1. The cilium 1 microscopic structure NSCT

2. The Cilium 2 intracellular trafficking NSCT

3. Glut 4 n cochlea photoreceptor Glucose transport cochlea Smooth muscle cilium

4. Organ fibrosis in Alström syndrome NSCT

5. Improvements with surgery https://weightloss.clevelandclinic.org/images/Reduction3.gif

6. 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

7. Exercise and insulin sensitivity NSCT

8. Effect of BMI on diabetes rate in Alström syndrome % NSCT

9. Within family diabetes trend progression Jan 2011Jan 2012 Weight Kg6974 HbA1c %5.57.5 Trigs mmol/l 2.14.5 Blood pressure 120/75142/90 ELF8.19.4 remission Jan 2011Jan 2012 Weight Kg7670 HbA1c %7.35.3 Trigs mmol/l 3.21.8 Blood Pressure 138/80110/72 ELF9.18.3

10. new treatments in type2 diabetes Incretins and glycaemic control 7,8 Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343. 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

11. Alström Non DM N=18 Alström DM N=40 Type 2 DM N=30 P value Type2 vs Alstrom DM Age yrs19.42224.1 BMI Kg/m 2 33.132.4(4.636.5(80.13 Height m160160.21650.07 Duration of diabetes Na8.74.6 HbA1c %5.2 9.78.60.14 Neuropathic symptoms 0030.1 % perception all 2g monofilament 8095360.001 %perceptionall1 0g monofilament 100 380.001 % perceived 128MHz vibration 10097720.001 neuropathy0034.6 Foot ulceration0016 Absence of neuropathy in Alström type 2 diabetes NSCT

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

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

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