4.diabetes basic

Gastro-intestinal system

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 entersenters reaches different bloodCell body partsMediated

by Insulin

Glucose used for various functionsExtra 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

• 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

Clickrole.wmv

Role 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

GLUCOSEGLUCOSE

INSULININSULIN

CELLCELL EnergyEnergy

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

Opening of Ca2+ channel

Ca2+K+

Metabolism Glucokinase

GlucoseGlucose

Glucose

GLUT 2

Insulin release

Glucose

Insulin release in non - diabetics

BETA CELL

Insulin receptors

Glucose

Glycogen

Metabolism

GLUT4Dephosphorylation

Translocation

Intracellular vesicle

pGLUT4

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 2 4 6 8 10 12 14 16 18 20 22 24

Time (Hours)

Meal Meal Meal

Basal Insulin Needs

Bolus insulin needs

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

Insulin release

glycogen synthesis glycogenolysis triglyceride synthesis ketogenesis gluconeogenesis

glucose uptake protein synthesis protein degradation glycogen synthesis glycogenolysis

glucose uptake triglyceride storage lipolysis

Stimulates Inhibits

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

InsulinResistance

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

Type I Diabetes Cell

• 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

• Controlled by weight loss, oral hypoglycemic agents and or

insulin

Type II Diabetes

TYPE I + TYPE II

Type I Diabetes Type II Diabetes

GLUCOSE

INSULIN

CELLCELL

DM – Type I / II

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

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.

Insulin Resistance

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

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

Insulinresistance

Glucose output Glucose uptake Glucose uptake

Hyperglycemia

Liver Muscle Adiposetissue

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.

InsulinResistance

Genetic susceptibility,

Obesity, Sedentary lifestyle

Type 2 diabetes

IRb-celldysfunction

Core defects in T2DM

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.

Évolution of diabetes

NormalCompensation

phaseDiabetes

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

Insulinresistance

Fasting blood glucose

Insulinsecretion

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

Abnormalglucose tolerance

Hyperinsulinemia,then -cell failure

Normal IGT* Type 2 diabetes

Insulin resistance

Increased insulinresistance

FPG Hyperglycemia

Insulinsecretion

*IGT = impaired glucose tolerance

Role of IR and -cell dysfunction in T2DM

International Diabetes Center (IDC), Minneapolis, 2000.

-12-12 -6-6 00 66 121200

100100

YearsYears

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%83%

More IR patients are progressing to T2DM

Haffner SM, et al. Circulation 2000; 101:975–980.

Arrest of K+ release

Opening of Ca2+ channel

Ca2+K+

GlucoseGlucose

Glucose

GLUT 2

Insulin release

Glucose

Insulin release in non-diabetics

Partial Arrest of K+ release Opening of Ca2+ channel

Less Glucose

GLUT 2

Insulin release

Glucose

Insulin release in diabeticsK+

Insulin receptors

Glucose

Glycogen

Metabolism

Translocation

pGLUT4

The non-diabetic peripheral cell

Insulin receptors

Glucose

Glycogen

Metabolism

Translocation

pGLUT4

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

PolyuriaOsmosis

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

Gastrointestinal

(gastroparesis, diarrhea)

Genitourinary

(uropathy/sexual

dysfunction)

Dermatologic

Diabetes – Chronic complications

Diabetes 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

DIABETICMACROVASCULARCOMPLICATIONS

Stroke

Peripheral Vascular Disease

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.

tio fo

Age Smoking Total cholesterol:HDL cholesterol

Insulinresistance

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

InsulinResistance 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

ResistanceIR

Insulin Resistance is linked to a range of Cardio Vascular risk factors

Zimmet P. Trends Cardiovasc Med 2002; 12:354–362.

~90% of people with

type 2 diabetes are

overweight or obese

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,

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

Management Strategies

NUTRITION EXERCISE

ICATIO

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

Glucose Release

Pancreas

LiverAdipose Muscle

Circulatory System

Glucose

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)

Metformin MOA

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.

Non-sensitizers Sensitizers

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

Bloodglucose 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

(Pioglitazone)

• PPAR-g activator

• insulin sensitivity

• No hypoglycemia

• Durability

• TGs, HDL-C, CVD

Pioglitazone

Pioglitazone MOA

Improved Insulin Sensitivity

Thiazolidinedione

InsulinResistance IR

-cellfunction

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

What does the

ADA / EASD

guidelines say?

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,

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:S11-63HDL = high-density lipoprotein; LDL = low-density lipoprotein;

PG = plasma glucose; TG = triglycerides.

Thank You

126 Figure – Normal insulin action pathway

Insulin Actions

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