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HMS Homeostasis II > Diabetes I - Basics and the Exocrine Pancreas > Flashcards

Diabetes I - Basics and the Exocrine Pancreas Flashcards

1
Q

Best techniques for imaging the pancreas

A

MRI provides the best pictures. CT is slightly less effective, but useful for an exploratory scan

Chest ultrasound is often limited due to the presence of bowel air surrounding the pancreas, however endoscopic ultrasound via the stomach or duodenum can well visualize pancreatic masses.

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2
Q

Embryology of the pancreatic islets

A

The islets develop from the parenchymatous tissue of the pancreas starting around the third month of gestation and scatter throughout the gland, with insulin secretion beginning around the 5th month of gestation

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3
Q

Pancreatic islets are innervated by . . .

A

Pancreatic islets are innervated by sympathetic, parasympathetic, and sensory neurons

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4
Q

The pancreatic islets are separated from the exocrine acinar tissue by ___

A

The pancreatic islets are separated from the exocrine acinar tissue by a thin capsule

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5
Q

Types of cell in pancreatic islets

A
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6
Q

The highest density of pancreatic islets is in the ___.

A

The highest density of pancreatic islets is in the tail of the pancreas

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7
Q

Insulin maturation/processing

A
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8
Q

Proinsulin

A

A small amount of proinsulin escapes cleavage and is secreted intact, along with insulin and C-peptide. Proinsulin has 7-8% of the biologic activity of insulin but has a longer half-life than insulin

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9
Q

C-peptide

A

C-peptide has no known biologic activity. It also has a longer half-life than insulin as it is not degraded by the liver. It may be a useful marker for detecting insulin production.

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10
Q

Insulin half-life

A

Insulin has a half-life is 3-5 minutes and it is degraded by insulinases in the liver, kidney and placenta.

As blood from the portal vein, into which insulin is secreted, enters the liver before reaching the systemic circulation, there is a large amount of firstpass metabolism with only 50% of insulin reaching the systemic circulation. This also allows the liver, one of the target organs of insulin, to be exposed to high levels of the hormone.

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11
Q

Kinetics of insulin secretion

A
  • Secreted in pulsatile manner in response to blood glucose level
  • Biphasic response:
    • An initial burst from release of premade insulin in secretory granules
    • If glucose elevation persists, insulin release at levels higher than basal secretion is continued from increased insulin synthesis.
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12
Q

Amylin

A
  • Aka islet amyloid polypeptide
  • Co-secreted with insulin from β-cells at a ratio to insulin of 1:100
  • Complementary functions to insulin
  • Decreases rate of stomach emptying, thus slowing the delivery of nutrients to the small intestine for absorption
  • Suppresses glucagon secretion
  • Promotes satiety
  • Absent in patients with type 1 diabetes, and amylin secretion is impaired in patients with type 2 diabetes.
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13
Q

Glucagon production

A
  • Derived from a large precursor protein, proglucagon
  • Proglucagon is produced in the small intestine and the islets.
    • In the small intestine, proglucagon is cleaved to glucagon-like peptide-1 (GLP-1), one of the incretin hormones.
    • In the α-cells, proglucagon is cleaved into glucagon.
  • Glucagon is secreted into the portal vein and has a half-life of 3-6 minutes due to inactivation by liver and kidney
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14
Q

Regulators of glucagon

A
  • Glucose inhibits glucagon secretion directly
  • Insulin, amylin and somatostatin exert paracrine effects to reduce glucagon secretion in the setting of high levels of glucose
  • Certain amino acids stimulate glucagon secretion
  • Catecholamines, gastrointestinal hormones (cholecystokinin [CCK], gastrin, and gastric inhibitory polypeptide [GIP]), and glucocorticoids promote glucagon secretion.
  • Both sympathetic and parasympathetic (vagal) stimulation promote glucagon release
  • High levels of circulating fatty acids suppress glucagon secretion
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15
Q

Glucagonomas

A
  • Usually arise from pancreas
  • 20% associated with MEN-1
  • Release miscellaneous cleavage products of proglucagon
  • Present with necrolytic migratory erythema, diabetes mellitus, weight loss, abdominal pain, changes to nails, lips and tongue and anemia
  • The tumors are usually large and easy to localize
  • Treatment includes somatostatin analogues and surgical resection
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16
Q

Somatostatin

A
  • Secreted from pancreas, stomach, and intestines
  • Very brief half-life of 3 minutes
  • Two forms: Somatostatin-14 (14 amino acids) predominates in the islet cell, and somatostatin-28 (28 amino acids) predominates in the small intestine
  • Released by δ-cells in response to the same stimuli that cause insulin secretion
  • Generalized inhibitory effect on virtually all gastrointestinal and pancreatic exocrine and endocrine functions
  • Prolongs gastric emptying time
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17
Q

Somatostatinoma

A
  • Extremely rare, often malignant with metastases at the time of diagnosis, arising from the pancreas or duodenum.
  • Symptoms: Mild diabetes mellitus, steatorrhea, gallstones.
  • Associated with VHL syndrome, Neurofibroatosis-1, and MEN-1
  • Treatment is with surgery and/or chemotherapy.
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18
Q

