Diabetes Mellitus and Metabolic Syndrome By: Susan Yu-Gan, MD, FPCP

Diabetes Mellitus and Metabolic SyndromeBy: Susan Yu-Gan, MD, FPCP

Definition

• refers to a group of common metabolic disorders that share the phenotype of hyperglycemia.

• Defect in metabolism of carbohydrates, fats and proteins due to relative/absolute deficiency in insulin secretion or action

• Result in severe complications

Diabetes is a serious disease

Morales D et al. for the NNHeS 2003-2004 Group. PSH-PLS Convention. Feb 2005.

Sy R et al. PJIM. 2003; 41: 1.-6.

*FBS > 125 mg/dL **FBS ≥101 mg/dL

Population = 80 M

DM Prevalence:

• *FBS : 3.4 %

• ** FBS : 6.6 %

• FBS/history : 4.6 %

DM Local Prevalence Rate

Filipino DM : 3.4 M

Numbers Of People With Diabetes: Regional Figures For 2007 And Estimates For 2025

0

10

20

30

40

50

60

70

80

90

100

Nu

mb

ers

wit

h d

iab

etes

(m

illi

on

s)

AFR EMM EUR NA SAC SEA WP

Region

2007

2025

International Diabetes Federation. Diabetes Atlas, 3rd edn. Brussels: IDF, 2006.

AFR, Africa; EMM, Eastern Mediterranean; EUR, Europe; NA, North America;SAC, South and Central America; SEA, South -East Asia; WP, Western Pacific

The Epidemic of Type 2

• Rise in the prevalence and incidence of type 2 diabetes . Why?– Increased awareness, more diagnosed– New ADA and WHO criteria – Longer life span– Obesity– Geographic variations

• Potential huge economic burden - complications

Walking the dogWalking the dog

Unique Features Of The Diabetes Epidemic In Asia

The increase in type 2 diabetes in Asia developed: – in a shorter time– in a younger age group– in people with a much lower BMI – in people with a high predisposition to insulin

resistance at a lesser degree of obesity than people of European descent

Yoon KH et al. Lancet 2006; 368: 1681–8.

ADA. Screening for Type 2 Diabetes. Diabetes Care 2003; 26(Suppl1):s21-s24

Risk Factors for Type 2 DiabetesRisk Factors for Type 2 Diabetes

Patient Patient CharacteristiCharacteristi

cscs

Medical Medical HistoryHistory

Clinical Clinical FindingsFindings

Age > 45 years old

Family history Hypertension

Overweight/Obesity (BMI > 25

kg/m2)

Coronary artery disease

Dyslipidemia

Physical inactivity Cerebrovascular accidents

Race-Asians Previous history of IFG/IGT/GDM

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26 (Suppl 1) S5-20

Screening Recommendations

Mass screening for type 2 diabetes in the general population is not recommended (Grade D, consensus)

Testing for diabetes should be performed every 3 years in those over 45 years of age (Grade D, consensus)

Who Should Be Screened?• All adults 45 y/o; and, if normal,

at 3-yr intervals

• Younger age and more frequently in those at risk

– Obese

– First degree relative with diabetes

– High risk ethnic group

– Hx of GDM or delivered baby > 9 lbs.

– Hypertension (BP140/90)

– Dyslipidemia (HDL 35 mg/dL and/or triglyceride 250 mg/dL

– Previous IFG or IGT

ADA. Diabetes Care 2000: 23 (suppl 1); 54-519

Confirming the Diagnosis of Type 2 Diabetes mellitus

Only possible through serum glucose measurement

FPG 126 mg/dL (after 8 hr fast)

Random Plasma Glucose 200 mg/dL w/ classic diabetes symptoms– Polyuria, polydipsia, unexplained

wt loss

OGTT value 200 mg/dL in the 2-h sample

Confirmed on at least 2 occasions

A1c not routine test for diagnosis (2006)

Methods for Diagnosing DMMethods for Diagnosing DM

ADA. Diabetes Care 2000:23(suppl.1); 54-519

Normal Pre-Diabetes (IFG and

IGT)

Diabetes Mellitus

FPG <100 mg/dL (5.6 mmol/L)

100-125 mg/dL (5.6-6.9 mmol/L)

> 126 mg/dL (7.0 mmol/L)

2hPG < 140 mg/dL (7.8 mmol/L)

140-199 mg/dL (7.8-11.0 mmol/L)

> 200 mg/dL (11.1

mmol/L)

Levels of Glycemia

ADA. Standards of medical care in diabetes. Diabetes Care 2004; 27 (Suppl 1):S13-34

Impaired Glucose Tolerance (IGT) and Impaired Fasting Glucose (IFG)

• IGT and IFG refer to a metabolic stage intermediate between normal glucose homeostasis and diabetes

