Type 1 & Type 2 Diabetes Flashcards
1
Q
What are the 2 metabolic pathways?
A
1) Anabolic pathways:
* synthesis of large molecules from small molecules (e.g. protein and glycogen synthesis)
* require energy (ATP)
2) Catabolic pathways:
* break down of large molecules to small molecules
* release energy (ATP) e.g. respiratory chain; oxidative
phosphorylation
2
Q
Anabolic hormones:
A
build fuel stores (insulin, growth
hormone)
3
Q
Catabolic hormones:
A
break down fuel stores (glucagon, cortisol, epinephrine)
4
Q
Glucose is the circulating form.
What is the storage form & major storage site?
A
glycogen
liver
5
Q
Fatty acids are the circulating form.
What is the storage form & major storage site?
A
triglycerides
adipose tissue
6
Q
Amino acids are the circulating form.
What is the storage form & major storage site?
A
proteins
muscle
7
Q
What is the absorptive (fed) state?
A
period after meal that food is digested (4-5 h)
8
Q
What is the Post-absorptive (fasting) state?
A
inter-digestive period that begins 5-6 h after meal
9
Q
What is the short and long fasting states states of Post-absorptive (fasting state)?
A
Short fasting:
Gluconeogenesis - The formation of glucose from non-hexose precursors
Long fasting:
- go to fatty acid ketones
- blood & liver
10
Q
Plasma glucose is tightly regulated by hormones:
A
- insulin, glucagon, epinephrine: fast acting (minutes)
- cortisol, growth hormone: long acting (hours)
11
Q
Normal plasma glucose:
A
3.9-8.3 mM (70-150 mg/dl)
12
Q
What is interesting about the brain?
A
- DEPENDENT on GLUCOSE as a PRIMARY energy
source (capable of using ketones e.g. fasting) - can NOT synthesize glucose
- can NOT store glycogen
13
Q
What is the #1 tissue affected when blood glucose is reduced?
A
BRAIN (b/c dependent on glucose as primary energy)
14
Q
What is the endocrine pancreas and what is each islet?
A
- Endocrine pancreas:
- 1-3% of total weight
- 0.5-1 x 106 islets
- Each islet:
- 50-500 μm diameter
- 2000-4000 cells
15
Q
β-cells (∼70%):
A
insulin, amylin
16
Q
α-cells (∼25%):
A
glucagon
17
Q
δ-cells (∼5%):
A
somatostatin
18
Q
PP cells:
A
Pancreatic polypeptide
19
Q
What is Somatostatin?
A
- found in islets (also hypothalamus, gut, stomach)
- released in response to nutrients (e.g. glucose)
- inhibitory actions on many tissues
20
Q
What is Islet amyloid polypeptide (IAPP; amylin)?
A
- co-secreted with insulin
- inhibits gastric emptying
- decreases appetite
- forms islet amyloid deposits in T2D
21
Q
What is Pancreatic polypeptide?
A
- vagal activation stimulates its secretion
- physiological role unclear - likely inhibits pancreatic
exocrine secretion
22
Q
Islets are ____ ______
A
heavily vascularized
23
Q
Blood flow within the islet is from ___-cells to ___-cells
A
β
α
24
Q
Islets innervation:
A
Both sympathetic and parasympathetic fibers
25
What is the structure of insulin?
● insulin is a 6 kDa peptide
● consists of 2 chains:
A-chain → 21 amino acids
B-chain → 30 amino acids
● A-chain and B-chain are linked by DISULFIDE BONDS
● Basic structure is highly conserved in most species e.g. beef → 2 aa pork → 1 aa
26
What is the synthesis process of insulin?
(synthesized in the:) rough endoplasmic reticulum
↓
Proinsulin
↓
proinsulin (9 kDa)
↓
Golgi apparatus
↓
insulin granules
↓
insulin and C-peptide
27
Proinsulin has __% of the bioactivity of insulin
<5&
(is much less - therefore not as effective as mature insulin)
28
What is the C-peptide?
involved in proinsulin processing
* secreted in equimolar amounts with insulin
* marker of insulin secretion from β-cells in diabetic patients
* biological action is not clear
29
How is insulin secretion regulated?
