Diabetes Mellitus and its Complications

Question 1

What are the classical symptoms of both types of diabetes?

Answer 1

Polyuria, polydipsia, polyphagia, and weight loss

Question 2

Give three hormonal causes of diabetes and their mechanisms.

Answer 2

1. Growth hormone excess - direct effect of growth hormone is prodiabetic -> increased lipolysis, increased gluconeogenesis, and decreased peripheral glucose uptake (explains why hyperglycemia inhibits it)
2. Cortisol / exogenous steroids - prolonged steroid use or hypercortisolism is diabetogenic
3. Prolonged epinephrine / stress -> increased glucose levels

Question 3

Describe the mechanism of the symptoms seen in severe insulin insensitivity (Type 2) or insulin deficiency (Type 1)?

Answer 3

Unopposed glucagon -> hyperglycemia, proteolysis for gluconeogenesis

Hyperglycemia -> increased plasma osmolality -> polydipsia

Hyperglycemia -> osmotic diuresis (exceed tubular maximum) -> polyuria and hypovolemia -> dehydration

Proteolysis and weight loss -> polyphagia

Question 4

What type of acid base imbalance occurs in insulin deficiency and why? What will the patient do to compensate?

Answer 4

1. Increased lipolysis -> ketogenesis, since liver thinks brain is starving (can’t get glucose in). Ketones are anions.
2. Circulation failure and tissue ischemia -> due to hypovolemia -> serum lactate levels increase -> further anion gap metabolic acidosis

Patient will be vomiting and breathing very rapidly / deeply (Kussmaul respirations)

Question 5

What are the changes in the kidney which occur due to diabetes? Grossly / microscopically.

Answer 5

Nephropathy -> diffuse / nodular glomerulosclerosis
Nonenzymatic glycation of small vessels (hyaline arteriolosclerosis) takes its toll

Efferent arterioles affected first -> glomerular hyperfiltration with microalbuminia -> nephrOTIC syndrome

Kimmelstiel-Wilson nodules will form in glomeruli

Eventually involves both afferent and efferent arterioles, leading to systemic hypertension

Question 6

How does sorbitol play a role in the pathogenesis of diabetes? What tissues lack the appropriate enzymes and how does this manifest?

Answer 6

Sorbitol pathway uses aldose reductase to capture glucose in cells, and then sorbital DH to regenerate fructose

LuRKS are tissues with insufficient sorbitol dehydrogenase to get rid of sorbitol if it is at high levels.
Sorbital is an osmotic agent which causes damage.
L = Lens = Cataracts
R = Retina = Retinopathy
K = Kidneys = Nephropathy (some contribution)
S = Schwann Cells = peripheral neuropathy

Question 7

What are the consequences of the large vessel non-enzymatic glycation in diabetes? What is the most common cause of death in diabetes?

Answer 7

Atherosclerosis - most important, increases strokes and MIs
Coronary artery disease
Peripheral vascular occlusive disease with gangrene -> common cause of limb amputations

Most common cause of death in diabetes is MI

Question 8

How are nerves typically affected in diabetes?

Answer 8

Neuropathy - motor loss, sensory (glove and stocking distrubution) loss, and autonomic degeneration
-> remember gastroparesis and nocturnal fecal incontinence due to loss of internal anal sphincter ind iabetes

Question 9

What is the diagnostic cutoff for HbA1c in diabetes and what is the treatment goal?

Answer 9

> 6.5% is likely diabetes, goal is 7% for control (reflects average blood glucose over 3 months)

Question 10

How can the diagnosis of diabetes be made via random glucose and fasting glucose?

Answer 10

Random glucose > 200 mg/dL

Fasting glucose > 126 mg/dL after 8 hours of fasting

Question 11

What is the glucose tolerance test and what is diagnostic for diabetes?

Answer 11

Give the patient 75g of glucose in water

If glucose is >200 mg/dL 2 hours after consumption, patient has diabetes

Question 12

Are type 1 / type 2 diabetes insulin requiring or dependent?

