1. Glucose Homeostasis Dr.Sarma.R.V.S.N
Glucose Homeostasis
Counter Regulation
Dr.Sarma.R.V.S.N
M.D., (Med) M.Sc., (Canada)
Consultant Physician
and Chest Specialist

2. Glucose Equilibrium – A Wonder !!
Normal Blood Glucose
Fasting state : 60 to 100 mg%
Postprandial : 100 to 140 mg %
What keeps the blood glucose in such a narrow range?
Why are we not becoming hypoglycemic when we fast?
Why is our blood sugar not shooting up to very high levels after a rich meal ?
What are the regulatory and counter regulatory hormones ?

3. Glucose Equilibrium – A Wonder !!
Normal Blood Glucose
Fasting state : 60 to 100 mg%
Postprandial : 100 to 140 mg %
What keeps the blood glucose in such a narrow range?
Why are we not becoming hypoglycemic when we fast?
Why is our blood sugar not shooting up to very high levels after a rich meal ?
What are the regulatory and counter regulatory hormones ?
Let us grasp some of the fascinating answers !!

4. Glucose Homeostasis Research Timeline
1552BC
1st Century AD
1776
18th Century
1869
1889
1983
2001
1552 BC: Ebers Papyrus in ancient Egypt. First known written description of diabetes.
1st Century AD: Arateus — “Melting down of flesh and limbs into urine.”
1776: Matthew Dobson conducts experiments showing sugar in blood and urine of diabetics.
Mid 1800s: Claude Bernard studies the function of the pancreas and liver, and their roles in homeostasis.
1869: Paul Langerhans identifies cells of unknown function in the pancreas. These cells later are named “Islets of Langerhans.”
1889: Pancreatectomized dog develops fatal diabetes.
1921: Insulin “discovered” — effectively treated pancreatectomized dog.
1922: First human treated with insulin. Eli Lilly begins mass production.
1923: Banting and Macleod win Nobel Prize for work with insulin.
1983: Biosynthetic insulin produced.
2001: Human genome sequence completed.
Glucose Homeostasis Research Timeline
George Ebers found the Ebers Papyrus in Egypt in The papyrus is the first known written description of diabetes, and while it is dated to 1552 BC, it contains references contained that date to earlier than 3000 BC. In the 1st Century AD, Arateus famously explained diabetes as the “melting down of flesh and limbs into urine.” Early physicians understood that polyuria (frequent urination) was a symptom of diabetes, but it was not until 1776 that Matthew Dobson was able to show that the sweet taste of a diabetic’s urine was attributed to glucose in the urine.
The “Experimental Period” of diabetes began in the mid-19th Century. The efforts of Claude Bernard, who studied the workings of the liver and pancreas in digestion; the identification by Paul Langerhans of cells of unknown function residing within the pancreas (later called “Islets of Langerhans”); and the pancreatectomy of a dog that resulted in fatal diabetes greatly expanded the understanding of diabetes and glucose homeostasis.
Research continued, and in 1921, insulin was used successfully to treat a pancreatectomized dog. The next year, a 14-year-old diabetic boy also was treated successfully with insulin. This resulted in the Nobel Prize for Medicine for Frederick G. Banting and John James Richard Macleod (both from the University of Toronto). Banting shared his monetary prize with his 22-year old research assistant, Charles Best. Macleod shared his winnings with a biochemist, James Collip. With the advent of molecular biology, research in diabetes led to new pharmaceutical approaches to treatment. In 1983, the first biosynthetic insulin became commercially available, increasing supply and making production relatively cheap, compared to harvesting insulin from pigs and cows. Then, in 2001, the initial draft of the Human genome sequence was completed. This detailed knowledge of man’s genetic composition is leading to new discoveries, but with the complex nature of diabetes (multiple genes, environmental component), the disease still remains largely a mystery.
References:
Langley, L.L. (Ed.). (1973). Homeostasis: Origins of the Concept. Langley, National Library of Medicine. Stroudsburg, PA:Dowden Hutchinson, and Ross Inc.
Sherwood, Lauralee. (1997). Human Physiology: From Cells to Systems (3rd ed.). West Publishing Co.

5. Cell growth and energy metabolism
Carbohydrates
Glucose
Pyruvate
CoA
Fatty acids
Fats
Amino acids
Acetyl-CoA
TCA Cycle
Kreb’s Cycle
Proteins
ATP

6. Intermediary Metabolism of Fuels

7. Intermediary Metabolism of Fuels
Clinical Pearl
All the fuels are inter changeable in the body
It is the total calorie restriction that is important in Obesity and T2D

8. Glucose-6-Phosphate – The Central Molecule

9. Glucose-6-Phosphate – The Central Molecule
Clinical Pearl
G-6-Phosphate is the Center Stage for CHO Metabolism
Glucose-6-Phosphate dehydrogenase (G6PD) is the crucial enzyme

10. Homeostasis of Glucose Counter Regulation Mechanisms
A steady maintenance of blood glucose with in a narrow range
Fasting state and fed states – their effects on BG
Rate of glucose appearance Ra
Rate of disappearance Rd must be in balance
Blood Glucose (BG) = Ra - Rd
Control systems
Glucose Receptors, GLUT 1-14
Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine etc.,
Insulin Signaling sequences, Glucagon signaling
Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue
Feedback loops
Negative feedback
Positive feedback
Homeostasis
Homeostasis means “steady state,” or internal balance, and is a recurrent theme in understanding how organisms function as a whole. A stable environment, maintained within narrow limits, is essential to all life.
Organisms constantly exchange energy and materials with their environments. The gains and losses must balance over some type of time interval. For example, as glucose enters the blood after a meal, excess glucose is transported to the liver to be converted to glycogen. Between meals, as glucose levels drop, the liver converts glycogen back to glucose and releases it into the bloodstream.
Homeostatic control systems have a receptor that detects change, along with a control center that directs the response to an effector. The body monitors internal conditions and makes corrections through biofeedback loops. In negative feedback loops, a change in the monitored variable triggers a response to counteract further change in the same direction. If excess heat is detected in the body, the brain signals the blood vessels near the surface of the body to dilate and the sweat glands to increase production. As body temperature nears normal, the brain reverses the process by slowing sweat production and constricting blood vessels.
In positive feedback loops, a change in the monitored variable triggers further action rather than reversing the action. A common example of a positive feedback loops occurs in blood clotting, with each clotting reaction activating another until the bleeding is stopped.
References:
Campbell, N.E. & Reece, J.B. (2002). Biology,(6th ed.). San Francisco: Benjamin Cummings.
Raven, P.H. & Johnson, G.B. (2002). Biology, (6th ed.). McGraw-Hill.

