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Endocrine and Reproductive Systems > CM- Diabetes > Flashcards

CM- Diabetes Flashcards

1
Q

What are the ADA criteria for diagnosing DM?

A
  1. fasting glucose >126 mg/dl
  2. random plasma glucose >200 mg/dl in a patient with classic symptoms:
    - polyuria, polydipsia, polyphagia
    - unexplained weight loss
    - hyperglycemic crisis
  3. HBA1c measurement >6.5%
    4, plasma glucose of >200, 2hr after the ingestion of orgal glucose load [75g anhydrous glucose dissolved in water]
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2
Q

What should be done if a person does NOT present with classic diabetic symptoms [polyuria, polydipsia, polyphagia, weight loss, hyperglycemic cris] but has a fasting glucose >126 or a random glucose >200?

A

Repeat the measurement to rule out lab error

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3
Q

What are the two uses for measuring HBA1c?

A
  1. diagnostic criteria for diabetes

2. long-standing role in monitoring efficacy of therapy

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4
Q

How does HBA1c help diagnose and monitor DM?

What 3 factors would compromise the clinical usefulness of the HBA1c test as a marker of glucose control?

A

HBA1c correlates with integrated levels of blood glucose over a 2month period.

Three things that could compromise this marker are:

  1. comorbid conditions that:
    - shorten RBC half life [HBA1c underestimates degree of chronic hyperglycemia]
    - lengthens RBC half life [overestimates chronic hyperglycemia]
  2. hemoglobinopathies
  3. recent blood transfusions
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5
Q

What are the 2 categories for increased risk for diabetes?

A

Pre-diabetes is a state of increased risk for developing frank diabetes.

  1. impaired fasting glucose [100-125mg/dl]
  2. impaired glucose tolerance [2hr values in oral glucose tolerance test of 140-199 mg/dl]

[HBA1c for prediabetic is 5.7 -6.4]

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6
Q

In a pre-diabetic patient, what determines whether there will be progression to DM?

A

The ability of the pancreas to secrete enough insulin to adequately control blood sugars is the pivotal factor.

Impaired insulin presents before hyperglycemia

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7
Q

What are the 2 fundamental pathophysiological defects that result in hyperglycemia?

A
  1. impaired insulin secretion [ or b-cell dysfunction]
  2. insulin resistance to insulin action at target tissue [liver, muscle, adipose tissue]
    - increased hepatic production
    - reduced peripheral glucose uptake
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8
Q

How does the anatomy of the pancreas regulate glucose-stimulated insulin secretion?

A

Arterioles in the center of the islets of Langerhans reflect systemic glucose levels to the B-cells.

  1. High blood glucose-> increase insulin release-> inhibit glucagon release from alpha cells
  2. low blood glucose-> decrease insulin release-> release inhibition of alpha cells-> increased glucagon release
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9
Q

Describe the process of glucose sensing and release from the B-cell.

A
  1. high Km GLUT2 actively transports glucose into beta cells at a rate proportional to serum glucose conc.
  2. glucokinase makes glucose G6P which traps it in the cell
  3. Subsequent glycolysis—> ATP
  4. ATP inhibits K channel –> membrane depolarization
  5. Depolarization opens voltage dependent Ca channel
  6. Ca-dependent release of insulin via exocytosis of insulin storage granules
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10
Q

How is insulin synthesized?

A

It is synthesized in beta cells as a preprohormone.
Carboxypeptidase cleaves it to yield alpha and beta chains joined by two disulfide bonds and a C-peptide chain which is co-secreted with insulin

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11
Q

What are the 2 phases of insulin secretion following a meal?

A
  1. First phase - within 10 minutes of the meal
    - regulation of glucose output by the liver
    - repression of glucagon secretion by alpha cells
  2. Over several hours
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12
Q

What is amylin?
Where is it secreted from?
What are its 3 functions?

A

It is a peptide co-secreted with insulin from the B-cell.

