The document discusses the gastrointestinal system and its organs including the mouth, stomach, pancreas, small intestine, and liver. It then describes the liver's functions of producing proteins and bile, storing vitamins and minerals, converting and utilizing fats and carbohydrates, and removing waste. The document notes that carbohydrates provide 60% of the body's energy, with proteins and fats each contributing around 10-12% and 30%, respectively. It outlines the journey of glucose from food to different body parts and its utilization and storage. Key steps in glucose utilization are its entry into cells, phosphorylation, and energy release.
3. Liver functions
• Production – plasma proteins,
blood clotting proteins, bile
pigments
• Storage – vitamins, minerals,
fat, glucose as glycogen
• Conversion/utilization – fats,
carbohydrates, proteins
• Removal – aged blood cells,
drugs or toxins, waste products
4. Energy source for body
• Proteins: 10-12%
• Fats: 30%
• Carbohydrates: 60%
5. Journey of Glucose
Food Carbohydrates Formation
formed of glucose
Glucose Glucose Glucose enters
enters reaches different blood
Cell body parts
Mediated
by Insulin
Glucose used for various functions
Extra glucose stored in a different form
6. Steps in utilization of glucose
Entry of glucose in cell
Phosphorylation of glucose
Release of energy
7. • Facilitates the transport of glucose into muscle and adipose
cells
• Facilitates the conversion of glucose to glycogen for storage
in the liver and muscle.
• Decreases the breakdown and release of glucose from
glycogen by the liver
Insulin-Carbohydrate Metabolism
8. • Stimulates protein synthesis
• Inhibits protein breakdown; diminishes gluconeogenesis
Insulin - Protein Metabolism
9. • Stimulates lipogenesis- the transport of triglycerides to
adipose tissue
• Inhibits lipolysis – prevents excessive production of ketones
or ketoacidosis
Insulin - Fat Metabolism
11. Endocrine function
• Hormones act on target tissues to exert its effect
• Produced by the islet of Langerhans – number of cells in each islet
vary from several hundred to millions
• Glucagon – alpha cells
– Secreted when blood glucose levels fall
• Insulin – beta cells
– Secreted when blood glucose levels rise
• Somatostatin – delta cells
– Secreted in response to any kind of food intake – suppresses both
insulin and glucagon and may extend the period of nutrient absorption
and utilization
12.
13. What is insulin?
• A hormone
– (from Greek - "to set in motion") is a chemical messenger from
one cell (or group of cells) to another.
• Insulin is the protein hormone produced by cells in the
pancreas that regulate levels of glucose and regulate
metabolism in glucose, fats, and proteins.
• Insulin is composed of 51 amino acids.
• Amino acids are the basic structural building units of proteins
• Its formula is C254 H377 N65 O75 S6.
14. Role of Insulin
• Hormone secreted by beta cells of
pancreas
• Controls the rate of entry of glucose
inside the cell
• Increases glucose utilization rate in
the cell
• Increases rate of glucose transport
in the cell by more than 10 times.
Hexamer of insulin
16. Regulation of Hormone Secretion
• Non-hormonal
– Control of release dependent
upon concentration of other
non-hormonal substance
(i.e., glucose)
17. Few Important Definitions...
• Glycolysis: Breakdown of glucose to release energy
• Glycogenesis: Formation of glycogen for storage from
unutilized glucose
• Glycogenolysis: breakdown of stored glycogen into
glucose
• Gluconeogenesis: formation of glucose from sources
other than carbohydrate (fat/protein) to meet energy
requirement
18. C-peptide
• Insulin manufactured and stored
as proinsulin (86 AA)
• C-peptide (31 AA) ensures correct
folding of protein
• Enzymatic cleavage (4 AA lost)
and equal amount released along
with insulin (51 AA)
• C-peptide levels measured to
assess insulin production
• No physiological role – used as an
insulin marker
20. Insulin Biosynthesis in the Beta Cell
Insulin gene codes for
pre-proinsulin
Release by exocytosis
Proinsulin
C-peptide
Glucose Insulin storage in
vesicles
21. Physiological Effects of Insulin
• Major target organs:
– Liver: insulin increases storage of glucose as
glycogen
– Muscle: insulin stimulates glycogen and protein
synthesis.
