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Endocrinology 1 > Beta Cell Physiology > Flashcards

Beta Cell Physiology Flashcards

1
Q

What are the characteristics of glucose-induced insulin release?

A

beta cells release insulin in response to glucose

glucose concentration dependence

ED50 (effective dose) = 150mg/dL (8.3mM)

threshold for glucose release = 72mg/dL (4mM)

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2
Q

What are the dynamics of glucose-induced insulin release?

A

1st phase = rapid release phase

  • readily releasible insulin from granules
  • changes in ions and membrane potential

2nd phase = priming phase

  • changes in biochemical pathways and activation of kinases
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3
Q

What is the glucose ‘priming’ of insulin release?

A

phenomenon in which beta cell responds to changes in glucose in incremental levels leading to an amplification of response

low glucose = ED50 = 8.3mM

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4
Q

what is insulin release like in vivo? How frequent? where does it occur most? How is it associated with type 2 diabetes?

A

pulsatile release

  • descrete insulin secretory burst that occur every 4-6mins in humans
  • most notable in portal circulation
  • increased insulin secretion results increased size or mass of insulin burst and increased frequency
  • regulated by neuronal, humoral, and metabolic mechanisms

Type 2 diabetes

  • associated with decreased mass of insulin burst, not a change in frequency of release - no change in frequency
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5
Q

How do human islets differ structurally from rodent islets?

A

rodent type 2 diabetes:

  • do not form any amyloid plaques
  • innervation punctates throughout islets and beta cells via direct innervation

human islets:

  • variation of amylin gene and get amyloid plaques, which is a marker of beta cell stress and diabetes
  • glucagon throughout islets
  • in human islet, focal innervating blood vessels
  • innervation affecets blood flow
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6
Q

What is the mechanism of glucose-induced insulin release?

A

coupled metabolism of glucose to insulin secretion

  1. glucose enters via GLUT1
  2. phosphorylated by glucokinase (**rate limiting for glucose-induced insulin release; glucose sensor in the beta cell due to being rate-limiting step of glycolysis of beta cells)
  3. pyruvate enters mitochondria and to TCA cycle with NADH
  4. TCA cycle increases ATP/ADP ratio
  5. increased ATP/ADP ratio closes K+-ATP channel
  6. depolarization of the cell
  7. depolarization leads to calcium influx via L-type voltage gated calcium channels
  8. calcium activates kinases
  9. mobilization of insulin granules and insulin release
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7
Q

How do sulfonylurea receptors affect the K+-ATP channel in terms of glucose-induced insulin release?

A

Sulfonylurea part of K+/ATP channel receptor

  • directly closes channel, depolarizing the cell, opening the voltage gated calcium channels
  • you don’t have to have glucose on board to stimulate insulin release **
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8
Q

Describe how glucokinase is the ‘glucose sensor’ in beta cells.

A

rate-limiting step of glycolysis in beta cells

Km of glucokinase for glucose is same as ED50 for glucose-induced insulin release = 8.3mM of glucose

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9
Q

How are the K+-ATP channel and sulfonylurea receptors?

A

K+-ATP Channel

  • ion pore is a tetramer of inward rectifying K+ channel
  • binds and closes in response to ATP binding site
  • each Kir6.2 subunit interacts with a regulatory sulfonylurea receptor (SUR) 1 subunit

Sulfonylurea receptor

  • binds sulfonylureas and closes the K+-ATP channel; stimulates insulin release independent of glucose concentration

* class of drugs do not have a wide therapeutic threshold and can cause hypoglycemia

  • binds diazoxide and opens the K+-ATP channel
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10
Q

What are other stimulators and modulators of insulin release?

A
  1. metabolized sugars (N-acetylglucosamine, fructose, mannose, galactose)
  2. Amino acids, fatty acids
    - require metabolism: arginine, leucine, lysine
    - metabolized and GPCR (GPR40) [trying to target and promote insulin release]: palmitate and oleate
  3. neuronal modulators
    - stimulators - ACh in human islets insulin release is likely increased due to increased blood flow
    - inhibitors - NE (receptor dependent) and somatostatin
  4. Gastrointestinal peptide hormones/incretins
    - stimulators - glucagon-like peptide 1(GLP-1) and glucose-dependent insulinotropic peptide (GIP) *great targets (require glucose) and do not necessarily cause hypogycemia
    - inhibitors - galinin, somatostatin
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11
Q

What is glucagon-like peptide 1 (GLP-1)?

