An Overview of Diabetes

Sid McNulty

Consultant Physician & Endocrinologist

Constructivism and Experiential learning and the brain

Sensory

IntegrativeMaking sense

IntegrativePlanning

‘Motor’(plus verbal)

Concrete experience

Active reflection

Abstract conceptualisation

Active experimentation

Neuronal networksTap into and build on what the learner already

knows

ACEi actions

K+ sparing

Diuretic

Antihypertensive

Postural hypotension

Insulin action Hypoglycaemia

Addison’sLack of RAAS driveLack of insulin antagonism

Cushing’s opposite of Addison’sand therefore opposite of:Insulin and diuretics, and therefore….

Blockage of RAAS

Diagnosis of Diabetes

WHO (adopted in UK 6/00):

Symptoms of hyperglycaemia plus 1 bloodRandom/2 hr plasma gluc > 11.1 mmol/l, or

Fasting plasma glucose > 7.0 mmol/l

In the absence of symptoms, there must be 2 plasma glucose results in the diabetic range on separate days.

Diagnostic dilemmaSensitivity: positives identified as positive

Specificity: negatives identified as negative

100% specificOver 10m longOver 15,000 mphOver 6,000 Km highNo false alarmsLots of false -ve

100% sensitiveOver 1m longOver 10mphOff the groundDon’t miss a strikeLots of false +ve

Lethal Disease XAffects 1 in 10,000100% fatal – horrible and painful deathFantastic test for it 99% (99% sensitive ie picks

up disease as disease, and 99% specific ie picks up normal as normal)

You have the test1 week later the resultsYou are positiveWhat is your probability you have disease?What do you do?

Please stand up

Condition

Positive Negative

TestResult

Positive True +ve False +ve +ve predictive valueTP/TP+FP

Negative False -ve True –ve -ve predictive valueTN/TN+FN

Sensitivity 99%TP/TP+FN x100

Specificity 99%TN/TN+FP x

100

A ‘Good’ Test

A ‘Good’ Test?

The Devil is in the detail!

Condition

Positive Negative

TestResult

Positive True +ve False +ve +ve predictive valueTP/TP+FP

Negative False -ve True –ve -ve predictive valueTN/TN+FN

Sensitivity 99%TP/TP+FN x100

Specificity 99%TN/TN+FP x

100

A ‘Good’ Test

What tests meansSensitivity: about the disease…the people you identify

with the disease/total number with the disease (TP/TP+FN)…if you have disease, you test positive

Specificity: about the disease…the people you identify without the disease/total number without the disease (TN/TN+FP)… if you don’t have disease you test negative

Positive predictive value: about the test…the number of people you test positive with the disease/total number you test positive (TP/TP+FP)… if you test positive, likelihood you have disease

Negative predictive value: about the test…the number of people you test negative without the disease/total number you test negative (TN/TN+FN)… if you test negative, likelihood you don’t have the disease

Gedankenversuch

Test: being called mags to diagnose being a woman

Male Female

True positive

Falsenegative

False positive

Truenegative

What being called mags meansSensitivity (disease): if you’re a woman, how likely

is it you’ll be called mags (low 1%)Specificity (disease): if you’re not a woman, how

likely is it you’ll not be called mags (v high 99.99%)

Positive predictive value (test): if you’re called mags, how likely are you to be a woman (high 99%)

Negative predictive value (test): if you’re not called mags, how likely you’re not a woman (poor 50%)

Lethal Disease XAffects 1 in 10,000100% fatal – horrible and painful deathFantastic test for it 99% (99% sensitive ie picks

up disease as disease, and 99% specific ie picks up normal as normal)

You have the test1 week later the resultsYou are positiveWhat is your probability you have disease?What do you do?

Please stand up, again

One million people1 in 10,000 with disease 1 in 100 with false +ve

1 in 10,000 with disease and +ve test ie 100 people

1 in 100 with +ve test and no diseaseie 10,000 people

One million peopleHow many have disease?1 in 10,000100 peopleHow many would test positive?1 in 10010,000If positive do you have disease? What is the positive predictive valueTP/TP+FP: 100/10,100ie 1 in 100 chance!Therefore – even the best test should be interpreted with clinical data, and should only be asked for in the right people (ETT ECGs, VQs etc etc)

What tests meansSensitivity: about the disease…the people you identify

with the disease/total number with the disease (TP/TP+FN)…if you have disease, you test positive

Specificity: about the disease…the people you identify without the disease/total number without the disease (TN/TN+FP)… if you don’t have disease you test negative

Positive predictive value: about the test…the number of people you test positive with the disease/total number you test positive (TP/TP+FP)… if you test positive, likelihood you have disease

Negative predictive value: about the test…the number of people you test negative without the disease/total number you test negative (TN/TN+FN)… if you test negative, likelihood you don’t have the disease

Incidence of Diabetes

The incidence is increasing steeply

World diabetic population is estimated to reach 221 million people by 2010 (double the number in 1994).

