Diabetes: Causes and consequences Carlos O. Mendivil , MD

What is Diabetes? It is: A syndrome Heterogeneous Characterized by high blood glucose Not curable as of today Potentially fatal (directly or indirectly)

There is always a deficit of What causes Diabetes Mellitus? Multifactorial Environmental factors Genetic factors There is always a deficit of INSULIN ACTION

What causes Diabetes Mellitus? Trends in the prevalence and incidence of diabetes and obesity in the US Obesity prevalence 9 25 Year ´63 ´05 Diabetes incidence % Diabetes prevalence ADA Scientific Sessions, Chicago, 2007

Why is there insuficient insulin action? 1 Secretory dysfunction in pancreatic beta cells Relative or absolute deficit of insulin secretion 2 Insulin resistance Insuficient tissue response to the actions of insulin, DESPITE NORMAL CONCENTRATIONS of insulin

How does diabetes affect the body ? Insuficient insulin action alters metabolism of: Lipids Carbohydrates - Proteins Complications Acute Chronic Life-threatening Severe Disabling - Debilitating Costly - Some of them may cause death

The chronic complications of diabetes Macrovascular Microvascular Coronary disease Nephropathy Neuropathy Cerebrovascular disease Retinopathy Peripheral Arterial disease + Orthopedic alterations Metabolic alterations Diabetic foot

Why are the complications of diabetes important? DM is the #1 cause of renal failure worldwide The kidney foundation: www.kidney.org

Why are the complications of diabetes important? Worlwide #1 cause of: Acquired blindness Amputation not due to trauma Contributes importantly to the risk of: Myocardial infarction (heart attacks) Cerebrovascular disease (strokes)

Diabetic retinopathy www.ambrosio-eye-care-boston.com

Diabetic nephropathy

The progression of diabetic nephropathy http://www.videolife.tk/video/ikGl7DPXUK0/Diabetic-Nephropathy.html

Diabetic neuropathy

The “diabetic foot”

Diabetes and erectile dysfunction

% Why are the complications of diabetes important? Diabetes and risk of myocardial infarction 45 % 20 18,8 3,5 NO DM NO prior MI NO DM Prior MI DM NO prior MI DM + prior MI Haffner et al NEJM 1997

Why are the complications of diabetes important? Because they can be avoided !! Joslin fifty year medal Given to patients who live at least 50 years after the diagnosis of type 1 diabetes More than 2,500 granted so far

Diagnosis of Diabetes Mellitus 1 Random plasma glucose 2 Fasting plasma glucose (FPG) 3 Oral glucose tolerance test (OGTT) 4 Glycated hemoglobin (A1c)

Fasting Postload A1c Normal IFG DM Normal IGT DM Pre- diabetes Normal 100 mg/dL 126 mg/dL Postload Normal IGT DM 140 mg/dL 200 mg/dL Pre- diabetes A1c Normal DM 6% 6.5%

What’s the difference ? Diabetes Care 2003; suppl 1:S5

When two different tests classify a patient differently, he must be classified in the most severe category

Which tests DO NOT diagnose diabetes ? Capillary glucose Fructosamine C peptide Insulinemia Triglycerides

Classification of Diabetes Mellitus

Classification of Diabetes Mellitus Type1 Type 2 Gestational Other types

Type 1 diabetes Destruction of beta cells Autoimmune process Total or near total insulin deficiency Insulin required for survival More incident in infancy and puberty High propensity to ketoacidosis Predilection for female gender and caucasian ethnicity

Classification of Diabetes Mellitus Type1 Type 2 Gestational Other types

Type 2 Relative secretory dysfunction of beta cells Relative insulin deficit Peripheral resistance to insulin actions 80% of patients are overweight More incident in adulthood and older age Less prone to ketoacidosis Not as much gender/ethnicity imbalance

Classification of Diabetes Mellitus Type1 Type 2 Gestational Other types

Any degree of carbohydrate intolerance Gestational diabetes Any degree of carbohydrate intolerance That is discovered during pregnancy

Classification of Diabetes Mellitus Type1 Type 2 Gestational Other types

What’s the origin of type 1 diabetes ?

