Back to Basics: Back to Basics: EndocrinologyEndocrinology

DiabetesDiabetes(Obesity, Metabolic (Obesity, Metabolic

Syndrome)Syndrome)

Which of the following Which of the following statements is true?statements is true?A.A. Type 1 diabetes is not diagnosed after age Type 1 diabetes is not diagnosed after age

5050

B.B. Type 2 diabetes is more strongly inherited Type 2 diabetes is more strongly inherited than type 1 diabetes.than type 1 diabetes.

C.C. The incidence and prevalence of DM-1 is on The incidence and prevalence of DM-1 is on the risethe rise

D.D. Gestational diabetes does not increase the Gestational diabetes does not increase the risk of developing diabetes in the future.risk of developing diabetes in the future.

E.E. People with type 2 diabetes never get DKAPeople with type 2 diabetes never get DKA

AnswerAnswer

B and CB and C

Classification of DiabetesClassification of Diabetes

Type 1 Type 1 Encompasses diabetes that is Encompasses diabetes that is

primarily a result of pancreatic beta primarily a result of pancreatic beta cell destruction and prone to DKA.cell destruction and prone to DKA.

Includes auto immune (anti islet cell Includes auto immune (anti islet cell antibody, and anti GAD) and antibody, and anti GAD) and unknown etiology.unknown etiology.

Classification of DiabetesClassification of Diabetes

Type 2Type 2 Primarily insulin resistance with a Primarily insulin resistance with a

relative insulin deficiency (but can relative insulin deficiency (but can develop into and include scenario of develop into and include scenario of predominant insulin secretory defect predominant insulin secretory defect with insulin resistance)with insulin resistance)

Diminishedinsulin

Hyperglycemia

Liver

1. Insulin deficiency

2. Excess glucose output

3. Insulin resistance

Pancreas

Muscle and fat

Excess glucagon

Islet

Diminishedinsulin

α-cell produces excess glucagon

β-cell produces less insulin

The pathophysiology of T2DM The pathophysiology of T2DM includes includes

three main defectsthree main defects

Classification of DiabetesClassification of Diabetes

Gestational Diabetes MellitusGestational Diabetes Mellitus

Onset or recognition of diabetes Onset or recognition of diabetes during pregnancyduring pregnancy

Other specific typesOther specific types MODY type 1-5MODY type 1-5 Cystic fibrosisCystic fibrosis Cushing’s syndrome etc.Cushing’s syndrome etc.

TYPE 1 Diabetes

10%

Beta cell destruction (usually autoimmune)

Low or absent

Required for survival

Often <30 (but can occur at any age)

Usually lean

Smaller

Acute, severe

Yes

No

Proportion of diabetes cases

Pathogenesis

Endogenous insulin secretion

Need for insulin therapy

Age of onset

Body habitus

Genetic component

Symptoms at onset

Ketoacidosis

Long-term complications present at dx?

TYPE 2 Diabetes

90%

Insulin resistance, relative insulin deficiency

Variable

Required in <50%, to improve control rather than for survival

Often >40 but even in kids

Often obese

Very large

Often mild, slow onset

Rare

Retinopathy ~20%, CVD relatively common

Diabetes mellitus is NOT a Diabetes mellitus is NOT a Mild DiseaseMild Disease

Stroke

2- to 4-fold increase in cardiovascular mortality and stroke3

Cardiovascular Disease

8/10 diabetic patients die from CV events4

Diabetic Neuropathy

Leading cause of non-traumatic lower extremity amputations5

Diabetic Retinopathy

Leading cause of blindness in

working-age adults1

Diabetic Nephropathy

Leading cause of end-stage renal

disease2

1. Fong DS et al. Diabetes Care 2003; 26(Suppl 1):S99-S102. 2. Molitch ME et al. Diabetes Care 2003; 26(Suppl 1):S94-S98. 3. Kannel WB et al. Am J Heart 1990; 120:672-6. 4. Gray RP and Yudkin JS. In: Textbook of Diabetes. 1997. 5. Mayfield JA, et al. Diabetes Care 2003; 26(Suppl 1):S78-S79.

