case 7: type 1 diabetes mellitus

Question 1

Diagnosis Standard for DM

Answer 1

– Guideline from American Diabetes Association (ADA)
* Diabetes
– Fasting plasma glucose ≥ 126 mg/dl (7.0 mmol/l) or
– or 2-hr plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during an oral
glucose tolerance test
– or a random plasma glucose ≥ 200 mg/dl (11.1 mmol/l)
– or Hb A1C ≥ 6.5%
– Q – What is A1C? Why is it an important indicator?
– Pre-diabetes – 100-125 mg/dl; normal – less than 100
mg/dl (from ADA)

Question 2

The Endocrine Pancreas

Answer 2

• Islets of Langerhans
  – β cells – 60%, secrete insulin
  – α cells – 25%, secrete
  glucagon
  – δ cells – somatostatin
• Pancreatic H regulate blood-
  glucose levels & influence
  cellular metabolism
  – Insulin -> (pure) anabolism
  – Glucagon -> (pure) catabolism
  – Target tissues – liver, skeletal
  muscle, adipocytes

Question 3

The Insulin Receptor – a RTK

Answer 3

• The insulin R is a type of receptor tyrosine kinases (RTK), the most
  prevalent enzyme-linked cell surface R
• 2 insulins binds to 2 RTK -> RTK dimerization -> RTK phosphorylation to
  tyrosine residues
• Insulin-RTK-Pi (phosphorylated RTK) -> induces cascade of reactions ->
  glucose uptake & anabolic effect

Question 4

Insulin – Mechanisms of Action

Answer 4

• High blood glucose levels ->
  increase insulin secretion
• -> insulin-R activation at
  target tissues
• -> increase insertion of glucose
  transporters 4 (recruitment
  of GLUT4) to cell membrane
  of insulin-sensitive cells
  (cardiac, skeletal muscle
  and adipocytes)
• GLUT4 – determinant of
  glucose homeostasis

Question 5

Metabolism and Hormones

Answer 5

• The body’s transition between
  anabolism and catabolism is
  mainly regulated by hormones:
  – Absorptive state – increase insulin
  secretion
  – Postabsorptive state – increase
  glucagon secretion
• Balance between anabolism and
  catabolism:
  – Antagonistic effects of insulin,
  glucagon, GH, T3, cortisol, and
  Epi balance anabolism and
  catabolism

Question 6

Absorptive State

Answer 6

• Absorptive state – overabundant of energy substrates -> increase insulin secretion
• Overall strategy – to lower blood levels of energy substrate (glucose, amino acids and fatty acids)
• When blood [insulin] increases -> increase anabolism and decrease catabolism
  – increase Insertion of glucose transporters 4 on skeletal, cardiac muscles & fat tissue
• increase Cellular uptake of glucose
  – increase Glycogenesis – increase entry of glucose into liver & skeletal muscle cells → increase glycogen storage
  – increase Lipogenesis – increase neutral fat in adipose cells
  – increase Cellular uptake of amino acids → increase proteins synthesis

Question 7

Postabsorptive State

Answer 7

• Postabsorptive state → decrease blood levels of glucose & fatty acids
• Overall strategy – to maintain blood glucose & fatty acids (why?) cells still need energy substrate for metabolic needs
• Low blood glucose & fatty acids → increase glucagon secretion:
  – → increase Glycogenolysis in the liver → increase blood glucose levels
  – Also → increase lipolysis (neutral fat to acid glycerol/fatty acid) → increase blood fatty acid levels (skeletal muscle, heart, liver, & kidneys use fatty acids as major source of fuel)
• increase Gluconeogenesis (non-carbohydrates into glucose) (starting in postabsorptive state) & ketogenesis (starting in mid- to long-term starvation)

protein degradation -> protein to amino acid

Question 8

Control of the Blood Glucose

Answer 8

• Absorptive state – increase blood [glucose] (main effect), increase blood [amino acid] → increase insulin secretion
  – Blood [glucose] increase → glucose binds to glucose transporter GLUT2 in β cells (GLUT2 is not insulin-regulated) → increase insulin secretion → glucose enters cells
  – Normal fasting [glucose] is 65–100 mg/dl
  – Insulin and glucagon normally prevent levels from rising above 170 mg/dl or falling below 50 mg/dl
• Post-absorptive or stressful state – increase glucagon
  – increase Glucagon secretion occurs only when decrease blood [glucose]
• Meals with high proteins and low in carbohydrates → increase secretion of both insulin and glucagon

