Diabetes etiology and pathogenesis Flashcards
Types of diabetes
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.
T1DM autoantibodies
ICA: Islet cell antibody
GADA: glutamic acid decarboxylase antibodies
Insulin autoantibodies.
Syndromes associated with diabetes
Downs
Klinefelter
Turner
GH
Cushings
Hyperthyroidism
Hyperglycemic Hyperosmolar State causes, symptoms, and treatment.
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
Ketoacidosis in adults, diagnosis and therapy
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
Diabetic ketoacidosis in children
blood glucose above 11 mM
metabolic acidosis, venous pH less than 7.3 or plasma bicarb less than 15mM
Ketosis, in blood or urine.
Diabetic keotacidosis treatment
Treatment: iv. hydration (saline) insulin K+ (monitoring needed)
iv. HCO3, potentially, if acidosis is severe
What are the glucose concentrations of normoglycemia
asymptomatic hypoglycemia
symptomatic hypoglycemia
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.
Why do we have to use venous plasma for glucose measurement when diagnosing diabetes
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
What is the level for hypoglycemia in diabetic patients?
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.
Treatment for hypoglycemia
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.
What is whipples triad?
symptoms that indicate a pancreatic insulinoma
fasting hypoglycemia, clinical symptoms of hypoglycemia, and immediate improvement on administration of IV glucose.
What are potential sources of artifacts, or false positives of hypoglycemia
Leukemia - excessive glycolysis in the sample by leukocytes
Polycytemia vera, same.
Complications of severe hypoglycemia
CNS dysfunction,
Coma
Death
Arrhythmia, sudden cardiac death.
Pancreatic islet cell tumors general info and common genetic mutations
- 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%
Beta cell tumors, insulinomas, general features, morphology, histology
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
Diagnositc tests for insulinoma
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
Gastrinomas,
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%.
Glucagonomas
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.
VIPoma
rare. VIP secretion
pancreatic cholera
watery diarrhea, hypokalemia, achlorhydria.
Hypokalemia symptoms
- 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
- Symptoms occur if plasma K+ is < 3.0 mmol/L
Somatostatinomas
Achlorhydria - due to gastin secretion
Cholelithiasis - due to cholecystokinin inhibition
Steatorrhea - also due to cholecystokinin
Lipid malabsorption syndrome, due to no bile secretion