– Adipose: insulin stimulates triglyceride storage
22. Date :12th Mar 09 Valid: 11th Mar 10
Arrest of K+ release
Ca2+
Opening of
Ca2+ channel
Ca2+
K+
K+ K+
ATP
Metabolism
Glucokinase
Glucose
Glucose
Glucose
GLUT 2
Insulin release
ATP
Glucose
Insulin release in non - diabetics
BETA CELL
23. Date :12th Mar 09 Valid: 11th Mar 10
Insulin receptors
Glucose
Glycogen
Metabolism
GLUT4
Dephosphorylation
Translocation
Intracellular vesicle
pGLUT4
ATP
The non - diabetic peripheral cell
24. Insulin secretion
• Insulin secretion increases almost 10 folds within 5 to 10
minutes of food intake.
• Insulin secretion is stimulated by glucose
25. The Basal/Bolus Insulin Concept
• Basal insulin
– Continuous, constant, low level secretion for 24 hours
– Suppresses glucose production between meals and overnight
– 40% to 50% of daily needs
• Bolus insulin (mealtime)- 2 phases
– Limits hyperglycemia after meals
– Immediate rise and sharp peak at 1 hour
– 10% to 20% of total daily insulin requirement at each meal
27. Phases of insulin release
• First phase
– Release starts as soon as food comes to the stomach
– Preformed stored insulin is released
– 10-fold increase in levels within 3-5 minutes
– Speeds up the use of glucose
– Within 5-10 minutes, insulin secretion decreases by half
• Second phase
– Rising glucose levels send signals to the beta cell nucleus
DNA produces mRNA mRNA produces more insulin
– Causes a less acute rise in insulin levels
– Reaches a plateau in 2-3 hours
31. • 1500BC – Egyptians recorded diabetes as polyuria
• 1st Century AD – diabetes described as “the melting down of flesh and
limbs into urine”
• 20th Century – children with Type 1 diabetes had life expectancy of 2
years
– Hypothesized that liver and pancreas were involved in some way,
although cause unknown
• 1922 – Frederick Banting & Co. successfully isolate insulin extract for
diabetes Type 1
• 2011 – Type 2 diabetes comprises roughly 90% of all diagnosed cases,
likely due to increased obesity and inactivity levels
History of Diabetes
32. Diabetes Mellitus
Derived from Greek roots
dia – through
bainein – to go
To go through – meaning syphon
Mellitus – Latin „mel‟ for „honey‟
Diabetes Mellitus – Sweet syphon
33. Diabetes – Definition
Diabetes Mellitus is a metabolic disorder caused
by reduced availability or diminished effectiveness
of insulin, characterized by hyperglycemia with or
without glycosuria.
34. Diabetes Mellitus
• Chronic medical condition
• Inability to properly utilize glucose
• Diabetes can cause acute medical emergencies
–Too much glucose (hyperglycemia)
–Too little glucose (hypoglycemia)
38. • Low or absent endogenous insulin
• Dependent on exogenous insulin for life
• Onset generally < 30 years
• 5-10% of cases of diabetes
• Onset sudden
– Symptoms: 3 P‟s: polyuria, polydypsia, polyphagia
Type I Diabetes
41. • Insulin levels may be normal, elevated or depressed
– Characterized by insulin resistance,
– diminished tissue sensitivity to insulin,
– and impaired beta cell function (delayed or inadequate
insulin release)
• Often occurs >40 years
Type II Diabetes
43. • Risk factors: family history, sedentary lifestyle, obesity and
aging
• Controlled by weight loss, oral hypoglycemic agents and or
insulin
Type II Diabetes
44. TYPE I + TYPE II
Type I Diabetes Type II Diabetes
GLUCOSE
GLUCOSE
INSULIN
CELL
CELL
46. Pathogenesis of DM
• Insulin resistance
• Impaired insulin secretion
• Excessive hepatic glucose production
47.
48. Pathogenesis of DM (Contd.)
Insulin Resistance:
• Decreased ability of insulin to act effectively on
peripheral tissue
• This resistance is relative, since increased levels of
insulin will normalize the Pl. glucose level
Mechanism – exact not known
• Decrease in insulin receptors or post receptor
defect
49. • Major defect in individuals with type 2 diabetes1
• Reduced biological response to insulin1–3
• Strong predictor of type 2 diabetes4
• Closely associated with obesity5
IR
1American Diabetes Association. Diabetes Care 1998; 21:310–314.