• IGT: 2hPG - 140 mg/dL to 199 mg/dL

• IFG: FBG - 100 mg/dL to 125 mg/dL

• Both are risk factors for future diabetes and cardiovascular disease

Etiologic Classification of Diabetes Mellitus

• Type 1 Diabetes

• Type 2 Diabetes

• Other specific types

• Gestational Diabetes Mellitus

Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26(Suppl 1):s5-s20

Type 1 Diabetes

• Results from autoimmune destruction of pancreatic beta-cells

• Absolute insulin deficiency

• Patients typically dependent on insulin for survival

• Patients may present with ketoacidosis as initial sign of the disorder


Type 2 Diabetes

• Insulin resistance and relative insulin deficiency

• Patients may or may not need insulin treatment to survive

• May remain undiagnosed for many years, as hyperglycemia develops slowly

• Associated with strong genetic predisposition

• Heterogenous


Other Specific Types

• Genetic defects of B cell function• Genetic defects in insulin action• Diseases of the exocrine pancreas• Endocrinopathies• Drug - or chemical - induced• Infections• Uncommon forms of immune-mediated

diabetes• Other genetic syndromes sometimes

associated with diabetes


Gestational Diabetes Mellitus (GDM)

• Any degree of glucose intolerance with

onset or first recognition during pregnancy

• Associated with increased perinatal

morbidity and mortality

• 6 weeks or more after pregnancy ends, the

woman should be reclassified

• High risk for type 2 DM.


Diagnosis of GDM with a 100-g or 75-g Glucose Load

mg/dL mmol/L

100-g Glucose Load Fasting 95 5.3

1 - h 180 10.0

2 - h 155 8.6

3 - h 140 7.8

75-g Glucose Load

Fasting 95 5.3

1 - h 180 10.0

2 - h 155 8.6

PANCREAS

• The pancreas is an elongated organ nestled next to the first part of the small intestine. The endocrine pancreas refers to those cells within the pancreas that synthesize and secrete hormones.

The endocrine portion of the pancreas takes the form of many small clusters of cells called islets of Langerhans or, more simply, islets. Humans have roughly one million islets.

• Pancreatic islets house three major cell types, each of which produces a different endocrine product:

• Alpha Cells (A cells) – secrete the hormone glucagon.

• Beta Cells (B cells) – produce insulin and are the most abundant of the islet cells.

• Delta Cells (D cells) – secrete the hormone somatostatin which is also produced by

a number of other endocrine cells in the body.

PANCREAS

Interestingly, the different cell types within an islet are not randomly distributed - beta cells occupy the central portion of the islet and are surrounded by a "ring" of alpha and delta cells. Aside from the insulin, glucagon and somatostatin, a number of other "minor" hormones have been identified as products of pancreatic islets cells.

PANCREAS

Structure of Insulin• Insulin is a rather small protein, with a molecular

weight of about 6000 Daltons.

• It is composed of two amino acid chains held together by disulfide bonds. When this two amino acid chains are split apart, the functional activity of insulin is lost.

• The amino acid sequence is highly conserved among vertebrates, and insulin from one mammal almost certainly is biologically active in another.

Insulin

INSULIN BIOSYNTHESIS

INSULIN BIOCHEMISTRY

Proinsulin- inactive chain of 86 a.a.

C Peptide- connecting peptide of 31 a.a.

Insulin – remaining 51 a.a. made up of chains A and B

INSULIN SECRETION

• Pancreas secrets 40-50 units insulin/day• Basal insulin conc. in fasting state 10 U/mL• Food ingestion, insulin conc.

8-10 min. initial increase

30-45 min peak

90-120 min. returns to baseline values.

• Control of Insulin Secretion

– Insulin is secreted primarily in response to elevated blood concentrations of glucose

– Some neural stimuli (e.g. site and taste of food) and increased blood concentrations of other fuel molecules, including amino acids and fatty acids, also promote insulin secretion.

– Glucose is transported into the B cell by facilitated diffusion through a glucose transporter; elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose within the B cell.

INSULIN

Control of Insulin Secretion

INSULIN

Parasympathetic Nervous System

Glucose Stimulus D i g e s t i v e

hormones

-Sympathetic nervous symtem

-Sympathetic Nervous system

Somastatin

Growth hormone ACTH

Glucagon

Insulin

+

+

+

+

+

+-

-

• Control of Insulin Secretion

– Elevated concentrations of glucose within the B cell ultimately leads to membrane depolarization and an influx of extra cellular calcium.

– The resulting increase in intracellular calcium is thought to be one of the primary triggers for exocytosis of insulin-containing secretory granules.

– An increased level of glucose within B cells also appears to activate calcium-independent pathways that participate in insulin secretion.

