Type 1 and Type 2 Diabetes - Southern Kentucky...
Transcript of Type 1 and Type 2 Diabetes - Southern Kentucky...
10/12/2017
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Type 1 and Type 2 Diabetes
Disease Overview
▪ David Escalante M.D.,
Endocrinology Diabetes and
Metabolism
▪ Assistant Professor of
Medicine, University of
Kentucky
▪ Private Practitioner at
Appalachia Health Service
Jellico, Tennessee
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3
b- and a-Cells in the Pancreas of Normal Individuals
b-Cells a-Cells
▪ Comprise about 70%–80% of
the endocrine mass of the
pancreas1,2
▪ Comprise about 15% of the
endocrine mass of the
pancreas1
▪ Located in the central portion
of the islet1,2
▪ Located in the periphery
of the islet1
▪ Produce insulin and amylin3▪ Produce glucagon1
▪ Insulin released in response to
elevated blood glucose levels1
▪ Glucagon released in response
to low blood glucose levels1
1. Cleaver O et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21–39.
2. Rhodes CJ. Science. 2005;307:380–384.
3. Kahn SE et al. Diabetes. 1998;47:640–645.
Pathophysiology
of Type 1 Diabetes
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Type 1 Diabetes Mellitus
• Characterized by absolute insulin deficiency
• Pathophysiology and etiology
– Result of pancreatic beta cell destruction
• Prone to ketosis
– Total deficit of circulating insulin
– Autoimmune
– Idiopathic
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Type of Diabetes in Youth by
Race/Ethnicity and Etiology
6AA, African American; AI, American Indian; API, Asian/Pacific Islander; IR, insulin resistant; IS, insulin sensitive; NHW, non-Hispanic white.
Dabelea D, et al. Diabetes Care. 2011;34:1628-1633.
62.9
43.732.5 33.3
16.1
54.5
19.8
21.3
18 15.1
12.9
19.5
11.1
6.6
9.4 10.8
3.2
10.1
6.2
28.340.1 40.8
67.8
15.9
0%
20%
40%
60%
80%
100%
NHW Hispanic AA API AI Total
Non-autoimmune + IR
Non-autoimmune + IS
Autoimmune + IR
Autoimmune + IS
SEARCH for Diabetes in Youth Study
(N=2291)
Dis
trib
uti
on
of
eti
olo
gic
ca
teg
ori
es
by
ra
ce
/eth
nic
ity
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Type 1 Diabetes Pathophysiology
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Inflammation
T cell
TNF-a IFN-g
FasL
Autoimmune Reaction
Macrophage
b-cell
CD8+ T cell
TNF-a
IL-1
NO
Class IMHC
Dendritic cell
b-cell Destruction
Class IIMHC
CD8, cluster of differentiation 8; FasL, Fas ligand; IFN-g, interferon g; IL-1, interleukin 1; MHC,
major histocompatibility complex; NO, nitric oxide; TNF-a, tumor necrosis factor a.
Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497.
• b-cell destruction
– Usually leading to
absolute insulin
deficiency
• Immune mediated
• Idiopathic
Pathophysiologic Features of
Type 1 Diabetes
• Chronic autoimmune disorder– Occurs in genetically susceptible individuals
– May be precipitated by environmental factors
• Autoimmune response against– Altered pancreatic b-cell antigens
– Molecules in b-cells that resemble a viral protein
• Antibodies– Approximately 85% of patients: circulating islet cell
antibodies
– Majority: detectable anti-insulin antibodies
– Most islet cell antibodies directed against GAD within pancreatic b-cells
8GAD, glutamic acid decarboxylase.
Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497.