A

incretin - released from L cells located in duodenum - activate w/ meal and preps beta cells for oncoming glucose

  • potentiates glucose-induced insulin release and increases beta cell neogenesis in experimental models

increases GLUT2 and insulin gene transcription

therapeutic problems: injection and turned over quickly in blood

Exendin 4 - analog from the Gila monster = Exenatide longer half life and potentiates insulin release

Dipeptidyl peptidase 4 (DPP4) inhibitors are designed to extend GLP-1 half life - block enzyme in plasma that turns over GLP-1

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12
Q

How do does acetylcholine affect glucose induced insulin release using second messengers?

A
  1. ACh binds to receptor
  2. activates phospholipase C
  3. generates DAG and IP3
  4. activates protein kinase C
  5. causes changes in calcium
  6. protein phosphorylatin
  7. potentiates glucose-induced insulin release

**ACh on its own does not increase insulin

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13
Q

How do does GLP-1 affect glucose induced insulin release using second messengers?

A
  1. binds to a GPCR
  2. activates Gs
  3. increase cyclic AMP (cAMP)
  4. activates protein kinase A and cAMP Exchange Factor
  5. potentiates glucose-induced insulin response
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14
Q

How is insulin biosynthesis regulated by glucose?

A

in general, glucose increases the biosynthesis of insulin

  • glucoses increases insulin mRNA stability by making more of the peptide; mRNA will be around longer and will be transcribed/translated more effectively
  • glucose increases the rate of insulin mRNA translation into insulin peptide
  • glucose increases insulin gene transcription

* involves the activation of beta cell specific transcription factors - Pdx1, beta2, and MafA

  • selective in beta cells and bind to genes that are important in pancreatic beta cells and regulates their transcription
  • what dictates whether a beta cell becomes a beta cell or not
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15
Q

What happens if you knockout Pdx1 in a rodent or have 2 defective copies of Pdx1 alleles in humans?

A

animal is born without a pancreas

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16
Q

What is the development of different cell types in pancreas?

A

endoderm progenitor -> pancreatic progenitor (Pdx1) -> endocrine progenitor (Ngn3) -> w/ Pdx1/beta2 and MafA -> beta cells

after Ngn3 -> w/ Arx/MafB -> alpha cells

17
Q

What are the mechanisms by which islet-enriched transcription factors may impact functional beta cells?

A

islet-enriched transcription factor (Pdx1)

  • > expression of other islet-enriched transcription factors (MafA)
  • > increase beta cell proliferation
  • > decrease beta cell apoptosis
  • > increase beta cell differentiation via hormone expression, processing, secretion; glucose and nutrient sensing (via MafA)
18
Q

What is maturity-onset diabetes of the young (MODY)?

A

heterogenous monogenic form of diabetes

autosomal dominant inheritance

onset of diabetes occurs at a young age (<25yrs of age)

defect in insuolin secretion

19
Q

What is the most common genetic loci associated with MODY?

A

MODY3 due to HNF-1 alpha

islet-enriched transcription factor, regulates gene expression of metabolic genes and insulin

20
Q

What is MODY2? MODY4? MODY6?

A

MODY2 = gene locus: glucokinase

  • rate-limiting step for glucose metabolism in beta cells

MODY4 = gene locus: Pdx1

  • islet-enriched trasncription factor, regulates pancreas development and beta cell differentiation, key regulator of insulin gene expression

MODY6 = gene locus: beta2

  • islet-enriched transcription factor, regulates insulin gene expression
21
Q

What are the genetic loci that are associated with monogenic forms of neonatal diabetes that are very severe?

A

KCNJ11 = inward rectifying K+ channel, K+-ATP channel

ABCC8 = sulfonylurea receptor

Glucokinase = rate-limiting step for glucose metabolism in beta cells, homozygous mutation

* different mutations in these genes can also cause persistent hyperinsulinemia hypoglycemia of infancy

22
Q

What is persistent hyperinsulinemia hypoglycemia of infancy?

A

activates insulin release pathway

diagnosed <1yr of age

characterized by uncontrolled insulin release and dangerous hypoglycemia

due to closure of channel and unregulated insulin release = ABCC8 (sulfonylurea receptor, autosomal recessive) and KCNJ11 (inward rectifying K+ channel, K+=ATP channel, autosomal recessive)

due to mutations leading to glucokinase gain of function = glucokinase (rate-limiting step for glucose metabolism in beta cells, autosomal dominant)

23
Q

What are the treatments of persistent hyperinsulinemia hypoglycemia of infancy?