Answer 12

Type 1 - always insulin dependent -> will die without

Type 2 - may be insulin requiring or not at all, typically not dependent -> will not die without.

Question 13

Which type of diabetes has a stronger genetic predisposition, and what HLA’s predipose you?

Answer 13

Type 2 diabetes has a stronger genetic predisposition than Type 1

HLA-DR3 and DR4 are associated with Type 1 diabetes though.
Think type 1 and not 2, associated with 3 and 4 “1,2,3,4”

Question 14

What gets diabetic ketoacidosis and what tends to precipitate it?

Answer 14

Usually Type 1 diabetics, because type 2 diabetics have some basal endogenous insulin which suppresses lipolysis (no ketone bodies will be generated). Can happen in type 2 diabetics with total beta cell failure.

Precipitated by stress (i.e. infection)

Question 15

What are the signs and symptoms of DKA?

Answer 15

DKA is Deadly
D - delirium / psychosis (from decreased brain perfusion due to hypovolemia)
K - Kussmaul respirations - deep / rapid breathing
A - abdominal pain, nausea / vomiting
D - Dehydration

Fruity odor can be smelled on breath due to exhaled acetone

Question 16

Will DKA present with hyperkalemia or hypokalemia? What is the overall treatment?

Answer 16

Hyperkalemia -> insulin is required to bring K+ into cells, and acidosis prevents Na/H exchanger from running, so K+ cannot be brought into cells as well.

Treatment is IV fluids, insulin AND K+
-> although they are hyperkalemic, their total body K+ is low due to diuresis. Insulin will restore their intracellular K+, causing hypokalemia

Question 17

What are the life-threatening complications of DKA?

Answer 17

1. Rhizopus infection (mucormycosis)
2. Cardiac arrhythmias - due to hyperkalemia
3. Cerebral edema - due to too rapid correction of hyperglycemia

Question 18

What can be seen in the pancreatic islets in Type 1 vs Type 2 diabetes?

Answer 18

Type 1 - T lymphocytic infiltration -> autoimmune destruction

Type 2 - amyloidosis - accumulation of AE amyloid from overproduction of insulin + amylin. Actual protein that accumulates is amylin.

Question 19

What is the life-threatening condition analogous to DKA seen commonly in Type 2 diabetics? What is the cause?

Answer 19

Hyperosmolar hyperglycemic nonketotic syndrome (HHNS)

Seen in Type 2 diabetics with limited ability to drink
-> a state of profound hyperglycemia-induced dehydration

Question 20

What is the pathogenesis of HHNS?

Answer 20

Hyperglycemia -> excessive osmotic diuresis -> dehydration

Serum osmolality will become very high (low water, glucose >500 mg/dL)
-> hypotension, neurological deficits, and coma.

Question 21

Will acidosis classically be seen in HHNS? What is the treatment?

Answer 21

Classically no, since ketone production is inhibited by presence of insulin.

Treatment is aggressive IV fluids and insulin therapy

Question 22

What is the mechanism by which insulin resistance during pregnancy is thought to arise? Why does this occur?

Answer 22

Human placental lactogen (HPL) is produced, which induces insulin resistance. Insulin resistance allows blood glucose levels to be slightly elevated to let the baby use glucose to develop.

It also stimulates lipolysis, allowing the mother to use ketone bodies for energy.

Question 23

How does maternal diabetes occur? When does it occur?

Answer 23

Human placental lactogen normally also stimulates an increase in insulin levels in the mother, to prevent diabetes. If the pancreatic beta cells cannot produce sufficient levels of insulin, maternal diabetes mellitus occurs

Occurs during 2nd or 3rd trimester, usually during the first pregnancy

Question 24

What are the possible fetal consequences of uncontrolled maternal diabetes?

Answer 24

Fetal anomalies due to hyperglycemia-induced oxidative stress.