Diabetes Complications: Diabetes Complications: MacrovascularMacrovascular

DM is a major risk factor for cardiac DM is a major risk factor for cardiac diseasedisease

Acute MI occurs 15-20 years earlier Acute MI occurs 15-20 years earlier in those with DMin those with DM

Heart disease accounts for Heart disease accounts for approximately 50% of all deaths approximately 50% of all deaths among people with diabetes in among people with diabetes in industrialized countries industrialized countries

REF: Diabetes in Ontario, An ICES Practice Atlas, 2002

Several large epidemiological Several large epidemiological studies have found a strong studies have found a strong relationship between relationship between glucose level and subsequent coronary glucose level and subsequent coronary

events, even at ‘pre-diabetes’ levels events, even at ‘pre-diabetes’ levels (IGT and IFG)(IGT and IFG)

glucose levels that are only modestly glucose levels that are only modestly elevated place patients at risk. elevated place patients at risk.

REF: Coutiho M. et al Diabetes Care 1999;22:233-240.& DECODE Study Group. Arch Intern Med 2001;161:397-404.

Diabetes Complications:Diabetes Complications: MacrovascularMacrovascular

Diabetes Complications: Macrovascular

Relationship between FPG and CHD

REF: Coutinho et al. Diabetes Care 1999;22:233-40.

Metaregression - 20 prospective studies n = 95,783 - follow-up 12.4 yrsFPG > 6 mmol/L: RR 1.38 (1.06-1.67)

Fasting glucose (mmol/L)

Rel

ativ

e R

isk

2.5

2

1.5

14 5 6 7 8 9

Diabetes….Diabetes…. Is the leading cause of non traumatic Is the leading cause of non traumatic

amputationamputation Increases the risk of amputation by 20 Increases the risk of amputation by 20

foldfold those living in the north or in low income those living in the north or in low income

neighborhoods and those with poor access neighborhoods and those with poor access to physician services are at particular risk to physician services are at particular risk for amputation.for amputation.

REF: Diabetes in Ontario, An ICES Practice Atlas, 2002

Diabetes Complications: Diabetes Complications: MicrovascularMicrovascular – Amputation– Amputation

DiabetesDiabetes Is a leading cause of adult-onset Is a leading cause of adult-onset

blindnessblindness Prevalence of diabetic retinopathy is ~ Prevalence of diabetic retinopathy is ~

70% in persons with type 1 and 40% 70% in persons with type 1 and 40% with person with type 2 diabetes. with person with type 2 diabetes.

REF: Diabetes in Ontario, An ICES Practice Atlas, 2002

Diabetes Complications: Diabetes Complications: MicrovascularMicrovascular – Retinopathy– Retinopathy

Diabetes Diabetes Is the leading cause of ESRDIs the leading cause of ESRD Increases the risk of developing ESRD Increases the risk of developing ESRD

by up to 13-foldby up to 13-fold

Refs: Meltzer S, et al CMAJ 1998; 159 (8 suppl):S1-S29, &

Parchman ML, et al Medical Care 2002; 40(2):137-144.

Diabetes Complications: Diabetes Complications: MicrovascularMicrovascular - - NephropathyNephropathy

DM-2 Risk FactorsDM-2 Risk Factors

Modifiable Risk FactorsModifiable Risk FactorsPhysical Activity Physical Activity

Obesity Obesity DietDiet

&&

Non-Modifiable Risk FactorsNon-Modifiable Risk FactorsEthnicityEthnicity

Family HistoryFamily History

Diabetes Risk Factors:Diabetes Risk Factors:ModifiableModifiable

0

1

2

Rel

ativ

e Ris

k

>7 4 to 7 2 to 4 .5 to 2 <0.5

Hours per week

Physical Activity: Relative Risk For Developing Diabetes

Source: Choi B, Shi F. Diabetologia 2001, 44:1221-1231.

0

0.5

1

1.5

2

rela

tive

ris

k

5 4 3 2 1quintiles based on fat/fibre content

Healthy Diet: Relative Risk for Developing DM

Source: Choi B, Shi F. Diabetologia 2001, 44:1221-1231.

