Diabetes Mellitus

And Pancreatic Neuroendocrine Tumors

I.

CARBOHYDRATE METABOLISM
A.

Average adult diet is 45% carbohydrate (starch, sucrose, lactose)

B.

Digestion and absorption

Starch and polysaccharides into mouth
action of salivary and GI Enzymes amylase
Monosaccharides (80% glucose)
absorbed in small intestine
Into blood via portal vein
Liver taken up by hepatic cells where glucose is metabolized
Muscle, other sites glucose used as energy source

C.

Glucose Metabolism
1. Glycogenesis.
2. Glycogenolysis.
3. Glycolysis.
4. TCA (Tricarboxylic acid or Krebs cycle).
5. Gluconeogenesis.
6. Hexose monophosphate shunt.

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Diabetes Mellitus
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D. Overview
Glucose is used for generating ATPs as a source of energy for many energy
requiring processes that go on in the body. The means for storing glucose is in the
form of glycogen in the liver and muscle. There must be a way for the body to
keep the glucose levels in the blood fairly constant and for each of the
previously discussed reactions to occur at the appropriate time as the bodys
need for glucose in different tissue changes. This is under the control of
various hormones. An important organ involved in this is the pancreas.
II.

PANCREAS
A.

Anatomy
1. Located in epigastrium in arms in duodenum. It has a head, body and tail
composed of acini and islets of Langerhans.
B. Physiology
1. Exocrine.

a.
b.

Trypsin, chymotrypsin, lipase, amylase, nuclease, peptidase.

Involved in digestion of proteins, fats, carbohydrates and nucleic acids.
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Diabetes Mellitus
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2. Endocrine.
a.

Beta cells insulin.

b.

Alpha cells glucagon.

c.

Delta cells somatostatin.

d.

PP cells pancreatic polypeptide.

e.

D1 cells vasoactive intestinal peptide (VIP).

f.

Enterochromaffin cells serotonin.

III.

HORMONAL CONTROL OF CARBOHYDRATE METABOLISM

A. Insulin
1. Small peptide consisting of an alpha chain (21 amino acids) connected by
2 disulfide bonds to a beta chain (30 amino acids).

2. Synthesis.

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Diabetes Mellitus
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Preproinsulin
Proinsulin
Insulin and C-peptide
3. Normal man secretes 50 units of insulin per day.
4. Actions of insulin.
a. Increased transport of glucose across cell membrane
hypoglycemia (increased peripheral utilization).
b. Glycogenesis increased
c. Glycolysis increased

hypoglycemia.
hypoglycemia.

d. Lipogenesis increased, lipolysis decreased (spares fats).

e. Gluconeogenesis decreased (spares proteins).
5. Factors affecting insulin secretion and synthesis.
a. Causes of increased insulin secretion and synthesis: glucose, food,
fatty acids, epinephrine, norepinephrine, corticosteroids, thyroid
hormone, ACTH, TSH, growth hormone, glucagon, stress,
exercise, tolbutamide, sulfonylureas.
b. Mechanism of increased insulin secretion.
c. Causes of decreased insulin secretion: starvation, insulin.
B. Glucagon
1. Composed of 29 amino acids.
2. Actions of glucagon.
a. Glycogenolysis increased

hyperglycemia.

b. Lipogenesis decreased, lipolysis increased.

c. Protein metabolism increased.

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Diabetes Mellitus
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3. Factors affecting glucagon secretion.
a. Hyerglycemia Decreased glucagon.
b. Hypoglycemia Increased glucagon.
C. Somatostatin
1. Peptide.
2. Action of somatostatin.
Inhibits release of glucagon
Decrease in glucose
Decrease in insulin
D. Pancreatic Polypeptide
1.

Islets and exocrine pancreas.

2.

Stimulation of gastric and intestinal enzymes.

3.

Inhibition of intestinal motility.

E. Vasoactive Intestinal Peptide (VIP)
1. Glycogenolysis increased hyperglycemia.
2. Stimulates gastrointestinal fluid secretion diarrhea.
F. Serotonin
1.