11. Homeostasis of Glucose Counter Regulation Mechanisms
A steady maintenance of blood glucose with in a narrow range
Fasting state and fed states – their effects on BG
Rate of glucose appearance Ra
Rate of disappearance Rd must be in balance
Blood Glucose (BG) = Ra - Rd
Control systems
Glucose Receptors, GLUT 1-14
Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine etc.,
Insulin Signaling sequences, Glucagon signaling
Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue
Feedback loops
Negative feedback
Positive feedback
Clinical Pearl
INSULIN v/s GLUCAGON and Rd V/s Ra
Homeostasis
Homeostasis means “steady state,” or internal balance, and is a recurrent theme in understanding how organisms function as a whole. A stable environment, maintained within narrow limits, is essential to all life.
Organisms constantly exchange energy and materials with their environments. The gains and losses must balance over some type of time interval. For example, as glucose enters the blood after a meal, excess glucose is transported to the liver to be converted to glycogen. Between meals, as glucose levels drop, the liver converts glycogen back to glucose and releases it into the bloodstream.
Homeostatic control systems have a receptor that detects change, along with a control center that directs the response to an effector. The body monitors internal conditions and makes corrections through biofeedback loops. In negative feedback loops, a change in the monitored variable triggers a response to counteract further change in the same direction. If excess heat is detected in the body, the brain signals the blood vessels near the surface of the body to dilate and the sweat glands to increase production. As body temperature nears normal, the brain reverses the process by slowing sweat production and constricting blood vessels.
In positive feedback loops, a change in the monitored variable triggers further action rather than reversing the action. A common example of a positive feedback loops occurs in blood clotting, with each clotting reaction activating another until the bleeding is stopped.
References:
Campbell, N.E. & Reece, J.B. (2002). Biology,(6th ed.). San Francisco: Benjamin Cummings.
Raven, P.H. & Johnson, G.B. (2002). Biology, (6th ed.). McGraw-Hill.

12. Normal, Hyper and Hypoglycemic statesRd
100 mg
Ra is the rate of appearance of Glucose
Rd is rate of disappearance of Glucose
When Ra = Rd; It is Euglycemic state Ra Rd
200 mg Ra Rd
200 mg Rd Ra
50 mg Ra Rd
50 mg
Ra > Rd; Ra ↑or Rd↓
Ra < Rd; Ra ↓or Rd ↑
HYPERGLYCEMIA
HYPOGLYCEMIA

13. Effect of CHO intake on Glucose Metabolism
Gluconeogenesis
Exogenous CHO
Glycogenolysis
Lipolysis Ra
GLUCAGON
INSULIN Rd

14. Glucose Homeostasis
-cells release Glucagon stimulate glycogen breakdown and gluconeogenesis
-cells release insulin stimulate glucose uptake by peripheral tissues
Lower Blood Glucose
Higher Blood Glucose
Food
Between meals
Glucose Homeostasis
Here is a diagram of glucose homeostasis. When we eat food, our blood glucose concentration rises, which stimulates insulin secretion from -cells and eventual glucose absorption by peripheral tissues. In between meals or in times of starvation, we are not taking in glucose and, therefore, experience a drop in blood glucose. During these times, the -cells release glucagon, which stimulates the liver to make glucose by glycogenolysis and gluconeogenesis, and thereby raise blood glucose to normal levels.
References:
Langley, L.L. (Ed.). (1973). Homeostasis: Origins of the Concept. Langley, National Library of Medicine. Stroudsburg, PA:Dowden Hutchinson, and Ross Inc.
Sherwood, Lauralee. (1997). Human Physiology: From Cells to Systems (3rd ed.). West Publishing Co.

15. High blood glucose affects the size of beta cells

16. Pancreatic Hormones Pancreas
Exocrine Pancreas – P Lipase, P amylase etc
Endocrine Pancreas – Islets of Langerhans
Hormones secreted are –
Alpha cells – Glucagon
Beta cells – Insulin
C cells - Somatostatin
D cells - Somatostatin
E cells - ?? Function
F cells - Pancreatic polypeptide (PPP)

17. Regulation of Blood Glucose levels
Glucose is the major source of energy for cells
Blood Glucose (BG) regulated by Insulin & Glucagon

18. Glucose Homeostasis – Insulin and Glucagon
Regulation of beta-cell size by the level of blood glucose

19. Glucose Homeostasis Chart
Liver breaks down glycogen to glucose
Raises blood glucose
Glucose uptake by muscle/fat tissue
Lowers blood glucose
Result
Glucagon
Insulin
Effector
-cell of the pancreas
-cell of the pancreas
Control Center
Glucose transporter
Receptor
Low Blood Sugar
Energy needs unmet
High Blood Sugar
Toxic to the cells - AGP
Condition
Glucose Homeostasis Chart
Glucose is used by many organisms as fuel, but it is vital that glucose levels be tightly regulated. Too little glucose will lead to starvation, while too much is toxic. Glucose homeostasis is accomplished through highly complex mechanisms involving many different molecules, cell types, and organs.
Briefly, when glucose enters the bloodstream (after the digestion of food), it is detected by specialized cells in the pancreas, called -cells. These cells respond to the rising blood-glucose concentration by releasing the enzyme, insulin. Insulin then signals to other tissues in the body (i.e., muscle cells and adipose tissue) to take in glucose to be used as energy (in muscle cells) or stored for later use (in adipose tissue). The result is a lowering of blood-glucose concentration to non-toxic levels.
In times of low glucose intake (between meals or in cases of starvation) the -cells of the pancreas release the enzyme, glucagon. This enzyme directs the liver to break down stored glycogen into glucose and release this glucose into the bloodstream, thereby raising blood-glucose concentration to a desired level. The glucose transporters expressed on the - and -cells that bind glucose are the receptors of this homeostatic system. The - and -cells, themselves, are the control centers. They process information from the receptors and respond to it in a way that will maintain a constant internal environment. Insulin and glucagon are the effectors. This system is complex; the - and -cells working continuously to achieve the optimal, homeostatic blood-glucose concentration.
References:
Langley, L.L. (Ed.). (1973). Homeostasis: Origins of the Concept. Langley, National Library of Medicine. Stroudsburg, PA:Dowden Hutchinson, and Ross Inc.
Sherwood, Lauralee. (1997). Human Physiology: From Cells to Systems (3rd ed.). West Publishing Co.

