Diabetes and

The Gastrointestinal Tract

Jeffrey I. Brown, M.D.

Knoxville Gastrointestinal Specialists

Diabetes and the Gastrointestinal Tract

-Defintions-Epidemiology-Diagnosis-Metabolic Syndrome-Organ Involvement-Treatment

-Pharmacology-Surgery

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

Diabetes - derivation

Diabetes: pass through

Diarrhea: flow through

Mellitus: honey

Insipid: without taste

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

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

Diabetes – Classification (cont.)

Gestational

Other

- corticosteroids

- glucagonoma

- somatostatinoma

- hemochromatosis

- pancreatitis

- etc.

Somatostatinoma Triad

- Gallstones

- Diabetes

- Diarrhea/Steatorrhea

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

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

Diabetes – Drug Therapy

Sulfonylureas – (Glyburide, Glipizide)

Biguanides – (Metformin)

Thiazolidinediones – (Avandia, Actos)

Alpha glucosidase inhibitors

GLP-1 receptor agonists

DPP-4 inhibitors

others

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

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

ADIPONECTIN

- an Adipoctyokine

- produced only in adipose tissue

- Insulin sensitizing

- anti-atherogenic

- low levels in the obese and type 2 diabetics

THAIZOLIDINEDIONES

- TROGLITAZONE (REZULIN)

- hepatotoxicity

- ROSIGLITAZONE (AVANDIA)

- cardiovascular risk

- PIOGLITAZONE (ACTOS)

- bladder cancer?

TZD’s: role in treating other conditions

- NON-ALCOHOLIC FATTY LIVER DISEASE

- POLYCYSTIC OVARY SYNDROME

- LIPODYSTROPHY (HIV)

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)

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

DIPETIDYL PEPTIDASE-4 INHIBITORS (DPP-4 INHIBITORS)

SITAGLIPTIN (JANUVIA)

SAXAGLIPTIN (ONGLYZA)

LINAGLIPTIN (TRADJENTA)

METABOLIC SYNDROME

Group of risk factors that indicate increased risk for:

- type 2 diabetes

- premature cardiovascular disease

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)

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

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

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% !

DIABETES – GI TRACT INVOLVEMENT

- ESOPHAGUS

- STOMACH

- SMALL/LARGE BOWEL

- LIVER/BILIARY

- PANCREAS

ESOPHAGUS

Abnormal Motility associated with diabetic neuropathy (75%)

Usually asymptomatic

GERD more common

Prone to Candida infection

STOMACH

Gastritis/Gastric Atrophy more common

Association with Pernicious Anemia

Reduced acid secretion

Decreased incidence of ulcer disease

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)

GASTROPARESIS - TREATMENT

- ANTIEMETICS

- DIET MODIFICATION

smaller/liquid meals

j tube feedings

TPN

- MEDICATIONS

metoclopramide

erythromycin

domperidone

- GASTRIC ELECTRICAL STIMULATION (GES)

GASTRIC ELECTRICAL STIMULATION

ENTERRA SYSTEM

pulse generator/electrodes

place surgically

GES

A) gastric pacing - improves gastric emptying

B) neurostimulation - controls nausea/vomiting

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

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

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%

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!!

NAFLD - TREATMENT

- slow/gradual weight loss

- control diabetes/hyperlipidemia

- pharmacologic treatment: TZD’s, others

- surgery:

bariatric - improvement in 90%

liver transplant

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.

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