Lipids - World diabetes foundation 2... · Slide no 9 • • • • • • • Type 1 Type2 Age...
Transcript of Lipids - World diabetes foundation 2... · Slide no 9 • • • • • • • Type 1 Type2 Age...
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
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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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• 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)