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Diabetes Update 2018:Pathogenesis of Diabetes
Katherine Lewis, MD, MSCR Assistant Professor, Endocrinology and Pediatric
EndocrinologyEndocrinology, Diabetes and Medical Genetics
Medical University of South CarolinaFebruary 3, 2018
Disclosures
I have no relevant disclosures or conflicts of interest related to this presentation
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Objectives
1. Review the pathogenesis of diabetes mellitus (DM)
2. Describe and differentiate type 1 and type 2 diabetes
3. State diagnostic criteria
National Diabetes Statistics
• 30.3 million people or 12.2% of the U.S. population have diabetes (2015)
• Diagnosed– 23.0 million people– 132,000 children and adolescents– 5% with type 1 diabetes
• Undiagnosed– 7.2 million people (23.8% are undiagnosed)
CDC, National Diabetes Statistics Report, 2017
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Prediabetes Statistics
Prediabetes among people aged 20 years or older, United States, 2015
• 84.1 million Americans (33.9% of population) age 18 and older had prediabetes based on fasting glucose or A1C
• 11.6% of these report being told by a health professional that they had this condition
CDC, National Diabetes Statistics Report, 2017
CASE 1A case of adolescent obesity
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CASE 118 year old man presents for evaluation of abnormal TSH and weight gain
• He has no significant past medical history• He has no symptoms of hypothyroidism • He denies polyuria, polydipsia, or fatigue• He enjoys playing video games
• His family history:– hyperlipidemia and hypertension (father)– Mother with gestational diabetes– diabetes and hyperlipidemia (PGF)– thyroid disease (MGF and p. aunt)– Hispanic ethnicity
CASE 1Exam:
BMI: 29
Mild acanthosis nigricansof neck
Lab results:
TSH 6.29; Free T4 2.2
Cholesterol 196, Triglycerides 748, HDL 23
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CASE 1
Repeat labs:
TSH 3.43, Free T4 0.99
Thyroid peroxidase Ab 34.8 Thyroglobulin Ab <20
CASE 1
Would you screen him for diabetes?
A) No, he is asymptomatic for symptoms of hyperglycemia
B) No, he is too young to have Type 2 diabetes
C) Yes, he is obese, he has multiple risk factors for type 2 diabetes
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CASE 1Diabetes Screening Guidelines for Adults
Overweight (BMI ≥ 25)*
Plus additional risk factors
Physical inactivityFirst‐degree relatives with diabetes
High‐risk ethnicityWomen who delivered baby >9 lb or who were diagnosed with GDM
Hypertension (≥ 140/90 or on therapy for hypertension)PCOS
A1C ≥ 5.7%, IGT, or IFG on previous testingOther clinical conditions associated with insulin resistance (severe
obesity, acanthosis nigricans)History of CVD
In absence of above, screen starting at age 45 years
Repeat testing at 3‐year intervals if normal; more frequent testing if higher risk or pre‐diabetes (yearly)
*At risk BMI may be lower in some ethnic groups.
CASE 1Diabetes Screening Guidelines for Adults
Overweight (BMI ≥ 25)*
Plus additional risk factors
Physical inactivityFirst‐degree relatives with diabetes
High‐risk ethnicityWomen who delivered baby >9 lb or who were diagnosed with GDM
Hypertension (≥ 140/90 or on therapy for hypertension)PCOS
A1C ≥ 5.7%, IGT, or IFG on previous testingOther clinical conditions associated with insulin resistance (severe
obesity, acanthosis nigricans)History of CVD
In absence of above, screen starting at age 45 years
Repeat testing at 3‐year intervals if normal; more frequent testing if higher risk or pre‐diabetes (yearly)
*At risk BMI may be lower in some ethnic groups.
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CASE 1
Would you screen him for diabetes?