Major Metabolic Effects of Insulin and
Consequences of Insulin Deficiency
Insulin effects: inhibits breakdown of triglycerides (lipolysis) in adipose tissue
• Consequences of insulin deficiency: elevated FFA levels
Insulin effects: inhibits ketogenesis
• Consequences of insulin deficiency: ketoacidosis, production of ketone bodies
Insulin effects in muscle: stimulates amino acid uptake and protein synthesis, inhibits protein degradation, regulates gene transcription
• Consequences of insulin deficiency: muscle wasting
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Clinical Presentation of
Type 2 Diabetes
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• Age ≥45 years
• Family history of T2D or
cardiovascular disease
• Overweight or obese
• Sedentary lifestyle
• Non-Caucasian ancestry
• Previously identified IGT, IFG,
and/or metabolic syndrome
• PCOS, acanthosis nigricans, or
NAFLD
• Hypertension (BP >140/90 mmHg)
• Dyslipidemia (HDL-C <35 mg/dL
and/or triglycerides >250 mg/dL)
• History of gestational diabetes
• Delivery of baby weighing
>4 kg (>9 lb)
• Antipsychotic therapy for
schizophrenia or severe bipolar
disease
• Chronic glucocorticoid exposure
• Sleep disorders
– Obstructive sleep apnea
– Chronic sleep deprivation
– Night shift work
Risk Factors for Prediabetes and
Type 2 Diabetes
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BP, blood pressure; HCL-C, high density lipoprotein cholesterol; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NAFLD,
nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome; T2D, type 2 diabetes.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
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Development of Type 2 Diabetes
Depends on Interplay Between Insulin
Resistance and β-Cell Dysfunction
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Insulin resistance
Insulin resistance
Abnormalβ-Cell
Function
Relative insulin
deficiency
Gerich JE. Mayo Clin Proc. 2003;78:447-456.
Type 2 diabetes
Normalβ-Cell
Function
Compensatory hyperinsulinemia
No diabetes
Genes &
environment
Genes &
environment
Etiology of β-cell Dysfunction
21Poitout V, Robertson RP. Endocrine Rev. 2008;29:351-366.
Genetic predisposition
Lean phenotype Obese phenotype
IGT, IFG Elevated FFA
Oxidative stress and glucotoxicity
Cellular lipid synthesis and glucolipotoxicity
Progressive b-cell failure and type 2 diabetes
Initial glucolipoadaptation (increased FFA usage)
Hyperglycemia
Glucolipotoxicity and glucotoxicity
EMBS, estimated metabolic body size; IGT, impaired glucose tolerance; NGT, normal glucose tolerance.
Weyer C et al. J Clin Invest. 1999;104:787-794.
Progression to Type 2 Diabetes:
“Falling Off the Curve”
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0
100
200
300
400
500
0 1 2 3 4 5
Glucose disposal (insulin sensitivity)
(mg/kg EMBS/min)
DIA
IGT
NGT
Progressors
NGT
NGTNGT
Nonprogressors
Pathophysiology of
Type 2 Diabetes
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Organ System Defect
Major Role
Pancreatic beta cells Decreased insulin secretion
Muscle Inefficient glucose uptake
LiverIncreased endogenous glucose
secretion
Contributing Role
Adipose tissue Increased FFA production
Digestive tract Decreased incretin effect
Pancreatic alpha cells Increased glucagon secretion
Kidney Increased glucose reabsorption
Nervous system Neurotransmitter dysfunction
DeFronzo RA. Diabetes. 2009;58:773-795
Tissues Involved in T2D
Pathophysiology
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Organ System Normal Metabolic Function Defect in T2D
Major Role
Pancreatic beta cells Secrete insulin Decreased insulin secretion
Muscle Metabolizes glucose for energy Inefficient glucose uptake
Liver
Secretes glucose during fasting periods to maintain brain
function; main site of gluconeogenesis (glucose production
in the body)
Increased endogenous glucose
secretion
Contributing Role
Adipose tissue (fat)
Stores small amounts of glucose for its own use. When fat
is broken down, glycerol is released, which is used by the
liver to produce glucose
Increased FFA production
Digestive tractDigests and absorbs carbohydrates and secretes incretin
hormonesDecreased incretin effect
Pancreatic alpha cells
Secrete glucagon, which stimulates hepatic glucose
production between meals and also helps suppress insulin
secretion during fasting periods
Increased glucagon secretion
Kidney
Reabsorbs glucose from renal filtrate to maintain glucose
at steady-state levels; also an important site for
gluconeogenesis (glucose production)
Increased glucose reabsorption
BrainUtilizes glucose for brain and nerve function
Regulates appetiteNeurotransmitter dysfunction
T2D, type 2 diabetes.