INSULIN

Volta

ge G

ate

dC

a C

han

nels

2+

Exocytosis of stored insulin

Ca2+

Glucose

Dep

olariz

atio

n

ATPproduction

K+

ATP sensitive Kchannel receptor

+

• Physiologic Effects of Insulin – Insulin is a key player in the control of

intermediary metabolism. – Insulin has profound effects on: – Carbohydrate metabolism

• Lipid metabolism• Significant influences on protein and mineral

metabolism• Consequently, derangements in insulin signaling

have widespread and devastating effects on many organs and tissues.

INSULIN

• The Insulin Receptor and Mechanism of Action– Like the receptors for other protein hormones, the receptor for insulin

is embedded in the plasma membrane.– The insulin receptor is composed of two alpha subunits and two beta

subunits linked by disulfide bonds. – The alpha chains are entirely

extra cellular and house insulin binding domains,while the linked beta chains penetrate through the plasma membrane.

INSULIN

• Insulin and Carbohydrate Metabolism– Insulin facilitates entry of glucose into muscle, adipose

and several other tissues.

– The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters of many tissues - muscle being a prime example

– The major transporter used for uptake of glucose called GLUT4 is made available in the plasma membrane through the action of insulin.

– Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose.

INSULIN

• Insulin and Carbohydrate Metabolism– It should be noted here that there are some tissues

that do not require insulin for efficient uptake of glucose: important examples are brain and the liver.

– This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.

– Insulin stimulates the liver to store glucose in the form of glycogen. A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen.

• When the supply of glucose is abundant, insulin “tells" the liver to bank as much of it as possible for use later.

INSULIN

Gluconeogenesis

Glycogenolysis

Glycogen synthesis

Lipogenesis

INSULIN EFFECTS ON LIVER

Glucose Uptake

Glycogen synthesis

Protein synthesis

INSULIN EFFECTS ON MUSCLE

Glucose uptake

Triglyceride synthesis

Lipolysis

INSULIN EFFECTS ON ADIPOSE TISSUE

• Insulin and Lipid Metabolism

– When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins.

– The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.

– Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids.

INSULIN

• Other Notable Effects of Insulin

– Insulin also stimulates the uptake of amino acids, again contributing to its overall anabolic effect.

– Insulin also increases the permeability of many cells to potassium, magnesium and phosphate ions.

– The effect on potassium is clinically important. Insulin activates Na/K ATPase in many cells, causing a flux of potassium into cells.

INSULIN

What happens to glucose in the body? EXTERNAL

DIET

DIGESTION

GLUCOSE

Glycolysis ENERGY

Glycogen STORAGE

Lipogenesis FATS STORAGE

Glycogenesis

Glycogenolysis

Pyruvates

+

Lactates

Amino acidsGlycerol

INTERNAL

Gluconeogenesis(Liver)

What happens between meals?Blood Glucose

Liver mobilizes glycogen stores

Break down of Glycogen=

GLYCOGENOLYSIS

Glucose

Blood stream

N.B. The liver is the only organ able to liberate glucose from its glycogen stores

What happens after a meal?

Blood glucose Blood glucose

Insulin and Glucagon RegulateNormal Glucose Homeostasis

Glucose output Glucose uptake

Glucagon(α cell)

Insulin(β cell)

Pancreas

Liver MuscleMuscleAdipose Adipose

tissuetissue

Fasting state Fed state

Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al,

eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

Major Pathophysiologic Defects in Type 2 Diabetes

Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168;

Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781; Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.

Hepatic glucoseoutput

Insulin resistance

Glucose uptake

Glucagon(α cell)

Insulin(β cell)

Liver

Hyperglycemia

Islet-cell Dysfunction

MuscleMuscleAdipose Adipose

tissuetissue

Pancreas

Incretin Hormones Regulate Insulin and Glucagon Levels

GLP-1 = glucagon-like peptide-1; GIP = glucose insulinotropic polypeptide Adapted from Kieffer T. Endocrine Reviews. 1999;20:876–913. Drucker DJ. Diabetes Care. 2003;26:2929–2940. Nauck MA et al.

Diabetologia. 1993;36:741–744. Adapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. Copyright © 1979 Springer-Verlag.

PancreasGut

Nutrient signals

● Glucose

Hormonal signals• GLP-1

• GIP

Glucagon(GLP-1)

Insulin (GLP-1,GIP)

Neural signals cells

cells

The Incretin Axis

Peptides released by the gut throughout the day and increased in response to meals — participate in normal glucoregulation

GLP-1 and GIP are the dominant incretins

Both stimulate insulin release from β-cells and GLP-1 inhibits glucagon release from -cells

The incretin axis is abnormal in patients with T2DM

Reduced release of GLP-1

Reduced response to GIP

Drucker DJ. Diabetes Care. 2003:2929-2940; Ahren B. Curr Diab Rep. 2003;3:365-372; Drucker DJ Gastroenterology. 2002;122:531-544.; Dunning BE, et al. Diabetologia. 2005;48:1700-1713.