. J Clin Invest 1994; 94:1714–1721. 3Bloomgarden ZT. Clin Ther 1998; 20:216–231.
4Haffner SM, et al. Circulation 2000; 101:975–980. 5Boden G. Diabetes 1997; 46:3–10.
Insulin Resistance
1American Diabetes Association. Diabetes Care 1998; 21:310–314.
2Beck-Nielsen H & Groop LC. J Clin Invest 1994; 94:1714–1721.
3Bloomgarden ZT. Clin Ther 1998; 20:216–231.
4Haffner SM, et al. Circulation 2000; 101:975–980.
5Boden G. Diabetes 1997; 46:3–10.
51. Pathogenesis of DM (Contd.)
Impair insulin secretion
• Initially insulin secretion increase in response to
insulin resistance to maintain normal blood
glucose levels
• In later stage beta cell failure develops due to
lipo and glucotoxicity - low insulin levels
52. Pathogenesis of DM (Contd.)
Increased hepatic glucose production
• Liver maintain Plasma glucose level during fasting
state by glycogenolysis and gluconeogenesis (A.A.,
F.A., glycerol)
• In DM because of insulin resistance, insulin fails to
suppress gluconeogenesis which leads to increased
blood glucose levels.
55. Diagnostic criteria for type 2 diabetes
Blood Glucose
Parameter
HbA1c FPG PPPG
Normal
< 6.5%
< 100 mg/dl < 140 mg/dl
Pre-diabetes ≥ 6.5 - 7% 100-125 mg/dl (IFG)
140-199 mg/dl
(IGT)
Diabetes ≥ 7% 126 mg/dl or above 200 mg/dl or above
56. Definitions
IGT impaired glucose tolerance –
– 2hr plasma glucose is between 7.8mmol/l (140mg/dl) and
11.0mmol/l (200mg/dl)
IFG impaired fasting glucose –
– Fasting plasma glucose is 6.1–6.9mmol/l (100–125mg/dl)
Diabetes-
– Confirmed fasting plasma glucose is ≥7.0mmol/l (126mg/dl)
– 2hr plasma glucose is ≥11.0mmol/l (200mg/dl)
57. Prediabetes & Diabetes
diabetesprediabetesnormoglycemic
100mg/dl 125 mg/dl
140 mg/dl 199 mg/dl
Fasting glucose
2hr Plasma glucose
Prediabetes is a condition in which the blood sugar level is higher than normal,
but not high enough to be classified as diabetes
59. Chronic
Hyperglycemia
Over secretion of
insulin to compensate
for insulin resistance1,2
High circulating
free fatty acids
Glucotoxicity2
Pancreas
Lipotoxicity3
-cell dysfunction
. Eur J Clin Invest 2002; 32:14–23., 2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–
22.,3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.
Why does the -cell fail?
1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23.
2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22.
3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.
60. What is -cell dysfunction?
• Major defect in individuals with type 2 diabetes
• Reduced ability of -cells to secrete insulin in
response to hyperglycemia
DeFronzo RA, et al. Diabetes Care 1992; 15:318–354.
63. Évolution of diabetes
Normal
Compensation
phase
Diabetes
DeFronzo R.A. et al., Diabetes Care (1998)
Insulin Resistance & Insulin Deficiency:
2 strongly linked mechanisms
At the time of diagnosis, both defects are already combined
Insulin
resistance
Fasting
blood glucose
Insulin
secretion
64. Type 2 diabetes
Years from
diagnosis
0 5-10 -5 10 15
Pre-diabetes
Onset Diagnosis
Insulin secretion
Insulin resistance
Postprandial glucose
Macrovascular complications
Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789;
Nathan DM. N Engl J Med. 2002;347:1342-1349
Fasting glucose Microvascular complications
Natural History of Type 2 Diabetes
65. Abnormal
glucose tolerance
Hyperinsulinemia,
then -cell failure
Normal IGT* Type 2 diabetes
PPPG
Insulin
resistance
Increased insulin
resistance
FPG
Hyperglycemia
Insulin
secretion
*IGT = impaired glucose tolerance
Role of IR and -cell dysfunction in T2DM
International Diabetes Center (IDC), Minneapolis, 2000.