Pancreatic polypeptide

A
  • Derives from a larger precursor molecule that is cleaved to active state
  • Produced by PP (also called F) cells of the islets.
  • Increases in response to a mixed meal, but not intravenous infusions of glucose/lipids/amino acids
  • Secretion is mediated via the vagus nerve
  • Physiology remains uncertain
  • Levels are higher in individuals with pancreatic endocrine tumors, as well as in a range of other conditions (old age, alcohol abuse, diarrhea, renal failure, hypoglycemia and inflammatory disorders).
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19
Q

Glucagon-like peptide-1

A
  • Secreted by intestinal L-cells in the distal ileum and colon.
  • Differential cleave product of proglucagon
  • Inactivated in the blood by dipeptidyl peptidase 4
  • Major effector of the incretin effect
  • Directly stimulates the production and secretion of insulin and somatostatin, and thereby indirectly inhibits the secretion of glucagon
  • Trophic factor for β-cells
  • Inhibits gastric emptying and gastric acid secretion in stomach
  • Inhibits appetite and induces weight loss by acting in brain
20
Q

Glucagon-like peptide-2

A
  • Another differential cleavage product of glucagon produce by L cells
  • Stimulates intestinal mucosal growth and nutrient absorption and inhibits motility
  • Physiology still unclear
21
Q

Incretin effect

A

Name given to the physiologic observation that ingesting glucose orally vs. intravenously leads to different insulin responses – the oral route leads to higher insulin levels

22
Q

Gatric inhibitory polypeptide

A
  • Secreted by K-cells of the duodenum and jejunum in response to glucose and lipids.
  • Functionally and structurally similar to GLP-1, but different gene
  • In addition to GLP-1-like effects, promotes differentiation of new adipocytes and drives lipogenesis and adipokine production in mature adipocytes
  • In bone, GIP stimulates osteoblasts and increases bone density.
23
Q

Latent autoimmune diabetes of adulthood

A
  • Very chronic and indolent form of type I diabetes mellitus
  • Older adults often present with a more indolent onset and may retain enough β-cell function at the outset to avoid ketosis
  • They eventually will lose β-cell mass and become insulin deficient
24
Q

Etiologies of diabetes resulting from damage to the endocrine pancreas

A
  • Trauma
  • Infarction
  • Severe pancreatitis
  • Pancreatic cancer
  • Surgical pancreatectomy
  • Cystic fibrosis
  • Hemochromatosis (“bronze diabetes”)
25
Q

Diabetes mellitus resulting from endocrinopathy

A
  • Excess of any glucose stress response hormone can induce high levels of insulin which lead to the development of insulin resistance
  • Hyperglycemia typically resolves when the hormone excess has been corrected
26
Q

Drug-induced hyperglycemia

A
  • Certain drugs can reduce the insulin release from β-cells (for example thiazide diuretics and β-blockers).
  • Most others increase insulin resistance (for example glucocorticoids, atypical antipsychotics, and protease inhibitors used in HIV therapy).
27
Q

Diagnosing diabetes

A
  • Fasting plasma glucose
  • Hemoglobin A1c
  • 75g oral glucose tolerance test
28
Q

Performing an accurate blood glucose measurement

A
  • Collect blood in tubes containing fluoride (prevents artifacts from white cell glycolysis after blood is extracted)
  • Glucometers that measure capillary blood glucose very useful for tracking of trends, but are less accurate then lab measurement, especially at low end
  • Continuous glucose monitors may be inserted to probe the interstitial fluid within adipose tissue every 15-30 minutes, but these are even less accurate. These are still useful for patients since they can be alerted to dramatic changes in their blood glucose and can mobify behavior appropriately
29
Q

Hemoglobin A1c

A
  • A glycated form of hemoglobin.
  • Reaction happens in proportion to the amount of glucose in the blood, thus providing a reflection of average blood sugar levels over the lifespan of the hemoglobin molecule, especially the last ~1 month
  • In normal individuals, this is about ~5.7% of hemoglobin
  • In treatment of diabetes, <7% A1c is a treatment target
  • Also affected by other hemoglobin variations, aspirin or renal failure, any condition that shortens erythrocyte lifespan (lowers A1c) or prolongs erythrocyte lifespan (raises A1c), and blood transfusions.
30
Q

Fructosamine

A
  • A glycated form of albumin and other proteins
  • Can be used instead of HbA1c
  • Reflects the glycemic control for the preceding 2-3 weeks due to albumin’s shorter halflife
  • Less subject to variation than HbA1c values (due to other complicating conditions and affects on blood discussed elsewhere)
31
Q

Clinical presentation of Type I Diabetes Mellitus

A
  • Hyperglycemia
  • Glycosuria
  • Polyuria and polydipsia
  • Hypovolemia and subsequent orthostatic hypotension, dizziness, lightheadedness
  • Weight loss (due to loss of anabolic effects of insulin, breakdown of muscle to form ketone bodies)
  • Diabetic ketoacidosis - metabolic anion gap acidosis, Kussmaul’s respirations, nausea, vomiting, impaired consciousness, shock, death
  • Blurred vision due to exposure of retina and lens to hyperglycemia
32
Q

