1. Dr Wayne Riback Senior Medical Advisor
Diabetes Mellitus
Dr Wayne Riback
Senior Medical Advisor

2. Diabetes is an increasing healthcare epidemic throughout the world
Global projections for the number of people with diabetes (20–79 age group), 2007–2025 (millions)
53.2
64.1
+21%
28.3
40.5
+43%
67.0
99.4
+48%
South and Central America
Africa
Eastern Mediterranean and Middle East
Europe
North America
South-East Asia
Western Pacific
24.5
44.5
+81%
46.5
80.3
+73%
The IDF found that, as a global phenomenon, the prevalence of diabetes is predicted to increase from 246 million in 2007 to 380 million by 2025, an increase of 55%.1 T2DM alone has reached epidemic proportions and affects approximately 5.9% of adults worldwide. The prevalence is increasing steadily and is expected to affect 7.1% of adults by the year In particular, the increase in T2DM is seen among younger people and in developing countries. Indeed, a disproportionate number of diabetic patients live in the Asia-Pacific region; approximately 81 million people with diabetes live in India and China compared with 19 million in the USA.1
In summary, these data provide an updated quantification of the current and growing public health burden of diabetes across the world. The human and economic costs of this epidemic have severe implications for healthcare resource use.
Reference
International Diabetes Federation. Diabetes Atlas 3rd Edition (2006): Page 5
10.4
18.7
+80%
16.2
32.7
+102%
Worldwide:
246 million people in 2007
380 million projected for 2025
IDF. Diabetes Atlas 3rd Edition – 2006

3. Diabetes prevalence in the Middle East and Africa is high and increasing
Prevalence rates and numbers of adults with diabetes (1,000s)
Pakistan
2007: 8.3% – 6, : 8.5% – 11,538
Tunisia
Lebanon
Morocco
Israel
Iran
Algeria
Egypt
Saudi Arabia
Iran
2007: 6% – 2, : 8.4% – 5,115
Pakistan
Saudi Arabia
2007: 13.5% – 1, : 15.7% – 3,610
Morocco
2007: 7.1% – 1, : 9.1% – 2,396
Lebanon
2007: 7.4% – : 9.1% – 267
Algeria
2007: 7.3% – 1, : 8.9% – 2,528
Global data from the IDF Diabetes Atlas 3rd Edition show that the prevalence of diabetes (T1DM and T2DM) in adults (age >20 years) in the Middle East and Africa is high and is set to increase dramatically during the next 18 years.1
The greatest increase in prevalence will occur in Saudi Arabia (13.5–15.7%), Egypt (10.1–12.2%), with Iran (6.0–8.4%) and Morocco (7.1–9.1%) also markedly increasing their prevalence rates.
In terms of the population developing diabetes, Iran and Saudi Arabia will see their diabetes population increasing by approximately 100%.
Reference
International Diabetes Federation. Diabetes Atlas 3rd Edition (2006).
Israel
2007: 7.8% – : 8.5% – 495
Tunisia
2007: 4.8% – : 6.2% – 535
South Africa
South Africa
2007: 4.5% – 1, : 4.4% – 1,279
Egypt
2007: 10.1% – 4, : 12.2% – 7,650
IDF. Diabetes Atlas 3rd Edition – 2006

4. How is South Africa performing with respect to DM Practices?
Diabetes Action Now Booklet – Adapted from Wild S. Diabetes care 27: ; 2004

5. Patients are uncontrolled with respect to HbA1c
100
69.4
% of patients
HbA1c>7%
HbA1c<7% 30
Table 33
Figures are given here as examples….
30.4
South Africa

6. Patients uncontrolled with respect to HbA1c
100
38.2 60
% of patients
HbA1c>8.4%
HbA1c<7%
HbA1c 7%- 8.4%
31.4 30
Table 33
Figures are given here as examples….
30.4
South Africa

7. Type 2 DM Patients are not adequately screened for complications
Percentage of patients who have never been screened in the last 12 months 45 35 25
South Africa 15
Screening of complications: Has your patient never been screened for …during the last 12 months ? We did not ask for the type of examination (clinical vs. ECG vs. lab testing etc.) for each. For example, as far as neurologic complications are concerned, we do not know if the absence of screening of neurologic complications means only the absence of physical examination (filament) or of nerve conduction testing.
Tables 318a-f
Figures are given here as examples…. 5
5.8
8.2
5.9
6.9
5.6
3.1
Cardio
Vascular
disease
Eye
Nerve
Kidney
Diabetic
Foot
ulcer
Lipid

