Lipids Carbohydrate Protein

Aminoacids Fatty Acids Glycerol

Mono/di-saccarides

Triglycerides Glycogen Protein

Fat Liver Muscle

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Microvascular Macrovascular

Diabetes-specific Diabetes-enhanced

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Plasma glucose (mmol/I)

Status FPG 2-hour post-OGTT

IFG ADA WHO IDF

6.1 and <7.0 6.1 and <7.0 >6.0 and <7.0

IGT ADA WHO IDF

7.8 but <11.1 7.8 but <11.1 7.8 but 11.0

†If measured

IFG = impaired fasting glucose

IGT = impaired glucose tolerance

OGTT = oral glucose tolerance test

HbA1c 5.7(6.0) – 6.4%

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International Diabetes Federation. IDF Diabetes Atlas. Seventh Edition. 2015

2000 2015 2040 151 million 415 million 642 million

1% reduction in BMI =

2.4 million cases of diabetes prevented in the US

1% reduction in HbA1c =

20% reduction in diabetes-related deaths

Epidemiology - the rule of halves

Slide no 9

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Type 1 Type2

Age young elderly

Onset abrupt slowly

Plasma insulin low high

Ketosis yes no

Weight thin obese

Genetic weak (HLA) strong

Treatment insulin Diet,OHA,Insulin

Complications micro/macro macro/micro

PATHOGENESIS

“Run” 5-8 %

Up to 25% Genetic

Epigenetic Environmental

• Off springs of GDM pregnancy have several fold higher risk

• Off springs of mothers with malnutrition have higher risk

Foetal programming?

Differentiated RNA- reading of DNA

EPIGENETIC ??

EVOLUTION

2/1/2017

URBANISATION

2/1/2017

Age-adjusted Percentage of U.S. Adults with Obesity or Diagnosed Diabetes

Obesity (BMI ≥30 kg/m2)

Diabetes

1994

1994

2000

2000

No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0%

No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%

2009

2009

OB E S I TY

D I A B E T E S

Increased Risk of T2DM with increasing BMI

Colditz GA et al.Ann Intern Med 1995

0

10

20

30

40

50

60

70

80

90

100

Age

-adj

uste

dre

lativ

e ri

skof

diab

etes

< 22 22 - 22.9 23 - 23.9 24 - 24.9 25 - 26.9 27 - 28.9 29 - 30.9 31 - 32.9 33 - 34.9 35 +

BMI (kg/m2)

Impaired insulin-mediated glucose disposal

Inappropriate endogenous glucose production

Hyperglycemia

Reduced/altered insulin secretion

+

-

-

peripheral glucose uptake

hepatic glucose production

Relative pancreatic insulin secretion

pancreatic glucagon secretion

Main Pathophysiological Defects in T2DM

gut carbohydrate delivery & absorption

incretin effect

HYPERGLYCEMIA

?

Normal /

normo-

glycaemia

Type 2

diabetes

Obese

normo-

glycaemia

Type 1

diabetes

The common denominator in the most common forms of diabetes is relative insufficient beta cell mass

Lean

Obese I n

s u l i n

s e

c r e

t i o n ( p m

o l / m

i n )

100

6 a.m. 2 p.m. 6 p.m. 6 a.m. 10 p.m. 2 a.m.

200

300

400

500

600

700

800

900

1000

Polonsky et al., 1988a

Adapted from UKPDS 16. Diabetes 1995;44:1249–58

Years from diagnosis

Beta

-cell

function (

%)

–10 –8 –6 –4 –2 0 2 4 –12

100

80

60

40

20

0

0 1 2 3 4

0.2

0.4

0

0.6

8

12

16

20

4

Glu

cose

(mm

ol/l)

Insu

lin (n

mol

/l)

0 1 2 3 4 hrs

0.20.2

0.4

0

4

8

0

Glu

cose

(mm

ol/l)

Insu

lin (n

mol

/l)

Normals

Owens D, et al 1995

MEAL TOLERANCE TEST

Type 2 : Fasting PG

< 10

10mmol/l

: Type 2 Diabetes Mellitus

4

5

6

7

8

9

10

11

12

0 60 120 180 240 300

TIME (min)

0

50

100

150

200

250

300

350

400

0 60 120 180 240 300

TIME (min) Pl

asm

a in

sulin

(pm

ol/l

)

Plas

ma

gluc

ose

(mm

ol/l

)

Inappropriate hepatic glucose production

Gluconeogenesis

Glycerol

Lactate

Amino acids

fructose

Glucose-6-Phosphate

Glucose

GlucokinaseGlucose-6-Phosphatase

PEPCK

Fructose 1-6-bisphosphatase

Glycogenolysis

GlycogenGlycogen Synthase

Glycogen phosphorylase

cAMP

GlucagonX

700

600

500

200

100

0 1440 1200 960 720 480 240 0

Time (min)

400

300

Before weight loss

After weight loss

Plasma glucose levels and insulin secretion rates in

obese people with Type 2 diabetes

Plasma glucose

(mmol/L) Insulin secretion rate

(pmol/m2/min)

24

20

16

12

8

4 1440 1200 960 720 480 240 0

Time (min)

Figure 1. A simplified model of the insulin signalling pathway that regulates

glucose transport in skeletal muscle

Insulin

receptor

GLUT4-

containing

vesicle

PDK 1/2

Tyrosine phosphorylation

ATP

Protein

Kinase B

(Akt)

p85

PI 3,4-P3 PI 3,4,5-P3

Phosphoinositide (PI) 3-kinase

SH2

domains

Atypical

protein kinase C

Translocation

to cell membrane

GLUT4

PKCζ

PKCλ

Cytoplasm

Cell-surface membrane Glucose Glucose

??

