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Williams: Disorders of Carbohydrates and Fat Metabolism > IV. Type 1 Diabetes Mellitus > Flashcards

IV. Type 1 Diabetes Mellitus Flashcards

1
Q

German pathologist who, in 1902, noted a small peri-islet cellular infiltrate on microscopic evaluation of the pancreas obtained at autopsy from a 10-year-old child with diabetes

A

Martin Schimdt

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2
Q

Who, in the 1920’s, drew attention to the relationship between the peri-islet infiltrate and the age of diabetes onset

A

Shields Warren

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3
Q

Pathologist who coined the term insulitis

A

Hanns von Meyenburg

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4
Q

Who won the Nobel Prize for purifying insulin from animal pancreata in the 1920’s

A

Banting and Best

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5
Q

4 islet cell autoantibodies / T1DM-associated autoantibodies

A

Anti-insulin autoantibodies (IAA)
Anti-glutamic acid dexarboxylase (GADA)
Anti-insulinoma-associated antigen 2 (IA2A)
Anti-zinc-transporter 8 (ZnT8A)

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6
Q

2 peaks of T1DM presentation in childhood and adolescence

A

A smaller peak between 5 and 7 years of age and a larger peak at or near puberty

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7
Q

Sex that is slightly more affected in T1DM

A

Males

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8
Q

Incidence of T1DM diagnosis is higher during these seasons

A

Autumn and winter

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9
Q

Being born in this season is associated with an increased likelihood for T1DM

A

Spring

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10
Q

TRUE or FALSE: T1DM patients can manifest insulin resistance.

A

TRUE

T1DM patients may present with diabetes characterized by high serum levels of fasting insulin or C-peptide but loss of stimulated insulin secretion.

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11
Q

TRUE or FALSE: Among African-American and Latino children and adolescents in the United States diagnosed with diabetes, almost one half lack any T1DM-associated autoantibody.

A

TRUE

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12
Q

T1D, T2D, both, or neither?

a. Rapid onset with very high to extremely high blood glucose levels, polyphagia, polydipsia, polyuria
b. Family history of autoimmune disease
c. Can be prevented
d. Can be reversed
e. Acute emergencies of hypoglycemia and ketoacidosis leading to hypoglycemic unawareness

A

a. T1D
b. T1D
c. T2D
d. Neither
e. Both

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13
Q

The most intensively studied animal model for T1DM

A

Nonobese diabetic (NOD) mouse

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14
Q

Findings of the Nonobese Diabetic Mouse Model

A

Same as with humans:

  • Housing conditions (i.e., environment) represent an important variable
  • Polygenic
  • Both destruction and replication/regeneration are present months before the onset of T1DM

Different from humans:

  • Strong female bias with respect to disease
  • T cells, not autoantibodies, appear to mediate the beta cell destruction
  • Insulitis lesion, the hallmark facet of T1DM, appears more intense and quantitatively obvious
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15
Q

Drug that is directly toxic to islet beta cells

A

Streptozotocin

In high doses, it rapidly induces diabetes. In low doses, a more chronic diabetes develops.

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16
Q

Histologic features of islet cells in T1D

A
  • Insulitis (mixed mononuclear, adjacent or within islet)
  • Loss of beta cells (increase with disease duration)
  • Hyper-expression of class I MHC
  • Beta cell necrosis/apoptosis (?)
  • Diminished insulin in remaining beta cells
  • Beta cell expression of interferon alpha
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17
Q

TRUE or FALSE: A more vigorous autoimmune response occurs when disease develops in young children.

A

TRUE

Immunoype as a function of age:
Younger age of onset associated with higher levels of CD20+ B cells, CD45+ cells, and CD8+ T cells, alongside fewer insulin-positive islets.
Older age at onset associated with lower levels of CD45+ cells and CD8+ T cells, as well as more insulin-positive islets.

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18
Q

Predominant immune cells in insulitic lesions

A

CD8+ T lymphocytes and macrophages

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19
Q

Definition of “insulitis”

A

Lesion of 3 islets containing more than 15 CD45+ cells in a pancreas

(defined by nPOD - Network for Pancreatic Organ donors with Diabetes)

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20
Q

TRUE or FALSE: The inflammation seen in type 1 diabetes spares the exocrine pancreas.

A

FALSE

Chronic inflammation, including enhanced CD8+ T-cell infiltration, is present in the exocrine pancreas in T1DM subjects. (appears to be subclinical)

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21
Q

What is “pseudoatrophic”?

A

Term that refers to remaining islets (alpha, delta, pancreatic polypeptide) that lack insulitis and beta cells

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22
Q

TRUE or FALSE: There is a notion that T1DM is a relapsing/remitting disease, with waves of immunologic destruction.

A

TRUE

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23
Q

Hypothesis for reduced pancreatic weight in T1D

A

Resulted from loss of insulinotrophic effects on the exocrine pancreas, as islets constitute only 1-2% of the entire pancreatic volume

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24
Q

Gross pathologic characteristics of the pancreas in T1D

A
  • Decreased overall weight
  • Atrophy of dorsal region
  • Exocrine atrophy
  • Hydrophic change (hypertrophy) (?)
  • Composed of pseudoatrophic (glucagon staining) islets in type 1D
  • Lobular loss of beta cells
  • Heterogenous lobular insulitis
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25
Q

2 main mechanisms of beta cell death in T1DM

A

Necrosis and Apoptosis

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26
Q

4 mediators of necrotic cell death in T1DM

A

T cells can induce necrosis following a release of cytolytic granules containing granzymes and perforin, which act on the beta cell membrane

Ischemia which may result from hyperexpression of extracellular matrix materials

Reactive oxygen species

Necrosis of beta cells may release factors, including post-translationally modified antigenic peptides or modifications of “normal” antigens that further stimulate the immune response and thereby perpetuate beta cell death by necrosis

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27
Q

Mediators of apoptosis in T1DM

A

Janus kinases (JAK1, JAK2) and nonreceptor tyrosine-protein kinase (TYK2) pathways

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28
Q

In the 25-year old concept of the natural history of T1DM, symptoms of the disease were thought to appear when __ to __% of pancreatic beta cells had met their demise.