ADA 2006 Late Breaking Clinical Presentation (Stein).

Demonstrated Effects of the Incretin HormonesGLP-1 and GIP

Is released from L cells in ileum and colon

Stimulates insulin response from β cells in a glucose-dependent manner

Inhibits gastric emptying

Reduces food intake and body weight

Inhibits glucagon secretion from α cells in a glucose-dependent manner

Effect on β-cell turnover in preclinical models

Is released from K cells in duodenum

Stimulates insulin response from β cells in a glucose-dependent manner

Has minimal effects on gastric emptying

Has no significant effects on satiety or body weight

Does not appear to inhibit glucagon secretion from α cells

Effect on β-cell turnover in preclinical models

GLP-1 GIP

Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606; Drucker DJ. Diabetes Care. 2003;26:2929–2940. Farilla L et al. Endocrinology. 2003;144:5149–5158.

Role of Incretins in Glucose Homeostasis

Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.

Ingestion of food

β cellsα cells

Release of gut hormones —

incretins*

PancreasGlucose-dependent

Insulin from β cells(GLP-1 and GIP)

Glucose uptake

by muscles

Glucose dependent Glucagon from

α cells(GLP-1)

GI tract

ActiveGLP-1 & GIP

DPP-4 enzyme

InactiveGIP

InactiveGLP-1

*Incretins are also released throughout the day at basal levels.

Glucose production

by liver

Blood glucose in fasting and

postprandial states

Fate of Glucose

• If energy is needed immediately, glucose is metabolized to produce energy via glycolysis.

• If more glucose is available than what the cells need immediately for energy, the extra glucose is converted to glycogen via a process called glycogenesis. Glycogenesis occurs primarily in liver cells and, to a limited extent, in muscle cells.

• When glucose is not immediately required for energy and the storage capacity for glycogen is reached in the liver and muscle, additional glucose can be oxidized or converted to fat.

GLUT 4 Transporters

Before After

DeFronzo RA. Med Clin N Am 2004; 88:787–835.

Prevention Treatment–10 10 YearsDiagnosis

Macrovascular complicationsMacrovascular complications

0

IGT/IFG Type 2 diabetes

Natural History Of Disease Progression

Microvascular complicationsMicrovascular complications

Blood glucose

-cell function

Insulin resistance

Glucose Homeostasis

Pancreas

Insulin receptors

(GLUT 4)

Glucose transport proteins

Cell

Insulin Action in Normal Tissues (Cellular Level)

Insulin receptors

(GLUT 4)



Cell

Insulin receptors

(GLUT 4)



Cell

Insulin receptors

(GLUT 4)



Cell

Insulin receptors

(GLUT 4)


Cell

Insulin Resistance

Insulin receptors

(GLUT 4)


Cell

Insulin Resistance

Insulin receptors

Cell

Insulin Resistance

Insulin receptors

(GLUT 4)


Cell

Insulin receptors

Cell

Insulin Resistance

INSULIN RESISTANCE Phase: Disease Progression Stage :

POST-Receptor Level Early stage - normal to IGT

Receptor Level Hyperinsulinemia- IGT to T2D

INSULIN RESISTANCE Phase: Disease Progression Stage :

Pre- Receptor Level Latter Part Stage - Beta-cell Dysfuntion

(Pancreatic exhaustion)

Pathogenesis of Type 2 Diabetes

ADA and IDF Guidelines:Treatment Goals for HbA1c, FPG, and PPG

ParameterNormalLevel

ADA Goal

IDF Goal

FPG, mg/dL(mmol/L)

<110(<6.1)

90–130(5.0–7.2)

<110 (<6.1)

PPG, mg/dL(mmol/L)

<140 (<7.8)

<180

(<10.0)

<145

(<8.1)

HbA1c 4%–6% <7%* <6.5%

*The HbA1c goal of an individual patient is to achieve an HbA1c as close to normal (<6%) as possible without significant hypoglycemia.

ADA=American Diabetes Association; IDF=International Diabetes Federation.

ADA. Diabetes Care. 2007;30(suppl 1):S4–S41; International Diabetes Federation. 2005:1–79.

