1

Prevention treatment and management of diabetes

and its complications

Dr.Yeoh Swee Inn

MBBS, M.MED(INT MED), FAMS, FACE

3

4

5

6 Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications for clinical

practice, 771–789, © 1999, with permission from Elsevier.

Development and progression of Type 2 DM

*Conceptual representation.

Progression of Disease

Impaired Glucose Tolerance

Insulin level

Insulin resistance

Hepatic glucose production

Diabetes Diagnosis

Post-prandial

glucose

Fasting glucose

β-cell function

Frank Diabetes

4–7 years

7

Major pathophysiologic defects :Type 2 DM

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

Hepatic

glucose

output

Insulin

resistance

Glucose uptake

Glucagon

(α cell)

Insulin

(β cell)

Liver

Hyperglycaemia

Islet-Cell Dysfunction

Muscle

Adipose tissue

Pancreas

8

EARLIER INTERVENTION

9

• 2006 Consensus statement from the ADA and EASD

–“Our consensus is that an HbA1c of ≥7 should serve as a call to action to initiate or change therapy…”

–“If lifestyle intervention and maximal tolerated dose of metformin fail to achieve or sustain glycaemic goals, another medication should be added within 2–3 months of the initiation of therapy or at any time when HbA1c goal is not achieved”

EASD=European Association for the Study of Diabetes.

Nathan DM et al. Diabetologia. 2006;49:1711–1721; International Diabetes Federation. 2005:1–79.

EARLIER INTERVENTION

10

•2005 Global Guideline by IDF

–“Begin with metformin unless evidence or risk of renal impairment, titrating the dose over early weeks to minimise discontinuation due to gastro-intestinal intolerance”

–“Step up doses, and add other glucose-lowering drugs, at frequent intervals until blood glucose control is at target levels”

EASD=European Association for the Study of Diabetes.

Nathan DM et al. Diabetologia. 2006;49:1711–1721; International Diabetes Federation. 2005:1–79.

22

Improved 24-hour glucose profile in

T2DM

23

Difference in 24-hour weighted LS mean glucose: –32.8 mg/dL (–1.82 mmol/L) p<0.001

Adapted from Brazg RL et al. Poster presented: at American Diabetes Association; June 10–14, 2005; San Diego, Calif.

Gluco

se (m

g/dL)

8:00 Day 1

13:00 19:00 0:00 Day 2

7:30

100

120

140

160

180

240

200

220 Dose 1 7:30

Dose 2 18:30

Breakfast Lunch Dinner

Placebo + metformin (n=13) Sitagliptin 50 mg b.i.d. + metformin (n=15)

Time

24

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

Parameter

Normal

Level

ADA

Goal

IDF

Goal

FPG, mg/dl

(mmol/L)

<110

(<6.1)

90–130

(5.0–7.2)

<100

(<5.5)

PPG, mg/dl

(mmol/L)

<140

(<7.8)

<180

(<10.0)

<140

(<7.8)

HbA1c 4%–6% <7%* <6.5%

*Reference to a nondiabetic range of 4.0% to 6.0% using a DCCT-based assay.

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

American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41; International Diabetes Federation. 2007:1–32.

Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.

25

Diabetes-Related Complications

UKPDF=United Kingdom Prospective Diabetes Study.

Data adjusted for age, sex, and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years.

Stratton IM et al. UKPDS 35. BMJ 2000;321:405–412.

EVERY 1%

reduction in HbA1c

REDUCED RISK

(P<0.0001)

1%

Diabetes-

related

deaths

Myocardial

infarctions

Microvascular

complications

Amputations or deaths

from peripheral

vascular disorders

Relative Risk N=3642

26

27

28

THE LANCET Vol 363 April 3, 2004

Asymptomatic :missing the boat of opportunity for diabetic complications

• Retinopathy: often not symptomatic

• Incipient Diabetic nephropathy is diagnosable

• Fatty liver not symptomatic

• Ischemic heart disease: diabetics “silent AMI”

• „Silent Stroke”

Modern living and the diabetic: circadian-metabolic link

• Major lifestyle modifications:

• 24 hour society

• Extended working hours

• Night work; sleep-wake cycle abnormal phase relationship

• Shift of eating hours towards late night

• Shift work and increased prevalence of obesity

SHIFT WORK AND SLEEP LOSS

• Shift workers get less sleep on average during the week than regular day workers

• 49% of shift workers average 6.5 hours of sleep per night.

• When the subjects ate and slept approx 12 hours out of phase from their habitual times their levels of Leptin decreased, post-meal sugars increased.

Circadian Clocks & obesity and Diabetes Endocrine News June 2011

• Timing of AMI and cardiovascular events (including thrombosis and AMI) peak in the morning

• Disorders of lipid absorption, lipogenesis and lipolysis display circadian rhythm

• Impaired nocturnal blood pressure: due to autonomic dysfubction

Shift work and sleep: Novel risk factors for obesity and DM

• When subjects ate and slept approx. 12 hours out of phase from their habitual times,

– their levels of satiety hormone leptin decreased,

– post-prandial glucose responses higher

– Shift workers experience shift misalignment

Shift work

• The desynchronised schedule causes insulin resistance and impaired insulin secretion

• Ghrelin and adiponectin (produced in GIT and adipose tissue) display diurnal expression rhythms

SHIFT WORKERS

• Sleep after night shift almost always involves sleep loss. Rarely exceeds 6 hours;49% average 6.5hours of sleep per night Proc. Natl Acad sci U.S.A. 2009;106: 4453-4458

Genetic Mice models

• MICE given access to a high fat diet during the light phase (their normal resting period ) gain more weight than mice with access to the same diet only during the dark phase (active period).

LIFESTYLE AND HEALTH

• Disturbance in circadian clock system : promotes weight gain

• Extended work shifts; increased risk of weight gain or metabolic syndrome

• Animal studies : circadian misalignment promotes obesity and glucose intolerance

References:

• Mahmoud et al JACC Cardiovas Interv, 2011, 4:183-190

• Paschos GK, Fitzgerald GA Circadian clocks and vascular function Circ Res. 2010; 106:833-841