T2DM + Obesity Flashcards
Adiponectin
- Synthesized by adipose tissue and serum concentration inversely correlated to body fat percentage
- Lower in diabetes
- Function:
–Increased insulin sensitivity
–Improved markers of insulin resistance
–Decreased gluconeogenesis
–Increased glucose uptake
–Increased beta oxidation of fatty acids
Leptin
Synthesized in white adipose and serum concentration directly correlated with total body fat (less in less weight)
senses energy stores
Inhibits appetite
Required for male and female reproductive function
stimulus: eating
Ghrelin
Synthesized from cells lining the fundus of the stomach and in epsilon cells of the pancreas
Rises before meals and falls after
Stimulates appetite
stimulus: fasting
Amylin
- Co-secreted from beta cells with insulin
- Contributes to glucose regulation
–Decreased appetite
–Slowed gastric emptying
–Reduction in gastric enzymes
–Suppression or glucagon
-Deficient in type 2 diabetes
GLP-1
- Secreted by L cells of the intestine in response to nutrients
- Rapidly metabolized by DPP-4
- Decreases serum glucose
–Pancreas
—Stimulates insulin secretion
—Inhibits glucagon secretion
—Increases beta cell mass
–GI tract
—Slows gastric emptying, leading to lower post-prandial glucose excursion
–CNS
—Decreases appetite through central actions on the hypothalamus
*GLP-1 analogues available as injected agents
*DPP-4 inhibitors decrease metabolism of endogenous GLP-1
IL-6
- Synthesized and secreted by adipose tissue
adipose contributes to up to 35% of circulating IL‐6 - stimulates recruitment and activation of macrophages in adipose
- in the liver, IL-6 promotes STAT3—SOCS‐3 pathway mediated impairment of insulin actions
- In muscle, IL‐6 promotes insulin‐regulated glucose metabolism
TNF-α
- secretion increased in adipose tissue from obese humans.
- induces insulin resistance by downregulating the tyrosine kinase activity of the insulin receptor and decreasing the expression of GLUT-4 - reduces lipoprotein lipase activity in white adipocytes,
- stimulates hepatic lipolysis
Prevention of T2DM
Breastfeeding
Lifestyle
- Improve sleep quality and quantity
- Decrease sedentary behaviours
- Increase both light and vigorous physical activity
- Reducing sugar-sweetened beverage consumption
- Limit screen time
In children with obesity, family-based healthy behaviour interventions
Risk factors of T2DM
- FHx T2DM in a 1st- or 2nd-degree relative
- High-risk population (e.g. people of African, Arab, Asian, Hispanic, Indigenous or South Asian descent)
- Obesity
- Impaired glucose tolerance (IGT)
- Polycystic ovary syndrome
- Exposure to diabetes in utero
- Acanthosis nigricans
- Hypertension and dyslipidemia
- Non-alcoholic fatty liver disease (NAFLD)
- Atypical antipsychotic medications
Target A1c T2DM
=7%
Health lifestyle for T2DM
60 minutes daily of moderate-to-vigorous physical activity
limiting recreational screen time to < 2 hours per day
Limiting sedentary (motorized) transport, extended sitting and time spent indoors throughout the day
When to start insulin on T2DM dx
DKA
A1C ≥9.0%
symptoms of severe hyperglycemia
Once-a-day basal insulin
Tx T2DM
- lifestyle = number 1
- metformin
- insulin
- other meds
Complications and comorbidities of T2DM
Neuropathy
Retinopathy
Nephopathy
Dyslipidemia
Hypertension
NAFLD
PCOS
OSA
Depression
Binge eating
Neuropathy screening in T2DM
- when and frequency
- screening test
yearly starting at dx
questions and exam
symptoms, vibration, touch, ankle reflex
retinopathy screening in T2DM
- when and frequency
- screening test
yearly starting at dx
7-standard field- stereoscopic-colour funds photography w interpretation by a trained reader
nephropathy screening in T2DM
- when and frequency
- screening test
yearly starting at dx
first AM ACR (or random)
dyslipidemia screening in T2DM
- when and frequency
- screening test
yearly starting at dx
fasting TC, HDL-C, TG, calculated LDL-C
hypertension screening in T2DM
- when and frequency
- screening test
at dx and every dm-related encounter
BP measurement with appropriate sized cuff
NAFLD screening in T2DM
- when and frequency
- screening test
yearly starting at dx
ALT and/or fatty liver on ultrasound
PCOS screening in T2DM
- when and frequency
- screening test
yearly clinical screening starting at dx for pubertal females
clinical assessment on hx and p/e for oligo/amenorrhea, acne, hirsutism
most common complication of T2DM
retinopathy
CVD prevention in T2DM
smoking cessation
inactivity
when to start statin in T2DM
In children with familial dyslipidemia and a positive family history of early CV events, a statin should be started if the LDL-C level remains >4.1 mmol/L after a 3- to 6-month trial of dietary intervention
Who should be screened for T2DM?