Diabetes Risk Factors:Diabetes Risk Factors:ModifiableModifiable

0

10

20

30

40

Rela

tive R

isk

<23 23-25 25-30 30-35 <35

BMI = wt/ (ht)2

Obesity: Relative Risk For Developing DM

Source: Choi B, Shi F. Diabetologia 2001, 44:1221-1231.

Diabetes Risk Factors:Diabetes Risk Factors:ModifiableModifiable

Relative risk for developing type 2 is Relative risk for developing type 2 is cumulative.cumulative. A physically inactive individual (less than 30 A physically inactive individual (less than 30

min/wk of exercise) min/wk of exercise) who consumes an unhealthy dietwho consumes an unhealthy diet and is modestly overweight (BMI 25-30) and is modestly overweight (BMI 25-30) would have a 30-fold increased (1.8*2*8) risk of would have a 30-fold increased (1.8*2*8) risk of

developing type 2 DM compared to the general developing type 2 DM compared to the general population, population,

which would translate to a lifetime risk of which would translate to a lifetime risk of nearly 100%nearly 100%

REF: Atlas of Diabetes 2nd Ed, Part 2, JS Sklyer, EditorREF: Atlas of Diabetes 2nd Ed, Part 2, JS Sklyer, Editor

Diabetes Risk Factors:Diabetes Risk Factors:ModifiableModifiable

Run away from diabetes

DM-2DM-2The Epidemic: The Epidemic: Non-Modifiable Non-Modifiable

Risk FactorsRisk FactorsEthnicityEthnicity

AgeAge

Family History / GeneticsFamily History / Genetics

The Epidemic: The Epidemic: Ethnic Groups at High Ethnic Groups at High

Risk for DMRisk for DM Aboriginal Aboriginal

LatinoLatino

South AsianSouth Asian

AsianAsian

African DescentAfrican Descent

77.1% of Canada’s immigrant 77.1% of Canada’s immigrant population are coming from population are coming from populations which from high risk populations which from high risk ethnic groupsethnic groups

7.3% 7.3% LatinosLatinos Central and South America, 7.3%Central and South America, 7.3%

57.0% Asian 57.0% Asian 12.8% African Decent12.8% African Decent

Caribbean and Bermuda, 5.5%Caribbean and Bermuda, 5.5% Africa, 7.3%Africa, 7.3%

Diabetes Risk Factors: Non-Modifiable Other High-risk Groups in Canada

REF: Statistics Canada, 1996 Census

Prevention strategiesPrevention strategies

Primary PreventionPrimary Prevention Prevent diabetes through reduction of Prevent diabetes through reduction of

modifiable risk factors in general modifiable risk factors in general populationpopulation

Secondary PreventionSecondary Prevention Screening those at high-risk for diabetesScreening those at high-risk for diabetes

Tertiary PreventionTertiary Prevention Upon diagnosis of diabetes, prevention of Upon diagnosis of diabetes, prevention of

complications morbidity, and mortalitycomplications morbidity, and mortality

REF: Diabetes Blueprint

Primary Prevention Primary Prevention ModelModel

GoalGoal Reducing modifiable risk factors for diabetesReducing modifiable risk factors for diabetes

Target Target General population & high-risk groups General population & high-risk groups

MessagesMessages Healthy lifestyle choicesHealthy lifestyle choices

Current Delivery Models of Primary Current Delivery Models of Primary PreventionPrevention Population HealthPopulation Health Primary CarePrimary Care

REF: Health Canada

Primary Prevention Model: Primary Prevention Model: Population HealthPopulation Health – National – National

CDS

Health Canada

NADA

GoalGoal Early identification of those with Early identification of those with

dysglycemia dysglycemia Target Target

High-risk individuals and groups High-risk individuals and groups MessagesMessages

Diabetes awarenessDiabetes awareness Current delivery model of secondary Current delivery model of secondary

prevention relies on primary careprevention relies on primary care

Secondary PreventionSecondary Prevention

Secondary Prevention: Secondary Prevention: Is It Effective?Is It Effective?

Yes….Yes…. Patients diagnosed with IGT can be Patients diagnosed with IGT can be

prevented from progressing to type 2 prevented from progressing to type 2 diabetes diabetes 58% reduction with lifestyle changes (DPP, 58% reduction with lifestyle changes (DPP,

DPS) DPS) 30% reduction with medication (DPP, Stop 30% reduction with medication (DPP, Stop

NIDDM) NIDDM)

Tertiary Prevention: Tertiary Prevention: Is it Effective?Is it Effective?

