Diabetes: Definition Pathophysiology Treatment Goals. By Scott Magee, MD, FACE

Diabetes: Definition Pathophysiology Treatment Goals By Scott Magee, MD, FACE

Disclosures No disclosures to report

Definition of Diabetes Mellitus Diabetes Mellitus comprises a group of disorders characterized by high blood glucose levels. Four major types: Type 1 Type 2 Gestational Diabetes secondary to other conditions

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

A1C Measures your average blood sugar over last 3 months

Hemoglobin A1C Correlation between HbA1C level and mean plasma glucose levels 5% 6% 7% 8% 9% 10% 11% 12% 97 mg/dl 126mg/dl 154mg/dl 183mg/dl 212mg/dl 240mg/dl 269mg/dl 298mg/dl A1C to eag Conversion Chart A calculator for converting A1c results is available at: http://professional.diabetes.org/eag

Diagnosis of Diabetes A1c > 6.5% OR FPG > 126 mg/dl OR Two-hour PG > 200 mg/dl during a 75 g OGTT OR In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose of > 200 mg/dl ADA Standards of Medical Care in Diabetes-2015

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

Normal Pancreatic Islet

Islet staining for Glucagon (R) and Insulin (L)

Autoimmune Isletitis

Models for Pathogenesis of T1DM van Belle TL, et al. Physiol Rev. 2011;91:79-118.

TYPE 1 DIABETES PRESENTATION * USUALLY MORE RAPID ONSET OF HYPERGLYCEMIC SYMPTOMS OVER WEEKS ESPECAILLY IN <20 YO * MARKEDLY ELEVATED GLUCOSE * OFTEN LEAN * OFTEN NEGATIVE FH * DKA AT PRESENTATION IS COMMON * MEASUREMENT OF AT LEAST 2 AUTOANTIBODIES AT DIAGNOSIS IS STANDARD OF CARE AND ARE PRESENT IN 80 TO 90 % OF ALL PTS AT DIAGNOSIS

Serum insulin (µu/ml) Normal Insulin Secretion 60 50 40 30 20 Bolus (meal) insulin needs Meal Meal Meal 10 0 Basal (background) insulin needs 0 2 4 6 8 10 12 14 16 18 20 22 24 Time

Plasma insulin Basal/Bolus Treatment Program With Rapid- Acting and Long-Acting Analogs Rapid (lispro, aspart, glulisine) Rapid (lispro, aspart, glulisine) Rapid (lispro, aspart, glulisine) Glargine or detemir 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Breakfast Lunch Dinner Bed

A1C levels and the risk of complications in type 1 diabetes Diabetes Control and Complications Trial Adapted from DCCT. Diabetes 1995;44:968-43.

Survival in Scotland: People with T1DM vs. general population SJ Livingstone et al, JAMA 2015: 3013 (1) 37-44

DCCT/EDIC: Long-Term Benefits of Early Intensive Glycemic Control Intensive glycemic control over a mean of 6.5 years reduced CVD complications by 57% after a mean of 17 years of follow-up Nathan DM, et al. N Engl J Med. 2005;353:2643-2653.

Prevalence of DM and Pre-DM in USA, 2012 T.M. Dall et al, Diabetes Care 2014; #37: 3172-3179.

Progression to Type 2 Diabetes Impaired Glucose Tolerance Or both Impaired Fasting Glucose Diabetes Prediabetes

Natural History of Type 2 Diabetes Years from diagnosis Incretin effect -Cell function 10 5 0 5 10 15 Onset Diagnosis Insulin resistance Insulin secretion Postprandial glucose Fasting glucose Prediabetes Microvascular complications Macrovascular complications Type 2 diabetes 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 30 Group. Diabetes. 1995;44:1249-1258

Factors that May Drive the Progressive Decline of -Cell Function Insulin Resistance Glucose Toxicity (hyperglycemia) Lipotoxicity (elevated FFA, TG) -Cell Dysfunction FFA = free fatty acids; TG = triglycerides. Kahn SE. J Clin Endocrinol Metab. 2001;86:4047-4058. Ludwig DS. JAMA. 2002;287:2414-2423.

