This document discusses the benefits of earlier insulinization for patients with type 2 diabetes. It provides evidence that introducing insulin therapy earlier in the disease process can help preserve pancreatic beta cell function and mass, leading to better long-term glycemic control and metabolic outcomes. The document reviews the mechanisms of beta cell dysfunction and failure in diabetes, and suggests that earlier insulin use can protect beta cells from glucotoxicity and lipotoxicity by inducing a period of rest. Clinical trials are cited showing improved glycemic control and remission of diabetes symptoms for up to 2 years with short-term intensive insulin therapy initiated early in the disease.

1. Earlier Insulinization >>
Better Outcomes
Prof. Abbas Oraby,MD
Prof. of Internal Medicine and Diabetes.
Faculty of Medicine –Zagazig University.

2. Normal Glucose Homeostasis Involves
Pancreatic Islet Cells in Normal Subjects
Insulin from β-cells
Blood glucose
homeostasis
Ingestion
of food
Pancreas
β-cells
α-cells
Glucagon
from α-cells
Glucose
production by
liver
Glucose
uptake by
adipose and
muscle tissue
Release of gut
hormones
GI tract
Glucose dependent
Glucose dependent

3. Glycemic control mechanisms
Coordinated Functioning Of Pancreatic Beta Cells And Alpha
Cells Is An Essential Component Of Normal Glycemic Control10

4. It involves 3 main steps :
Insulin release :
1. Translocation of insulin granules.
2. Docking of insulin granules.
3. Fusion of insulin granules.

5. Two essential components of the
cytoskeletal elements :
Translocation of insulin granules :
1. Microtubules (formed of tubulin
subunits).
2. Microfilaments (Actin + Myosin).

6. Microtubules form a network radiating from
the perinuclear region outwords.
It gives the way but not the force
The framework provides the
mechanical pathway along
which secretory granules move
toward the exocytic sites close
to the plasma membrane.

7. The motive force to propel granules along the
microtubules is provided by the interaction
between :
It gives the force but not the way
ATP Ca+
Granule transport
Filamentous
actin +
Phosphorylated
myosin

8. Ca+
is essential for almost all steps
involved in insulin release, thus factors
increasing intracellular Ca+
will augment
insulin release.
Mechanisms involved in increasing intra-
cytoplasmic Ca+
:
 Ca-influx from outside.
 Inhibition of Ca-reuptake by
intracellulas stores.
 Increased Ca-sensitivity.
x
Ca++
Store

9. Increased intracellular Ca+
is essential for
granules translocation and fusion hence release
of insulin.
Each B-cell contains up to 500 Ca channels
Glucose
ATP-sensitive
K+
channel
K retention
3
Depolarization
4
Glucokinase
TranslocationATP
Voltage-gate
Ca channel
Fusion
Ca+
5
6
Glucose
1
G-6-P
2
GLUT2 X

10. Normal IGT Type 2
INSULIN
RESISTANCE
INSULIN
SECRETION
FPG/PPG
HbA1c↑
Type 2 Diabetes is a Dual Problem
Adapted from Type 2 Diabetes BASICS. Minneapolis, MN: International Diabetes Center; 2000
Schematic Representation of the Natural Progression of Type 2
Diabetes

11. The defect of insulin secretion in DM2 is
related to 2 compenents:
1- Insulin deficiency
2- Disturbed kinetics of insulin secretion.

12. Disturbed Kinetics:-
1- Loss of the 1st
phase of insulin
secretion.
2- Decreased 2nd
phase.

13. Non-diabetic
T2DM

14. β-cellmass(%)
~65%
β-cell deficit in T2DM
Modified from Butler AE, et al. Diabetes 2003;52:102–10.