Therapy for Type 2 DM

• Lifestyle changes– Diet– Exercise– Stop smoking– Glycemic control– Prevent complications– Prevent disease

progression

• Pharmacologic– Glycemic control– Prevent complications– Prevent disease

progression– Treat co-morbid

conditions– Minimal side effects

Nutrient Composition of the Therapeutic Lifestyle Change (TLC) Diet

Nutrient Recommended IntakeCarbohydrate 50% to 60% of total calories; mostly from

food rich in complex carbohydrates

Fiber 20-30 g/day

Protein Approximately 15% of total calories

Cholesterol <200 mg/day

Total Calories Balance energy intake and expenditure; should include at least moderate physical activity

Executive Summary of the Third Report of the National Cholesterol Education Program(NCEP) Expert Panel Detection, Evaluation, and Treatment of High Blood Cholesterol

in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497

Glucose

Adipose tissue

Gut

Stomach

Liver

BiguanidesMuscle

Pancreas

Sulphonylureas and meglitinides

Insulin

-glucosidase inhibitors

Thiazolidinediones

GLP-1

GLP-1 analogues

Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1(Suppl. 1):S32–S40.Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.Pratley RE & Salsali A. Curr Med Res Opin 2007; 23:919–931.Todd JF & Bloom SR. Diabet Med 2007; 24:223–232.

Primary Sites Of Action Of Oral Anti-diabetic Agents

DPP-4 inhibitors

DPP-4

Insulin Secretagogues: Basic Characteristics

• Mechanism of action:– Increase basal and postprandial insulin secretion

• Therapeutic efficacy:– Decreases HbA1c 1%-2%*

• Recommended dosing:– Sulfonylureas: 1-2x daily – Repaglinide, nateglinide: 3x daily

• Adverse effects:– Weight gain, hypoglycemia

*Results vary according to clinical trial design, individual patient characteristics, and data analyses.

Amaryl PI. Hoechst Marion Roussel, August 1997; DiaBeta PI. Hoechst Marion Roussel, September 1997; Glucotrol PI. Pfizer, September 1993; Glynase PI. Pharmacia & Upjohn, February 1999; Micronase PI. Pharmacia & Upjohn, January 1999; Prandin PI. Novo Nordisk, October 1998.

Sulfonylureas

• Tolbutamide

• Chlorpropamide

• Glibenclamide/Glyburide

• Gliclazide

• Glipizide

• Glimepiride

Guideline for Use of SULFONYLUREAS

Action Generic Trade Name Preparation Daily Dose

Short Tolbutamide Rastinon 500 mg tablet 1/2 - 6 tabs

Inter-mediate

Glibenclamide

Gliclazide

Glipizide

Glimepiride

EugluconDaonil

Orabetic

Diamicron MRDiamicron DianormGlubitor

Minidiab OD

SolosaNorizec

2.5/5.0 mg tab5.0 mg tablet5.0 mg tablet

30 mg tablet

80 mg tablet80 mg tablet

5/10 mg tab

1,2,3 mg tab

1/2 - 3 tabs

1 - 4 pre-breakfast

1/2 - 4 tabs

½ -6 tabs1-4 mg

Long Acting

Chlorpropamide Diabenese 250 mg tablet 1/2 - 2 tabs

Meglitinides

• Also stimulates insulin secretion by the pancreas

• Shorter acting than sulfonylureas

• Targets the postprandial elevation of blood sugar

Meglitinides

• Repaglinide

• Nateglinide

Biguanides (Metformin)

• Suppresses hepatic glucose output

• An insulin sensitizer

• May cause Lactic acidosis

• Contraindicated in patients with hepatic and renal insufficiency and in patients with hypoxemia

MetforminAction Reduce liver glucose production

Insulin sensitivity Yes (liver predominantly)

Hepatic glucose output Reduced

Serum insulin No effect

Hypoglycaemia No

Lipids Reduced

Onset of action Moderate

Weight Neutral or reduced

Effectiveness over time Reduced

Safety GI effectsDrug interactionsRenal insufficiency (Lactic acidosis)

Alpha-glucosidase inhibitors§ Three agents marketed: acarbose

voglibose andmiglitol

§ Inhibit the alpha-glucosidase enzyme involved inthe breakdown of complex carbohydrates intoglucose and other simple sugars in the intestine

§ Delay the absorption of carbohydrates following meals

§ Acarbose is positioned for treatment of mealtimeglucose spikes

§ Suitable for combination with sulfonylureas

Acarbose

Action Reduced glucose absorption

Insulin sensitivity No effect

Hepatic glucose output No effect

Serum insulin No effect

Hypoglycaemia No effect

Lipids No effect

Onset of action Moderate

Weight Neutral or reduced

Effectiveness over time Uncertain (at 3 years)

Safety GI effectsHepatic (LFT elevation)Drug interactions (few

Thiazolidinediones

• Insulin sensitizers

• Acts by activation of PPAR

• Must monitor liver enzymes

• Side effects include fluid retention, edema, anemia

Thiazolidinediones

• Troglitazone

• Rosiglitazone

• Pioglitazone

Hepatic (Inc LFT in Troglitazone)Drug interactions (few)Weight gain ? Edema ?