- ≥3 risk factors in nonpubertal children beginning at 8 years of age or ≥2 risk factors in pubertal children. Risk factors include:
1) Obesity (BMI ≥95th percentile for age and gender)
2) Member of a high-risk ethnic group (e.g. African, Arab, Asian, Hispanic, Indigenous or South Asian descent)
3) First-degree relative with type 2 diabetes and/or exposure to hyperglycemia in utero
-4) Signs or symptoms of insulin resistance (including acanthosis nigricans, hypertension, dyslipidemia, NAFLD [ALT >3X upper limit of normal or fatty liver on ultrasound]) - PCOS
- IFG and/or IGT
- Use of atypical antipsychotic medications
How to screen for T2DM?
an A1C and a FPG or random plasma glucose
What are high risk groups for T2DM
African,
Arab,
Asian,
Hispanic,
Indigenous
South Asian descent
What is recommended for physical activity for children
≥60 minutes of moderate-to-vigorous physical activity daily,
When to start insulin in T2DM?
A1C >/=9.0%
severe metabolic decompensation (DKA)
can be weaned once glycemic targets met
start metformin same time unless DKA present
What is OGTT?
abnormal?
1.75 g/kg (max 75 g) anhydrous glucose dissolved in water
check BG at baseline and 2h later
abnormal = ≥11.1 mmoL/L
What are IFG and IGT
IFG: Fasting BG above normal but not in diabetes range
fasting BG 5.6-6.9
IGT: Can be euglycemic in daily lives (normal/near normal HbA1C) but Hyperglycemia when challenged with OGTT
OGTT BG 7.8-11.1
Metformin
Class:
Mech of Action
Lowers A1C by:
Weight:
SE:
Class: biguanide
Mech of Action:
- Enhance insulin sensitivity in liver and peripheral tissues by activation of AMP-activated protein kinase
- Inhibits hepatic glucose production
Lowers A1C by: 1%
Weight: Neutral
SE: GI symptoms (Nausea, diarrhea)
Where is GLP1 secreted
What does it do
What degrades it
secreted by L-cells in the small intestine in response to food
increases insulin secretion proportionate to BG concentrations
suppresses glucagon
prolongs gastric emptying
promotes satiety.
rapidly degraded by DPP- IV
GLP1 RA
Class:
Drugs:
MOA (3):
A1C decrease:
Weight:
SE:
Class: Incretin
Drugs:
Short acting: exenatide, lizisenatide
Long acting: liraglutide, semaglutide, dulaglutide, exenatide ER
LE SLED
MOA (3):
- Increases glucose dependent insulin release
- Slows gastric emptying
- Inhibits glucagon release
A1C decrease: 0.6-1.4%
Weight: loss 1.1-4.4kg
SE: GI side effect
Pancreatitis
Thyroid C Cell malignancy**
DPP4i
Class:
Drugs:
MOA (3):
A1C decrease:
Weight:
SE:
Class: Incretin
Drugs:
Aloglipton
Linagliptin
Saxagliptin
Sitagliptin
LASS
MOA (3):
- Inhibits the enzyme that breaks down incretins,
Leads to:
- Increases glucose dependent insulin release
- Slows gastric emptying
- Inhibits glucagon release
A1C decrease: 0.5-0.7%
Weight: neutral
SE:
Risk heart failure (saxagliptin)
Pancreatitis
Severe joint pain
SGLT2i
MOA:
Drugs:
A1C Reduction:
Weight:
SE:
MOA: reduces glucose reabsorption by the kidneys
== glucosuria
Drugs:
Canagliflozin
Dapagliflozin
Empagliflozin
–>CDE
A1C Reduction: 0.5-0.7%
Weight: loss 2-3kg
Side effects:
Genital myocotic infections
UTI
DKA euglycemic (rare)
Sulfonylurea
Class:
Drugs:
MOA:
A1C reduction:
Weight:
Side effects:
Class: Insulin secretagogue
Drugs:
Gliclazide
Glimepride
Glyburide
MOA: Activates sulfonylurea receptor on B-cell to stimulate insulin secretion
A1C reduction: 0.6-1.2%
Weight: Gain 1.2-3.2kg
Side effects: Hypoglycemia
what kind of drug is liraglutide, semaglutide
GLP1 RA
what kind of drug is Saxagliptin
DPP4i
Glimepride -what kind of drug
Sulfonylurea
Insulin secretagogue
Glyburide - what kind of drug
Sulfonylurea
Insulin secretagogue
Definition of obesity
> 2yo:
Overweight: BMI 85th - <95th %ile for age and sex
Obese: BMI >95th %ile
Extremely obese: >120% of the 95th percentile or >35 kg/m2