8. Type 2 DM Patients with complications
Percentage of patients who have diabetes complications 45 35 25
South Africa 19 15 17
Screening of complications: Has your patient never been screened for …during the last 12 months ? We did not ask for the type of examination (clinical vs. ECG vs. lab testing etc.) for each. For example, as far as neurologic complications are concerned, we do not know if the absence of screening of neurologic complications means only the absence of physical examination (filament) or of nerve conduction testing.
Tables 48-53
Figures are given here as examples…. 14 12 5 8 4
Coronary
Artery
disease
Eye
Nerve
Kidney
Diabetic
Foot
ulcer
PVD

9. T2 DM: Only few patients have an HbA1c tested every 6 Months
100 90
99% 80 70 60
% of patients
South Africa 50 40 30
41% 20
Table 33
Figures are given here as examples 10 2%
In the last
12 months
Every
6 months
Every
3 months

10. The burden of diabetes on healthcare systems
Diabetes accounts for between 5% and 10% of any nation’s health budget
Three times the healthcare resources are being spent on treating diabetes complications compared with that spent on controlling diabetes before the onset of complications
The cost of type 2 diabetes in Europe (CODE-2) study evaluated more than 7,000 patients with type 2 diabetes in eight European countries: Belgium, France, Germany, Italy, The Netherlands, Spain, Sweden and the UK
The average yearly cost per patient was €2,834, the greatest proportion of which was accounted for by hospitalization costs
Reference
Jonsson B. Diabetologia 2002;45:S5–S12
CODE-2: cost of type 2 diabetes in Europe
Jonsson B. Diabetologia 2002;45:S5–S12
Status of diabetes management

11. Pathogenesis of type 2 diabetes mellitus

12. Insulin-glucose profile after meal
Breakfast
Lunch
Dinner
Plasma insulin
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time

13. Type 2 diabetes mellitus (T2DM) requires progressive therapy
T2DM is a progressive disease characterised by increased insulin resistance and decreasing pancreatic β-cell function1
At diagnosis, patients may have already lost approximately 50% of β-cell function2
An ideal treatment regimen for T2DM should provide:
Continuity of care as the disease progresses
Flexibility to adapt to individual needs
Type 2 diabetes mellitus (T2DM) develops because of a progressive decline in pancreatic -cell function and decreasing insulin sensitivity in peripheral tissues.
The -cells may compensate for peripheral insulin resistance by increasing insulin output. Eventually the -cells fail to produce sufficient insulin, and hyperglycaemia and diabetes ensue.
During insulin resistance, increased hepatic glucose production and reduced glucose uptake by skeletal muscle both contribute to hyperglycaemia.
Insulin also fails to suppress lipolysis in adipose tissue, resulting in increased concentrations of circulating free fatty acids (FFAs). FFAs stimulate gluconeogenesis, triglyceride synthesis and glucose production in the liver, and further impair glucose utilisation by skeletal muscle.
Excess circulating glucose and FFAs act on cells and tissues to inhibit insulin secretion and action. This is referred to as gluco-lipotoxicity.
The progressive nature of T2DM requires a progressive treatment strategy.
Reference
Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995–1015.
Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995―1015.
Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.

14. Decreasing -cell function as part of the progression of T2DM
100
Time of diagnosis ? 80 60
Normal -cell function by HOMA (%)
Pancreatic function
~50% of normal 40 20
―10 ―8 ―6 ―4 ―2 2 4 6
Six-year follow-up data from the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the decline in -cell function as T2DM progresses.
At the time of diagnosis, -cell function is already reduced by approximately 50% and continues to decline regardless of therapy.
Severe -cell failure results in insulin deficiency and a subsequent requirement for insulin therapy.
Reference
Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.
Time (years)
HOMA=homeostasis model assessment
Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.

