1.

Metabolic branch points

2. Metabolism in fed and fasting states

3. Hormones in fuel metabolism

4. Interrelationship of metabolism

5. Organ specific metabolism

6. Diabetes mellitus
Metabolic branch points of Glucose-6-phosphate
Glucose 6-phosphate may be converted to:
1. Glucose in gluconeogenic tissues

2. Glucose 1-phosphate which is used in glycogen synthesis

3. Pyruvate through glycolysis.

4. Ribose 5-phosphate, a substrate for nucleic acid synthesis, via the pentose
phosphate pathway.
Metabolic branch point of pyruvate
Pyruvate is the degradation product of anaerobic glycolysis and glucogenic amino
acids

1. can be converted to acetyl CoA by pyruvate dehydrogenase

2. Oxaloacetate in gluconeogenesis.

3. Alanine via transamination.

4. Lactate in muscle tissue

Cont.…

Figure 6. Metabolic branch point of pyruvate

Metabolic branch points of acetylCoA
Pathways interaction
• The citric acid cycle links carbohydrate and fat metabolism and is involved in the
metabolism of amino acids.

• It provides an important control point for regulating metabolite flow in these

pathways

• The enzyme of the glycolytic pathway link up the metabolism of glucose and
other carbohydrates with fat and amino acid metabolism
Metabolic interaction

Figure 8. Pathway interactions: Major oxidative pathways may also act as routes
linking other pathways.
Figure 9: Interrelationship of metabolism at the cellular level
Metabolic Effects of different Hormones
1. INSULIN STIMULATES UTILIZATION OF NUTRIENTS
• Insulin stimulates glycogen, fat, protein synthesis and glycolysis while inhibiting glycogenolysis
and gluconeogenesis by reversing cAMP-induced phosphorylation

This is achieved by two mechanisms

1. Insulin stimulates cAMP phosphodiesterase, which degrades cAMP to AMP.

2. Insulin stimulates phosphatase-1, the enzyme that dephosphorylates the important targets
of the cAMP-activated protein kinase A: stimulated glycogen synthase

3. The basal metabolic rate (BMR) is the amount of energy that a resting person consumes in
the post absorptive” state 8 to 12 hours after the last meal.
INSULIN STIMULATES UTILIZATION OF NUTRIENTS
Insulin stimulate
1. glucose uptake in muscle and adipose via recruitment of GLUT-4 transporters w/c are located in
intracellular storage vesicles

• This move to the cell surface and fuse with the plasma membrane

1. glycogenesis in liver and muscle via activation of GS;

2. amino acid uptake and protein synthesis in most tissues

3. fat synthesis in liver, lactating mammary glands and, to a lesser extent, adipose tissue via
activation of ACC.

• Note: Insulin affects enzymatic activity by covalent dephosphorylation and transcriptional

regulation
• Most of the other insulin effects included here are actions on the rate of
synthesis or degradation of the affected enzyme.

• Insulin acts indirectly by promoting the dephosphorylation of

phosphofructokinase-2/ fructose-2,6-bisphosphatase, thereby increasing the
level of fructose-2,6-bisphosphate.

• Insulin acts by promoting the dephosphorylation of the enzyme

Insulin stimulates glucose metabolism are different in different tissues

• Insulin decreases the activity of intracellular of hormone sensitive lipase (HSL)

• Increases the activity of membrane-associated extracellular LPL enzymes that

degrade TAGs carried in circulating LP particles (CMs and VLDLs), respectively.

• In contrast, insulin increases expression of the gene for LPL in adipocytes

• Insulin activates a phosphatase that dephosphorylates (inactivates) HSL

• In contrast, hepatocytes contain the insulin-insensitive GLUT-2 but insulin have

GLUT-4 on muscle and adipocyte cell membranes which very sensitive .
Insulin stimulates glucose metabolism are different in different tissues

• Blood glucose levels rise with the blunt insulin receptor on their surface of adipocytes
and muscle cells : due to a decrease in function GLUT-4

• Glucose metabolism in brain and erythrocytes is not insulin dependent

• They must keep consuming glucose, even in the fasting state, when the insulin level is low.