Question 9

Regulation of Insulin & Glucagon

Answer 9

• Effect of autonomic nerves
  – Sympathetic effect - “fight or flight”, enhances glucagon secretion, stress hyperglycemia
  – Parasympathetic effect - “rest and repair”, “+” insulin
• Effect of hormones
  – Glucose in gut → increase GIP (glucose-dep. insulinotropic peptide, or
  gastric inhibitory peptide) secretion → increase insulin secretion, decrease
  gastric motility
  – Cholecystokinin (CCK) → increase insulin secretion, increase secretion of bile
  and pancreatic digestive enzymes
  – increase Blood glucose, amino acids, fatty acids → increase GLP-1 (glucagon-
  like peptide, incretin) major increase insulin, β cell proliferation & decrease
  appetite (potent anti-hyperglycemic)

Question 10

Type 1 Diabetes Mellitus

Answer 10

• Diabetes mellitus (DM) – chronic increase in blood [glucose]
• Type 1 DM (juvenile-onset, insulin-dependent (ID) DM
  – Occurs mainly at juvenile age, ~5% of DM patients
• Autoimmunity (virus)
  – Killer T cells target glutamate decarboxylase in β cells → β cells
  destroyed (α cells intact) → decrease insulin
• Hyperglycemia due to:
  – Lack of insulin → glucose cannot enter cells through GLUT-4
  – increase Glucagon/insulin ratio → increase glycogenolysis in liver → increase glucose exit
  into blood from liver → hyperglycemia
  – Lack of insulin → rate of lipolysis > rate of lipogenesis → increase fatty acid
  in blood
  – Fatty acids converted to ketone bodies → hyperketonemia →
  ketoacidosis → coma
• Osmotic (due to presence of glucose in urine bc blood glucose levels too high bc filtered from glomerulus and cannot be reabsorbed from filtrate, glucose drags water into filtrate) diuresis (excessive amount of urine production due to osmotic pressure) → glucosuria, dehydration

Question 11

Type 2 Diabetes Mellitus

Answer 11

• Also called non-insulin-dependent (NIDDM)
• Account for 95% of DM patients
• Insulin resistance – cells fail to respond to insulin actions
  – When fat and muscle cells fail to respond adequately to circulating
  insulin, blood glucose levels rise
• Blood [insulin] may be high or normal until late stage
• Slow to develop, genetic factors play a role
• Occurs mostly in mid-age people who are overweight
• Treatment – change in lifestyle:
  – Increase exercise → ↑ GLUT-4 in the skeletal muscle cells
  – Weight reduction – ↑ fiber in diet, ↓ saturated fat
• Diet – ↑ polyunsaturated fatty acids → ↑ cell membrane fluidity →
  ↑ insulin R’ # → ↑ affinity of insulin to its receptors → ↓ insulin resistance (theory)

Question 12

Oral Glucose Tolerance Test

Answer 12

• A person drinks a glucose solution and blood samples are taken periodically
• Normal person’s rise in blood [glucose] after drinking solution is reversed to normal in 2 hrs
• Blood [glucose] levels in DM patients remain > 200 mg/dl 2 hr following glucose ingestion
• The test measures:
  – Ability of β cells to secrete insulin (insulin
  secretion)
  – Ability of insulin to lower blood glucose (insulin- resistance)
• Reactive hypoglycemia
  – Symptoms of hypoglycemia
  – Insulin injections → insulin shock

right upper figure: y axis is blood glucose level, x axis is time

Question 13

Glycated (Glycosylated) Hb

Answer 13

• When blood glucose enters RBC, Hb is non-enzymatically glycated (glycosylated) to lysine residue in the –NH2 terminus
  of proteins/peptides
• The fraction of glycated Hb (HbA1C), normally 3-5%, is proportional to blood glucose levels (as long as blood glucose level is in normal range between 55-99 ml/dl there will be around 3-5% hemoglobin that’s glycosylated)
• Once a Hb molecule is glycosylated, it remains that way until
  its degradation into bilirubin
• The HbA1C level reflects the blood glucose concentration over the preceding ~8 weeks (RBC lifespan is ~120 days) (if person has abnormally high glucose level, the RBCs that have been glycosylated, half will be degraded)(hemoglobin A1c level reflects overall concentration of blood glucose level in past 8 weeks)
• Glycated hemoglobin (HbA1C) has higher O2 binding affinity
  than hemoglobin

Question 14

HbA1C and Diabetes Mellitus

Answer 14

• An elevated blood [HbA1c] indicates poor blood glucose control such as in diabetes mellitus.
• A buildup of glycosylated hemoglobin within the red cell reflects the average level of glucose to which the cell has been exposed during its life cycle.
• Question – Glycosylated hemoglobin [HbA1c] has higher O2 binding affinity than hemoglobin, is it good or bad for O2 transport?