It has 3 functions:

  1. suppress glucagon secretion
  2. slow gastric emptying
  3. promote satiety
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13
Q

What are the 3 primary insulin target tissues?

How does insulin act on these tissues?

A

Muscle, liver, fat

  1. Insulin binds the TyrKin IR on the tissue
  2. Autophosphorylation of the receptor makes binding sites for signaling molecules
  3. signal transduction pathways regulate gene expression and activity of the rate-limiting met. enzymes
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14
Q

What is the effect of insulin on fat and muscle?

A

It promotes glucose uptake in fat and muscle by stimulating translocation of GLUT1 and GLUT4 to the cell membrane

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15
Q

How does the influence of insulin for glucose uptake differ for liver, muscle and fat?

A

Insulin promotes translocation of GLUT1 and GLUT4 to take up glucose in fat and muscle.

Glucose uptake in liver cells is insulin-independent, so when there is insulin deficiency, glucose is preferentially tansported into liver cells

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16
Q

When there is insulin deficiency, which target tissue preferentially transports glucose into its cells?

A

Liver because glucose uptake is insulin-independent.

Muscle and fat cannot take up glucose because they require insulin to translocate their GLUT channels

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17
Q

What are the 3 ways insulin inhibits glucose production and promotes glucose storage? What is the rate-limiting enzyme/metabolite for each process?

A
  1. inhibit hepatic gluconeogenesis - PEPCK
  2. inhibit glycogenolysis- glycogen phosphorylase
  3. promote glycogen synthesis - glycogen synthase
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18
Q

What is the effect of insulin on fat metabolism?

A

Insulin will:

  1. promote fatty acid storage
  2. inhibit fatty acid breakdown
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19
Q

What are the 5 ways insulin promotes fatty acid storage and inhibits FA breakdown?

A
  1. breaks down TGs into FFA from circulating lipoproteins to take up into fat cells [LPL]
  2. biosynthesis of TGs from FFA in fat cells
  3. inhibit breakdown of TGs in fat cells [HSL]
  4. stimulate FA synthesis [FAS]
  5. suppress FA oxidation [malonyl coA–I carnitine palmitoyl transferase I]
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20
Q

What is the effect of insulin on protein?

A

Insulin promotes protein synthesis and storage by:

  1. promoting protein synthesis by increasing translation initiation and EFs
  2. suppress protein catabolism
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21
Q

What can hypoglycemia lead to?

A
  1. confusion
  2. seizure
  3. coma
  4. death
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22
Q

What are the 5 factors that help protect against hypoglycemia?

A
  1. Insulin [decreases]
  2. glucagon [increases]
  3. GH [increases]
  4. catecholamines [increases]
  5. glucocorticoids
23
Q

As glucose falls within the physiological range, what is the first defense against hypoglycemia?
What processes are begun?
Who is this defense lost in?

A

The first defense is decrease insulin secretion.
Insulin will fall to 0 as glucose approaches 60-70

Low insulin –> gluconeogenesis, glycogenolysis increasing hepatic output of sugar

This first line of defense is lost in DM patients with insulin or agents that promote secretion because insulin cannot fall physiologically

24
Q

How does glucagon defend against hypoglycemia?

A

When glucose falls below the physiological range, and insulin is shut off, glucagon will increase.

Glucagon increases hepatic output of glucose by:

  1. stimulating glycogen breakdown
  2. inhibiting glycogen synthesis
  3. gluconeogenesis
25
Q

What is the effect of catecholamines (esp. epi) on hypoglycemia?

A

As glucose falls below the physiologic range, the adrenal medulla secretes epi which:

  1. stimulates B2receptor mediated promotion of gluconeogenesis and glycogenolysis
  2. decrease glucose utilization in muscle
  3. promote mobilization of gluconeogenic substrates from muscle (lactate, alanine) and fat (glycerol)
  4. promote symptoms [tremor, palpitation, nervousness]
26
Q

How does GH counter hypoglycemia?

