Diabetes

Question 1

Diabetes mellitus

Answer 1

Diabetes mellitus – is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces.
Uncontrolled diabetes results in very high blood glucose concentrations
Both are characterized by frequent urination. Mellitus (sweet urine), Insipidus (unsweetened)!

Question 2

Oral Glucose Tolerance Test

Answer 2

Determines the rate of glucose removal from blood.

Patients fast (10-16 h), drinks 1.75 g glucose/kg body weight with maximum of 75 g in five minutes.

Blood glucose concentrations are determined (mg/dl) before glucose consumption and at intervals thereafter.

Fasting blood glucose of > 126 mg/dl suggests diabetes.

After 2 hours OGTT levels between 140 and 200 mg/dl indicate impaired tolerance, > 200 confirms diabetes.

Question 3

Diabetes Insipidus

Answer 3

Diabetes Insipidus – Characterized by excessive thirst and excretion of large amount of dilute urine. Results from malfunction of the vasopressin/antidiuretic hormone system
Both are characterized by frequent urination. Mellitus (sweet urine), Insipidus (unsweetened)!

Question 4

Type of diabetes characterized by excessive thirst and excretion of large amount of dilute urine. Results from malfunction of the vasopressin/antidiuretic hormone system

Answer 4

Diabetes Insipidus

Question 5

Type of diabetes that is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces.
Uncontrolled diabetes results in very high blood glucose concentrations
Both are characterized by frequent urination. Mellitus (sweet urine), Insipidus (unsweetened)!

Answer 5

Diabetes mellitus

Question 6

Difference between type I and type II diabetes

Answer 6

Type I diabetes – Develops when the body produces little or no insulin.

Type II diabetes – Develops when the body becomes resistant to insulin.

Question 7

Type I diabetes

Answer 7

Previously called insulin-dependent (IDDM) or juvenile-onset diabetes.
Develops when the body’s immune system destroys pancreatic beta cells (insulin producers).
Accounts for 5% to 10% of diagnosed cases.
Usually strikes children and young adults.
No known way to prevent or cure.
Treated with injected insulin by syringe or pump.

Question 8

Type II diabetes

Answer 8

Previously called insulin-independent (IIDM) or adult-onset diabetes.
Accounts for 90% of all cases of diabetes.
Begins as insulin resistance.
As the need for insulin rises, the pancreas gradually loses ability to produce it.
Associated with older age, obesity, family history of diabetes, history of physical inactivity, and race.
Exercise and losing weight reduce chance of developing Type II diabetes and improve outcome.
Treated with injected insulin or other drugs.

Question 9

Insulin-dependent diabetes

Answer 9

Type I diabetes
Previously called insulin-dependent (IDDM) or juvenile-onset diabetes.
Develops when the body’s immune system destroys pancreatic beta cells (insulin producers).
Accounts for 5% to 10% of diagnosed cases.
Usually strikes children and young adults.
No known way to prevent or cure.
Treated with injected insulin by syringe or pump.

Question 10

Insulin-independent diabetes

Answer 10

Type II diabetes
Previously called insulin-independent (IIDM) or adult-onset diabetes.
Accounts for 90% of all cases of diabetes.
Begins as insulin resistance.
As the need for insulin rises, the pancreas gradually loses ability to produce it.
Associated with older age, obesity, family history of diabetes, history of physical inactivity, and race.
Exercise and losing weight reduce chance of developing Type II diabetes and improve outcome.
Treated with injected insulin or other drugs.

Question 11

Type I vs Type II diabetes cause

Answer 11

Type I: Results from autoimmune destruction of beta cells

Type II: Results from insulin resistance and impaired insulin secretion

Question 12

Type I vs Type II diabetes age of onset

Answer 12

Type I: Usually in children

Type II: Usually in adulthood

Question 13

Type I vs Type II diabetes insulin requirements

Answer 13

Type I: Die without insulin due to ketoacidosis (increased ketobodies which acidify blood)
Type II: Usually can survive without insulin

Question 14

Why does a diabetic patient urinate frequently?

Answer 14

The body tries to get rid of glucose through the urine in the kidneys, and glucose is highly solvated and so brings much water with it

Question 15

Symptoms of diabetes mellitus

Answer 15

Frequent urination (body tries to rid blood of high glucose through urine, brings water with it) (Renal threshold ~170 mg/dl).
Excessive thirst (body tries to dilute excess glucose with water).
Extreme hunger.
Unusual weight loss
Increased fatigue
Irritability
Blurred vision (glucose attacks and modifies lens proteins)

Question 16

What fasting blood glucose level indicates possible diabetes?

