Diabetes MellitusDiabetes Mellitus

Prof Fawaz Ammari F.R.C.P (London)

JUST (University)

Diabetes Mellitus Diabetes Mellitus

DefinitionClassificationEtiologyDiagnosisTreatmentComplication

C peptideProinsulinInsulinMW

Ca2+-dependent endopeptidases

A Chain

B Chain

PC2(PC3)

PC3

Insulin release: normal levelsInsulin release: normal levels

Units: 1 U = 36 µg, i.e. 28 U/mgDaily secretion in humans: 40 - 50 UBasal plasma insulin: 12 µU/mlPostprandial insulin: up to 90 µU/ml

Basal

Meal

G

luc

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g/d

l 120

100

80

80

60

40

20

Insu

lin,

U/m

l

Minutes 0 30 60 90 120

Insulin metabolismInsulin metabolism Secreted into portal circulation

50% of degradation in liver50% of degradation in other target tissues and

kidneyEnzymatic degradation follows receptor-

mediated endocytosis

Plasma half-life: 3 - 5 min.– Circulates as free monomer

glycogen synthesis glycogenolysis triglyceride synthesis ketogenesis gluconeogenesis

glucose uptake protein synthesis protein degradation glycogen synthesis glycogenolysis

glucose uptake triglyceride storage lipolysis

StimulatesStimulates InhibitsInhibits Liver

Skeletal Muscle

Adipose tissue

Promotes anabolic Promotes anabolic processesprocesses

Inhibits catabolic Inhibits catabolic processesprocesses

Effects of insulin:Effects of insulin:

Abnormalities due to insulin deficiencyAbnormalities due to insulin deficiency Hyperglycemia

– Underutilization of glucose– Overproduction of glucose

Increased lipolysis Acidosis - Increased conversion of fatty acids to

ketoacids (acetoacetic and -hydroxybutyric) Increased plasma triglycerides and LDL; decreased

HDL Osmotic diuresis, plasma hyperosmolarity, dehydration,

hypovolemia, polydipsia Depletion of intracellular and whole-body K+

Definition of DMDefinition of DM

D M is a group of metabolic diseases characterized by hyerglycemia resulting from defects in insulin secretion .insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction,and failure of various organ,especially the eye,kidneys,heart,and blood vessels.

150

221

300

100

150

200

250

300

350

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2000 2010 2025

The worldwide pandemic of The worldwide pandemic of type 2 diabetestype 2 diabetes

International Diabetes Federation Diabetes Atlas 2000; Amos et al. Diabet Med 1997;14 (Suppl 5):S1-S85.

Prevalence of type 2 diabetes in selected populations aged 30-64 years (Age standardised)

Polynesian Cook Islands

0 10 20 30 40 50

Pima Indian

Asian Indian Fiji

Chinese Mauritius

Hispanic US

Black US

White US

Polynesian

Bantu

China

Prevalence (%)

Country 1995 (millions) Country 2025 (millions)

Rank

1 India 19.4 India 57.2

2 China 16.0 China 37.6

3 U.S. 13.9 U.S. 21.9

4 Russian Fed. 8.9 Pakistan 14.5

5 Japan 6.3 Indonesia 12.4

6 Brazil 4.9 Russian Fed. 12.2

7 Indonesia 4.5 Mexico 11.7

8 Pakistan 4.3 Brazil 11.6

9 Mexico 3.8 Egypt 8.8

10 Ukraine 3.6 Japan 8.5

All other countries 49.7 103.6

Total 135.3 300.0

Top ten countries for estimated number of adults with diabetes, 1995 and 2025

Diabetes Mellitus in the US: Diabetes Mellitus in the US: Health Impact of the DiseaseHealth Impact of the Disease

DiabetesDiabetesBlindnessBlindness**

Renal Renal failure* failure*

Amputation*Amputation*

Life expectancy Life expectancy 55to 10 yrto 10 yr

CardiovascularCardiovasculardisease disease 2X to 4X2X to 4X

*Diabetes is the no. 1 cause of renal failure, new cases of blindness, and nontraumatic amputations*Diabetes is the no. 1 cause of renal failure, new cases of blindness, and nontraumatic amputations

Nerve damage in Nerve damage in 60% to 70% of patients60% to 70% of patients

6th leading cause of 6th leading cause of death death

Diabetes StatisticsDiabetes Statistics. October 1995 (updated 1997). NIDDK publication NIH 96-3926. . October 1995 (updated 1997). NIDDK publication NIH 96-3926. Harris MI. In: Harris MI. In: Diabetes in America. Diabetes in America. 2nd ed. 1995:1-13. 2nd ed. 1995:1-13.