66. -12 -6 0 6 12
0
20
40
60
80
100
Years
Diagnosis
UKPDS 16 diabetes 1995, 44:1249-1258
Progressive -cell Failure in Type 2 Diabetes
67. Insulin resistant;
low insulin secretion (54%)
Insulin resistant;
good insulin secretion (29%)
Insulin sensitive;
good insulin
secretion (1%)
Insulin sensitive;
low insulin secretion (16%)
83%
More IR patients are progressing to T2DM
Haffner SM, et al. Circulation 2000; 101:975–980.
68. Date :12th Mar 09 Valid: 11th Mar 10
Arrest of K+ release
Ca2+
Opening of
Ca2+ channel
Ca2+
K+
K+ K+
ATP
Metabolism
Glucokinase
Glucose
Glucose
Glucose
GLUT 2
Insulin release
ATP
Glucose
Insulin release in non-diabetics
69. Date :12th Mar 09 Valid: 11th Mar 10
Partial Arrest of K+ release Opening of
Ca2+ channel
Ca2+
K+
K+ K+
ATP
Metabolism
Glucokinase
Less Glucose
GLUT 2
Insulin release
ATP
Glucose
Glucose
Glucose
Insulin release in diabetics
K+
70. Date :12th Mar 09 Valid: 11th Mar 10
Insulin receptors
Glucose
Glycogen
Metabolism
GLUT4
Dephosphorylation
Translocation
Intracellular vesicle
pGLUT4
ATP
The non-diabetic peripheral cell
71. Date :12th Mar 09 Valid: 11th Mar 10
Insulin receptors
Glucose
Glycogen
Metabolism
GLUT4
Dephosphorylation
Translocation
Intracellular vesicle
pGLUT4
ATP
The diabetic peripheral cell
72.
73. Absolute Insulin Deficiency Relative Insulin Deficiency
No Glucose oxidation
(lack of energy)
Excessive Hunger
(polyphagia)
More Glucose production (from
glycogen, amino acids and Glycerol)
Kidney retains (up to 160-180 mg%)
Above 160-180 mg %
Glycosuria
Polyuria
Osmosis
Water loss
Polydipsia
What goes wrong in diabetes?
74. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Symptoms of Diabetes
75. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Diagnosis of Diabetes
Polyuria – Increased micturition
Polydipsia – Increased thirst
Polyphagia – Increased hunger
Fatigue
Skin infections
Impotence
Tingling, numbness
76. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Diagnosis: Long Term Control
77. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Glycated Hb (Hb A1c)
• Increased blood glucose level leads to an
increase in non enzymatic glycation of Hb.
• It reflects glycaemic control over past 2-3
months.
• Normal = < 6%
78. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Chronic Complication of Diabetes Mellitus
Microvascular Macrovascular
Eye Disease
Retinopathy
(nonproliferative/proliferative)
Macular edema
Cataracts
Glaucoma
Neuropathy
Sensory ,motor & Autonomic
Nephropathy
Coronary artery disease
Peripheral vascular disease
Cerebrovascular disease
Other
Gastrointestinal
(gastroparesis, diarrhea)
Genitourinary
(uropathy/sexual
dysfunction)
Dermatologic
79. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Diabetes – Chronic complications
80. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
92. Bonora E, et al. Diabetes Care 2002; 25:1135–1141.
Insulin Resistance is as strong a risk
factor for Cardio Vascular Disease.
Hanley AJ, et al. Diabetes Care 2002; 25:1177–1184.
Bonora E, et al. Diabetes Care 2002; 25:1135–1141.
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Age Smoking Total cholesterol:
HDL cholesterol
Insulin
resistance
93. Present in > 80% of people
with type 2 diabetes1
Approximately doubles the
risk of a cardiac event2
Implicated in almost half of
CHD events in individuals with
type 2 diabetes2
Insulin
Resistance
IR
1Haffner SM, et al. Circulation 2000; 101:975–980.,2Strutton D, et al. Am J Man Care 2001; 7:765–773.
Insulin Resistance is closely linked to
Cardio Vascular Disease
1Haffner SM, et al. Circulation 2000; 101:975–980.
2Strutton D, et al. Am J Manag Care 2001; 7:765–773.