15. β-cell apoptosis in T2DM
Butler AE, et al. Diabetes 2003;52:102–10.
Lean
(non-diabetic)
Obese
(non-diabetic)
Obese
T2DM
0.00
0.25
0.50
0.25 *
*p<0.05 vs obese non-diabetic

16. Non-diabetic
T2DM

17. Pool-hypothesis
ATP
ADP
Modified from Rorsman P, et al. News Physiol Sci 2000;15:72–7.
I. Defective mobilisation
II. ⇑ insulin requirements
RR-Pool
Reserve-Pool
Depletion of insulin stores

18. Insulin Deficiency:
1-↓ mature insulin.
2- ↓ C-peptide.
3- ↓ Pro-insulin.
Immune- reactive insulin.
PI/IRI

19. Factors for progressive loss of B-cell
function & mass:
- Glucotoxicity.
- Lipotoxicity.
- Inflammatory cytokines and leptin.
- Islet cell amyloid.
- Reduced B-cell mass and dysfunction.

20. Glucotoxicity
Nonphysiological and potentially
irreversible B-cell damage caused by
chronic exposure to supra-physiological
glucose concentration with characteristic
decreases in insulin synthesis and
secretion caused by decreases insulin
gene expression.
Glucotoxicity is irreversible

21. B-cell exhaustion
- A physical depletion of B-cell insulin
stores secondary to prolonged chronic
stimulation with glucose on non-
glucose secretagogues.
- No defect in insulin synthesis.
- The B-cell function fully recovers as it
rests.
Exhaustion is reversible

22. B-cells Gluose-induced apoptosis
Physiological Increase
(100-200 mg%)
Longer & higher increase
Insulin Secretion ↑Proinsulin
synthesis
Long-term increase
of cystosolic Ca+
Excess
protein influx
through ER
ER stress
Apoptosis

23. ER Stress
β-cell dysfunctionInsulin resistance
β-cell apoptosis
Chronic inflammation
Obesity
Atherosclerosis
Endoplasmic reticulum stress

24. Hyperglycemia
↑ Reactive oxygen species (ROS)
Oxidative stress
Apoptosis

25. Interplay between B-cell exhaustion & glucotoxicity
Excess insulin secreation
Prolonged hyperglycemia
Insulin depletion from B-cell (Exhausion)
Hyperglycemia
More, prolonged hyperglycemia
ER Stress ROS ↑Ca++ Cytokines
Irreversible B-cell damge
& ↑ apoptosis (Glucotoxicity)
Beta-cell
Rest

26. • The concept of B-cell rest was first
introduced 30 years before.
• The K channel opener diazoxide was
used to inhibit insulin secretion in DM2
patients receiving insulin.
• Re-accumulation of insulin stores in B-
cell restored the insulin response to a
combined stimulation with glucagon
plus tolbutamide.

27. K-channels opener
(Diazoxide & NN414)
B-cell rest
Better functions
(B-cell preserve)
↓ Cytosolic Ca++
Re-accumulation
of insulin stores
↓ Apoptosis

28. Diazoxide induces B-cell preserve by:
1-Blocking insulin screation (rest)
2-Reducing cytosolic Ca++
(anti-apoptosis)

29. The hypothesis
Induction of B-cell rest early in type 2
diabetes restore B-cell functions and
delay further B-cell destruction.

30. The approach
- Intensive insulin therapy
- Early in type 2 diabetes.

31. (The Evidence)
Many reports in the last few years
proved the beneficial effects of short term
intensive insulin therapy (2-3 weeks), early
in DM2 with remission extended up to 2
years and maintained better metabolic
profile after 4 years follow up.
- Alvarsson et al., 2003
- Ryan et al., 2004
- Orabi A, 2006
- Xu Wen et al., 2009

32. (The recommendation)
Early Insulinzation
ADA & CASD consensus 2008.

33. Current ADA / EASD guidelines
Lifestyle +
metformin
Add basal insulin
or SU
Intensify therapy
e.g. ‘basal plus’
1
2
3
Nathan DM, et al. Diabetes Care 2009;32:193–203.

