Diabetes Mellitus

Chapter 41

Diabetes Mellitus

Introduction

Normal Glucose Homeostasis

REGULATED BY:

1. Glucose production in the liver2. Glucose uptake and utilization by peripheral tissues

(skeletal muscle)3. Actions of hormones

Normal glucose levels: 70-120mg/dl

• FXN of Insulin: to increase the rate of glucose transport into certain cells of the body

Glucose Metabolism: Words you need to know!

• Gluconeogenesis: formation of glucose from excess amino acids, fat, and other noncarbohydrate sources.

• Glycogenesis: formation of glycogen.

• Lipogenesis: formation of fats

• Glycogenolysis: process that coverts glycogen to glucose.

• Glycolysis: hydrolysis of glucose to pyruvate.

• Lipolysis: catabolic degradation of triacylglycerol.

Glucose Metabolism

Breaking down stored glycogen

Production of glucose from a.a. & other substances

Synthesis of glycogen

Cellular Respiration

PANCREAS

Exocrine

Endocrine

Islets

Alpha Cells glucagon

Beta Cells proinsulin

Delta Cells somatostatin (suppress insulin and glucagon)

F cells Pancreatic Polypeptide (PP) cells

Epsilon Cells make gherlin, which causes hunger

INSULIN• FAT

–IN-creased glucose uptake– IN-creased lipogenesis– DE-creased lipolysis

• MUSCLE– IN-creased glucose uptake– IN-creased glycogen synthesis– IN-creased protein synthesis

• LIVER– DE-creased gluconeogenesis– IN-creased glycogen synthesis– IN-creased lipogenesis

Regulation of Glucose Metabolism

• HORMONAL REGULATION• Glucose–dependent insulinotropic

polypeptide (GIP) • Glucagon-like peptide 1 (GLP-1)

– from cells in the gut– stimulate the production of insulin and inhibit

glucagon

Hormonal Regulation of Glucose Metabolism

• Insulin: blood glucose

• Glucagon: blood glucose

• Cortisol and adrenal corticosteroids: blood glucose

• Epinephrine: blood glucose

• Growth hormone: blood glucose

• Thyroxine: blood glucose

• Somatostatin: inhibits insulin and glucagon

• Gastric Inhibitory peptide: stimulates insulin release

Insulin and Glucagon

GlucagonInsulinSomatostatin

Insulin and Glucagon↑ Glycolysis

↑ Lipogenesis

↑ Glycogenesis

↑ Glycogenolysis

↑ Gluconeogenesis

Metabolic Action of Insulin

Liver Adipose Muscle

Inhibits GlycogenolysisGluconeogenesisKetogeneis

Lipolysis Protein break down Amino acid release

Simulates Glycogen fatty acid synthesis

Glycerol and fatty acid synthesis

Glucose uptake and metabolismAmino acid uptakeSynthesis of proteinGlycogenesis

Fed State Fasting State

Glucose provides primary energy sourceAmylin acts on area postrema (AP)

INSULIN dominated

Glucose is produced by glycogenolysis and gluconeogenesis

GLUCAGON dominates

Regulation of Glucose Metabolism

• EXERCISE– Initially insulin levels drop

and glucagon and catecholamine levels rise

• STRESS– Production of stress

hormones (corticosteroids and catecholamines) increase production of glucose

– Increase production of FFAs – Lead to hyperglycemia

Diabetes Mellitus

Who has Diabetes Mellitus

• 16 Million in the USA• 1 Million/yr• 50K people die of it per year in the USA

What is diabetes mellitus?

• GLUCOSE INTOLERANCE

• How do you diagnose DM?• More than one fasting plasma glucose level

(>126)• Elevated plasma glucose in response to an oral

glucose tolerance test (>200)• Polydipsia, polyphagia, polyuria

TWO* Types of DMType 1• Genetic• Autoimmune• Childhood (juvenile)

onset• Antibodies to beta

cells, insulitis• Beta cell depletion• NON-OBESE patients

Type 2• Genetic, but diff. from Type

1• NOT autoimmune• Adult, or maturity onset,

e.g., 40’s, 50’s• Insulin may be low, BUT,

peripheral resistance to insulin is the main factor

• OBESE patients

* MODY might be regarded as the third type

Classification of Diabetes Mellitus

Classification of Diabetes Mellitus

Pathogenesis of Diabetes Mellitus

• HLAs: expression of certain HLAs is associated with increased susceptibility to type I diabetes.

• Viruses: are considered initiating factors in autoimmune cause of type I diabetes.

• Insulin receptor defects: Insulin resistant: can be due to malfunction in insulin receptor, but the

cause is not known. In type II diabetes.

Antibodies to insulin receptor: in type II diabetes.

• Glucose transport: low levels of glucose transporters in type I and II diabetes.

Pathogenesis of Diabetes Mellitus

• Type I diabetes mellitus: caused by destruction of

islet cells as a result of autoimmune reaction to -cells.

• Type II diabetes mellitus: caused by a defect in

glucose transport after insulin binds to its receptor.

Type 1 DM

Genetic susceptibilityEnvironmental factorsImmunologically mediated destruction of beta cellsPeak about 10-14 years of age

• A 12-year-old female is newly diagnosed with type 1 diabetes mellitus (DM). Which of the following is the most likely cause of her disease?