A

It is less important than glucagon and catecholamines but it:

  1. increases release of FA from fat–> ketones
  2. increase gluconeogenesis and glycogen breakdown in the liver
27
Q

How is glucose metabolism perturbed in the absence or deficiency of insulin?

A

When insulin is absent, there will be:

  1. decreased uptake into muscle/fat leading to glycogen breakdown, decreased glycogen synth.
  2. gluconeogenesis/glycogenolysis increase in the liver
  3. counter-reg hormones are high promoting MORE gluconeogenesis/glycogenolysis
28
Q

What are the effects of low/absent insulin on lipid metabolism?

A
  1. increased lipolysis and FA mobilization from fat leads to rising serum FFA
  2. FFA taken up by the liver get oxidized to acetyl CoA –> ketone bodies, acetone, acetoacetate, B-hydroxybutrate
  3. ketone bodies accumulate in circulation (ketonemia) and are peed out (ketonuria) –>metabolic acidosis {DKA}
29
Q

How do type 1 DM and type 2 DM differ in their handling of fat metabolism?

A

DM1 - insulin is essentially zero so there is severely increased lipolysis, FA mobilization. They are more likely to get DKA

DM2- enough insulin is made to prevent lipolysis and FA oxidation [thought to be because enough insulin/amylin inhibits glucagon]. There is less ketosis, but also the lack of acid leads to SEVERLY increased glucose in serum and dehydration. Hyperosmolar nenketotic coma.

30
Q

How does low insulin affect protein metabolism?

A
  1. increased metabolism in muscles –> production of AA
  2. AA are substrates for gluconeogenesis in liver–>NH4 and urea production
  3. excess nitrogen is lost in urine –> azoturia
31
Q

What are the 2 major categories of diabetes?

A

Type I (juvenile onset) IDDM- insulin dependent DM

Type II (adult onset) NIDDM - non-insulin dependent DM

32
Q

Why do patients with Type1 diabetes have little/no insulin secretion capacity?

A

Beta cells have been destroyed by T-cell mediated autoimmunity

33
Q

What is the natural history of IDDM?

A
  1. Genetic predisposition
  2. Environmental trigger
  3. T-cell autoimmunity
  4. pre-diabetes [IVGTT, glucose intolerance}
  5. diabetes
34
Q

What autoantibodies have been associated with type 1 diabetes?

A
  1. ICA [islet cell antibody]
  2. insulin Ab [IAA]
  3. glutamic acid decarboxylase [GAD65]
  4. Tyr phosphatase insulinoma-associated antigen 2 [IA2, IA2b]
35
Q

What is it called when type 1 DM has a less severe mode in adults?

A

Latent Auntoimmune Diabetes of Adulthood - progressive death of beta cells that still result from autoimmune destruction of the pancreatic islet

36
Q

A patient presents to you with DKA, but none of the normal immune markers of type 1 DM. The person was obese, but has lost significant amounts of weight. They have mild ketosis–>DKA.

What is the likely diagnosis?
What will occur to insulin requirements over the months after diagnosis?

A

type 1b DM = idiopathic diabetes

Over the months after diagnosis, they will have dramatic decreases in their insulin requirements and get switched to oral agents

37
Q

What factors lead to type 2 DM?

What causes the presentation of disease?

A

there is NO autoimmune component, however, there is a genetic disposition along with obesity and sedimentary lifestyle.

Insulin resistance develops in fat, muscle, liver. To compensate, the beta cells secrete more insulin to maintain glucose in normal range.
Eventually, this fails and serum glucose increases postprandially and in the fasting state.

38
Q

Why do patients with type 2 diabetes present with polyuria and polydipsia?

A

Eventually the glucose is too much for the kidney to reabsorb and this causes osmotic diuresis [from glucose in the urine].
Loss of free water–> increased thirst and polydipsia

39
Q

Epidemiologically, what factors correlate positively with insulin resistance?