A) No, he is asymptomatic for symptoms of hyperglycemia
B) No, he is too young to have Type 2 diabetes
C) Yes, he is obese, he has multiple risk factors for type 2 diabetes
CASE 1
Prediabetes• Impaired fasting glucose and
impaired glucose tolerance are risk factors for development of diabetes and cardiovascular risk
• Associated with dyslipidemia with elevated triglycerides
• low HDL,
• And hypertension
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CASE 1: Prediabetes
Lifestyle intervention (n = 1079):• Weight loss ≥ 7% through low
cal/low fat diet• ≥150 minutes/week of exercise
moderate intensityMetformin 850 mg bid (n = 1073)
CASE 2A case of increased thirst…
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CASE 2
• A 60 year old woman returns for follow‐up of asymptomatic primary hyperparathyroidism
• She notes increased fatigue, thirst, and urination
• She has a past medical history of discoid lupus, hypertension, CKD, COPD, coronary artery disease, and depression
CASE 2
• She smokes a half pack a day and drinks 4‐5 beers on the weekends
• She has a family history of diabetes, hyperlipidemia, and hypertension in her brother
• Exam:
• b.p. 122/82
• BMI 28
• She has acanthosisnigricans noted on the back of her neck.
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CASE 2
• Lab results:
– Calcium of 10.2 mg/dl
– PTH 82.4 pg/ml,
– 25‐OH vitamin D 25.4 ng/ml
However, you note that her chemistry also shows…
Glucose 248 mg/dl
What is her diagnosis?
CASE 1Diagnosis of Diabetes
A1C ≥ 6.5%*
OR
FPG ≥ 126 mg/dL *
OR
2‐hour PG ≥ 200 mg/dL* during an OGTT
OR
In patient with classic symptoms or hyperglycemic crisis, random plasma glucose ≥ 200 mg/dL
*In absence of unequivocal hyperglycemia, resultshould be confirmed by repeat testing
A1C 6.6%
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Classification of DiabetesClassification of Diabetes Features
Type 1 diabetesA. Immune mediatedB. Idiopathic
β‐cell destruction leading to absolute insulin deficiency
Type 2 diabetes Insulin resistance +/‐ insulin deficiency
Other specific types A. Genetic defects of β‐cell funtionB. Genetic defects in insulin actionC. Diseases of exocrine pancreasD. EndocrinopathiesE. Drug or chemical inducedF. InfectionsG. Uncommon forms of immune‐
mediated diabetesH. Other genetic syndromes associated
with diabetes
Type 1 Diabetes
• 50% of patients diagnosed before age 20 years
• 50% of patients diagnosed after age 20 years
– Often mistaken for type 2 diabetes—may make up 10% to 30% of individuals diagnosed with type 2 diabetes
• Type 1 diabetes is due to autoimmune ß‐cell destruction
– leading to absolute insulin deficiency
EURODIAB ACE Study Group. Lancet. 2000;355:873‐876;Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4:308‐315
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Type 1 Diabetes
EURODIAB ACE Study Group. Lancet. 2000;355:873‐876;Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4:308‐315
Stage 1 Stage 2 Stage 3
Stage • Autoimmunity• Normoglycemia• Presymptomatic
• Autoimmunity• Dysglycemia• Presymptomatic
• New‐onsethyperglycemia
• Symptomatic
Diagnostic Criteria
• Multiple autoantibodies
• No IGT or IFG
• Multiple antibodies• FPG 100‐125 mg/dl• 2‐h PG 140‐199
mg/dl• A1C 5.7‐6.4% or
≥10% increase
• Clinical symptoms• FPF ≥ 126*• 2‐h PG ≥ 200*• A1C ≥ 6.5%*• Classic symptoms,
hyperglycemic crisis
Consider referring first degree relatives of those with type 1 DM to risk assessment in clinical research study: www.diabetestrialnet.org
Type 2 Diabetes: Pathogenesis in a Nutshell
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CASE 2Classification of Diabetes Features
Type 1 diabetesA. Immune mediatedB. Idiopathic
β‐cell destruction leading to absolute insulin deficiency
Type 2 diabetes Insulin resistance +/‐ insulin deficiency
Other specific types A. Genetic defects of β‐cell funtionB. Genetic defects in insulin actionC. Diseases of exocrine pancreasD. EndocrinopathiesE. Drug or chemical inducedF. InfectionsG. Uncommon forms of immune‐
mediated diabetesH. Other genetic syndromes associated
with diabetes
Type 2 Diabetes: Pathogenesis in a Nutshell (cont.)