20. The Six Mechanisms of Transport - CM2 1 3 6 4 5

21. Membrane Transport Proteins

22. Channel Proteins

23. Cell Membrane - Transporters

24. ATP Powered Receptors

25. GLUCOSE ABSORPTION IN THE GI TRACT
Glucose Transport
FIRST STEP
GLUCOSE ABSORPTION IN THE GI TRACT

26. Intestinal Cell Transport

27. Intestinal Cell Transport
Clinical Pearl
New approach in T2D, MS and Obesity - GLUT-2 Blockers

28. The First Messengers from GI tract
THE MESSERGERS
INCRETINS – GLP1 and GIP_

29. Entero-Insular Axis of Secretion
Insulin secretion is also increased
By intestinal polypeptide hormones
GLP-1 (glucagon like peptide) [exendin-4]
Glucose-dependent insulinotropic peptide(GIP)
GLP-1 and GIP are called Incretins
Cholecystokinin and by pancreatic Glucagon.
Insulin secretion is decreased by pancreatic somatostatin.

30. New Drugs for T2D- Incretin (GLP-1 and GIP) Function Enhancers
Entero-Insular Axis of Secretion
Insulin secretion is also increased
By intestinal polypeptide hormones
GLP-1 (glucagon like peptide) [exendin-4]
Glucose-dependent insulinotropic peptide(GIP)
GLP-1 and GIP are called Incretins
Cholecystokinin and by pancreatic Glucagon.
Insulin secretion is decreased by pancreatic somatostatin.
Clinical Pearl
New Drugs for T2D- Incretin (GLP-1 and GIP) Function Enhancers

31. Response to Elevated Blood Glucose
In the post prandial state (after a meal)
Remember there are two separate signaling events
First signal is from the ↑ Blood Glucose to pancreas
To stimulates insulin secretion in to the blood stream
The second signal from insulin to the target cells
Insulin signals to the muscle, adipose tissue and liver to permit to glucose in and to utilize glucose
This effectively lowers Blood Glucose

32. Response to Elevated Blood Glucose
In the post prandial state (after a meal)
Remember there are two separate signaling events
First signal is from the ↑ Blood Glucose to pancreas
To stimulates insulin secretion in to the blood stream
The second signal from insulin to the target cells
Insulin signals to the muscle, adipose tissue and liver to permit to glucose in and to utilize glucose
This effectively lowers Blood Glucose
Clinical Pearl
Insulin secretion must be triggered – First Signal
Secreted Insulin must trigger Glucose uptake – Second signal
T2D may result from failure of either or both

33. Glucose induced Insulin secretion
Glucose enters the beta cells through uniporter GLUT 2
Oxidative phosphorylation
ATP closes the ATP gated K+ channel and depolarizes the cell membrane
Depolarization opens the voltage gated Ca+ channels
Ca+ enters the beta cells
This leads to exocytosis of Insulin and secretion

34. Glucose induced Insulin secretion
Glucose enters the beta cells through uniporter GLUT 2
Oxidative phosphorylation
ATP closes the ATP gated K+ channel and depolarizes the cell membrane
Depolarization opens the voltage gated Ca+ channels
Ca+ enters the beta cells
This leads to exocytosis of Insulin and secretion
Clinical Pearl
Closure of KATP Channels by Glucose is fundamental
Glucose is necessary to stimulate Insulin
Insulin is necessary to let in glucose

35. K+ATP Channel Closed by ↑ BG and SU

36. K+ATP Channel Closed by ↑ BG and SU
Clinical Pearl
SU Group close KATP Channels – Secrete Insulin
Differences in action of SU are because of the differences
in their action on KATP Channels
3. Gliclazide and Glimiperide just hit the SUR closure and stop

37. Intricacies in the Beta Cell

38. K+ ATP – Sulfonylurea Receptor
K+ ATP channel has two sub units – Kir6.2 and regulatory sulfonylurea receptor(SUR)
ATP gated K+ channel is coupled to SUR
K+ channel can be closed independently of glucose
This leads to increased insulin secretion
SUR1 are ATP binding transporters superfamily

39. K+ ATP – Sulfonylurea Receptor
K+ ATP channel has two sub units – Kir6.2 and regulatory sulfonylurea receptor(SUR)
ATP gated K+ channel is coupled to SUR
K+ channel can be closed independently of glucose
This leads to increased insulin secretion
SUR1 are ATP binding transporters superfamily
Clinical Pearl
Glibenclamide, Tolbutamide cause prolonged closer of the SUR
This causes prolonged and intense pressure on Beta cells
This is the cause of late hypoglycemia with these SUs
Beta cell apoptosis sets in fast after a few years of use

40. (F)PHHI (Familial) Persistent Hyperinsulinemic Hypoglycemia of Infancy
Unregulated insulin secretion
Profound hypoglycemia and brain damage
Manifests at birth or at first year of life
Under diagnosed
Probably the cause of undiagnosed postnatal deaths
Defect is KATP Channels mutation –
Persistent closure with continuous trigger for Insulin release
Treatment is pancreatectomy – (95% of pancreas)

41. K+ATP Channel Opening is Cardio-protective

42. K+ATP Channel Opening is Cardio-protective
Clinical Pearl
Glibenclamide, Tolbutamide close the SUR in myocardium
This effect is deleterious to heart in ischemia

43. Tyrosine Kinase Pathway - Insulin

44. Tyrosine Kinase Pathway - Insulin
Clinical Pearl
Tyrosine Kinase (TK) phosphorylation is the fundamental step
Its failure stops further cascade of intracellular signals
This is one of the possible mechanisms of Insulin Resistance
PPAR- Gamma (Pioglitazone) enhances TK signaling pathway

45. Insulin Receptor (IR) Insulin Receptor is a tyrosine kinase.
Consists of 2 units -dimerize when bound with insulin.
Inside cell - auto phosphorylation occurs,
Increasing tyrosine kinase activity.
Insulin Receptor phosphorylates intracellular signaling molecules.
Stimulates insertion of GLUT-4 proteins
which let in glucose
Stimulate glycogen, fat and protein synthesis.

