Slide 1

Pathophysiology of Diabetes Mellitus

Lisa Knight, MD

October 6, 2017

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Slide 2 Disclosures

• No financial disclosures

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Slide 3 Lecture Objectives

• Be familiar with the physiology of diabetes mellitus

• Understand the differences between type 1 and type 2 diabetes

• Be aware of treatment options for patients with type 1 and type 2 diabetes

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Slide 4 Literal definitions

• Diabetes

– Greek word meaning “siphon” or “to pass through”

• Mellitus

– Latin word meaning “honey”

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Slide 5 Early Diabetes Treatments

1000 AD: Greek physicians recommended horseback riding to

reduce excess urination

1800s Bleeding, blistering, and doping were common

Early 1900s Oat cure, potato therapy, milk diet, rice cure, and

opium

1915 Leading American diabetologist, recommended a

starvation diet Admitted to the hospital

Coffee with whiskey Q2 hrs until no glucosuria (from 7a until 7p)

Usually lasted about 5 days

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Slide 6 Diabetes: Major Therapeutic Breakthrough

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Slide 7 VIII. Diseases of the exocrine pancreas

A. Cystic fibrosis

B. Trauma/pancreatectomy

C. Neoplasia

D. Pancreatitis

E. Hemochromatosis

IX. Endocrinopathies

A. Acromegaly

B. Cushing’s syndrome

C. Glucagonoma

D. Pheochromocytoma

E. Hyperthyroidism

F. Somatostatinoma

G. Aldosteronoma

X. Drug or Chemical-Induced

A. Corticosteroid-induced

B. Others

X. Infections/Critical Illness

XI. Uncommon forms of immune-mediated diabetes

A. Stiffman syndrome

B. Type B insulin resistance

X. Gestational Diabetes Mellitus

I. Type 1 diabetes

II. Type 2 diabetes

III. Atypical diabetes (Flatbush)

IV. Latent Autoimmune Diabetes in Adults (LADA)

V. Neonatal diabetes

A. Transient

B. Permanent

VI. Maturity-Onset Diabetes of Youth (MODY)

A. MODY1

B. MODY2

C. MODY3

D. MODY4

E. MODY5

F. MODY6

G. MODY7

VII. Mitochondrial Diabetes

VII. Genetic defects in insulin action

A. Type A insulin resistance

B. Rabson-Mendenhall syndrome

C. Leprechaunism

D. Lipoatrophic diabetes

The ADA recognizes >50 different forms of diabetes

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Slide 8 The pancreas has two compartments:

Exocrine pancreas

Endocrine pancreas

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Slide 9 Endocrine Pancreas

• Islets of Langerhans

– α Cells – Glucagon

– β Cells – Insulin

– δ Cells - Somatostatin

Target CellPancreas

Insulin

Glucose

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Slide 10 If insulin is lacking:

• Decreased/absent production

• Decreased sensitivity of target tissues

Target CellPancreas

Insulin

Glucose

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Slide 11 Insulinopenia: Glucosuria

Hyperglycemia → Glucosuria → Polyuria → Polydipsia → DehydrationNocturiaNocturnal enuresis

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Slide 12 Insulinopenia: Fat Mobilization

Adipose Tissue

Gly

cero

l Bac

kbo

ne

Fatty Acid

Fatty Acid

Fatty Acid

Ketone Bodies (Ketoacids)1. β-hydroxybutyrate2. Aceto-acetate3. Acetone

↑ Ketoacids → Binding with Bicarbonate (HCO3) → Metabolic AcidosisCompensatory Respiratory Alkalosis(Kussmaul respirations)Nausea/Vomiting/Abdominal PainAltered Mental Status

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Slide 13 Insulinopenia: Diabetic Ketoacidosis

• Normal blood pH is 7.35-7.45Degree of DKA pH HCO3 Level

Mild 7.21-7.3 11-15

Moderate 7.11-7.2 6-10

Severe ≤ 7.1 ≤ 5

• Remember, patients with diabetes can have ketosis / ketonuria / ketonemia in the ABSENCE of DKA

• Mortality rate is only 1-2%

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Slide 14 Insulinopenia: Hemoglobin A1c