15. Multiple factors may drive progressive decline of b-cell function
Hyperglycaemia
(glucose toxicity)
Insulin resistance
b-cell
(genetic background)
Protein
glycation
“lipotoxicity”
elevated FFA,TG
External factors that influence the function of the beta cells ( there has been a lot of data published by Roger Unger on the effects of lipotoxicity
Amyloid
deposition

16. Both FBG and PPBG contribute to overall hyperglycaemia
Onset of diabetes
350
300
250
200
150
100 50
19.4
16.7
13.9
11.1
8.3
5.5
2.8
PPBG
Plasma
glucose
(mg/dl)
FBG
Plasma
glucose
(mmol/l)
250
200
150
100 50
Relative
-cell
function
(%)
Insulin resistance
Insulin
level
-cell failure
Obesity IGT T2DM
Uncontrolled
hyperglycaemia
Clinical
features
Risk for diabetes complications with uncontrolled hyperglycaemia
T2DM is a progressive disease characterised by declining pancreatic -cell function leading to decreased insulin levels.
-cell dysfunction begins some 10–12 years before diabetes is diagnosed. Typically, by the time of diagnosis, approximately 50% of -cell function has already been lost.1
When the secretion of insulin cannot keep pace with the underlying insulin resistance, impaired glucose tolerance (IGT) and T2DM develop.
The natural progression of T2DM is prolonged; many key features such as insulin resistance and macrovascular changes occur before hyperglycaemia develops and before T2DM is diagnosed.2
Exposure to metabolic dysregulation substantially increases the risk of developing macrovascular (e.g. stroke, ischaemic heart disease and peripheral vascular disease) and microvascular (e.g. retinopathy, nephropathy and neuropathy) complications at a later date.2
References
Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.
Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995–1015.
Years
–10 –
FBG=fasting blood glucose; IGT=impaired glucose tolerance; PPBG=postprandial blood glucose.
Adapted from Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995―1015.

18. 24-hour plasma glucose profile in T2DM and healthy subjects
400 20
T2DM
300 15
Plasma glucose (mg/dl)
200
Plasma glucose (mmol/l) 10
100 5
Healthy subjects
Meal
Meal
Meal
06:00
10:00
14:00
18:00
22:00
02:00
06:00
In patients with T2DM, excess exposure to hyperglycaemia is linked to an increase in fasting plasma glucose concentration.
Specifically targeting fasting hyperglycaemia will, therefore, lower the entire 24-hour plasma glucose profile and should be the primary aim of therapy.
Reference
Hirsch IB, et al. Clin Diabetes 2005;23:78–86.
Time of day (hours)
Comparison of 24-hour plasma glucose levels in healthy subjects vs patients with diabetes (p<0.001). Adapted from Hirsch I et al Clin Diab 2005;23:78-86

19. Guidelines provide HbA1c, FBG and PPBG targets
Normal
ADA/EASD1&3
Targets for Diabetic Patients
AACE4
IDF5
SEMSDA
HbA1c* (%)
<6.01
<7.0†
6.5
<6.5
<7.0
FBG, mmol/l
(mg/dl)
<5.52
(<100)
3.97.2
(70130)
6.0
(110)
<6.0
(<110)
<7.0
(<130)
PPBG, mmol/l
(mg/dl)
<7.8**1
(<140)
<10.0**
(<180)
7.8**
(140)
<8.0**
(<145)
<8.0
(<145)
*DCCT referenced assays: normal range 4–6%; **1–2 hours postprandial; †ADA/EASD guidelines recommend HbA1c levels as close to normal (<6%) as possible without significant hypoglycaemia1,5
AACE=American Association of Clinical Endocrinologists; ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes; IDF=International Diabetes Federation
The most recent HbA1c target set by the American Diabetes Association (ADA) is <7%, with the aim of restoring HbA1c to normal values (<6%) without significant hypoglycaemia.1
A consensus statement from the ADA and the European Association for the Study of Diabetes (EASD) recommends that an HbA1c value 7% should prompt the initiation or adjustment of treatment. The goal of treatment should be to achieve an HbA1c value as close to the healthy range (<6%) as possible or, at a minimum, decrease HbA1c to <7%.2
The ADA and EASD recognise that this goal is not appropriate or practical for some patients, and advocate an assessment of the potential risks and benefits of an intensified regimen for each individual patient.2
References
1. ADA. Diabetes Care 2006;29(suppl 1):S4–42.
2. Nathan DM, et al. Diabetologia 2006;49:1711–21.
ADA. Diabetes Care 2006;29(suppl 1):S4–S42.
ADA. Diabetes Care 2006;29(suppl 1):S43–8.
ADA/EASD Consensus Algorithm - Nathan DM, et al. Diabetologia 2006;49:1711–21
AACE. Endocr Pract 2002;8(suppl 1):40–82.
IDF. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation,