DeFronzo RA. Diabetes. 2009;58:773-795
Natural History of Type 2
Diabetes
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Figure courtesy of CADRE.
Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25;
Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349;
UKPDS Group. Diabetes. 1995;44:1249-1258
Fasting glucose
Type 2 diabetes
Years from
diagnosis0 5–10 –5 10 15
Prediabetes
Onset Diagnosis
Postprandial glucose
Macrovascular complications
Microvascular complications
Insulin resistance
Insulin secretion
b-Cell function
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Dashed line = extrapolation based on Homeostasis Model Assessment (HOMA) data.
Data points from obese UKPDS population, determined by HOMA model.
Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.
b-cell Loss Over Time
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UKPDS
Type 2 Diabetes
b-C
ell
Fu
nc
tio
n (
%)
Years from Diagnosis
25 –
100 –
75 –
0 –
50 –
l
-12
l
-10
l
-6l
-2
l
0
l
2
l
6
l
10
l
14
PostprandialHyperglycemia
Impaired Glucose
Tolerance
Müller WA, et al. N Engl J Med. 1970;283:109-115.
Normal Glucose Homeostasis and Pre- and
Postmeal Insulin and Glucagon Dynamics
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Premeal Postmeal
Insulin Insulin
Glucagon
HGP
Glucagon
HGP
Just enough glucose to meet metabolic needs between meals
Modest postprandial increase with
prompt return to fasting levels
Glucose (mg %)
Glucagon (pg/mL)
Time (min)
-60 0 60 120 180 240
Meal120
90
60
30
0
140
130
120
110
100
90
Insulin (µU/mL)
360
330
300
270
240
110
80
Normal (n=11)
Hyperglycemia in Type 2 Diabetes Results from
Abnormal Insulin and Glucagon Dynamics
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Premeal Postmeal
Insulin Insulin
Glucagon
HGP
Glucagon
HGP
FPG PPGGlucose (mg %)
Insulin (µU/mL)
Glucagon (pg/mL)
Time (min)
-60 0 60 120 180 240
Meal120
90
60
30
0
140
130
120
110
100
90
360
330
300
270
T2D (n=12)
Normal (n=11)
240
110
80
T2D, type 2 diabetes.
Müller WA, et al. N Engl J Med. 1970;283:109-115.
Acute Insulin Response Is
Reduced in Type 2 Diabetes
29IRI, immunoreactive insulin.
Pfeifer MA, et al. Am J Med. 1981;70:579-588.
Pla
sm
a IR
I
(µU
/ml)
Time (minutes)
20 g glucose infusion
2nd phase1st
-300
20
40
60
80
100
0 30 60 90 120
120Normal (n=85)
Type 2 diabetes (n=160)
Defective Insulin Action
in Type 2 Diabetes
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Le
g G
luc
os
e U
pta
ke
(mg
/kg
le
g w
t p
er
min
)
Time (minutes)
0
P<0.01
12
1801401006020
8
4
0
To
tal
Bo
dy
Glu
co
se
Up
tak
e
(mg
/kg
• m
in)
T2DNormal
0
7
6
5
4
3
2
1
T2D, type 2 diabetes.
DeFronzo RA. Diabetes. 2009;58:773-795; DeFronzo RA, et al. J Clin Invest. 1985;76:149-155.