• Insulin’s most important effect on fat metabolism is a powerful inhibition of lipolysis in

adipose tissue.

• In the liver excess carbohydrate convert to fat through glycolysis, pyruvate dehydrogenase
reaction, and fatty acid biosynthesis
Table Metabolic Effects of Insulin
2. GLUCAGON MAINTAINS THE BLOOD
GLUCOSE LEVEL
• During starvation, the body covers most of its energy needs from adipose
tissue–derived fatty acids.
• However, neurons and other specialized cell types, such as erythrocytes, cannot
oxidize fatty acids and therefore depend on a steady supply of glucose
• Glucagon is specialized for the maintenance of a normal blood glucose level
during fasting.
• Its secretion from the pancreatic α-cells increases in response to hypoglycemia
• Epinephrine and norepinephrine, produced from Tyr in the adrenal medulla and
sympathetic nervous system, stimulate glucagon secretion from pancreatic cells.
• Amino acids (e.g., Arg) derived from a protein containing meal, also induce
glucagon release.
Glucagon
• Glucagon bound to its membrane GPCR on hepatocytes promotes d/t effects mediated through protein
phosphorylation by PKA.
• FA oxidation,
• ketogenesis,
• glycogenolysis, and
• gluconeogenesis,

Note: Hepatic FA oxidation supplies ATP and NADH for gluconeogenesis and acetyl CoA for ketogenesis.

• Epinephrine inhibits insulin secretion and, when bound to its GPCR, is the primary signal in adipocytes
for the PKA-mediated activation of HSL and subsequent lipolysis that provides FAs to the liver.

• It also promotes glycogenolysis.

Figure 13 Glucagon bound to its membrane
GPCR on hepatocytes
Metabolic effect of glucagon
Glucagon effect

Figure 12 . Mechanism of Glucagon released from αcells of

pancreas in metabolism
Insulin vs Glucagon
Catecholamines hormones
• The catecholamines are stress hormones& are released
• during physical exertion,
• in response to psychological stress.
• Stress usually meant the need to be prepared for physical effort: the flight-or-
fight response
• The catecholamines can raise:
• the cellular cAMP level through β-adrenergic receptors and
• the calcium level through α1-adrenergic receptors.
• Muscle and adipose tissue have mainly β-adrenergic receptors, and the liver has
both β and α1 adrenergic receptors
Catecholamines
The catecholamines are functional antagonists of Insulin that raise the blood levels
of glucose and fatty acids.

• They are not very important for blood glucose regulation under ordinary
conditions, but their release is potently stimulated by hypoglycemia.

• Therefore hypoglycemic episodes in metabolic diseases are always accompanied

by signs of excessive sympathetic activity

• including pallor, sweating, and tachycardia .

Table Metabolic Effects of Norepinephrine &Epinephrine
stress hormone

• The glucocorticoids prepare the body for the action of epinephrine.

• They stimulate the synthesis of the adipose tissue lipases.

• They also increase gluconeogenesis from amino acids by causing net protein breakdown
in peripheral tissues and inducing phosphoenolpyruvate(PEP) carboxy kinase in the liver.

• Excess glucose-6-phosphate produced by gluconeogenesis is diverted into;

• Glycogen synthesis, thus providing more substrate for epinephrine-induced

glycogenolysis

• Glucocorticoids and catecholamines

Stress hormone

• they are stress hormones w/c are troublemakers rather than lifesavers
• Patients suffering from infections, autoimmune diseases, malignancies, injuries,
surgery, or psychological upheaval have elevated levels of these hormones
• the actions of the glucocorticoids are synergistic with epinephrine, but there is an
important difference
• Epinephrine works through the second messengers cAMP and calcium, whereas
• the glucocorticoids are mainly gene regulators.
• Therefore epinephrine induces its effects in a matter of seconds,
• but most glucocorticoid effects are cumulative over hours to days.
Stress hormone

During an extended any stress

• cortisol induced the lipases in his adipose tissue and built up the glycogen stores in
his liver, soon epinephrine immediately stimulated the release of fatty acids from
adipose tissue and of glucose from the liver

• Cortisol-induced protein breakdown leads to negative nitrogen balance and muscle

wasting.

