Earlier Insulinization >> Better Outcomes

Prof. Abbas Oraby,MDProf. of Internal Medicine and Diabetes.

Faculty of Medicine –Zagazig University.

Normal Glucose Homeostasis Involves Pancreatic Islet Cells in Normal Subjects

Insulin from β-cells

Blood glucose homeostasis

Ingestion of food

Pancreas

-cells -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

Glycemic control mechanisms

Coordinated Functioning Of Pancreatic Beta Cells And Alpha Cells Is An Essential Component Of Normal Glycemic Control10

It involves 3 main steps :

Insulin release :

1. Translocation of insulin granules.

2. Docking of insulin granules.

3. Fusion of insulin granules.

Two essential components of the

cytoskeletal elements :

Translocation of insulin granules :

1. Microtubules (formed of tubulin

subunits).

2. Microfilaments (Actin + Myosin).

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.

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

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.

xCa++ Store

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 retention3

Depolarization

4

Glucokinase

TranslocationATP

Voltage-gate Ca channel

Fusion

Ca+

5

6

Glucose

1

G-6-P

2

GLUT2 X

Normal IGT Type 2

INSULINRESISTANCE

INSULINSECRETION

FPG/PPGHbA1c↑

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

The defect of insulin secretion in DM2 is

related to 2 compenents:

1- Insulin deficiency

2- Disturbed kinetics of insulin secretion.

Disturbed Kinetics:-

1- Loss of the 1st phase of insulin

secretion.

2- Decreased 2nd phase.

Non-diabetic

T2DM

-ce

ll m

ass

(%)

~65%

-cell deficit in T2DM

Modified from Butler AE, et al. Diabetes 2003;52:102–10.

-cell apoptosis in T2DM

Butler AE, et al. Diabetes 2003;52:102–10.

Lean(non-diabetic)

Obese(non-diabetic)

ObeseT2DM

0.00

0.25

0.50

0.25 *

*p<0.05 vs obese non-diabetic

Non-diabetic

T2DM

Pool-hypothesis

ATPADP

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

Insulin Deficiency:

1- mature insulin.

2- C-peptide.

3- Pro-insulin.

Immune- reactive

insulin.

PI/IRI

Factors for progressive loss of B-cell

function & mass:

- Glucotoxicity.

- Lipotoxicity.

- Inflammatory cytokines and leptin.

- Islet cell amyloid.

- Reduced B-cell mass and dysfunction.

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

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

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

ER Stress

-cell dysfunctionInsulin resistance

-cell apoptosis

Chronic inflammation

Obesity

Atherosclerosis

Endoplasmic reticulum stress

Hyperglycemia

Reactive oxygen species (ROS)

Oxidative stress

Apoptosis

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-cellRest

• 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.

K-channels opener(Diazoxide & NN414)

B-cell rest

Better functions

(B-cell preserve)

Cytosolic Ca++

Re-accumulationof insulin stores

Apoptosis

Diazoxide induces B-cell preserve by:

1-Blocking insulin screation (rest)

2-Reducing cytosolic Ca++ (anti-apoptosis)

The hypothesis

Induction of B-cell rest early in type 2

diabetes restore B-cell functions and

delay further B-cell destruction.

The approach

- Intensive insulin therapy

- Early in type 2 diabetes.

(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

(The recommendation)

Early Insulinzation

ADA & CASD consensus 2008.

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.

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

ADA/EASD Target

6.0

7.0

8.0

9.0

10.0

Baseline

Time (weeks)

12

Hb

A1

c (

%)

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%

4020 study: Insulin glargine provides better HbA1c control than TZD after OHA failure

Incidence of hypoglycaemia was similar for both treatment groups

Risk of severe hypoglycaemia and severe nocturnal hypoglycaemia reducedby 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 mainlyobserved 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

Hyp

og

lyca

emia

NPH

Glargine

A1c

~ ~ 0.4–0.6% ? ?

The impact of hypoglycaemia on A1c

A “qualified A1c” by hypoglycaemiaThe quest for a better basal insulin…

RANDOMISATION

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 afterachieving FPG <7.0 mmol/L. No second glargine dose was allowed.

−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

Dosing frequency and daily dose are lower with insulin glargine vs detemir: 1-year data

Once-daily dosing Daily insulin dose

Pa

tie

nts

(%

)

Rosenstock J, et al. Diabetologia 2008;51:408–16.

At

stu

dy

en

d (

U/k

g/d

ay)

*103 of the 104 patients who required twice-daily dosing were switched within 12 weeksChanges in HbA1c were similar

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 from If positive…insulin replacement can be considered right from the outset ! the outset !

• CV event-reduction outcome study• Opportunity to assess -cell preservation

Gerstein HC, et al. Am Heart J 2008;155:26–32.

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