Pathophysiology of Diabetes and Prediabetes: Dagogo-Jack

Question 1

Recall the steps in insulin synthesis, processing from proinsulin and its byproduct, C-peptide and mechanism of insulin secretion.

Answer 1

Insulin is generated as a pre-pro peptide and is then processed to generate two fragments, mature insulin and C-peptide. Insulin is stored in secretory granules alongside C-peptide, and upon stimulation of the Beta cells by glucose (glu enters via GLUT2, K+ exit is inhibited by ATP, cell depolarizes, Ca2+ enters), it is released into the blood by exocytosis.

Question 2

Understand diagnostic criteria for diabetes and prediabetes and the difference between type 1 and type 2 diabetes.

Answer 2

Pre-diabetes Dx:
::Fasting glu: 100-125mg/dl
::OGTT: 2 hrs post 75g glu- 140-199mg/dl
::HbA1c: 5.7-6.4%

Diabetes Dx:
::Fasting glu: >125mg/dl
::OGTT: 2 hrs post 75g glu- >199mg/dl
::HbA1c: >6.5 %

T1DM- (5-10% cases) juvenile onset autoimmune destruction of pancreatic islet cells that leads to insulin deficiency and thus elevated blood glucose. Severe insulin deficiency. Prone to ketoacidosis. Lifelong tx required. Twin concordance 50%.

T2DM- (90-95% cases) Adult onset. Cells become insulin insensitive due to chronically elevated levels of glu and insulin. Insulin overstimulates receptors, so they become desensitized and more insulin is required to activate them. There is also B cell dysfunction in the pancreas. Pancreas can not produce insulin fast enough. Progressive insulin deficiency. Ketoacidosis less freq. Twin concordance 80%.

Question 3

Become familiar with the current understanding of the pathophysiology of T1DM.

Answer 3

There is a genetic predisposition to T1DM:
HLA-DQ7 is protective
HLA-DQ8 is susceptible
HLA-DR4/DR4 overrides protective DQ alleles

It is believed that viral, bact’l, and envr. triggers stimulate macrophages to release cytokines that cause B cell destruction. In the non-susceptible population, there will be complete recovery. In the genetically susceptible population, there will be autoimmunity against B cells and resulting T1DM.

Question 4

Become familiar with the current understanding of the pathophysiology of T2DM.

Answer 4

Risk factors for T2DM include, but are not limited to:
Family hx, age, ethnicity, obesity, HTN, dyslipidemia, major mental illness, gravada w/ >9lb fetus, medications.

Chronically elevated levels of insulin and glu lead to insulin insensitivity. Over time, B cells lose ability to produce glucose and supplementation of insulin is needed, as well as glucophages (1st line tx).

Insulin resistance: very high
Acute insulin secretion: Blunted
Beta cell mass: way down
Post-prandial glucagon: way up (body thinks glu levels are low)
Post-prandial amylin*: low

BIG PICTURE: Decreased insulin sensitivity, decreased insulin secretion, increased SGLT2 expression (reabsorbing glu from urine), decreased suppression of glucagon.

*amylin is another product released alongside insulin by Beta cells that is supposed to augment insulin’s actions in post-prandial glu control

Question 5

Become familiar with the current understanding of the pathophysiology of Prediabetes.

Answer 5

Same defects as in T2DM but less severe.

Question 6

What causes hypoglycemia in the non-diabetic population?

Answer 6

Severe illness (hepatic failure, renal failure, sepsis)
GI surgery
Factitious: Sulfonylurea or insulin
Insulinoma (rare)
Other tumors
Adrenal insufficiency
Drugs: pentamidine, sulfonamides, quinine, quinolones

Question 7

Describe the estimated mg/dl glu values for landmark pathological events.

Question 8

Describe some risk factors for hypoglycemia in T1DM.

Answer 8

Inadequate caloric consumption (skipped meals, illness)
Incr. insulin sensitivity (weight loss, exercise, impr. fitness, meds)
Impaired glu production (EtOH, liver damage, renal failure)

ANTECEDENT EPISODES OF HYPOGLYCEMIA

Question 9

How might hypoglycemia cause death?

Answer 9

::Incr. Qtc interval (measure of the time between the start of the Q wave and the end of the T wave)
-incr. symp. activity red. serum K+ and promotes Ca influx
-Insulin lowers serum K+, red. K+ efflux, and prolongs cardiac repolarization
-hypoglycemia reduces HERG channel conduction that mediates K+ efflux.
::Activation of proinflammatory mechanisms (ICAM, VCAM, E-selectin, VEGF, IL-6)
::Incr. platelet activation
::Decr. systemic fibrinolytic balance by incr. in PAI-1 (plasminogen activator inhibitor-1)