Obesity, Insulin resistens, type 2 diabetes: Patofysiologi & lidt Farmakologi.

Obesity, Insulin resistens, type 2 diabetes: Patofysiologi & lidt Farmakologi.

Aetiology of Diabetes by Age of Diagnosis Type 2 LADA (1½) (Latent autoimmune diabetes in adults) Type 1 MODY (Maturity onset diabetes in the young) MIDD (mitochondrial diabetes and deafness) 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 Age of diagnosis

Type 2 Diabetes Glucose (mmol/l) Healthy Time during 24 hrs. Praet, S.F.E. et al. Clinical Science, 2006

mmol/l 16 14 12 10 8 6 4 2 0 Glucose tolerance Patient with Type 2 Diabetes Healthy person -60-30 0 30 60 90 120 150 180 210 0 1 2 3 Hours

Insulin action. Much more than glucose uptake! Muscle: Increase glucose uptake GLUT4 translocation & blood flow Increase glycogen synthesis Increased protein synthesis + proteolysis Increased potassium uptake Stimulation of uptake of ketone bodies

Insulin action. Much more than glucose uptake! Liver: Decreased glucose output, due to: Decreased gluconeogenesis + increased glycogen synthesis Decreased formation of ketone bodies Increased lipid synthesis Re-esterification of FFA with glycerol phosphate (from glycolysis or glycerol) Stimulation of enzymes involved in lipid synthesis (Acetyl-CoA carboxylase + fatty acid synthase) Indirectly by increased Manolyl CoA which inhibits Carnitine acyltransferase) Increased protein synthesis + proteolysis

Insulin action. Much more than glucose uptake! Adipose tissue: Increased glucose uptake Inhibition of lipolysis Hormone Sensitive Lipase inhibition Stimulation of lipoprotein lipase (in capillaries around adipocytes) Hydrolyses the triglyceride that resides in e.g. VLDL and chylomicrons to FFA and monoacylglycerol. FFA is then taken up by the adipocytes. Increases potassium uptake

Spectrum of diabetes subgroups T2D : Type 2 Diabetes (>35 yr; C-peptide > 0.6 nm; GAD ab < 10) T1D : Type 1 Diabetes (<35 yr; C-peptide <0.2 nm; GAD ab >20) MODY : Maturity Onset Diabetes in the Young LADA : Latent Autoimmune Diabetes in Adults (< 35 yr; GAD ab > 20 (light: 10-20)) Groop, L. & Poicot, F. Molecular and Cellular Endocrinologi, 2014

Risiko faktorer Genetisk arv Erhvervet Fedme Inaktivitet Andre Acromegali Mb. Cushings Lipodystrophy Insulin resistens Relativ insulin mangel Nedsat glukose tolerance Øget ß-cell insulin produktion Kompensatorisk hyperinsulinemi Normal glukose tolerance ß-cell dysfunktion 1. Type 2 Diabetes 2. Defekt insulin sekretion 3. Øget hepatisk glukose produktion Risiko faktorer Genetisk arv Erhvervet Glucotoxicity Lipotoxicity

Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults Obesity (BMI 30 kg/m 2 ) 1994 2000 2013 No Data <14.0% 14.0% 17.9% 18.0% 21.9% 22.0% 25.9% > 26.0% Diabetes 1994 2000 2013 No Data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% >9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

Visceral Fat Distribution Normal Type 2 Diabetes

Link Between Obesity and Type 2 Diabetes: Nurses Health Study 120 100 80 Age-Adjusted Relative Risk 60 40 20 0 <22 22-22.9 23-23.8 24-24.9 25-26.9 27-28.9 29-30.9 31-32.9 33-34.9 >35 BMI (kg/m 2 ) Colditz GA, et al. Ann Intern Med. 1995;122:481-486.

Fordeling på socialgruppe % 16 14 12 10 8 6 4 2 0 Overvægtige Fede Socialgruppe I Socialgruppe II Socialgruppe III Socialgruppe IV Socialgruppe V Socialgruppe VI Due P, Holstein BE. Skolebørnsundersøgelsen. 2. rev. udg. København: Københavns Universitet - Institut for Folkesundhedsvidenskab; 2003.