Diabetes Mellitus in the US: Diabetes Mellitus in the US: Higher Mortality RiskHigher Mortality Risk

45456464

65657474

7575

Relative Risk*Relative Risk*

Age Group (yr)Age Group (yr) MenMen WomenWomen

Geiss LS et al. In: Geiss LS et al. In: Diabetes in America. Diabetes in America. 2nd ed.2nd ed. 1995:233-257.1995:233-257.

*For persons with type 1 or 2 diabetes vs nondiabetic individuals*For persons with type 1 or 2 diabetes vs nondiabetic individuals

3.43.4

2.02.0

1.61.6

4.64.6

3.13.1

2.02.0

Annual Healthcare Costs for DiabetesAnnual Healthcare Costs for DiabetesPatients, 1992 ($ Billions)Patients, 1992 ($ Billions)

DME = durable medical equipmentDME = durable medical equipment Rubin RJ et al. Rubin RJ et al. J Clin Endocrinol MetabJ Clin Endocrinol Metab. 1994;78:809A-809F.. 1994;78:809A-809F.

ProfessionalProfessionaloffice visitsoffice visits$11.0 (10%)$11.0 (10%)

Emergency roomEmergency room$1.3 (1%)$1.3 (1%)

Drugs and DMEDrugs and DME$9.9 (9%)$9.9 (9%)

Home healthcareHome healthcare$4.0 (4%)$4.0 (4%)

DentalDental$1.4 (1%)$1.4 (1%)

Inpatient hospitalInpatient hospital$65.2 (63%)$65.2 (63%)

Outpatient hospitalOutpatient hospital$12.5 (12%)$12.5 (12%)

$105 Billion$105 Billion

Type 1 diabetesType 1 diabetes* (* (-cell destruction, usually leading to-cell destruction, usually leading to

absolute insulin deficiency) absolute insulin deficiency)– immune mediatedimmune mediated– idiopathicidiopathic

Type 2 diabetesType 2 diabetes* (may range from predominantly insulin* (may range from predominantly insulin

resistance with relative insulin deficiency to a predominantlyresistance with relative insulin deficiency to a predominantly

secretory defect with insulin resistance)secretory defect with insulin resistance)– adult onsetadult onset– obesityobesity

Impaired glucose toleranceImpaired glucose tolerance Gestational diabetesGestational diabetes

Classification of Diabetes MellitusClassification of Diabetes Mellitus

ADA. ADA. Diabetes Care. Diabetes Care. 1997;20:1183-1197.1997;20:1183-1197.

*Patients with any form of diabetes may require insulin treatment at some *Patients with any form of diabetes may require insulin treatment at some stage of their disease; such use of insulin does not, of itself, classify the patientstage of their disease; such use of insulin does not, of itself, classify the patient

Genetic defects of Genetic defects of -cell function-cell function Genetic defects in insulin actionGenetic defects in insulin action Diseases of the exocrine pancreasDiseases of the exocrine pancreas EndocrinopathiesEndocrinopathies Drug- or chemical-inducedDrug- or chemical-induced Physiologic stress (eg, infection)Physiologic stress (eg, infection) Uncommon forms of immune-mediated diabetesUncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated Other genetic syndromes sometimes associated

with diabeteswith diabetes

Etiologic Classification of Diabetes MellitusEtiologic Classification of Diabetes Mellitus

ADA. ADA. Diabetes Care. Diabetes Care. 1997;20:1183-1197.1997;20:1183-1197.

Criteria for the Diagnosis of Diabetes: Criteria for the Diagnosis of Diabetes: 1997 ADA Guidelines1997 ADA Guidelines

Plasma Glucose Level (mg/dL)Plasma Glucose Level (mg/dL)

*Third criterion: *Third criterion: 200 mg/dL casual plasma glucose (regardless of time since last meal) 200 mg/dL casual plasma glucose (regardless of time since last meal) plus symptoms of diabetes (polyuria, polydipsia, unexplained weight loss)plus symptoms of diabetes (polyuria, polydipsia, unexplained weight loss)

Stage of Stage of Glycemic ControlGlycemic Control

Fasting Plasma Fasting Plasma GlucoseGlucose

OGTT OGTT (2-hr Postload Glucose)(2-hr Postload Glucose)

<100<100

100 –100 – 125 125

126126

<140<140

140 –140 – 199 199

200200

ADA. ADA. Diabetes Care.Diabetes Care.1997;20:1183-1197.1997;20:1183-1197.