Stimulation of

glucose transport

Phosphoinositide-

dependent

kinase

Insulin

β β

α α

IRS

p110

Leptin Resistin

Adverse cardiometabolic effects of

products of adipocytes

Adipose

tissue

↑ IL-6

↓ Adiponectin

↑ Leptin

↑ TNFα

↑ Adipsin

(Complement D)

↑ Plasminogen

activator inhibitor-1

(PAI-1)

↑ Resistin

↑ FFA

↑ Insulin

↑ Agiotensinogen

↑ Lipoprotein lipase

↑ Lactate

Inflammation

Type

2 diabetes

Hypertension

Atherogenic

dyslipidaemia

ThrombosisAtherosclerosis

Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

Elevated lipid levels are detrimental

in type 2 diabetes

MUSCLE

TG accumulationInsulin resistance

B CELLS

TG accumulation

Disturbed insulin

secretion

(hyperinsulinaemia)

FFA TG

Hormones

Increased

hepatic glucose output

(hyperglycaemia)

LIVER

• Increased VLDL

• Decreased HDL

• Increased small dense LDL

Atherosclerosis

Fat Topography In Metabolic Syndrome

Hi TG

Hi FFA

Intramuscular Fat

Intrahepatic Fat

Subcutaneous Fat

Intraabdominal Fat

DeFronzo, JCEM, 2014

Low HDL

Cholesterol

IGT/IFG or

type 2 diabetes Central Obesity

WHR > 0.9 men

> 0.8 women

or BMI > 30 kg/m²

Microalbuminuria

UAE 20 µg min

Insulin resistance

(glucose uptake below

lowest quartile)

Triglycerides 150 mg/dl

& HDL-Ch < 35/39 mg/dll

Blood pressure

140/90 mmHg

METABOLIC SYNDROME

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•

•

•

•

–

–

–

–

–

–

–

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•

•

• Metformin

• Sulfonylurea (long and short acting)

• DPP4 inhibitors

• Thiazolidinediones

• SGLT2

• Acarbose

• GLP-1 agonist

• Insulin ( OD, BID, TID, CSII )

• Medication for concomitant diseases

Figure 1. A simplified model of the insulin signalling pathway that regulates

glucose transport in skeletal muscle

Insulin

receptor

GLUT4-

containing

vesicle

PDK 1/2

Tyrosine phosphorylation

ATP

Protein

Kinase B

(Akt)

p85

PI 3,4-P3 PI 3,4,5-P3

Phosphoinositide (PI) 3-kinase

SH2

domains

Atypical

protein kinase C

Translocation

to cell membrane

GLUT4

PKCζ

PKCλ

Cytoplasm

Cell-surface membrane Glucose Glucose

??

Stimulation of

glucose transport

Phosphoinositide-

dependent

kinase

Insulin

β β

α α

IRS

p110

Effects of GLP-1

Stomach: Gastric emptying Acid secretion

Brain: Hypothalamus: appetite , satiety food intake

Ileum: Synthesis (from proglucagon), Secretion (after meals, glucose, fat)

Endocrine pancreas: Secretion: β-cells: insulin secretion α-cells: glucagon secretion δ-cells: somatostatin secretion Biosynthesis: (Pro-)insulin β-cell mass: Neogenesis , replication apoptosis

Muscle

Adipose tissue:

Lipolysis (indirect)

Glucose uptake (?) Glycogen synthesis (?)

Liver: Glucose production (?)

Heart: Glucose uptake Ejection fraction

TYPE 2 DIABETES : Treatment Targets Good Poor Bl.Glucose (mM)

HbA1c (%) <7.0 >8.5

Lipids (mM) Cholesterol <5.2 >6.5 HDL-C >1.1 <0.9 fasting triglycerides <1.7 >2.3

BMI (kg.m2) <25 >27 <24 >26

BP (mmHg) <135/85 >160/95

STOP SMOKING

Intensive (SU/Ins) vs. Conventional glucose control

(photocoagulation, vitreous haemorrhage, renal failure)

HR (95%CI)

(fatal or non-fatal myocardial infarction or sudden death)

Intensive (SU/Ins) vs. Conventional glucose control

HR (95%CI)

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Access to care - Type 2

11.15 N (%) of patients seen regularly at clinic (e.g. 4 times a year) 11.16 N (%) of patients with regular screening for late complications (micro- and/or

macro vascular) (e.g. yearly) 11.17 N (%) patients receiving regular glucose test at clinic (HbA1c, BG profile,

PPG, FPG, RPG) (each visit) 11.18 N (%) of patients who do regular HMBG (e.g. daily or weekly) 11.19 N (%) of patients within agreed target for glucose control (HbA1c, BG profile,

PPG, FPG, RPG, urine glucose) 11.20 N (%) of patients with improvements in metabolic control

11.13 N (%) of patients with reduction in BMI

11.14 N (%) of patients with normal BP (<140/90)

11.15 N (%) of patients with reduction in BP

11.16 N (%) of patients with neuropathy, retinopathy or nephropathy

11.17 N (%) of patients with macro vascular complications

11.18 N (%) of patients with improvements in KAP (Knowledge, Attitude and

Practises)