• Because the stress hormones oppose the metabolic effects of insulin,

• seriously ill patients have insulin resistance and poor glucose tolerance.
Table Metabolic Actions of Cortisol & Other Glucocorticoids
Organ specific metabolism
Liver in fed state

• The liver is responsible for the maintenance of blood glucose levels.

• During the fed state, the liver takes up excess glucose and amino acids stores it as
glycogen / fatty acids.

• Some glucose is metabolized by the pentose phosphate pathway for use in

biosynthetic reactions by the liver /produce NADPH

• The liver manage the plasma lipoproteins

• Amino acid levels are also elevated in the blood after a meal, and this wealth of
raw materials is managed by the liver in one of several ways.
Fed state
• Amino acids are used directly by the liver for synthesis of new proteins.

• Insulin promotes the uptake of branched-chain amino acids (valine, leucine,

and isoleucine) by muscle and stimulating on muscle protein synthesis

• Some of the excess amino acids are released into bloodstream for utilization by
other tissues or alternatively, metabolized their carbon skeletons to store for later
use to produce energy.
Metabolism in fed state
Liver metabolism during fasting
Adipose tissue

• where much of the body’s energy reserves are stored as fats, specifically
triacylglycerols, so its role after a
• meal is to convert any excess fuel to fat.
• Insulin action increases glucose uptake by individual fat cells and this accelerates
metabolic activity.
• The rate of glycolysis is increased to provide Acetyl CoA for energy in TCA ,
• Acetyl CoA for fatty acid synthesis (triacylglycerols) using glycerol 3-phosphate
. Besides pentose phosphate pathway is stimulated to
• produce NADPH, which may be needed later for fatty acid
synthesis
• There is net synthesis of glycogen for storage
Adipose tissue metabolism

• FA synthesis is not a major pathway in human adipocytes under most conditions,

• Adipocytes obtain FAs primarily from the degradation of exogenous(dietary)
TAGs in CMs exocytosis from intestine and endogenous TAGs in VLDLs
exocytose from liver.
• LPL attached to the endothelial lining of capillaries in adipose tissue (and
activated by apoC II on LP surfaces) degrades the TAGs to glycerol and FAs.

• Note: In adipose tissue, insulin upregulates LPL expression.

• It also causes HSL dephosphorylation and inactivation, thereby inhibiting
intracellular lipolysis.
Major metabolic pathways in adipose tissue in the absorptive
state
Adipose tissue
• GLUT-4, found in muscle and adipose tissue, is sequestered in intracellular
vesicles.
• In response to insulin, the transporters move to the plasma membrane and allow
blood glucose uptake.
• Mutations that decrease GLUT-4 trafficking would prevent glucose uptake and
cause hyperglycemia.
• Note: In T1D, the lack of insulin results in intracellular retention of GLUT-4 and,
consequently, hyperglycemia.]
Adipose

Fig.17 adipose tissue have insulin receptor GLUT-4

3. Skeletal muscle

• is the major consumer of metabolic fuel and oxygen, owing to its great mass
compared with other tissues.
• stores glucose in the fed state, but cannot release glucose into circulation
• Insulin promotes increased glucose uptake by skeletal muscle.
• The glycogen stores of muscle are not extensive and can be depleted within a few
minutes of intensive exercise,
• but the high level of glucose 6 phosphate availability after a meal allows
glycogen synthesis to replenish the stores.
• Insulin action and the availability of adequate energy and amino acids stimulate
net synthesis of muscle protein, with suppression of protein degradation
Muscle tissue meatbolism

• A key metabolic differences exist between muscle and liver is that insulin greatly
stimulates the transport of glucose into muscle cells but only slightly stimulates
its transport into liver cells.