Plasma IRI (µu/ml) Acute Insulin Response Is Reduced in Type 2 Diabetes 1st 2nd phase 120 100 20 g glucose infusion Normal (n=85) Type 2 diabetes (n=160) 80 60 40 20 0-30 0 30 60 90 120 Time (minutes) 33 IRI=immunoreactive insulin. Pfeifer MA, et al. Am J Med. 1981;70:579-588.

Total Body Glucose Uptake (mg/kg min) Leg Glucose Uptake (mg/kg leg wt per min) Defective Insulin Action in T2DM 7 12 6 5 4 8 3 2 1 4 P<0.01 0 Normal T2DM 0 0 20 60 100 Time (minutes) 140 180 DeFronzo RA, et al. J Clin Invest. 1979;63:939-946; DeFronzo RA, et al. J Clin Invest. 1985;76:149-155. 34

Mechanisms of hyperglycemia in T2DM

Median A1C (%) Traditional Monotherapies Do Not Maintain A1C Control Over Time United Kingdom Prospective Diabetes Study (UKPDS) 10 9 8 7 6 0 0 3 6 Time From Randomization (Years) ADA Goal 9 12 15 Conventional* Insulin Glibenclamide (glyburide) Metformin *Conventional therapy defined as dietary advice given at 3-month intervals where FPG was targeted at best levels feasible in clinical practice. If FPG exceeded 270 mg/dl, then patients were re-randomized to receive non-intensive metformin, chlorpropamide, glibenclamide, or insulin. If FPG exceeded 270 mg/dl again, then those on SU would have metformin added. If FPG exceeded 270 mg/dl after this, then insulin was substituted. Adapted with permission from UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854-865.

Gestational Diabetes Gestational Diabetes Mellitus (GDM) is diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes. ASA Standards of Medical in Diabetes 2015.

Diagnosis of GDM One Step Two Step 75 G OGTT 100 G OGTT Fasting: > 92 mg/dl Fasting: > 95 mg/dl 1h: > 180 mg/dl 1h: > 180 mg/dl 2h: > 153 mg/dl 2h: > 155 mg/dl 3h: > 140 mg/dl One abnormal Two abnormal

Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study 6 yr international study Approximately 25,000 pregnant women Studied association of various levels of glucose intolerance during the 3 rd trimester on risk of adverse outcomes of the baby Macrosomia strong association (4-6 times) Hyperinsulinemia-strong association (10 times) from low to high in range C-section-weak association Hypoglycemia-weak association New Findings in Gestational Diabetes-the HAPO Study, Metzger, et al Diabetes Voice, May 2009. Volume 54. Special Issue

Target Blood Glucose in Pregnancy Fasting 1 hour 2 hour ACOG <95 130-140 <120 ADA <105 <155 <130 ACE 60-90 <120

GDM Complications Macrosomia

Effects of treatment of GDM on outcomes. Jovanovic, Endocrine Practice; Vol. 14, No. 2, March 2008

Why test blood glucose? Adjunct to and verification of A1c Allows patient and provider to evaluate response to therapy and assess if glycemic targets are being met Results can be useful in preventing hypoglycemia and adjusting diet, exercise and medications

When to test? Intensive Insulin Therapy Pre meals Occasionally post prandial Bedtime Pre/post exercise Suspected hypoglycemia During treatment for hypoglycemia Before critical tasks (driving)

Date Breakfast Lunch Dinner Bedtime 3/12 112 3/13 3/14 136 3/15 3/16 89 3/17 3/18 114

Grid analysis of SMBG

Date Breakfast Lunch Dinner Bedtime 3/12 102 90 189 3/13 115 103 3/14 105 130 3/15 96 119 3/16 89 127 3/17 120 95 3/18 112 164 3/19 104 122 3/20 117 145

Grid analysis of SMBG

Date Breakfast Lunch Dinner Bedtime 3/10 3/9 120 107 63 174 3/10 105 86 88 120 3/11 112 139 72 158 3/12 99 122 94 105 3/13 72 124 55 180 3/14 133 99 109 112 3/15 92 103 116 96 3/16 86 88 59 200 3/17 104 128 100 99 3/18 131 115 72 127

Grid analysis of SMBG

Questions