Classification & Risk Factors for Diabetes Mellitus Frank Schwartz, MD FACE Prof. of Endocrinology J O Watson Chair for Diabetes Research Director: The OU Diabetes Institute

Objectives of Lecture Present an overview of the common forms of Diabetes Mellitus Review the pathogenesis of each Describe the risk factors for developing each

Definition of Diabetes Mellitus A chronic disorder of carbohydrate & fat metabolism….. due to absolute/or relative deficiency in insulin secretion……. &/or ineffective biological responses to insulin….. resulting in hyperglycemia

Diagnostic Criteria for Diabetes Mellitus Normal Impaired Glucose Tolerance Diabetes Mellitus Fasting Glucose (mg/dl) <100 100-125 >126 2 Hour Post Glucose Load (mg/dl) <140 >140 but <200 <200

Classification of Diabetes Mellitus

Two Major Forms of Diabetes Mellitus Type 1 Diabetes (T1DM) -Absolute insulin deficiency resulting from beta-cell destruction….. usually caused by an autoimmune process Type 2 Diabetes (T2DM) -Biological ineffectiveness of insulin action (Insulin resistance) and/or beta cell secretory defects…..a major factor is thought to be acquisition of visceral obesity in genetically susceptible individuals

Type 1 Diabetes Mellitus (T1DM) Caused by beta cell destruction -Pattern A: autoimmune process -Pattern B: unknown cause (viral?) Occurs most commonly during childhood, adolescence, & early adulthood….. but can occur at any age including persons > 40 Latent Autoimmune Diabetes of Adulthood (LADA)

Type 2 Diabetes Mellitus T2DM) Most common form of diabetes accounting for >90 % of all cases Occurs most commonly in adulthood, but prevalence in children & adolescents is increasing rapidly Risk is highly correlated with acquisition of visceral obesity …. resulting in insulin resistance & “relative” insulin deficiency

Other Common Forms of Diabetes Mellitus Impaired Glucose Tolerance (IGD) -Abnormal glucose levels but not fulfilling criteria for diagnosis of type 2 diabetes -> 50 % risk of going on to develop DM Gestational Diabetes (GD) -Development of DM during pregnancy which usually resolves following pregnancy Secondary Diabetes -Glucose intolerance induced by another disease which resolves when condition is treated/corrected

Gestational Diabetes (GD) Defined as onset of diabetes induced by pregnancy which resolves following the pregnancy 50% life-time risk of progression to T2DM during lifetime Can be prevented with life-style intervention Both T1DM & T2DM can also occur during pregnancy

Secondary Diabetes Diabetes & glucose intolerance induced by another medical condition, which then resolves following the resolution of that medical condition

Overlapping Forms of Diabetes Mellitus

Double Diabetes or Diabetes 1.5 The occurrence of insulin deficiency & insulin resistance in same patient Children who have T1DM….but with a family history of T2DM….. are more prone to obesity & insulin resistance Tend to have much greater insulin requirements than other patients their age @ which is especially accelerated at puberty

What Causes T1DM?

Pathogenesis of T1DM Viral or immune cell mediated destruction of β-Cell which results in a rapid or progressive decline in Insulin production “Immune markers” for T1DM may occur years before the onset of disease

Factors Contributing To Development of T1DM Genetic susceptibility Environmental triggers Abnormalities in immune regulation (inherited vs acquired?) Loss of self tolerance (inherited vs acquired?)

Family History & Risk For Developing T1DM 0.4% occurrence rate in persons with no family history of T1DM 6-11% in offspring of person with T1DM 5% in siblings of person with T1DM 30-40% in identical twins > 90% of individuals with new- onset T1DM have no family history!!!