(B-cell)
stimulated by:
- nutrients (GLUCOSE, AA's, ketones)
- GI hormones (released after meal - GIP, GLP-1)
- islet hormones (glucagon)
- increase PNS
inhibited by:
- somatostatin
- increase SNS
- prolonged glucose + FFA (toxic can lead to destruction)
30
As [glucose] increases, insulin secretion ___
increases
31
What is the cellular mechanism of insulin secretion?
glucose --(glucose transporter)--> glucose --(glucokinase)--> G-6-P --> increase ATP --(inhibit)--> ATP-dependent K+ channel --> membrane depol. --(stimulate)--> voltage-gated Ca2+ channel --(stimulate)--> increase Ca2+ --(insulin vesicles)--> insulin
32
Insulin receptor is a _____ composed of two α- and β-subunits and acts as an ____ (tyrosine kinase)
glycoprotein
enzyme
33
Insulin has __ _____ _____proteins
NO plasma carrier
34
Insulin has NO plasma carrier proteins
Therefore, it has ____ plasma half-life (___ min)
SHORT
3-5 min
35
∼___% of insulin is removed during ___ pass through ___
~50%
1st
liver
36
Describe the biological effects of insulin
↓ Insulin, causes ↓ glucose
37
What are the major target tissues for insulin?
- skeletal muscle
- adipose tissue
- liver
38
Insulin ___ glucose uptake in ____ and ____ ____ by regulating glucose transporter (GLUT_)
↑
muscle and adipose tissue
4
39
Glucose transporter in LIVER (GLUT _) is ___ regulated by insulin
2
NOT
40
What is the most important hormone in ↑plasma glucose?
glucagon
41
What is glucagon?
* Glucagon is a single chain polypeptide (29 amino acids)
* Molecular weight: ∼ 3.5 kDa (small peptide)
α cells --> proglucagon --prohormone convertase 2 --> glucagon
42
What happens when glucagon attaches to the glucagon receptor?
G-protein activates Adenylate cyclase --> ATP-->cAMP --> cAMP-dependent protein kinase A --> biological effects
43
What is the regulation of glucagon secretion?
Stimulated by:
- nutrients (decrease glucose, AA's)
- hormones: GIP
- increase PNS, increase SNS
Inhibited by:
- nutrients (increase glucose, FA's)
- hormones (somatostatin, GLP-1)
44
What is the role of glucagon in glucose regulation?
* Glucagon OPPOSES the metabolic actions of insulin
* The major site of action: LIVER
* Important metabolic effects of glucagon in the liver:
- Carbohydrates
- Fat
- Protein
45
What is the regulation of blood glucose by insulin & glucagon?
* Insulin ↓ plasma glucose by promoting glucose UPTAKE & its STORAGE
* Glucagon ↑ plasma glucose by increasing liver GLUCOSE OUTPUT
46
Glucocorticoids – Cortisol (hormone in regulation of carbohydrate metabolism)
* counter-regulatory to insulin action
* contributes to maintenance of plasma glucose levels during FASTING
* mechanism: increase hepatic GLUCONEOGENESIS (counteracts insulin)
47
Catecholamines – Epinephrine (hormone in regulation of carbohydrate metabolism)
* mobilizes glucose stores
* decreases glucose uptake by liver
* inhibits insulin production
48
Glucagon-like peptide-1 (GLP-1) (hormone in regulation of carbohydrate metabolism)
* an incretin hormone released by small intestine
* stimulates insulin release from β-cells
* promotes β-cell proliferation
* suppresses glucagon release
* slows gastric emptying and glucose absorption
* stimulate satiety centre
49
Growth hormone (hormone in regulation of carbohydrate metabolism)
* antagonizes insulin effect
* inhibits insulin action
* decreases glucose uptake
50
Primary β-cells occasionally ____.
replicate
51
In a normal person there is a ____ BALANCE between
β-cell replication and β-cell death.