20. SEMSDA Guidelines 2009

22. (insulin sensitisers)
T2DM is a progressive condition
Metformin
(insulin sensitisers)
Lifestyle
changes
Insulin
Secretagogue
Post Meal Glucose
Glucose (mg/dL)
Fasting Glucose
Insulin Resistance
Normal Function
% of
Insulin Level
At risk for DM
Beta cell dysfunction
Years of Diabetes
Risk for diabetes complications
Adapted from: UKPDS 33: Lancet 1998; 352, DeFronzo RA. Diabetes. 37:667, 1988.
Saltiel J. Diabetes. 45: , Robertson RP. Diabetes. 43:1085, 1994.
Tokuyama Y. Diabetes 44:1447, Polonsky KS. N Engl J Med 1996;334:777.
©2000 International Diabetes Center. All rights reserved

23. The most powerful agent we have to control glucose
Insulin
The most powerful agent we have to control glucose

24. Balancing Good Glycemic Control with a Low Risk of Hypoglycemia…
Key Point
Essentially, the key to good insulin therapy is to balance good glycemic control with a low risk of hypoglycemia.
Hypoglycemia 24

25. Imagine consulting room on Monday with the following:
59 years old male working as a financial manager – sedentary work most of the times during the week – works long hours.
Over week-ends he enjoys hiking
Type 2 diabetes diagnosed 12 years ago
He has hypertension, dyslipidaemia.

26. Case study (continued)
Current medication:
Glimepiride 4 mg/day
Metformin 1g bd
Irbesartan 300 mg/day
Rosuvastatin 10 mg/day
Disprin CV 1/day

27. Case study (continued)
Body mass index = 30
Waist circumference = cm
BP = 120/74 mm Hg
No diabetes complications
HbA1c = 8.9%
FBG of 9-10 mmol/l
PPBG up to 15 mmol/l

28. What will be prescribed?
More than 200 combinations of insulin and oral agents are possible:
Intensified insulin – basal-bolus or MDI
Basal-plus
Conventional – premix
Basal-oral
Basal – Glargine, Detemir, NPH
Bolus – Glulisine, Lispro, Aspart, Human Regular,
Premix- Regular or Rapidacting bolus component
Different % combinations

29. Relative contribution of FBG and PPBG to HbA1c
The relative contribution of PPBG is predominant in subjects with moderate diabetes, whereas the contribution of FBG increases as diabetes worsens 60
Postprandial
Fasting 40
Relative contribution of FBG vs PPBG (%) 20
This study analysed the daytime glycaemic profiles of 290 individuals with T2DM controlled by diet or oral hypoglycaemic agents (OHAs).1
Blood-glucose concentrations were determined during fasting and postprandial periods.
Fasting blood glucose (FBG) and post-prandial PPBG contribute to overall hyperglycaemia in individuals with T2DM to varying degrees according to HbA1c levels. In individuals with poor glycaemic control (HbA1c >7%) the relative contribution of FBG is greater than that of PPBG.2 PPBG is the major contributor when HbA1c is near to target.
References
Monnier L, et al. Diabetes Care 2003;26:881–5.
Monnier L, et al. Diabetes Care 2002;25:737–741.
<7.3
7.3–8.4
8.5–9.2
9.3–10.2
>10.2
HbA1c (%)
Adapted from Monnier L, et al. Diabetes Care 2003;26:881–5.

30. Plasma glucose (mg/dl) Plasma glucose (mmol/l)
Treating fasting hyperglycaemia lowers the entire 24-h plasma glucose profile
Hyperglycaemia due to an increase in fasting glucose
400
T2DM 20
300 15
Plasma glucose (mg/dl)
200
Plasma glucose (mmol/l) 10
Normal
100 5
Meal
Meal
Meal
06.00
10.00
14.00
18.00
22.00
02.00
06.00
In patients with T2DM, excess exposure to hyperglycaemia is caused by an increase in fasting plasma glucose concentration.
Specifically targeting fasting hyperglycaemia will, therefore, lower the entire 24-hour plasma glucose profile and should be a primary aim of therapy.
References
Hirsch IB, et al. Clin Diabetes 2005;23:78–86.
Time of day (hours)
Comparison of 24-hour glucose levels in control subjects versus patients with diabetes (p<0.001). Adapted from Polonsky K, et al. N Engl J Med 1988;318:1231―1239.
Copyright © 2007 Massachusetts Medical Society. All rights reserved. 30