Answer 16

126 mg/dl suggests diabetes

Question 17

What blood glucose level two hours after administration of an oral glucose tolerance test indicate diabetes?

Answer 17

After 2 hours OGTT levels between 140 and 200 mg/dl indicate impaired tolerance, > 200 mg/dl confirms diabetes.

Question 18

endosome

Answer 18

In cell biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway originating from the plasma membrane. Molecules or ligands internalized from the plasma membrane can follow this pathway all the way to lysosomes for degradation, or they can be recycled back to the plasma membrane. Molecules are also transported to endosomes from the trans-Golgi network and either continue to lysosomes or recycle back to the Golgi. Endosomes represent a major sorting compartment of the endomembrane system in cells.

Question 19

What enzyme mediates glucose uptake?

Answer 19

Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose over a plasma membrane. Because glucose is a vital source of energy for all life, these transporters are present in all phyla. The GLUT or SLC2A family are a protein family that is found in most mammalian cells. 12 GLUTS are encoded by human genome. GLUT is a type of uniporter transporter protein.

Question 20

What enzyme mediates glucose uptake in response to insulin?

Answer 20

GLUT4
Found in adipose tissues and striated muscle (skeletal muscle and cardiac muscle), it is the insulin-regulated glucose transporter. Responsible for insulin-regulated glucose storage.

Question 21

Where are GLUT4 enzymes “stored”?

Answer 21

Inside the cell in cell membrane vesicles

Question 22

What happens in the cell in response to insulin?

Answer 22

The insulin binds to the insulin receptor, which causes vesicles with embedded GLUT4 glucose transporters to fuse with the membrane, increasing uptake of glucose into the cell

Question 23

What happens in the cell in response to low insulin?

Answer 23

Parts of the plasma membrane containing GLUT4 glucose transporters are pinched off via endocytosis to form vesicles

Question 24

What is the ciclic pathway of GLUT4 carrying vesicles inside the cell?

Answer 24

small vesicles carrying GLUT4 fuse with the membrane in response to higher insulin levels. When insulin drops, endocytosis of parts of the membrane with GLUT4 reforms the small vesicles. These vesicles fuse with the endosome for recycling. New small vesicles with GLUT4 bud off the endosome, ready to be reincorporated into the membrane in response to insulin.

Question 25

Where is insulin produced?

Answer 25

in β endocrine cells of the pancreas

The pancreas contains:
exocrine cells, which secrete digestive enzymes in the form of zymogens

endocrine cells in clusters, the islets of Langerhans. The islets contain α, β , and δ cells (also known as A, B, and D cells, respectively), α cells produce glucagon; β cells, insulin; and δ cells, somatostatin

Question 26

Increased insulin levels do what to glucose uptake in muscle and adipose tissue, and this is accomplished by effecting what enzyme?

Answer 26

insulin increases glucose uptake in muscle and adipose tissue by increasing the surface expression of GLUT4 glucose transporters (fusing small vesicles with membrane)

Question 27

Increased insulin levels do what to glucose uptake in the liver, and this is accomplished by effecting what enzyme?

Answer 27

insulin increases glucose uptake in the liver by increasing activity of hexokinase IV (aka glucokinase, phosphorylates glucose to glucose-6-phosphate when glucose levels are high: 4–10 mmol/L (72–180 mg/dl)

Question 28

Increased insulin levels do what to glycogen synthesis in liver and muscle, and this is accomplished by effecting what enzyme?

Answer 28

Insulin increases glycogen synthesis in liver and muscle by promoting a net decrease in the extent of phosphorylation of glycogen synthase, the rate-limiting enzyme in the pathway of glycogen synthesis, which increases its activity.

Question 29

Increased insulin levels do what to glycogen breakdown in the liver and muscle, and this is accomplished by effecting what enzyme?