A

85 to 90%

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29
Q

Steps in the 25-year old concept of the natural history of T1DM

A
  1. Precipitating events may occur in utero
  2. Genetic predisposition likely the key driver or linkage to immune abnormalities
  3. Beyond “precipitating”, environment may influence entire natural history
  4. While overall loss of beta cells is potentially linear, may be relapsing/remitting
  5. Multiple islet autoantibodies (>=2) may represent “Asymptomatic” T1D
  6. Increasing glucose excursions as one approaches symptomatic onset
  7. Some T1D patients produce low-level C-peptide long after onset
  8. Beta cell mass not always zero in long-standing patients
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30
Q

Pivotal discovery from combined analysis of data generated in the BABYDIAB, DAISY, and DIPP studies

A

Once two or more anti-islet autoantibodies are present in a given individual, the individual’s 10-year risk for developing diabetes ranges from 60% in older seroconverters (>3 years) to 75% in those who seroconvert before 3 years of age.

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31
Q

Table 36.2 T1DM Clinical Research Consortia and Natural History Trials, page 1409

A

*

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32
Q

TRUE or FALSE: Most persons (>85%) in whom T1DM develops have a first-degree relative with the disease.

A

FALSE

Most persons (>85%) in whom T1DM develops DO NOT have a first-degree relative with the disease.

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33
Q

2 countries with highest incidence of T1DM

A

Finland and Sardinia

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34
Q

Percentage risk of T1DM in families

A
  • Monozygotic twin 50%, but incidence varies with age of index twin
  • Dizygotic twin 6%
  • Sibling 3.2% (through adolescence); 6% lifetime
  • Both parents ~10%
  • Father 4.6%
  • Mother 2%
  • Offspring 1%
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35
Q

Progression of disease among discordant monozygotic twins, based on the period of discordance and the age at which the disorder developed in the index twin

A

The hazard rate for development of diabetes decreased as the period of discordance increased.

If T1DM developed in the index twin after age of 25 years, the concordance rate was <10%. If it developed in the index twin before age 5 years, the concordance rate was 70% after 40 years of follow-up.

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36
Q

The most important loci determining the risk of T1DM reside within the ___ on chromosome ___ and, in particular, the ___ molecules.

A

The most important loci determining the risk of T1DM reside within the MHC on chromosome 6p21 and, in particular, the MHC class II molecules (DR, DQ, and DP).

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37
Q

2 molecules which are the major determinants of T1DM susceptibility

A

DR and DQ

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38
Q

Molecules that provide dominant protection from T1DM

A
  1. HLA-DQA101:02-DQB106:02 (termed DQ6)
  2. HLA-DRB1*14:01
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39
Q

The protective haplotype HLA-DRB115:01-
DQA101:02-DQB1*06:02 is present in __% of the general population and in fewer than __% of patients with T1DM.

A

20%
3%

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40
Q

Simple rule regarding determination of high-risk haplotypes

A

The presence of aspartic acid at position 57 of the DQbeta chain and arginine at DQalpha 52 is associated with T1DM risk.

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41
Q

TRUE or FALSE: The longest group of nucleotide repeat elements located upstream (also known as 5’) of the insulin gene was associated with decreased diabetes risk.

A

TRUE

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42
Q

Third confirmed gene (vs. mere loci) influencing T1DM risk

A

PTPN22

A gene encoding a lymphoid-specific phosphatase that influences T-cell receptor signaling

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43
Q

The most characteristic difference related to age at diabetes onset

A

Presence of higher levels of IAA in children who develop the disease at an early age (e..g, <5 years).

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44
Q

The best single marker for diabetes development in young children

A

Anti insulin antibodies (IAA)

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45
Q

In those children in whom autoantibodies arise during the first 3 years of life, ___ often appear first. In contrast, ___ are more often positive in adults who develop T1DM.

A

IAA
GADA

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46
Q

TRUE or FALSE: Monogenic diabetes can develop spontaneously.

A

TRUE

In most cases of monogenic diabetes, the gene mutation is inherited; in the remaining cases, the gene mutation develops spontaneously.

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47
Q

2 main forms of monogenic diabetes

A

Neonatal diabetes and maturity-onset diabetes of the young, with ND far less common than MODY.

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48
Q

At what age does neonatal diabetes occur.

A

In newborns through the first 6 months of life

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49
Q

TRUE or FALSE: Neonatal diabetes is transient and usually resolves at 6 months of life.

A

FALSE

For approximately one half of those with ND, the condition is lifelong, yet for the remainder, the condition disappears during infancy but can reappear later in life.

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50
Q

Manifestations of neonatal diabetes

A

Mimic those of T1DM
May be small for gestational age (i.e., IUGR)
Protracted growth and weight gain

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51
Q

What is the most common form of neonatal diabetes mellitus?

A

Transient neonatal diabetes with mutation of ZAC/HYMAI

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52
Q

Regarding the most common form of neonatal diabetes mellitus:
a. Gene or syndrome?
b. Typical age at onset?
c. Type of inheritance?
d. Able to cause IUGR?
e. Transient or permanent?
f. Treatment?

