Glucose Metabolism

Type II

strongly associated with obesity, hypertriglyceridemia, and insulin resistance

glycogenolysis needed:

glucagon promotes phosphorylation of glycogen synthase and phosphorylation of glycogen phosphorylase. => Glucagon can possitively (glycogenolysis) and negatively (glycogenesis) regulate

Sucrose and Lactose

hydrolyzed into their monosaccharide components (by sucrase and lactase, respectively) which can then be used as a fuel source (glucose undergoes glycolysis to pyruvate, which can be used to generate ATP)

Pentose phosphate pathway (PPP)

i. Breaks down glucose oxidatively into ribose 5 phosphate and NADPH 1. R5P used to make DNA/RNA 2. NADPH used as energy source in cellular functions ii. Breaks down R5P in non-oxidative reactions to form intermediates of glycolysis

Primary functions in health and well-being of Gluconeogensis

i. During anaerobic conditions or fasting state, it allows the creation of glucose from other precursors 1. During anaerobic conditions, Pyruvate must be converted to lactate in order to free an NADH into NAD+ to continue anaerobic glycosis due to lack of O2 [for TCA/ETC] 2. This increases lactic acid in blood, which is taken up by liver and converted back into pyruvate and glucose ii. Glycerol from adipose tissue -> glucose iii. Lactate -> glucose [liver] iv. Glycogen -> glucose [glycogenolysis]

Primary functions in health and well-being of Glycolysis

i. Leads to production of ATP which is essential for cellular functions ii. Also produces compounds that are intermediates of other biosynthetic pathways

Gluconeogenesis

i. Pyruvate is converted into glucose. ii. Glycerol and AA's can also be converted into glucose. iii. NOT fatty acids - these will only be converted into Acetyl CoA

Glycogenesis (glycogen synthesis)

i. Synthesis of glycogen from glucose a. Promoted by insulin, prohibited by glucagon b. Carried out by glycogen synthase

Exergonic reactions

release free energy (often catabolic processes - break down of compounds)

Endergonic

require free energy (Anabolic processes - synthesis of compounds)

Reduction

addition of e- to a molecule

Fed state

blood glucose is high -> HIGH insulin -> glycogenesis + glycolysis

Lactose

Galactose + Glucose a. dietary source - milk, sugar

Anaerobic

No O2. Glucose -> pyruvate -> lactate net 2 ATP produces ATP faster

The red cells is dependent on dependent on glucose/glucose 6-phosphate as an energy source

The blood lacks mitochondria, and cannot use fatty acids as fuel: this is because fatty acid derivatives enter at different points in TCA.

The brain is dependent on glucose/glucose 6-phosphate as an energy source

The brain is dependent on glucose because fatty acids cannot pass through the blood-brain barrier, rendering this source of energy unavailable.

In glycogennolysis, glucose is

a product <- glycogen

In gluceoneogenesis, glucose is

a product <- pyruvate

Diabetes insipidus

due to a deficiency of ADH - results in failure of kidneys to reabsorb water

Type I

little or no insulin production. i. Often due to a viral infection in youth - Antibodies to that virus cross react and destroy beta cells of the pancreas

Normoglycemia

normal fasting plasma glucose concentration is 70-100 mg/dl

glycogenesis needed:

insulin promotes DEphosphorylation of glycogen synthase and DEphosphorylation of glycogen phosphorylase => Insulin can only posstively regulate

Know why glucose is not a primary energy fuel inresting skeletal muscle,

○ ACTIVE: glucose is preferred because anaerobic glycolysis can produce energy the fastest. ○ RESTING: FAs = primary fuel; FA oxidation produces ATP at a good enough rate for resting sk. muscle

GSD1a

○ aka Von Gierke disease ○ deficiency of G6Pase activity (necessary to release free glucose into the blood by the liver). ○ result: hypoglycemia, lactic acidosis, enlarged liver (glycogen buildup), ○ both gluconeogenesis and glycogenolysis impaired

● GSD1b

○ defect in the transport protein that moves G6Pase from the cytosol into ER lumen of hepatocytes (because G6Pase are normally found in the ER of hepatocytes) ○ very similar to GSD1a ○ uncooked cornstarch given as a bedtime snack because it breaks down to glucose slowly keeping glucose

Why glucose is not a primary energy fuel in liver

○ saves glucose for other tissues. prefers to use a-keto acids and FAs ○ will metabolize some glucose only after a meal (i.e. when [glucose] high)

Oxidation

- removal of e- from a molecule

Hemolytic anemia.

A deficiency in G6PD impairs the cell's ability of the cell to form NADPH which is needed to maintain glutathione in a reduced state. Glutathione must be in the reduced state in the cell in order to remove free radicals from the cell. A deficiency in NADPH will cause the RBC to lyse leading to severe hemolytic anemia. NADPH also maintains the reduced states of sulfhydryl groups in proteins, including Hemoglobin. Oxidation of the sulfhydryl groups in proteins leads to the formation of Heinz bodies - denatured proteins that form insoluble masses that attach to the RBC membranes. Additional oxidation also causes the RBCs to become rigid - spleen then removes them from circulation.

