Diabetes Update 2018: Pathogenesis of Diabetes

Transcription

1 Diabetes Update 2018: Pathogenesis of Diabetes Katherine Lewis, MD, MSCR Assistant Professor, Endocrinology and Pediatric Endocrinology Endocrinology, Diabetes and Medical Genetics Medical University of South Carolina February 3, 2018 Disclosures I have no relevant disclosures or conflicts of interest related to this presentation 1

2 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,

3 Prediabetes Statistics Prediabetes among people aged 20 years or older, United States, 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 1 A case of adolescent obesity 3

4 CASE 1 18 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 Exam: BMI: 29 Mild acanthosis nigricans of neck CASE 1 Lab results: TSH 6.29; Free T4 2.2 Cholesterol 196, Triglycerides 748, HDL 23 4

5 CASE 1 Repeat labs: TSH 3.43, Free T 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 5

6 CASE 1 Diabetes Screening Guidelines for Adults Overweight (BMI 25)* Plus additional risk factors Physical inactivity First degree relatives with diabetes High risk ethnicity Women 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 testing Other 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 1 Diabetes Screening Guidelines for Adults Overweight (BMI 25)* Plus additional risk factors Physical inactivity First degree relatives with diabetes High risk ethnicity Women 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 testing Other 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. 6

7 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 7

8 CASE 1 Prediabetes Fasting glucose 108 A1C 6% 8

9 CASE 1: Prediabetes Lifestyle intervention (n = 1079): Weight loss 7% through low cal/low fat diet 150 minutes/week of exercise moderate intensity Metformin 850 mg bid (n = 1073) CASE 2 A case of increased thirst 9

10 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 acanthosis nigricans noted on the back of her neck. 10

11 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 1 Diagnosis 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, result should be confirmed by repeat testing A1C 6.6% 11

12 Classification of Diabetes Classification of Diabetes Type 1 diabetes A. Immune mediated B. Idiopathic Type 2 diabetes Features β cell destruction leading to absolute insulin deficiency Insulin resistance +/ insulin deficiency Other specific types A. Genetic defects of β cell funtion B. Genetic defects in insulin action C. Diseases of exocrine pancreas D. Endocrinopathies E. Drug or chemical induced F. Infections G. Uncommon forms of immunemediated diabetes H. 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: ; Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4:

13 Type 1 Diabetes Stage 1 Stage 2 Stage3 Stage Autoimmunity Normoglycemia Presymptomatic Diagnostic Criteria Multiple autoantibodies No IGT or IFG Autoimmunity Dysglycemia Presymptomatic Multiple antibodies FPG mg/dl 2 h PG mg/dl A1C % or 10% increase New onset hyperglycemia Symptomatic 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: EURODIAB ACE Study Group. Lancet. 2000;355: ; Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4: Type 2 Diabetes: Pathogenesis in a Nutshell 13

14 Classification of Diabetes Type 1 diabetes A. Immune mediated B. Idiopathic Type 2 diabetes Other specific types CASE 2 Features β cell destruction leading to absolute insulin deficiency Insulin resistance +/ insulin deficiency A. Genetic defects of β cell funtion B. Genetic defects in insulin action C. Diseases of exocrine pancreas D. Endocrinopathies E. Drug or chemical induced F. Infections G. Uncommon forms of immunemediated diabetes H. Other genetic syndromes associated with diabetes Type 2 Diabetes: Pathogenesis in a Nutshell (cont.) 14

15 Natural History of Type 2 Diabetes Impaired glucose tolerance Undiagnosed diabetes Known diabetes Insulin resistance Insulin secretion Postprandial glucose Fasting glucose Microvascular complications Macrovascular complications Adapted from Ramlo Halsted BA, Edelman SV. Prim Care. 1999;26: Etiology of Type 2 Diabetes Impaired Insulin Secretion and Insulin Resistance Genes and environment Impaired insulin secretion Insulin resistance Impaired glucose tolerance Type 2 diabetes Progressive hyperglycemia and high free fatty acids 15

16 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 Illustration by Kaitlin Jones Hyperglycemia In Type 2 Diabetes Insulin Resistance: Receptor And Postreceptor Defects Increased Glucose Production Glucose Insufficient Glucose Disposal X Liver Peripheral Tissues (skeletal muscle) DeFronzo et al. Diabetes Care. 1992;15: Pancreas Impaired Insulin Secretion 16

17 Beta Cells of Pancreas Secrete Less Insulin Decline of Cell Function in the UKPDS Illustrates Progressive Nature of Diabetes cell function100 (% of normal by HOMA) 80 60? Time of diagnosis 40 Pancreatic function = 50% of normal HOMA=homeostasis model assessment Years Adapted from Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21 S25; UKPDS. Diabetes. 1995;44:

18 Altered Cell Mass and Function in Islets From Subjects With Type 2 Diabetes Decreased Skeletal Muscle Glucose Uptake 18

19 Insulin Resistance and Skeletal Muscle Insulin mediated glucose clearance rates in leg skeletal muscle Dela, Int J Biochem & Cell Biology. 2013, 45: Increased Lipolysis by Adipose Tissue 19

20 Mechanism of Glucotoxicity and Lipotoxicity The Glucosamine Hypothesis Glucose FFA Glucose FFA Other pathways Increased glucosamine Other pathways Impaired insulin secretion from cell Insulin resistance in muscle and fat FFA=free fatty acid Hawkins M et al. J Clin Invest. 1997;99: ; Rossetti L. Endocrinology. 2000;141: High FFA Levels Cause Peripheral and Hepatic Insulin Resistance Glucose Measurements During High Insulin Levels Insulin Insulin + fat infusion 300 * 200 * *P< Peripheral glucose uptake FFA=free fatty acid Boden G, Chen X. J Clin Invest. 1995;96: Hepatic glucose output 20