A

a. ZAC/HYMAI
b. Birth to 3 months
c. Autosomal dominant; Spontaneous
d. Yes
e. Transient
f. Initially, treat with insulin; reduce dosage as needed; when diabetes recurs, treat with diet modification and physical activity; may also require insulin

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53
Q

Regarding the most common form of PERMANENT neonatal diabetes mellitus:
a. Gene or syndrome?
b. Typical age at onset?
c. Type of inheritance?
d. Able to cause IUGR?
e. Transient or permanent?
f. Treatment?

A

a. KCNJ11 (affecting the Kir6.2 protein)
b. 3-6 months
c. Autosomal dominant (10%); Spontaneous
d. Yes
e. Permanent
f. Treated with insulin in the past but often can be treated with oral sulfonylureas

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54
Q

TRUE or FALSE: MODY patients are generally overweight.

A

FALSE

MODY patients are generally NOT overweight.

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55
Q

Children of a MODY parent have a __% chance of inheriting the disease.

A

50%

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56
Q

Components of the Autoimmune Polyendocrine Syndrome Type 1, and the mutation

A

T1DM, mucocutaneous candidiasis, hypoparathyroidism, Addison disease, and hepatitis (MATHH)

Mutation (usually autosomal recessive) of the AIRE gene on chromosome 21 (may play an important role in maintaining self tolerance, as well as influence the expression of what immunologists term peripheral antigens (e.g., insulin) in the thymus)

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57
Q

Syndrome associated with overwhelming neonatal autoimmunity, in which most children die in the first few days of life or in infancy

A

X-Linked Polyendocrinopathy, Immune Dysfunction, and Diarrhea (Scurfy Gene)

“XPID” or “IPEX” (Immunodysregulation polyendocrinopathy enteropathy x-linked syndrome)

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58
Q

What is the mode of inheritance and mutation of XPID?

A

X-linked recessive disease affecting only boys, with a frequent clinical history of a lack of male births

Mutation of the gene encoding fork-head box P3 (FOXP3), which functions as transcription factor and master switch for regulatory (suppressor) CD4+CD25+CD127-/low T lymphocytes

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59
Q

Proven therapy of XPID/IPEX syndrome

A

Bone marrow transplantation

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60
Q

Table 36.5 Characteristics of Monogenic Diabetes, pages 1414-1415

A

*

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61
Q

Most common form of MODY

A

MODY 3

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62
Q

Second most common form of MODY

A

MODY 2

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63
Q

Only form of MODY which can cause lower than normal birth weight

A

MODY 2

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64
Q

Proteins affected by the different MODY types

A

MODY 1 - Hepatocyte nuclear factor 4 alpha
MODY 2 - Glucokinase
MODY 3 - Hepatocyte nuclear factor 1 alpha
MODY 4 - Insulin promoter factor 1
MODY 5 - Hepatocyte nuclear factor 1 beta
MODY 6 - Neurogenic differentiation factor 1

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65
Q

Mode of inheritance of all types of MODY

A

Autosomal dominant

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66
Q

Only form of MODY wherein mild hyperglycemia may be present at birth; otherwise, early childhood

A

MODY 2

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67
Q

TRUE or FALSE: All types of MODY are permanent.

A

TRUE

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68
Q

Type of MODY in which medications are usually not required

A

MODY 2

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69
Q

Type/s of MODY in which oral sulfonylureas are the primary treatment

A

MODY 1 and 4

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70
Q

Type of MODY in which the initial treatment is diet modification

A

MODY 3 (2 also)

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71
Q

Type/s of MODY in which insulin is the primary treatment

A

MODY 5 and 6

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72
Q

Summary of proteins affected and treatments of MODY

A

MODY 1 - Hepatocyte nuclear factor 4 alpha (SU)
MODY 2 - Glucokinase (Diet modification and physical activity)
MODY 3 - Hepatocyte nuclear factor 1 alpha (Diet Modification)
MODY 4 - Insulin promoter factor 1 (SU)
MODY 5 - Hepatocyte nuclear factor 1 beta (Insulin)
MODY 6 - Neurogenic differentiation factor 1 (Insulin)

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73
Q

TRUE or FALSE: No single enviromental agent has been identified in the pathogenesis of type 1 diabetes.

A

TRUE

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74
Q

The hypothesis that states that childhood obesity increases the insulin demand, overloading the islet cells and accelerating beta-cell autoimmune damage
a. Accelerator and overload hypotheses
b. Copenhagen model
c. Hygiene hypothesis
d. Fertile field hypothesis
e. Old friends hypothesis
f. Threshold hypothesis

A

A

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75
Q

The hypothesis that proposed that beta-cell destruction results from interactions between the environment, immune system, and the beta cells themselves in genetically susceptible individuals
a. Accelerator and overload hypotheses
b. Copenhagen model
c. Hygiene hypothesis
d. Fertile field hypothesis
e. Old friends hypothesis
f. Threshold hypothesis

A

B

76
Q

The hypothesis that attributes the rising incidence of autoimmune disorders to the decline in infections with reduced stimulation of the immune system
a. Accelerator and overload hypotheses
b. Copenhagen model
c. Hygiene hypothesis
d. Fertile field hypothesis
e. Old friends hypothesis
f. Threshold hypothesis

A

C

77
Q

The hypothesis that proposes that microbial infection induces a temporary state in which other antigens can more easily react to yield autoreactive T cells.
a. Accelerator and overload hypotheses
b. Copenhagen model
c. Hygiene hypothesis
d. Fertile field hypothesis
e. Old friends hypothesis
f. Threshold hypothesis