Answer 29

Insulin decreases glycogen breakdown in liver and muscle by indirectly dephosphorylating glycogen phosphorylase a, reforming the inactive glycogen phosphorylase b. Insulin indirectly activates a phosphodiesterase that converts cAMP to AMP. This activity removes the second messenger (generated by glucagon and epinephrine) and inhibits PKA. In this manner, PKA can no longer cause the phosphorylation cascade that ends with formation of (active) glycogen phosphorylase a. These modifications initiated by insulin end glycogenolysis in order to preserve what glycogen stores are left in the cell and trigger glycogenesis (rebuilding of glycogen).

Question 30

Key differences between hexokinase I-III and hexokinase IV

Answer 30

Hexokinases I, II, and III are referred to as "low-Km" isozymes because of a high affinity for glucose (below 1 mM). Hexokinases I and II follow Michaelis-Menten kinetics at physiologic concentrations of substrates. All three are strongly inhibited by their product, glucose-6-phosphate. Molecular weights are around 100 kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites.
Hexokinase IV (glucokinase) can only phosphorylate glucose if the concentration of this substrate is high enough; its Km for glucose is 100 times higher than that of hexokinases I, II, and III. Hexokinase IV is monomeric, about 50kD, displays positive cooperativity with glucose, and is not allosterically inhibited by its product, glucose-6-phosphate.

Question 31

Glycogen phosphorylase

Answer 31

Glycogen phosphorylase breaks up glycogen into glucose subunits:

(α-1,4 glycogen chain)n + Pi ⇌ (α-1,4 glycogen chain)n-1 + α-D-glucose-1-phosphate.

Glycogen is left with one fewer glucose molecule, and the free glucose molecule is in the form of glucose-1-phosphate. In order to be used for metabolism, it must be converted to glucose-6-phosphate by the enzyme phosphoglucomutase.

Although the reaction is reversible in solution, within the cell the enzyme only works in the forward direction as shown below because the concentration of inorganic phosphate is much higher than that of glucose-1-phosphate.

Question 32

Increased insulin levels do what to glycolysis in the liver and muscle, and this is accomplished by effecting what enzyme?

Answer 32

Insulin activates glycolysis in the liver and muscle by activating protein phosphatase, which dephosphorylates the PFK-2 complex and causes its PFK2 activity to be favoured over its FBPase2 activity; via Protein Phosphatase and PFK2, insulin increases [F-2,6-BP], which activates glycolysis by allosteric activation of PFK1, signalling an abundance of glucose

Question 33

Increased insulin levels do what to Acetyl-CoA synthesis in the liver and muscle, and this is accomplished by effecting what enzyme?

Answer 33

Insulin increases Acetyl-CoA synthesis in liver and muscle cells by indirectly dephosphorylating E1 of pyruvate dehydrogenase the first enzyme (and rate-limiting) of the pyruvate dehydrogenase complex, which activates it.
The pyruvate dehydrogenase complex contributes to transforming pyruvate into acetyl-CoA by a process called pyruvate decarboxylation (Swanson Conversion). Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, so pyruvate dehydrogenase contributes to linking the glycolysis metabolic pathway to the citric acid cycle and releasing energy via NADH.

Question 34

Increased insulin levels do what to fatty acid synthesis in the liver, and this is accomplished by effecting what enzyme?

Answer 34

Insulin increases fatty acid synthesis in the liver by activating acetyl-CoA carboxylase

Question 35

Increased insulin levels do what to triacylglycerol synthesis in adipose tissue, and this is accomplished by effecting what enzyme?

Answer 35

Increases triaceylglycerol synthesis in adipose tissue by activating lipoprotein lipase. LPL isozymes are regulated differently depending on the tissue. For example, insulin is known to activate LPL in adipocytes and its placement in the capillary endothelium. By contrast, insulin has been shown to decrease expression of muscle LPL. Muscle and myocardial LPL is instead activated by glucagon and adrenaline. This helps to explain why during fasting, LPL activity increases in muscle tissue and decreases in adipose tissue, whereas after a meal, the opposite occurs.

Question 36

Increased insulin levels do what to lipolysis?

Answer 36

Insulin increases inhibit lipolysis (breakdown of TAGs) resulting in a net increase of lipids

Question 37

glycation

Answer 37

Glycation (sometimes called non-enzymatic glycosylation) is the result of typically covalent bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme.

Class specific: formation of a Schiff Base (R2C=NR’ (R’ ≠ H)) by reaction of glucose with lysine (Lys, K) residues of proteins.