FPG, fasting plasma glucose; HGP, hepatic glucose production; T2D, type 2 diabetes.
DeFronzo RA, et al. Metabolism. 1989;38:387-395.
Elevated Fasting Glucose in
Type 2 Diabetes Results From
Increased HGP
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Ba
sa
l H
GP
(mg
/kg
• m
in)
FPG (mg/dL)
2.0
2.5
3.0
3.5
4.0
100 200 300
r=0.85
P<0.001
Control
T2D
0
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*P≤.05.
Nauck M, et al. Diabetologia. 1986;29:46-52.
The Incretin Effect Is Diminished
in Type 2 Diabetes
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Normal Glucose Tolerance
(n=8)
Type 2 Diabetes
(n=14)IV Glucose
Oral Glucose
0 60 120 180
240
Pla
sm
a G
luco
se (
mg
/dL
)
180
90
0
0 60 120 180
Pla
sm
a G
luco
se (
mg
/dL
) 240
180
90
0
**
* **
* * *
0 60 120 180
C-P
ep
tid
e (
nm
ol/L
)
Time (min)
30
20
10
00 60 120 180
C-p
ep
tid
e (
nm
ol/L
)
Time (min)
30
20
10
0
Actions of GLP-1 and GIP
GLP-1
• Released from L cells in ileum and colon
• Stimulates insulin release from b-cell in a glucose-dependent manner
• Potent inhibition of gastric emptying
• Potent inhibition of glucagon secretion
• Reduction of food intake and body weight
• Significant effects on b-cell growth and survival
GIP
• Released from K cells in duodenum
• Stimulates insulin release from b-cell in a glucose dependent manner
• Minimal effects on gastric emptying
• No significant inhibition of glucagon secretion
• No significant effects on satiety or body weight
• Potential effects on b-cell growth and survival
33Drucker DJ. Diabetes Care 2003;26:2929-2940.
Renal Glucose Reabsorption
in Type 2 Diabetes
• Sodium-glucose cotransporters 1 and 2
(SGLT1 and SGLT2) reabsorb glucose in the
proximal tubule of kidney
– Ensures glucose availability during fasting periods
• Renal glucose reabsorption is increased in
type 2 diabetes
– Contributes to fasting and postprandial
hyperglycemia
– Hyperglycemia leads to increased SGLT2 levels,
which raises the blood glucose threshold for
urinary glucose excretion34
Wright EM, et al. J Intern Med. 2007;261:32-43.
90% of glucose
SGLT1
(180 L/day) (90 mg/dL) = 162 g glucose per day
10% of glucose
Glucose
No Glucose
S1
S3
Normal Renal Handling of
Glucose
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SGLT2
Abdul-Ghani MA, et al. Endocr Pract. 2008;14:782-790.
Increased SGLT2 Protein Levels
Change Glucose Reabsorption
and Excretion Thresholds
36TmG, glucose transport maximum.
Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14:782-790.
27090
Re
na
l G
luc
os
e R
ea
bs
orp
tio
n
TmG
180
TmG
Blood Glucose Concentration
(mg/dL)
Reabsorption
increases
27090 180
Blood Glucose Concentration
(mg/dL)
Excretion
threshold
increases
Re
na
l G
luc
os
e E
xc
reti
on
Reabsorption Excretion
Hypothalamic Dopaminergic
Tone and Autonomic Imbalance
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In diabetes:
Low dopaminergic tone in
hypothalamus in early
morning
Sympathetic tone
HPA axis tone
Hepatic gluconeogenesis
FFA and TG
Insulin resistance
Inflammation/hypercoagulation
Impaired glucose metabolism
Hyperglycemia
Insulin resistance
Adverse cardiovascular pathology
37Fonseca V. Dopamine Agonists in Type 2 Diabetes. New York, NY: Oxford University Press; 2010.
