeogenic supply does not decrease, in fact it is elevated. The mix of carbon sources is different. Glycerol supply decreases because of a decrease in lipolysis. Lactate supply does not decrease primarily because of the high rates of glycolysis in skeletal muscle. Amino acid supply increases as amino acids derived from dietary protein are directly delivered into the portal vein. During exercise lactate supply from working muscle helps support the increased gluconeogenic demand of exercise.

The transport and uptake of amino acids, glycerol, and lactate are regulated differently. The liver is extremely efficient at taking up glycerol. Greater than 60% of glycerol delivered to the liver is removed on first pass. This fraction remains constant in response to increase or decrease in insulin, glucagon, and epinephrine which are important regulators of gluconeogenesis. In contrast amino acid removal is very sensitive to glucagon and to a lesser extent insulin. Glucagon is a potent stimulator of the transport of glucogenic amino acids by the liver. About 20% of these amino acids are removed on first pass; first pass extraction can increase to more than 60% in the presence of an increase in glucagon. Insulin can stimulate amino acid transport but the response is much smaller than that of glucagon. Lactate uptake by the liver is complex because the liver can produce lactate during high rates of glycogen breakdown. However, in the fasting state the primary driver is the availability of lactate. When lactate is increased along with increases in glucagon the liver can become an efficient consumer of lactate, supporting the gluconeogenic response, for example, as is seen in exercise.

In this chapter we will talk about the gluconeogenic path ways and the sites of regulation. These sites are clearly important in fine-tuning how substrates enter and flow through the gluconeogenic pathway. However, substrate supply and substrate transport can override this regulation by mass action. For example, one might expect that gluconeogenesis decreases after a meal as insulin goes up and glucagon level falls, which should inhibit the gluconeogenic enzymes. However, what is found is gluconeogenesis persists. Delivery and transport of substrates are sustained offsetting the downregulation of the enzymes. However, the liver does not release the gluconeogenic-derived carbon; it diverts it into glycogen to augment meal-derived glycogen synthesis (indirect glycogen synthesis).

In disease states associated with hyperglycemia (eg, infection and diabetes) gluconeogenesis is inappropriately increased. In critically ill patients in response to injury and infection gluconeogenic supply is very high (elevated lactate, increased lipolysis, increased protein catabolism). Combined with the underlying insulin resistance and high glucagon levels it drives gluconeogenesis and induces hyperglycemia, which is associated with poor outcomes. In insulin deficiency (diabetic ketoacidosis) as is seen in Type 1 diabetes, in the absence of insulin and very high glucagon the unopposed lipolysis and protein catabolism amplifies the hyperglycemia. Hyperglycemia leads to changes in osmolality of body fluids, impaired blood flow, intracellular acidosis, and increased superoxide radical production, resulting in deranged endothelial and immune system function and impaired blood coagulation.

With liver failure gluconeogenesis is impaired and hypoglycemia develops despite the fact that substrate supply is high and there is severe insulin resistance and very high glucagon levels. In this case, the inability to support energy production in the liver (impaired citric acid cycle flux and ureagenesis) starves the gluconeogenic pathway of the energy required to support the synthesis of glucose.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الفكرية ينظم مجلسًا عزائيًّا في دولة بوروندي الإفريقية

العتبة العباسية المقدسة تواصل إقامة مجالسها العزائية لإحياء شهر المحرَّم

سماحة السيد الصافي يدعو إلى التدبر في القرآن والاستفادة منه في مواجهة تحديات الحياة

ضمن برنامج التطوير الحسيني التاسع.. جمعية كشافة الكفيل تقيم مهرجان الكشاف الحسيني

المزيد

الآخبار الصحية

دراسة تكشف علاقة خطيرة بين عمر الأم وصحة مولودها

دراسة تحذر.. اضطراب نوم بسيط قد يسبب الموت المبكر ؟

الاستحمام بالماء الساخن.. راحة مؤقتة وأضرار دائمة للبشرة

ماذا يحدث للجسم عند تخطي وجبة الإفطار؟

المزيد

الآخبار التكنلوجية

كيف تساعد الصيانة الوقائية في الحفاظ على كفاءة التكييف في سيارتك ؟

في ظاهرة غريبة حيرت العلماء.. كوكبنا قد يسجل أقصر يوم في التاريخ هذا الصيف!

السد الصيني العملاق يعيق دوران الأرض ويغيّر شكلها ؟

السعودية تطلق 10 تجارب علمية إلى محطة الفضاء الدولية

المزيد

مواضيع ذات صلة

Glycogen Metabolism is Regulated by A Balance in Activities Between Glycogen Synthase & Phosphorylase

cAMP Activates Glycogen Phosphorylase

Cyclic AMP Integrates The Regulation of Glycogenolysis & Glycogenesis

Glycogenolysis is not the Reverse of Glycogenesis, it is A Separate Pathway

Glycogenesis Occurs Mainly in Muscle & Liver

The Oxidation of Pyruvate to Acetyl-COA is The Irreversible Route from Glycolysis to The Citric Acid Cycle

Glycolysis is Regulated at Three Nonequilibrium Reactions

Tissues That Function Under Hypoxic Conditions or have Intrinsically High Rates of Glucose Oxidation Produce Lactate

Glycolysis Constitutes The Main Pathway of Glucose Utilization

Glycolysis Can Function Under Anaerobic Conditions

Regulation of the Citric Acid Cycle Depends Primarily on a Supply of Oxidized Cofactors

The Citric Acid Cycle Takes Part in Fatty Acid Synthesis