31. INSULIN TACTICS Twice Daily Split–Mixed Regimens
Regular
Lispro
Lispro
Lispro
Insulin Effect
Reg
Reg
Insulin Effect
NPH
NPH
NPH
NPH B L S HS B B L S HS B
Meals
Meals

32. Case study Max OAD HbA1c = 8.9% FBG of 9-10 mmol/l
PPBG up to 15 mmol/l Hb

33. More physiologic insulin replacement = Basal – Bolus/ Basal-Plus

34. Type 2 DM Rx Strategies : ‘Basal-Plus’ therapy
FBG <6mM but HbA1c >7.0% (>6.5%)
introduce Glulisine before meal with max BG
excursion >7.8mM (>10mM) 12
OHAs +
glargine 8
Glucose (mmol/l) 4
Glulisine* 8 12 18
22.00 hrs
Breakfast
Lunch
Snack
Dinner
glargine
Metformin no change (2g/d)
Glimepiride, gliclazide SR no change,
Glibenclamide, gliclazide no change, reduce or stop pre-dinner dose
Meglitinides need to stop pre-dinner dose
*Start Glulisine 4 units based on SMBG if PPBG >/=7.8 mM
Titrate upwards by 2 units every 5-7 days to achieve PPBG <7.8mM 34

35. Insulin treatment options in type 2 diabetes
Basal Plus therapy
long-acting insulin
+ rapid acting analog with 1-2 meals
+/- oral agents
Conventional
Insulin Therapy
2-3 injections
mix of regular insulin / rapid-acting insulin analog and long-acting insulin
Prandial / Intensified
Insulin Therapy
Short acting insulin or rapid insulin analog prandially
long-acting insulin
Basal insulin therapy
Long-acting insulin
+/- oral agents

36. Insulins Class of insulin Product Action onset Action duration
Peak/max
Human Insulins
Shortacting
Actrapid
Humulin R
30 min
8 hrs
2.5-5hrs
Intermediate-acting: Isophane Zinc suspension
Humulin N
Protaphane
Humulin L
1.5hr
2.5 hrs
16hrs
20hrs
4-12hrs
7-15hrs
Biphasic/Premixed
Actraphane (30/70)
Humulin 30/70
Mixtard 20/80
24 hrs
2-12 hrs
Inhaled Insulins
Exubera*
Analogue insulins
Ultra shortacting
Humalog
Novorapid
Glulisine*
10-20 min
3-5 hrs
1-3 hrs
Intermediate-acting
Detemir
14 hours (hypoglycaemic effect
6-8 hours
Biphasic/premixed
Humalog mix 25
Novomix 30
15-18 hrs
1-4hrs
Longacting
Lantus (Glargine)
1 hr
24 hrs
No peak

37. Onset and Duration of Insulin Preparations
Gummerson, Irene. Insulin analogues revisited, Hospital Pharmacist, April 2003, vol. 10, p

38. The Ideal Basal Insulin …
Mimics normal pancreatic basal insulin secretion
Long-lasting effect
Smooth peakless profile
Reproducible and predictable effects
Reduced nocturnal hypoglycemia
Once-daily administration for convenience
Pharmacodynamic effects similar to insulin pump

39. Plasma insulin (U/mL)
Basal/Bolus Treatment Program with Rapid-Acting and Long-Acting Analogs 75
Breakfast
Lunch
Dinner
Aspart or Lispro
Aspart or Lispro
Aspart or Lispro 50
Plasma insulin (U/mL) 25
Glargine
Basal/Bolus Treatment Program with Rapid-Acting and Long-Acting Analogs
This is ideal therapy.
Most patients are unwilling or unable to take 4 injections per day, which brings us to the rationale for NovoLog® Mix 70/30.
Time
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Verbal communication from Bode, BW. Atlanta, Ga; Feb