Cincotta AH. In: Hansen B, Shafrir E, eds. Insulin Resistance and Insulin Resistance Syndrome. New York, NY: Taylor
& Francis; 2002:271-312.
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ADDICTION
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DSM-5
Changes to DSM in new edition: no longer dichotomy between abuse and dependence
Addiction now the preferred term instead of dependence.
Addiction now seen as a continuum.
Substance use disorder requires 2 of following:
tolerance inability to stop
withdrawal problems excessive spending or effort
use more than intended to obtain
reduced involvement continued use
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What is addiction?
• heroin addiction
• cocaine addiction
• alcohol addiction (“alcoholism”)
• marijuana addiction
• amphetamine addiction
• nicotine addiction
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What is addiction?
• sex addiction??
• gambling addiction??
• food addiction??
• shopping addiction????
• internet addiction????
• cell phone addiction????
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Why do some people
become addicted while
others do not?
Vulnerability
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True or False
Prescription medications are the most abuse substances in
the United States?
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True or False
It is safer to abuse prescription medications than street
drugs?
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True or False
Most people who abuse prescription drugs get them from a drug
dealer?
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Where do People Obtain Prescription Drugs?
70% of people who abuse
prescription medicine get them from
a FRIEND or RELATIVE47
DA Neurotransmiter
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DA Pathway
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DOPAMINE RECEPTOR
1) Decreased in DM2
2) Control Food Intake
3) Energy Expenditure
4) Glucose Metabolism
5) Increase Resistance
6) Control Insulin Secretion (acute +, chronic -)
7) Insulin and DA ReUptake (acute +, chronic -)
8) Increase Liver Production Glucose
9) Lipid Metabolism Increase Lipolysis, FFA
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Dopamine Related
1) Schizophrenia/ Depression
2) Restless Leg Syndrome
3) ADHD
4) Prolactinoma
5) Nausea, Vomiting
6) Parkinson and other Movement disorders
7) Obesity?
8) Metabolic Syndrome?
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Pharmacologic Use
1) Movement Disorders
2) Prolactinomas
3) Nausea, Vomiting
4) Motility Disorders
5) Mood Disorders
6) Psychotic Disorders
7) ADHD
8) Pain
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ALCOHOL
1) Increase in CARB intake
2) Increased Hypoglycemia
3) Decrease hypoglycemia awareness
4) Confusion over hypoglycemia
5) Chronic use increase nerve damage
6) Blurry vision Vasodilation of eye vessels
7) Decrease activity of secretague
8) Dyslipidemia
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SMOKING
1) Increase Vascular Disease
2) Increase Cancer
3) Decrease Control
4) Increase Renal Disease
5) Increase Neuropathic Pain
6) Increased Amputations
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STIMULANTS
1) Hyperglycemia
2) Hypoglycemia
3) Weight Loss
4) Insulin Resistance
5) Increase MI and CVA
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Benzodiazepine
1) Insulin Resistance
2) Increase Sedentary Life
3) Increase Metabolic Syndrome
4) Weight Gain
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Narcotics
1) Increase Insulin Resistance
2) Decrease Insulin Secretion
3) Change in appetite
4) Memory Change
5) Mood change
6) Weight Change
7) Bowel Habit Change
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CANABIS
1) Decrease in Glucose in Intoxication
2) Increase in Fat Deposition
3) Increase Appetite
4) Short Term Memory Loss with Decrease compliance
5) Decrease coordination
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ANTIPSYCHOTICS
1) Increase Insulin Resistance
2) Decrease Insulin secretion
3) Increase Weight Mainly Central
4) Dyslipidemia
5) Increase Prolactin
6) Increase DM
7) Cardiovascular Disease
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ACTION POINTS
1) Avoid Dopamine Altering Medication
2) Aggressive Life Intervention to Minimize Effects
3) Pharmacologic Therapy
4) Seek Professional and Spiritual Help
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▪ OPEN DISCUSION