46. -subunits -subunits
+3HN
NH3+ S
Insulin
-S-S-
-subunits
EXTRACELLULAR
-OOC - S S
COO
+3HN
NH3+
Plasma
membrane
CYTOPLASM
Transmembrane
domain
Tyrosine
kinase
domain
-OOC
COO-
-subunits
Figure 2. The insulin receptor. Insulin binding to the -chains transmits a signal through the transmembrane domain of the -chains to activate the tyrosine kinase activity

47. Extracellular 3
IRTK (R)
phosphorylated/
activated 1
insulin
binds L R 2
IRTK (L)
activated OP P P P
Cytoplasm P
ATPs P
Phosphorylation
catalyzed by IRTK (L)
ADPs
Figure 3. Activation of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation

48. Extracellular 3
IRTK (R)
phosphorylated/
activated 1
insulin
binds L R 2
IRTK (L)
activated 4
IRTK (L)
phosphorylated OP PO OP P
ATPs
ADPs
Phosphorylation
catalyzed by IRTK (L)
ATPs
ADPs P P P P P
Cytoplasm
Figure 3. Activation of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation

49. Insulin Signaling – TK Receptor phosphorylation
Binding of insulin to the TK Receptor causes
Transphosphorylation of tyrosines on the receptor
Phosphotyrosine residues bind to
IRS-1 (insulin receptor substrate – adopter protein)

50. Insulin Receptor (IR) A key regulator of growth signaling
IR is hetero-tetramer
Insulin binding induces conformation change and stimulation of receptor Tyrosine kinase activity
IR auto-phosphorylates and phosphorylates downstream second messengers, like IRS (Insulin Receptor Substrate)
Obesity down regulation of IR
Diabetes up regulation of IR

51. Receptor tyrosine kinases
Epidermal Growth Factor (EGF) Receptor Auto-phosphorylation of TK (Obesity)
The interaction of the external domain of a receptor tyrosine kinase with the ligand, often a growth factor, up-regulates the enzymatic activity of the intra cellular catalytic domain, which causes tyrosine phosphorylation of cytoplasmic signaling molecules.

52. Receptor tyrosine kinases
Epidermal Growth Factor (EGF) Receptor Auto-phosphorylation of TK (Obesity)
The interaction of the external domain of a receptor tyrosine kinase with the ligand, often a growth factor, up-regulates the enzymatic activity of the intra cellular catalytic domain, which causes tyrosine phosphorylation of cytoplasmic signaling molecules.
Clinical Pearl
Up regulation of TK receptor (autophosphorylation) in obesity
Leads to Glucose entry into cells with out insulin signal

53. Insulin Signaling – PKB and MAPK pathways
Ras independent signaling – The PKB Signaling and
Ras dependent – The MAPK Signaling
Ras independent through activation of Protein Kinase B
Responsible for immediate non-genomic effects
Ras dependent – Activation of
Mitogen Activated Protein Kinase (MAPK) pathway
Responsible for genomic effects

54. Insulin Signaling – PKB and MAPK pathways

55. Insulin Signaling – PKB and MAPK pathways
Clinical Pearl
Ras independent signaling cascade – PI3P – PKB
Ras dependent signaling cascade – MAP Kinase

56. Glucose Uniporter - GLUTs

57. Glucose Uniporter - GLUTs
Clinical Pearl
Translocation of GLUT-4 to cell surface is crucial for Glu. uptake
Insulin resistance is usually due to failure of this step

58. Ras Independent – PI3K - PKB Signaling
IRS1 binds PI3 kinase through SH2 domain
This phosphorylates PIP2 to PIP3
Increased concentration of PIP3 recruits
PKB to the plasma membrane
PKB is phosphorylated by
two membrane associated kinases PKC λ and ξ
Active PKB is released into the cytosol
Where it translocates glucose transporter (GLUT-4)
GLUT-4 (uniporter) moves on to the membrane
GLUT-4 lets Glucose in and increases glucose uptake

59. PIP Signaling Pathway

60. Ras - Independent Insulin Signaling

61. Insulin and PI3K Signaling

62. Ras Independent PO OP Extracellular Space Cytoplasm = GLUT-4
Active IRTK 
tyr-OH
IRS
ATP
ADP
[1] IRTK
catalyzed 
tyr-OP
IRS
p85
[2] activated
by docking
active IRS 
tyr-OP
IRS
PI-3K 
tyr-OP
IRS 
tyr-OP
IRS 
tyr-OP
IRS
active
IRS
PIP2
PIP3
Figure 5. Mechanism for insulin to mobilize GLUT-4 transporter to the plasma membrane in muscle & adipose tissue.
IRS, insulin-receptor substrate;
IRTK, insulin receptor tyrosine kinase;
PI-3K, phosphatidyl-inositol kinase;
PDK; phospholipid-dependent kinase
PKB, protein kinase B +
[4] signals Golgi to traffic GLUT-4 to
membrane
PDK
PKB
GOLGI

63. Ras Dependent – MAPK Signaling
At the same time…
Phosphorylated insulin receptor binds
to adapter protein SHC through GRB2
GRB2 also has SH3 domains that bind and activates Sos
Binding of Sos to inactive Ras causes a
conformational change that permits release of
GDP and binding of GTP (activation of Ras)
Sos is a GEF for monomeric G protein Ras
Sos dissociates from activated Ras
Linking insulin receptor to Ras

64. Ras - Dependent Insulin Signaling

65. Ras Dependent – MAPK Signaling
Activated Ras passes the signal to raf kinase
Raf activates a cascade of kinases (MAP Kinase cascade)
Mitogen Activated Protein Kinases (MAP Kinases)
Highly conserved kinase cascades
Last kinase in the cascade has to be double phosphorylated
It has high specificity (since it is double phosphorylation)

66. Ras Dependent Activated IRTK PO OP Glucose Extracellular Cytoplasm
GLUT-4
Glucose transport
(muscle/adipose)
Signal transduction
(e.g., phosphorylation of IRS, SHC, PLC)
metabolic
responses
Activation of protein
phosphatase
KINASE CASCADE
(protein phosphorylation)
Dephosphorylation of:
glycogen synthase
glycogen phosphorylase
phosphorylase kinase
acetyl CoA carboxylase
hormone-sensitive lipase
phosphofructokinase-2
pyruvate kinase
HMG CoA reductase
regulatory kinases
mitogenic
response
Cell growth
and replication
DNA synthesis
NUCLEUS
mRNA synthesis
Protein
synthesis

67. Ras Dependent – MAPK Signaling
MAPK regulates the activity of transcription factors
Active MAPK translocates to the nucleus
It phosphorylates several transcription factors
And production of more GLUT4

68. Glucose Entry in to the Cell
Insulin/GLUT4 is not the only pathway
Insulin-dependent, GLUT 4 - mediated
Cellular uptake of glucose into muscle and adipose tissue (40%)
Insulin-independent glucose disposal (60%)
GLUT 1 – 3 in the Brain, Placenta, Kidney
SGLT 1 and 2 (sodium glucose symporter)
Intestinal epithelium, Kidney

69. Fatty Acid Dysregulation impairs Insulin action

70. Fatty Acid Dysregulation impairs Insulin action
Clinical Pearl
Excess FFA – cause dysregulation of IR
GLUT-4 function is impaired – Insulin Resistance

71. Cyclic AMP Pathway - Glucagon
Off switch
PDE inactivates cAMP
PDE stops signal transduction.
Caffeine inhibits PDE!

72. Glucose controls Insulin and Glucagon release

73. Liver and Kidney Major source of net endogenous glucose production
Accomplished by gluconeogenesis and glycogenolysis when glucose is low
And of glycogen synthesis when glucose is high.
Can oxidize glucose for energy and convert it to fat which can be incorporated into VLDL for transport.

