dr. rafn benediktsson saturday, october 17, 2015 i´m your keyhole surgeon…

Dr. Rafn Benediktsson Friday, April 21, 2023

I´m your keyhole surgeon…...


Samfelld mæling blóðsykurs án stun(g)u


Non-diabetic Insulin and Glucose Profiles

30

20

10

07 8 9 101112 1 2 3 4 5 6 7 8 9

Insulin

Glucose

a.m. p.m.

Breakfast Lunch Supper75

50

25

0 Basal insulin

Basal glucose

Insulin(µU/mL)

Glucose(mg/dL)

Time of Day


Limitations of Regular Human Insulin

Slow onset of activity

Should be given 30 to 45 minutes before meal

Inconvenient for patients

Long duration of activity

Lasts up to 12 hours

Potential for late postprandial hypoglycaemia (4-6 hours)

Need for additional snack


B28LYS

B29PRO

S

S

S S

S

S

A-chain

B-chain

1

1

21

30

[Lys (B28), Pro (B29)] - Human Insulin Analogue (recombinant DNA origin)

INSULIN LISPRO (Humalog®)


INSULIN LISPRO: Serum Insulin Levels (ng/ml) After Subcutaneous Injection in Healthy Volunteers ( n=10 )

0 1 2 3 4 5 6 7 8 9 10 11 12

5

4

3

2

1

0

Time (Hours)

Howey DC et al. Diabetes 1994; 43: 396-402.

Humalog®

Humulin® R


Dissociation of Insulins

Regular Human Insulin

10-3 M 10-3 M 10-5 M 10-8 M peak time2-4 hr

formulationcapillary membrane

Humalog®

10-3 M 10-3 M 10-3 M peak time1 hr

formulation transient


Optimal Interval Between Injection and Meal to Achieve Best Glycaemic Control

Mean Time MeanTime

(mg/dl) (min) (mg/dl) (min)

Daily Average 117.9 -22.5 119.8 -63.8

2-hour Postprandial 126.5 -18.8 136.8 -58.8

Humalog® Humulin® R

Source: Howey et al. 1995. Clin Pharmacol 58:459-469.

Blood Glucose


Glucose Excursion (mmol/L)

Mean ± 95% C.I.

Humulin® R / Humalog® (n= 354) Humalog® / Humulin® R (n = 344)

2-Hour Postprandial Glucose Excursions With Insulin Lispro and Regular Human Insulin in NIDDM Patients

Months

* ** * * * **p<.054

3

2

1

0

0 1 2 3 4 5 6


Months Within Period

Episodes / 30 daysMean ± 95% C.I.

4

3

2.3

0 1 2 3

Hypoglycaemic Rate in NIDDM Patients With Insulin Lispro and Regular Human Insulin

Humulin® R (n = 709)

Humalog ® (n = 713)


HbA1c for NIDDM Patients Treated With Insulin Lispro or Regular Human Insulin

Mean HbA1c (%)

Humulin® R Humalog ® Treatment

Months Within Period

9.0

8.8

8.6

8.4

8.2

8.0

0 1 2 3


Postabsorptive hyperglycaemia með Lispro

Ciofetta: Diabetes Care, Volume 22(5).May 1999.795-800


Repaglinide v glibenclamide

Damsbo: Diabetes Care 1999;22:789-794


Efnaskiptavilla

Type 2 diabetes or impaired glucose tolerance

Obesity

Dyslipidaemia

Blood pressure

Insulin resistance

Hyperinsulinaemia (initially)

Atherosclerosis


Weight change in overweight DM2 in UKPDS

-5

0

5

10

0 2 4 6 8 10

wei

ght

chan

ge (

kg)

Years from randomisation

ChlorpropamideConventional GlibenclamideInsulin Metformin


Ein heimsókn er ekki nóg !