A

D

78
Q

The hypothesis that implicates dietary exposure as a possible direct regulator of the immune system and of self-tolerance by altering gut microbiota and intestinal permeability
a. Accelerator and overload hypotheses
b. Copenhagen model
c. Hygiene hypothesis
d. Fertile field hypothesis
e. Old friends hypothesis
f. Threshold hypothesis

A

E

79
Q

The hypothesis that suggests that the etiologic influences of genetics and environment, when evaluated as intersecting and reciprocal odds-ratio-based trend lines, result in a method to define the attributable risk for T1DM
a. Accelerator and overload hypotheses
b. Copenhagen model
c. Hygiene hypothesis
d. Fertile field hypothesis
e. Old friends hypothesis
f. Threshold hypothesis

A

F

80
Q

TRUE or FALSE: Environmental agents can act as both a trigger and modulator of the pathogenesis of T1DM.

A

TRUE

It is increasingly accepted that enviromental agents may contribute far beyond an initial triggering and rather act throughout the natural history of T1DM development, such as modulating the ongoing autoimmune process.

81
Q

The best evidence, if not the only strong evidence, for a specific environmental agent to contribute to T1DM pathogenesis involves ___.

A

Congenital rubella infection (mechanism currently unknown)

82
Q

Most often discussed (biologic) agents associated with T1DM

A

Entroviruses

83
Q

TRUE or FALSE: Childhood vaccine timing has been proven to influence the development of T1DM.

A

FALSE

84
Q

Dietary factor that has been associated with T1DM
a. Breastfeeding or bovine milk ingestion
b. Late (>6 months) introduction of cereals
c. High vitamin D level
d. High omega-3 fatty acids

A

A

Factors:
- Breastfeeding or bovine milk ingestion
- Early (<3 months) introduction of cereals
- Low vitamin D level
- Low omega-3 fatty acids

85
Q

TRUE or FALSE: An individual’s timeline to diabetes onset could be determined by the severity of the autoimmune attack rather than the initial beta-cell mass.

A

FALSE

An individual’s timeline to diabetes onset could be determined NOT by the severity of the autoimmune attack but the starting point for beta-cell mass.

(Beta-cell mass likely mostly determined in the first two decades of life.)

86
Q

TRUE or FALSE: Reduced weight can distinguish the pancreas of patients with long-standing T1DM from pancreas of new-onset T1DM and non-T1DM patients with anti-islet autoantibodies.

A

FALSE

Reduced pancreatic weight affects not only subjects with long-standing T1DM, but also recent-onset T1DM and nondiabetic persons with anti-islet autoantibodies.

87
Q

TRUE or FALSE: Serum levels of trypsinogen, which are indicative of exocrine pancreas function, are reduced in patients with long-standing T1DM, in those with recent-onset T1DM, and in nondiabetic individuals with anti-islet autoantibodies.

A

TRUE

88
Q

TRUE or FALSE: Most persons who are within 1 year of developing overt T1DM have no second-phase insulin secretion after intravenous glucose administration (glucose given at 0.5g/kg over 5 mins, and insulin levels measured before and 1 and 3 minutes after glucose infusion).

A

FALSE

First-phase

89
Q

TRUE or FALSE: HbA1c increases progressively (although in the normal range) 1 or 2 years before overt hyperglycemia develops.

A

TRUE

90
Q

TRUE or FALSE: Impaired fasting glucose and impaired glucose tolerance are usually present within 6 months before the onset of overt T1DM.

A

TRUE

91
Q

Why is C-peptide measured to assess remaining beta cell function?

A

Because it is released in equimolar concentrations with insulin but does not undergo hepatic extraction and has a longer half-life in circulation.

Usually measured in the fasting state, after intravenous glucagon, or with a standard liquid meal.

Associated with impressive metabolic benefit, as shown in the Diabetes Control and Complications Trial (DCCT).

92
Q

2 features that strongly indicate transient hyperglycemia instead of T1DM

A

Absence of anti-islet autoantibodies
Normal first-phase insulin secretion during an intravenous glucose tolerance test

93
Q

Most reliable predictive biomarker of T1DM identified to date

A

Seroconversion to anti-islet autoantibody positivity

94
Q

Beta-cell death assays measure ___ from blood or serum which are released from necrotic beta cells.

A

Cell-free unmethylated insulin DNA

95
Q

___ (Elevated or reduced?) serum proinsulin/C-peptide ratio measured under fasting conditions implies impaired processing of proinsulin and C-peptide within the beta cell, suggesting duress related to metabolic, oxidative, or immunologic stress.

A

Elevated

96
Q

Index60 has been introduced as a clinical/diagnostic biomarker measuring functional beta-cell mass. The test requires an OGTT with calculations incorporating the log-adjusted fasting C-peptide level, 60-minute C-peptide level, and 60-minute blood glucose level. What is the value considered indicative of T1DM onset?

A

An Index60 value greater than 2 in an individual with anti-islet autoantibodies is considered indicative of T1DM onset.

