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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