Question 15

Questions

Answer 15

• Glycosylated hemoglobin [HbA1c] has higher O2 binding
  affinity than hemoglobin. This patient’s [HbA1c] is 7.2%
  (normal 3.0-5.6%).
  – Is there a decline in PAO2, PaO2, or PvO2?
  – Is there a decline of the Hb-O2 saturation rate in this patient?
  – Is there a decline of the O2 content in this patient?
  – What are the similarities and differences of (1) anemia; (2) CO poisoning; and (3) abnormally high [HbA1c]

Question 16

Gas Partial Pressures in the Body

Answer 16

PO2 at arterial blood (PaO2) = 100
PO2 at interstitial fluid = 40
PO2 at cytosol = 23
PO2 at mitochondria = around 0 (mm Hg)
- mitochondria usually very efficient at using O2, so very little there bc what is present is being used for oxidative phosphorylation

Question 17

Diffusion Rates & Diffusion Capacity

Answer 17

• Diffusion rate (Fick’s Law )
  – The net diffusion rate of a gas
  across a membrane over time
  – Is proportional to the surface area of
  the membrane, proportional to the P
  gradient and inversely proportional
  to the thickness of the membrane
  – V̇̇ gas = (A/T) * D * (P1 - P2)
• A = tissue surface area; T =
  tissue thickness (< 0.5 μm)
• D = diffusion constant of a gas
• P1-P2 = P gradient across the
  tissue barriers
• D  (solubility of gas/square root m.w.)
• Diffusing capacity of lungs – DL = (A/T) . (P1-P2) (ml/min/mm Hg)
  – DL varies among individuals

diffusion capacity is proportional to surface area and inverse to thickness of diffusion barrier

diffusion capacity is proportional to diffusion gradient (higher pressure gradient, the easier it is for net diffusion from barrier to occur)
fresh air contains higher po2 which generates higher pressure gradient

as long as diffusion barrier is normal, diffusion is not a problem

Question 18

The Concept of “Dissolved O2”

Answer 18

• Gases can exist in either in gas phase or in liquid
  phase (dissolved in blood plasma)
• Dissolved gas molecules also exert partial P.
•  Gas molecules dissolves in blood plasma  
  [gas] in blood plasma   P
• At equilibrium, the # of gas molecules entering
  (dissolving in) the plasma equals the # of gas
  molecules leaving the plasma to air phase
• At equilibrium does not mean that the # of gas
  molecules (concentration) in the air and the
  liquid are equal
• At equilibrium
  – PAO2 (gas phase) = 100 mm Hg
  – PaO2 (liquid phase) = 100 mm Hg

Question 19

The Concept of “Dissolved O2”

Answer 19

• Gases can exist in either in gas phase or in liquid
  phase (dissolved in blood plasma)
• Dissolved gas molecules also exert partial P.
• ↑ Gas molecules dissolves in blood plasma → ↑ [gas] in blood plasma → ↑ P
• At equilibrium, the # of gas molecules entering
  (dissolving in) the plasma equals the # of gas
  molecules leaving the plasma to air phase
• At equilibrium does not mean that the # of gas
  molecules (concentration) in the air and the
  liquid are equal
• At equilibrium
  – PAO2 (gas phase) = 100 mm Hg
  – PaO2 (liquid phase) = 100 mm Hg

Question 20

P Gradient and O2 Transport

Answer 20

• In lungs – PAO2 (105 mm Hg) > PvO2
  (40 mm Hg) → net diffusion from
  alveoli to blood → PaO2 (95-100 mm
  Hg) → most dissolved O2 diffuse from
  plasma to RBC cytosol (40 mm Hg) →
  O2 binding to Hb
• In peripheral tissues – PaO2 in plasma
  (95-100 mm Hg) > PO2 in interstitial
  fluid (IF, 40 mm Hg) → dissolved O2
  diffuse from plasma to IF → ↓ PO2 in
  blood plasma → O2 is released from
  Hb to plasma → dissolved O2 to
  tissue cells