Yes…Yes… Strong evidence for tertiary prevention Strong evidence for tertiary prevention

particularly for microvascular diseaseparticularly for microvascular disease DCCT, UKPDSDCCT, UKPDS And for macrovascular as legacy effect And for macrovascular as legacy effect

(UKPDS and EDIC follow up studies)(UKPDS and EDIC follow up studies) How to translate this evidence into How to translate this evidence into

practice?practice?

Tertiary PreventionTertiary Prevention

GoalsGoals Glucose, blood pressure, and lipid Glucose, blood pressure, and lipid

control to reduce the development of control to reduce the development of complicationscomplications

Complication screening for early Complication screening for early identification and managementidentification and management

Why are Obesity and Type 2 DM

Increasing in Frequency? More sedentary lifestyles More sedentary lifestyles Worldwide changes in urbanization and nutritionWorldwide changes in urbanization and nutrition Aging population due to demographic growth rates Aging population due to demographic growth rates

(baby boomers) and increased life expectancy (baby boomers) and increased life expectancy

www.who.int and www.idf.org accessed March 16, 2006

ObesityObesity The most common metabolic condition in The most common metabolic condition in

industrialized nationsindustrialized nations Statistics Canada: 48% of Canadians Statistics Canada: 48% of Canadians

between ages 20-64 yr are overweight between ages 20-64 yr are overweight (BMI>25)(BMI>25)

Associated with dyslipidemia, impaired Associated with dyslipidemia, impaired glucose tolerance and insulin resistanceglucose tolerance and insulin resistance

Risk factor for developing metabolic Risk factor for developing metabolic syndrome, type 2 Dm, cardiovascular syndrome, type 2 Dm, cardiovascular diseasedisease

Huge economic costsHuge economic costs

Obesity in Canada: 1978/79 to 2004

Data from Canadian Community Health Survey www.statcan.ca/Daily/English/050706/d050706a.htm

Quick Facts:Quick Facts:

% of obese children increased from 3% to 8%

Among adults, the increase was even more dramatic: from 14% to 23%, a total of 5.5 million people

About 30% of baby boomers (aged 45 to 64) are obese

Weight Management Weight Management StrategiesStrategies

Eating pattern modificationEating pattern modification Behaviour therapy ( including group therapy)Behaviour therapy ( including group therapy) Appetite suppression eg. SibutramineAppetite suppression eg. Sibutramine Fat malabsorption, orlistatFat malabsorption, orlistat Bariatric surgery (Roux en Y, gastric banding)Bariatric surgery (Roux en Y, gastric banding)

Energy ExpenditureEnergy Expenditure Non exercise associated thermogenisis Non exercise associated thermogenisis

(NEAT)(NEAT) ExerciseExercise

Canada’s Food guide to Canada’s Food guide to healthy eatinghealthy eating

Promote a diet with 30% or less Promote a diet with 30% or less energy from fat, 15-20% energy energy from fat, 15-20% energy from protein and 50-55% from from protein and 50-55% from complex carbohydratescomplex carbohydrates

Despite a decrease from 40% of Despite a decrease from 40% of energy from fat in U.S. diet in 1965 energy from fat in U.S. diet in 1965 to 34% in 1991, incidence of obesity to 34% in 1991, incidence of obesity increasedincreased

Metabolic SyndromeMetabolic Syndrome

A constellation of risk factors A constellation of risk factors Significantly increased CVD Significantly increased CVD

risksrisks Significantly increased risks for Significantly increased risks for

type 2 diabetestype 2 diabetes

Clinical Features of the Clinical Features of the Metabolic SyndromeMetabolic Syndrome

Abdominal obesityAbdominal obesity HyperglycemiaHyperglycemia Atherogenic dyslipidemiaAtherogenic dyslipidemia HypertensionHypertension Proinflammatory stateProinflammatory state Prothrombotic stateProthrombotic state

IDF Classification of the IDF Classification of the Metabolic SyndromeMetabolic Syndrome

