Download - Diabesity (Diabetes and Obesity)
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Diabesity - 21st century pandemic
Diabesity is now the single greatest contributor to chronic disease
Obesity will soon become the leading cause of death
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Aims of this forum
Open forum to discuss management of Diabesity
Forum will be interactive
New studies in this field will be presented
Emerging treatments in Diabesity will be discussed
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Aims of this forum
External speaker
Discussion of case studies
Website to be launched
Expand to regional forum and National
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Meeting Three monthly
Clinical leads in Primary care (Two doctors and two nurses)
Members will be contacted via email
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Obesity can alter the natural history of T2DM
by virtue of the role of visceral fat with its
Proinflammatory
Prothrombotic
Proinsulin resistant environments.
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Ramlo-Halsted BA, et al. Prim Care 1999;26:771–789.
Impaired insulin production & secretion
The underlying defects: insulin resistance and -cell dysfunction
Insulin resistance (IR)
- Hyperinsulinaemia - Normal glucose tolerance
IR + declining insulin levels + impaired glucose tolerance
- Failure of β-cell to adapt to IR
Impaired responsivenessto insulin
↑FFA levels
Sedentary lifestyle
Diet Obesity
Type 2 diabetes
Glucotoxicity
-cell dysfunction
Genetic predispositions
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Physiological functions
• Incretins are hormones secreted by intestinal endocrine cells in response to nutrient intake
• Glucose-dependent insulin secretion, postprandial glucagon suppression and slowing of gastric emptying
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Incretins were identified when it was observed that orally ingested glucose provoked a higher insulin response than comparable glucose administered intravenously
This well-described phenomenon is called the ‘incretin effect’
The incretin effect accounts for ~60% of total insulin release following a meal
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The two primary incretin hormones are GLP-1 and GIP
• Circulating GIP and GLP-1 levels are regulated by multiple factors2
– Low in the basal fasting state, rise rapidly following a meal due to neuronal, neuroendocrine, and direct nutrient stimulation of intestinal cells
1Wei Y, et al. FEBS Lett 1995;358:219–224; 2Drucker DJ. Diabetes Care 2003;26:2929–2940.
GLP-1 GIP30 amino acid peptide1 42 amino acid peptide2
Synthesised and released by L cells of ileum and colon2
Synthesised and released from K cells of jejunum and duodenum2
Sites of action1:
Pancreatic β-cells and α-cells
GI tract
CNS
Lungs
Heart
Sites of action2:
Pancreatic β-cells
Adipocytes
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The incretin effect is reduced in patients
with Type 2 diabetes
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GLP-1 is a more potent insulin secretagogue than GIP in patients with type 2 diabetes
Mean (SE); N = 18.Nauck MA, et al. J Clin Invest 1993;91:301–307.
Low-dose GIP or GLP-1 (7–36 amide)High-dose GIP or GLP-1 (7–36 amide)
GLP-1 (7–36 amide)GIPHyperglycaemic clamp
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Patients with type 2 diabetesNormal subjects
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Therapeutic potential
GIP secretion is normal, but its action is diminished
GLP-1 secretion is diminished, but its action is preserved
Glucagon, secreted from pancreatic α-cells, is also elevated in type 2 diabetes
GLP-1 suppresses glucagon secretion from pancreatic α-cells in a glucose-dependent manner, suppressing hepatic glucose outputt
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GLP-1 effects in humansUnderstanding the natural role of incretins
Adapted from 1Nauck MA, et al. Diabetologia 1993;36:741–744; 2Larsson H, et al. Acta Physiol Scand 1997;160:413–422; 3Nauck MA, et al. Diabetologia 1996;39:1546–1553; 4Flint A, et al. J Clin Invest 1998;101:515–520; 5Zander et al. Lancet 2002;359:824–830.
GLP-1 secreted upon the ingestion of food
1.-cell:enhances glucose-dependent
insulin secretion in the pancreas1
3.Liver: reduces hepatic glucose
output2
2.α-cell:suppresses postprandial
glucagon secretion1
4.Stomach: slows the rate of gastric emptying3
5.Brain:promotes satiety and
reduces appetite4,5
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Change in body weight over time, Exenatide with metformin
ITT population, N = 336 (Placebo, N = 113; exenatide 5 µg, N = 110; exenatide 10 µg, N = 113)*P ≤ 0.05 ** P ≤ 0.001 compared to placeboDeFronzo RA, et al. Diabetes Care 2005;28:1092–1100.
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-0.3 ± 0.3 kg
-2.8 ± 0.5 kg
-1.6 ± 0.4 kg
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Placebo BD Exenatide 5 µg BD Exenatide 10 µg BD
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Change in body weight over time, Exenatide with sulphonylurea
ITT population, N = 377 (Placebo, N = 123; exenatide 5 µg, N = 125; exenatide 10 µg, N = 129); *P ≤ 0.05 vs placeboBuse J, et al. Diabetes Care 2004;27:2628–2635.
-0.6 kg
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Placebo BD Exenatide 5 µg BD Exenatide 10 µg BD
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Case studies
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DR age 48 years
T2DM 14 years
Metformin, Gliclazide, Lantus 56 units
Weight 142Kg BMI 52 Kg/m2
HbA1C 7.6%
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Fasting blood glucose 5.6mmol/l
Post prandial 8.8 mmol/l
Recurrent hypoglycaemia at night
Daily supper
Lantus switched to morning
Solution??
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Reduce Lantus
Correct Post prandial Glucose
Stop Supper
Weight loss after 6 months 23KG
HbA1C 6.8%
Lantus reduced to 22units
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Case Study 2
EB 56 years House wife
Type 1 diabetes sine age 22years
Weight 112Kg BMI 48 Kg/m2
Also is hypertensive and has angina
On Lantus 66 units
Novarapid 12 units TDS
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HbA1C 8.6%
Add Metformin
Weight 106 Kg after three months
Lantus down to 50 units
HbA1C 8.0%Metformin full dose
After three months Orlistat added with guidance
Lantus 36 units
HbA1C 7.4%
Weight 98 Kg
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MA 62 years
T2DM 8 years
Weight 102 Kg BMI 56 Kg/m2
HbA1C 10.3 %
On Metformin, Lantus 64 units BD
Increasingly tired
And
Day time sleepiness
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OSA ruled out
? Hypogonad
Testosterone 6.6 nmol/l
Testosterone replacement
After 4 months reduced Lantus to 32 units BD due to hypoglycaemia
Weight 90KG
HbA1C 8.1%
No day time sleepiness !!!!!!!
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Next Forum
Presentation of GAME and LOOKAHEAD
Case discussion
External Speaker (TBC)
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