Question 21

Hb-O2 Dissociation Curve

Answer 21

• X-axis denotes PO2 (mm Hg), Y-axis denotes O2 saturation rate (%) or O2
  content (ml O2 /dl blood)
• (Left panel) → The higher the PO2, the higher Hb-O2 saturation rate
• (Right panel) → The curve of “total” and the curve of Hb-bound almost
  overlap, why?
• greater the O2 content is because of O2 associated w hemoglobin
• dissolved accounts for very very small amount in terms of total O2 content
• total amount of o2 carried in blood, one bound to Hb accounts for 98%

po2 determines O2 content
change of po2 determine O2 saturation rate

o2 content= total amount of o2 carried in blood, transported as dissolved o2 + o2 associated with Hb

Question 22

Hb-O2 Dissociation Curve and [Hb]

Answer 22

• The effects of Hb concentrations on the Hb-O2 dissociation curve
  – (Left panel) – → in [Hb] → ↑ in O2 content
  – (Right panel) – → in [Hb] → no ↑ in Hb saturation rate
• Hb saturation rate depends on PO2, NOT Hb concentrations
• In patients with anemia → ↓ O2 content, no change in Hb saturation
  rate (assuming diffusion capacity is normal)

left figure: higher hemoglobin concentration, higher the O2 content bc the more hemoglobin available more O2 bound?)
- o2 content depends on Hb saturation rate

right figure: higher hemoglobin concentration, higher O2 content BUT if you measure hemoglobin saturation at same po2, regardless hemoglobin at saturation rate it’s all the same around 98%, so saturation rate of hemoglobin w O2 affected by po2 is not affected by hb concentration
as long as diffusion barrier is normal, saturation rate will be the same

Question 23

Can You Answer the Questions below?

Answer 23

• Glycosylated hemoglobin [HbA1c] has higher O2 binding
  affinity than hemoglobin. This patient’s [HbA1c] is 7.2%
  (normal 4.0-5.6%).
  – Is there a decline in PAO2 (as long as diffusion barrier and inspiratory muscles are normal it should be high), PaO2 (100 mm Hg), or PvO2(40 mm Hg)?
  – Is there a decline of the Hb-O2 saturation rate in this patient? no as long as PaO2 is normal
  – Is there a decline of the O2 content in this patient? as long as Hb is normal then O2 is normal
• What are the similarities and differences of (1) anemia; (2) CO poisoning; and (3) abnormally high [HbA1c]?
  1. anemia O2 concentration is low
  2. CO poisoning Hb is high but Hb-O2 binding variable is low because it depends on severity of CO, CO already occupies some Hb, then they can no longer bind w O2
  3. high A1c they can bind to O2, so O2 content is not changed, but O2 bound to A1c it’s difficult for that O2 to be unloaded at peripheral tissue, so high O2 content but some can’t be unloaded bc of high percentage of A1c of glycosylated Hb

Question 24

Diagnosis

Answer 24

• From the clinical observations
  – Hyperphagia (polyphagia), polyuria and polydipsia – the big 3 diabetes signs
• From the lab test:
  – ↑ Blood glucose, ↑ blood ketone bodies and ↑ blood HbA1C
  – ↑ Urine glucose and ↑ urine ketone bodies
  – Almost undetectable blood insulin level
• Diagnosis – diabetes mellitus (DM)
  – Which type (1 or 2) of DM?

Question 25

Diabetes Mellitus – Introduction

Answer 25

• Diabetes – (Greek) siphon, or passing through (kidneys)
• Diabetes mellitus – excessive sweet urine
  – A group of diseases that affect how your body uses blood glucose
  – A group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion,
  insulin action, or both
  – Consequences – the chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of
  various organs, especially the eyes (blindness), kidneys (renal failure), nerves (neuropathy) , heart (congestive heart failure), and blood vessels (complications)
• Diabetes insipidus – flat urine, social disorder

Question 27

The Arrangement of Catabolism

Answer 27

• The fuel substrates (energy substrates)
  – Central fuel substrate – glucose (glc)
  – Other sources include monosaccharides, fatty acids, and amino acids
• The furnace
  – Glycolysis – first and fast but low yield (2 ATP)
• Does NOT require O2
• Accumulate of pyruvate/lactate without going to the next step (TCA cycle) may alter pH (acidosis)
  – Main one – TCA (Kreb) cycle, slow but fruitful (each molecule of pyruvate or acetyl CoA can generate 38 ATP)
  – Acetyl-CoA enters TCA cycle in mitochondria, oxidized to CO2 + H2O, and produces ATP