Normal Normal

IFGIFGoror

IGTIGT

Diabetes*Diabetes*

Glucose Tolerance CategoriesGlucose Tolerance Categories

American Diabetes Association. Diabetes Care. 2007;30(suppl 1)

FPG 2-h PPG (OGTT)

126

60

80

100

120

140

160

180

200

Plasma glucose(mg/dL)

Normal

Diabetes Mellitus

240

220

Diabetes Mellitus

Normal

IGT

IFG

Plasma glucose(mmol/L)

11.1

7.0

5.5

Pathogenesis of Type I DMPathogenesis of Type I DM

Environment ?Environment ?

Viral infe..??Viral infe..??Genetic Genetic

HLA-DR3/DR4HLA-DR3/DR4

Severe Insulin deficiencySevere Insulin deficiency

ß cell Destructionß cell Destruction

Type I DMType I DM

Autoimmune Insulitis Autoimmune Insulitis

Pathogenesis of Type II DMPathogenesis of Type II DM

EnvironmentEnvironment

Obesity ???Obesity ???ß cell defectß cell defect

GeneticGenetic

ß cell ß cell

exhaustionexhaustion Type II DMType II DM

Insulin resistanceInsulin resistance

Relative Insulin Def.Relative Insulin Def.

IDDMIDDM

Abnormal SecretionAbnormal Secretion

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

Natural History of Type 2 Natural History of Type 2 DiabetesDiabetes

Macrovascular complicationsMicrovascular complications

Insulin resistanceInsulin resistance

ImpairedImpairedglucose toleranceglucose tolerance

UndiagnosedUndiagnoseddiabetesdiabetes Known diabetesKnown diabetes

Insulin secretionInsulin secretion Postprandial glucose

Fasting glucoseFasting glucose

Type-I Type-I Type-IIType-II

Age: < 40 Years Duration: Weeks Ketonuria: Common Insulin- Dependent Autoantibody: Yes Family History: No Insulin levels: very low Islets: Insulitis Complications:

– Acute & Metabolic

> 40 Years Months to years Rare Independent * No Yes Normal or high * Normal / Exhaustion Complications

– Late and vascular.

Clinical FeatureClinical Feature Polyuria and thirst Weakness or fatigue Polyphagia and weight loss Blurring of vision Vulvovaginitis or pruritus Nocturnal enuresis Asymptomatic May presented with acute complication May presented with late complications

Management of DiabetesManagement of Diabetes

DIETDIETEXERCISEEXERCISEOHAOHAINSULININSULIN

Adapted from Nathan DM, et al. Diabetologia 2006;49:1711–21

A new sense of urgency to treat more effectively and quickly

• Lifestyle intervention (HbA1c ↓1–2%)

• Metformin (HbA1c ↓1.5%)

STEP 1 Initial therapy

STEP 2 After 2–3 months select

1 additional agent

STEP 3 Adjust therapy

• Basal insulin (HbA1c ↓1.5–2.5%)

• Sulfonylureas (HbA1c ↓1.5%)

• Thiazolidinedione (HbA1c ↓0.5–1.4%)

•Start or intensify insulin therapy

• Add a third oral agent if cost-effective

•

Type 2 diabetes is a progressive disease with steadily worsening glycemia

Addition of medication is the rule – not the exception – to maintain treatment goals

HbA1c ≥ 7%

HbA1c ≥ 7%

First international consensus EASD/ADA June First international consensus EASD/ADA June 06 06

Call to action : Call to action : 3 steps to keep control3 steps to keep control

DIETDIET Diet is the coroner stone of manag of DM There is no stander diabetic diet Diet must be individualized Flexibility in use ordinary food is important Diet must be of adequate calories for maintaining

weight for adult,normal growth for children,increased metabolic needs in pr

Diet must contain 10-20% of protein 20-30% fat and 50-60% carbohydrate

Fiber intake must be increase

Control of blood glucoseControl of blood glucose is is essentialessential in diabetic patients in diabetic patients

with any possible method with any possible method ((DietDiet, , Oral agentsOral agents, or , or InsulinInsulin))

Otherwise, The Otherwise, The complicationscomplications of diabetes will appearof diabetes will appear

Pathophysiology of Type 2 DMPathophysiology of Type 2 DM

Insulin resistance insulin receptor number insulin receptor kinase activity– Post-receptor defects GLUT4 translocation from impaired signaling