All blood sugars are reducing molecules. Enzyme-controlled addition of sugars to protein or lipid molecules is termed glycosylation; glycation is a haphazard process that impairs the functioning of biomolecules, whereas glycosylation occurs at defined sites on the target molecule and is required in order for the molecule to function.

Question 38

polyol pathway in terms of diabetes

Answer 38

Glucose -> Sorbitol -> Fructose
Also called the sorbitol-aldose reductase pathway, the polyol pathway appears to be implicated in diabetic complications, especially in microvascular damage to the retina, kidney, and nerves.

Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues.

While most cells require the action of insulin for glucose to gain entry into the cell, the cells of the retina, kidney, and nervous tissues are insulin-independent, so glucose moves freely across the cell membrane, regardless of the action of insulin. The cells will use glucose for energy as normal, and any glucose not used for energy will enter the polyol pathway. When blood glucose is normal (about 100 mg/dl or 5.5 mmol/l), this interchange causes no problems, as aldose reductase has a low affinity for glucose at normal concentrations.

In a hyperglycemic state, the affinity of aldose reductase for glucose rises, causing much sorbitol to accumulate, and using much more NADPH, leaving less NADPH for other processes of cellular metabolism.[5] This change of affinity is what is meant by activation of the pathway. The amount of sorbitol that accumulates, however, may not be sufficient to cause osmotic influx of water.

NADPH acts to promote nitric oxide and glutathione production, and its deficiency will cause glutathione deficiency as well. A glutathione deficiency, congenital or acquired, can lead to hemolysis caused by oxidative stress. Nitric oxide is one of the important vasodilators in blood vessels. Therefore, NADPH prevents reactive oxygen species from accumulating and damaging cells.

Excessive activation of the polyol pathway increases intracellular and extracellular sorbitol concentrations, increased concentrations of reactive oxygen species, and decreased concentrations of nitric oxide and glutathione. Each of these imbalances can damage cells; in diabetes there are several acting together. It has not been conclusively determined that activating the polyol pathway damages microvasculature.

Question 39

Glucometer

Answer 39

Glucose measuring device. Determines blood glucose concentrations at that moment. Changes rapidly.

Question 40

Hemoglobin A1c

Answer 40

Glycated hemoglobin (hemoglobin A1c, HbA1c, A1C, or Hb1c; sometimes also HbA1c or HGBA1C) is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods. It is formed in a non-enzymatic glycation pathway by hemoglobin’s exposure to plasma glucose. HbA1c is a measure of the beta-N-1-deoxy fructosyl component of hemoglobin. Normal levels of glucose produce a normal amount of glycated hemoglobin. As the average amount of plasma glucose increases, the fraction of glycated hemoglobin increases in a predictable way. This serves as a marker for average blood glucose levels over the previous 3 months (but past 2 weeks most important) prior to the measurement as this is the lifespan of red blood cells.

Question 41

What are the ranges for human haemoglobin A1c levels?

Answer 41

Normal 5%, extreme 13%, try to keep below 7%

Question 42

For every ___% reduction in glycodated A1c, ___% decrease in risk of vascular complications.

Answer 42

For every 1% reduction in glycodated A1c, 10% decrease in risk of vascular complications.

Question 43

A1c % to mean blood sugar

Answer 43

A1c (%)	Mean blood sugar (mg/dl)	
6			135	
7			170	
8			205	
9			240	
10			275	
11			310	
12			345

Question 44

What is the favoured hypothesis for why obesity is associated with increases in type II diabetes?

Answer 44

Enlarged adipocytes (due to overeating) produce macrophage chemotaxis protein (MCP-1), causing macrophages from immune system to invade and inflame adipose cells. Macrophages in fat cells produce TNFα which favours fatty acid export from adipocytes to myocyte (muscle), forming ectopic lipid deposits. Ectopic deposits interfere with transport of GLUT4 vesicles to membrane surface, producing insulin resistance.

Question 45

Why is high glucose bad?

Answer 45

Inappropriate glycation of proteins.
During prolonged hyperglycemia, glucose can react nonenzymatically with the NH3 group on the amino terminus of hemoglobin. This form, called HbA1c, can account for more that 12% of the total hemoglobin in a diabetic patient.
Diabetic cataracts are caused by increased glycation of lens proteins, making the lens of the eye cloudy.
Glycated proteins and lipoproteins can be recognized by macrophages, which can lead to accelerated atherosclerosis.
Glycated proteins have altered activities, solubilities, and degradation properties.