Question 28

Glucose – Tissue Requirements

Answer 28

• Brain – glucose is the preferred energy source except in prolonged starvation (uses ketone bodies)
• RBCs have an absolute requirement for glucose. Why? (mature RBCs do not contain mitochondria or nucleus, without mitochondria they cannot go through TCA cycle, oxidative phosphorylation, or electron transport chain so they have to use glycolysis to generate energy in RBCs, cannot use acetyl CoA since it eventually needs O2)
• Muscle cells:
  – White muscle fibers use glucose for
  anaerobic glycolysis
  – Red muscle fibers (rich in myoglobins for O2 binding) rely mainly
  on fatty acids (yields more energy than glucose, and has low hydrocarbon chain, every 2 hydrocarbon chain forms 1 acetyl CoA through beta oxidation) (at rest) and glucose (during exercise). Why? during exercise, individual needs more ATP sooner, using fatty acid is slower and glucose is faster
• Adipose tissue – glucose is used for:
  – Lipid synthesis (generation of NADPH & glycerol as substrates)
• Lactation results in a heavy glucose demand. Why? in order to form lactose, glucose is needed to be converted to lactose
• Fetus has a heavy glucose demand. Why? fetus can use glucose through glycolysis, it’s not as well established as most enzymes required for krebs cycle, oxidative phosphorylation, and ETC fetus cannot use acetyl CoA as easy as glucose

Question 29

Glucose Transporters

Answer 29

• Glucose is polar:
  – Cell membranes are impermeable to glucose
  – Transport through biological membranes requires specific transport proteins
• Passive transport
  – Molecule movement by such transporter proteins occurs by facilitated
  diffusion, i.e. energy independent
  – Glucose transporters (GLUTs) – bi-directional, depending on
  concentration gradient (from high conc. to low conc)
• Active transport – co-transporters
  – Transport of glucose through the apical membrane of intestinal and kidney epithelial cells (from low concentration to high requires energy)
  – Sodium-glucose transport proteins (SGLTs) – concentrate glc inside the cells, using the energy provided by cotransport of Na+ down their electrochemical gradient

Question 30

GLUTs

Answer 30

Liver hepatocytes are insulin sensitive but do not contain GLUT4. Why?
Pancreas β cells do NOT have GLUT4. Why?

Question 31

Question – Hyperglycemia is a
chronic disorder, why would
hypoglycemia be so acute and
dangerous?

Answer 31

• Concept – food intake is not 24-7 → body need to :
  – Absorptive state – within 3-4 hours after last meal, anabolism
  – Post-absorptive state – retrieve it quickly in times of want, catabolism

Question 32

The Signals for The Absorptive State

Answer 32

• Insulin – secreted by β cells of
  pancreatic islet of Langerhan
• Glucagon – secreted by α cells of
  pancreatic islet of Langerhan
• Absorptive state – ↑ blood [glc] → ↑
  [insulin], ↓ [glucagon] → ↑
  insulin/glucagon ratio (IG ratio)
  – ↑ Uptake of glc
  – ↑ Glycogenesis in liver & muscle cells
  – ↑ Lipogenesis – ↑ triglyceride storage
  in adipose cells
  – ↑ Cellular uptake of amino acids and
  synthesis of proteins
  glucagon
  insulin

Question 33

The Signals for Post-Absorptive State

Answer 33

• Postabsorptive – ↓ blood [glc] → ↓[insulin], ↑ [glucagon] → ↓ insulin/glucagon ratio
  – ↑ Glycogenolysis
  – ↑ Lipolysis
  – ↑ Protein degradation
  – ↑ Gluconeogenesis – formation of glc from non- carbohydrate sources
  – Starting from short-term starvation – ↑ ketogenesis –
  formation of ketone bodies