Safety

DurableEffectiveness over time

IncreasedWeight

Moderate to lateOnset of action

Generally positiveLipids

No effectHypoglycaemia

DecreasedSerum insulin

Slight decreaseHepatic glucose output

IncreasedInsulin sensitivity

Insulin sensitizerAction

Thiazolidinediones

Indications for Insulin in Type 2 Diabetes

• Hyperglycemia despite maximum doses of oral agents

• Decompensation due to intercurrent events e.g., infection, acute injury, or other stress

• Development of severe hyperglycemia with ketonemia and/or ketonuria

• Uncontrolled weight loss

Indications for Insulin in Type 2 Diabetes

• Perioperative in patients undergoing surgery

• Pregnancy

• Renal or hepatic disease

• Allergy or other serious reaction to oral agents

Tier 1: Well-validated core therapiesTier 1: Well-validated core therapies

At diagnosis:

Lifestyle+

Metformin

STEP 1STEP 1

Tier 2: Less well-validated therapies

Lifestyle + Metformin+

Intensive insulin

STEP 3STEP 3

Lifestyle + Metformin + GLP-I agonists

No hypoglycemiaWeight loss

Nausea/vomiting

Lifestyle + Metformin + Pioglitazone

No hypoglycemiaOedema/CHF

Bone loss


Basal insulin


Sulfonylurea

STEP 2STEP 2

Lifestyle + Metformin+ Pioglitazone+ Sulfonylurea

Lifestyle + Metformin+ Basal Insulin

Algorithm for the Metabolic Management of Algorithm for the Metabolic Management of Type 2 DiabetesType 2 Diabetes

DiabeticRetinopathy

Leading causeof blindness

in adults1,2

DiabeticNephropathy

Leading cause of end-stage renal disease3,4

CardiovascularDisease

Stroke

2- to 4-fold increase in

cardiovascular mortality and stroke5

DiabeticNeuropathy

Leading cause ofnon-traumatic lower

extremity amputations7,8

8/10 individuals with diabetes die from CV

events6

Type 2 diabetes is associated with serious complications

1UK Prospective Diabetes Study Group. Diabetes Res 1990; 13:1–11. 2Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 3The Hypertension in Diabetes Study Group. J Hypertens 1993; 11:309–317. 4Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 5Kannel WB, et al. Am Heart J 1990; 120:672–676.

6Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences. 7King’s Fund. Counting the cost. The real impact of non-insulin dependent diabetes. London: British Diabetic Association, 1996. 8Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.

Hyperglycemia

Neuropathy– Peripheral– Autonomic

Biology of Microvascular Complications

Kidney Nerves

RetinopathyCataractGlaucoma

Nephropathy– Microalbuminuria– Gross albuminuria

Blindness Kidney failure Amputation

Death and/or disability

Eye

Metabolic injury to large vessels

Heart Brain Extremities

Cardiovascular disease Acute coronary

syndrome Myocardial infarction

(MI) Congestive heart

failure

Cerebrovascular disease Transient

ischemic attack Stroke Cognitive

impairment

Peripheral vascular syndrome Ulcers Gangrene Amputations

Biology of Macrovascular Complications

Impact of Type 2 Diabetes on Macrovascular Disease

• Largest cause of morbidity and mortality

• Risk of CVD increased 2- to 4-fold

• Higher case fatality vs non diabetic individuals

• Reduced survival post–MI, post–CABG, and particularly post–PTCA

• Risk of stroke and peripheral vascular disease substantially increased

Betteridge DJ. Acta Diabetol. 1999;36:S25-S29. Nesto R. Acta Diabetol. 2001;38:S3-S8.

Diabetic Macroangiopathy

• Atherosclerosis– Atherosclerosis begins to appear in most diabetics

whatever their age, within a few year of onset of diabetes.

– The susceptibility of diabetics to atherosclerosis is due to several factors:

• Hyperlipidemia• HDL Levels are reduced in type 2 diabetics • Diabetics have increased platelet adhesiveness and

response to aggregative agents.

• Most type 2 diabetic patients are obese and hypertensive

which further contributes to Atherosclerosis

CLINICAL PRESENTATION OF MACROANGIOPATHY

• Stroke– Estimated relative risk of stroke in diabetes mellitus:– 2 – 8%– Mainly due to the atherosclerosis of the cerebral vessels

leading to the rupture and ischemia of the cerebral tissue.