Question 46

Effect of insulin resistance in type II diabetes

Answer 46

Patients still make insulin but are “insulin resistant”
Insulin can be present at normal or elevated levels
However, response is impaired. pancreatic β-cells don’t make enough insulin to control glucose synthesis in the liver or to stimulate glucose uptake by skeletal muscle.
Gluconeogenesis occurs in the liver even though there is enough glucose available.
Fatty acid synthesis is also not shut off causing hypertriacylglycerolemia and high VLDL
80-90 % of all cases of diabetes are type 2, many people with type 2 diabetes are undiagnosed

Question 47

sulfonylureas

Answer 47

sulfonylureas: stimulate insulin secretion from b-cells
Glipizide (Glucatrol), oral, once daily
Acts by blocking K+ channels in the β-cells. By partially blocking the K+ channels, the β-cells spends spend more time in the calcium release stage of cell signaling, leading to an increase in calcium. The increase in calcium will initiate more insulin release from each β-cell.

Question 48

metformin

Answer 48

metformin: reduces liver gluconeogenesis
oral, several formulations
reduction of hepatic gluconeogenesis, decreased absorption of glucose from the intestines, and reduced insulin insensitivity
mechanism uncertain
stimulates hepatic enzyme AMP-activated protein kinase
often taken together with thiazolidinediones

Question 49

thiazolidinediones

Answer 49

thiazolidinediones: sensitize peripheral tissues to insulin
Thiazolidinediones or TZDs act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPARγ (gamma). The normal ligands for these receptors are free fatty acids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes regulating glucose and fat metabolism.
Rosiglitazone, oral

Question 50

peroxisome proliferator-activated receptor

Answer 50

In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms.

Question 51

alpha glucosidase inhibitors

Answer 51

alpha glucosidase inhibitors: slow glucose adsorption
Miglitol, oral, take at start of meal
slows the digestion of starch in the small intestine, so that glucose from the starch of a meal enters the bloodstream more slowly, and can be matched more effectively by an impaired insulin response or sensitivity. Effective by themselves only in the earliest stages.

Question 52

What hormone is the pancreas secreting in the “feeding state”?

Answer 52

insulin

Question 53

What hormone is the pancreas secreting in the “fasting (or diabetic) state”?

Answer 53

glucagon

Question 54

Describe the fasting state

Answer 54

The fasting state: the glucogenic liver. After some hours without a meal, the liver becomes the principal source of glucose for the brain. Liver glycogen is broken down, and the glucose 1-phosphate produced is converted to glucose 6-phosphate, then to free glucose, which is released into the bloodstream. Amino acids from the degradation of proteins in liver and muscle, and glycerol from the breakdown of TAGs in adipose tissue, are used for gluconeogenesis. The liver uses fatty acids as its principal fuel, and excess acetyl-CoA is converted to ketone bodies for export to other tissues; the brain is especially dependent on this fuel when glucose is in short supply

Question 55

Describe the feeding state

Answer 55

The well-fed state: the lipogenic liver. Immediately after a calorie-rich meal, glucose, fatty acids, and amino acids enter the liver. Insulin released in response to the high blood glucose concentration stimulates glucose uptake by the tissues. Some glucose is exported to the brain for its energy needs, and some to adipose and muscle tissue. In the liver, excess glucose is oxidized to acetyl-CoA, which is used to synthesize fatty acids for export as triacylglycerols in VLDLs to adipose and muscle tissue. The NADPH necessary for lipid synthesis is obtained by oxidation of glucose in the pentose phosphate pathway. Excess amino acids are converted to pyruvate and acetyl-CoA, which are also used for lipid synthesis. Dietary fats move via the lymphatic system, as chylomicrons, from the intestine to muscle and adipose tissues.

Question 56

Increased glucagon levels do what to glycogen breakdown in the liver, and this is accomplished by effecting what enzyme?

Answer 56

Increased glucagon levels increase the breakdown of glycogen to glucose in the liver. Like epinephrine, glucagon stimulates the net breakdown of liver glycogen by activating glycogen phosphorylase (catabolic) and inactivating glycogen synthase (anabolic); both effects are the result of phosphorylation of the regulated enzymes, triggered by cAMP.

Question 57

Increased glucagon levels do what to glycogen synthesis in the liver, and this is accomplished by effecting what enzyme?

