Regulation of Blood Sugar Level at the Whole Animal

1
Regulation of Blood Sugar Level at the Whole
Animal
Course MPB 333

• Owen McGuinness
• January 11, 2010

Contact info Phone [phone] Office 831C Light
Hall e-mailOwen.mcguinness_at_vanderbilt.edu
2
Regulation of Glucose Homeostasis the Metabolic
Challenge of Insulin Resistance
3
What is a normal fasting Glucose concentration?

• Normal fasting levellt110 mg/dl
• Impaired glucose intolerance110-125 mg/dl
• Diabetes mellitusgt125mg/dl

4
Where is glucose?
5
Glucose diffuses down a concentration gradient
Diffusion
Glucose ? mg/dl
Glucose 100 mg/dl
ISF
Cell
Capillary
6
If the arterial glucose100 mg/dl and insulin is
at a basal concentration, what is the glucose
concentration in a muscle cell?

1. 100 mg/dl
2. Slightly less than 100 mg/dl (98 mg/dl)
3. Very low 2 mg/dl
4. Greater than 100 mg/dl

7
3. Very low 2 mg/dl
Cell
Glu-6P
Glu
A
V
GLU 100 mg/dl
GLU 98 mg/dl
Blood flow
8
Multiple Metabolic Fates of Glucose
GLUT
Glucose
HK II
Glucose-6 P
GS
PFK
Glycogen
PDH
Pyruvate
CO2 H2O
Lactate
9
If arterial glucose100 mg/dl ,what is the
interstitial glucose concentration outside a
muscle cell?

1. 100 mg/dl
2. Slightly less than 98 mg/dl
3. Very low 2 mg/dl
4. Greater than 100 mg/dl

10
2. Slightly less than 98 mg/dl
Cell
Glu-6P
Glu
A
V
GLU 100 mg/dl
GLU 98 mg/dl
Blood flow
11
Steady State
Plasma Glucose
InOut
OutClearance x Concentration
12
Relationship between Mass and Concentration
13
Glucose mass (70 kg individual)

• Total body water (TBW)60 Body Weight
• 42 L TBW (0.60 70 kg)
• Extracellular fluid volume (ECF)1/3 TBW
• 14 L ECF volume of distribution of glucose
• Glucose 100 mg/dl1 mg/ml1 g/L
• 14 grams glucose in ECF
• 9 g/hr flux rate rate of liver glucose
  production

14
Glucose Ingestion (75 g)
Plasma Glucose (14 g)
InOut9 g/h
OutClearance x Concentration
15
Ingest 75 grams glucose

• 75 grams in 300 ml water (2 cokes)
• Assuming it takes about 20 min to absorb the
  glucose (225 g/h)
• By 180 minutes the glucose concentration returns
  to normal
• Removed 5.3 times the mass of glucose in the body
  in 180 min

16
75 grams
17
75 g glucose load

• If you did nothing
• glucose level exceed 500 mg/dl

18
CNS
?
?
6 g/hr
Brain
Glucagon Insulin
Insulin


Muscle Fat
Liver
Glucose90 mg/dl
3 g/hr
9 g/hr
Overnight fasted state
19
?Cholinergic
CNS
50 g/hr
Intestine
6 g/hr
Brain
? Insulin
?or ? Glucagon ?Insulin


Muscle Fat
Liver
12 g/hr
32 g/hr
?Glucose130 mg/dl
Fed state
20
CNS
5 g/hr
Brain
?Glucagon ?Insulin
? Insulin


Muscle Fat
7 g/hr
Liver
2 g/hr
?Glucose70 mg/dl
Ketones
Prolonged fasted state
21
CNS
Adrenergic
6 g/hr
Brain
?Glucagon ?Insulin
?Insulin


Increased Muscle Energy Demand
Muscle Fat
Liver
Glucose90 mg/dl
40 g/hr
46 g/hr
Fight or Flight state
22
CNS
6 g/hr
Brain
?Glucagon

Muscle Fat
Liver
lt1 g/hr
?Glucosegt300 mg/dl
26 g/hr
Kidney
19 g/hr
Ketones
Type I Diabetic state ( loss of insulin
secretion)
23
Net Organ Uptake
(A-V) flow uptake
24
Hepatic vein
25
Net Splanchnic uptake
Splanchnic bed liver Intestine Spleen pancreas
(Artery-HepaticVein) flow uptake
26
Splanchnic Bed
Producer and/or glucose consumer Liver Intestine
27
Splanchnic metabolism during hyperglycemia
Diabetic
Non-Diabetic

• Persistent glucose production in diabetic (i.e.
  negative balance)
• Failure to take up glucose with additional
  insulin
• The failure to activate uptake and suppress
  production both contribute

Low insulin
High insulin
28
Individuals with type II diabetes The liver
produces glucose despite high glucose levels
29
Insulin Resistant

• Tissue glucose uptake increases in proportion to
  the available glucose
• Insulin facilitates this process in tissues that
  respond to insulin
• ?transport
• ?phosphorylation
• ?Glycogen synthesis
• ?Glucose oxidation
• Insulin resistance impairs this process

Normal
30
Steady State
Plasma Glucose
InOut
OutClearance x Concentration
31
Diabetes Trends Among Adults in the
U.S.,(Includes Gestational Diabetes)BRFSS,
1990,1995 and 2001
Source www.cdc.gov.
32
CNS
6 g/hr
Brain
Glucagon ??Insulin
?? Insulin


Muscle Fat
Liver
Glucose120 mg/dl
3 g/hr
9 g/hr
Overnight Fasted Insulin Resistant state
33
Compensation for insulin resistance

• Increase insulin secretion
• Mild to severe hyperglycemia (Diabetes Type II
  NIDDM) because of inadequate pancreas
  compensation
• Glucose production by liver and uptake by
  peripheral tissues can be normal or increased

34
Tools used in vivo to assess glucose homeostasis
and insulin action
35
(No Transcript)
36
MEASUREMENT OF GLUCOSE PRODUCTION IN VIVO
Tracer Method ( dilution principle) 3-3H
Glucose infusion Data analysis with two
compartment model A-V Difference Method
Blood glucose difference across organ Blood
flow across organ
37
x
38
(No Transcript)
39
(No Transcript)
40
(No Transcript)
41
(No Transcript)
42
Sampling site Portal Vein and Artery

• If you infuse a substance into the portal vein,
  the concentration of the substance in the portal
  vein will be greater than in any other vessel

43
(No Transcript)
44
Impact of insulin on tissues

• Enhance muscle glucose uptake
• Decrease liver glucose production
• Decrease arterial glucose level
• Inhibit lipolysis
• To prevent hypoglycemia exogenous glucose is given

45
The gold standard for quantifying insulin
sensitivity in vivo
Exogenous Glucose Infusion rate (GIR)
Primed-constant Insulin Infusion
Variable Glucose Infusion
46
Defronzo RA et al AJP E214,1979
47
Peripheral insulin sensitivity
48
(No Transcript)
49
Hepatic Insulin Sensitivity
Basal Insulin
50
Peripheral vein
51
Diabetes and insulin resistance

• Insulin resistance
• Normal or elevated insulin levels
• Inappropriately increased lipolysis
• Insulin ineffective and in many cases pancreatic
  defects limit adaptation
• Underlying inflammation can aggravate defects

52
The End