TIGHT
52
Any factor that INCREASES the RATE of β-cell DEATH will cause ______.
diabetes
53
What is Diabetes Mellitus?
Diabetes is a chronic metabolic disorder characterized by hyperglycemia resulting from IMPAIRED INSULIN SECRETION and/or ACTION.
* Diabetes = “siphon” or “running through”
* Mellitus = sweet
54
What is the MOST common endocrine disorder?
diabetes mellitus
55
What is the prevalence of diabetes?
* ~463 million people suffer from diabetes in the world
* Over 2 million Canadians have diabetes
* Currently, 1 in 3 Canadians has diabetes or prediabetes
* Diabetes contributes to death of >40,000 Canadians per year
* Financial burden of diabetes and its complications is about $3.6 billion/year in Canada
56
What is the mechanism of hyperglycemia in diabetes?
* Absolute (T1D) or relative (T2D) insulin deficiency
1) Increase in hepatic glucose output
2) Decrease in glucose uptake
57
Type 1 diabetes:
* juvenile onset, ketosis-prone diabetes
* previously named INSULIN-DEPENDENT diabetes mellitus
(IDDM)
* usually occurs <30 years
* incidence: ~1:250
* 10% of diabetic cases
* due to AUTOIMMUNE destruction of β-cells
* involves both GENES and ENVIRONMENTAL factors
58
T1D is an autoimmune disease:
* T lymphocyte infiltration of islet (INSULITIS)
* Several circulating islet cell ANTIBODIES (ICAs) against β-cell proteins (e.g. insulin, GAD) are produced
* Associated with other autoimmune diseases (e.g. Hashimoto’s thyroiditis)
59
T1D has an environmental component:
* Viruses associated with T1D (e.g. coxsackie virus B4, mumps, rubella)
* Diet associated with T1D (e.g. infants fed cow milk)
60
T1D has genetic component:
* Many GENETIC loci associated with T1D were identified
* Close association with major histocompatibility complex (MHC) class II
* MHC genes encode human leukocyte antigens (HLAs) => presentation of antigens to the immune system
* HLA-DR or HLA-DQ alleles can predispose or protect e.g. HLA-DR4 => ~10X increase risk
61
What are possible triggers of autoimmunity in T1D?
* Molecular mimicry:
Immune system by mistake attacks β-cell proteins
that share structural similarity with foreign antigen.
* Bystander activation:
Islet inflammation stimulates activation of β-cell
specific T cells (e.g. viral infections)
* beta-cell apoptosis:
- environmental trigger of β-cell death (e.g. virus) - phagocytosed by antigen presenting cells (APCs) - present β-cell antigens to immune system
- initiate immune response
62
Role of T cells in β-cell destruction in T1D:
* Both CD4+ (helper) and CD8+ (cytotoxic) T cells are involved
* T cells that recognize β-cell antigens (e.g. GAD, insulin) are
found in islets during T1D
* β-cell specific CD8+ cytotoxic T cells are the major cell type contributing to β-cell death in T1D
63
Type 2 diabetes:
* Adult-onset, ketosis-RESISTANT diabetes
* Previously called non-insulin-dependent diabetes
(NIDDM)
* Typically patients are >45 years
* Increasing in children (associated with obesity)
* Incidence: 1 in 20
* 90-95% of diabetic cases
* Symptoms can be absent or minimal (SLOW ONSET)
* Patients are usually OVERWEIGHT (70-80%)
64
Genetic and environmental factors both contribute to pathogenesis of T2D:
* Genetic component:
- about 100% concordance in monozygotic twins
- frequent in certain ethnic groups
* Environmental component:
- associated with sedentary life style and high fat
65
Multiple genes are involved in pathogenesis of T2D:
Rare single gene mutations:
- insulin receptor
- mitochondrial DNA
- proinsulin
- prohormone convertase 1
- leptin
- PPAR (peroxisome proliferator-activated receptor)
* Mature onset diabetes of the young (MODY), autosomal dominant, early onset T2D
66
T2D is associated with defects in...