A
  1. obesity [BMI]
  2. visceral adiposity [waist circumference] ** better correlation than obesity
  3. Acanthosis nigricans [thickening/hyperpigmentation of the folds of skin at neck, elbow, axilla, groin, knee]
40
Q

In type II diabetes, a long asymptomatic period of insulin resistance and compensatory hyperinsulinemia precedes overt diabetes. What complications can arise during this “asymptomatic” time?

A

Macrovascular complications like:

  1. atherosclerosis
  2. peripheral vascular disease
41
Q

What is the octet of metabolic abnormalities associated with type 2 diabetes?

A
  1. impaired insulin secretion by pancreas
  2. excessive hepatic glucose output
  3. decreased glucose uptake into muscle
  4. insulin resistance in the brain
  5. increased glucagon from alpha cells
  6. increased lipolysis of fat
  7. increased glucose reabsorption by kidney
  8. decreased incretin effect from GI
42
Q

What are incretins?

A

glucagon-like peptide 1 and gastric inhibitory peptide [GLP1 and GIP] are released from the GI tract in response to a meal and act as endocrine hormones on beta cells of the pancreas to release insulin.

43
Q

What is MODY?

A

Mature onset Diabetes of the young.
It is a non-ketotic DM that has its onset before the age of 25 and is inherited in an autosomal dominant fashion.
There are 9 current diseases reported

ALL cases so far have a defect in glucose-stimulated release of insulin from B cells

44
Q

What is the defect in MODY 2?

What do most other MODY genes encode?

A

mutation if glucokinase which is key in glucose sensing and insulin release from the B- cell .

Most other MODY genes encode TFs that control pancreatic development

45
Q

How does MODY present like type1 diabetes? How does it present like type 2?

A

Type 1 - young age, not obese or insulin resistant

Type 2- adequately controlled with oral antidiabetes drugs, not prone to ketosis

46
Q

A patient presents with insidious onset diabetes. They have acanthosis nigricans, and an insulin reserve. What type of diabetes is this?

A

Type 2

47
Q

A patient presents with acute onset diabetes with DKA and autoantibodies. What type of diabetes is this?

A

type 1

48
Q

What is gestational DM?

A

It is normal to have insulin resistance during pregnancy because of increases in human placental lactogen, glucocorticoids, progesterone, TNFa and FFA. B cell compensation occurs.

In women who had risk for future DM2 may get GDM where glucose intolerance is first diagnosed in pregnancy

49
Q

What are the pregnancy risks associated with GDM?

A
  1. pre-eclampsia
  2. polyhydramnios
  3. asymptomatic bacteria and UTIs
  4. fetal stillbirth
  5. macrosomia (>4000g)
  6. neonatal hypoglycemia
50
Q

How are women screened for GDM during pregancy?

A

There is a 2 step protocol btwn weeks 24 and 28.

  1. 50g glucose challenge test - if blood glucose at 1hr exceeds threshold then:
  2. 100g glucose tolerance test over 3 hrs
51
Q

What is treatment for GDM?

A
  1. diet and exercise
  2. insulin
  3. metformin and glyburide
52
Q

What happens to glucose tolerance when a woman with GDM gives birth?

A

She can revert to normal or can progress to type 2.
The GDM showed a predisposition to DM and risk of progression.

Women who have impaired glucose tolerance on oral glucose tolerance tests 6-12 wks post-partum are more likely to progress to type 2

53
Q

What “other conditions” can be associated with DM?

A
  1. genetic defects in insulin action
  2. disease of exocrine pancreas [pancreatitis, trauma, infiltrative]
  3. endocrinopathies [acromegaly, Cushing]
  4. drugs [roids]
  5. infections [CMV, rubella]
    6/ genetic syndrome [wolfram]

Endocrine and Reproductive Systems (27 decks)

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