8%

9%

10%

11%

12%

13%

14%

ADA Goal

7-7.5%

5.6%HbA1c of 5.6% or less is normal

for people without diabetes

Average Blood Sugar Over 3 Months

150-165 mg/dL

180 mg/dL

210 mg/dL

240 mg/dL

270 mg/dL

300 mg/dL

330 mg/dL

360 mg/dL

Low HbA1c

High HbA1c

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Slide 15 Elevated HbA1c: Diabetes Complications

Endothelial Cell Dysfunction

• Cerebrovascular Disease– Stroke

– TIA

• Coronary Artery Disease – MI

– CHF

• Peripheral Vascular Disease– Ulceration

– Gangrene

– Amputation

• Eye– Retinopathy

– Cataracts

– Glaucoma

• Nephropathy– Microalbuminuria

– Gross Albuminuria

– Renal Failure

• Neuropathy– Peripheral

– Autonomic

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Slide 16 Diabetes Mellitus: Diagnostic Criteria

• FBS ≥ 126 mg/dL on at least 2 occasions

• RBS ≥ 200 mg/dL

– In the presence of sx of diabetes

• 2 hour OGTT (75 grams or 1.75 mg/kg)

– FBS ≥ 126 mg/dL

– RBS ≥ 200 mg/dL

• HbA1c ≥ 6.5%

ADA Position Statement. Diabetes Care. 2010; 33(1): S62-S69

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Slide 17 Minor Glycemic Abnormalities: Pre-Diabetes

• Impaired Fasting Glucose

– Fasting BG ≥ 100 but < 126 mg/dL

• Impaired Glucose Tolerance

– 2 hour glucose ≥ 140 but < 200 mg/dL

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Slide 18

CD8

T-cell

CD4

T-cell

T1D is a T-cell mediated, autoimmune disease

Islet

autoantigen

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Slide 19 What Causes Type 1 Diabetes?

Genetics

Environment Immune

system

• Concordance is 35-50% amongst monozygotic twins

• Incidence is 1 in 300 in U.S. (0.33%)

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Slide 20

TIME

Natural History of Type 1 Diabetes

BE

TA

CE

LL

MA

SS

DIABETES

GENETIC

PREDISPOSITION BETA CELL INJURY

GENETICALLY AT-

RISKENVIRONMENTAL TRIGGER

LOSS OF ≥ 80% β CELL MASS

So at diagnosis, there may be 20% of β-cell mass remaining

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Slide 21 Concept of Glucotoxicity

• Chronic hyperglycemia

– Acts as a β-cell toxin

• Inhibits insulin secretion

• Once glycemic control improves

– 20% of remaining β–cells recover function

HONEYMOON PHASE

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Slide 22 What Causes Type 2 Diabetes?

GeneticsEnvironment

InsulinResistance

Impaired Fasting GlucoseImpaired Glucose Tolerance

Type 2 Diabetes Mellitus

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Slide 23 Differences Between T1DM and T2DM

TYPE 1 DIABETESInsulin deficiency

INABILITY to utilize glucose at the cellular level

Breakdown of fat and formation of keto-acids

Diabetic ketoacidosis (DKA) develops

Hyperglycemia with glucosuria and polyuria

TYPE 2 DIABETESInsulin resistance

DECREASED utilization of glucose at the cellular level

Hyperglycemia with glucosuria and polyuria

Chronic dehydration and micro-and macrovascular complications

Non-ketotic hyperosmolarsyndrome develops

OVER WEEKS OVER YEARS

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Slide 24 Nonketotic Hyperosmolar Syndrome

• Triad– Hyperglycemia

• Range 807-2580 mg/dL

– Hyperosmolarity• Range 330-410 mOsm/kg

– Mild metabolic acidosis • With minimal ketosis

• HCO3 levels were > 15 and only negative to small ketones in most patients

• Mortality rate varies between 20-60%

Cochran JB, et al. Am J Emer Med. 2006; 24: 297-301

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Slide 25 Diabetes: Clinical Presentation

Symptoms

• “The Polys”

• Polyuria

• Polydipsia

• Polyphagia

• Nocturia or nocturnal enuresis

• Weight loss

• Visual changes

• Fatigue

• N/V

• Altered mental status

Signs

• Dehydration:

