Continued……

Diabetes mellitus

1. Emergencies2. Complications3. Treatment

Diabetic EmergenciesHyperglycemic

HHNC: Hyperosmolar Hyperglycemic Nonketotic Coma

DKA: Diabetic Ketoacidosis

HypoglycemicDiabetic Coma or

Insulin Reaction

HHS: Hyperglycemic Hyperosmolar State Effects Type 2 Diabetics Prominent later in life Elevated Blood Glucose leads to increase in serum osmolarity This results in Diuresis and Fluid Shift. Increased Urination causes body wide depletion of Water and

Electrolytes.Extreme Dehydration

Physical Signs TachycardiaOrthostatic VitalsPoor Skin TurgorDrowsiness and

lethargyDeliriumComa

SymptomsNausea/vomitingAbdominal painPolydipsiaPolyuria

Treatment IV FLUIDS !!!!!

Bolus of Normal Saline/ half normal saline will help to reverse the overwhelming dehydration

Insulin? NEXT

DKA: Diabetic KetoacidosisDereased Insulin or Insulin resistance leads to Elevated

Blood Glucose levels

However, Cellular Glucose is Low without insulinEquivalent to Starvation

As a result the body attempts to CompensateUses Glucose storesBreaks Down Fat and Protein

In an attempt to save the Heart and Brain, the body produces Ketone Bodies from fatty acids

Acetoacetate, Beta-hydroxybutyrate, Acetone

Excessive Ketones lead to AcidosisBeta-hydroxybutyrate is a carboxylic Acid

Physical SignsAltered mental status TachycardiaTachypnea or

hyperventilation (Kussmaul respirations)

Normal or low blood pressure

Lethargy and weaknessFeverAcetone odor of the breath

reflecting metabolic acidosis

SymptomsOften insidiousFatigue and malaiseNausea/vomitingAbdominal painPolydipsiaPolyuriaPolyphagiaWeight lossFever

TreatmentFluids!!!!!

It is important to initiate Fluid Ressusitation Begin With Normal Saline

InsulinThis Will Start in the Emergency Dept.

HypoglycemiaTreatment

Patient’s will present with Altered Mental StatusSupplemental OxygenVitalsIV Fluids MonitorGlucometry

Glucose < 80 mg/dL, Considered Hypoglycemia

TreatmentGlucose Supplementation

Oral GlucoseJuice, Non- Diet Soda Oral Glucose Solution

D10250cc Bolus

D50 25 gram glucose in 50ml water, IV

GlucagonNaturally Occurring Hormone, From Pancreas Alpha-CellsBreaks Down Stored Glycogen to Glucose1U = 1mg Given IM/SC

Pediatric 0.025 mg/kg IM/SC to max dose 1mg

Blood GlucometryMeasurement of Blood

Glucose levelsHospital labs evaluate

Serum Glucose (10-15% higher)

Requires a small sample of bloodNo IV’s or Phlebotomy

Only seconds to obtain results

Glucometry Technique1. Wash hands with soap and warm water and dry

completely or clean the area with alcohol and dry completely.

2. Prick the fingertip with a lancet.3. Hold the hand down and hold the finger until a small

drop of blood appears; catch the blood with the test strip.

4. Follow the instructions for inserting the test strip and using the SMBG meter.

5. Record the test result.

CHRONIC COMPLICATIONS INCHRONIC COMPLICATIONS INDIABETES MELLITUSDIABETES MELLITUS

MAJOR DETERMINING FACTORS

Duration

Glycemic Control ( Hb A 1 C)

Type 1 vs. Type 2

Macrovascular Damage Affects Large (Named) Arteries:

Coronary Arteries

Coronary artery disease

MI

Carotid/Cerebral Arteries

Stroke

TIA

Lower Extremity Arteries

Peripheral vascular disease

Microvascular Damage Affects:

Retinas

proliferative and non proliferative

blindness

Glomeruli

diabetic nephropathy

Nerves

diabetic neuropathy small fibre/ large fibre

Microvascular Damage Causes:

Blindness

End-Stage Renal Disease

Neuropathy >>> Amputations

The Role of Insulin

High insulin levels as seen in insulin resistance

MAY be contributory to the development of:

Hypertension

Atherosclerosis

So HOW does diabetes damage blood vessels?

Best understood mechanism is by non-enzymatic glucosylation (glycation) of proteins and other macromolecules.

Other mechanisms postulated include changes in NADP+ and NADH levels associated with alternative glucose metabolic fates when usual pathways are saturated.

Chronic hyperglycemia causes increased glycation of proteins, resulting in Advanced Glycation Endproducts (AGEs)

These can cause damage through loss of function, turning on/off signal pathways within cells, or alteration in gene expression.

One of the proteins which is glycated is Hemoglobin. Because it is found in the blood, it is convenient to measure as HbA1c.

Because RBCs (and thus Hb) survive in the blood for 90-120 days, the HbA1c provides a means to assess glycemic control over this period.

Insulin therapy who needs what are the types How to administer

A chain

B chain

Beta cells have channels in their plasma membrane that serve as glucose detectors. Beta cells secrete insulin in response to a rising level of circulatingglucose.