• BCAAs are catabolized primarily by muscles, the primary location of BCAA

transaminase that initiates their degradation.

• Note :Metabolism of straight-chain amino acids occurs primarily in the liver,

which has low levels of BCAA transaminase.]
Major metabolism in muscle during absorptive state
4. Brain tissue
• Although contributing only 2% of the adult weight, the brain accounts for a consistent 20%
of the basal oxygen consumption of the body at rest.

• Because the brain is vital to the proper functioning of all organs of the body, special priority
is given to its fuel needs

• The brain is dependent on blood glucose (requiring 140 g/day) because it has limited
supplies of glycogen and TAGs.

• Additionally, FFAs do not efficiently pass through the BBB, thus making little contribution to
ATP production in brain
Major metabolic pathways in brain in the absorptive state
 ll. Metabolism in the Fasting State
During the fasting state (4–24 hours after the last meal), blood
glucose levels begin to fall, precipitating major changes in metabolism
with a switch over from an anabolic state to a catabolic condition in
order to maintain blood glucose levels
Glucagon/ Insulin levels increase in the blood.
The glucagon target the liver cell
It is secreted by the α cells of the pancreas in response to a
low blood-sugar level in the fasting state .
A. Metabolism in the Fasting State in liver
it has critical role as central organ for synthesis and distribution of fuel,the
liver export of glucose to peripheral tissues during a short-term fast.

The decreased insulin/glucagon ratio leads to inhibition of glycogen

synthesis and increased glycogenolysis to supply some of the body’s
glucose needs
 Metabolism in the Fasting in liver
1. Stimulation of degradation of glycogen
• Glucagon binds to cell surface receptors and activates
adenylate cyclase, causing cAMP levels in liver cells to
rise
• cAMP activates protein kinase A, which phosphorylates and
inactivates glycogen synthase
• At the same time, protein kinase A stimulates glycogen
degradation by a two step mechanism.
• Protein kinase A phosphorylates & activate phosphorylase
kinase.
• This enzyme, in turn, phosphorylates and activates glycogen
phosphorylase
• PKA also phosphorylates HSL.
45
 Metabolism in the Fasting in liver…
Glycogenolysisis an immediate, short-lived response to fasting,
whereas gluconeogenesisis slower, sustainable, and dependent on
proteolysis and lipolysis
The two metabolic priorities in fasting are to
• (a) maintain adequate blood glucose levels for
glucose- dependent tissues (e.g., RBCs) and
• (b) provide KBs to supply energy to tissues that can use
KBs (e.g.,
muscle and brain), thereby decreasing glucose use
• [Note:KB availability results in decreased muscle
proteolysis.]

46
 Metabolism in the Fasting in liver….
2. STIMULATION OF GLUCONEOGENESIS
• Hormonal changes cause peripheral tissues to release
precursors that provide carbon for gluconeogenesis,
specifically lactate, amino acids, and glycerol.
• Regulatory mechanisms promote the conversion of
gluconeogenic precursors to glucose
• These mechanisms prevent the occurrence of
potential futile cycles, which would continuously convert
substrates to products while consuming energy but
producing no useful result

47
 Metabolism in the Fasting in liver….
• Gluconeogenesis is stimulated in the liver and blocks glycolysis
by lowering
the level of F-2,6-BP
• Additional effects include an increase in TAG and protein
catabolism resulting in increased availability of FAs for
oxidation and glycerol and glucogenic amino acids for
gluconeogenesis.
• The rise in gluconeogenesis causes hyperglycemia
• By 24 hours of fasting, gluconeogenesis provides all the blood
glucose
• [ Note: Glucose is generated from the glucose 6-P product of both
processes by hepaticand (renal) glucose 6-phosphatase.]