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Adapted from Ramlo‐Halsted BA, Edelman SV. Prim Care. 1999;26:771‐789
Natural History of Type 2 Diabetes
Macrovascular complicationsMicrovascular complications
Insulin resistance
Impairedglucose tolerance
Undiagnoseddiabetes Known diabetes
Insulin secretionPostprandial glucose
Fasting glucose
Etiology of Type 2 DiabetesImpaired Insulin Secretion and Insulin Resistance
Type 2 diabetes
Genes and environment
Impaired insulin secretion
Insulin resistance
Impaired glucose tolerance
Progressive hyperglycemiaand high free fatty acids
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Illustration by Kaitlin Jones
Eight Mechanisms Which Lead to Hyperglycemia in Type 2 Diabetes
1. Beta cells: Decreased insulin Secretion
2. Skeletal Muscle: Decreased Glucose Uptake
3. Adipose Tissue: Increased lipolysis
4. Alpha cells: increased glucagon
5. Liver: increased hepatic glucose production
6. Neurotransmitter dysfunction
7. Decreased incretin effect
8. Increased glucose reabsorption
Insulin Resistance: Receptor And Postreceptor Defects
Peripheral Tissues(skeletal muscle)
Insufficient GlucoseDisposal
Increased GlucoseProduction
Impaired Insulin Secretion
Glucose
Pancreas
Liver
X
Hyperglycemia In Type 2 Diabetes
DeFronzo et al. Diabetes Care. 1992;15:318-368.
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Beta Cells of Pancreas Secrete Less Insulin
‐cell function(% of normal by HOMA)
Adapted from Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21‐S25;UKPDS. Diabetes. 1995;44:1249‐1258
Years
0
20
40
60
80
100
10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6
Time of diagnosis?
HOMA=homeostasis model assessment
Decline of ‐Cell Function in the UKPDS Illustrates Progressive Nature
of Diabetes
Pancreatic function= 50% of normal
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Altered ‐Cell Mass and Function in Islets From Subjects With Type 2 Diabetes
Decreased Skeletal Muscle Glucose Uptake
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Insulin Resistance and Skeletal Muscle
Insulin mediated glucose clearance rates in leg skeletal muscle
Dela, Int J Biochem & Cell Biology. 2013, 45: 11‐15.
Increased Lipolysis by Adipose Tissue
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Glucose FFA
FFA
Increasedglucosamine
Otherpathways
Otherpathways
Glucose
Impaired insulinsecretion from ‐cell
Insulin resistancein muscle and fat
Mechanism of Glucotoxicity and Lipotoxicity
The Glucosamine Hypothesis
Hawkins M et al. J Clin Invest. 1997;99:2173‐2182; Rossetti L. Endocrinology.2000;141:1922‐1925
FFA=free fatty acid
Insulin
Insulin + fat infusion
Glucose Measurements During High Insulin Levels
0
100
Peripheral glucose uptake
Hepatic glucose output
*
*
High FFA Levels CausePeripheral and Hepatic Insulin
Resistance
*P<0.05200
300
400
500
Boden G, Chen X. J Clin Invest. 1995;96:1261‐1268
FFA=free fatty acid
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• A meal contains 6 to 20 times the glucose content of the blood
• Normally, postprandial hyperglycemia is regulated by
– Clearance of ingested glucose by the liver– Suppression of hepatic glucose production– Peripheral clearance of glucose
Regulation of Postprandial Glucose
• In impaired glucose tolerance or diabetes, glucose regulation is impaired by
– Delayed and reduced insulin secretion– Lack of suppression of glucagon – Hepatic and peripheral insulin resistance
• Postprandial hyperglycemia results
Impaired Regulation ofPostprandial Glucose
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Increased Hepatic Glucose Production
DeFronzo RA. Diabetes. 1988;37:667‐687
Increased Hepatic Glucose OutputCorrelates With Fasting Plasma Glucose
4.0
3.5
3.0
2.5
2.0
1.5
Fasting plasma glucose (mg/dL)
Glucose output(mg/kg/min)
50 100 150 200 250 300
r=0.847P<0.001
Normal
Type 2 diabetesConclusion:FBG<140 did nottrigger HGP increase,but increase in HGPwas seen FBG>140.HGP does not play early role in fastinghyperglycemia of T2DM
HGP observed via glucoseturnover studiesduring post absorptivestate
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Substances That Promote Positive Energy Balance (Weight Gain)
C
Substances That Promote Negative Energy Balance (Weight Loss)
C
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CASE 2
• Lab results:
– Calcium of 10.2 mg/dl
– PTH 82.4 pg/ml,
– 25‐OH vitamin D 25.4 ng/ml
However, you note that her chemistry also shows…
Glucose 248 mg/dl
What is her diagnosis?