Impaired islet function– Loss of first phase insulin secretion secretion of proinsulin– Defective pulsatile insulin secretion– Deposition of islet amyloid polypeptide

Treatment of Type 2 DiabetesTreatment of Type 2 Diabetes

Diet and exercise– 80 % of Type 2 diabetics are obese caloric intake

physical exercise – first line of treatment – recent clinical trial showed that exercising at

least 30 minutes a day reduces Type 2 risk more effectively than medication

} insulin sensitivity

Treatment of Type 2 DiabetesTreatment of Type 2 Diabetes

Monotherapy with oral agentCombination therapy with oral agentsInsulin +/- oral agent

–insulin required in 20-30% of patients

With duration of the disease, more intensive therapy With duration of the disease, more intensive therapy is required to maintain glycemic goalsis required to maintain glycemic goals

Oral Drug Therapy for Type 2 DMOral Drug Therapy for Type 2 DM

Sulfonylureas Repaglinide

Nateglinide Biguanides Thiazolidinediones Acarbose

Miglitol

}}}

Insulin secretagogues

Insulin sensitizers

Inhibitors of CHO absorption

Sulfonylureas: Metabolism & Excretion Sulfonylureas: Metabolism & Excretion

Metabolized in the liverHepatic dysfunction will alter pharmacokinetics

ExcretionSecond generation: significant fecal excretion

Glyburide -50%Glimeperide - 40%

Clinical Uses of SulfonylureasClinical Uses of Sulfonylureas

Hypoglycemic agents for treatment of Type 2 diabetes mellitus

Act by increasing endogenous insulin secretion not indicated for Type 1

Most effective when ß cell function has not been severely compromised

Increased insulin secretion favors lipogenesis Most appropriate in non- or mildly obese Up to 160 % of ideal body weight

Adverse Effects of SulfonylureasAdverse Effects of Sulfonylureas

Severe hypoglycemia– Overdose – Early in treatment– Most common with glyburide

Weight gainErythema, skin reactionsBlood dyscrasias (abnormal cellular elements)Hepatic dysfunction and other GI

disturbances

Pregnancy

Surgery

Severe infections

Severe stress or trauma

Severe hepatic or renal failure

Insulin therapy should be used in all of these

Contraindications for SulfonylureasContraindications for Sulfonylureas

METFORMIN (Profile)

Class: biguanideMode of action: - Decreases hepatic glucose production

- Enhances muscle glucose uptake* As monotherapy or combination with other drugs* Useful in obese pationts with dyslipedemiaContraindications: renal failure - Cr>1.5 mg/dl - liver failure

Congestive heart failure - DKA - SepsisDye procedures (temporarily discontinue) alcoholism

Adverse Effects: Lactic acidosis (very rare) - Anorexianau sea - diarrhea (transient)

No weight gain - No hypoglycemia - No hyperinsulinemia

REPAGLINIDE (Profile)REPAGLINIDE (Profile)REPAGLINIDE (Profile)REPAGLINIDE (Profile)

Class: Meglitinides

Mode of Action: Stimulating release of insulin via distinct beta cell bindings sites a part from sulfonylurea binding site

* Benzoic acid derivatives* has greater effect postprandially* Fast onset and offset action

Contraindication: DKA - Type 1 diabetes - hypersensitivity

Adverse effects: hypoglycemia - hypersensitivity - weight gain

ACARBOSE (Profile)ACARBOSE (Profile)ACARBOSE (Profile)ACARBOSE (Profile)Class: alpha -Glucosidase inhibitor

Mode of Action: - inhibiting alpha-glucosidase locally in small intestine- Slows intestinal absorption of carbohydrates- reduces postprandial hyperglycemia

* As monotherapy or combination with sulfonylurea* Most useful in patients with exaggerated postprandial

hyperglycemia

Contraindications: IBD, Ulcer, malabsorption, partial intestinal obstraction

Adverse Effects: Flatulence - bloating (very common but may subside over the time)

* monitoring of transaminase / 3 months

ROSIGLITAZONEROSIGLITAZONEROSIGLITAZONEROSIGLITAZONE

Class: thiazolindendione

Mode of Action: binds to peroxisome profilerator - activated receptor -gamma regulation of glucose and fatty acid metabolism (young et al 1998)

* Significantly improved FBS & HbA1C in type 2 diabetics ( clinical investigator news 1998)