48
 Metabolism in the Fasting in liver….
3. STIMULATION OF LIPOLYSIS
• The hormonal changes that occur during fasting Catecholamine-
mediated HSL activation causes degradation of adipose TAGs to
FAs and glycerol
• Glycerol are sent into blood and taken up by the liver
for gluconeogenesis
• Fatty acids become the major fuel of the body and are oxidized to
CO2 and H2O by various tissues, which enables these tissues to
decrease their utilization of glucose
• The FAs are oxidized to acetyl CoA, which is used for ketogenesis
(rather than being oxidized), because the rise in NADH from FA
β- oxidation inhibits the TCA cycle in a prolonged fast .
• ketone bodies made , enter the blood and serve as an additional
fuel source for the muscle and the brain.
49
 Metabolism in the Fasting in liver….
• The liver is unable to use KBs (it lacks thiophorase), and they
are sent out for use by nonhepatic tissues (e.g., brain and
muscle)
• Both muscle and liver use fatty acids as fuel when the blood-
glucose level drops. Thus,
• the blood-glucose level is kept at or above 80 mg/dl by three
major factors:
(1)the mobilization of glycogen by the liver and the release
of glucose, by hyperglycemic hormone
(2) the release of fatty acids by adipose tissue, and
(3) the shift in the fuel from glucose to fatty acids by
muscle and the liver the release of amino acids from muscle
protein
50
Fig 19. Metabolic and fuel movements during early stages of fasting. Glycogenolysis and
glyconeogenesis are speeded up to maintain normal blood glucose level, and ketone
body synthesis is increased for use as fuel molecules (FA fatty acids, KB ketone bodies).
51
 Fasting State metabolism con’t…
B Skeletal muscle
in its resting state can satisfy most of its energy needs by
oxidation of fatty acids taken up from blood, and during the early
stages
fasting,of protein degradation in the muscle is increased.
• Some of the carbons skeletons derived by removal of the
amino groups from the amino acids can be used for
synthesis of glucose via gluconeogenesis.
• Some a/acid carbon skeletons yield acetyl CoA and are used
for synthesis fuel, ketone bodies, which become
more important as the fast extends past 24 hours

• .

52
 Fasting State metabolism con’t…
C. In adipose tissue
It reduced glucose availability via the blood and
the low insulin/ glucagon ratio lead to net degradation of TAG to
their component fatty acids and glycerol to meet the energy
needs of most tissues (exception of the CNS).
1. The fatty acids are oxidized to provide the energy needs of the
adipocytes themselves.
2.As the fast progresses, more of the adipose-derived fatty acids are
transported in the blood stream as complexes with albumin and
taken up by the liver.
3. The glycerol backbones from triacylglycerol breakdown are sent
to the liver for use in gluconeogenesis.

53
D. Brain tissue
• The energy needs of the
brain and other glucose-
requiring organs are
satisfied during the post-
absorptive period through
provision of glucose by the
liver

Fig 20 Energy level during different time fed state

54
 llI. Metabolism During Starvation
If fasting extends past 2 days, which is considered to be a
long-term fast further changes in fuel synthesis and use by
several organs can occur, principally a conversion from a
glucose economy to one dominated by ketone bodies as fuel
In addition to the effects of a low insulin/glucagon ratio, long-term
changes in metabolism during starvation are induced by the
corticosteroid & cortisol.

55
 lll. Metabolism During Starvation in hepatic tissue
A. Metabolism During Starvation in hepatic tissue
The liver is again the major organ that synthesizes the principal
long-term fuel, ketone bodies
eg acetoacetate, and B-hydroxybutyrate, which are made from both
amino acids and fatty acids.
• In prolonged fasting, triacylglycerol degradation in adipose tissue
becomes maximal and sustained.
• Protein breakdown in skeletal muscle can only be sustained
for 10–14 days,
• further degradation of protein would severely compromise
contractile capability.
• Within a few days of fasting, the brain adapts to be able to utilize
ketone bodies as fuel and becomes less dependent on glucose.