• Coronary Heart Diseases√ Ischaemic heart disease – Type 2 diabetics develop CHD at a young age– The 5-Years risk of ischaemic events is doubled– Worse outcome post –MI

PATHOPHYSIOLOGY OF THE DIABETIC FOOT

PATHOPHYSIOLOGY OF THE DIABETIC FOOT

atherosclerosis Of the leg vessels

Infection(contributes to

tissue necrosis)

Peripheral neuropathy

claudication ulceration gangrene rest pain

Ischemia (Often bilateral) Sensory deficit

Autonomic dysfunction

Diabetic Neuropathy

• Numbness, tingling or pain in the toes, feet, legs, hands, arms and fingers

• Wasting of muscles of feet or hands• Indigestion, nausea or vomiting• Diarrhea or constipation• Dizziness or faintness due to a drop in postural

blood pressue• Problems with urination• Erectile dysfunction (impotence) or vaginal

dryness• Weakness

INFECTIONS

Hyperglycemia favors Development of infection

Urinary tract Infection

Skin infection

Respiratory tract infection

Treatment of infectionAnd improved blood glucose

Control

DIABETIC RETINOPATHY

One of the most threatening aspects of DM’s the development of visual impairment

• Epidemiology

– Leading cause of blindness in Western countries– Retinopathy is the most common complication of diabetes.– Risk factors are: duration of diabetes, poor BG control,

high– Blood pressure, hypercholesterolemia, proteinuria.

• Symptoms– Reduction in visual

acuity

– Reduction in visual fields

– Reduction in vision of colors

DIABETIC RETINOPATHY

DIABETIC NEPHROPATHY

• A major cause of end-stage renal disease and dialysis.

• The kidneys are usually the most severely damaged organs in diabetics

• Diabetic nephropathy with proteinuria is a common serious complication affecting Type 1 and Type 2 diabetes.

• Affect 25% of the diabetics

Natural History of Diabetic Nephropathy

Definition of Abnormal Albumin Excretion

UAER UAER Urinary(mg/24H) (mcg/min)

albumin/

creatinine

(mg/gm)

Normal < 30 < 20 < 30

Microalbuminuria 30 – 300 20 – 200 30 – 300

Macroalbuminuria > 300 > 200 > 300

Measurements

• Albumin to creatinine ratio

• 24 hour urine collection

• Timed collection (4 H or overnight)

• Screen for with reagent strips

False Positives

• Short time hyperglycemia

• Exercise

• Acute febrile illness

• UTI

• Marked hypertension

• CHF

Microvascular Complications of Diabetes

Stage UAE

Rate

(μg/min)

Blood

Pressure

Glomerular

Filtration rate

(GFR)

Histological

Changes

1

Hyperfiltration

0 – 20 Normal Increased by

20 – 50 %

Increased

Glomerular size

1

Normoalbuminuria

0 – 20 Normal Increased by

20 – 50 %

Basement

Membrane (BM)

thickening

2

Microalbuminuria

21 – 200 Normal or

elevated

Still high, but

declines with

proteinuria

BM thickening

Mesangial

expansion

3

Proteinuria

>200 Elevated Decline

~10ml/min/yr

Pronounced

abnormalities

4End-stage renal

Failure

>200 Hypertension <10ml/min Advanced

glomerulopathy

Stages of diabetic nephropathy(Adapted from Mogensen 1999)

Risk Factors DM Nephropathy

Poor glycemic control and insulin resistance

Hypertension

Albuminuria

Smoking

High dietary intake of protein

Hyperlipidemia

Microvascular Complications of Diabetes

• Microalbuminuria predicts cardiovascular morbidity and mortality as well as renal disease

• Treatment should delay or prevent the progression of microalbuminuria to proteinuria

• Trials have shown that therapeutic strategies should include:

- intensive glycaemic control

- aggressive control of blood pressure (ACE inhibitors)

Diabetic Nephropathy: Therapeutic Strategies

Treatment Recommendations for Diabetic Patients with Albuminuria/Nephropathy

• In the treatment of albuminuria/nephropathy, both ACE inhibitors and ARBs can b used:

– In hypertensive and non-hypertensive T1 DM: ACE-inhibitors are the initial agents of choice

– In hypertensive and non-hypertensive T2 DM: ARBs are the initial agents of choice

Diabetes Care. 2002;25(1):S33

Strategies for Preventing Complications of Diabetes

• Control blood glucose– HbA1c below 7%– FBS below 110 mg%– RBS below 160 mg%

• Control blood pressure– Below 130/80

• Control lipids– LDL below 100 mg%– HDL above 45 for males and 55 for females– Triglycerides below 150 mg%

• Weight loss• Stop smoking

Summary of Recommendations for Adults With Diabetes

Glycemic Control

A1C <7.0%*

Preprandial plasma glucose 90-130 mg/dL (5.0-7.2 mmol/L)

Postprandial plasma glucose† <180 mg/dL (<10.0 mmol/L)

Blood pressure <130/80 mmHg

Lipids‡

LDL <100 mg/dL (<2.6 mmol/L)

Triglycerides <150 mg/dL (<1.7 mmol/L)

HDL >40 mg/dL (1.1 mmol/L)§*Nondiabetic range of 4.0-6.0% using DCCT-based assay†PPG made 1-4 h after beginning of meal