21 Increased Glucagon by Alpha Cells Glucagon in Type 2 Diabetes 21

22 Regulation of Postprandial Glucose 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 Impaired 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 22

23 Increased Hepatic Glucose Production Increased Hepatic Glucose Output Correlates With Fasting Plasma Glucose 4.0 Glucose output (mg/kg/min) Conclusion: FBG<140 did not 2.0 trigger HGP increase, but increase in HGP1.5 was seen FBG>140. HGP does not play early role in fasting hyperglycemia of T2DM DeFronzo RA. Diabetes. 1988;37: Fasting plasma glucose (mg/dl) HGP observed via glucose turnover studies during post absorptive state Normal r=0.847 P<0.001 Type 2 diabetes 23

24 Neurotransmitter Dysfunction Energy Balance: Afferent and Efferent Signals 24

25 Substances That Promote Positive Energy Balance (Weight Gain) C C Substances That Promote Negative Energy Balance (Weight Loss) 25

26 Decreased Incretin Effect Incretins and Glycemic Control 26

27 Exenatide: Effect on the Cell Incretin Use Schwartz, S. Postgraduate Medicine 2014, 5:

28 Increased Glucose Reabsorption Kidney 28

29 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 insulindependent 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 Common relative Ethnicity Predominantly white More common in minorities Frequency of HLD DR3, Increased Not increased DR4, DQB1*0201, *0302 Islet Autoantibodies Present Absent 29

30 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 Metformin Reduces hepatic glucose output, reduces insulin resistance Thiazolidinedione Reduces insulin resistance in skeletal muscle DPP 4 Inhibitors Increase endogenous GLP 1 and GIP, increasing endogenous insulin in glucosedependent fashion GLP 1 agonists Stimulates insulin through glucosedependent process; reduces glucagon and slows gastric emptying Sulfonylureas/Glinides Release of insulin from beta cells Features Low risk of hypoglycemia GI side effects; risk of lactic acidosis May see modest weight loss Low risk of hypoglycemia Fluid retention, increased fracture risk Weight gain Low risk of hypoglycemia Possible pancreatitis/pancreatic cancer risk Weight neutral Low hypoglycemic risk Possible pancreatitis; C cell hyperplasia in rodents Weight loss Hypoglycemia risk Weight gain 30

31 Type 2 Diabetes Agents Medication Alpha glucosidase inhibitors Inhibits polysaccharide absorption Sodium glucose cotransporter 2 inhibitors (SGLT2) Inhibition of glucose reabsorption in kidneys Bromocriptine Mesylate Short acting dopamine agonist Colesevelam Bile acid sequestrant Features Bloating, flatulence, diarrhea Low risk of hypoglycemia Urinary and GU infections Weight loss Low hypoglycemia risk Nausea and orthostasis Cannot be used in patients on antipsychotic medications Low hypoglycemia risk GI side effects 31

32 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 32

33 CASE 3 A 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) 33

34 CASE 3 Exam: BMI 26.9 (99 th percentile for age); 111/52 Mild acanthosis nigricans of 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 T Thyroid peroxidase Ab 34.8 Thyroglobulin Ab <20 34

35 CASE 3 Criteria for Screening for Type 2 Diabetes in Children Overweight (BMI >85 th percentile, weight for height >85 th percentile, or weigh >120% of ideal for height Plus 2 of the following: Family history of type 2 diabetes in 1 st or 2 nd degree relative Race/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 35

36 CASE 3 The family was counseled on lifestyle intervention, and she was referred to a multidisciplinary clinic for childhood obesity CASE 3 She 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 36

37 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 IFG B) 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 37

38 CASE 3 Would you repeat screening for diabetes? A) No, recent screening showed IFG B) 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 38

39 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

40 CASE 3 Classification of Diabetes Type 1 diabetes A. Immune mediated B. Idiopathic Type 2 diabetes Other specific types Features β cell destruction leading to absolute insulin deficiency Insulin resistance +/ insulin deficiency A. Genetic defects of β cell funtion B. Genetic defects in insulin action C. Diseases of exocrine pancreas D. Endocrinopathies E. Drug or chemical induced F. Infections G. Uncommon forms of immunemediated diabetes H. Other genetic syndromes associated with diabetes Classification of Diabetes Classification of Diabetes Type 1 diabetes A. Immune mediated B. Idiopathic Type 2 diabetes Features β cell destruction leading to absolute insulin deficiency Insulin resistance +/ insulin deficiency Other specific types A. Genetic defects of β cell funtion B. Genetic defects in insulin action C. Diseases of exocrine pancreas D. Endocrinopathies E. Drug or chemical induced F. Infections G. Uncommon forms of immunemediated diabetes H. Other genetic syndromes associated with diabetes 40

41 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 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,

42 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, 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 insulin Fajans & Bell, Diab Care, 34, 2011: Up to Date. Classification of diabetes mellitus and genetic diabetic syndromes,

43 Genetic Syndromes Associated with Diabetes Mellitus Thomas, CC. Med Clin N Am. 99 (2015): Drug Associated Diabetes Mellitus Thomas, CC. Med Clin N Am. 99 (2015):

44 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: Summary of Pathophysiology 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 44

45 Summary of Pathophysiology 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 Questions? 45