Induction of Autoimmunity Pathogenesis of T1DM Genes + Environment Immune Regulation Induction of Autoimmunity Trigger ? Virus Beta Cell Destruction Type 1 Diabetes

Viral Induction of Insulitis Beta Cell Viral Replication IFIH1 ii) Induction of Innate Immune Response & β Cell Death Type 1 IFNs Viral Antigen i) Direct β Cell Lysis & Death MHC Class I CD8+ T-cell Self Antigens: IAA, GAD iii) Induction of Autoimmune Response & b Cell Death Viral Induction of Insulitis

Natural History of T1DM -Cell mass 100% Time (Months) ? Viral Trigger Initiation of autoimmune response Detection of circulating autoantibodies (ICA, GAD65, IAA, IAA-2) Progressive loss of beta-cell mass induced by CD4+ & CD8+ cells Glucose intolerance < 15-20 % of -cells are “functional” remain Genetic predisposition Insulitis -Cell injury “Pre”-diabetes Diabetes Time (Months) Eisenbarth GS. N Engl J Med. 1986;314:1360-1368

Schematic For Viral Initiation of T1DM Genetic Predisposition HLA DR3/4 SNP’s Beta cell mass Viral Infection of β cell Activation of TLR3 in T cells & Macrophages & stimulation of NKT cell invasion Induction of Autoimmune Insulitis Pathologic expression & activation of TLR3 NF-κB, IFNγ, & STAT-3 ICA, GAD65, IA-2AA TH1 , NKT cells Resolution of Viral or Autoimmune Insulitis Variable Progression to T1DM-B Variable Progression to T1DM-A

Prevention of T1DM: How Can We Approach This? There are no specific genetic markers Most patients with new-onset T1DM have no family history Detection of Islet-Cell antibodies (ICA’s) are not 100% specific…. & these are usually only checked in first degree relatives of persons with diabetes

Potential Therapeutic Targets for Preventing/Reversing T1DM

Conclusions There are at least two patterns of T1DM…one is autoimmune mediated (Pattern A) & the other (Pattern B) is probably viral mediated Onset of T1DM following initiation of insulitis is variable & spontaneous recovery can occur These patients require life-long insulin therapy

What Causes T2DM?

Risk Factors for T2DM Family history/genetics Obesity Western life-style Tobacco use Lack of exercise Hypertension & Hyperlipidemia Gestational diabetes

Impaired insulin secretion Pathogenesis of T2DM Genes and environment + Impaired insulin secretion Insulin resistance Impaired glucose tolerance Type 2 diabetes

Natural History of T2DM Post Meal Glucose Fasting Glucose 350 250 Fasting Glucose Glucose 150 50 Insulin Resistance 300 Relative Function 200 The relationship of increased postprandial and fasting glucose levels, insulin resistance, and insulin levels in subjects with type 2 diabetes are illustrated in this figure. Bergenstal RM, Kendall DM, Franz MJ, Rubenstein AH. Management of type 2 diabetes: a systematic approach to meeting standards of care. II: Oral agents, insulin and management of complications. In Endocrinology, 4th ed, 2001. De Groo LJ and Jameson JL, editors. WB Saunders Co, Phila. (Originally published in Type 2 Diabetes BASICS, ©200 International Diabetes Center, Minneapolis). Used with permission. 100 At risk for Diabetes Insulin Level Beta Cell Failure -10 -5 5 10 15 20 25 30 Years of Diabetes Bergenstal, ©2000 International Diabetes Center Used with permission.

Major Factors Involved In Pathogenesis of T2DM Insulin Resistance -Acquisition of visceral obesity…leads to Lipotoxicity, & impaired Insulin signaling Beta Cell Secretory Defects -Impaired first phase insulin release secondary to Lipotoxicity, Glucotoxicity, & loss of Incretion secretion

Visceral Fat Topography “Bubba” depicting visceral adiposity. Visceral adipose tissue is in close proximity to vital organs including the pancreas.

Visceral Obesity  Insulin Resistance Hypertrophic Fat Cells Increased Free Fatty Acids Cellular Defects in Insulin Signaling Mitochondrial Dysfunction It has been firmly established that visceral obesity leads to cellular defects in insulin signaling, hypertrophy of fat cells, increased free fatty acids, and mitochondrial dysfunction. Smith, S. and Ravussin, E. Curr Diab Rep. 2002;2:223-230.

