Are you Struggling to Control of your Diabetes and Weight?
People who are overweight or obese are more prone to developing Type 2 diabetes. Those who have Type 1 and Type 2 diabetes with weight problems struggle to control their blood sugar levels. Research shows that people with diabetes find it more difficult to lose weight than those without diabetes.
Weight loss significantly improves blood sugar control and also reduces the risk of getting complications from diabetes. However, whilst attempting to lose weight, people with diabetes find it hard to restrict their intake of food since eating less may trigger hypoglycaemia (low blood sugar). All these facts explain the need for specialist input in management of weight in people with diabetes.
This Slideshow gives you insight to Diabesity
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2. Diabesity - 21st century pandemic
Diabesity is now the single greatest
contributor to chronic disease
Obesity will soon become the
leading cause of death
3. 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
4. Aims of this forum
External speaker
Discussion of case studies
Website to be launched
Expand to regional forum and National
7. Obesity can alter the natural history of T2DM
by virtue of the role of visceral fat with its
Proinflammatory
Prothrombotic
Proinsulin resistant environments.
24. Ramlo-Halsted BA, et al. Prim Care 1999;26:771–789.
Impaired insulin production
& secretion
The underlying defects:
insulin resistance and β-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 responsiveness
to insulin
↑FFA
levels
Sedentary
lifestyle
Diet Obesity
Type 2 diabetes
Glucotoxicity
β-cell dysfunction
Genetic
predispositions
26. 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
27. 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
28. 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
1
Wei Y, et al. FEBS Lett 1995;358:219–224; 2
Drucker DJ. Diabetes Care 2003;26:2929–2940.
GLP-1 GIP
30 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
29. The incretin effect is reduced in
patients
with
Type 2 diabetes
0
20
40
60
80
0 30 60 90 120 150 180
Time (min)
*
* *
** *
*
0
20
40
60
80
0 30 60 90 120 150 180
Time (min)
Oral Glucose
30. 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)
GIP
Hyperglycaemic clamp
Insulin(pmol/L)
0 30 60 90 120 150 180 210
0
250
500
750
1000
1250
1500
1750
2000
Time (min)
0 30 60 90 120 150 180 210
0
250
500
750
1000
1250
1500
1750
2000
Time (min)
Patients with type 2 diabetesNormal subjects
31. 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
32. GLP-1 effects in humans
Understanding the natural role of incretins
Adapted from 1
Nauck MA, et al. Diabetologia 1993;36:741–744; 2
Larsson H, et al. Acta Physiol Scand 1997;160:413–422; 3
Nauck MA, et
al. Diabetologia 1996;39:1546–1553; 4
Flint A, et al. J Clin Invest 1998;101:515–520; 5
Zander et al. Lancet 2002;359:824–830.
GLP-1 secreted upon
the ingestion of food
1.β-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
33. 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 placebo
DeFronzo RA, et al. Diabetes Care 2005;28:1092–1100.
*
**
*
-0.3 ± 0.3 kg
-2.8 ± 0.5 kg
-1.6 ± 0.4 kg
Time (weeks)
5 10 15 20 25 300
-4
-3
-2
-1
0
1
**
**
** **
*
Mean(±SE)changeinbody
weightfrombaseline(kg)
Placebo BD Exenatide 5 µg BD Exenatide 10 µg BD
34. 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 placebo
Buse J, et al. Diabetes Care 2004;27:2628–2635.
-0.6 kg
-0.9 kg
-1.6 kg
Mean(±SE)changeinbody
weightfrombaseline(kg)
Time (weeks)
0 10 20 30
-2.00
-1.50
-1.00
-0.50
0
*
-1.75
-1.25
-0.75
-0.25
5 15 25
Placebo BD Exenatide 5 µg BD Exenatide 10 µg BD
45. DR age 48 years
T2DM 14 years
Metformin, Gliclazide, Lantus 56 units
Weight 142Kg BMI 52 Kg/m2
HbA1C 7.6%
46. Fasting blood glucose 5.6mmol/l
Post prandial 8.8 mmol/l
Recurrent hypoglycaemia at night
Daily supper
Lantus switched to morning
Solution??
47. Reduce Lantus
Correct Post prandial Glucose
Stop Supper
Weight loss after 6 months 23KG
HbA1C 6.8%
Lantus reduced to 22units
48. 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
49. 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
50. 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
51. 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 !!!!!!!
DISCUSSION The development of type 2 diabetes involves defects in multiple organ systems which can be exacerbated by a number of factors, including diet and lifestyle, genetic causes and dysregulation of lipid and carbohydrate metabolism. Initially, insulin resistance is associated with hyperinsulinaemia and normal glucose tolerance. β -cell dysfunction manifests as impaired insulin production and failure to secrete sufficient insulin to compensate for insulin resistance. Eventually, demand for insulin outweighs β -cell capacity, leading to impaired glucose tolerance, escalating hyperglycaemia, and type 2 diabetes. Ramlo-Halsted BA, et al. Prim Care 1999;26:771–789.
DISCUSSION GLP-1 and GIP represent the dominant peptides responsible for the ‘incretin effect’. Bioactive forms of both GLP-1 and GIP are short-lived, with active plasma half-lives of ~2–7 minutes. Degradation is by dipeptidyl peptidase IV (DPP-IV). Drucker DJ. Diabetes Care 2003;26:2929–2940.