56
 Starvation in hepatic tissue con’t…
• Ketogenesis can result in metabolic acidosis if production
outpaces use because the KBs acetoacetate and β -
hydroxybutyrateare organic acids
• Their dissociation in aqueous solutions produces H , thereby
decreasing blood pH.
• [ Note: KBs spare glucose for glucose-dependent tissues (e.g.,
RBCs), reducing gluconeogenesis and preserving muscle.]

B Skeletal muscle
Cortisol promotes net protein breakdown in skeletal muscle
to provide amino acids as precursors for gluconeogenesis and
ketone body synthesis (ketogenesis).

57
 Starvation in hepatic tissue con’t…
• In long-term fasting ( starvation), KBs are the brain’s primary
fuel
source.
• β-Hydroxybutyrate is oxidized to acetoacetate, which is
converted by thiophorase to acetoacetyl CoA that is cleaved to
two acetyl CoA for oxidation in the TCA cycle.
• Gucose metabolism decreased in both adipose and muscle tissue
in the fasting state b/c :
• Glucose metabolism in adipose and muscle tissue is decreased in
the fasting state because these tissues contain insulin-
dependent GLUT-4.
• Consequently, they are not able to take up glucose from the
blood when insulin is low.

58
 Non-hepatic Tissues during Starvation …
C .Adipocytes tissue
• Cortisol also increases the rate of triglyceride
breakdown (lipolysis) in adipose tissue & It
caue releasing the FFAs from intracellular
lipolysis into the blood, and to make KBs in
liver ,Glycerol for formation of glucose
D. brain tissue :
Beside glucose , brain adapt to use of the
alternative fuel, ketone bodies, which is derived
mainly from degradation of fatty acids

Fig 21 brain adapt to use of the

alternative fuel, ketone bodies,
59
Figure 22 . Metabolic activities of major organs during long-term fasting. With glycogen
stores in the liver and muscle depleted, gluconeogenesis is the sole means of providing
for the glucose needs of some organs, while many organs, even the brain, adapt to use of
the alternative fuel, ketone bodies, which is derived mainly from degradation of fatty
acids. FA, fatty acids; PPP, pentose phosphate pathway; TAG, triacylglycerol. 73
 Absorptive State Summary
In the absorptive state:
1. Blood glucose levels and the insulin/ glucagon ratio are increased.
2.Circulating TAG-rich LPs (CMs primarily but also VLDLs) are increased.
3.Amino acids from digestion are available in the blood.
4. KBs are virtually absent.
5.Synthesis of glycogen, TAGs, and proteins is increased.
• A useful “ rule of thumb” for the absorptive state is that covalently regulated
enzymes involved in nutrient storage processes (e.g., hepatic PK, the kinase
domain of hepatic PFK-2, GS, and ACC) are active when they are
dephosphorylated.
• PDH also is active when dephosphorylated, thereby allowing the
conversion of glucose to acetyl CoA for FA (and cholesterol) biosynthesis.
• Enzyme induction (e.g., of ACC) in response to hormonal signals also plays a
role

61
 An autoimmune
disease beta cell
s are destroyed
by immune
system

Figure : Comparison of type 1 and type 2 diabetes.