97
Q

Microbiome factors that is believed to protect against T1DM
a. High Bacteroides to Firmicutes ratio
b. Presence of butyrate-producing bacteria
c. Low diversity and poor stability of the gut microbial community

A

B

Microbiome factors that have been suggested as biomarkers of T1DM:
- High Bacteroides to Firmicutes ratio has been associated with anti-islet autoimmunity
- Presence of butyrate-producing bacteria (may protect against T1DM by promoting synthesis of mucin and reducing intestinal leakiness)
- Low diversity and poor stability of the gut microbial community are associated with T1DM

98
Q

Staging of T1DM based on the joint position of ADA, JDRF, and Endocrine Society

A

Stage 1: Presence of 2 or more anti-islet autoantibodies with normoglycemia (presymptomatic)

Stage 2: Progression to dysglycemia in the setting of 2 or more anti-islet autoantibodies (presymptomatic)

Stage 3: Meets ADA criteria for the diagnosis of diabetes (symptomatic)

99
Q

Immunosuppressive agent that has been shown to prevent further loss of C-peptide secretion and improve metabolic function when it was administered in recent-onset T1DM cases

A

Cyclosporine

100
Q

A single course of this therapy decreased the loss of C-peptide secretion over a 12- to 24-months period in new-onset T1DM patients, but didn’t go into phase III

A

Anti-CD3

101
Q

Anti-CD3 monoclonal antibody that delayed progression to clinical T1DM in high-risk patients

A

Teplizumab

102
Q

Basic concept behind the use of immunologic vaccination in preventing or reversing T1DM

A

Induction of regulatory T lymphocytes that target a given beta-cell antigen and, on encountering the target antigen (e.g., insulin, GAD) in the context of the vaccine formula or route of administration, produce cytokines and cell-mediated effects that suppress autoimmunity and tissue destruction.

103
Q

___ Route of insulin treatment that, although didn’t document an overall benefit of insulin, showed a statistically significant delay in progression to diabetes in the subgroup with higher levels of IAA at entry.

A

Oral insulin

104
Q

TRUE or FALSE: Improved results for pancreatic transplantation occur in the setting of pancreas transplantation alone versus concurrent kidney transplantation.

A

FALSE

Improved results for pancreatic transplantation occur in the setting of simultaneous pancreas and kidney transplantation versus transplantation of pancreas alone.

105
Q

TRUE or FALSE: T1DM patients who underwent pancreas transplantation can experience recurrence of diabetes.

A

TRUE

Can recur as a result of mechanisms considered attributable to either recurrence autoimmunity or, more often, allograft rejection

106
Q

What is the Edmonton protocol?

A

Protocol for islet (vs pancreas) transplant which involved meticulous islet isolation techniques, transplantation of islets from multiple pancreata, avoided the use of steroids, and utilized an immunosuppressive regimen involving the drug rapamycin and resulted in improved outcomes for patients with T1DM.

107
Q

Drawbacks and limitations of stem cell or xenogeneic islet cell transplantation

A

Quantitative paucity of suitable organ donor tissues

Complications associated with immune suppression

Beta cells do not exist in isolation but rather as part of the islets of Langerhans, and hence generating cell therapy in the absence of a full complement of islet cells must be considered in the context of hormonal counterregulation

108
Q

What is the Hirata syndrome?

A

Insulin Autoimmune Syndrome

Extremely high concentrations of autoantibodies reacting with human insulin in the absence of exogenous insulin therapy –> Hypoglycemia

Most common in Asian descent

109
Q

2 agents associated with the development of Insulin Autoimmune Syndrome

A

Sulfhydryl-containing medications, particularly methimazole
Alpha-lipoic acid

110
Q

Treatment of Insulin Autoimmune Syndrome

A

Stopping the sulfhydryl-containing medications, particularly methimazole, as well as alpha-lipoic acid

(For more than 75% of patients, the disease remits)

111
Q

TRUE or FALSE: Essentially all patients treated with recombinant human insulin produce anti-insulin antibodies.

A

TRUE

112
Q

TRUE or FALSE: Most studies show no relationship between the presence of anti-insulin antibodies and complications associated with T1DM.

A

TRUE

But there are reports correlating insulin antibodies with macrosomia.

113
Q

Usual mode of therapy for allergic reactions to insulin analogues (though most are due to allergies to lubricants, preservatives, and plastics in bottles, stoppers, syringes, and needles)

A

Substituting the type of formulation of insulin and administration of oral antihistamines or topical mast cell stabilizers for immunoglobulin E-mediated local reactions, followed by insulin desensitization or addition of small amounts of glucocorticoids to the insulin injected for local delayed hypersensitivity reactions

114
Q

Components and treatment of the syndrome of Anti-Insulin Receptor Autoantibodies

A

Hypoglycemia, hypercatabolism, severe acanthosis nigricans, and insulin resistance

Various forms of immunosuppression (mixed success)

115
Q

Peak age for presentation of T1DM

A

At or during puberty (with a smaller peak in children between 5 and 7 years of age)

116
Q

TRUE or FALSE: In children, the onset of symptoms of T1DM is insidious, whereas it can occur over a brief period in older persons.

A

FALSE

In children, the onset of symptoms can occur over a brief period, and families may be able to date the onset with considerable accuracy. In older persons with T1DM, the onset of symptoms may be insidious over months, and many are mistakenly diagnosed as having T2DM by screening during this asymptomatic period.

117
Q

On diagnosis of T1DM, the plasma glucose concentrations at presentation are usually in the range of ___ to ___ mg/dL.

A

300 to 500 mg/dL

118
Q

At the time of diagnosis, C-peptide level (a surrogate marker for insulin secretion) is generally in the ___ range and declines over time.

A

Low-normal

119
Q

In reference laboratories, pancreatic autoantibodies are present in approximately ___% of individuals at diagnosis.
a. 20%
b. 54%
c. 86%
d. 98%

A

D

120
Q

TRUE or FALSE: The likelihood for residual beta-cell function is greater with an earlier age of onset of disease.