IV.

Carcinoid syndrome.

DIABETES MELLITUS GENERAL

A. Definition systemic chronic disorder of carbohydrate, fat and protein
metabolism characterized by an absolute or relative insulin deficiency, fasting
hyperglycemia, glycosuria and increased incidence of atherosclerosis,
microangiopathy, nephropathy and neuropathy.

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Diabetes Mellitus
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B. Incidence affects approximately 25 million Americans (8% of population) and
346 million worldwide (WHO).
C. Race.
D. One of top 10 killers in U.S.
V.

DIAGNOSIS
A. Diabetes

1.

Fasting plasma glucose: >126 mg/dl.

2.

Random plasma glucose: >200 mg/dl.

3.

2-hour plasma glucose: >200 mg/dl during oral glucose tolerance test.

4.

Glycated hemoglobin (HbAlc) >65%.

B. Impaired Glucose Tolerance (Prediabetes)

1.

Fasting plasma glucose: 100-125 mg/dl.

2.

2-hour plasma glucose: 140-199 mg/dl.

3.

Glycated hemoglobin (HbAlc): 5.7 6.4%.

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Diabetes Mellitus
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VI.

DIABETES MELLITUS CLASSIFICATION

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Diabetes Mellitus
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VII.

PATHOGENESIS
A. Type 1 Diabetes Mellitus
1.

Autoimmune.
a. Islet destruction.
b. Autoimmune response to beta cell antigens.
1) Failure of self-tolerance in I cells specific for islet antigens.
2) Islet cell antibodies.

2.

Genetic Susceptibility.
a. Multiple genetic susceptibility loci.
b. HLA gene cluster on chromosome 6p21.
c. Non-HLA genes.

3.

Environmental Factors.
a. Viral infection cross reacting antibody to beta cells?
B. Type 2 Diabetes Mellitus

1.

Genetic Susceptibility.

2.

Environmental Factors.
a. Obesity particularly central obesity.
b. Lack of exercise.

3.

Metabolic Defects.

a.

Insulin resistance failure of target tissues to respond normally to insulin.

b.

Decreased insulin secretion due to beta cell dysfunction.

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Diabetes Mellitus
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C. Monogenic Forms of Diabetes

1.

Genetic Defects in Beta Cell Function.

a.

Heterogeneous group of genetic defects.

b.

Maturity onset diabetes of the young (MODY).

1) Resembles Type 2 Diabetes.
2) Occurs in younger patients.
3) Mutations in one of six genes.

2.

Genetic Defects that Impair Tissue Response to Insulin.

a.

Insulin receptor mutations.

b.

Lipoatrophic diabetes.

1)

Hyperglycemia.

2)

Loss of adipose tissue.

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Diabetes Mellitus
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D. Diabetes and Pregnancy
1.

Pregestational (overt) diabetes.

a.

Increased stillbirths and congenital malformations.

b.

Excess birth weight.

c.

2.

Obesity and diabetes later in life in child.

Gestational diabetes.
a. Excess birth weight.
b. Obesity and diabetes later in life in child.
c. Usually resolves in mother following delivery.
E. Pathogenesis of chronic complications
(Relationship of metabolic changes and systemic complications?)

1.

Advanced glycation end products.

2.

Activation of Protein Kinase C.

3.

Intracellular hyperglycemia with disturbances in polyol pathways and oxidative stress.

4.

Hexose amine pathway activation with increased fructose-6-phosphate and glycation of proteins.

VIII.

PATHOLOGY OF DIABETES MELLITUS

A. Pancreas
1.

Reduction in size and number of islets; Increase in size and number of islets (compensatory
hyperplasia) seen in early diabetes or infants of diabetic mothers.

2.

Beta cell degranulation depletion of insulin stores.

3.

Hyaline replacement of islets collagen or amyloid.

4.

Insulitis usually a lymphocytic infiltrate.