Answer 57

Increased glucagon levels decrease glycogen synthesis in the liver. Like epinephrine, glucagon stimulates the net breakdown of liver glycogen by activating glycogen phosphorylase (catabolic) and inactivating glycogen synthase (anabolic); both effects are the result of phosphorylation of the regulated enzymes, triggered by cAMP.

Question 58

Increased glucagon levels do what to glycolysis in the liver, and this is accomplished by effecting what enzyme?

Answer 58

Glucagon inhibits glucose breakdown by glycolysis in the liver, resulting from an increased amount of cAMP which activates PKA. Protein kinase A inactivates the PFK-2 domain of the bifunctional enzyme via phosphorylation, however this does not occur in skeletal muscle. The F-2,6-BPase domain is then activated which lowers fructose 2,6-bisphosphate (F-2,6-BP) levels. Because F-2,6-BP normally stimulates phosphofructokinase-1(PFK1), the decrease in its concentration leads to the inhibition of glycolysis and the stimulation of gluconeogenesis.

Question 59

Increased glucagon levels do what to gluconeogenesis from amino acids in the liver, and this is accomplished by effecting what enzyme?

Answer 59

Glucagon stimulates glucose synthesis from amino acids in the liver by lowering the concentration of fructose 2,6-bisphosphate, an allosteric inhibitor of the gluconeogenic enzyme fructose 1,6-bisphosphatase (FBPase-1). Recall that [fructose 2,6-bisphosphate] is ultimately controlled by a cAMP-dependent protein phosphorylation reaction.

Question 60

Increased glucagon levels do what to fatty acid mobilisation in the adipose tissue, and this is accomplished by effecting what enzyme?

Answer 60

Although its primary target is the liver, glucagon (like epinephrine) also affects adipose tissue, activating TAG breakdown by causing cAMP-dependent phosphorylation of perilipin and hormone-sensitive lipase. The activated lipase liberates free fatty acids, which are exported to the liver and other tissues as fuel, sparing glucose for the brain. The net effect of glucagon is therefore to stimulate glucose synthesis and release by the liver and to mobilize fatty acids from adipose tissue, to be used instead of glucose by tissues other than the brain. All these effects of glucagon are mediated by cAMP-dependent protein phosphorylation.

Question 61

Increased glucagon levels do what to ketogenesis, and this is accomplished by effecting what enzyme?

Answer 61

Fatty acids are oxidized to acetyl-CoA, but as oxaloacete is depleted by the use of citric acid cycle intermediates for gluconeogenesis, entry of acetyl-CoA into the cycle is inhibited and acetyl-CoA accumulates. This favours the formation of acetoacetyl-CoA and ketone bodies. After a few days of fasting, the levels of ketone bodies in the blood rise as they are exported from the liver to the heart, skeletal muscle, and brain, which use these fuels instead of glucose

Question 62

What hormone besides glucagon is elevated in the “fasting (diabetic) state”

Answer 62

epinephrin

Question 63

Increased glucagon levels do what to gluconeogenesis from oxaloacetate in the liver, and this is accomplished by effecting what enzyme?

Answer 63

Glucagon stimulates glucose synthesis from oxaloacetate by gluconeogenesis in the liver by stimulating of the synthesis of the gluconeogenic enzyme PEP carboxykinase.

Question 64

Increased glucagon levels do what to gluconeogenesis from glycerol in the liver, and this is accomplished by effecting what enzyme?

Answer 64

Glucagon stimulates glucose synthesis from glycerol by gluconeogenesis in the liver by inhibiting the glycolytic enzyme pyruvate kinase (by promoting its cAMP-dependent phosphorylation), thus blocking the conversion of phosphoenolpyruvate to pyruvate and preventing oxidation of pyruvate via the citric acid cycle. The resulting accumulation of phosphoenolpyruvate favours gluconeogenesis.