A

FALSE

The likelihood for residual beta-cell function is greater with an older age of onset of disease.

121
Q

Frequency of initial visits for diabetes care of T1DM patients

A

Initial visits usually entail 2 to 3 sequential days of multidisciplinary visits, followed by visits in 2 to 3 weeks, then 1 to 2 months later. Thereafter, diabetes follow-up care generally occurs quarterly.

122
Q

Physical parameters to be monitored on clinic visits, and frequency

A

Weight, height, and vital signs at every quarterly visit

Tanner staging should be performed at least annually for pediatric patients

Timely screening for complications and cardiovascular risk factors

123
Q

TRUE or FALSE: In the DCCT, the conventional therapy group yielded an HbA1c that is 2% lower than the intensive insulin group.

A

FALSE

Intensive insulin therapy yielded superior control to conventional insulin therapy, with HbA1c levels that were approximately 2% lower in the intensively treated group than in the conventionally treated group (medians of 7% and 9% respectively), and also experienced a 35% to 76% reduction in the occurrence of microvascular complications, and continued to demonstrate a reduced risk of both micro- and macrovascular complications and overall mortality. (DCCT-EDIC)

124
Q

ADA HbA1c targets

A

Adults <7%
Younger children <7.5% (recently lowered with the advent of insulin analogues and the data that intensive insulin therapy confers no additional risk to neurocognitive function in young children)

125
Q

Frequency of HbA1c monitoring

A

Quarterly

126
Q

HbA1c targets by:
International Society for Pediatric and Adolescent Diabetes (ISPAD)
National Institute for Health and Clinical Excellence Guidelines (UK)
American Association of Clinical Endocrinologists

A

ISPAD <7%
NIH and Clinical Excellence Guidelines <=6.5%
AACE <=6.5%

Must be personalized and tailored to individual needs and consideration of risk of severe hypoglycemia

127
Q

Frequency of nutrition education in T1DM

A

Generally provided by a registered dietitian annually

128
Q

Principles of general nutrition in terms of standard composition of macronutrients, fat intake, and portions of fruit and vegetables

A

50% of energy intake as carbohydrate, 20% as protein, and 30% as fat

<10% of energy intake as saturated fat, <10% as PUFA, >10% as MUFA

5 portions of fruits and vegetables daily

129
Q

TRUE or FALSE: Low carbohydrate diets are beneficial in T1DM patients.

A

FALSE

Very low carbohydrates should be avoided, as such diets can lead to elevations in lipid levels and there can be risk for ketosis

130
Q

TRUE or FALSE: Strict and precise carbohydrate counting is essential.

A

FALSE

Under- or overestimating the carbohydrate content by 5 to 7 g, or by +/- 15%, does not produce significant hypo- or hyperglycemia

It is more important to be consistent rather than exact with carbohydrate counting, because the former is associated with better glycemic control.

131
Q

Recommendations for physical activity and exercise for adults

A

At least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic activity each week plus muscle-strengthening activities on 2 or more days each week

*Should receive medical clearance before embarking on an exercise program

132
Q

Recommendations for physical activity and exercise for youth

A

60 minutes or more of daily physical activity, which should include muscle- and bone-strengthening activities on 3 or more days each week

*Should receive medical clearance before embarking on an exercise program

133
Q

What is the lag effect of exercise?

A

Hypoglycemia can occur during and immediately following the activity, and again 7 to 11 hours after the exercise. This likely results from enhanced insulin sensitivity, blunted counterregulatory hormone release, and increased glucose uptake by the liver and skeletal muscles to replenish glycogen stores after exercise.

134
Q

Blood glucose levels that should hinder exercise

A

<100 mg/dL
>=350 mg/dL (until corrected with insulin)

Also should not exercise when not feeling well or if with significant ketosis

135
Q

Ways to prevent hypoglycemia due to exercise

A

To prevent hypoglycemia, one should begin exercise with a glucose of 100 mg/dL or higher and plan to ingest carbohydrates during and/or after the exercise according to its duration and intensity.

Alternatively, one can reduce bolus insulin doses, by approximately 50% as a starting point, for any meal or snack within 2 hours of the planned activity.

For those receiving CSII, basal rates can be lowered by approximately 50% or even suspended for periods of 1 to 2 hours for exercise based on the patient’s needs.

136
Q

Amount of carbohydrate that should be ingested during and/or after exercise

A

One can consider providing 0.25 g to up to 1.00 g of carbohydrate per minute of exercise when the activity lasts 40 minutes or longer, individualized based on the person’s size, his or her needs, and past experience.

137
Q

Ways to manage the lag effect of late hypoglycemia risk after exercise

A

Basal rates can be reduced by approximately 20% for up to 6 hours at bedtime for those treated with CSII, or long-acting insulin doses can be reduced by approximately 20% at bedtime.

138
Q

Definition of “significant ketosis” which should hinder exercise

A

More than small urinary ketones or a blood hydroxybutyrate level of 1.5 mmol/L or more

139
Q

Table 36.6 Insulin Types and Action Profiles, page 1427

A

*

140
Q

Initial management in pediatric patients with newly diagnosed diabetes

A

Resuscitation with oral or intravenous fluids to rehydrate and correct electrolyte imbalances
Administration of insulin to halt lipolysis and reverse hepatic gluconeogenesis and ketogenesis
Commencement of diabetes education

141
Q

Typical starting insulin dose for young children and postpubertal adults who are not obese and do not present in DKA

A

0.3 to 0.5 units/kg per day

50% of the TDD delivered as once-daily dose of basal insulin and 50% given as boluses

142
Q

Typical starting insulin dose for young children who are obese, in puberty, or following presentation with DKA

A

May receive a starting dose of 1 unit/kg per day

50% of the TDD delivered as once-daily dose of basal insulin and 50% given as boluses

143
Q

What is the individualized insulin-to-carbohydrate ratio and how to compute?