74. Metabolic Effects of Insulin - in the Liver

75. Muscle Can convert glucose to glycogen.
Can convert glucose to pyruvate through glycolysis - further metabolized to lactate or transaminated to alanine or channeled into the TCA cycle.
In the fasting state, can utilize FA for fuel and mobilize amino acids by proteolysis for transport to the liver for gluconeogenesis.
Can break down glycogen
But cannot liberate free glucose into the circulation.

76. Metabolic Effects of Insulin - in the Muscle

77. Adipose Tissue (AKA fat)
Can store glucose by conversion to fatty acids and combine these with VLDL to make triglycerides.
In the fasting state can use fatty acids for fuel by beta oxidation.

78. Effects of Insulin - in the Adipose tissue

79. Metabolic Effects of Glucagon

80. Insulin – Anabolic and Glucagon - Catabolic
Metabolic Action
Insulin
Glucagon
Glycogen synthesis ↑ ↓
Glycolysis (energy release)
Lipogenesis
Protein synthesis
Glycogenolysis
Gluconeogenesis
Lipolysis
Ketogenesis

81. Glucose Uniporters - GLUTs
Transport can work in both directions

82. The GLUT – Glucose Transporters
14 transporters of Glucose are identified
Their genes are located and cloned
The function of some is yet under evaluation
Some genetic defects produce specific diseases like GLUT-1-DS
In breast and prostate cancer GLUT- 11 is hyper expressed and supplies the high needs of glucose to the cancer cells. – Anti GLUT – 11 drugs might be a therapeutic approach for these cancers.

83. The GLUT – Glucose Transporters
14 transporters of Glucose are identified
Their genes are located and cloned
The function of some is yet under evaluation
Some genetic defects produce specific diseases like GLUT-1-DS
In breast and prostate cancer GLUT- 11 is hyper expressed and supplies the high needs of glucose to the cancer cells. – Anti GLUT – 11 drugs might be a therapeutic approach for these cancers.
Clinical Pearl
GLUT -1 DS – a genetic disorder of Glucose metabolism
Anti GLUT -11 drugs in breast & prostate Ca are underway

84. Glucose Transporter Proteins - GLUTs
GLUT Responsible for feeding muscle during exercise (that is how exercise lowers blood glucose) Placenta, BB, RBC, Kidney and many tissues. Low in liver. Mainly “house keeping”
GLUT – 2 – Uniporter of glucose into the beta cells and stimulates insulin secretion. Beta cells of pancreas. Liver, small intestinal epithelium, Kidney. Has high Km (60 mM). Never saturates.
GLUT - 3 – Insulin independent glucose disposal in to the tissues. Abundant in neuronal tissue, placenta and kidney. It feeds the high glucose requirement with out insulin.

85. Glucose Transporter Proteins - GLUTs
GLUT Responsible for feeding muscle during exercise (that is how exercise lowers blood glucose) Placenta, BB, RBC, Kidney and many tissues. Low in liver. Mainly “house keeping”
GLUT – 2 – Uniporter of glucose into the beta cells and stimulates insulin secretion. Beta cells of pancreas. Liver, small intestinal epithelium, Kidney. Has high Km (60 mM). Never saturates.
GLUT - 3 – Insulin independent glucose disposal in to the tissues. Abundant in neuronal tissue, placenta and kidney. It feeds the high glucose requirement with out insulin.
Clinical Pearl
The GLUT-3 Receptors are Insulin independent
In brain GLUT-3 mediate glucose uptake
In placenta also GLUT-3 mediate Glucose uptake
Foetal growth is not affected very much in IR

86. Glucose Transporter Proteins – GLUTs contd..
GLUT – 4 – Insulin dependent – It is the main channel for glucose entry into cells. Muscle, Heart and adipose tissues depend on GLUT –4 for glucose entry in to cells
GLUT – 5 – Rich in small intestine and conduct absorption of dietary glucose and fructose transport. Mediate glucose for spermatogenesis
GLUT – 6 – Pseudo gene – Mediates none so far
GLUT – 7 – Only in liver endoplasmic reticulum and it conducts glucose back out – G6P transporter in ER
SGLT 1 and 2 - Sodium - Glucose symporter in the intestinal epithelium and renal tubular epithelium

87. Glucose Transporter Proteins – GLUTs contd..
GLUT – 4 – Insulin dependent – It is the main channel for glucose entry into cells. Muscle, Heart and adipose tissues depend on GLUT –4 for glucose entry in to cells
GLUT – 5 – Rich in small intestine and conduct absorption of dietary glucose and fructose transport. Mediate glucose for spermatogenesis
GLUT – 6 – Pseudo gene – Mediates none so far
GLUT – 7 – Only in liver endoplasmic reticulum and it conducts glucose back out – G6P transporter in ER
SGLT 1 and 2 - Sodium - Glucose symporter in the intestinal epithelium and renal tubular epithelium
Clinical Pearl
GLUT-4 is main Glucose transporter in all tissues
It cannot function without TK signaling of Insulin

88. Brain Converts glucose to CO2 and H2O.
Can use ketones during starvation.
Is not capable of gluconeogenesis.
Has no glycogen stores.