Type 1 versus Type 2 Diabetes
Type 1 diabetes Type 2 Diabetes
Usual Clinical course Insulin‐dependent Initially non insulin‐dependent
Usual age of onset <20 years (but 50% over 20 years)
>40 years but increasingly earlier
Body weight Usually lean Usually obese
Clinical onset Often acute Subtle, slow
Ketosis‐prone Yes No
Family history ≤ 15% with first degree relative
Common
Ethnicity Predominantly white More common in minorities
Frequency of HLD‐DR3, DR4, DQB1*0201, *0302
Increased Not increased
Islet Autoantibodies Present Absent
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CASE 2• What is the next best step for this patient?
A) Start a basal insulin
B) Start metformin
C) Diabetes education
D) Reassurance that her A1C is only mildly elevated
E) B&C
F) None of the above
Type 2 Diabetes Agents
Agent Features
MetforminReduces hepatic glucose output, reduces
insulin resistance
Low risk of hypoglycemiaGI side effects; risk of lactic acidosisMay see modest weight loss
ThiazolidinedioneReduces insulin resistance in skeletal
muscle
Low risk of hypoglycemiaFluid retention, increased fracture riskWeight gain
DPP‐4 InhibitorsIncrease endogenous GLP‐1 and GIP,
increasing endogenous insulin in glucose‐dependent fashion
Low risk of hypoglycemiaPossible pancreatitis/pancreatic cancer riskWeight neutral
GLP‐1 agonistsStimulates insulin through glucose‐
dependent process; reduces glucagon and slows gastric emptying
Low hypoglycemic riskPossible pancreatitis; C‐cell hyperplasia in rodentsWeight loss
Sulfonylureas/GlinidesRelease of insulin from beta cells
Hypoglycemia riskWeight gain
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Type 2 Diabetes Agents
Medication Features
Alpha‐glucosidase inhibitorsInhibits polysaccharide absorption
Bloating, flatulence, diarrhea
Sodium‐glucose cotransporter 2 inhibitors (SGLT2)
Inhibition of glucose reabsorption in kidneys
Low risk of hypoglycemiaUrinary and GU infectionsWeight loss
Bromocriptine MesylateShort acting dopamine agonist
Low hypoglycemia riskNausea and orthostasisCannot be used in patients on anti‐psychotic medications
ColesevelamBile acid sequestrant
Low hypoglycemia riskGI side effects
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CASE 2
• What is the next best step for this patient?