DISCUSSION The β -cell secretory response to glucose ingestion, as measured by increases in plasma insulin, was reduced in patients with type 2 diabetes. Patients with type 2 diabetes exhibited a greater β -cell secretory response than control subjects, as indicated by higher insulin secretion levels, during the 180-minute course of intravenous glucose infusion. BACKGROUND Differences in insulin response to oral and intravenous glucose administration, which are attributed to factors other than glucose itself, describe the incretin effect; the incretin effect appears to be reduced in patients with type 2 diabetes. Measured insulin and C-peptide responses to a 50 g oral glucose load and an isoglycaemic intravenous infusion. Additionally, an attempt was made to correlate incretin effects to GIP responses. Insulin measurements are shown here. Plasma insulin responses were studied for 14 patients with type 2 diabetes in this study and 8 metabolically healthy control subjects. Nauck MA, et al. Diabetologia 1986;29:46–52
DISCUSSION In patients with type 2 diabetes, GLP-1, in contrast to GIP, retains much of its insulinotropic activity. Both GIP and GLP-1 augmented insulin secretion in a dose-dependent fashion. With GLP-1 infusion, the maximum insulin effect in patients with type 2 diabetes approached 71% of the maximum insulin effect in subjects without diabetes (no statistical difference). With GIP infusion, the maximum insulin effect in patients with type 2 diabetes was 46% of the maximum insulin effect in subjects without diabetes ( P < 0.05). BACKGROUND The graphs represent immunoreactive insulin plotted against time (minutes) during hyperglycaemic clamp experiments with and without the infusion of synthetic human GIP or GLP-1. The data for the graphs of this slide were derived from a study of the insulinotropic effect of intravenously administered synthetic human GLP-1 and GIP (N = 9 for each patient group). Nauck MA, et al. J Clin Invest 1993;91:301–307
DISCUSSION Decreased GLP-1 secretion is found in patients with type 2 diabetes 1 ; however, it’s ability to stimulate glucose-dependent insulin secretion is preserved 1,2 . Another hormone, glucagon, is secreted by the α - cells of the pancreas and is elevated in type 2 diabetes. Glucagon stimulates hepatic glucose release. GLP-1 suppresses glucagon secretion from pancreatic α - cells in a glucose-dependent manner 3 , suppressing hepatic glucose output 4 . Therefore, incretin hormones, specifically GLP-1, have sparked interest in the treatment of type 2 diabetes 5 . 1 Nauck MA, et al. J Clin Invest 1993;91:301–307 2 Nauck M, et al. Diabetologia 1986;29:46–52 3 Nauck MA, et al. Diabetologia 1993;36:741–744 4 Larsson H, et al. Acta Physiol Scand 1997;160:413–422 5 Drucker DJ. Diabetes Care 2003;26:2929–2940 .
DISCUSSION This diagram demonstrates the GLP-1 effects in humans and the role these effects play in normal physiology. Upon the ingestion of food, plasma glucose levels increase postprandially. GLP-1 is secreted from intestinal L cells and provides a stimulus to the β -cells to release insulin in a glucose-dependent manner. When plasma glucose levels return to normal, the action of GLP-1 decreases 1 . GLP-1 also suppresses glucagon levels that are inappropriately elevated in patients with type 2 diabetes 1 . Lower glucagon levels leads to decreased hepatic glucose output 2 . In the stomach, GLP-1 slows the rate of gastric emptying, which reduces the rate at which meal-derived glucose appears in the circulation 3 . In the brain, GLP-1 promotes satiety and reduces appetite, which leads to a feeling of fullness and a reduction in food intake 4,5 . All these actions help maintain overall glucose homeostasis. 1 Nauck MA, et al. Diabetologia 1993;36:741–744 2 Larsson H, et al. Acta Physiol Scand 1997;160:413–422 3 Nauck MA, et al. Diabetologia 1996;39:1546–1553 4 Flint A, et al. J Clin Invest 1998;101:515–520 5 Zander et al. Lancet 2002;359:824–830.
DISCUSSION Progressive, dose-dependent reduction in weight was seen in exenatide-treated patients. At Week 30, weight changes from baseline were -2.8 ± 0.5 kg (10 µg), -1.6 ± 0.4 kg (5 µg) for exenatide treated patients ( P < 0.001 vs placebo 10 μ g and P < 0.001 vs placebo 5 μ g). No special weight loss programmes, exercise programmes, or standardised diets were used in the study. STUDY BACKGROUND A 30-week triple-blind, phase III study; patients with type 2 diabetes randomised to placebo, exenatide 5 or 10 µg BD with metformin, ITT, N = 336.
DISCUSSION Reduction in weight was seen in both exenatide arms, but greater weight loss was observed in the exenatide 10 µg BD arm. At Week 30, weight changes from baseline were -1.6 ± 0.3 kg (10 µg), -0.9 ± 0.3 kg (5 µg; not significantly different vs placebo) and -0.6 ± 0.3 kg (placebo). No special weight loss programmes, exercise programmes, or standardised diets were used in the study. STUDY BACKGROUND A 30-week triple-blind, phase III study; patients with type 2 diabetes randomised to placebo or exenatide 5 or 10 µg BD with sulphonylurea, ITT, N = 377.