89. Know Our Brain !! Brain is the major glucose consumer
Consumes 120 to 150 g of glucose per day
Glucose is virtually the sole fuel for brain
Brain does not have any fuel stores like glycogen
Can’t metabolize fatty acids as fuel
Requires oxygen always to burn its glucose
Can not live on anaerobic pathways
One of most fastidious and voracious of all organs
Oxygen and glucose supply can not be interrupted

90. Know Our Brain !! Clinical Pearl
Brain is the major glucose consumer
Consumes 120 to 150 g of glucose per day
Glucose is virtually the sole fuel for brain
Brain does not have any fuel stores like glycogen
Can’t metabolize fatty acids as fuel
Requires oxygen always to burn its glucose
Can not live on anaerobic pathways
One of most fastidious and voracious of all organs
Oxygen and glucose supply can not be interrupted
Clinical Pearl
Brain does not need Insulin for glucose uptake
The GLUT-3 Receptors mediate it without Insulin
In hypoglycemia we need to give Glucose only

91. Second Signaling
Now Insulin that is secreted in to the blood starts the second signaling event
Insulin binds to the Insulin Receptors (IR) on the muscle and fat cells
Muscle and fat cells increase glucose uptake
This leads to lowering of blood glucose

92. Insulin – C peptide Insulin is dimer of two peptides
Each peptide consists of A and B chains
A has 21 amino acids
B has 30 amino acids
2 chains are linked by pair of S – S bonds
C peptide has 35 amino acids and is cleaved

93. Insulin – C peptide Clinical Pearl
Insulin is dimer of two peptides
Each peptide consists of A and B chains
A has 21 amino acids
B has 30 amino acids
2 chains are linked by pair of S – S bonds
C peptide has 35 amino acids and is cleaved
Clinical Pearl
Insulin Analogs are substitutions of AA in α and ß chains
Insulin Glargine, Insulin aspart, Insulin lispro etc., RAIA, LAIA

94. Preproinsulin – Proinsulin – Insulin

95. Preproinsulin – Proinsulin – Insulin
Clinical Pearl
C – Peptide assay is simpler, less costly than Insulin assay
It is the surrogate for endogenous Insulin secretion
It is not affected by exogenously administered Insulin
It is not largely influenced by food intake

96. PPAR Family of Nuclear Receptors
Peroxisome Proliferator Activated Receptors

97. PPAR Family of Nuclear Receptors
Peroxisome Proliferator Activated Receptors
Clinical Pearl
PPAR alpha are essential regulators of serum lipids
PPAR gamma are essential for Insulin Sensitivity
In Insulin Resistance the PPAR Gamma are inactivated
Glitazones enhance the PPAR Gamma activity

98. The Role of Pancreas Insulin Hypoglycemic hormone
Beta cells of pancreas
Two chain polypeptide – Anabolic in nature
Receptor interactions
Intracellular interactions
Transporters
Clinical correlation

99. Insulin - Mechanism of action
Insulin binds to its trans-membrane receptor.
β subunits of the receptor become phosphorylated
Receptor has intrinsic tyrosine kinase activity.
Intracellular proteins are activated/inactivated—
IRS-1, IRS-2 and seven PI-3-kinases
GLUT-4, Transferrin, LDL-R, IGF-2-R move to the cell surface.
Cell membrane permeability increases:
Glucose, K+, amino acids, PO4 enter

100. Insulin Insulin Release
In a 24 hour period, 50% of the insulin secreted is basal and 50% is stimulated.
The main stimulator for secretion is glucose.
Amino acids also stimulate insulin release, especially lysine, arginine and leucine.
This effect is augmented by glucose.

101. Control of Insulin Secretion
Glucose interacts with the GLUT-2 transporter on the pancreatic beta cell.
Glucose enters the cell releases - hexokinase→ G-6-P
Increased metabolism of glucose → ATP →
Excess of ATP- blocks ATP dependent K channels →
Membrane depolarization →
↑ Cytosolic Ca++ →
This stimulates degranulation and
Releases ↑ insulin secretion.

102. Control of Insulin Secretion
Insulin secretion is also increased by
Growth hormone (acromegaly)
Glucocorticoids (Cushings’)
Prolactin (lactation)
Placental lactogen (pregnancy)
Sex steroids

103. ↑ transport of glucose into cells, ↓ gluconeogenesis, ↓ glycogenolysis
Regulation of Insulin Secretion
Summary of feedback mechanism for regulation
↑ blood glucose ↓
↑ insulin
↑ transport of glucose into cells,
↓ gluconeogenesis, ↓ glycogenolysis
↓ blood glucose
↓ insulin

104. Role of Insulin Metabolic Effects of Insulin
Main effect is to promote storage of nutrients
Paracrine effects
Decreases Glucagon secretion
Carbohydrate metabolism
Lipid metabolism
Protein metabolism and growth

105. Role of Insulin Carbohydrate metabolism Increases uptake of glucose
Promotes glycogen storage
Stimulates glucokinase
Inhibits gluconeogenesis
Inhibits hepatic glycogenolysis
Inactivates liver phophorylase

106. Sources of Glucose in to blood
Glucose is derived from 3 sources
Intestinal absorption of dietary carbohydrates
Glycogen breakdown in liver and in the kidney.
Only liver and kidney have glucose-6-phosphatase.
Liver stores grams of glycogen, a 3 to 8 hour supply.
Gluconeogenesis, the formation of glucose from precursors
These include lactate and pyruvate, amino acids (alanine and glutamine), and to a lesser degree, from glycerol

107. Fasting State Short fast Utilizes free glucose (15-20%)
Break down of glycogen (75%)
Overnight fast
Glycogen breakdown (75%)
Gluconeogenesis (25%)
Prolonged fast
Only 10 grams or less of liver glycogen remains.
Gluconeogenesis becomes sole source of glucose
Muscle protein is degraded for amino acids.
Lipolysis generates ketones for additional fuel.

108. Role of Insulin Lipid Metabolism Insulin promotes fatty acid synthesis
Stimulates formation of α-glycerol phosphate
α-glycerol phosphate + FA CoA = TG
TG are incorporated into VLDL and transported to adipose tissues for storage.
Insulin inhibits hormone-sensitive lipase,
Thus decreasing fat utilization.

109. Role of Insulin Protein Metabolism and Growth
Increases transport of amino acids
increases mRNA translation and new Proteins,
A direct effect on ribosomes
Increases transcription of selected genes,
Especially enzymes for nutrient storage
Inhibits protein catabolism
Acts synergistically with growth hormone

110. Role of the Pancreas Lack of insulin
Occurs between meals, and in diabetes.
Transport of glucose and amino acids into the cells decreases, leading to hyperglycemia.
Hormone sensitive lipase is activated,
Causing TG hydrolysis and FFA release.
↑ FFA conversion in liver →
Phospholipids and cholesterol →
Lipoproteinemia,
FFA breakdown leads to ketosis and acidosis.