A) Start a basal insulin
B) Start metformin
C) Diabetes education
D) Reassurance that her A1C is only mildly elevated
E) B & C
F) None of the above
CASE 2• Diabetes education
– Medical nutrition therapy• Diet history revealed poor food choices including regular soda, potato chips, hot dogs, candy, and cookies
– Physical activity
– Tobacco counseling
– Recommendation of yearly eye exam and dental care
– Encouraged follow‐up of hypertension and hyperlipidemia
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CASE 3A case of childhood obesity
CASE 3
7 year old girl presents for evaluation of abnormal TSH and weight gain
• She has no significant past medical history• She has no symptoms of hypothyroidism • She denies polyuria, polydipsia, or fatigue• There is no history of gestational diabetes
in her mother
• Her family history:– hyperlipidemia and hypertension (father)– diabetes and hyperlipidemia (PGF)– thyroid disease (MGF and p. aunt)
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CASE 3
Exam:
BMI 26.9 (99th percentile for age); 111/52
Mild acanthosis nigricansof neck
She is pre‐pubertal
Lab results:
TSH 6.29; Free T4 2.2
Cholesterol 196, Triglycerides 748, HDL 23
CASE 3
Repeat labs:
TSH 3.43, Free T4 0.99
Thyroid peroxidase Ab 34.8 Thyroglobulin Ab <20
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CASE 3
Criteria for Screening for Type 2 Diabetes in Children
Overweight (BMI >85th percentile, weight for height >85th
percentile, or weigh >120% of ideal for height
Plus 2 of the following:
Family history of type 2 diabetes in 1st or 2nd degree relativeRace/ethinicity (Native American, African American, Latino,
Asian American, Pacific Islander)Signs of insulin resistance or conditions associated with insulin resistance (Acanthosis nigricans, hypertension, dyslipidemia,
PCOS, born SGA)Maternal history of diabetes or gestational diabetes during
child’s gestation
Age of initiation: 10 years or onset of puberty
Frequency: every 3 years
Glucose 103, A1C 5.7%
CASE 3
Prediabetes
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CASE 3
The family was counseled on lifestyle intervention, and she was referred to a multi‐disciplinary clinic for childhood obesity
CASE 3She returned 4 months later:• She lost 7lbs but family reported no recent
efforts at lifestyle modification due to recent death in the family, winter weather, etc.
• She had been ill and was diagnosed with Strep throat so she had not been eating well due to sore throat
• She had been complaining of some abdominal pain
• She had some possible increased thirst and urination but this was thought to be related to trying to soothe her sore throat
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CASE 3
Labs done 2 months prior:
• Cholesterol 199, Triglycerides 260, HDL 37, LDL 110
• Glucose 103, insulin 19.5
CASE 3
Would you repeat screening for diabetes?A) No, recent screening showed IFGB) Yes, she has weight loss and possibly
some increased thirst and urination in the setting of past IFG
C) No, she is pre‐pubertal and therefore low risk for Type 2 diabetes
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CASE 3
Would you repeat screening for diabetes?A) No, recent screening showed IFGB) Yes, she has weight loss and possibly
some increased thirst and urination in the setting of past IFG
C) No, she is pre‐pubertal and therefore at low risk for Type 2 diabetes
CASE 3
A1C and glucose were checked in clinic:
• Glucose: 403
• A1C: 10.4%
• Urine dipstick: negative ketones
Diagnosis: Diabetes mellitus—Type 1 diabetes or Type 2 diabetes
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CASE 3
She was admitted to the hospital for initiation of insulin and diabetes education:• She was started on 0.6 units/kg/day for
doses of a basal‐bolus regimen• Glargine 13 units hs, and Aspart 1/20g• She was seen by the diabetes educator,
registered dietician, and social worker• Family committed to increased efforts at
lifestyle modification
CASE 3
Six weeks later, she returned to clinic having tapered off of insulin:• 11 pound weight loss and poor appetite
• A1C improved to 7.5%• Diabetes antibodies positive:
– Glutamic acid decarboxylase Ab >250
– Human insulin Ab 0.5
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CASE 3Classification of Diabetes Features
Type 1 diabetesA. Immune mediatedB. Idiopathic
β‐cell destruction leading to absolute insulin deficiency
Type 2 diabetes Insulin resistance +/‐ insulin deficiency
Other specific types A. Genetic defects of β‐cell funtionB. Genetic defects in insulin actionC. Diseases of exocrine pancreasD. EndocrinopathiesE. Drug or chemical inducedF. InfectionsG. Uncommon forms of immune‐
mediated diabetesH. Other genetic syndromes
associated with diabetes
Classification of DiabetesClassification of Diabetes Features
Type 1 diabetesA. Immune mediatedB. Idiopathic
β‐cell destruction leading to absolute insulin deficiency
Type 2 diabetes Insulin resistance +/‐ insulin deficiency
Other specific types A. Genetic defects of β‐cell funtionB. Genetic defects in insulin actionC. Diseases of exocrine pancreasD. EndocrinopathiesE. Drug or chemical inducedF. InfectionsG. Uncommon forms of immune‐
mediated diabetesH. Other genetic syndromes associated
with diabetes
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Ketosis‐prone Type 2 Diabetes
• “Flatbush diabetes”, area in city of Brooklyn, NY where this type of DM first described
• Commonly nonwhite and overweight or obese with acute defects in insulin secretion and no islet cell autoantibodies
• Following treatment, some insulin secretory capacity is recovered
• Initially Rx with insulin, then treated as type 2 diabetes with oral agents +/or diet
Up to Date. Syndromes of ketosis‐prone diabetes mellitus. January 2017.