<2yo:
Obese: Sex-specific weight for recumbent length is >/=97.7th %ile on the WHO charts
Endocrine causes of obesity
What is an important clinical sign
GH deficiency,
hypothyroidism, or
Cushing syndrome
stature and height velocity are decreased
Comorbidities of Obesity/Overweight
Prediabetes/T2DM
Dyslipidemia
Prehypertension/hypertension
Sleep apnea
NAFLD
Proteinuria and focal segmental glomerulosclerosis
Early subclinical atherosclerosis
Hyperandrogenemia/PCOS
Slipped capital femoral epiphysis and pseudotumor cerebri
Cardiovascular disease (CVD) morbidity
Premature mortality in adulthood
who should have genetic testing for obesity
patients with extreme early onset obesity (before 5 years of age) and that have clinical features of genetic obesity syndromes (in particular extreme hyperphagia) and/or a family history of extreme obesity
What are genetic obesity syndrome with developmental delay?
Prader Willi syndrome
AHO
SIM1 deficiency
BDNF/TrkB deficiency
Bardet Biedl syndrome
TUB deficiency
What are genetic obesity syndrome without developmental delay?
Alstrom syndrome
MC4R deficiency (melanocortin 4 receptor)
SH2B1 deficiency
KSR2 deficiency
Leptin deficiency
Leptin receptor deficiency
POMC deficiency
PCSK1 deficiency
Prader willi - inheritance
dominant
genetics of PWS
A methylation disorder caused by the deletion of a critical segment on the paternally inherited chromosome 15q11.2-q12, loss of the entire paternal chromosome 15 with the presence of 2 maternal copies (uniparental maternal disomy), or an imprinting defect that can be sporadic or due to a mutation of the paternally derived imprinting control site of the 15q13 region
Sulfonylureas
Sulfonylureas bind to the SUR1 regulatory component of the K/ATP channel and causes it to be inhibited.
Which is turn activated the voltage gated Ca channel and causes insulin release
What are the hormonal regulators of weight?
Leptin
genes in monogenic obesity
LEP: Leptin gene mutation
LEPR: Leptin receptor gene mutation
POMC
MC4R
PCSK-1
NTFK2
SIM1
BDNF (BIG DADDY NEEDS FOOD)
comorbidities of obesity
NAFLD
GERD
Hiatal hernia
Gallstones
Pancreatitis
T2DM
OSA
Hypertension
Coronary heart disease
endocrine disorders associated with obesity
● Cushing syndrome
● GH deficiency
● Hypothyroidism
● Pseudohypoparathyroidism 1a
hormones or proteins that stimulate appetite
● Agouti-related peptide (AGRP)
● NPY
● Ghrelin
hormones that suppress appetite
● Leptin
● Polypeptide Y (PPY)
● CCK
● GLP-1
● POMC
● PP (pancreatic polypeptide)
● Insulin
types of bariatric surgery
- Laparoscopic Adjustable Gastric Banding (LAGB)
- Roux-en-Y Gastric Bypass - most effective
- Laparoscopic Sleeve Gastrectomy
chronic complications of bariatric surgery
● Dumping syndrome
● Hypoglycemia
● Malnutrition
● Vitamin Deficiencies
● Anemia
● GERD
● Bowel obstruction
● Hernia
features of metabolic syndrome
○ hypercholesterolemia
○ T2DM
○ Brain - Pseudo-tumor cerebri
○ Lungs - OSA
○ Heart - Hypertension
○ Kidney - Microalbuminuria
○ Liver/GI - NAFLD, gallstones, pancreatitis
○ Ovaries - PCOS, Infertility
○ MSK - Joint pain/osteoarthritis and Blount’s
○ Psych - Increased mental health disorders
○ Extremities - Gout & hyperuricemia
causes f hirsutism
· PCOS
· Androgen producing tumor
· Metabolic syndrome
· Adrenal adenoma/carcinoma
· Exogenous testosterone
· Aromatase deficiency
· Ovotestis DSD
mechanism of PCOS
exact mechanism has not been well defined
- ovary has insulin receptors and IGF receptors
■ It has been suggested that insulin has a stimulatory effect on CYP17α. - In the adrenals:
■ Some studies have shown that insulin increases secretion of 17α-hydroxyprogesterone and DHEAS in response to ACTH. - Insulin directly inhibits SHBG production increase the circulating bioavailable androgen level.