A. A familial, autosomal dominant gene defectB. Obesity and lack of exerciseC. Immune destruction of the pancreasD. Hyperglycemia from eating too many sweets

Pathogenesis of Type I Diabetes

Type 2 DM

Type 2 DM

• RESISTANT TO THE ACTION OF INSULIN• Very common: many undiagnosed cases• Interactions of metabolic, genetic, &

environment• RISK FACTORS: high BMI (intra-abdominal

obesity), family history of DM2, ethnic minority, female gender

• Insulin is less able to facilitate entry of glucose into live, skeletal muscles, adipose tissue

• Pancreas eventually “burns out”

Pathogenesis of Type II Diabetes

MODY (Maturity Onset Diabetes of the Young)

• Multiple types• 2-5% of diabetics• Primary beta cell defects• Multiple genetic mechanisms, especially

GLUCOKINASE mutations

Hyperglycemia in type 2 diabetes mellitus is a result of:

A. insulin deficiency.B. hyperinsulinemia and insulin resistance.C. glucagon deficiency.D. liver dysfunction.

Clinical Manifestations of Type I Diabetes

Symptomatic manifestations of insulin deficit in Diabetes

Classification of DiabetesDM: Type 1Absolute insulin deficiency

DM: Type 2Insulin resistance

Pre-diabetes:IGT & IFG

Gestational diabetes mellitus

Complications

of

Diabetes Mellitus

Complications of Diabetes Mellitus

• Retinopathy

• Neuropathy

• Angiopathy

• Nephropathy

• Infection

• Hyperlipidemia and atherosclerosis

• Hypoglycemia (insulin shock/ insulin

reaction, too much Insulin)

• Diabetic ketoacidosis (Too little insulin)

• Protein glycation NEPHROSCLEROSIS

RETINOPATHY

Chronic Complications of DM• Microvascular disease: capillary basement

membrane thickening—ischemia– Retinopathy– Diabetic nephropathy

• Macrovascular disease: unrelated to the severity of disease—causes much morbidity & mortality; glycosylated end products & high serum lipids cause atherosclerosis--ischemia– Coronary artery disease– Stroke– Peripheral arterial disease

• Diabetic neuropathies: most common complication in Western countries, nerve cell damage—more sensory than motor

• Infection: sensory impairment, hypoxia (glycosylated RBCs), increased pathogens like glucose, decreased blood supply, abnormal WBCs)

Acute Complications: Hypoglycemia

Insulinopenia (in type I diabetes)

Use of fatty acids from triglycerides as a major source of energy

Fatty acid degradation

­ Production of acetyl CoA

­ Production of keto acids (ketone bodies)(acetoacetate, -hydroxybutyrate)

Acute Complications: Diabetic ketoacidosis

Diabetic Ketoacidosis

A 19-year-old female with type 1 diabetes mellitus was admitted to the hospital with the following lab values: serum glucose 500 mg/dl (high); urine glucose and ketones 4+ (high); arterial pH 7.20 (low). Her parents state that she has been sick with the “flu” for a week. Which of the following statements best explains her acidotic state?

A. Increased insulin levels promote protein breakdown and ketone formation.

B. Her uncontrolled diabetes has led to renal failure.C. Low serum insulin promotes lipid storage and a

corresponding release of ketones.D. Insulin deficiency promotes lipid metabolism and ketone

formation.

Acute Complications Protein glycation

• Nonenzymatic binding of free amino groups of proteins to glucose and other sugars.

• Protein glycation commonly occurs in RBCs, glumeruli, nerve cells, and other tissues.

• Extent of protein glycation is proportional to extracellular glucose concentration.

• Excessive glycation causes alterations in protein’s physical and biochemical properties.

• New research suggest that many diabetes complications are caused by glycation of specific proteins.

Diagnostic Tests for Diabetes Mellitus

Function tests in diabetes• Postprandial plasma glucose• Oral glucose tolerance test

Other tests in diabetes• Glucose• Glycated hemoglobin• Albumin (protein)• Insulin• Keto acids• Hydrogen ion• Electrolytes• Osmolality• Body fluid volume• Anion gap• BUN• Lipids

Both tests measure clearance rate of glucose load from the blood.

Postprandial plasma glucose:• A high in carbohydrate meal is used (75 g glucose drink is preferred) as

carbohydrate load.• Plasma glucose is measured 2 hours after carbohydrate ingestion.• Two postprandial tests with glucose levels 200 mg/dl are suggestive of diabetes.

Oral glucose tolerance test (OGTT): under controlled conditions.

• Carbohydrate intake is controlled 3 days before the test.• Glucose load is 40 g glucose/m2 body area.• Blood glucose is measured 2 hours after glucose load.• Glucose level 200 mg/dl is suggestive of diabetes.

Function tests in diabetes

Fasting plasma glucose:• Repeated levels 126 mg/dl…strongly suggest diabetes.

• Levels 100 – 126 mg/dl …impaired fasting glucose.

• Increase in fasting plasma glucose is directly proportional to severity of diabetes mellitus.

Urinary glucose:• Renal threshold for glucose is 180 g/dl, and in diabetics it is

increased to 300 mg/dl.

Urinary glucose is a poor marker for diabetes mellitus.

Glucose

• Type I diabetics: fasting plasma insulin is low.

• Type II diabetics: fasting plasma insulin is normal, it is

high if plasma glucose 250 mg/dl

Insulin

• Measured in both blood and urine.

• Plasma keto acids may be normal even though urinary keto acids are high, this is due to increase urinary excretion of keto acids from renal compensation to low pH.

• Controlled diabetics should have both normal plasma and urinary keto acid levels.

Keto acids

• Urinary protein (microalbuminuria) is one of the earliest signs of glomerular nephropathy.

• Albumin / creatinine 20-30 mg/day suggests microalbuminuria.

• Without intervention macroalbuminuria (>300mg/day)– Leading cause of end stage renal disease in US

Albumin

Risk factors for developing Diabetes Mellitus

Treatment - Diabetes Mellitus