62
 TYPE 1 DIABETES
 The disease is characterized by an absolute deficiency of
insulin caused by :
o an auto - immune attack on the β cells of the pancreas However,
o symptoms appear abruptly when 80–90% of the β cells have been destroyed
 it is not possible to diagnose the disease prior to
appearance of symptoms
 At this point, the pancreas fails to respond
adequately to ingested glucose &result in chronic
hyperglycemia ,with elevated risk for ketoacidosis and a
variety of long-term complications,
 including retinopathy, neuropathy, nephropathy, and cardiovascular
complications.
 Insulin therapy is required to restore metabolic control
 promotes glucose uptake by tissues
 inhibits gluconeogenesis, lipolysis, and proteolysis
 Metabolic Changes in Type 1 Diabetes
• Insulin dependent diabetes mellitus (IDDM) was once called
juvenile onset diabetes because:-
– it usually appears in childhood or in the teens, but it is
not limited to these patients.
• Untreated, IDDM is characterized by hyperglycemia, hyper-
lipoproteinemia (chylomicrons and VLDLs) and severe ketoacidosis
• IDDM besides being a disease of defects in carbohydrate
metabolism alone, diabetes causes abnormalities in fat and protein
metabolism in such patients as well.
• The hyperglycemia results in part from the inability of the insulin
dependent tissues to take up plasma glucose from diet
• The decrease insulin /glucagon ratio can promote more
• gluconeogenesis process from muscle protein as
precursor
77
 Metabolic Changes in Type1D con’t…
• The ketoacidosis results from increased lipolysis in the adipose
tissue and accelerated fatty acid oxidation in liver.
• the products of which are NADH, acetyl CoA, and ATP.
• The buildup of ATP and NADH inhibits TCA cycle enzymes,
pushing acetyl CoA to ketogenesis
• Excessive KB production can result in DKA
• Hyper chylomicronemia (hypertriglyceridemia ) is the result of low
lipoprotein lipase activity in adipose tissue capillaries
– an enzyme dependent on insulin for its synthesis.
• [ Note:FAs in excess of the liver’s capacity to oxidize them
are converted to TAGs and secreted as VLDLs, contributing to
hypertriglyceridemia.]
• Although insulin therapy does not cure the diabetes, its use
markedly alters the clinical course of the disease. 78
 Metabolic Changes in Type1D con’t…

Figure 23 Inter tissue relationships in type 1 diabetes

66
 Metabolic Changes in Type1D con’t…
•The metabolic disruption in type 1 diabetes is due to decrease
insulin /glucagon action in liver, muscle, and adipose
tissues.
Elevated levels of blood Glucose and ketones are the
hallmarks
of untreated type 1 diabetes mellitus.
Ketosis results from increased mobilization of fatty acids from
adipose tissue, combined with accelerated hepatic fatty acid β-
oxidation
Failure of insulin to suppress, gluconeogenesis in liver
leads to ;
over production of new glucose, which cause the elevation
of blood glucose
b/c no uptake of dietary glucose by muscle and adipose. 67
 Metabolic Changes in Type1D con’t…
• In the absence of insulin and in response to glucagon
stimulation, triacylglycerol
degradation in adipose tissue and the flood of
fatty acids reaching the liver leads to;
– ketone body synthesis .
• Tight control of blood sugar, by injections of insulin per day
has now been proved to reduce the microvascular
complications of diabetes (renal and retinal diseases).

68
 TYPE 1 DIABETES con’t …
• In some ways, the metabolic profile of a patient with
uncontrolled type 1 diabetes resembles that of the starved
patient, except the absence of insulin
• But the ketoacidosis of diabetes is much more severe
than in starvation & associated with
hyperglycemia.
• Peripheral tissues (such as kidneys , skeletal muscle, and
adipose) recepters retain normal responsiveness to insulin,
so management of the disease involves subcutaneous insulin
injection with monitoring of blood glucose several times per
day.

82
Ketone Bodies are an Alternate Energy Source During Fasting
/prolong

Figure 24 Ketone Bodies are energy Source During Fasting /prolong

Short-term fast: Fatty acids are source of ketone bodies

Long-term fast: Amino acids are source of ketone bodies

70
 TYPE 2 DIABETES MELLITUS
• Non insulin dependent diabetes mellitus (NIDDM) accounts for
80–90% of the diagnosed cases of diabetes and is also called
maturity onset diabetes
• It usually occurs in middle aged obese people
• Non insulin dependent diabetes is characterized by hyperglycemia
often with hypertriglyceridemia.
• The ketoacidosis characteristic is not commonly observed
• Increased levels of VLDL are probably the result of increased
hepatic triacylglycerol synthesis stimulated by hyperglycemia
and hyperinsulinemia.

