• Introduction• Function of the Endocrine Pancreas

• Insulin• Glucagon• Incretins• Somatostatin

• Diabetes Mellitus• Type 1 Diabetes• Type 2 Diabetes• Measures of Glycemic Control• Ketone Testing

• Hypoglycemia• Hypoglycemic Disorders

• Inborn Errors of Carbohydrate Metabolism• Defects in Galactose Metabolism• Defects in Fructose Metabolism

• Lactic Acidosis

• Carbohydrates are major constituents of physiological systems.

• The concentration of glucose in blood is normally controlled within narrow limits

Function of the Endocrine Pancreas

• as both an endocrine and exocrine organ in the control of carbohydrate metabolism

• Exocrine • Amylase

• The endocrine pancreas secretes four hormones

• Disease states occur when insulin concentrations are inappropriate for given blood glucose levels.

Processing of proinsulin to insulin. Green circles represent cysteine residues that participate in disulfide bonding.

Diabetes Mellitus: Introduction

• a group of diseases in which blood glucose levels are elevated• Deficient insulin secretion and/or abnormal action.• the most common set of disorders of carbohydrate metabolism

• The prevalence of diabetes• 33% of males and 39% females

• A chronic disease, responsible for significant morbidity, mortality & cost.

• People with diabetes are at least two to four times more likely to have heart disease and cerebrovascular disease

• Criteria for the diagnosis of diabetes• Pre-diabetes

• Impaired fasting glucose• Impaired glucose tolerance• at increased risk for cardiovascular & cerebrovascular diseases.

Diagnosis of Pre-Diabetes and Diabetes Mellitus

Diagnosis of Gestational Diabetes Mellitus

the metabolic syndrome

• A cluster of clinical disorders• Increased risk of cardiovascular disease & of developing diabetes• The criteria defining the metabolic syndrome

• the presence of three or more of the following: • impaired fasting glucose• blood pressure ≥ 130/85 mmHg• Waist circumference > 102 cm in men and > 88 cm in women,• Serum triglycerides ≥ 150 mg/dL (1.695 mmol/L• HDL-cholesterol < 40 mgfdL (1.036 mmol/L) in men and < 50 mg/dL (1.295 mmol/L) In

women.• Most commonly, these individuals are insulin resistant and have smaller, denser, more

atherogenic LDL-cholesterol particles.

• The most common forms of diabetes are type 1 and type 2 diabetes (Table).

• Uncommon causes of diabetes (Table)

Classification of Diabetes Mellitus

Classification of Diabetes Mellitus (Cont'd)

Classification of Diabetes Mellitus (Cont'd)

Characteristics of Type 1 and Type 2 Diabetes Mellitus

Type 1 Diabetes

• Antibody markers of beta cell destruction are commonly present before and at the time of the onset of the diabetes

• antibodies to the 65-kDa isoform of glutamic acid decarboxylase (GAD65)• insulin autoantibodies (IAA) • and islet cell antigen 512 autoantibodies (ICA512l.

• ICA512 are autoantibodies to parts of the tyrosine phosphatase IA-2 antigen.

• Greatest risk • High titers of multiple autoantibodies.• Detection of at least two autoantibodies is associated • GAD65 has the highest sensitivity (91%) • IAA are more common in young children who develop type I diabetes, whereas

GAD65 is more common in adults.

• The 'pre-diabetes' period of gradual and progressive beta cell destruction can last for months, years or decades

• First phase insulin release

Type 2 Diabetes

Measures of Glycemic Control

• Glycosylated hemoglobin (GHb) is formed nonenzymatically by the two-step reaction

• HbA1C definition • as the hemoglobin A that is irreversibly glycosylated at one or both N-

terminal valines of the p-chains of the tetrameric hemoglobin molecule, including hemoglobin that may also (but not solely be glycosylated on lysine residues.

• an index of average blood glucose levels over the past 2-4 months.

Correlation Between HbA1C and Mean Plasma Glucose Levels

Glycemic Goals

• GHb assays vary in reliability in the presence of a variety of factors.• carbamylated hemoglobin can occur with uremia • hypenriglyceridemia and hyperbilirubinemia, and salicylates • Hemoglobinopathies • Transfusions • Chronic alcohol or opiate use, iron deficiency and lead poisoning• Vitamins C and E • sample storage effects • Hemolysis• splenectomy, • people without diabetes have HbA1C levels between 4-6%.

• glycosylated proteins or glycosylated albumin• glycemic control over narrower periods of time.

• useful in patients for whom HbA)( assays are inaccurate• hemoglobinopathies and hemolytic anemias

• However, their clinical utility has not been firmly established.

Ketone Testing

• beta-hydroxybutyric acid, acetoacetic acid and acetone• Particularly important for individuals with type 1 diabetes mellitus to

detect ketosis.• determining the etiology of hypoglycemic disorders• The ratio of beta-hydroxybutyrate acid to acetoacetic acid is greatly

increased in DKA

Diabetic ketoacidosis (DKA)