40. Current Strategies for Improving the Therapeutic Potential of GLP-1
Agents that mimic the actions of GLP-1 (incretin mimetics)
DPP-IV–resistant GLP-1 derivatives (dipeptidyl peptidase)
Examples: GLP-1 analogues, albumin bound GLP-1
Novel peptides that mimic some of the glucoregulatory actions of GLP-1
Exenatide
- Victoza (NovoNordisk)
- Syncria (GSK – Phase II)
Agents that prolong the activity of endogenous GLP-1
DPP-IV Inhibitors
Drucker DJ, et al. Diabetes Care. 2003;26: ; Baggio LL, et al. Diabetes. 2004;53:

41. GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins
Promotes satiety and reduces appetite
Alpha cells:
↓ Postprandial glucagon secretion
DISCUSSION
By decreasing β-cell workload and improving β-cell response, GLP-1 is an important regulator of glucose homeostasis.
Upon food ingestion, GLP-1 is secreted into the circulation.
GLP-1 increases β-cell response by enhancing glucose-dependent insulin secretion.
BACKGROUND
GLP-1 is secreted from L cells of the small intestine.
GLP-1 decreases β-cell workload, hence the demand for insulin secretion, by:
Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (β-cell workload)
Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon
Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on β-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output
Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake
Effect on Beta cell: Drucker DJ. Diabetes. 1998;47:
Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160:
Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160:
Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39:
Effects on CNS: Flint A, et al. J Clin Invest. 1998;101:
Liver: ↓ Glucagon reduces hepatic glucose output
Beta cells: Enhances glucose-dependent insulin secretion
Stomach: Helps regulate gastric emptying
Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes. 1998;47:

42. GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins
Promotes satiety and reduces appetite
Alpha cells:
↓ Postprandial glucagon secretion
DISCUSSION
By decreasing β-cell workload and improving β-cell response, GLP-1 is an important regulator of glucose homeostasis.
Upon food ingestion, GLP-1 is secreted into the circulation.
GLP-1 increases β-cell response by enhancing glucose-dependent insulin secretion.
BACKGROUND
GLP-1 is secreted from L cells of the small intestine.
GLP-1 decreases β-cell workload, hence the demand for insulin secretion, by:
Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (β-cell workload)
Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon
Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on β-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output
Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake
Effect on Beta cell: Drucker DJ. Diabetes. 1998;47:
Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160:
Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160:
Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39:
Effects on CNS: Flint A, et al. J Clin Invest. 1998;101:
Liver: ↓ Glucagon reduces hepatic glucose output
Beta cells: Enhances glucose-dependent insulin secretion
Stomach: Helps regulate gastric emptying
Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes. 1998;47:

43. The Incretin Effect Demonstrates the Response to Oral vs IV Glucose
Oral Glucose IV Glucose 11
2.0 *
1.5
Incretin Effect
DISCUSSION
Despite the same plasma glucose profiles, there are significant differences in the -cell response to oral versus (vs) intravenous glucose, as measured by C-peptide.
BACKGROUND
This was a crossover study involving healthy subjects.
Six young healthy subjects were given a 25, 50, or 100 g oral glucose load or isoglycaemic intravenous glucose infusions. The 50-g data is shown above.
C-peptide may be a better measure of insulin secretion than plasma insulin, because C-peptide levels are not affected by hepatic insulin extraction.
This difference in C-peptide levels in response to oral vs intravenous glucose suggests that other factors (incretins), and not merely the direct actions of plasma glucose, affect the insulin secretory response.
5.5
C-peptide (nmol/L)
1.0
Venous Plasma Glucose (mmol/L)
0.5
0.0 02 01 02 60
120
180 01 60
120
180
Time (min)
Time (min)
Mean ± SE; N = 6; *P .05; = glucose infusion time.
Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63: Copyright 1986, The Endocrine Society.

44. The Incretin Effect Is Reduced in Patients With Type 2 Diabetes
Intravenous Glucose
Oral Glucose
Control Subjects
Patients With Type 2 Diabetes 80 80 60 60
DISCUSSION
The -cell secretory response to glucose ingestion, as measured by increases in plasma insulin, was reduced in patients with diabetes.
Patients with diabetes exhibited a greater -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
This study with type 2 diabetes and 8 metabolically healthy control subjects.
Insulin (mU/L) 40 40 * * 20 20 30 60 90
120
150
180 30 60 90
120
150
180
Time (min)
Time (min)
*P ≤.05 compared with respective value after oral load.
Nauck MA, et al. Diabetologia. 1986;29: Reprinted with permission from Springer-Verlag © 1986.