111. Insulin Resistance Associated with obesity
Underlying metabolic defect in
Type 2 diabetes
Polycystic ovarian disease
Associated with
Hypertension, gout, high triglyceride
30% of general population

112. What causes insulin resistance?
Decreases in receptor concentration
Decreases in tyrosine kinase activity,
Changes in concentration and phosphorylation of IRS-1 and IRS-2,
Decreases in PI3-kinase activity,
Decreases in glucose transporter translocation,
Changes in the activity of intracellular enzymes.

113. What causes insulin resistance?
Decreases in receptor concentration
Decreases in tyrosine kinase activity,
Changes in concentration and phosphorylation of IRS-1 and IRS-2,
Decreases in PI3-kinase activity,
Decreases in glucose transporter translocation,
Changes in the activity of intracellular enzymes.
Clinical Pearl
T2D is mostly a question of Insulin Resistance
Drugs which improve Insulin resistance are crucial
Quantitative deficiency is only a late feature in T2D

114. The Role of Pancreas Other pancreatic hormones Somatostatin
14 amino acid paracrine factor
Potent inhibitor of glucagon release
Stimili: glucose, arginine, GI hormones
It is anti GH (somatotrophin) in its actions
Pancreatic polypeptide
36 amino acids, secreted in response to food
Glucagon

115. Counter Regulatory Hormones
Early response
Glucagon
Epinephrine
Delayed response
Cortisol
Growth hormone

116. Counter Regulatory Hormones
Glucagon
Acts to increase blood glucose
Secreted by alpha cells of the pancreas
Chemical structure 29 amino acids
Derived from 160 aminoacid proglucagon precursor
GLP-1 (Glucagon Like Peptide -1)
The most potent known insulin Secretagogue
It is made in the intestine by alternative processing of the same precursor
Intracellular actions

117. Role of Glucagon Metabolic Effects of Glucagon
Increases hepatic glycogenolysis
Increases gluconeogenesis
Increases amino acid transport
Increases fatty acid metabolism (ketogenesis)

118. Role of Glucagon Clinical Pearl
Metabolic Effects of Glucagon
Increases hepatic glycogenolysis
Increases gluconeogenesis
Increases amino acid transport
Increases fatty acid metabolism (ketogenesis)
Clinical Pearl
Glucagon is the treatment for hypoglycemia
Glucagon Kit – 1 mg s/c or IM or IV injection –
In 2 to 3 minutes recovery
Costs Rs. 400 per dose

119. Glucagon Secretion Stimulation of Glucagon secretion
Blood glucose < 70 mg/dL
High levels of circulating amino acids
Especially arginine and alanine
Sympathetic and parasympathetic stimulation
Catecholamines
Cholecystokinin, Gastrin and GIP
Glucocorticoids

120. Responses to decreasing Glucose levels
Glycemic theshhold
Physiological effects
Role in counter regulation
↓ Insulin
mg%
↑ Ra (↓ Rd)
Primary First Defense
↑ Glucagon
mg%
↑ Ra
Primary Second Defense
↑ Epinephrine
↑ Ra ↓ Rd
Critical Third Defense
↑ Cortisol, GH
Not Critical
↑ Food ingestion
mg%
↑ Exogenous Glucose
< 50mg% no cognitive change

121. Role of Epinephrine Epinephrine
The second early response hyperglycemic hormone.
This effect is mediated through the hypothalamus in response to low blood glucose
Stimulation of sympathetic neurons causes release of epinephrine from adrenal medulla .
Epinephrine causes glycogen breakdown, gluconeogenesis, and glucose release from the liver.
It also stimulates glycolysis in muscle
Lipolysis in adipose tissue,
Decreases insulin secretion and
Increases glucagon secretion.

122. Role of Cortisol and GH These are long term hyperglycemic hormones
Activation takes hours to days.
Cortisol and GH act to decrease glucose utilization in most cells of the body
Effects of these hormones are mediated through the CNS.

123. Cortisol Cortisol is a steroid hormone
It is synthesized in the adrenal cortex.
Synthesis is regulated via the hypothalamus (CRF) and anterior pituitary (ACTH).
Clinical correlation: Cushing’s Disease

124. Growth Hormone (GH) GH is a single chain polypeptide hormone.
Source is the anterior pituitary somatotrophs.
It is regulated by the hypothalamus.
GHRH has a stimulatory effect.
Somatostatin (GHIF) has an inhibitory effect.
Clinical correlation: Gigantism and Acromegaly cause insulin resistance.
Glucose intolerance—50%
Hyperinsulinemia—70%

125. What is T2D or T1D ?

126. Normal, T2D and T1D Normal Subject Type 2 Diabetes (T2D)
High blood glucose
Detected by -cells
-cells release insulin
Peripheral cells respond to insulin & take up glucose
Lower blood glucose
Normal Subject
Type 2 Diabetes (T2D)
High blood glucose
Poor function of -cells
-cells release of insulin is inadequate or inefficient
Peripheral cells poorly respond to insulin and glucose up take is poor
Blood glucose remains high
Type 1 Diabetes (T1D)
High blood glucose
No -cells to detect & respond
Insulin secretion is nil
Peripheral cells have no insulin to respond and take up glucose
Blood glucose remains high
-cells destroyed by autoimmune reaction
Type 1 Diabetes Mellitus
This diagram shows where in the glucose metabolic pathway Type 1 diabetics differ from healthy individuals.
Type 1 diabetes is an autoimmune disorder, meaning the body’s immune system is not functioning properly and attacks the body itself. In Type 1 diabetes, the antibodies produced by the immune system bind to the -cells, which then are destroyed by specialized immune cells. Because the -cells are destroyed, no insulin is produced, and therefore, the peripheral tissues (muscle and fat) do not receive a signal that allows for glucose uptake. Ultimately, this condition causes glucose levels in the bloodstream to remain high. Individuals with Type 1 DM are dependent on exogenous (produced outside the body) sources of insulin.
References:
Langley, L.L. (Ed.). (1973). Homeostasis: Origins of the Concept. Langley, National Library of Medicine. Stroudsburg, PA:Dowden Hutchinson, and Ross Inc.
Sherwood, Lauralee. (1997). Human Physiology: From Cells to Systems (3rd ed.). West Publishing Co.
Blood glucose remains very high

