4.diabetes basic

Gastrointestinal system
• Mouth
• Stomach and
duodenum
• Pancreas
• Small intestine
• Liver and other organs

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

Energy source for body
• Proteins: 10-12%
• Fats: 30%
• Carbohydrates: 60%

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

Steps in utilization of glucose
Entry of glucose in cell
Phosphorylation of glucose
Release of energy

• 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

• Stimulates protein synthesis
• Inhibits protein breakdown; diminishes gluconeogenesis
Insulin - Protein Metabolism

• Stimulates lipogenesis- the transport of triglycerides to
adipose tissue
• Inhibits lipolysis – prevents excessive production of ketones
or ketoacidosis
Insulin - Fat Metabolism

Pancreas
• Exocrine function
– Digestive enzymes
• Pancreatic amylase
• Pancreatic lipase
• Trypsin
• Chymotrypsin
• Carboxypolypeptidase
• Nuclease
• Endocrine function
– Hormones
• Insulin
• Glucagon
• somatostatin

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

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.

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

Regulation of Hormone Secretion
• Non-hormonal
– Control of release dependent
upon concentration of other
non-hormonal substance
(i.e., glucose)

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

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

GLUCOSE
INSULIN
CELL Energy
How the body uses Food

Insulin Biosynthesis in the Beta Cell
Insulin gene codes for
pre-proinsulin
Release by exocytosis
Proinsulin
C-peptide
Glucose Insulin storage in
vesicles

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

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

Insulin receptors
Glucose
Glycogen
Metabolism
GLUT4
Dephosphorylation
Translocation
Intracellular vesicle
pGLUT4
ATP
The non - diabetic peripheral cell

Insulin secretion
• Insulin secretion increases almost 10 folds within 5 to 10
minutes of food intake.
• Insulin secretion is stimulated by glucose

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

0
10
20
30
40
50
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (Hours)
Meal Meal Meal
Basal Insulin Needs
Bolus insulin needs
Seruminsulin(mU/L)

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

glycogen synthesis glycogenolysis
triglyceride synthesis ketogenesis
gluconeogenesis
glucose uptake
protein synthesis protein degradation
glycogen synthesis glycogenolysis
glucose uptake
triglyceride storage lipolysis
Stimulates Inhibits
 Liver
 Skeletal Muscle
 Adipose tissue
Promotes anabolic
processes
Inhibits catabolic
processes
Effects of insulin:

Glucose metabolism
&
Diabetes mellitus

• 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

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

Diabetes – Definition
Diabetes Mellitus is a metabolic disorder caused
by reduced availability or diminished effectiveness
of insulin, characterized by hyperglycemia with or
without glycosuria.

Diabetes Mellitus
• Chronic medical condition
• Inability to properly utilize glucose
• Diabetes can cause acute medical emergencies
–Too much glucose (hyperglycemia)
–Too little glucose (hypoglycemia)

Diabetes
Insulin
Release
Insulin
Resistance
Diabetes

Diabetes Mellitus
Types of Diabetes
• Type 1 Diabetes
• Type 2 Diabetes
• Gestational Diabetes

Action of Insulin on the Cell Metabolism

• 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

• Genetic component to disease
Type I Diabetes

• 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

• Risk factors: family history, sedentary lifestyle, obesity and
aging
• Controlled by weight loss, oral hypoglycemic agents and or
insulin
Type II Diabetes

TYPE I + TYPE II
Type I Diabetes Type II Diabetes
GLUCOSE
GLUCOSE
INSULIN
CELL
CELL

Pathogenesis of DM
• Insulin resistance
• Impaired insulin secretion
• Excessive hepatic glucose production

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

• 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.

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

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.

Diagnosis of Diabetes
 Polyuria – Increased micturition
 Polydipsia – Increased thirst
 Polyphagia – Increased hunger
 Fatigue
 Skin infections
 Impotence
 Tingling, numbness

Diagnosis of diabetes
Symptoms + Elevated blood glucose level
OR
Elevated blood glucose levels on two occasions

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

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)

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

Insulin
resistance
 Glucose output  Glucose uptake  Glucose uptake
Hyperglycemia
Liver Muscle Adipose
tissue
IR
Insulin Resistance – Reduced response
to circulating insulin

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.

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.

Insulin
Resistance
Genetic
susceptibility,
Obesity,
Sedentary lifestyle
Type 2 diabetes
IR
-cell
dysfunction
Core defects in T2DM
Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.

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

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

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.

-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

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.

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

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+

Insulin receptors
Glucose
Glycogen
Metabolism
GLUT4
Dephosphorylation
Translocation
pGLUT4
ATP
The non-diabetic peripheral cell

Insulin receptors
Glucose
Glycogen
Metabolism
GLUT4
Dephosphorylation
Translocation
pGLUT4
ATP
The diabetic peripheral cell

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?