BOTH insulin action (↑insulin resistance) and insulin secretion
67
Early diabetes:
“impaired glucose tolerance (IGT)”
* abnormal OGTT but normal fasting glucose
* treated with diet and exercise
68
Overt, but mild, diabetes:
* moderate fasting hyperglycemia (∼7 mM)
* insulin resistance present
* insulin secretion present but insufficient
* treat with exercise, diet, oral hypoglycemic drugs
69
Advanced diabetes:
* severe fasting hyperglycemia (>9 mM)
* insulin secretion greatly impaired (β-cell failure)
* patients often require insulin therapy
70
What are possible causes of progressive B-cell failure in T2D?
* Glucolipotoxicity:
Prolonged exposure to high levels of glucose and free fatty acids is toxic to β-cells
* β-cell exhaustion:
Islet β-cells become "exhausted” in the presence of increasing insulin resistance and hyperglycemia.
* Islet amyloid deposits:
Toxic amyloid deposits formed by aggregation of islet amyloid polypeptide (IAPP; amylin) are found in most patients with T2D
* Islet inflammation:
Growing evidence suggests that islet inflammation plays a key role in pathogenesis of T2D
71
In healthy individuals ∼50% of total daily insulin is secreted during ___ periods, which suppresses lipolysis, proteolysis, and glycogenolysis.
BASAL
72
The remainder of insulin secretion is postprandial. Insulin is released from islet β-cells in a ______ manner in response to ______ arterial _____ concentration.
biphasic
increased
glucose
73
1st phase consists of a ____ spike lasting ∼10 min followed by 2nd phase, which reaches _____ at 2–3 hrs.
brief
plateau
74
In response to a meal, there is a _____ release of pre- formed insulin stored in β-cell granules.
RAPID
75
This "first phase" of insulin release ____ peripheral use of prandial nutrients, inhibits hepatic glucose production, thereby limits postprandial glucose increase.
promotes
76
The first-phase insulin secretion BEGINS WITHIN 2 ____ of nutrient ingestion and continues for 10 to 15 minutes.
minutes
77
The second phase of prandial insulin secretion follows, and is sustained until ______ is restored.
normoglycemia
78
It is widely believed that _____ first and second phase insulin release are ____ in patients with T2D.
BOTH
impaired
79
Evidence suggests that impaired insulin release in T2D occurs:
- at early stages of diabetes
- precedes insulin resistance
- represent primary genetic risk factor predisposing
to T2D
80
The number of islet resident _____ is ELEVATED in pancreatic islets from patients with T2D
macrophages
81
Chronic inflammation in T2D:
● Islet amyloid formation is a pathologic characteristic of patients in T2D.
● Islet amyloid is formed by aggregation of the β-cell hormone islet amyloid polypeptide (IAPP) or amylin.
● Amyloid formation contributes to islet inflammation in patients with T2D.
82
_____ formation contributes to islet inflammation in patients with T2D.
amyloid
83
What is the proposed role for Fas receptor in β-cell death in T2D?
* Normal β-cells do not express cell death Fas receptor at detectable levels.
* β-cells normally do express Fas ligand.
* Expression of Fas receptor is up-regulated in β-cells in conditions that cause β-cell stress such as exposure to cytokines or elevated glucose.
84
Progressive LOSS of pancreatic __-cells is the major problem in both T1D and T2D although the underlying mechanisms are different.
β
85
β-cell apoptotic factors in T1D and T2D:
1. high glucose
2. high FFAs
3. cytokines
4. islet amyloid (only T2D)
5. damage of exocrine pancreas
86
What is the main risk factor for T2D (slide 71 has all)
overweight or obesity (ABDOMINAL obesity)
(**increase risk if you have this over someone else)
87
What is the diagnosis of diabetes?