Over 1.4 million people in the United Kingdom (3% of the pop) have diagnosed diabetes mellitus, with perhaps another million as yet undiagnosed.

Amos AF et al.The rising global burden of diabetes...Diabetic Med 1997;14(suppl 5):S1-85.

Types of diabetes

Type 1 (IDDM)

Absolute insulin deficiency

ß-cell failure

Young, thin

Prone to DKA

Type 2 (NIDDM)

Relative insulin deficiency

Insulin resistance

Old, ↑BMI (kg/m2)

Usually on tablets or diet (can be on insulin)

No DKA : instead HONK

Insulin balance with age T1DM

0

20

40

60

80

100

120

insulin reqinsulin T1

‘Event’

Obesity and T2DM

Obesity

Inactivity

Insulin resistance

Hyperglycaemia

Micro- and macro-vascular complications

Hypertension

Dyslipidaemia

Endothelial dysfunction

Prothombotic state

The Progress to T2DM

Wt 70 kg

Requires 60 U

Panc Res 200 U

Level: 60 U

Normal

Wt 100 kg

Requires 150 U

PR 200 U

Level: 150 U

‘Normal’

Wt 70 kg

Requires 60 U

Panc Res 100 U

Level: 60 U

Normal

Wt 100 kg

Requires 150 U

Panc Res 100 U

Level: 100 U

DM & Hyperinsulin

NORMAL T2DM

12 v 121 v 1210 units?8 v 81 v 810 units/hr?

50 v 501 v 5010 units/50ml?

1010 units Actrapid at 100 mls/hr?

Insulin balance with age T2DM

0

20

40

60

80

100

120

insulin T1insulin T2

Insulin balance with age T2DM

0

20

40

60

80

100

120

insulin req0insulin T1insulin T2

Why worry with diabetic in-patients

Avoid emergencies:Main aim of your Mx

Plus tighten peri-operative glucose control

Diabetic emergencies

Hypoglycaemia

HyperglycaemiaDKA: Type 1

HHS/HONK: Type 2

HypoglycaemiaBMs 2-4

Autonomic symptoms: Sympathetic

Sweaty, agitated, nausea, shaky, pale, hungry

BMs 0-2

Neuroglycopenic:

Confusion, aggression, agitation, coma, hemiparesis etc

Mechanism of Normoglycaemia

β cell

Proinsulin

Insulin C Peptide

↓ Glucose

Pancreas

Pancreas

Glucagon Glycogen Liver

↑ Glucose

Mechanism of Hypoglycaemia

β cell

Proinsulin

Insulin C Peptide

↓ Glucose

Pancreas

Pancreas

Glucagon Glycogen Liver

↑ Glucose

1.Sulphonylureas

3.Exogenous

4.Lack of antagonist(cortisol etc)

5.IGF 2

6.Excess use

2.Excess

7.Lack of

8.Lack of

Treatment of HypoTreatment:

IV glucose 50ml 50%

IM glucagon 1 mg

?Treat causesteroids (Addison’s, NICTH)

surgery (Insulinoma, NICTH)

Diazoxide & high dose BFZ (Paliative Insulinoma)

DSN review/ Psych review

Presentation & definition of DKA

Young, thin, T1DM

Poly-uria, -dypsia, weight loss (passing sugar water)

SOB (kussmal - blowing off CO2 to ↓pH), dehydrated, ↓ BP, vasodilated, drowsy

Raised blood glucose (>15 mmol/L)

Metabolic acidosis:pH <7.3, Bicarb <15 mmol/L

Ketosis: ketostix > ++

Mechanism of DKA

Intercurrent illness

Increased counter-regulatory hormones (Cats and cortisol)

Severe insulin deficiency

Hyperglycaemia

Mechanism of DKA

Hormone-sensitive lipase

TriglycerideNon-esterified fatty acids

Acetoacetate

3-HydroxybutyrateAcetone

Glycerol

+

Insulin

-

Mechanism of DKA

Intercurrent illness

Increased counter-regulatory hormones (Cats and cortisol)