Question 34

Glucose Trapping & Glycogenesis

Answer 34

• What is glucose trapping?
  – Intracellular glucose phosphorylated into
  glc-6-P by glucokinase or hexokinase
• Why is glucose trapping necessary?
  – GLUTs transport of glc is bi-directional (with pressure gradient, glucose will always be transported from high to low concentration, when there’s a lot of glucose and transporters into cell, there will be an increase in cytosolic glucose)
  – Intracellular [glc] → osmotic pressure
  – Once glc → glc-6-P (cannot pass through
  GLUTs)
• Cellular uses of gIc-6-P
  – Glycolysis
  – Glycogenesis and glycogenolysis (in liver & skeletal muscle)
  – The uronic acid pathway (hepatic conjugation of endogenous and
  exogenous lipophilic compounds)
  – Triose phosphates (glycerol for triglyceride & phospholipids)
  – The hexose monophosphate shunt (HMS) → NADPH

glucose is kept inside the cell by phosphorylating glucose

Question 35

Glycogen – General Concept

Answer 35

• The major storage form of carbohydrate – liver (~99%)
  – Liver (6-8% wet weight)&raquo_space; muscle tissue (<1%)&raquo_space;> adipose tissue
  – Present in cytosol, exists in vivo in highly hydrated granules (65%)
• Liver glycogen (~125 g)
  – Serves as a glucose reserve for maintaining blood glucose levels
  – Levels fluctuate with food intake
• Muscle glycogen – as fuel reserve for ATP within muscle
  – Exercise triggers glycogenolysis to form ATP
  – Red muscle fibers – aerobic respiration
• High in myoglobin and mitochondria
• Provides energy for long sustained activities
  – White muscle fibers – anaerobic respiration
• Have more capacity for glycogenolysis & glycolysis
• Glycogen is converted to lactate primarily

Question 36

Question – How might the body know when to store and when to retrieve the fuel substrates?

Answer 36

when to convert glucose into glycogen

That is the reason insulin and glucagon come into play for the energy metabolism

when insulin is high and glucagon is low, body is in anabolic state, so more glycogen, protein and neutral fat installed

if insulin is low and glucagon is high, body is in catabolic state, so converts polysaccharide into monosaccharide, convert neutral fat into glycerol and fatty acid, convert protein into amino acid

Question 37

Diabetes Mellitus – Stats

Answer 37

• # 1 Endocrine disorder
• Prevalence of diabetes mellitus in U.S.
  – In 2018, 34.2 million Americans, or 10.5% of the population
• In 2011, 25.8 million Americans, or 8.3% of population
  – Age > 65, 14.3 million, or 26.8% of population
  – Pre-diabetic – 88 million (2015)
  – Race and ethnic differences (in general oriental and american indians are at higher prevalence)
• Worldwide stats…
  – Type 1 DM (5-10%) vs. type 2 DM (90-95%; ~100% in Mexico)
  – Among Type 1 DM – Northern Europeans higher (declines in southern hemisphere)
  – Among Type 2 DM – Eastern Asians higher

Question 38

Diabetes Mellitus – Classification

Answer 38

• Type 1 diabetes (~5-10%) – due to β-cell destruction, usually leading to absolute insulin deficiency
• Type 2 diabetes (~90-95%) – due to a progressive insulin secretory defect on the background of insulin resistance
• Gestational diabetes mellitus – diabetes diagnosed during pregnancy (fetal placental hormones eg. cortisol) (if cortisol is too high, cause enlargement of fetus and cause dystocia)
• Other specific types of diabetes due to other causes:
  – Genetic defects in β-cell functions
  – Genetic defects in insulin actions
  – Drug- or chemical-induced diabetes (such as in the treatment of HIV/AIDS or after organ transplantation

Question 39

Differential Diagnosis for DM

Answer 39

• Criteria for Type 1 DM
  – Low blood insulin level (absorptive or post-absorptive)
  – High fasting blood glucose, over 1000 mg/dl of glucose present in blood plasma
  – Further tests are needed? Ab test
• Criteria for Type 2 DM
  – High fasting insulin level (until late stage) even when fasting blood glucose is normal (insulin resistance)

Question 40

Pathogenesis of Type 1 DM (1)

Answer 40

• Formerly insulin-dependent diabetes (IDDM) or juvenile-onset diabetes
• Result from chronic autoimmune destruction of β cells
• By the time the patients first presents, 80-90% β cell destruction has already occurred
• The autoimmune response is against altered pancreatic β cell antigens, mostly are directed against glutamic acid decarboxylase (GAD) within β cells

cytotoxic t lymphocytes used to destroy beta cells

Question 41

Pathogenesis of Type 1 DM (2)

Answer 41

• Molecules in β cells that resemble viral proteins – Coxsackie B4 virus (GI & heart), German measles, mumps, rotavirus
• Majority also have detectable anti-insulin Ab
• Occurring in genetically susceptible individuals, may be precipitated by environmental factors