Latent Autoimmune Diabetes in Adults (LADA)
• Heterogeneous group
• On spectrum of insulin deficiency between type 1 and type 2 diabetes
• Those with high titers of GAD65 antibodies have lower body mass index and less endogenous insulin secretion
• Anti‐GAD antibodies (or ICA) indicate need for insulin and increase risk for developing ketoacidosis
Up to Date. Classification of diabetes mellitus and genetic diabetic syndromes, 2017.
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Maturity Onset Diabetes of the Young (MODY)
• Heterogeneous disorder characterized by non‐insulin dependent diabetes diagnosed at a young age (<25 years)
• Autosomal dominant transmission
• Lack of autoantibodies
• Generally do not develop DKA
• Most common form of monogenic diabetes, accounting for 2‐5% diabetes
• Misclassified as having either type 1 or type 2 diabetes
• Some may respond to sulfonylureas
Up to Date. Classification of diabetes mellitus and genetic diabetic syndromes, 2017.
Genetic Abnormalities of MODY• Hepatocyte nuclear factor ‐4‐alpha (was called MODY1) (<10%)
– Rx: Sulfonylurea
• Glucokinase gene (was called MODY 2) (15‐31%)
– Rx: mild DM, no meds
• Hepatocyte nuclear factor‐1‐alpha (was called MODY 3) (52‐65%)
– Rx: Sulfonylurea, glinides
• Insulin promoter factor 1 (was called MODY 4) (rare)
• Hepatocyte nuclear factor‐1‐beta (was called MODY 5) (rare)
• Neurogenic differentiation factor‐1 (was called MODY 6) (rare)
Note: Some MODYs need insulinFajans & Bell, Diab Care, 34, 2011: 1878‐1994Up to Date. Classification of diabetes mellitus and genetic diabetic syndromes, 2017.
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Genetic Syndromes Associated with Diabetes Mellitus
Thomas, CC. Med Clin N Am. 99 (2015): 1‐16.
Drug Associated Diabetes Mellitus
Thomas, CC. Med Clin N Am. 99 (2015): 1‐16.
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Newer Atypical Antipsychotics
• Side effects: weight gain
• Diabetogenic effects: glucose dysregulation
– Clozapine
– Olanzapine
– Risperidone
– Quetiapine
– Aripiprazole
• Increased risk of T2DM, metabolic syndrome and dyslipidemia
• Rare cases of DKA
Guenette, et. al. Psychopharmacology. 2013, 226: 1‐12.
• Type 1 diabetes
– The main abnormality is insulin deficiency
• Type 2 diabetes
– Both insulin deficiency and insulin resistance contribute
• Glucotoxicity and lipotoxicity
– Poor metabolic control worsens insulin deficiency and insulin resistance
Summary of Pathophysiology
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• Basal hyperglycemia
– Basal insulin levels and hepatic response mainly determine fasting plasma glucose
• Postprandial hyperglycemia
– Early insulin release, glucagon suppression, and hepatic and muscle responses to insulin response determine postprandial glucose
Summary of Pathophysiology
Questions?