Severe insulin deficiency

Hormone-sensitive lipase

TriglycerideNon-esterified fatty acids

Acetoacetate

3-HydroxybutyrateAcetone

Glycerol

+ +

+

Hyperglycaemia

Mechanism of DKA

Hyperglycaemia Ketone bodies

Osmotic diuresis Vomiting Acidosis

Electrolyte

depletionDehydration Vasodilatation

Hypotension Hypothermia

Management of DKA General

NG tubeReduced consciousnessGastroparesis

IV access? Central line only if indicated

Catheter?UTI may have precipitated DKADehydrated and immunosuppressedSerious risk of introducing ascending infectionTherefore only if not PU’d in 3 hours

Remove / treat precipitator (low threshold for Abs)?Heparin (coma or Osmolality >350 mOsm/L)

Management DKA SpecificT1DM

Acute decompensation

pH <7.3, Bicarb <15, Ketosis, Gluc >15

IV insulin 0.1 unit/kg/hr = 6-8 units/hr

IV fluids 5 Ltr/24hr

? Abs (WCC/Temp mean little)

No Bicarb

Inform your senior

13th May 2010

Died July 1997

Retired last year and still facing 12 charges!

HyperOsmotic NonKetotic Coma (AKA) Hyperglycaemic HyperOsmolar Syndrome

Presentation & DefinitionIn Type 2 DM

Longer Hx -poly-uria/dypsia

Dehydration, ↓BP, unwell

High RBG (usually >>30 mmol/L)

Osmolality >350

(Na+ + K+) x2 + Urea + Glucose = Osmol

Management of HHS SummaryT2DM, older, co-morbidity, more sick

Osmol > 350 mmol/Ltr

Gluc usually >>30 mmol/Ltr

Same general management as DKA

IV insulin 0.1 units/kg/hr = 6-8 units/hour

IV fluids 3-5 Ltr/24hr

Go more gentle!

?Full heparin dose

Abs, MI screen etc

Inform your senior

GKI/Alberti (to give insulin to T1DM)

15 units Actrapid

500 ml 10% Dextrose

10 mmol KCl

80-100ml/hour

If BMs high add another 5 units (and on)

If BMs low add 5 units less (and on)

Check K 1 hour before bag change

Restart sc insulin 1/2 hour before eating

Complications & DiabetesMicrovascular v Macrovascular

‘KNIVES’

K - kidneys

N - nerves

I - impotence, infection

V – vascular (IHD, CVA, PVD)

E - eyes

S - skin infections

Macrovascular risk factors

Male

Age

Family History

Other Vascular Disease:CVA, TIA

LVH

Diabetes

Hypertension

Lipids:↑Chol, ↑LDL, ↓HDL, ↑ TGs

Smoking

Obesity

Exercise

Diabetic complications

Prevention of complications

Risk reduction – relative versus absolute

Risk elimination

Residual risk

Intervention studies - Drug X

Reduces total chol 70%Reduces LDL 50%Increases HDL 10%Would you take it?

Surrogate markersLosing weight reduces cholLosing weight by losing legs

Reduces relative risk of MI 50%Would you take it?

Relative risk reduction

RR↓ 50%

RR↓ 50%

RR↓ 50%

Risk of AE Relative versus absolute risk

RR↓ 50%

Absolute risk reduction

Absolute risk reduction

Absolute risk reduction

Lies, damn lies and statistics6/49 x 5/48 x 4/47 x 3/46 x 2/45 x 1/44 =

720/10,068,347,520 =

1 in 13,983,816

Increase your relative risk by 100%

To 1 in 6,991,908

Absolute risk increase 1 in 13 million

Reduce your relative risk by 50%

1 in 27,967,632

Absolute risk reduction 1 in 13 million

Numbers Needed to Treat….

100 patients

10 events

100 patients

5 events

Relative risk reduction 50%

Treat 100 people, 5 events prevented, therefore treat 20 to prevent 1

This maybe all that we can offer you

1000 patients

10 events

1000 patients

5 events

Relative risk reduction 50%

Treat 1000 people, 5 events prevented, therefore treat 200 to prevent 1

Intervention studies - Drug X

Reduces total chol 70%Reduces LDL 50%Increases HDL 10%Would you take it?

Surrogate markersLosing weight reduces cholLosing weight by losing legs

Reduces relative risk of MI 50%Would you take it?Serious adverse event 1% per yearWould you take it?

What does risk reduction mean?

What was not going to happenWhen does this not happen

What did happenin spite of intervention..When did you cause this?

What didn’t happen with intervention…When does this not happenWhen did you prevent this?

RR reduction 50% with 20% side effects

What was not going to happenPlus SEPrimum non nocere First do no harm!