- Insulin decreases IGFBP-1 increase free IGF-1 act in similar manners to insulin
treatment for PCOS
1) Estrogen-progestin oral contraceptive
- Progestin suppresses LH and thus ovarian androgen production; it also antagonizes the endometrial proliferative effect of estrogen
- Estrogen increases SHBG reducing bioavailable androgen
2) Progestin therapy
-For endometrial protection as progestin antagonizes the endometrial proliferative effect of estrogen
3) Metformin
-Use metformin if the woman also has T2DM or IGT who fail lifestyle modification
- If menstrual irregularity who cannot take or do not tolerate HC metformin is second line
- Metformin likely plays its role in improving ovulation induction in women with PCOS through a variety of actions, including reducing insulin levels and altering the effect of insulin on ovarian androgen biosynthesis, theca cell proliferation, and endometrial growth.
4) Spironolactone
- Anti-androgen – antagonist of the androgen receptor
5) GnRH agonists
- Suppress LH and FSH secretion suppression of ovarian hormone production – for hirsutism treatment
- Need to “add-back” estrogen-progestin therapy for bone protection
HbA1C target for pregnany
<7
signs to suspect monogenic diabetes
-Age <6 months
-Only mild hyperglycemia
-Family history in an autosomal dominant fashion
-No complications (not in guidelines)
-Low insulin requirements if any (<0.5U/kg/day)
-Family or personal hx of neonatal diabetes
-Normal BMI and no clinical sx of insulin resistance
- No acanthosis nigricans or signs of insulin resistance
types of cells in pancreas and what they do
A-cell (alpha): Glucagon
- Raises blood glucose
B-cell (beta): Insulin
- Lowers blood glucose
D-cell (delta): Somatostatin
- Inhibits alpha and beta cells (caps against extremes of glucose)
PP-cell: Pancreatic polypeptide
- Levels rise in response to hypoglycemia and in fasting; may enhance insulin sensitivity
what is the cutoff a1c for t2dm
6.5%
what is BDNF mutation
-BDNF(brain-derived neurotrophic factor) deficiency
BDNF directly inhibits food intake so disruption leads to increased food intake and obesity and hyyperhagia (close to the gene causing WAGR - Wilms tumour, Aniridia, GU abnormalities and Mental retardation); haploinsufficiency of BDNF associated with increased spontaneous food intake, severe early-onset obesity and hyperactivity as well as cognitive impairment
MC4R mutation
most common mutation in obesity
no developmental delay
no syndromic features
what meds are approved for weight loss in children
orlistat
reducing fat absorption and can decrease BMI
factors released by adipose tissues and how they affect insulin sensitivity
i. Adiponectin** only one opposite to others!!
1. Levels reduced in obesity
2. Fall in adiponectin coincides with insulin resistance
ii. Leptin
1. Levelscorrelatewithdegreeofobesity
2. Increasesinsulinresistance
iii. Inflammatocy cytokines
1. IL-6andCRPincreasedinobesity
2. HighlevelspredictdevelopmentofT2D–promotesinsulinresistnace
iv. Visfatin
1. Insulinmimeticeffectsonadipo-genesisinvitro 2. Increasesinsulinresistance
v. Resistin
1. Important role in development of hepatic insulin resistance in rodents, roles less clear in humans
vi. FA – increases resistance
vii. Retinal BP4 - increases resistance
viii. Chemokine molecules - increases resistance
Levels of evidence
a. Level 1
i. Systematic Overview or meta-analysis of high-quality RCT
ii. High Quality RCT - Double blind, ITT analysis, f/u at least 80%, adequate
power to answer question
b. Level2
i. RCT or systematic overview not meeting criteria of Level
c. Level 3
i. Non-randomized clinical trial or cohort study with indisputable results d. Level4
i. Other
Phases of a clinical trial
1: Is the treatment safe?
2: Does the treatment work?
3: Is it better than what’s already available?
4: What else do we need to know?