71
 TYPE 2 DIABETES
• The greater the adipose tissue mass , the greater the
production of TNFα , which acts to impair insulin receptor
function.
• An inverse relationship between insulin levels and the
number of insulin receptors present on the plasma
membranes.
• In addition, there are defects within insulin responsive
cells at sites beyond the receptor.
Dysfunctional B-cells results from inadequate glucose sensing to stimulate inulin
secretion ,elevated glucose levels in the b/d
Factor that can damage or destroys B- cells can be hyperglycimia, glucotoxicity ,
lipotoxicity , hy poxia & ROS
Glucotoxicity : it is decrease in insulin secretion & increase in inulin resistance due
to chronic hyperglycemic is know accepted in Glucose toxicity& it worsening dm
by affecting the secretion of B-cells
72
 TYPE 2 DIABETES
• Insulin is present at normal to elevated levels in this form of the
disease.
• Obesity often precedes the development of insulin independent
diabetes and appears to be the major contributing factor
• Obese patients are usually hyper insulinemic.
• Very recent data implicate increased levels of expression of tumor
necrosis factor-α (TNFα) in adipocytes of obese individuals as a
cause of the resistance.
 insulin resistance when our body cells resists the normal effect of
insulin & fall to up take glucose
It is universal present in almost obese individual with typ-2 DM
Cause
• Genetics , aging , excess body weight , lack of exercise &
smoking
• Avoid saturated fats & trans fats which boosts insulin
resistance 73
 TYPE 2 DIABETES con’t…
• Although there is an insulin, it is not as high as in a person who
is obese
• In other words, there is a relative deficiency in the
insulin supply from the β- cells.
• Therefore, this disease is caused not only by insulin resistance
but also by impaired β -cell function resulting in relative insulin
deficiency.
• Diet can often control the disease in the obese diabetic
• If the patient can be motivated to lose weight, insulin receptors
will increase in number, and the post-receptor abnormalities
will improve, which will increase both tissue sensitivity to insulin
and glucose tolerance

74
Figure 25 Non-insulin dependent diabetes mellitus.

75
 Type 2 Diabetes…
• The non insulin dependent diabetic tends not to develop
ketoacidosis but nevertheless develops many of the same
complications as the insulin dependent diabetic, that is, nerve, eye,
kidney, and coronary artery disease
• Hypertriacylglycerolemia with secretion of increased VLDL can lead
to long-term elevated risk of atherosclerosis, although this is a
complicated, multifactorial process.
– Other long-term complications are similar to those caused by
type 1 diabetes, likely due to the chronic hyperglycemia
• An acute complication of T2D is a hyperosmotic Hyperglycemic
state (most common in the elderly) that presents with very
high blood glucose levels,
• severe dehydration, and altered mental status, Coma and
death can result.
76
 Type 2 Diabetes…
• Most obese individuals with insulin
resistance do not develop T2D, the most
common form of diabetes, because still-
functional pancreatic cells produce
suffi-cient insulin to maintain normal
blood glucose levels.
• [ Note:Patients who do develop T2D
have a combination of insulin resistance
and dysfunctional cells but do not
require insulin to sustain life.]

Figure 25. Obesity fosters

insulin resistance via changes
in adipose secretions

77
 TYPE 2 DIABETES con’t…
• In insulin resistance, normal (or elevated) insulin levels fail to
elicit the expected biologic response. Obesity fosters insulin
resistance (shown) via changes in adipose secretions.
• The major secretory changes include increased inflammatory
cytokine(e.g., IL-6) and leptin production and decreased anti-
inflammatory adiponectin production.
• Inflammation contributes to insulin resistance (and to CHD).

78
 Metabolic Alterations in Dm con’t…

Fig.: Metabolic changes in diabetes mellitus

79
 2 Diabetes con’t…
When lifestyle changes alone are insufficient to manage
blood glucose levels, a variety of hypoglycemic agents can be
used.
• Sulfonylureas, stimulate insulin secretion by the beta cells.
• Biguanides such as metformin suppress liver
gluconeogenesis and enhance insulin action in muscle..

80
THANKS !!

81