What did happenin spite of intervention..When did you cause this?Plus SE

What didn’t happen with intervention…When did you prevent this?Plus SE

Maximilien François Marie Isidore de Robespierre (May 6, 1758–July 28, 1794),

On ne peut pas faire d'omelette sans casser des oeufs

You can't make an omelette without breaking eggs

Primum non nocere

Risk of crossing the roadPark cars

Eyes closed

Heavy traffic

Run out

Pedestrian crossing

Wait for green man

Look both ways

Walk briskly don’t run

No guarantee to be or not be run over

NB you do get to the other side.The prevention of accident happens in definite time frame

Prevention of macrovascular complications

Primary prevention

All T2DM & most T1DM (10y risk <15%)

Tight glycaemic control (~UKPDS & DCCT)

Tight BP control (UKPDS)

Tight lipid management

Aspirin, ACE I/AT2A, smoking, BMI

Secondary prevention

Hx of CVA, MI, IHD, PVD, Amputation

Glycaemia in T2DM

HbA1c 2/12 marker (area under the curve)

Mean 5.4%, SD 0.4%

i.e. normal <6.2

HbA1c <7.5 <6.5

Normality

Mean1 SD

2 SDs3 SDs

68%

95%

99%

HbA1c: mean 5.4%, SD 0.4%

5.4% 6.2%

68%

95%

99.5%

7.0%4.6%

2.5% ‘normal population’

0.25%

Oral HypoglycaemicsMetformin (if BMI >24)

500 - 1000mg b.d - t.d.s

Side effects - GI….lactic acidosis

Contraindications - CRF, CCF, hepatic problems

No weight gain, no hypos

Gliclazide (if BMI <22)

40 - 320mg per day (od - bd)

Side effects weight gain & hypos

Glitazones (pioglitazone > rosiglitazone), acarbose etc

Hypoglycaemics

Incretins – Exanatide, gliptins

Insulins:

long v short

free v pre-mixed

human v pork v analogue

?CSII etc

Combination with OHA

Normal person

0

2

4

6

8

10

12

14

16

18

1 3 5 7 9 11 13 15 17 19 21 23

IsulinGlusose

BD Mix

0

5

10

15

20

25

30

35

40

shortlong

7am 6pm

Breakfast

Lunch

Dinner

Snack

Basal Bolus

0

5

10

15

20

25

30

35

1 3 5 7 9 11 13 15 17 19 21 23

BasalBolus

am short

Lunch short

Dinner short

Evening background

Titrating Insulin-BD mix

BM reading Insulin

7 am Nocte long

Noon Mane short

6 pm Mane long

10 pm Nocte short

Titrating Insulin-Basal Bolus

BM reading Insulin

7 am Nocte basal

Noon Mane short

6 pm Noon short

10 pm Supper short

Lipid loweringDiet/lifestyle/co-morbid/smoking

CVS equivalent (or CVS risk >15%@10 yr)

LDL/Total Chol (>2.0/4.0) - Statins

HDL/Trigs (<1, >2.2) - ? Fibrates

Statins - Simva 40, Atova 40-80mg noctegood for total and LDL chol

Fibrates - Fenofibrate micro 267mg mane

good for trigs and HDL

Nicotinic acid - good for trigs and HDL

Ezetimibe - add on therapy, Omacor - post MI

ABCD tool

Anti-hypertensivesACE I/AT2A

Ramipril 2.5 - 10mg, Irebesartan 150 - 300mg

Partic if: CCF, IHD, MI, nephropathy, CVA

CI: pregnant, renovascular disease (watch Creat)

Thiazide diuretics (low dose!) - BFZ 2.5 mg o.d

β blockers - atenolol 50mg

Partic if MI, IHD, CCF

CCB - Amolidipine 5-10mg o.d

α blockers - Doxazosin XL 4-16mg (BPH)

Central acting etc

Microvascular Complications

Retinopathy

Nephropathy

Neuropathy

Erectile dysfunction

Prevention of microvascular complications

Primary prevention

Tighten control:

Glycaemia, BP, Lipids

Aspirin, ACE I, Anti Obesity

Secondary prevention

Catch & Treat early (as above, laser Rx etc)

Therefore screen for them

Funduscopy, feet inspection, urine & blood tests

Annual Screen

HbA1c/Lipids/Creat/BP/Wt

Alb:Creat Ratio

Feet - pulses, sensation (10g MF), ulcers

Eyes - dilated funduscopy, VAs

Kidneys - BP/ACR/Creat

Smoking status

Mx T2DM ConclusionsLifestyle: Smoking, Diet, Exercise & Weight

Annual screen for complications

Glycaemic control (UKPDS Metformin > Glic)

CVS Risk Calculation (>15%) v Equiv

Lipid controlLFD, Statin, ?Fibrates

BP controlACE I, ATII, Diuretics, β Blocker, CCB, other

Other drug Rx: Aspirin,?anti obesity,?anti smoking, ?HRT

Questions?