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

Diagnosis of Diabetes
 Polyuria – Increased micturition
 Polydipsia – Increased thirst
 Polyphagia – Increased hunger
 Fatigue
 Skin infections
 Impotence
 Tingling, numbness

Diagnosis: Long Term Control

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%

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

Diabetes – Chronic complications

ClickMan.wmv
Diabetes Complications

DIABETIC
MICROVASCULAR
COMPLICATIONS

Underlying cause:
 AGE formation
 Increased Free Radicals
 Lipid Peroxidation
Diabetic Retinopathy

Underlying cause:
 AGE formation inside Arterioles of Glomerulus
Diabetic Nephropathy

Underlying cause
 Insufficient blood supply to nerves connecting peripheral parts.
 Microvascular AGE
Diabetic Neuropathy

DIABETIC
MACROVASCULAR
COMPLICATIONS

Underlying cause:
 Plaque formation and Thrombogenesis.
 LDL oxidation and Lipid imbalance
Coronary Artery Disease

Underlying cause:
 Disturbed or altered Systolic and Diastolic Blood-Pressure
Hypertension

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

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.

Atherosclerosis
Hyperglycemia
Dyslipidemia
Hypertension
Damage to blood vessels
Clotting abnormalities
Inflammation
Insulin
Resistance
IR
Insulin Resistance is linked to a range of
Cardio Vascular risk factors
Zimmet P. Trends Cardiovasc Med 2002; 12:354–362.

Obesity as a risk factor
World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease
Surveillance,
Goals of Therapy
 TO MAINTAIN BLOOD GLUCOSE AT NEAR-NORMAL LEVELS
(70-120MG/DL)
 REDUCE THE RISK OF COMPLICATIONS

Management Strategies
SELF
MEDICATIONS
MONITORING
EDUCATION

Management of Diabetes
 Diet
 Exercise
 Weight Management
 OHA
 Insulin

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

Diabetes : Pathogenesis
Circulatory System
Pancreas
Defective
Insulin
Secretion
FFA
Liver
Adipose Muscle
Circulatory System
Glucose
FFA

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?

• 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

Diabetes Medications
• Biguanides Ex:Metformin
• Sulfonylureas Ex:Tolbutamide, Glipizide, Glimepiride
• Meglitinides Ex:Repaglinide, Nateglinide
• Alpha Glucosidase Inhibitors Ex:Acarbose, Miglitol, Voglibose
• Thiazolidinediones Ex:Pioglitazone
• DPP4 inhibitors Ex:Sitagliptin, Vildagliptin, Saxagliptin
• GLP-1 analogs Ex:Exanatide, Liraglutide
• Insulin

 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.

• 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)

Myocardial
infarction
All-cause mortality
Sulfonylureas/Insulin
Myocardial
infarction
Significant
All-cause
mortality
Significant
Metformin
21% 8% 39% 36%
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.
Decreasing Insulin Resistance Decrease
Macro Vascular complications
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.

12-monthcombinedeventrate(%)
0
10
20
30
40
Non-sensitizers Sensitizers
50
60
Kao JA, et al. J Am Coll Cardiol 2004; 43:37A.
Insulin sensitizers reduce CV events in T2DM
J Am Coll Cardiol 2004; 43:37A.

• 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

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

• Ex: Repaglinide, Nateglitinide
• Stimulate insulin secretion when there is glucose present in
the blood stream
• Used with meals
Meglitinides

• Example: Acarbose, Miglitol, Voglibose
• Delay the conversion of carbohydrates into glucose during
digestion
• Major side effect gas/bloating limits use
Alpha-Glucosidase Inhibitors

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

Class Mechanism Advantages
TZDs
(Pioglitazone)
• PPAR-g activator
•  insulin sensitivity
• No hypoglycemia
• Durability
•  TGs,  HDL-C,  CVD
Pioglitazone

Pioglitazone MOA
Improved Insulin Sensitivity
Thiazolidinedione

+
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.

• 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

• 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

• Rapid Acting
• Intermediate Acting
• Long Acting
• Premixed Insulin
Insulin

PG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012

ANTI-HYPERGLYCEMIC THERAPY
Glycemic targets
- HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l])
- Pre-prandial PG <130 mg/dl (7.2 mmol/l)
- Post-prandial PG <180 mg/dl (10.0 mmol/l)
- Individualization is key:
 Tighter targets (6.0 - 6.5%) - younger, healthier
 Looser targets (7.5 - 8.0%+) - older, comorbidities, hypoglycemia
prone, etc.
PG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012
ADA-EASD Position Statement:
Management of Hyperglycemia in T2DM

Diabetes Care, Diabetologia., 19 April 2012 [Epub ahead of print]

American Diabetes Assoc. Goals
HbA1C < 7.0% (individualization)
Preprandial glucose 70-130 mg/dL (3.9-7.2 mmol/l)
Postprandial glucose < 180 mg/dL
Blood pressure < 130/80 mmHg
Lipids
LDL: < 100 mg/dL (2.59 mmol/l)
< 70 mg/dL (1.81 mmol/l) (with overt CVD)
HDL: > 40 mg/dL (1.04 mmol/l)
> 50 mg/dL (1.30 mmol/l)
TG: < 150 mg/dL (1.69 mmol/l)
Guidelines for Glycemic, BP, & Lipid Control
ADA. Diabetes Care. 2012;35:S11-63
HDL = high-density lipoprotein; LDL = low-density lipoprotein;
PG = plasma glucose; TG = triglycerides.

126
Figure – Normal insulin action pathway
Insulin Actions

4.diabetes basic

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