Question 41

metabolic pathway for fuel substrate

Answer 41

glucose goes through glycolysis to form pyruvate which generates 2 ATP molecules, pyruvate converted to Acetyl CoA, Acetyl CoA enters kreb cycle then oxidative phosphorylation and electron transport chain, each molecule of Acetyl CoA can generate 36 or 38 ATP
- if excessive glucose, storage form is glycogen (polysaccharide in liver and muscle)
- acetyl CoA can also be formed from triglyceride (neutral fat) which can be dissociated into glycerol and fatty acid, fatty acid can be converted to acetyl CoA through beta oxidation
- acetyl CoA used to generate ATP and form ketone bodies
- proteins can be dissociated into amino acids, aa can form urea and excreted through urine, some glycogenic amino acids can be used to form glucose through gluconeogenesis, some aa can form acetyl CoA and used as energy source

-acetyl coa -> krebs cycle -> through oxidative phosphorylation and electron transport chain it will generate O2 to produce ATP

pyruvate can form acetyl CoA but acetyl CoA cannot form pyruvate, cannot go back to form glucose

refer to picture

Question 42

Development of T1DM

Answer 42

By the time the patients first presents, 80-90% β cell destruction has already occurred

Question 43

Questions

Answer 43

1. Why would there be odor of acetone on breath?
2. Why would the blood and urine ketone levels
   elevated?
3. What are ketone bodies used for metabolism?

Question 44

Body’s Fuel Use over Time of Starvation

Answer 44

• Plasma glucose levels over time (relatively stable)
• The time courses for glycogenolysis(within 24 hours it’s totally gone), gluconeogenesis (increase 4 hours after last meal but decrease after about 3 days from last meal)
• Plasma free fatty acids (FFAs) & ketone bodies (KBs) pick up more and more after 3 days of starvation

figure: 0 hours = time of last meal, different substrates relatively abundant
glucose level starting from time of meal to 24 hours, to 3 to 14 to 24 days starvation, blood glucose level can still be maintained at relatively stable condition but exogenous glucose (from diet) depletes very rapidly and completely used within 4 hours of meal

after about 3 hours after last meal glycogenolysis (converting glycogen to glucose) starts to increase in liver, storage capacity is limited, so starts to decline after 6-8 hours after meal, within 24 hours it’s completely depleted

4 hours after last meal, gluconeogenesis (converts neutral fat to fatty acid) starts to occur, which keeps blood glucose level within reasonable range, when decline in glycogenolysis the body relies on gluconeogenesis to maintain glucose level, adipose starts to convert to free fatty acid

after about on day after last meal, ketone bodies start to pick up, significant increase about 2-3 days after last meal, ketone bodies used as energy source, formation is from fatty acids occurring in the liver and can still maintain blood glucose within normal range even though gluconeogenesis starts to decline after 3 days after last meal

Question 45

Gluconeogenesis – Substrates

Answer 45

• glucogenic amino acids (not lipogenic)
• glycerol (can convert to glucose but fatty acids can NOT convert to glucose)
• lactic acid (formed during anaerobic glycolysis
• acetyl CoA and ketone bodies cannot serve as substrate

refer to picture

Question 46

Gluconeogenesis – Introduction

Answer 46

• Gluconeogenesis – the generation of gIc-6-P from non- sugar carbon substrates (glucogenic amino acids, lactate,
  glycerol, propionate)
• Clinical relevance – gluconeogenesis is essential for life
  – RBCs have the absolute requirement of glucose as an energy source (cannot use TCL cycle bc no mitochondria or nucleus) (can only use glycolysis)
  – The brain neurons, kidney medulla, lens, cornea, testis & many tissues are dependent on glc as an energy source
  – Hypoglycemia → brain dysfunction → coma
  – In ruminants and carnivores – a continual, ongoing process
• Often associated with ketogenesis

Question 47

Gluconeogenesis – When & Where

Answer 47

• When – whenever ↓ intracellular [glc] due to ↓ blood [glc] (starvation) or ↓ glc entry into cells (insulin resistance)
  – 1. When glycogen stores are depleted (during periods of fasting, starvation, intense exercise, or diabetes mellitus)
  – 2. When tissues are temporarily starved for O2 so that cells can only perform glycolysis → pyruvate → lactate
  – 3. When amino acids or fats are catabolized for energy (keto diet, Atkins diet, intermittent fasting)
• Where – mainly in liver, a little in cortex of kidneys