95. Obesity as a risk factor
World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity
96. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease
Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Goals of Therapy
TO MAINTAIN BLOOD GLUCOSE AT NEAR-NORMAL LEVELS
(70-120MG/DL)
REDUCE THE RISK OF COMPLICATIONS
97. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Management Strategies
SELF
MEDICATIONS
MONITORING
EDUCATION
98. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Management of Diabetes
Diet
Exercise
Weight Management
OHA
Insulin
99. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Treatment of Type 2 Diabetes
• Monotherapy with oral agent
• Combination therapy with oral agents
• Insulin +/- oral agent
–insulin required in 20-30% of patients
With duration of the disease, more intensive therapy is required
to maintain glycemic goals
101. Address the underlying
pathophysiology,
including treatment of
insulin resistance and
Beta cell function
Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.
How can diabetes care and outcomes
be improved?
102. • By 2030, India will become the Diabetic Capital of
the World
• DM is the leading cause of blindness, End Stage
Renal Disease and Amputations
• Over 60% of ESRD is due to Diabetes
• 70 % Diabetics die of – CHD, CVD
• Leading cause of non traumatic LL amputation
• So, screen all for Diabetes and for risk factors
India Diabetes Fast Facts
104. Glucose output
Insulin resistance
Biguanides
Insulin
secretion
Sulfonylureas/
meglitinides
Carbohydrate
breakdown/
absorption
-glucosidase
inhibitors
Insulin
resistance
Thiazolidinediones
Primary sites of action of
Oral Anti-diabetic agents
1Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.
2Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endo. Metab 1999; 13:309–329.
105. • Biguanides (Metformin) lowers the production of glucose
made in the liver
• Well accepted as the drug of first choice in Type II
• Major side effects are GI
• Lactic acidosis rare but serious side effect
Biguanides:(Glyciphage-Metformin)
109. • Oldest of oral medecine
• Until 1995 the only meds available
• 1st gen- Tolbutamide
• 2nd gen-Glipizide, Glibenclamide, Gliclazide
• 3rd gen- Glimeperide
• Stimulate the pancreas to release more insulin, hypoglycemia
can be side effect
Sulfonylureas
110. Glimepiride MOA
Forced closure of
K+ATP Channel
by Glimepiride
Glucose metabolism &
Increase in ATP
Decreased K efflux
Depolarization of
Membrane
Voltage-gated Ca
Channels open
Translocation of
Granules and Exocytosis
Insulin release
Glucose entry into
cells
Closes ATP-dep.
K Channel
111. • Ex: Repaglinide, Nateglitinide
• Stimulate insulin secretion when there is glucose present in
the blood stream
• Used with meals
Meglitinides
112. • Example: Acarbose, Miglitol, Voglibose
• Delay the conversion of carbohydrates into glucose during
digestion
• Major side effect gas/bloating limits use
Alpha-Glucosidase Inhibitors
113. Blood
glucose control
GI
tract
Ingestion
of food
Villi of Small Intestine
Voglibose
Alpha Glucosidase Enzyme
Glucose
Prolongs glucose absorption
due to reversible inhibition
of enzyme
Retards sudden
absorption of glucose
Voglibose
116. +
HbA1c
Insulin
Resistance IR
-cell
function
Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.
The dual action of TZDs
1Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.
2Rosenblatt S, et al. Coron Artery Dis 2001; 12:413–423.
117. • Dipepityl Peptidase 4 inhibitor-slows the inactivation of
GLP-1 and GIP (glucose-dependent insulinotropic
polypeptide)
• Example: Sitagliptin, Saxagliptin, Vildagliptin
• Very minimal side effects, weight neutral
• Most effective when used with metformin
DPP-4 Inhibitors
118. • Exenatide-originally isolated from the saliva of Gila monster Lizard
• Shares several of the coregulatory effects of the incretin glucagon-
like peptide-1(GLP-1)
• Improves glucose dependent insulin secretion
• Restores first phase insulin response
• Suppresses inappropriate glucagon secretion
• Slows rate of gastric emptying
• Increases satiety
• BID injection, main side effect nausea/weight loss
Incretin Mimetics
Ultimately, more intensive insulin regimens may be required (see Figure 3.)Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a 2-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycaemia (e.g. HbA1c ≥10.0-12.0%). Consider beginning with insulin if patient presents with severe hyperglycemia (≥300-350 mg/dl [≥16.7-19.4 mmol/l]; HbA1c ≥10.0-12.0%) with or without catabolic features (weight loss, ketosis, etc).