A

The number of grams of carbohydrate covered by 1 unit of insulin (roughly 450 divided by the total daily insulin dose)

144
Q

What is the individualized correction factor (or sensitivity factor or sensitivity index) and how to compute?

A

The expected decrease in blood glucose resulting from 1 unit of insulin (approximately 1650 divided by the total daily insulin dose)

145
Q

How do we compute for the bolus dose with the meal or snack?

A

The sum of the calculated carbohydate coverage and the calculated blood glucose correction

Step 1: Count cabrbohydates
- 60 g

Step 2: Determine insulin to-carbohydrate ratio
- If TDD is 20 units - 450 divided by 20 = 22.5 grams of carbohydate is covered by 1 unit of insulin (1:22.5)
- If 60 g meal - 60 divided by 22.5 = 2.7 units needed to cover for 60 g meal

Step 3: Determine the amount of insulin required to correct for the premeal blood glucose level using the individualized correction factor
- If target premeal blood glucose level is 120 mg/dL, and actual level is 220 mg/dL, need to decrease blood sugar by 100 mg/dL
- If TDD is 20 units - 1650 divided by 20 = 82.5 decrease in blood glucose from 1 unit of insulin
- To decrease blood glucose by 100 - 82.5 divided by 100 = 0.825 units needed

Step 4: Add Steps 2 and 3 = 3.525 units or simply 4 units bolus dose

146
Q

Administration of rapid acting insulin should not be more frequent than

A

Every 3 hours to avoid hypoglycemia from “stacking” of insulin action, since action time is 3 hours

147
Q

Accuracy standard for glucose meters

A

At least 95% of blood glucose meter results should fall within +/- 15 mg/dL for blood glucose <100 mg/dL and within +/- 15% for blood glucose >=100 mg/dL performed with a reference method

148
Q

Frequency of blood glucose monitoring for persons with T1DM

A

At least 4 times daily and up to 10-12 times daily

149
Q

Continuous glucose monitoring, continuous subcutaneous insulin infusion, and artificial pancreas, pages 1429-1433

A

*

150
Q

Adjunctive treatment that has been FDA approved for use in children with T1DM
a. Pramlintide
b. Metformin
c. GLP1-RA
d. DPP4i
e. SGLT1i
f. SGLT2i

A

None of the above

No adjunctive treatments have been FDA approved for use in children with T1DM.

151
Q

Adjunctive treatment that has been FDA approved for use in adults with T1DM
a. Pramlintide
b. Metformin
c. GLP1-RA
d. DPP4i
e. SGLT1i
f. SGLT2i

A

A

152
Q

Regarding pramlintide:
a. Drug class
b. HbA1c reduction
c. Weight loss
d. Most frequent side effect

A

a. Injectable amylin analogue
b. Modest 0.3-0.6%
c. Modest 0.4-1.3kg
d. Nausea

153
Q

TRUE or FALSE: Individuals with T1DM have reduced GLP1 production, leading to ineffective glucagon suppression.

A

FALSE

Individuals with T1DM have normal GLP1 production but dysregulation between the pancreas and the gut, leading to ineffective glucagon suppression.

154
Q

Mode of reporting for glucose time in range as well as time in hyper- or hypoglycemia

A

Should be reported per unit time, as in the percentage of the values in the specified range of 24 hours/day

155
Q

Definition of a clinically meaningful episode of hypoglycemia in CGM

A

15 minutes or more of consecutive CGM readings less than 54 mg/dL

156
Q

TRUE or FALSE: Transition in care from pediatric to adult health care should begin at 18 years old.

A

Transition is considered as the process that begins during adolescence when the teen accepts more diabetes self-care responsibilities and attends part of the diabetes encounter without parents or guardians.

157
Q

Definition of DKA

A

Hyperglycemia (blood glucose >200 mg/dL)
Ketonemia (blood beta-hydroxybutyrate >=3 mmol/L or moderate/large urine ketones)
Acidosis (venous pH <7.3 or serum bicarbonate <15 mmol/L)

158
Q

Pathophysiology of DKA

A

Relative or absolute insulin deficiency –> Increase in glucagon and accompanying increases in epinephrine, norepinephrine, cortisol, and growth hormone levels –> Catabolic state in the periphery, mobilizing substrates to the liver –> Increased production of glucose and ketone bodies

Osmotic diuresis –> dehydration, loss of electrolytes
Vomiting

Cycle of additional stress hormone production

159
Q

Renal threshold for glucose

A

Approximately 180 mg/dL

160
Q

Patients who are at a greater risk of DKA at diagnosis

A

Young (<5 years)
Do not have a first-degree relative with T1DM
Lower socioeconomic status

But most cases of DKA, in fact, occur in those with established diabetes

161
Q

TRUE or FALSE: Insulin pump use is associated with higher rates of DKA compared with MDI, due to insulin pump failure.

A

FALSE

Insulin pump use is actually associated with lower rates of DKA compared with MDI, although insulin pump failure is an important cause of hyperglycemia, ketonemia, and DKA.

162
Q

TRUE or FALSE: Monitoring of ketones using urine ketone strips is preferred over blood ketone meters.

A

FALSE

Monitoring of ketones using blood ketone meters that measure beta-hydroxybutyrate is preferred over monitoring of urine ketone strips, due to easier sampling, lower rates of hospitalization/emergency department visits, and the potential for earlier and more accurate identification of clinical worsening or improvement.

