This document discusses the prevention, treatment, and management of diabetes and its complications. It covers the pathophysiology of type 2 diabetes, including the progression from insulin resistance to impaired glucose tolerance to frank diabetes. It emphasizes the importance of earlier intervention and tighter control of blood glucose and HbA1c levels to reduce complications. Shift work and disrupted sleep-wake cycles can increase the risk of obesity and diabetes by disturbing circadian rhythms and metabolic functions.

1. Prevention treatment and
management of diabetes
and its complications
Dr.Yeoh Swee Inn
MBBS, M.MED(INT MED), FAMS, FACE
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6. Development and progression of Type 2 DM
Progression of Disease
Insulin resistance
Hepatic glucose production
Insulin level
β-cell function
4–7 years
Post-prandial
glucose
Fasting glucose
Impaired Glucose Tolerance Frank Diabetes
Diabetes Diagnosis
Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications for clinical
6
*Conceptual representation.
practice, 771–789, © 1999, with permission from Elsevier.

7. Major pathophysiologic defects :Type 2 DM
Islet-Cell Dysfunction
Glucagon
(α cell)
Pancreas
Insulin Insulin
(β cell) resistance
Hepatic
glucose
Glucose uptake
output
Hyperglycaemia
Muscle
Liver
Adipose
tissue
Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
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EARLIER INTERVENTION
• 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.

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EARLIER INTERVENTION
• 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.

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22. Improved 24-hour glucose profile in 23
T2DM
Placebo + metformin (n=13)
Sitagliptin 50 mg b.i.d. + metformin (n=15)
Breakfast Lunch Dinner
240 Dose 1 Dose 2
7:30 18:30 Difference in 24-hour weighted LS mean glucose:
220 –32.8 mg/dL
(–1.82 mmol/L) p<0.001
200
Glucose (mg/dL)
180
160
140
120
100
8:00 13:00 19:00 0:00 7:30
Day 1 Day 2
Time
Adapted from Brazg RL et al. Poster presented: at American Diabetes Association; June 10–14, 2005; San Diego, Calif.

23. ADA and IDF Guidelines:
Treatment Goals for HbA1c, FPG, and PPG
Normal ADA IDF
Parameter Level Goal Goal
FPG, mg/dl <110 90–130 <100
(mmol/L) (<6.1) (5.0–7.2) (<5.5)
PPG, mg/dl <140 <180 <140
(mmol/L) (<7.8) (<10.0) (<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. 24
Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.

24. Diabetes-Related Complications
Relative Risk
N=3642
EVERY 1% REDUCED RISK
reduction in HbA1c (P<0.0001)
Diabetes-
related
deaths
Myocardial
infarctions
1%
Microvascular
complications
Amputations or deaths
from peripheral
vascular disorders
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.
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32. THE LANCET Vol 363 April 3, 2004

33. 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”

34. 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

35. 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.

36. 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

37. 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

38. 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

39. 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

40. 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).

41. 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

42. 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