Fordeling etnisk baggrund 14 12 % 10 8 6 4 2 Danske Indvandrere fra rige lande Indvandrere fra fattige lande 0 Overvægt Fedme Due og Rasmussen 2007

Metformin Sulfonylurinstof SGLT2- hæmmer DPP-4 hæmmer GLP-1- receptor agonister Insulin Kombination af: metformin + 2 af ovenstående Insulin (+ metformin og GLP-1)

Metformin Metformin (DDD: 1,12-1,50) Sulphonylurinstof Gliclazid (0,80) Diamicron Glimepirid (0,23) Amaryl Glipizid (1,13) Mindiab Glibenclamid (3,75) Hexaglucon Tolbutamid (4,27) Arcosal Repaglinid (3,27) NovoNorm GLP-1- receptoragonist SGLT2- hæmmer Forxiga (16,-) Invokana (16,-) Jardiance (11,-) Pioglitazon Actos DPP-4 hæmmer Januvia (14,-) Galvus (14,-) Onglyza (14,-) Trajenta (13,-) Komb. præp. Combination of: metformin Vipidia (11,-) + 2 of the Trulicity above (32,-) (Metformin) Xigduo Vokanamet Synjardy SGLT2 = Sodium GLucose co-transporter 2 Komb. præp. (Metformin) Janumet Eucreas Jentadueto Komboglyze Vipdomet (Pioglitazon) Incresync Victoza (34,-) Byetta (22,-) Bydureon (36,-) Lyxumia (32,-) Insulin Hurtigtvirkende (Identisk med human insulin) Actrarapid (7,-) HumulinRegular (7,-) InsumanRapid (10,-) (Insulin analoger) NovoRapid (11,-) Humalog (11,-) Apidra (10,-) Blandingsinsulin (Hurtigt/Middellangt /Langt:) NovoMix (11,-) HumalogMix (12,-) Ryzodeg (25,-) Basalinsulin HumulinNPH (7,-) Insulatard (7,-) Levemir (14,-) Lantus (14,-) Toujeo (14,-) Abasaglar (12-) Tresiba (?)

Tabel 1: Insuliners og insulinanalogers virkningsvarighed efter subkutan injektion. Virkning indtræder efter ca. timer Maksimal virkning efter ca. timer Virkning varer ca. timer Hurtigt virkende insulin Actrapid ½ 2-3 7-8 Humulin Regular ½ 2-3 7-8 Insuman Rapid Solostar ½ 2-3 7-8 Intermediært virkende insulin (NPH) Humulin NPH 1½-2 4-8 18-36 Insulatard 1½ 4-12 24 Kombination af hurtigt og intermediært virkende insulin Mixtard 30*) ½ 2-8 24 Insulinanaloger Hurtigt virkende insulinanalog Apidra ¼ ½-3 2-5 Humalog ¼ ½-3 2-5 NovoRapid ¼ ½-3 2-5 Kombination af hurtigt og intermediært virkende insulinanalog Humalog Mix25 KwikPen ¼ 1 18-36 NovoMix ¼ 1-4 24 Langtidsvirkende insulinanalog Abasaglar KwikPen 4 6-12 >24 Lantus 4 6-12 > 24 Levemir 3-4 6-12 > 24 Toujeo 4 6-12 > 24 Tresiba ¼ Jævnt fordelt over 24 timer Total virkningstid efter enkelt injektion >42 timer Kombination af hurtigt virkende og langtidsvirkende insulinanalog Ryzodeg ¼ Jævnt fordelt over 24 timer Total virkningstid efter enkelt injektion >42 timer

The ADDITION study ~3000 patients with type 2 diabetes (new diagnose) 343 general practices in Denmark, the Netherlands, and the UK Routine care Intense focus on management of hyperglycaemia, blood pressure, and cholesterol levels by medical treatment and promotion of healthy lifestyles Composite endpoint: - Cardiovascular death - Myoardial infarction - Stroke - Revascularisation - Amputation Griffin, S.J. et al. Lancet, 2011

Look AHEAD study. 5145 patients with type 2 diabetes. Usual care or Intensive counseling, education and motivation Endpoint: Composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. Wing et al. NEJM, 2013 The look AHEAD research group