163
Q

Insulin dosing during sick days

A

Supplemental rapid-acting insulin boluses:
While ketones persist - every 2 to 3 hours
For ketones with hypoglycemia - consider reducing basal rates for a short period of time for patients on insulin pumps
For ketones, hypoglycemia, and decreased oral intake over a prolonged period - consider reducing the insulin glargine dose for patients on MDI and basal rates for those on insulin pumps

*Also, depending on ketone level and blood sugar level, might even have to increase bolus dose (see Table on page 1436)

164
Q

Target oral fluid intake during sick days to prevent or treat dehydration

A

A reasonable target oral fluid intake is 0.5 to 1.0 ounce per year of age per hour (maximum 8 ounces/hour).

165
Q

Type of drink for hydration during sick days depending on blood glucose level

A

If blood glucose is <=250 mg/dL, rehydrate with sugar-containing clear liquids (e.g., sports drinks, soda, popsicles, oral electrolyte solution)

If blood glucose is >250 mg/dL, give sugar-free clear liquids (e.g., water, diet soda, seltzer, diet juices)

166
Q

Frequency of education on sick day management and DKA prevention

A

ADA: Yearly

167
Q

Glucagon Mini-Dosing for sick days when blood sugars remain low and ketones remain elevated

A

Age <2 years: 20 ug
Age 2-15 years: 10 ug per year of age (range 20-150)
Age >15 years: 150 ug

168
Q

Patients and families should be aware that they should seek immediate medical attention for:

A
  • Signs of dehydration
  • Prolonged vomiting for more than a few hours
  • Persistent hyperglycemia (>250-300 mg/dL)
  • Ketones that do not improve after 12 hours
  • Symptoms of DKA (abdominal pain, nausea, vomiting, fruity-smelling breath, hyperventilation, or altered mental status)
169
Q

Immediate initial treatment of DKA

A

Fluid replacement, typically with one or two intravenous fluid boluses with normal saline, 10 mL/kg each, followed by continuous cautious rehydration with the goal of replacing the estimated fluid deficit over the first 24 to 48 hours

170
Q

Timing and dosing of insulin drip in the treatment of DKA

A

Initiation of insulin drip at a rate of 0.05 to 0.1 units/kg per hour, without an insulin bolus, should begin at last 1 hour after fluid replacement is started.

171
Q

Target decrease of blood glucose during treatment for DKA

A

Blood glucose should fall gradually at a rate of 50 to 75 mg/dL per hour

172
Q

Typical content of fluid replacement in DKA

A

Fluid should typically contain saline with potassium, phosphate, and acetate

173
Q

TRUE or FALSE: The rate of fluid administration and sodium chloride content of fluids during treatment for DKA have been shown to result in decline in mental status, clinically apparent brain injury, and poor short-term memory and IQ.

A

FALSE

174
Q

Risk factors for cerebral edema in DKA

A

Young age (<5 years)
New-onset T1DM
Longer duration of symptoms
Lower initial pH
Higher initial BUN
Treatment with bicarbonate
Serum Na concentrations increasing during initial treatment of DKA

175
Q

Prevalence of autoimmune diseases in T1DM patients are higher in:

A

Older age
Female sex
Non-Hispanic white race

176
Q

Most common autoimmune disorder associated with T1DM

A

Thyroid disease (approximately 20%)

177
Q

Recommendation on screening and monitoring for thyroid disease in T1DM patients

A

ADA and ISPAD recommend measuring thyroid antibodies and TSH levels soon after diagnosis, and every 1 to 2 years, and sooner if the patient develops any new symptoms or signs concerning for thyroid dysfunction

178
Q

What to do if TFTs are slightly abnormal at the time of T1DM diagnosis

A

This may be due to sick euthyroid syndrome, and TFTs should be reassessed once glycemic control improves

179
Q

TRUE or FALSE: Subclinical hypothyroidism has been associated with decreased linear growth velocity and increased risk of symptomatic hypoglycemia, while celiac disease has been associated with increased glycemic variability and unexplained hypoglycemia.

A

TRUE

180
Q

Second most common coexistent autoimmune disorder in patients with T1DM

A

Celiac disease

181
Q

Prevalence of celiac disease is higher in

A

Younger at T1DM diagnosis
White race

182
Q

Measure that mitigates the risk of celiac disease in those at increased risk for celiac disease and T1DM

A

Introduction of gluten-containing foods between 4 and 6 months of age (compared with introduction in the first 3 months of life or in the seventh month or later)

183
Q

ADA and ISPAD recommendations for screening for celiac disease in children with T1DM

A

ADA: Soon after diagnosis, then rescreen within 2 years and again after 5 years

ISPAD: Soon after diagnosis, then rescreen every 1-2 years

Screening includes IgA tissue transglutaminase antibodies. If found to be deficient, send IgG-specific antibody tests

More frequent screening may be necessary if symptoms develop or in children who have a first-degree relative with celiac disease

Typically, a biopsy is done to confirm the diagnosis

184
Q

Interventions if screening for celiac disease is positive and once diagnosis is confirmed

A

Refer to gastroentereology before prescribing a gluten-free diet

Refer to a dietitian experienced in managing both diabetes and celiac disease

185
Q

Trial that found that IAA is first autoantibody, followed by GADA

A

BABYDIAB

186
Q

Trial that found that IAA is first autoantibdoy, followed by GADA

A

BABYDIAB

Williams: Disorders of Carbohydrates and Fat Metabolism (6 decks)

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