* Fasting plasma glucose (FPG) ≥7.0 mmol/L Fasting: no caloric intake for at least 8 hours
* A1C ≥6.5% (in adults)
* 2 h plasma glucose (PG) in a 75 g OGTT ≥11.1 mmol/L
OGTT: oral glucose tolerance test
* Random PG ≥11.1 mmol/L
Random: any time of the day, without regard to the interval since the last meal
88
In the ABSENCE of symptomatic HYPERGLYCEMIA, if a SINGLE LAB TEST result is in the diabetes range, a _____ confirmatory lab test (FPG, A1C, 2hPG in a 75 g OGTT) MUST be done on another day.
repeat
*need 2 measurements on 2 diff. days for confirmation of diabetes
89
What are the acute complications of diabetes?
* glucosuria: glucose appears in urine
* polyuria: frequent urination
* polydipsia: excessive thirst
* polyphagia: excessive food intake
* ketoacidosis
↓insulin→↑lipolysis→↑fatty acids→liver→ketones
90
What are chronic complications of diabetes?
* Neuropathy:
- loss of sensation due to damage of
nerve fibers (e.g. heat, cold, pain)
- high blood glucose changes the metabolism of nerve cells
- reduced blood flow
* Nephropathy:
- has a slow onset
- may result in severe kidney failure
- patients may need dialysis or kidney transplant
* Cardiovascular disease: - atherosclerosis
- high blood pressure
- myocardial infarction
* Retinopathy: damage of retina
* Cataract: damage of lens
- Both may cause BLINDNESS
91
Treatment strategies for T1D:
Insulin therapy
* patients with T1D need exogenous insulin
* insulin can not be administered orally
* insulin preparations:
porcine, bovine & **recombinant human insulin
* inhaled powder insulin
92
Who discovered insulin?
Drs Banting & Best (took out dog's pancreas - became diabetic)
a kid with T1D was underweight and then a year later with insulin therapy gained weight b/c insulin is a growth factor as well
93
What is an advantage & disadvantage of Islet transplantation in T1D?
* Advantage: provides an ENDOgenous source of insulin
* Disadvantage: requires life-time immunosuppressive therapy
94
What are the treatment strategies for T2D?
* START with DIET modifications and exercise for weight loss (weight loss+ regular exercise:↓risk of progression).
* If not effective, treat with oral anti-hyperglycemic agents (e.g. metformin).
* If blood glucose is not controlled by oral agents, insulin therapy is needed.
* Individualize therapy choice based on characteristics of the patient and the agent.
* Choose initial therapy based on blood glucose level.
* Reach target within 3-6 months of diagnosis.
95
What is Gestational diabetes?
* It develops during pregnancy
* Typically occurs in week 24 - 28 of gestation
* Higher risk of developing T2D in future
* Physiological state of insulin resistance requiring higher
insulin levels during pregnancy
* Placental hormones provoke ↑blood glucose which can affect
growth and welfare of baby
* Most cases are asymptomatic
* Resolves after pregnancy
96
What are complications of gestational diabetes for the mother?
* high blood pressure
* pre-eclampsia (a serious complication of pregnancy
that can threaten lives of both mother and baby)
* major symptoms:
- hypertension
- proteinuria (protein in urine) - edema of hands and feet
* risk of future gestational diabetes or T2D
97
What are complications of gestational diabetes for the baby?
* excessive birth weight (macrosomia)
* early (preterm) birth and respiratory distress syndrome
* low blood glucose (hypoglycemia)
* seizures (due to severe episodes of hypoglycemia)
* risk of T2D later in life
98
Insulin excess is characterized by _______
HYPOglycemia (↓blood glucose levels)
99
What are common causes & major symptoms of hyperinsulinemia?
* Common causes:
- high dose of insulin
- β-cell tumors
* Major symptoms:
- depressed brain function
- unconsciousness
- death
100
What is the Dawn Effect?
* RISE in the BLOOD GLUCOSE in early morning caused by counter-regulatory hormones.
* Leads to ELEVATED FASTING blood glucose (FBG) in T1D and T2D patients.
* Results in body needing MORE INSULIN in early morning.
* Detected by SELF-MONITORING blood glucose (SMBG) at EARLY morning (2-3 am).
