1. Diabetes and The Gastrointestinal Tract Jeffrey I. Brown, M.D. Knoxville Gastrointestinal Specialists

2. Diabetes and the Gastrointestinal Tract -Defintions -Epidemiology -Diagnosis -Metabolic Syndrome -Organ Involvement -Treatment -Pharmacology -Surgery

3. ENDOCRINE CELLS of the GI TRACT Alpha cells  glucagon Beta cells  insulin Delta cells  somatostatin G cells  gastrin I cells  CCK (cholecystokinin) K cells  GIP (glucose dependent insulinotropic peptide) L cells  GLP-1 (glucagon like peptide-1) S cells  secretin

4. Diabetes - derivation Diabetes: pass through Diarrhea: flow through Mellitus: honey Insipid: without taste

5. Diabetes- Epidemiology (USA) - 26 million diabetics (8.3%) - undiagnosed in 27% - 79 million pre-diabetics - 1 in 3 US adults with diabetes a/o metabolic syndrome - increased risk: Blacks, Hispanics, Native Americans

6. Diabetes - Classification Type I - immune mediated - one million Americans - insulin virtually absent - requires insulin treatment Type II - insulin resistance - beta cell failure - defect in compensatory insulin secretion - genetic/environmental causes

7. Diabetes – Classification (cont.) Gestational Other - corticosteroids - glucagonoma - somatostatinoma - hemochromatosis - pancreatitis - etc.

8. Somatostatinoma Triad - Gallstones - Diabetes - Diarrhea/Steatorrhea

9. Diabetes- Diagnosis ADA Criteria 1.Hemoglobin A1C ≥ 6.5% * 2.FPG ≥ 126 mg/dl 3.2 hour PG ≥ 200 mg/dl during OGTT * 4.In patient with classic symptoms and random PG ≥ 200 mg/dl * Criteria 1 & 3 confirmed by repeat testing

10. Diabetes - diagnosis Hemoglobin A1C (Hb A1C) - Revised diagnostic criteria (2010) - Hb A1C ≥ 6.5 % - correlates with mean glucose concentration - correlates with diabetic complications - convenient - less sensitive than plasma glucose measurements  fewer individuals diagnosed with diabetes

11. Diabetes – Drug Therapy Sulfonylureas – (Glyburide, Glipizide) Biguanides – (Metformin) Thiazolidinediones – (Avandia, Actos) Alpha glucosidase inhibitors GLP-1 receptor agonists DPP-4 inhibitors others

12. Diabetes – Drug Therapy: Metformin Primary action on liver First line therapy for type 2 diabetes Avoid in those with liver or kidney problems No weight gain GI side effects (20%) – nausea/vomiting, diarrhea, pain

13. Diabetes – Drug Therapy: Thiazolidinediones (TZD’s) - Insulin sensitizing agents - Reverses insulin resistance - Consistently lowers glucose levels - Associated with weight gain, edema, anemia - Increases Adiponectin levels

14. ADIPONECTIN - an Adipoctyokine - produced only in adipose tissue - Insulin sensitizing - anti-atherogenic - low levels in the obese and type 2 diabetics

15. THAIZOLIDINEDIONES - TROGLITAZONE (REZULIN) - hepatotoxicity - ROSIGLITAZONE (AVANDIA) - cardiovascular risk - PIOGLITAZONE (ACTOS) - bladder cancer?

16. TZD’s: role in treating other conditions - NON-ALCOHOLIC FATTY LIVER DISEASE - POLYCYSTIC OVARY SYNDROME - LIPODYSTROPHY (HIV)

17. INCRETIN HORMONES GLUCAGON LIKE PEPTIDE-1 (GLP-1) GLUCOSE DEPENDENT INSULINOTROPIC PEPTIDE (GIP) - increases food (glucose) induced insulin secretion - decreases glucagon secretion - rapid degradation by DPP-4 (dipeptidyl peptidase 4)

18. INCRETIN THERAPY EXENATIDE (BYETTA) GLP-1 agonist Saliva of Gila Monster T ½  2.4 hours Nausea/weight loss Pancreatitis/pancreatic cancer? LIRAGLUTIDE (VICTOZA) GLP-1 analog T ½  12 hours Nausea/vomiting/diarrhea Pancreatitis

19. DIPETIDYL PEPTIDASE-4 INHIBITORS (DPP-4 INHIBITORS) SITAGLIPTIN (JANUVIA) SAXAGLIPTIN (ONGLYZA) LINAGLIPTIN (TRADJENTA)

20. METABOLIC SYNDROME Group of risk factors that indicate increased risk for: - type 2 diabetes - premature cardiovascular disease