B. Diabetic microangiopathy (arteriolosclerosis) and basement membrane thickening
1. Capillaries of skin, muscle, retina, kidney
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Diabetes Mellitus
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2. Renal tubules, nerves
C. Atherosclerosis
1.

Myocardial infarction secondary to coronary atherosclerosis.

2.

Cerebral Stroke.

3.

Gangrene of lower extremities.

D. Kidneys
1. Diffuse glomerulosclerosis is the most common alteration. It is
characterized by diffuse thickening of the basement membrane with
proliferation of mesangial cells and the deposition of excess mesangial
matrix.
2. Nodular glomerulosclerosis (Kimmelstiel-Wilson Disease) represents a
more advanced form of glomerulopathy in which laminated oval or
spherical hyaline masses are found in the peripheries of the glomeruli.
These masses are PAS-positive and represent nodular deposits of
mesangial matrix.
3. Exudative lesions (fibrin caps or capsular drops) may appear as
homogenous eosinophilic deposits within a glomerular tuft. These
exudative lesions are composed of plasma proteins and are PASpositive.
4. Arteriolosclerosis occurs in the kidney as it does in other organs and
contributes to renal failure; this finding is termed nephrosclerosis.
5. Both acute and chronic pyelonephritis occur with greater frequency in
diabetics as part of their enhanced susceptibility to infections of all kinds.
Certain specific extreme forms may develop such as necrotizing papillitis
in which the tips of the renal pyramids are destroyed.
6. Glycogen accumulation (also termed glycogen nephrosis or the ArmanniEbstein lesion) occurs in renal tubular epithelial cells as a consequence of
prolonged hyperglycemia and glycosuria. Pathologically, the tubular cells
have clear cytoplasm and basally displaced nuclei due to glycogencontaining cytoplasmic vacuoles. This change is usually thought to be a
pre-terminal event and is most frequently demonstrated at autopsy.
7. Clinical

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Diabetes Mellitus
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a. Microalbuminaria

Macroalbumiaunia (nephrotic syndrome).

b. Hypertension.
c. Renal failure.
E. Eyes
1.

Retinopathy.

a.

Preproliferative retinal microaneurysms, edema, exudates, hemorrhages.

b.

Proliferative neovascularization and fibrosis.

2.

Cataracts

3.

Glaucoma
F. Nervous System

1.

Distal symmetric peripheral neuropathy affects both motor and sensory nerves of lower
extremities (secondary to microangiopathy or primary myelin degeneration).

2.

Involvement of autonomic nerves.

a.

Sexual impotence.

b.

Bladder dysfunction.

c.

Bowel dysfunction.
G. Skin
1. Infection.
2. Diabetic xanthomas correlation with Type IV hyperlipidemia; firm
yellow nodules on elbows, knees, back and buttocks.
H. Other infections

IX.

PATHOPHYSIOLOGY OF DIABETES
A. Lack of insulin activity leads to inability of glucose to enter the peripheral cells
(muscle, fat) and to glucose release from the liver.

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Diabetes Mellitus
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B. These in turn lead to glycogen depletion of the liver, protein breakdown in
muscles and fat breakdown in the adipose cell.
C. These changes lead to elevated glucose, amino acids, fatty acids and ketone
bodies in the serum.
D. Ketone bodies and glucose exceed the renal threshold and spill over into the urine
with resultant osmotic diuresis (loss of H2O and electrolytes).
E. Intracellular H2O is lost resulting in cellular dehydration.
F. Osmoreceptors of the thirst centers of the brain are stimulated resulting in intense
thirst.
X.

CLINICAL
A. General symptoms
1. 3 Ps polyuria, polydipsia, polyphagia.
2. Weight loss, fatigue, infections.
B. Diabetic Ketoacidosis Acute complication
A syndrome whose main features are hyperglycemia, hyperosmolality,
dehydration and ketoacidosis, which occurs because of an absolute or relative
insulin deficiency. The hyperglycemia and resultant hyperosmolality leads to an
osmotic diuresis with renal loss of glucose, electrolytes (Na, K) and H2O. Despite
total body potassium depletion, serum potassium is increased as a result of shift
out of cells into serum, secondary to acidosis, decreased insulin and increased
glucose. After treatment can develop severe hypokalemia.
The fatty acids that are released from adipose tissue go to the liver where they are
converted to acetyl CoA. The acetyl CoA is diverted almost entirely to ketone
body formation:
acetoacetic acid-acetone
Acetyl CoA

Acetoacetyl CoA
B hydroxybutyric acid

These ketone bodies cannot be utilized by the liver but do enter the circulation to be
utilized by other tissues. In addition, there is marked hypertriglyceridemia. The
mortality of diabetic ketoacidosis is 5-15%.

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Diabetes Mellitus
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Symptoms: Thirst, polyuria, weight loss, anorexia, fatigue, nausea, vomiting, abdominal
pain, hyperventilation (Kussmaul breathing) fruity odor on breath, dehydration,
drowsiness. 10% will be comatose.
Treatment: 1. Fluid and NaC1 replacement (often 5 liters).
2. Insulin replacement.
3. K replacement.
C. Hyperosmolar Nonketotic Coma Acute complication
1. Decreased or absent insulin secretion can manifest itself as hyperglycemia
without ketosis and with osmotic diuresis, severe dehydration and eventual
coma.
2. Must consider the diagnosis in a middle aged or elderly diabetic who
presents in coma without hyperventilation and without the odor of ketones
on his breath.
3. The laboratory diagnosis rests on the presence of 3+ to 4+ glycosuria,
extreme hyperglycemia (600-1200 mg/dl) in the absence of ketoacidosis.
D. Hypoglycemia Acute complication
1. Complication of insulin or oral hypoglycemic treatment, missing a meal,
excess exercise.
2. Initial symptoms (shaking, sweating, palpitations) secondary to
catecholamine release.
3. Later symptoms (confusion, coma) a result of hypoglycemia on CNS.
4. Treatment: Rapid oral or I.V. glucose
a. Rebound hyperglycemia Somogyi phenomenon; secondary to
counterregulatory hormones.
E. General Therapy of Diabetes (not under acute conditions)
1. Diet low carbohydrate, balanced diet.
2. Drugs oral hypoglycemics are of questionable value but are still in use
(mainly adult onset).
3. Synthetic Insulin needed for all cases of juvenile onset and for those
adult onset diabetics who do not respond to diet and drugs.

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Diabetes Mellitus
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Insulin overdosage can lead to hypoglycemia, coma, and death.

A diagnostic problem for the physician is when a known diabetic
comes to the emergency room in coma. Is he hyperglycemic
(diabetic ketoacidosis or hyperosmolar nonketotic coma) or is he
having an insulin reaction with hypoglycemia and coma? The
physician draws the blood work but immediately gives glucose.
If the patient was hypoglycemic he will immediately respond.

XI.

LABORATORY TESTS

A. Glucose
1. Urine
a. Unreliable because glycosuria depends upon individuals renal
threshold.
TESTS FOR SUGARS IN URINE
Copper Sulfate Reduction
(Benedict Solution, Clinitest Tablets

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Glucose Oxidase Strips

Diabetes Mellitus
And Pancreatic Neuroendocrine Tumors
Sugars detected
(minimum concentration)

Glucose (150-250 mg/dl)

Galactose
Lactose
Fructose
Maltose
Pentose
Ascorbic acid
Homogentisic acid
Many antibiotics
Phenothiazines
Salicylates
Levodopa
X-ray contrast Media

False-positive

False-negative

Glucose (50 mg/dl)

Hydrogen peroxide or
hypochlorite in container

Ascorbic acid
Homogentisic acid
Large amounts of salicylates

*Sucrose is not detected by either test. It is rarely found in urine except for occasional
instances when patient has deliberately added table sugar to urine sample.
In: Clinical Interpretation of Laboratory Tests
Frances K. Widman, 1983, 9th edition, F.H. Davis Publisher, p508.
2. Plasma or Serum
a. Fasting blood sugar above 126 mg/dl on 2 or more occasions.
b. Random glucose over 200 mg/dl.
c. Glucose Tolerance Test 2 hour sample greater than 200 mg/dl.
1)

Prior diet of greater than 150 gm of carbohydrate daily and no alcohol for 3 days before test.

2)

Unrestricted activity for 3 days before test.

3)

No eating or drinking for 12 hours before test.

4)

Should not be taking salicylates, diuretics, anticonvulsants, steroids or oral contraceptives.

5)

Glucose dose 75 gm for adult or 1.75 gm/Kg for children.

6)

Draw blood at fasting, 30, 60, 90, 120 minutes.

B. Acetone
1. Urine

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Diabetes Mellitus
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2. Blood
C. Osmolality
1.

Serum
a. Normal: 285-319 mosmol/Kg H2O.
b. Osmolality = 2 [Na +K] + Glucose + BUN
18
2.8

2.

Urine depends on state of hydration (50-1400 mosmol/Kg H2O).

D. Glycosylated Hemoglobin (HbA1C)

1.

Current methods of assessing diabetic control include blood and urine glucose measurement
which reflect acute changes and may not be adequate indicators of long term diabetic control. A
more useful technique may be the identification of hemoglobin A1C, a hemoglobin A with a
glucose attached. It is increased in diabetics and may return to normal (3-5 weeks) with good
control. Indication of glucose level over 6-12 week period of time.

2.

Normal: 3-6% of hemoglobin.

E. Insulin levels

1.

Performed using a radioimmunoassay method. Fasting levels are usually less than 20mU/ml.
Measurement of insulin appears to have little clinical value except in diagnosis of spontaneous
hypoglycemia.
F. Insulin antibodies

1.

Some diabetic patients on long term insulin therapy develop antibodies to insulin. The effect of
these antibodies is to inhibit the action of the administered insulin. Naturally, these patients do
not respond to insulin therapy and the effects of their disease intensify. The detection of the
presence of insulin antibodies will help explain sudden diminished responses to usual therapy.
G. C-peptide measurement

XII.

1.

Also used in differentiating between true and factitious hypoglycemia, based on the fact that
endogenous insulin will have accompanying C-peptide while exogenous insulin does not.

2.

True hypoglycemia: High insulin, high C-peptide, hypoglycemia. Factitious hypoglycemia:

High insulin, no C-peptide, hypoglycemia.
PANCREATIC NEUROENDOCRINE TUMORS

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Diabetes Mellitus
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A. Criteria for Malignancy
1.
2.

Metastases.
Vascular invasion.

3.

Local invasion.
B. Functional vs. Nonfunctional
C. Hyperinsulinism (Insulinoma)
1. Beta cell tumor causing episodic hypoglycemia.
2. Confusion, stupor, loss of consciousness.
a.

Precipitated by fasting, exercise.

b.

Relieved by feeding or glucose.

3. Usually solitary.
4. 90% benign.
5. Amyloid deposition.
6. Treatment resection.
D. Zollinger Ellison Syndrome (Gastrinoma)
1. Zollinger Ellison syndrome - pancreatic islet cell tumor, gastric acid
hypersecretion, severe peptic ulceration GI tract.
2. 50% locally invasive or have metastasized at time of diagnosis.
3. May be associated with MEN 1.
4. Clinical diarrhea, epigastric pain.
5. Treatment inhibit acid secretion, resection.
E. Other rare pancreatic neoplasms

1.

Alpha cell tumors - glucagonoma.

2.

Delta cell tumors somatostatinoma.

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Diabetes Mellitus
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3.

VIPoma - watery diarrhea, hypokalemia, achlorhydria.

4.

Carcinoid - serotonin.

5.

Pancreatic polypeptide - secreting tumor.

6.

Multihormonal tumors.

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