• Tachycardia

• Sunken eyes

• Decreased skin turgor

• Dry mucous membranes

• Delayed capillary refill

• Acidosis

• Tachypnea

– Kussmaul respirations

– Abnormal “fruity odor”

• Nonspecific abdominal tenderness

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Slide 26 Insulin Formulations

Rapid-Acting: Novolog (aspart), Humalog (lispro), Apidra (glulisine)

Short Acting: Regular

Intermediate Acting: NPH

Long-Acting: Levemir (detemir)

Long-Acting: Lantus (glargine)

Novolog 70/30Humalog 75/25

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Slide 27 Insulin Regimen Options

Insu

lin A

ctio

nIn

sulin

Act

ion

Time of Day

Time of Day

Split/Fixed with NPH and Rapid-Acting

Basal/Bolus with Lantus and Rapid-Acting

8am

8am

12pm

12pm

5pm

5pm

9pm

9pm

8am

8am

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Slide 28 Most Common Insulin Regimens

Basal/Bolus Injections

• Long Acting Insulin given once daily (usually QHS)

• Rapid Acting Insulin– Insulin to Carb Ratio

• e.g. 1:10

– Correction formula

• e.g. BG-120/30

Insulin Pump

• Pre-programmed pump settings (by endo)– Basal rate-continuous

infusion of rapid-acting insulin

– Insulin to Carb Ratio

– Correction Formula

• Insulin to Carb Ratio can be used as often as the patient eats• Correction formula should not be used more than every 2-3 hours

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Slide 29 Abnormal Blood Glucose Symptoms

Hypoglycemia

• Shaky

• Sweaty

• Anxious

• Dizzy

• Hunger

• Blurry Vision

• Weakness/Fatigue

• Confusion/Altered Mental Status

• Irritable

Hyperglycemia

• Polydipsia

• Polyuria

• Headaches

• Trouble concentrating

• Blurry Vision

• Fatigue

• Irritability

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Slide 30 Hyperglycemia Management

• If BG ≥240 mg/dL, check urinary ketones– Follow diabetes action plan provided by endocrine provider

• Small/trace negative ketones– Give correction dose of insulin per action plan– Resume normal BG checking/management

• Moderate ketones– Give correction dose of insulin +1 unit– Encourage water intake– Recheck BG level and urine ketones in 2 hours and repeat

• Large Ketones– Give correction dose of insulin +2 units– Encourage water intake– Recheck BG level and urine ketones in 2 hours and repeat

– If by the 3rd check, urine ketones remain moderate or large, call the endocrine provider

– On insulin pump—consider pump site change if moderate or large ketones develop

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Slide 31 Hypoglycemia Management

• In general, BG < 70 mg/dL

– If unconscious, having a seizure, or unable to tolerate PO, give glucagon 1 mg (>20 kg) or 0.5 mg (<20kg) IM

– If tolerating PO, give 15-20 grams of simple CHO and recheck BG in 15-20 minutes (repeat if still < 70 mg/dL)

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Slide 32 Management: Type 2 Diabetes

HbA1c >9% or significant ketosis or ketoacidosis

Diagnosis

HbA1c ≤ 9% and mildly symptomatic or

asymptomatic without ketosis

Insulin; diet/exercise; Metformin

Diet/exercise; Metformin

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Slide 33 Metformin

• Biguanide

• Mechanisms of action

– Decreases hepatic glucose output

– Increases peripheral tissue insulin sensitivity

• First line oral medication for pediatric type 2 diabetes

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Slide 34 Excerpt from the Discovery of Insulin

By: Micheal Bliss

A physician’s description of the painful wasting death of many people with diabetes before insulin was discovered:

"Food and drink no longer mattered, and often could not be taken. A restless drowsiness shaded into semi-consciousness. As the lungs heaved desperately to expel carbonic acid (as carbon dioxide), the dying diabetic took huge gasps of air to try to increase his capacity. 'Air hunger' the doctors called it, and the whole process was sometimes described as 'internal suffocation.' The gasping and sighing and sweet smell lingered on as the unconsciousness became a deep diabetic coma. At that point the family could make its arrangements with the undertaker, for within a few hours death would end the suffering."

DIABETES THEN…

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Slide 35 DIABETES NOW…

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Slide 36

Questions?

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