34. Blicklé JF, et al. Diabetes Obes Metab 2009;11(4):379–386
TULIP: initiating Insulin Glargine improves glycaemic
control more than intensifying lifestyle management in
Type 2 diabetes
Randomized study in 211 insulin-naïve subjects with T2DM, who initiated Insulin Glargine in combination with OADs or
intensification of lifestyle management + OADs for 9 months

35. ADA/EASD
Target
6.0
7.0
8.0
9.0
10.0
Baseline
Time (weeks)
12
HbA1c(%)
Insulin glargine
Pioglitazone
186 24 4830 36 42 Endpoint
6.8%
7.6%
Meneghini LF, et al. ADA 2005 (abstract).
48-week randomised trial in 173 patients with uncontrolled
T2DM on MET or SU for ≥3 months and HbA1c 8–12%
4020study: Insulin glargine provides better HbA1c
control than TZD after OHA failure
Incidence of hypoglycaemia was similar for both treatment groups

36. Risk of severe hypoglycaemia and severe nocturnal hypoglycaemia reduced
by 46% (p = 0.04) and 59% (p = 0.02), respectively, with insulin glargine
0.931 (0.771, 1.123); p = 0.455
0.591 (0.486, 0.718); p < 0.001
0.711 (0.586, 0.862); p = 0.001
Odds ratio
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
Overall
Nocturnal
Daytime
Symptomatic hypoglycaemic events
Increased riskReduced risk
Risk reduction mainly
observed at night
Rosenstock J, et al. Diabetes Care 2005;28:950−5.
Mean (CI)
Insulin glargine reduces hypoglycaemic
risk versus NPH in T2DM: Meta analysis

37. Hypoglycaemia
NPH
Glargine
A1c
~~ 0.4–0.6% ??
The impact of hypoglycaemia on A1c
A “qualified A1c” by hypoglycaemia
The quest for a better basal insulin…

38. R
A
N
D
O
M
I
S
A
T
I
O
N
Insulin-naive patients
with T2DM on 1 to 2
OHAs for ≥4 months
HbA1c 7.5–10%
(n = 582)
Insulin glargine once daily in
evenings + OHAs (n = 291)
Detemir once daily in evenings* +
OHAs (n = 291)
Treatment phase
52 weeks
Insulin glargine versus detemir
added to an OHA regimen
Rosenstock J, et al. Diabetologia 2008;51:408–16.
*An additional morning detemir dose was permitted if pre-dinner plasma glucose was >7.0 mmol/L after
achieving FPG <7.0 mmol/L. No second glargine dose was allowed.

39. −1.5% −1.5%
Similar rates of hypoglycaemia with insulin glargine and insulin detemir
Rosenstock J, et al. Diabetologia 2008;51:408–16.
Similar improvements in glycaemic
control with insulin glargine and detemir

40. Dosing frequency and daily dose are lower with
insulin glargine vs detemir: 1-year data
Once-daily dosing Daily insulin dose
Patients(%)
Rosenstock J, et al. Diabetologia 2008;51:408–16.
Atstudyend(U/kg/day)
*103 of the 104 patients who required twice-daily dosing were switched within 12 weeks
Changes in HbA1c were similar

41. 12,612
>6,000 standard step-therapy>6,000 standard step-therapy>6,000 early glargine>6,000 early glargine
FPG goal: <95 mg/dL
(<5.3 mmol/L)
HbA1C goal: <7%
Start: 2003 Follow-up: Extended to 7 years Final results: 2011
ORIGIN trial: Study design
•Prediabetes and early T2DM with CVD
If positive…insulin replacement can be considered right fromIf positive…insulin replacement can be considered right from
the outset !the outset !
• CV event-reduction outcome study
• Opportunity to assess β-cell preservation
Gerstein HC, et al. Am Heart J 2008;155:26–32.

42. ACCORD VADT ADVANCE ORIGIN
Number of patients 10,251 1,792 11,140 12,612
Age (years) 62 60 66 64
Diabetes duration
(years)
10 11.5 8 5
Macrovascular
complications (%)
35 40 32 66
Baseline HbA1c (%) 8.3 9.4 7.5 6.5
Intensive Rx target A1c < 6% A1c < 6% A1c ≤ 6.5 % FBG
≤ 5.3 mmol/L
Intervention Multiple drugs Multiple drugs Gliclazide ±
others
Glargine ± others
ORIGIN trial:
Comparison with other CV outcome studies