1. Heart - transposition of the great arteries, ASD / VSD
2. CNS - neural tube defects
3. Large for gestational age (macrosomia)
4. Intrauterine growth retardation (if there is placental insufficiency due to vascular disease)
5. Caudal regression syndrome

Question 25

What is the spectrum of caudal regression syndrome which can happen in diabetes?

Answer 25

1. Anal atresia - minimal developmental field defect
2. Sirenomelia - “mermaid syndrome” - dysgenesis of entire lower trunk i.e. lower extremity fusion and lack of normal rotation

Question 26

What type of insulin is stored in secretory granules before export? How is it made?

Answer 26

Preproinsulin made in RER. Presignal is cleaved and it sits in the vesicles as proinsulin.

Proinsulin is cleaved at time of secretion, and both C peptide and insulin are secreted.

Question 27

What is amylin and what secretes it? What is its function

Answer 27

A hormone which is co-secreted with insulin by beta cells

Functions to decrease gastric emptying and decrease glucagon secretion in order to prevent post-prandial glucose spike

Question 28

What are the two phases of insulin secretion? Which one do Type 2 diabetics lose?

Answer 28

1. First phase - Acute reaction to eating - release of stored hormone
2. Second phase - release of newly synthesized and processed hormone

First phase (acute reaction) seems to be most lost in Type 2 diabetes, not enough of a postprandial insulin spike

Question 29

What type of receptor is the insulin receptor? What tissues have notably insulin dependent and insulin independent transport mechanisms?

Answer 29

Insulin - receptor tyrosine kinase (think of the tire swing in sketchy)

Insulin dependent - adipose tissue, striated muscle (GLUT4) - think of the donuts and ham in sketchy

Insulin Independent - Brain, RBCs, Intestine, Liver, Kidney

Question 30

What tissues possess the bidirectional GLUT2 insulin receptor?

Answer 30

Pancreatic beta cells, liver, kidney, and small intestine

Question 31

What are the two pathways through which insulin signals? Which one is impeded vs not in Type 2 diabetes and what does this explain?

Answer 31

1. MAPK pathway - cell growth and proliferation pathway - not affected in Type 2 diabetes -> explains why Type 2 diabetes is associated with higher cancer risks
2. PI3K signalling - glucose import and glycogen / protein / lipid synthesis pathway - affected in Type 2 diabetes

Question 32

What HbA1c levels are classified as prediabetes? Is this condition associated with health risks? What’s the management?

Answer 32

5.7-6.4% (<6.5). Also impaired 2 hour OGTT (>140), or impaired fasting glucose.

Increasesd risk of atherosclerotic disease, and 10% progress to diabetes per year.

Management is lifestyle modifications

Question 33

What antibodies are often positive in Type 1 diabetes?

Answer 33

1. Anti-islet cell antibodies
2. Anti-insulin antibodies
3. Anti-glutamic acid decarboxylase antibodies

Question 34

What is the only good adipokine in diabetes and is it high or low?

Answer 34

Adiponectin -> increases insulin sensitivity.

Activated by glitazones (increased PPARy activity)

Question 35

When do risk of macrovascular vs microvascular complications onset in diabetes?

Answer 35

Macrovascular - with impaired glucose tolerance, as in prediabetes (reason for increased cardiovascular effects)

Microvascular - when glucose levels start rising (postprandial spikes first) -> reason why diabetes brings out microvascular changes

Question 36

What is the most common acute complication of diabetes and what are the symptoms of this?

Answer 36

Hypoglycemia

• > adrenergic symptoms: sweating, tremor, tachycardia
• > neuroglycopenic symptoms: Headache, dizziness, convusion, coma

Question 37

What drug is an amylin analog and when should it be given?

Answer 37

Pramlintide

Should be given during mealtimes, with insulin.

Remember, amylin decreases gastric emptying and decreases glucagon.

Question 38

How should you start trying to control diabetes?

Answer 38

Early and aggressive combination pharmacologic therapy to keep glucose controlled