Lipotoxicity The pathologic changes in organs resultant from elevated fat levels in blood or tissues, as in the diabetic liver. A good general definition of lipotoxicity is the pathologic changes in organs resultant from elevated fat levels in blood or tissues, as in the diabetic liver as defined by medilexicon. However, in terms of type 2 diabetes lipotoxicity is thought of as the pathologic effect of fat on insulin signaling (i.e. insulin resistance) that manifests in glucose intolerance and T2DM. http://www.medilexicon.com/medicaldictionary.php?t=50859

Ectopic Deposition of Fat in T2DM Hi TG’s Hi FFA’s Intramuscular Islet Cells Subcutaneous Here Bubba is depicting ectopic deposition of fat in insulin target tissues that causes lipotoxicity. Intrahepatic Intra- abdominal

Acylation-Stimulating Protein Adipokines TNF- IL-6, IL-8 MCP-1 TGF  FGF EGF IGF-1 IGFBP Bone Morphogenic Protein Fatty acids Lysophospholipid Lactate Adenosine Prostaglandins Glutamine Visfatin Resistin Adipose Tissue Adiponectin Unknown Factors Adipsin Agouti Here are some of the adipokines produced from adipocytes. Most adipokines are involved in the development of insulin resistance, beta cell dysfunction and T2DM like TNFa, and IL-6. Adiponectin, on the other hand is a “good” adipokine that normally enhances insulin sensitivity, glucose tolerance, and fatty acid oxidation in muscle. However, its blood concentration is reduced in obese people and those with T2DM. Estrogen Retinol Angiotensin-II PAI-1 Leptin Angiotensin Acylation-Stimulating Protein

Insulin Signaling Defects in T2DM Mechanism of Insulin Resistance

This slide graphically depicts insulin signaling defects and insulin resistance. Baudry et al., 2002

Natural History of T2DM Post Meal Glucose Fasting Glucose 350 250 Fasting Glucose Glucose 150 50 Insulin Resistance 300 Relative Function 200 The relationship of increased postprandial and fasting glucose levels, insulin resistance, and insulin levels in subjects with type 2 diabetes are illustrated in this figure. Bergenstal RM, Kendall DM, Franz MJ, Rubenstein AH. Management of type 2 diabetes: a systematic approach to meeting standards of care. II: Oral agents, insulin and management of complications. In Endocrinology, 4th ed, 2001. De Groo LJ and Jameson JL, editors. WB Saunders Co, Phila. (Originally published in Type 2 Diabetes BASICS, ©200 International Diabetes Center, Minneapolis). Used with permission. 100 At risk for Diabetes Insulin Level Beta Cell Failure -10 -5 5 10 15 20 25 30 Years of Diabetes Bergenstal, ©2000 International Diabetes Center Used with permission.

Glucotoxicity As the beta cell begins to decompensate, post- prandial & then fasting glucose levels rise Once BS’s are elevated…..Hyperglycemia itself has an adverse effect on insulin release from beta cell Note to myself: How does hyperglycemia induce adverse effects on insulin release from beta cell?

Glucotoxicity: Effect of Glucose Levels on Insulin Release FPG (mg/dL) 79-89 90-99 100-114 115-149 150-349 N 24 20 7 3 12 800 600 400 200 -100 15 30 60 90 120 Relative Acute Insulin Response (% Increase) Fasting glucose level above 115 mg/dl will inhibit post-meal first phase insulin release by >50%!!!! Time (minutes)

Summary Acquisition of visceral obesity, ectopic fat deposition in liver, muscle, & beta cells are major factors in pathogenesis of T2DM Excessive adipokine production by visceral adipocytes are key contributors to the development of Lipotoxicity & Insulin Resistance

Summary Glucotoxicity contributes to impaired insulin release Impaired incretin secretion contributes to impaired insulin release & excessive glucagon secretion

Summary Eventual β-Cell exhaustion & cell death are the final result of this process Most persons with T2DM exhibit insulin deficiency by 8 years