6

7

8

9

0 3 6 9 12 15

Hb

A 1c (

%)

Years from randomisation

Conventional

Intensive

6.2% upper limit of normal range

ukpds


Áhrif heimafræðslu á sykurstjórn

HbA1c

4

6

8

10

12

Í byrjun 6 mán 12 mán 18 mán

SamanburðarhópurRannsóknarhópur

Couper et al. Diabetes Care 1999

P = 0,0001

P = 0,06


Life expectancy increases with weight loss among obese type 2 diabetic patients

Weight loss (kg) in first 12 months

Lean et al. Diabet Med, 1990; 7: 228-33

Life expectancy(years)

18

16

14

12

10

8

0

0 2 4 6 8 10 12 14 16

95% confidence interval


The discovery of Orlistat

Summer 1980: Soil sample obtained from Mallorca, Spain

By April 1981: 1200 micro-organisms screened for pancreatic lipase-inhibitory activity in 3165 fermentation broths. Streptomyces toxytricini

produced a compound with highest activity and greatest stability

October 1982: Lipstatin isolated and purified; structure elucidated

April 1983: Orlistat synthesised. More stable, hydrogenated derivative of

lipstatin


Orlistat inhibits lipase activity

Lipaseactive

site

Stable complex resists hydrolysis

Orlistat

CHONH

OH

OO O O

H2NCO

O OOH OO


Effect of Orlistat (Xenical®) on faecal fat excretion

Study days

Guerciolini, Int J Obesity 1997; 21 (Suppl. 3): S12-23

30

25

20

15

10

5

0

Mean faecal fat (g/day)

-5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Orlistat 120 mg tid


Weight loss with Orlistat is sustained over 2 years

Week

-4

–4.45%

–7.58% *

0 12 24 36 52 64 80 104

-10

-5

0

Rossner S, et al. Obes Res.

Change in body weight

(%)

Orlistat 120 mg (n=241)

Placebo (n=236)

*p<0.001


Orlistat promotes weight loss among obese type 2 diabetes patients


Week Hollander P, et al.

Diabetes Care 1998; 21: 1288-94

– 8

– 6

– 4

– 2

0

– 5 0 4 12 20 28 36 44 52

Placebo (n=159)Change in body weight

(%)

– 6.2%*

– 4.3%

* p<0.001


Orlistat significantly improves serum fasting glucose

Week

Change in fastingplasmaglucose(mmol/L)

Placebo (n=159)


* p<0.001

1.2

0

0.2

0.4

0.6

0.8

1.0

– 0.2

– 0.4

– 0.6 – 5 0 4 12 16 24 36 44 52

0.54

– 0.02*

Adapted from Hollander P, et al. Diabetes Care 1998; 21: 1288-94


Orlistat significantly reduces the need for oral hypoglycemic medication

Placebo (n=156)


*p<0.05

0

– 5.0

– 10.0

– 15.0

– 20.0

– 25.0

Meanchangein dose(%)

– 9%

– 23%*

Adapted from Hollander P, et al. Diabetes Care 1998; 21: 1288-94


Orlistat significantly improves serum cholesterol in obese type 2 diabetics

Placebo

Orlistat 120 mg

Adapted from Hollander P, et al.Diabetes Care 1998; 21: 1288-94

LDL-C(mg/dL)

Cholesterol (mg/dL)

Weight loss (% of initial weight)

5–10%Gain/0–5% >10%

* **

** *

-10

+10 0

-20

-10

-30

+10 0

-20

* p<0.05


Insulin Resistance and cell Dysfunction Produce Hyperglycemia in Type 2 Diabetes

Pancreatic -cell Insulin Resistance

Liver

Hyperglycemia

Islet -cell DegranulationReduced Insulin Content

Muscle(TG Adipose Tissue

Decreased Glucose Transport and Activity (Expression) of GLUT-4

Increased Lipolysis

Elevated Plasma FFAs

+ -

Low PlasmaInsulin

Increased Gucose Output

ElevatedTNF


Thiazolidinediones (PPAR activators)

Troglitazone

Rosiglitazone

Pioglitazone

MCC-555 og KRP-297


Peroxísóm

Frumulíffæri sem m.a. tekur þátt í

Niðurbroti H2O2

Framleiðslu glycerololípíða

Efnaskiptum kólesteróls

Oxun fitusýra

Í nagdýrum virkjuð af

Peroxisome Proliferator-Activated Receptor

– nokkrar undirtegundir (, , )


Binding á DR-1 svæði virkja gen sem tjá

prótein sem “þroska” viðkomandi frumu.

