Cell Growth & Energy metabolism

Carbohydrates
Glucose Pyruvate

Fatty acids

Fats

Amino acids
TCA Cycle
Krebs
Cycle

Proteins
ATP
Glucose-6-Phosphate (G6P)
The Central Molecule
 Glucose Homeostasis
Normal Blood Glucose
Fasting state : 60 to 100 mg%
Postprandial : 100 to 140 mg %

Control systems
Glucose Receptors, GLUT 1-14
Controlling Hormones, Insulin, Glucagon, Cortisol,
Epinephrine etc
Effector Cells Muscles, Liver, Brain, Heart and Adipose
tissue
Feedback loops
Negative feedback

Positive feedback
 Glucose Homeostasis
Lower Blood Glucose Between meals

-cells release
Glucagon
stimulate glucose
stimulate glycogen uptake by peripheral
breakdown and tissues
gluconeogenesis
-cells release insulin

Food
Higher Blood Glucose
 Blood glucose regulation
When we eat food, our blood glucose
concentration rises, which stimulates insulin
secretion from -cells and eventual glucose
absorption by peripheral tissues.

After a meal - glucose enters the blood and taken

up by tissues, excess glucose is transported to the
liver to be converted to glycogen (Glycogenesis).
 In between meals or starvation, we are not
taking in glucose and, therefore, 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.
 Glucose is the major source of energy for cells
Blood Glucose (BG) regulated by Insulin &
Glucagon mainly
Glucose Homeostasis Insulin & Glucagon
Glucose Transport & Absorption in GIT
 Response to Elevated blood glucose
In the post prandial state (after a meal)
There are two separate signaling events
First signal is from the Blood Glucose to
pancreas
to stimulate insulin secretion into 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
 Glucose Entry to the Cell
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
 Liver & Kidney
Major source of net endogenous glucose production:
Accomplished by gluconeogenesis (Liver & Kidney) and
glycogenolysis (Liver) when blood glucose is low and
Glycogenesis (Liver) when blood glucose is high.
Can oxidize glucose for energy and convert it to fat
(Liver) which can be incorporated into VLDL for
transport.
Metabolic effects of insulin in liver
 Muscle
Can convert glucose to glycogen (Glycogenesis)
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 to glucose but cannot
liberate free glucose into the circulation.
Metabolic effects of insulin in Muscle
 Adipose tissue
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.
Effects of insulin in Adipose tissue
Metabolic effects of Glucagon
 Glucose Transporter Proteins (GLUTs)
GLUT - 1 - 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.
 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
 Brain
Brain is the major glucose consumer
Consumes 120 to 150 g of glucose per day
Glucose is virtually the sole fuel for the brain
Converts glucose to CO2 and H2O
Brain does not have any fuel stores like glycogen
Is not capable of gluconeogenesis
Cant metabolize fatty acids as fuel
Therefore blood glucose level should be
maintained always in a normal range
 Requires oxygen always to burn its glucose
Can not live on anaerobic pathways
Therefore oxygen and glucose supply can not be
interrupted

Can use ketone bodies as a fuel during prolong

starvation
Regulation by feed back mechanism
blood glucose

insulin

transport of glucose into cells,
gluconeogenesis, glycogenolysis

blood glucose

insulin
 Role of Insulin
On Carbohydrate metabolism
Increases uptake of glucose
Promotes glycogen storage
Stimulates glucokinase
Inhibits gluconeogenesis
Inhibits hepatic glycogenolysis
Inactivates liver phophorylase
On Lipid Metabolism
Insulin promotes fatty acid synthesis
Stimulates formation of -glycerol phosphate
-glycerol phosphate + Fatty acyl CoA = TG
TG are incorporated into VLDL and transported to
adipose tissues for storage.
Insulin inhibits hormone-sensitive lipase (HSL)
Thus decreasing fat utilization.
On 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
 Diabetes Mellitus
DM is a group of syndromes characterized by raised
fasting blood glucose caused by a relative or
absolute deficiency in insulin.
Can be separated into two groups-
Type 1 (Insulin-dependent DM)
Type 2 (Non-insulin-dependent DM)

The incidence & prevalence of type 2 is increasing

because of increasing prevalence of obesity and
sedentary lifestyles.
Comparison of type 1 and type 2 DM
Type 1 Diabetes Type 2 Diabetes
Age of Onset Usually during Frequently after age
childhood or puberty, 35, symptoms
symptoms develop develop gradually
rapidly
Nutritional status at Frequently under Obesity usually
the time of disease nourished present
onset
Prevalence 10% of diagnosed 90% of diagnosed
diabetics diabetics
Genetic predisposition Moderate Very strong
Defect of Deficiency B cells are destroyed, Insulin resistance
eliminating production combined with
of insulin inability of B cells to
produce appropriate
quantities of insulin
 Type 1 Diabetes Type 2 Diabetes

Frequency of Ketosis Common Rare

Plasma Insulin Low to absent High early in disease,
low in disease of long
duration

Acute Complications Ketoacidosis Hyperosmolar coma

Treatment with Oral Unresponsive Responsive
hypoglycemic drugs

Treatment Insulin is always Diet, exercise, oral

necessary hypoglycemic drugs,
+/- Insulin
 Type 2 Diabetes mellitus
Most common form, develops gradually
Detected by routine screening tests.
Common symptoms- Polyuria & polydipsia
Defects- Insulin resistance or dysfunctional
cells or combination
Metabolic alterations- mild
Diagnosis- Fasting Blood glucose >126mg/dl
 Metabolic changes in type 2 DM
Hyperglycemia- caused by increased hepatic
production of glucose combined with diminished
peripheral use
Ketosis- usually minimal or absent because of
presence of insulin & diminishes hepatic ketogenesis
Hypertriacylglycerolemia- in liver- fatty acids are
converted to TAG which are secreted in VLDL.
Because of lipoprotein lipase activity is low in
diabetics, chylomicrons & VLDL are elevated.
 HbA1C (Glycosylated Hb)
Glucose + Protein Glycosylation
products (Hb) (HbA1c)

Early Glycosylation products are chemically

reversible (hours). Later they form a more stable
Amadori product

Glycosylation is directly related to the level of

blood glucose level.
 Learning outcome
Explain how glucose homeostasis is maintained in
the body
Discuss the metabolic derangements associated
with Diabetes