127. Type 2 Diabetes Mellitus
Peripheral Tissue Insulin Resistance v. Time
-cell Insulin
Production v. Time
Disease Progression
Diabetic
Relative Insulin Resistance
Pre-Diabetic
-cell Insulin Production
Age
Type 2 Diabetes Mellitus
Type 2 diabetes is most common in older individuals, because it takes time for this disease to develop (for this reason, we say it has an insidious onset). The classic model of Type 2 diabetes shows us that over time, the peripheral tissues become insulin resistant. In other words, the body is no longer responding to the insulin signal. Therefore, after glucose ingestion, even in the presence of insulin, the blood glucose concentration remains too high. Furthermore, because the liver is also resistant to insulin, glycogenolysis and gluconeogenesis are not terminated. Thus, the body has a high blood glucose concentration due to the inability of the peripheral tissues to take in glucose AND because the liver is synthesizing glucose.
As seen in the simplified second graph, -cell Insulin Production v. Time, we see that the -cell compensates for resistance by increasing the production of insulin. The -cell is able to produce enough insulin to overcome the resistance and maintain normal blood glucose levels. However, eventually, the -cell becomes exhausted from this work over-load. At that point, the peripheral tissues are resistant to insulin and the body is not producing enough insulin for a normal individual.
This process does not happen overnight. As the graph illustrates, an individual may have normal glucose homeostasis for the majority of his/her life. However, as insulin resistance progresses and -cell function is diminished, a person will become “pre-diabetic.” At this stage of the disease, a person may not know that he/she is affected. Nonetheless, his or her body is gradually losing its ability to control blood glucose levels. As the disease progresses, full-blown diabetes ensues and treatment options become more and more limited.
Although insulin resistance usually develops over years, there is an alarming increase in the incidence of Type 2 diabetes among children. Many believe this trend is a result of less active children who may not be exercising sufficiently or eating healthy foods.
Diabetes is a complex disease, and as you have learned from the previous slides, there is more than one way to become diabetic. The end result is the same for both Type 1 and Type 2 diabetes, if left untreated: loss of glucose homeostasis, which can be fatal.
References:
Langley, L.L. (Ed.). (1973). Homeostasis: Origins of the Concept. Langley, National Library of Medicine. Stroudsburg, PA:Dowden Hutchinson, and Ross Inc.
Sherwood, Lauralee. (1997). Human Physiology: From Cells to Systems (3rd ed.). West Publishing Co.
Normal Glucose Homeostasis
Time in years
Time in years
Birth

128. T2D – It is Question of Balance !
PERIPHERAL INSULIN
RESISTANCE
ß-CELL MASS
& FUNCTION
Non-Diabetic State
Diabetic State

129. Pathology of Type 2 Diabetes

130. Time Sequence of Events in T2D

131. Insulin Kinetic Defect in T2D

132. Relative -Cell Function
Natural History of T2D
Slide 1-25
CORE
Obesity IGT* Diabetes Uncontrolled
Hyperglycemia
Post-meal Glucose
Plasma
Glucose
Fasting Glucose
120 (mg/dL)
Relative -Cell Function
Insulin Resistance
Natural History of Type 2 Diabetes
This time slide shows changes in glucose uptake and beta-cell insulin secretion beginning in the prediabetic states of obesity and impaired glucose tolerance (IGT).
Typically, type 2 diabetes begins with obesity and a period of impaired glucose tolerance before symptomatic diabetes is diagnosed. Ultimately, type 2 diabetes can reach the stage of uncontrolled hyperglycemia when beta-cells fail to produce insulin.
The top chart shows the changes in fasting and postprandial plasma glucose and at the bottom are the changes in insulin function and insulin resistance.
In the prediabetic state, insulin secretion rises to compensate for insulin resistance. During obesity, and even in the early phase of the IGT, hyperinsulinemia sufficiently controls plasma glucose levels to keep postmeal and fasting glucose at the normal level, below 125 mg/dL. (DeFronzo, 1992)
100 (%)
Insulin Level
-20
-10 10 20 30
*IGT = impaired glucose tolerance
Years of T2D

133. Net Beta Cell Mass
Neoformation
Apoptosis
Replication
b-cell mass

134. Net Beta Cell Mass Clinical Pearl
Neoformation
Apoptosis
Replication
b-cell mass
Clinical Pearl
Crucial determinant of the course of T2D patient
Beta cell apoptosis is the cause of secondary OHA failure

135. THE FORMULA FOR ß-CELL MASS -
Net Beta Cell Mass
THE FORMULA FOR ß-CELL MASS -
(Mitogenesis + Size + Neogenesis) - Apoptosis = Growth
(Mitogenesis + Size + Neogenesis) > Apoptosis
Increased ß-mass (i.e. compensation for insulin resistance):
Apoptosis > (Mitogenesis + Size + Neogenesis)
Decreased ß-mass (i.e. Type-2 diabetes):

136. Approaches to lower Blood Glucose

137. Approaches to lower Blood Glucose
Clinical Pearl
Various approaches to treat T2D and T1D
To restore normoglycemia is the goal
These approaches have additive effect

138. Evolution of the Modern Cardio-metabolic Man
Grotesque not in physical appearance alone !!

139. Fatty Acid Oxidation - What is the Switch ?
Glucose
Stearoyl CoA Desaturase (SCD)
Thrifty Gene Hypothesis

140. Fatty Acid Oxidation - What is the Switch ?
Glucose
Clinical Pearl
SCD SWITCH MANIPULATION might be the answer
Stearoyl CoA Desaturase (SCD)
Thrifty Gene Hypothesis

141. The Web of Cardio-metabolic pathogenesis

142. Leptin Produced almost exclusively by adipose tissues
Regulates appetite via ‘satiety signal’ to Hypothalamus
Has beneficial effects on muscle fat oxidation and insulin resistance
These are compromised by Leptin insensitivity
Has a suggested role in the development of various cardiac risk factors – including high blood pressure

143. Adipsin (ASP) ASP – Acylation Stimulation Protein
Role in the uptake and esterification of Fatty Acids
Facilitates fatty acid storage through Triacylglycerols
Stimulates Triacylglycerol synthesis via Diacylglycerol Acyl Transferase (DGAT)
Stimulates translocation of GLUT to cell surface
ASP release is induced by HDLc

144. Adiponectin Significant homology to complement factor C1q
Accumulates in vessel walls in response to ET injury
Reduced in obesity
Weight loss causes increase in its levels
Reduced in patients with CAD
Beneficial effects on CAD may be through
Inhibition of mature macrophage function
Modulation of endothelial inflammatory response
Inhibition of TNFα induced release of adhesion molecules

145. WISH YOU ALL A HAPPY NEW YEAR