Question 65

explain the mobilisation of triacylglycerols stored in adipose tissue

Answer 65

Mobilisation of triacylglycerols stored in adipose tissue: When low levels of glucose in the blood trigger the release of glucagon, (1) the hormone binds its receptor in the adipocyte membrane and thus (2) stimulates adenylyl cyclase, via a G protein, to produce cAMP. This activates PKA, which phosphorylates (3) the hormone-sensitive lipase and (4) perilipin molecules on the surface of the lipid droplet. Phosphorylation of perilipin permits hormone-sensitive lipase access to the surface of the lipid droplet, where (5) it hydrolyzes triacylglycerols to free fatty acids. (6) Fatty acids leave the adipocyte, bind serum albumin in the blood, and are carried in the blood; they are released from the albumin and (7) enter a myocyte (muscle cell) via a specific fatty acid transporter. (8) In the myocyte, fatty acids are oxidized to CO2 (β-oxidation, TCA, respiration), and the energy of oxidation is conserved in ATP, which fuels muscle contraction and other energy-requiring metabolism in the myocyte.

Question 66

How does glucose regulate insulin secretion in b cells?

Answer 66

When the blood glucose level is high, glucose enters the pancreatic β-cell through GLUT2 and is phosphorylated by hexokinase IV (high Km, affinity 4–10 mM (72–180 mg/dl)) for entry into glycolysis, raising intracellular [ATP], closing K+ channels in the plasma membrane and thus depolarizing the membrane. In response to the change in membrane potential, voltage-gated Ca(2+) channels open, allowing Ca(2+) to flow into the cell. (Ca(2+) is also released from the endoplasmic reticulum, in response to the initial elevation of (Ca2+) in the cytosol.) Cytosolic [Ca(2+)] is now high enough to trigger insulin release by exocytosis. The numbered processes are discussed in the text.

Question 67

How do sulfonylurea drugs work?

Answer 67

Sulfonylureas bind to an ATP-sensitive K+(KATP) channel on the cell membrane of pancreatic beta cells. This inhibits a tonic, hyperpolarizing (Vm more negative) efflux of potassium, thus causing the electric potential over the membrane to become more positive (Vm approaching negative 0). This depolarization opens voltage-gated Ca(2+) channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro)insulin

Question 68

How is insulin secretion controlled in pancreatic beta cells?

Answer 68

Voltage-gated calcium channels and ATP-sensitive potassium ion channels are embedded in the cell surface membrane of beta cells. These ATP-sensitive potassium ion channels are normally open and the calcium ion channels are normally closed. Potassium ions diffuse out of the cell, down their concentration gradient, making the inside of the cell more negative with respect to the outside (as potassium ions carry a positive charge). At rest, this creates a potential difference across the cell surface membrane of -70mV.

When the glucose concentration outside the cell is high, glucose molecules move into the cell by facilitated diffusion, down its concentration gradient through the GLUT2 transporter. Since beta cells use glucokinase to catalyze the first step of glycolysis, metabolism only occurs around physiological blood glucose levels and above. Metabolism of the glucose produces ATP, which increases the ATP to ADP ratio.

The ATP-sensitive potassium ion channels close when this ratio rises. This means that potassium ions can no longer diffuse out of the cell. As a result, the potential difference across the membrane becomes more positive (as potassium ions accumulate inside the cell). This change in potential difference opens the voltage-gated calcium channels, which allows calcium ions from outside the cell to diffuse in down their concentration gradient. When the calcium ions enter the cell, they cause vesicles containing insulin to move to, and fuse with, the cell surface membrane, releasing insulin by exocytosis.

Question 69

Hypoglycemia

Answer 69

Hypoglycemia – Low blood sugar. Happens very fast - minutes to hours when too much insulin is injected. Can lead to coma and death.

Question 70

Diabetic Ketoacidosis

Answer 70

Diabetic Ketoacidosis – Ketoacidosis causes dehydration, labored breathing, coma and death. Happens more slowly, many hours to days. More often in type I because in type 2 insulin is inhibiting lipolysis (fat breakdown) and beta oxidation (production of acetyl-CoA from fat).

Question 71

Common chronic diabetic complications

Answer 71

Cardiovascular disease and stroke (2-4 times higher in diabetics). Smoking makes much worse.

High blood pressure (Hypertension) – Most diabetics have high blood pressure.

Blindness (Diabetic retinopathy) – most common reason for blindness in working age.

Chronic renal disease (kidney failure) – 10 -20% of diabetic have nephropathy. Diabetes is the leading cause of end-stage renal disease.

Nerve Disease (Peripheral neuropathy) - 60 – 70% of diabetics have impaired sensation or pain in hands or feet.

Amputations - Most common reason for non-traumatic amputations – usually toes, feet, etc.