Insulin is a small protein consisting of an A chain of 21 amino acids linked by two disulfide (S—S) bridges to a B chain of 30 amino acids.

Who need insulin medicineType I (insulin dependent) diabetes patients whose body

produces no insulin.Type 2 diabetes patients that do not always produce enough

insulin.

Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s)

Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version.

Insulin drug evolution

Stage 3 Insert the human insulin gene into E. coli and culture the recombinant E.coli to produce insulin (trade name = Humulin®). Yeast is also used to produce insulin (trade name =

Novolin®) (1987).

Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog® and

NovoLog®) or slower (Lantus®) than regular human insulin.

Types of insulin

Regular insulins

Insulin analogs

Pre-mixed insulin

Short peptide mimics

Regular insulins:

Human insulin: Humulin® (from E.coli),

Novalin® (from yeast) NPH - neutral protamine Hagedorn (NPH), protamine mixed.

Lente® insulin / Ultralente® insullin- zinc added

Atrapid yellow short actingPeak 2- 4 hrsTotal duration of action 6 hrs

Insulatard green intermediate actingPeak 4- 6 hrsTotal duration of action 8 – 10 hrs

Split and mixed doseTotal insulin needFBS – 50 10 = total requirement2/3 rd as insulatard1/3 rd as atrapid

2/3 rd in morning 1/3 rd at night

How to monitorMorning atrapid – prelunchMorning insulatard 6 pm RBS

Evening atrapid – bed time Night insulatard FBS

How to administer insulin1.Subcutaneous2.Never mix NPH/ glargine

with other insulin3.Rotate sites4.Deltoid, abdomen, thigh

Every area has different amount of blood supply and absorption varies

Change sites once in ten to fourteen days

Chronic insulin therapy may lead to lipodystrophy

Insulin Analogs:

Fatty Acid Acylated insulins

Insulin Lispro (Humalog®) (1996)

Insulin Aspart (NovoLog®) (2000)

Insulin Glargine (Lantus®) (2002)

Insulin Detemir (Levemir®) (Jun.,2005)

Insulin Glulisine (Apidra®) (Jan., 2006)

Diabetes – Oral Medications

Sulfonylureas

Biguanides

Thiazolidinediones

Alpha-glycosidase inhibitors

Meglitinides

Sulfonylureas : stimulate β cells to produce more insulin

1st generationtolbutamidetolazamideChlorpropamide

2nd generationglipizideGlyburidemicronized glyburide

3rd generation glimepiride

Sulfonylureas interact with receptors on pancreatic b-cells to block ATP-sensitive potassium channels

This, in turn, leads to opening of calcium channelsWhich leads to the production of insulin

Biguanides : improves insulin’s ability to move glucose into cells (esp. muscle)

Metformin

- Metformin was first described in the scientific literature in 1957 (Unger et al). - It was first marketed in France in 1979 but did not receive FDA approval for Type 2 diabetes until 1994.

Metformin is a widely used monotherapy, and also used in combination with the sulfonylureas in treatment of type 2 diabetes

Thiazolidinediones (TZD’s) : make cells more sensitive to insulin (esp. fatty cells)

PioglitazoneRosiglitazone

TZD s binds to and activates the gamma isoform of the

- peroxisome proliferator-activated receptor (PPAR ).γ

-PPAR is a member of the steroid hormone nuclear receptor γsuperfamily,

- and is found in adipose tissue, cardiac and skeletal muscle, liver and placenta

PPAR - γ

Thiazolidinediones

GlucoseInsulin

resistanceInsulin andproinsulin

HDL2

PAI-1

Other vasculareffects

Anti-inflammatory effects CRP, IL-6

ROS, MCP-1P47phox

TNFα

? Cardiovascular implications

PPAR

ACR

MMP-9

sdLDL

HDL2

Vasc react.

Αlpha – glycosidase inhibitors :

Block enzymes that help digest starches

slowing the rise in blood glucose.

Polysacchride to monosachhride conversion is blocked

Better for post prandial glucose control

One with each mealS/E flatulenceAGI’s

- Precose ® (acarbose),

- Glyset ® (miglitol)

Meglitinides : Stimulate more insulin production ; dependant upon level of glucose present

Repaglinide

Nateglinide

Sulfonylureas stimulate cells βBiguanides improves insulin’s ability to move glucose Thiazolidinediones cells more sensitive to insulin Alpha-glycosidase inhibitors Block enzymes that help

digest starches Meglitinides stimulate cells (dependant upon glucose β

conc.)

Diabetes – Oral MedicationsSummary

To conclude….

2 major types of diabetes (3 with Gestational)

Type 1 => insulin dependant (5-10%)Type 2 => may treat with oral medication which may

alter insulin production &/or sensitivity ; disease often succumbs to insulin dependence (>90%)

Diabetes is a leading cause of blindness, kidney failure, amputation, heart attack, stroke, and premature death.

Target FBS 90 – 130 mg/dL HbA1C < 7

These complications can be minimized!Early Diagnosis of DM Monitoring for complicationAggressive treatment of co-risk factorsTeam approach - access to multiple specialists