Dr. Rafn Benediktsson Friday, April 21, 2023
I´m your keyhole surgeon…...
Dr. Rafn Benediktsson Friday, April 21, 2023
Samfelld mæling blóðsykurs án stun(g)u
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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®)
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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)
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
Postabsorptive hyperglycaemia með Lispro
Ciofetta: Diabetes Care, Volume 22(5).May 1999.795-800
Dr. Rafn Benediktsson Friday, April 21, 2023
Repaglinide v glibenclamide
Damsbo: Diabetes Care 1999;22:789-794
Dr. Rafn Benediktsson Friday, April 21, 2023
Efnaskiptavilla
Type 2 diabetes or impaired glucose tolerance
Obesity
Dyslipidaemia
Blood pressure
Insulin resistance
Hyperinsulinaemia (initially)
Atherosclerosis
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
Orlistat inhibits lipase activity
Lipaseactive
site
Stable complex resists hydrolysis
Orlistat
CHONH
OH
OO O O
H2NCO
O OOH OO
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
Orlistat promotes weight loss among obese type 2 diabetes patients
Orlistat 120 mg (n=162)
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
Dr. Rafn Benediktsson Friday, April 21, 2023
Orlistat significantly improves serum fasting glucose
Week
Change in fastingplasmaglucose(mmol/L)
Placebo (n=159)
Orlistat 120 mg (n=162)
* 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
Dr. Rafn Benediktsson Friday, April 21, 2023
Orlistat significantly reduces the need for oral hypoglycemic medication
Placebo (n=156)
Orlistat 120 mg (n=157)
*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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
Thiazolidinediones (PPAR activators)
Troglitazone
Rosiglitazone
Pioglitazone
MCC-555 og KRP-297
Dr. Rafn Benediktsson Friday, April 21, 2023
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 (, , )
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
PPAR bindlar
Dr. Rafn Benediktsson Friday, April 21, 2023
PPAR, insúlínónæmi og fituvefur
Dr. Rafn Benediktsson Friday, April 21, 2023
Insúlín ónæmi án offitu !
Diabetic ketoacidosis
Leprechaunism
Rabson Mendenhall Syndrome
Type A/B insúlín ónæmi með
hyperandrogenaemiu
Lipodystrophy / atrophy
HIV-1 / Protease inhibitors
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
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
Dr. Rafn Benediktsson Friday, April 21, 2023
(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
Dr. Rafn Benediktsson Friday, April 21, 2023
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 ?
Dr. Rafn Benediktsson Friday, April 21, 2023
Sitthvað fleira ?
Dr. Rafn Benediktsson Friday, April 21, 2023
Samanburður á töflumeðferð
Eftir DeFronzo, Annals of Internal Medicine 1999