The natural history of type 1 diabetes Loss of first peak of insulin secretion Environmental trigger 100% IGT IFG Genetic susceptibility Auto immunity % intact beta cells T1DM Compl Time

The natural history of type 1 diabetes % intact beta cells 100% Time Genetic susceptibility

Genetic susceptibility to type 1 diabetes RISK MARKERS HLA Class II HLA DR HLA DQ IDDM 1-12 markers HLA Gene cluster in chromosome 6p Class 1 A B C Class 2 DP DQ alfa DR DQ beta

x x Lymphocyte selection during embryonic life Pre-T lymphocyte Recognizes very well x “Half recognizes” Does not recognize x Pre-T lymphocyte Proteins of the body Thymus dendritic cell T-cell receptor HLA class II molecule

Hypotheses about HLA and type 1 diabetes Some class II HLA’s present self-antigens better Sme HLA class II activate helper lymphocytes better Some HLA’s class II activate regulatory T Lymphocytes better

The natural history of type 1 diabetes Environmental trigger % intact beta cells 100% Time Genetic susceptibility

The natural history of type 1 diabetes Environmental trigger % intact beta cells 100% Time Genetic susceptibility Auto immunity

IAA ICA GADA IA-2 How is the autoimmune process manifested? Insulin Antibodies ICA Islet Cell Antibodies GADA Glutamic Acid Decarboxylase Antibodies IA-2 Ab’s against IA-2 phosphatase

The natural history of type 1 diabetes Environmental trigger Loss of first insulin Secretory peak % intact B cells 100% Genetic susceptibility Auto immunity IGT IFG T1 DM What determines the speed of progression ?

Determining factors in the progression of type 1 diabetes Earlier age at diagnosis Faster progression Age Faster progression Sex Male Faster progression # of antibodies More Ketoacidosis at diagnosis Faster progression

The natural history of type 1 diabetes Environmental trigger Loss of first insulin Secretory peak Genetic susceptibility Auto immunity IGT IFG T1 DM Compl

What is the origin of type 2 diabetes ? The Natural History of Insulin Secretory Dysfunction and Insulin Resistance in the Pathogenesis of type 2 Diabetes Mellitus Journal of Clinical Investigation, Vol 104 #6 Sep 1999

Type 2 diabetes is characterized by 4 basic metabolic Disturbances: Obesity Insulin resistance Insulin secretory dysfunction Increase in hepatic glucose production (HGP)

404 individuals from the Gila River community in Arizona Methods 1982 404 individuals from the Gila River community in Arizona Clinical history, physical exam, routine labs Measurement of: Body composition Insulin sensitivity Fat distribution Hepatic glucose production Glucose tolerance Yearly follow-ups for over a decade (11 yrs) Bogardus et al, JCI 2000

Insulin response pmol/L Fasting 120 min post 30 m post Progressors Nonprogressors NGT IGT DM2 200 400 600 800 1000 1200 1400 1600 1800 2000 pmol/L

Insulin sensitivity in muscle NGT DM2 NTG 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5 Progressors Nonprogressors (mg/Kg EBMS/min) M

Acute Insulin Response Beta cell function 500 Progressors 450 Nonprogressors 400 350 300 Acute Insulin Response (microUI/ml) 250 200 150 100 50 NTG NTG IHC NGT DM2 NGT

Liver glucose production 5 Progressors 4,5 Nonprogressors 4 3,5 3 (mg/Kg EBMS/min) EGO 2,5 2 1,5 1 0.5 NTG NTG IHC NGT DM2 NGT

DM2 Genetically “weak” beta cell Unhealthy lifestyle Adiposity Free fatty acids TNF-a Adiposity Insulin resistance Greater demands for b cell More secretion Loss of 1st insulin secretion peak - IGT Secretory dysfunction Increased liver glucose production IFG DM2

What’s the origin of type 2 diabetes ? Sedentary life Caloric imbalance Loss of 1st insulin Secretion peak % beta cell function 100% Genetic Susept. Excess adiposity Insulin resistance DM2 IFG or IGT Compl

Threshold for insulin actions - Muscle glucose uptake - K+ uptake by cells - Stimulation of protein synthesis - Effects on gene expression - Inhibition of lipolysis 100 mUI/mL Insulin effects 20 mUI/mL Just inhibition of lipolysis

When does diabetes give you symptoms ? 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 mg/dL Glucose escapes into urine Total reabsorption of filtered glucose

Origin of the symptoms of type 2 diabetes Deficit of insulin action Severe Lipolysis Hiperglycemia b-oxidation Polyuria Glycosuria Ketogenesis Dehydration Nutrient loss Ketonemia Polydipsia Polyphagia Weight loss Acidosis Ketonuria

Some interesting observations on the environmental determinants of type 2 diabetes

Depressed mood and risk of diabetes Hu et al. Arch Int Med 2010

Urinary BPA in type 2 diabetics Lang et al. JAMA 2008

How to prevent it ? Tuomilehto NEJM 2001

Thank you