Diabetes mellitus

causes hyperglycemia due to decreased insulin (Type 1) or decreased insulin sensitivity of target tissues (Type 2)

glycogen synthase:

rate limiting enzymes of glycogenesis Active: DEphosphorylated / inactive: phosphorylated.

Insulin acts as

+ regulator for glycolysis

Glucagon

- released from pancreas under starved conditions (glucose deficiency) a. elevates blood glucose by promoting breakdown of glycogen in liver and inhibiting glycogen synthesis b. can be stimulated by epinephrine

Insulin

- released under fed conditions a. lowers blood glucose by promoting synthesis of glycogen, stimulating glycolysis, and inhibiting gluconeogenesis

glycogen phosphorylase:

rate limiting enzymes of glycogenolysis Active: phosphorylated / inactive: DEphosphorylated

Why the glucose from glucose 6-phosphate can "escape" the liver into the bloodstream but not from most other tissue cells. And know why this is important in the

1. For glucose to leave the liver, phosphate must be removed a. The enzyme to remove the phosphate - glucose-6-phosphatase - is only present in the liver (and a few other tissues) 2. Importance - Liver is one of main areas for glucose storage (as glycogen) by gluconeogenesis from Amino Acids and the degradation of a. During overnight fast, the liver maintains blood-glucose levels by gluconeogenesis from Amino Acids and the degradation of glycogen

Active skeletal muscle is dependent on glucose/glucose 6-phosphate as an energy source

Active skeletal muscle uses glycolysis to produce ATP quickly, as fatty acid oxidation is a slower, aerobic process. Resting muscle, however, uses fatty acids. Ex: Sprinting vs marathon running

Anabolic/anabolism

Anabolic processes require Free energy [G], are endergonic, and create higher energy molecules

Catabolic/catabolism

Catabolic processes release G, are exergonic, and break down higher energy molecules

Why (and how) the glycolytic and pentose phosphate pathways interact to meet the needs of cells for ATP, NADPH, and pentoses, under varying conditions.

Glycolysis can provide direct formation of ATP anaerobically and formation of acetyl CoA (for the citric acid cycle) aerobically. The pentose phosphate pathway (PPP) can provide ribose, deoxyriboses, or pentose for RNA, DNA, ATP, etc. and NADPH for reductive biosynthesis pathways: i. Oxidative reactions that lead to production of NADPH and pentose ii. Non-oxidative reactions that => intermediates of glycolysis phosphates (such as ribose-5-phosphate) iii. If the cell does just needs NADPH and doesn't need ribose-5-phosphate, the ribose can be converted into intermediates of the glycolytic pathway (glyceraldehyde-3-phosphate and fructose-6-phosphate). In the glycolytic pathway, they can be metabolized to form ATP. If the cell does not need ATP, the pentoses from PPP can go through gluconeogenic pathway to be converted back to glucose.

Sucrose

Glucose + Fructose a. Dietary source - table sugar, fruit

Glycogenolysis (glycogen degradation)

Is the degradation of glycogen into G6P a. Promoted by glucagon, inhibited by insulin b. Occurs when blood sugar low c. Carried out by phosphorylated glycogen phosphorylase - Glycogen phosphorylase is phosphorylated by Epinephrine, glucagon. Dephosphorylation of this enzyme caused by insulin

Aerobic

O2. Glucose -> pyruvate -> acetyl CoA which takes part in TCA

Glycolysis

Oxidation of glucose to pyruvate. This may be aerobic: pyruvate will continue into the TCA cycle after being converted into acetyl CoA Or anaerobic: Pyruvate is converted into lactate

Pentose phosphate pathway (PPP)

Phase I [oxidative RNXs] Glucose converted into NADPH and R5P. Phase II [non-oxidative RNX's] Link R5P into intermediates of glycolysis

Redox reactions

Reactions involve the transfer of e- from one molecule (reducing agent) to the another (oxidizing agent) Ex. In glycolysis, glucose is oxidized to pyruvate and NAD is reduced

In glycogenesis, glucose is

a substrate -> glycogen

In Glycolysis, Glucose is

a substrate -> pyruvate

In pentose phosphate pathway, glucose is

a substrate -> ribose 5 phosphate and NADPH

Hyperglycemia

blood glucose level above 100 mg/dl a. Fasting serum glucose greater than 126 mg/dl is diagnostic of diabetes mellitus

Hypoglycemia

blood glucose levels drop below 60 mg/dl a. symptoms of hunger, sweating, trembling b. cortisol becomes elevated (gluconeogenesis is initiated using amino acids and it requires the presence of cortisol)

Fasting state:

blood glucose low -> HIGH glucagon -> glycogenolysis + gluconeogenesis

Glucagon acts as

both a + and - regulator under each pathway (Gluconeogenesis vs glycolysis)

Glucose transporters (GLUTs)

mediate absorption of monosaccharides glucose, galactose, and fructose. Bind to target monosacharride on one side of membrane and undergo a conformational change to release it to the other side. i. SGLT1 - cotransports one molecule of glucose along with two Na+ from the intestinal lumen to cytosol of enterocytes; uses secondary active transport ii. GLUT5 - used for the uptake or release of fructose from the cell; uses facilitated diffusion