The cilium 1 microscopic structure NSCT

The Cilium 2 intracellular trafficking NSCT

Glut 4 n cochlea photoreceptor Glucose transport cochlea Smooth muscle cilium

Organ fibrosis in Alström syndrome NSCT

Improvements with surgery

INSULIN EFFECTS ON INTERMEDIARY METABOLISM PLASMA HEPATOCYTE GLUCOSE GLUT RECEPTOR GLYCOGEN GLUCOKINASE PHOSPHORYLASEGLYCOGEN SYNTH FRUCTOSE 6 PHOS GLYCOLYSIS LACTATE PYRUVATE GLUCONEOGENESIS CHOLESTEROL MEVALONIC ACID HMG CoA PYRUVATE ACETYL CoA KETONE BODIES TCA CYCLE REDUCTASE MELONYLFATTY ACIDS CoA CARNITINE ACYL TRANSFERASE TRIGLYCERIDE OXIDATIVE PHOSPHORYLATION 30ATP INSULIN SENSITIVE LIPOPROTEIN LIPASE FA + GLYCEROL TG ADIPOCYTE VLDL MITOCHONDRION INSULIN SENSITIVE రర VLDL LDL HDL

Exercise and insulin sensitivity NSCT

Effect of BMI on diabetes rate in Alström syndrome % NSCT

Within family diabetes trend progression Jan 2011Jan 2012 Weight Kg6974 HbA1c % Trigs mmol/l Blood pressure 120/75142/90 ELF remission Jan 2011Jan 2012 Weight Kg7670 HbA1c % Trigs mmol/l Blood Pressure 138/80110/72 ELF9.18.3

new treatments in type2 diabetes Incretins and glycaemic control 7,8 Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153– Miller S, St Onge EL. Ann Pharmacother 2006;40: Active GLP-1 and GIP Release of incretin gut hormones Pancreas Blood glucose control GI tract  Glucagon from alpha cells (GLP-1) Glucose dependent Alpha cells Increased insulin and decreased glucagon reduce hepatic glucose output Glucose dependent  Insulin from beta cells (GLP-1 and GIP) Beta cells Insulin increases peripheral glucose uptake Ingestion of food DPP-4 enzyme rapidly degrades incretins NSCT

Alström Non DM N=18 Alström DM N=40 Type 2 DM N=30 P value Type2 vs Alstrom DM Age yrs BMI Kg/m ( (80.13 Height m Duration of diabetes Na HbA1c % Neuropathic symptoms % perception all 2g monofilament %perceptionall1 0g monofilament % perceived 128MHz vibration neuropathy Foot ulceration0016 Absence of neuropathy in Alström type 2 diabetes NSCT

Organ fibrosis in Alström syndrome transplant ?prevention, TIPS, partial transplant Transplant, Valve dysfunction NSCT

Diabetes Renal dysfunction High lipids hypertension Carotid atheroma PVD Duplex-PVD Coronary artery disease NSCT

What diet? What Exercise? Reduced carbohydrate Bespoke Weight training Horse riding Walking Swimming Cycling Dancing NSCT