A

dextrose infusion

diazoxide (opens K+-ATP channel)

nifedipine

somatostatin analogs - block insulin release

glucagon - block insulin release

partial pancreatectomy

24
Q

How do pancreatic beta cells fail in type 2 diabetes?

A

Predisposing genes (obesity, beta cell capacity [mass], insulin resistance) AND environment (physical activity [less] and abundance of food [bad food]) -> insulin resistance

  • > beta cell compensation (beta cell hypertrophy and hyperplasias; increased basal insulin release) -> mild hyperglycemia/hyperlipidemia/hyperinsulinemia
  • > beta cell decompensation (reduced glucose-induced insulin release, reduced insulin release to non-glucose secretagogues, depletion of insulin stores, reduced beta cell mass (apoptosis)
  • cannot release enough insulin-> diabetes mellitus (hyperglycemia, relative hypoinsulinemia)
25
Q

What are the modulating factors of type 2 diabetes?

A

peak beta cell mass

genetics

in utero environment

diet/nutrition

26
Q

Describe normal adipose tissue and how it relates to normal glucose tolerance.

A

pre-adipocytes -> mature adipocytes

muscle and liver response:

increase adiponectin

decrease leptin

decrease resistin

decrease TNF

decrease IL-6

decrease MCP-1

Normal insulin sensitivity AND normal beta cell composition -> normal glucose tolerance

27
Q

Describe dysfunctional adipose tissue and how it relates to type 2 diabetes?

A

pre-adipocytes -> hypertrophic adipocytes (large, storing a lot of lipid, but limited ability to store lipid), necrotic adipocytes (adipocytes become inflamed), increased macrophages

  • > ectopic fat (starts storing lipid in muscle and liver and is associated with dysfunctional tissue)
  • > decrease adiponectin, increase leptin, increase resistin (causes insulin resistance), increase TNF, increase IL-6, and increase MCP-1 (promotes and brings in macrophages and T cells to stimulate tissue inflammation)

impaired beta cell compensation AND insulin resistance -> type 2 diabetes

28
Q

What are the proposed mechanisms for beta cell dysfunction?

A
  1. glucose toxicity, glucolipotoxicity = oxidative stress, altered glucose handling, accumulation of triacylglyceride and long chain fatty acids, reduction in expression of beta cell selective genese including: insulin, Pdx-1, MafA [sensitive to hyperglycemia, decreased expression], endoplasmic reticulum (ER) stress - unfolded protein response
  2. islet amyloid (IAPP or amylin) = intracellular oligomers (accumulates inside beta cells during T2D), ultimately leading to extracellular plaques
  3. islet inflammation = see more macrophages and T cells
  4. incretin hormone dysregulation = no longer responding as well to GLP-1 or relase of GLP-1 is altered
  5. insulin resistance = beta cells themselves have insulin receptors that can become insulin resistant and causes beta cell dysfunction
29
Q

What is the natural history of beta cell oss in type 1 diabetes?

A
  1. genetic predisposition
  2. precipitating event triggers immune system alterations
  3. overt immunologic abnormalities, but normal insulin release as beta cell mass decreases
  4. progressive loss of insulin release, glucose normal; beta cell mass continues to decrease
  5. C-peptide present, but overt diabetes; beta cell mass almost completely depleted
  6. no C-peptide, loss of glycemic control; beta cell mass completely depleted
30
Q

What did the diabetes control and complications trial find?

A

demonstrated that the incidence and severity of diabetes complications are relative to the degree of glycemic control

  • conventional treatment with insulin vs. tight-controlling regulation of blood glucose

tighter the glycemic control, the lower the incidence and severity of complications

the DCCT results support the notion that beta cell replacement therapies may be employed to prevent diabetic complication

31
Q

What are the problems of a pancreas transplantation surgery?

A

transplant kidney AND pancreas

highly invasive surgery, requires immunosuppression

32
Q

What changed in islet transplantation from before to the edmonton trial?

A

6% successful before:

Edmonton trial: 800,000 islets injected into the portal vein to regulate blood glucose levels, would lodge in the liver to do so

  1. multiple transplantations/multiple donors
  2. no glucocorticoids (nasty on pancreatic beta cells)
  3. lower levels of FK506 (tracrolimus)
    - additional problems: 1.7mil w/ T1D, only 5000 suitable pancreases/yr
33
Q

What is the recent advancement in making surrogate pancreatic beta cells?

A

Approach: introduced Pdx1, MafA, and Ngn3 into cultured pancreatic acinar cells

Accomplishment: produced insulin secreting cells that corrected hyperglycemia when transplanted in type 1 diabetic mice

Endocrinology 1 (17 decks)

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