Adverse effects: Rosiglitazone = placebo

However; minor anemia - fluid retention -

weight gain

New Diabetes AgentsNew Diabetes Agents Pramlintide

– Synthetic Amylin– Taken as pre-meal subcutaneous injections

Insulin is continued– Type 2 and Type 1 patients

Exenatide– Incretin mimetic

Possesses the effects of GLP-1 Resistant to breakdown by DPP-4

– Twice daily subcutaneous injections with pen device– Type 2 DM patients not controlled on sulfonylurea, metformin or TZD

Sitagliptin, Vildagliptin– DPP-4 inhibitors– Once daily oral agent– Type 2 DM patients as monotherapy or combination with metformin, glimepiride or

TZD

                                                                   

InsulinInsulin Insulin is a protein hormone consisting of two long-

chain peptides (the A-chain containing 21 amino acids and the B-chain containing 30) which are connected by two pairs of sulphur atoms (termed disulphide bridges).

Porcine insulin differs from human insulin in only a single amino acid

Bovine insulin has only two additional substitutions.

Insulin structureInsulin structure The structure

(amino-acid sequence) of human insulin.

Each small circle refers to an amino acid.

The highlighted residues are those that differ in porcine and bovine insulins, as show.

Insulin type Onset Duration Peak Other Characteristics

Rapid acting (R)

0.5-1h 6-8h 2-3h SQ injection does not produce sharp physiologic peak; give 30 min before

meal

Very rapid acting (lispro,

aspart, glulisine)

0.25-0.5h

4-6h 1-2h Give 10-15 min before meals

Intermediate (N)

2-4h 10-14h 4-8h Do not pre-mix with very rapid acting insulins

Long acting

(glargine, detemir)

gradual ~24h None or small

Must not be diluted or mixed with any other insulin or

solution

Insulin PreparationsInsulin Preparations

0 4 8 12 16 20 24

from LillyDiabetes.comUltra fast/ultra short-acting

Short-acting

Intermediate-acting

Long-acting

Ultra long-acting

lispro

regular

NPH

lente

ultralente

glarginefrom lantus.com

Pla

sm

a [I

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breakfast

4 8 12 4 8 12 4 8 12

am pm am

breakfast

lunchsnack

dinner

Insulin treatment regimensInsulin treatment regimensConventional insulin treatment

– 1 or 2 daily subcutaneous injections– mixture of short- and intermediate or long-acting insulins

regular

lente

totaltotal

Insulin treatment regimensInsulin treatment regimensIntensive insulin treatment

– Frequent monitoring of blood glucose– 3 or more daily injections of insulin– Some regular alone, some combined regular and

intermediate- or long-acting– Adjusted to needs of individual patient

4 8 12 4 8 12 4 8 12

am pm am

4 8 12 4 8 12 4 8 12

am pm am

regularlente

4 8 12 4 8 12 4 8 12

am pm am

lisproglargine

4 8 12 4 8 12 4 8 12

am pm am

Insulin treatment regimensInsulin treatment regimensContinuous subcutaneous insulin infusion

– Insulin pump with lispro or regular insulin– Programmed basal delivery

allows control of “dawn phenomenon”

– Patient-triggered bolus before meals

Incidence of DKA is increased vs. that with multiple daily injections

Continuous infusionregular or

lispro 4 8 12 4 8 12 4 8 12

am pm am

Guideline on dosage of insulinGuideline on dosage of insulin

The correct dose of insulin is that which achieve the best glycemic control

The daily insulin dose is 0.5-0.6 iu/kg /dailyThe start dose for normal wt patient 15-20iuThe start dose for obese patient 25-30 iu2/3 of the dose in the morning 1/3 in the eve1/3 rapid acting 2/3 intermediate acting

Insulin dosage depends on Insulin dosage depends on many factorsmany factors

Age Weight Stage of puberty Duration of diabetes Nutritional intake Exercise patterns Results of BG monit Intercurrent illness

Adverse Effects of Insulin TherapyAdverse Effects of Insulin TherapyHypoglycemia

– Especially dangerous in Type 1 diabetics– Glucose or glucagon treatment

Allergy and resistance to insulin– Local cutaneous reactions or systemic– Switch to less antigenic form or desensitization

Lipohytertrophy– Due to lipogenic effect of insulin when small area used for frequent injections– Absorption from such sites is unpredictable

Lipoatrophy– Due to impurities: switch to highly purified insulin– Lipogenic effect of insulin can repair lesion

Insulin edema- transient, rare