Þannig breytast t.d. pre-adipocytar í

fullþroska fitufrumur (adipocyta)

PPAR tilheyrir “steroid receptor superfamily”

Tjáning mismunandi ísóforma PPAR er

vefjasértæk og þau virkja mismunandi og oft gagnstæð efnaferli

Eftir samspil við HSP72 myndar PPAR heterodimer með RxRa og binst DNA á sértækum DR-1 svæðumÝmsar fitusýrur virkja

PPAR sem aftur hafa áhrif á umbrot fitusýra


PPAR bindlar


PPAR, insúlínónæmi og fituvefur


Insúlín ónæmi án offitu !

Diabetic ketoacidosis

Leprechaunism

Rabson Mendenhall Syndrome

Type A/B insúlín ónæmi með

hyperandrogenaemiu

Lipodystrophy / atrophy

HIV-1 / Protease inhibitors


HIV-1, proteasa blokkar, lipodystrophy og sykursýki

HIV-1 protease-inhibitor treatments are associated with a syndrome of peripheral

lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidaemia, and

insulin resistance. The catalytic region of HIV-1 protease, to which protease inhibitors

bind, has approximately 60% homology to …………...cytoplasmic retinoic-acid binding

protein type 1 (CRABP-1) ………………………….... We hypothesise that protease

inhibitors inhibit CRABP-1-modified, …………….. synthesis of cis-9-retinoic acid, a key

activator of the retinoid X receptor; and ….(PPAR-) heterodimer, ………….. contributes

to central fat deposition ……………., insulin resistance, and, in susceptible individuals,

type 2 diabetes………………...Carr et al. Lancet 1998; 352: 1881-83


Rosiglitazone Enhances Insulin Action by Modulating Tissue Lipid Supply

Rosiglitazoneand Insulin

PPAR

Preadipocyte

Adipocyte

IncreasedDifferentiation

Reversal of TNF-InducedInsulin Resistance

Increased Insulin Sensitivity and Capacity for Glucose Disposal/Lipid Storage

Reduced Lipolysis, Glycerol, & FFAs

Availability

Skeletal Muscle

Liver

Euglycemia

IncreasedGlucose Disposal

ReducedHepatic Glucose Output

PPAR

GLUT-4

TG


Rosiglitazone Reduces Hyperinsulinemia, Triglycerides and Fatty Acids in the Obese Mouse

Insulin Triglycerides FFAs

(nmol/l) (mmol/l) (mmol/l)

Control 0.94 ± 0.22 (8) 1.44 ± 0.12 3.47 ± 0.47

Rosiglitazone 0.52 ± 0.25 (8) 0.94 ± 0.09 2.82 ± 0.25*** *** **

Results are means ± S.D. from 6-8 animals

Young et al. Diabetes 1995;44:1087-1092


Rosiglitazone Increases Islet Area and Density in Pancreatic Islets of db/db Mice

Pancreatic sections were immunohistochemically stained for insulin.

Control Rosiglitazone

Scale 100 m (enlarged view)

Lister CA et al. Diabetologia. 1998;41(suppl 1):660


(Error bars = 95% CI)

Rosiglitazone (8 mg Daily) Is Equivalent toGlibenclamide After 1 Year - HbA1c

SU RSG 4 mg daily RSG 8 mg daily

Mea

n C

hang

e in

HbA

1c

Fro

m B

asel

ine

(%)

-1.0

-0.8

-0.6

-0.4

-0.2

0

-0.72%

-0.27%

-0.53%

95% CI for 8 mg daily vs SU <0.5% i.e. efficacy equivalent(n=202)

(n=195)

(n=189)

Lönnqvist. Diabetologia 1999; 42, suppl 1: A231


Aukaverkanir tengdar PPAR virkjum

Side effect Relative frequency

Weight gain +++

Raised LDL-cholesterol ++

Fluid retention +

Drug interactions +

Hepatotoxicity +

Cardiac hypertrophy ?

Induction of colon polyps ?

Side effect Relative frequency

Weight gain +++

Raised LDL-cholesterol ++

Fluid retention +

Drug interactions +

Hepatotoxicity +

Cardiac hypertrophy ?

Induction of colon polyps ?


Sitthvað fleira ?


Samanburður á töflumeðferð

Eftir DeFronzo, Annals of Internal Medicine 1999

dr. rafn benediktsson saturday, october 17, 2015 i´m your keyhole surgeon…

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