Clinical presentation of Type II Diabetes Mellitus

A
  • Many asymptomatic and only found on routine fasting blood glucose screenings
  • Skin infections, vaginal candidiasis, and pruritus common
  • When hyperglycemic will present with type I diabetes symptoms (polyuria, polydipsia, blurred vision, paresthesia, fatigue, possibility of DKA)
  • Many overweight or obese
  • Acanthosis nigricans
  • Peripheral neuropathy, vision loss, and/or other long-term complications
33
Q

Acanthosis nigricans

A

A dark velvety skin finding often seen with skin tags and associated with insulin resistance.

34
Q

95% of patients with type 1 diabetes have . . .

A

95% of patients with type 1 diabetes have the HLA haplotypes DR3 or DR4

35
Q

___ is protective against later development of type I diabetes.

A

Breast-feeding is protective against later development of type I diabetes.

36
Q

Stiff person syndrome

A
  • A neurologic disorder that is characterized by very high levels of glutamic acid decarboxylase (GAD) antibodies.
  • The target of GAD antibodies is an enzyme that catalyzes the synthesis of GABA from glutamate. This enzyme is also present in the central nervous system (CNS).
  • It is thought that the antibody may lead to reduced GABA levels in the CNS, which leads to the progressive rigidity and fluctuating muscle spasms
  • Although GAD antibodies are found in both type 1 diabetes and stiff person syndrome, only about 30% of individuals with stiff person syndrome have type 1 diabetes.
37
Q

Sensitivty and specificity of various autoantibodies for diagnosing type I diabetes

A
38
Q

Adipokines

A
  • Signaling molecules (hormones and cytokines) secreted by adipose tissue, some of which can affect insulin signaling.
  • These include adiponectin, TNF-α, interleukin-6, leptin, resistin
  • Adiponectin enhances insulin signaling; adiponectin levels decrease with increasing fat mass.
  • In contrast, levels of the other adipokines increase as the total amount of fat stored in adipose tissue increase. These decrease the insulin sensitivity of the adipocytes and further increase their release of free fatty acids
39
Q

The Randle hypothesis

A

That engorged adipocytes, especially adipocytes in the visceral compartment (around the abdominal organs), release more fatty acids, which can inhibit glycolysis and insulin-stimulated glucose removal in the muscle

In addition, once the adipocytes are “full,” ectopic lipid storage in liver and muscle can decrease insulin sensitivity in these organs.

40
Q

Role of PPAR-γ

A
  • Peroxisome proliferator-activated receptor gamma (PPAR-γ)
  • Transcription factor that is expressed in many tissues
  • In adipose tissue, it exerts several beneficial effects, including promoting lipid storage in adipose tissue (rather than in ectopic locations), inhibiting production of adipokines and proinflammatory cytokines, and promoting the anti-inflammatory state in macrophages.
41
Q

Pseudoacromegaly

A

Can occur in type II diabetes due to the IGF-1-like effects of insulin at sites other than its primary metabolic targets

42
Q

Most people with insulin resistance . . .

A

Most people with insulin resistance do not have diabetes.

This is because the β-cells can compensate for insulin resistance by producing more insulin and by becoming hyperplastic. Individuals who develop type 2 diabetes therefore also have a defect in this compensatory response

This is in part due to toxic effects of elevated glucose and free fatty acid levels on β-cells.

43
Q

The metabolic syndrome

A
  • Cluster of symptoms that patients with insulin resistance and visceral obesity often present with
  • Visceral obesity with a high waist circumference
  • Insulin resistance with prediabetes
  • Hypertension
  • Dyslipidemia
  • Higher risk of coronary artery disease and stroke
44
Q

Prevention of Type II Diabets in Prediabetic Patients

A
  • Lifestyle modifications
    • Hypocaloric diet
    • Exercise (150 min/week)
    • Smoking cessation
  • Medications
    • Metformin
    • Thiazolidinediones and α-glucosidase inhibitors up-and-coming
  • Screening
    • Overweigh/obese patients
    • Above age 40
    • Otherwise high risk
45
Q

Type I vs Type II Diabetes table

A
46
Q

Who needs exogenous insulin?

A

All type I diabetes patients

Many type II diabetes patients

47
Q

Properly injecting insulin

A
  • May use a vial and syringe, insulin pen, or insulin pump
  • Inject subcutaneously in abdomen, thigh, buttocks, or upper arm
  • Correct dosage depends on insulin-to-carbohydrate ratio
    • ​Consequently, there is an insulin correction/sensitivity factor, which which represents the drop in blood glucose (in mg/dL) after injecting 1 unit of insulin
  • Prandial insulin is taken with a meal to help carb absorption
  • Correctional insulin is taken to prevent hyperglycemia
  • Time until onset, peak action, and duration vary with the type of insulin injected

HMS Homeostasis II (35 decks)

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