Lecture 3 Lm

Lecture 3 Impaired Glucose Metabolism: Diabetes Mellitus

• Normal plasma glucose: 3.9-8.3 mM • Plasma glucose is tightly regulated by hormones: Insulin: ↓ Plasma glucose

• Glucagon Epinephrine Cortisol Growth hormone

↑ Plasma glucose

Regulation of Blood Glucose by Insulin High blood glucose

Blood vessel

Muscle

+

+

Pancreas

Insulin

+ Adipose tissue

_

Glucagon

_ Liver Glucose production

↑Glucose uptake ↑Glucose storage Fig 15 handout

Regulation of Blood Glucose by Glucagon Blood vessel Pancreas

+ Glucagon

Low blood glucose

Peripheral tissues Glucose

+

Glucose production

Liver

Fig 15 handout

Diabetes Mellitus Definition: A chronic metabolic disorder characterized by hyperglycemia resulting from impaired insulin secretion and/or action.

Hyperglycemia: ↑ in blood glucose

• Diabetes = “siphon” or “running through” Large urine volume

• Mellitus = sweet Glucose in urine

• Diabetes is the most common endocrine disorder.

Criteria for Diagnosis: Each of the following:

• Symptoms + random plasma glucose >11.1 mM (200 mg/dl)

• Fasting plasma glucose >7 mM (126 mg/dl) • Oral glucose tolerance test (OGTT): 2-h plasma glucose >11.1 mM (200 mg/dl)

Classification of Diabetes Type 1 Diabetes - Insulin-dependent diabetes mellitus (IDDM) - Juvenile-onset diabetes Type 2 Diabetes - Non-insulin-dependent diabetes mellitus (NIDDM) - Adult-onset diabetes

Characteristics of Type 1 Diabetes - Hypoinsulinemia (↓insulin levels) - 10% of diabetic cases - Patients require insulin - Age of onset: childhood - Ketoacidosis (↑ketones in blood)

Etiology of Type 1 Diabetes • Autoimmune disease • Selective destruction of β cells by T cells • Several circulating antibodies against β cells • Cause of autoimmune attack: unknown • Both genetic & environmental factors are important

Etiology of Type 1 Diabetes Environmental Factors

e.g.

Viruses Coxsackie Mumps Rubella

Babies

Cow milk

May attack β cells

Nutrients e.g. Cow milk

Antibodies against cow insulin Closely resembles human insulin

Genetic Factors • There is a close correlation between type 1 diabetes & some classes of MHC genes

- e.g. genes encoding HLA-DR & HLA-DQ - They can either ↑ the risk of diabetes or protect against the disease MHC: major histocompatibility complex HLA: human leukocyte antigen

Role of HLA Molecules in Antigen Presentation T-cell receptor

HLA molecule

T-cell Antigen Activated Immune response

Antigen presenting cell (APC) Fig 16 handout

Characteristics of Type 2 Diabetes - Impaired insulin action - Insulin secretion is normal or increased - 90% of diabetic cases - Age of onset: adulthood - Associated with obesity - Ketoacidosis: rare - Most patients don’t require insulin

Type 2 Diabetes Impaired Insulin Action

β Cell Dysfunction/Death

ß-Cell ↑ Glucose Production

↓ Glucose Utilization

Impaired Insulin Secretion

Etiology of Type 2 Diabetes • Response to insulin is decreased - ↓glucose uptake (muscle, fat) - ↑glucose production (liver)

• The mechanism of insulin resistance is unclear

• Both genetic & environmental factors are involved

• Post insulin receptor defects

Mechanism of Hyperglycemia in Diabetes Absolute (type 1 diabetes) or relative (type 2 diabetes) insulin deficiency: - An increase in hepatic glucose output - A decrease in peripheral glucose uptake & utilization

Increase in Hepatic Glucose Output ↓insulin ↓inhibitory effect on glucagon secretion ↑glucagon

Liver gluconeogenesis & glycogenolysis ↑ plasma glucose

Decrease in Glucose Uptake Muscle

Adipose tissue

↓insulin

↓insulin

↓glucose & amino acid uptake ↑protein breakdown

↑lipolysis ↓lipogenesis

↑plasma glucose ↑plasma amino acids

↑plasma fatty acids

Glucose Metabolism (Resting State) Fig 17 handout

CNS ∼6 g.h-1

Pancreas Glucagon +

Liver

∼10 g.h-1

Insulin +

Glucose

∼4 g.h-1

Brain

Liver Muscle Fat

Glucose Metabolism (Type 1 Diabetes) Fig 17 handout

CNS ∼6 g.h-1

Pancreas ↑Glucagon +

Liver

>20 g.h-1

Brain Insulin

<1 g.h-1

↑Glucose >14 g.h-1

Kidney

Liver Muscle Fat

Complications of Diabetes Acute complications • Glucosuria: glucose appears in urine • Polyuria: frequent urination • Polydipsia: excessive thirst • Polyphagia: excessive food intake • Ketoacidosis

↓insulin→↑lipolysis→↑fatty acids→liver→ketones

Chronic complications • neuropathy: loss of sensation due to damage of

nerve fibres (e.g. heat, cold, pain) - high blood glucose changes the metabolism of nerve cells - reduced blood flow

Sensory neuropathy

Chronic complications, Cont’d • Cardiovascular disease:

- atherosclerosis - high blood pressure - myocardial infarction

Chronic complications, Cont’d • Retinopathy: damage of retina • Cataract: damage of lens • Both may cause blindness

Chronic complications, Cont’d • Nephropathy:

- has a slow onset - may result in severe kidney failure - follow up: proteinuria

Treatment of Diabetes Type 1 Diabetes

• Insulin therapy - patients need exogenous insulin - insulin can not be administered orally - insulin preparations: porcine, bovine & recombinant human insulin - inhaled powder insulin

Treatment of Type 1 Diabetes, Cont’d • Pancreatic islet transplantation Isolated islets from pancreas are transplanted to the diabetic patients. Advantage: Provides an endogenous source of insulin Disadvantage: Patients need life-time immunosuppressive therapy

Treatment of Diabetes Type 2 Diabetes

• Exercise, diet & weight loss • Oral glucose lowering drugs - stimulate insulin secretion from β cells - suppress liver glucose output - increase insulin sensitivity - slow down glucose absorption from GI tract after meal

Hyperinsulinemia • Insulin excess is characterized by hypoglycemia (↓blood glucose levels)

• Common causes: - high dose of insulin - β cell tumors

• Major symptoms: - depressed brain function unconsciousness death