21. METABOLIC SYNDROME 3 of 5 criteria - Central (truncal) obesity: waist circumference > 40” (men) > 35” (women) - Glucose ≥ 100 mg/dl - Blood pressure ≥ 130 mm Hg sys./ ≥ 85 mm Hg dias. - serum triglycerides > 150 mg/dl - HDL cholesterol < 40 mg/dl (men) < 50 mg/dl (women)

22. BODY MASS INDEX (BMI) - A proxy for human body fat - body weight (Kg) divided by height (m) squared - underweight < 18.5 - normal 18.5 – 25.0 - overweight 25.0 – 30.0 - obese 30.0 – 35.0 (Class I) - severe obesity 35.0 – 40.0 (Class II) - extreme [morbid] obesity 40.0 – 50.0 (Class III) - super [morbid] obesity 50.0 – 60.0 - super-super [morbid] obesity > 60.0

23. BARIATRIC SURGERY - Definition: any surgical treatment for obesity - markedly reduces co-morbidities - consider if : BMI > 40.0 > 35.0 with co-morbid conditions - types of surgery: - restrictive - malabsorptive - both

24. BARIATRIC SURGERY HEALTH BENEFITS - DIABETES REVERSED (90%) - HYPERLIPIDEMIA CORRECTED (70%) - HYPERTENSION RELIEVED (70%) - FATTY LIVER RESOLVES (90%) - SLEEP APNEA MARKEDLY IMPROVED - GERD SYMPTOMS RELIEVED - BACK/JOINT PAIN IMPROVED - OVERALL REDUCTION IN MORTALITY – 89% !

25. DIABETES – GI TRACT INVOLVEMENT - ESOPHAGUS - STOMACH - SMALL/LARGE BOWEL - LIVER/BILIARY - PANCREAS

26. ESOPHAGUS Abnormal Motility associated with diabetic neuropathy (75%) Usually asymptomatic GERD more common Prone to Candida infection

27. STOMACH Gastritis/Gastric Atrophy more common Association with Pernicious Anemia Reduced acid secretion Decreased incidence of ulcer disease

28. STOMACH - GASTROPARESIS - seen in upto 60% - symptoms include: nausea, vomiting, pain, bloating, early satiety - occurs in those with longstanding disease (autonomic neuropathy) - worsened by hyperglycemia (poor diabetic control)

29. GASTROPARESIS - TREATMENT - ANTIEMETICS - DIET MODIFICATION smaller/liquid meals j tube feedings TPN - MEDICATIONS metoclopramide erythromycin domperidone - GASTRIC ELECTRICAL STIMULATION (GES)

30. GASTRIC ELECTRICAL STIMULATION ENTERRA SYSTEM pulse generator/electrodes place surgically GES A) gastric pacing - improves gastric emptying B) neurostimulation - controls nausea/vomiting

31. GASTRIC ELECTRICAL STIMULATION - 10 YEAR DATA - Greater Symptom Reduction - Improved Gastric Emptying  normalized in 23% - Decreased Hb A1C levels  translates to fewer complications - Significant Weight Gain - Reduction in Hospitalization Days - Reduced Medication Usage (for gastroparesis) McCallum, et al, Clin. Gastro & Hep. 9(4):314-319

32. DIABETES – SMALL INTESTINE/COLORECTUM DIABETIC DIARRHEA NEUROPATHY RELATED BACTERIAL OVERGROWTH CELIAC DISEASE MEDICATION RELATED CONSTIPATION - 20% FECAL INCONTINENCE DECREASED SPHINCTER TONE BLUNTED RECTAL SENSATION COLON CANCER  obesity related

33. DIABETES – LIVER/BILIARY HIGHER INCIDENCE OF ACUTE HEPATITIS B 1.4 vs 0.7 per 100,000 patients GALLSTONES MORE FREQUENT (2X) lithogenic bile hypomotility prophylactic cholecystectomy? STEATOSIS in upto 80%

34. DIABETES - NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) Most common form of liver disease in USA (6-30 million) Spectrum of disease: - simple steatosis - steatohepatitis (NASH) - cirrhosis  develops in 20% of NASH patients Risk Factors: female diabetes obesity hyperlipidemia *** cryptogenic cirrhosis  70% obese/50% diabetic!!

35. NAFLD - TREATMENT - slow/gradual weight loss - control diabetes/hyperlipidemia - pharmacologic treatment: TZD’s, others - surgery: bariatric - improvement in 90% liver transplant

36. DIABETES - PANCREAS Acute pancreatitis more common in type 1 diabetes (2X) Diabetes - risk factor for pancreatic cancer New onset diabetes  can be early sign of pancreatic cancer Chronic pancreatitis: exocrine  endocrine insufficiency.

37. CONCLUSION Epidemic of Diabetes & Obesity Hemoglobin A1C used for diagnosis of diabetes ( ≥ 6.5%) BMI definition and use in classification of obesity Gut hormone manipulation in treatment (incretin hormones) Benefits of GES and Bariatric Surgery