Question 48

From Gluconeogenesis to Lipolysis

Answer 48

• Gluconeogenesis & lipolysis starts ~4 hrs after last meal
• Starting >2 days after the last meal – ↑ lipolysis → ↑↑ ketogenesis; ↓ gluconeogenesis → spare proteins
  – ↑ Production of free fatty acids & ketone bodies
  – Ketone bodies are mainly for brain’s use → reduces dependency upon glucose

Question 49

The Nitrogen-Sparing Effect of Fat

Answer 49

• The nitrogen-sparing effect of fat (adipose tissue)
  – The body converts more fat into free fatty acids (through lipolysis) and ketone bodies (KBs, through ketogenesis)
  – The nitrogen-sparing effect helps to restrain the uptake and utilization of glc by tissues → liver (main) & kidney are under
  less pressure to perform gluconeogenesis
  – The nitrogen-sparing effect of fat spares oxidation of amino acids in muscle proteins (important for breathing and movement) → maintains muscle proteins
• Free fatty acids take preference over ketone bodies in muscle tissue as fuel → spares ketone bodies for utilization by brain

Question 50

Procedure of Ketogenesis

Answer 50

• Produced by the hepatic mitochondria
• Ketone bodies (acetoacetate, β-OH-
  butyrate, acetone) – misnamed, they
  are not “bodies“, they are acids and ketones
  – Acetone – metabolically inert (don’t produce any ATP), the fruity smell on the breath and in the urine
  – Acetoacetate (ketone) and β-OH-butyrate – can be used as energy substrates (but not acetone)
  – β-OH-butyrate is not a ketone

Question 51

Utilization of Ketone Bodies

Answer 51

• Liver cannot convert β-OH-butyrate or acetoacetate to acetoacetyl CoA for liver’s own use as the energy substrates. As
  such, ketone bodies are diffused into the blood plasma
• Ketone bodies can be used by all the cells that contain mitochondria, including brain neurons
• The use of ketone bodies reduces gluconeogenesis from amino acid carbon skeletons, thus slowing the loss of essential proteins
• β-OH-butyrate, acetoacetate → acetoacetyl CoA → 2 acetyl CoA for ATP production or lipid biosynthesis
• Ketone bodies are important substrates for complex lipid biosynthesis for fetus

Question 52

Advantages of Converting FFA into KBs

Answer 52

• The limitations of free fatty acids as fuel
  – In plasma, free (long-chain) fatty acids are hydrophobic, must be bound to albumin to be soluble
  – → The free fatty acids-albumin complex cannot cross the blood- brain-barrier and the placental barrier
• Ketone bodies are freely soluble in plasma
  – → Do not require albumin for their transport
  – → Diffuse across these barriers easily
  – → Can provide important fuel for the CNS and for the fetus during starvation
• Ketone bodies can also serve as building blocks for essential lipids (by converting to acetyl CoA)

Question 53

Disadvantage – Diabetic Ketoacidosis

Answer 53

• In untreated patients with type 1 diabetes mellitus:
  – Decline in circulating insulin → ↓ insulin/glucagon ratio → a reduced supply of glucose to cells → ↑ in fatty acid oxidation
  – → ↑Production of acetyl-CoA → ↑ ketone body production that exceeds the ability of peripheral tissues to oxidize them
  – → Ketone bodies are relatively strong acids with pKa ~ 3.5
  – → ↑ Blood [H+] → ↓ blood pH → ketoacidosis
• This acidification of the blood is dangerous chiefly because it impairs the ability of hemoglobin to bind O2 (extreme right-shift of the Hb-O2 dissociation curve)

Question 54

Question

Answer 54

What is the similarity between type 1 DM patients and individuals suffering from long-term starvation?
- DM ketogenesis is out of control but ketone bodies from starvation is only temporary
Have you heard of intermittent fasting or ketogenic diet? Are ketone bodies good or bad for the body?

Question 55

More Beneficial Effects of Ketone Bodies

Answer 55

• Metabolic adaptations to fasting (>10 hrs):
  – ↑ Lipolysis in fat cells (↑ free fatty acids FFA → ↑ KB in liver )
  – FFA → ↑ liver production of fibroblast growth factor 21 (FGF21) → ↑
  beneficial functions in many body organs (muscle, heart, brain etc.)
  – KB → ↑ ATP in cells; ↑ stress resistance; ↑ synaptic plasticity; ↑ neurogenesis; ↓ inflammation

Question 56

limited storage of capacity of glycogen

Answer 56

left figure: