Diabetes etiology and pathogenesis

Question 1

Types of diabetes

Answer 1

Type 1,

Type 2

LADA: Latent Autoimmune Diabetes of the Adult

MODY: Maturity onset diabetes of the young, associated with specific monogenic defects: GCK1, glucokinase. HNF1A, GCK, HNF4A, IPF1, HNF1B, NEUROD1. Involved in insulin synthesis or secretion.

MIDD: Maternally Inherited Diabetes and Deafness. Mitochondrial DNA mutation.

Gestational Diabetes: Pancreatic function is not sufficient for increased demang. 5-10% of pregnant women. 45% of these patients will develop DM within the next 10 years.

Question 2

T1DM autoantibodies

Answer 2

ICA: Islet cell antibody

GADA: glutamic acid decarboxylase antibodies

Insulin autoantibodies.

Question 3

Syndromes associated with diabetes

Answer 3

Downs

Klinefelter

Turner

GH

Cushings

Hyperthyroidism

Question 4

Hyperglycemic Hyperosmolar State causes, symptoms, and treatment.

Answer 4

Typically in Type 2. Rarely in Type 1

A stressor usually intiates it: infection, drugs, stroke, AMI, pancreatitis

• Serum glucose becomes massively high, above 33mM, ranges between 40-100mM
• Serum osmolality is above 320 mOsm/kg
• low insulin, high glucagon
• no ketoacidosis
• onset is slow, stakes several days.
• 30-50% lethality, from

Severe dehydration from massive osmotic diuresis, hyperosmolarity, hypovolemia, centralization, renal insufficiency, hypovolemic shock.

Severe risk for DVT and other thrombosis, stroke, focal neurological deficits.

Treatment:

• correction of the dehydration with intravenous fluids,
• give anticoagulants,
• reduction of the blood sugar levels with insulin,
• management of the underlying/triggering conditions

Question 5

Ketoacidosis in adults, diagnosis and therapy

Answer 5

Diagnosis

• Nitroprusside Sodium: Detects ketones in urine.
• Hyperglycemia 20-40mM
• Glucosuria
• Ketones in blood
• Acidosis, pH below 7.35
• Hyperkalemia
• Osmotic diuresis
• dehyrdration
• Cl- decreases
• Bicarbonate decreases
• Also develops slowly over days
• mortality 5-10%, 20% in elderly

Signs and sypmtoms

• Kusmaul breathing
• Breath smells like acetone
• Nausea, vomiting
• abdominal pain
• muscle contractions
• increased heart rate
• low blood pressure

Question 6

Diabetic ketoacidosis in children

Answer 6

blood glucose above 11 mM

metabolic acidosis, venous pH less than 7.3 or plasma bicarb less than 15mM

Ketosis, in blood or urine.

Question 7

Diabetic keotacidosis treatment

Answer 7

Treatment:  iv. hydration (saline)  insulin  K+ (monitoring needed)

 iv. HCO3, potentially, if acidosis is severe

Question 8

What are the glucose concentrations of normoglycemia

asymptomatic hypoglycemia

symptomatic hypoglycemia

Answer 8

Normal glucose range: 3.9-6.1 mM

3.9 mM is the cutoff for hypoglycemia: Glucagon, Cortisol are induced, insulin is suppressed, but symptoms of hypoglycemia are not apparent. (equals about 50mg/dL)

2.8-3.1 mM Hypoglycemia symptoms occur in non-diabetic patients.

Question 9

Why do we have to use venous plasma for glucose measurement when diagnosing diabetes

Answer 9

 Concentration in whole blood is about 15% lower than in the plasma

 Reason: red blood cells contain more dry material

 Venous blood glucose cc. is about 0,5–1 mmol/l lower than capillary blood glucose cc. as a consequence of insulin effect

 Reason: cellular glucose uptake

Question 10

What is the level for hypoglycemia in diabetic patients?

Answer 10

Diabetic patients have an unpredictable floor for hypoglycemia, and are recommended to be concerned about hypoglycemia at a self-monitored plasma conenctration of 3.9mM.

Probably due to the chronic el;evated glucose and increased homeostatic set points.

So if a diabetic has glucose of 3.9 or a little lower, they should, avoid exertion, eat carbohydrates, avoid driving and consider lowering insulin dose.

Question 11

Treatment for hypoglycemia

Answer 11

Administer IV glucose (aka dextrose) solutions

200-300mL of 10% dextrose solution

Also/alternatively Glucogon may be administered, but is not effective in drunk patients.

Question 12

What is whipples triad?

Answer 12

symptoms that indicate a pancreatic insulinoma

fasting hypoglycemia, clinical symptoms of hypoglycemia, and immediate improvement on administration of IV glucose.

Question 14

What are potential sources of artifacts, or false positives of hypoglycemia

Answer 14

Leukemia - excessive glycolysis in the sample by leukocytes

Polycytemia vera, same.

Question 15

Complications of severe hypoglycemia

Answer 15

CNS dysfunction,

Coma

Death

Arrhythmia, sudden cardiac death.

Question 16

Pancreatic islet cell tumors general info and common genetic mutations

Answer 16

• Pancreatic islet cell tumors, aka PanNETs, Pancreatic Neuroendocrine tumors
• 2% of all pancreatic neoplasms
• Occur mostly in adults
• May be single or multifocal
• Metastsize to the liver
• Can secrete pancreatic enzymes or be non-secretory, non-secretory ones present with mass effects or obstruciton of pancreatic head, and general symptoms of a large neoplasm, bad prognosis.
• All have malignant potential, and 65-80% are overtly malignant from the start. except pancreatic insulinomas.
• The proliferative/mitotic counts using Ki-67 is the best predictor of outcome.
• Are often part of MEN1 syndrome.
• Loss of PTEN or TSC2 tumor suppressor genes, disinhibition of the mTOR oncogenic pathway.
• 50% have ATRX or DAXX mutations, but rarely both. indicating that they are a critical and overlapping function.
• Insulinomas have high 90% 5yrS
• Gastrinomas 50-70
• vipoma glucagonoma 40-60%
• somatostatinoma 20-40%
• non-secretory 30-50%

Question 17

Beta cell tumors, insulinomas, general features, morphology, histology

Answer 17

Are the most common type of inslet cell tumor

Secrete functional insulin and can produce clinical hypoglycemia.

Whipples triad, fasting hypoglycemia and clinical symptoms, rapidly curing by dextrose administration. indicates insulinoma.

Insulinomas are not malignant and are usually cured by surgical resection., probably because their symptoms cause such an early presentation, they are usually identified at less than 2cm in diameter

Usually solitary,but can also be multifocal or ectopic from the pancreas: wall of the stomach, duodenum, followed by jejunum, Meckels, and ileum

Malignant insulinomas do occur, at less than 10% of all insulinomas. Malignancy is based on local invasion or metastases.

Histologically they look like huge islets, with regular cords of cells and normal vasculature organization, and normal granulation of islet cells. Even malignant ones have minimal anaplasia, and may be encapsulated.

Extracellular amyloid deposition is seen in many insulinomas

Question 18

Diagnositc tests for insulinoma

Answer 18

Hypoglycemia and high plasma insulin in a fasted state

IV insulin suppression test: should suppress C-peptide in normal patients. C-peptide remains high in insulinoma

To locate:

CT

MRI

ERCP: endoscopic retrograde cholangiopancreatogram

Question 19

Gastrinomas,

Answer 19

Arise in the:

• duodenum
• pancreas
• peri-pancreatic soft tissue.

The high gastrin excretion causes Zollinger-Ellison syndrome:

• excessive gastric acid secretion
• severe peptic ulceration, multiple ulcers
• these ulcers are unresponsive to normal therapy,
• occur in unusual locations, ie, the jejunum –> this is very strongly indicative of gastrinoma.
• diarrhea due to excessive gastric motility

These are very often malignant, over half have metastasized at presentation/diagnosis.

25% are part of MEN-1 syndrome. MEN-1 associated gastrinomas are often multifocal and sporadic ones are usually single.

Like insulinomas, they histologically look like well differentiated pancreatic islet cells, rarely any anaplasia. Despite this they are usually malignant, 60-80%.

Question 20

Glucagonomas

Answer 20

Rare alpha cell tumor

Secondary type 2 diabetes mellitus

the hallmark symptoms is: Necrolytic migratory erythema, seen in 70%

Erythematous, blisters and red swelling across areas of friction, abdomen, perineum, groin, axillae, mouth.

Diagnosis: high blood serum glucagon levels, with normo/hyperglycemia.

Octreotide inhibition is used for treatment, . Octreotide is a somatostatin analog, and suppresses glucagon release to manage symptoms.

Treatment is surgical resection.

Question 21

VIPoma

Answer 21

rare. VIP secretion

pancreatic cholera

watery diarrhea, hypokalemia, achlorhydria.

Hypokalemia symptoms

• 1. Symptoms occur if plasma K+ is < 3.0 mmol/L
     2. Weak and tired legs
     3. Fatigue
     4. Myalgias
     5. Hypoventilation due to respiratory muscle weakness
     6. Paralysis
     7. Nocturia, polyuria, polydipsia

Question 22

Somatostatinomas

Answer 22

Achlorhydria - due to gastin secretion

Cholelithiasis - due to cholecystokinin inhibition

Steatorrhea - also due to cholecystokinin

Lipid malabsorption syndrome, due to no bile secretion