‡NCEP/ATP III guidelines: for TG>200 mg/dL, use non-HDL cholesterol = TC-HDL§For women, HDL goal >50 mg/dL

Diabetes Care 2004; 27(Suppl1):S15-S35

What is the Metabolic Syndrome

• A group of metabolic risk factors in one person. • Central obesity • Atherogenic dyslipidemia - mainly high triglycerides and

low HDL cholesterol • Insulin resistance or glucose intolerance• Prothrombotic state (e.g., high fibrinogen or plasminogen

activator inhibitor [–1] in the blood) • Raised blood pressure (130/85 mmHg or higher) • Proinflammatory state (e.g., elevated high-sensitivity C-

reactive protein in the blood)

Clinical Identification - Any 3 of the followingMetabolic Syndrome

LOW HDL-C Men < 40 mg/dL (1.0 mmol/L)

Women < 50 mg/dL (1.2 mmol/L)

HIGH Triglycerides≥ 150 mg/dL(≥ 1.7 mmol/L)

Abdominal ObesityMen > 40 inches (>102 cm)

Women > 35 inches (>88 cm)(Waist circumference)

Hypertension ≥ 130 / ≥ 85 mmHg

Fasting Glucose≥100 mg/dL≥ 5.5 mmol/L

NCEP-ATP III – JAMA 2001

New IDF Definition of Metabolic Syndrome

Waist circumference Plus 2 of the

ff: (cm)

Europids FBS >5.6 (100mg/dL) >94 male >80 female TRIG >1.7 (150mg/dL) South Asians >90 male HDL < 0.9 (<40mg/dL) M >80 female <1.1

(<50mg/dL) F Chinese >90 male BP >130 systolic >80 female >85

diastolic Japanese >85 male >90 female www.idf.org

Prevalence (%)1998 2003-2004

Low HDL 65 54Obesity (BMI>30) 3.2 5Obesity (WHR 1/0.85) 34.9Smoking 34.8 Hypertriglyceridemia 9 21 Hypertension 17.2 17.4 DM 3.9* 3.4*

4** 4.6** 6.6 ***

Metabolic Syndrome (NCEP) 14.2 12.4

Morales D et al. for the NNHeS 2003-2004 Group. PSH-PLS Convention. Feb 2005.

Sy R et al. PJIM. 2003; 41: 1.-6.

*FBS > 125 mg/dL ** FBS or history *** FBS ≥101 mg/dL

Risk Factors Among Filipinos

genetic predisposition excess body fat (abdominal

obesity) sedentary lifestyle physical inactivity

Ford ES et al. JAMA. 2002; 287: 356-9.

Risk Factors for Metabolic Syndrome

• While the pathogenesis of the metabolic syndrome and each of its components is complex and not well understood, central obesity and insulin resistance are acknowledged as important causative factors.

IDF Consensus 2004Recommendations for Treatment

• Primary InterventionIDF recommends that primary management for

the MS is healthy lifestyle promotion. This includes :

* moderate calorie restriction ( to achieve a 5-10% loss of BW in the 1st year )

* moderate increase in physical activity

* change in dietary composition

IDF Consensus 2004Recommendations for Treatment

• Secondary intervention * In people for whom lifestyle change is not

enough and who are considered to be at high risk for CVD, drug therapy may be required to treat the metabolic syndrome.

* However, specific pharmacological agents are not yet available.

* It is currently necessary instead to treat the individual components of the metabolic syndrome.

IDF recommended treatment of the individual components of the metabolic syndrome.

• Atherogenic dyslipidemia Primary aims for therapy : * Lower Tg * Raise HDL * Reduce LDL

Options : * Fibrates * Statins


• Elevated blood pressure In patients with established diabetes, anti-

HPN therapy should be introduced at BP ≥130/≥80 mmHg.

Options : * ACEI and ARB. Effect of lowering of BP

per se more important than the drug itself? * No particular agents have been identified

as being preferable for HPN patients with MS.


• Insulin resistance and hyperglycemia There is growing interest in the possibility

that drugs that reduce IR will delay the onset of type 2 DM and will reduce the CVD risk when the MS is present.

Cardiovascular Risk Factors and Therapies

↑ LDL cholesterol

↓ HDL cholesterol

↑ Triglycerides

↑ Blood Pressure

↑ Blood Glucose

↑ Waist Circumference

↓ Insulin Sensitivity

↑ Thrombotic risk

Lipid Modifiers

Anti-hypertensives

Anti-diabetic agents

Weight Loss Agents + Diet and exercise

Insulin sensitizers

Anti-platelet agents

NCEP-ATP III / IDF

criteria for the

metabolic syndrome

Documents

Diabetes Mellitus and Metabolic Syndrome By: Susan Yu-Gan, MD, FPCP