5.6 mmol/L 5.6 mmol/L Fasting Fasting glucoseglucose

130 Syst. or diast. 130 Syst. or diast. 85 mm 85 mm Hg or RxHg or Rx

Blood Blood pressurepressure

1.10 1.10 WomenWomen

0.900.90 MenMen

1.71.7HDL cholesterolHDL cholesterol

Men Men Waist C.Waist C. Women Women

94 cm 94 cm (37 in)(37 in) 80 cm 80 cm (31.5 in)(31.5 in)

90 cm 90 cm (35 in)(35 in) 80 cm 80 cm (31.5 in)(31.5 in)

85 cm 85 cm (33 in)(33 in) 90 cm 90 cm (35 (35 in)in)

Central obesityCentral obesity Europids, Mid-Europids, Mid-easteast S. Asians, S. Asians, ChineseChinese JapaneseJapanese

Cut PointsCut Points

Plus any 2 of the following for Plus any 2 of the following for diagnosis:diagnosis:

Inadequate evidence to recommend routine measurement of insulin resistance (e.g., plasma insulin), proinflammatory state, or prothrombotic state in the diagnosis of the metabolic syndrome

TriglyceridesTriglycerides

Risk FactorsRisk Factors

Metabolic SyndromeMetabolic Syndrome

A common condition associated with A common condition associated with increased cardiovascular disease risksincreased cardiovascular disease risks

Treatment is aimed at lifestyle Treatment is aimed at lifestyle modification to achieve desirable body modification to achieve desirable body weight and reduce abdominal obesityweight and reduce abdominal obesity

Multiple medical therapy may be Multiple medical therapy may be required to achieve metabolic targets required to achieve metabolic targets (lipids, glucose and BP)(lipids, glucose and BP)

Lifestyle modification benefits Lifestyle modification benefits everyone!everyone!

Definitions of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance

(IGT) and Diabetes

Fas

ting

Glu

cose

(mm

ol/

L)

3.5

4.5

5.5

6.5

7.5

8.5

3 4 6 8 10 12 14

2-h Post-load Glucose (mmol/L)

Diabetes

IFG + IGT

NormalGlucose

IGT

IFG6.1

6.9

7.8 11.1

* 1. ADA Diabetes Care 2006;29(Suppl 1):S47,2. CDA Can J Diabetes 2003;27(Suppl 2):S7, 3.WHO 1999 NDC/NCS.99.2 accessed Mar 2 2006 from www.who.int

5.6*

Screening for Type 2 Screening for Type 2 DiabetesDiabetes

6.1-6.9 mmol/L do OGTT5.6-6.0 plus risk factor(s) for DM do OGTT

2hPG in a 75-g OGTT

Every 3 years in individuals 40 years of age Earlier and/or more frequently in individuals with

additional risk factors

FPG

CDA 2003 Clinical Practice Guidelines. Can J Diabetes 2003;27:S11

Therapeutic Therapeutic strategies for the strategies for the management of management of type 2 diabetes.type 2 diabetes.

Targets for Metabolic Targets for Metabolic Control: Control:

Glucose ControlGlucose Control DM-1 and DM-1 and DM-2DM-2

(2008 CDA Guidelines)(2008 CDA Guidelines)Target for Target for Most PatientsMost Patients

A1CA1C 7.07.0

PreprandialPreprandial 4.0 – 7.04.0 – 7.0

2 h 2 h PostprandialPostprandial

5.0 – 10.05.0 – 10.0

5.0-8.0 if not 5.0-8.0 if not at A1c targetat A1c target

Targets for Targets for Glucose ControlGlucose Control Preconception Preconception and in Pregnancyand in Pregnancy (2008 CDA Guidelines)(2008 CDA Guidelines)

Target for Target for Most PatientsMost Patients

A1CA1C

7.0 and 7.0 and <6.0% if <6.0% if

safely safely acheivedacheived

PreprandialPreprandial 3.8-5.2 3.8-5.2 mmol/Lmmol/L

1h 1h PostprandialPostprandial 5.5-7.75.5-7.7

2 h 2 h PostprandialPostprandial

5.0 – 6.65.0 – 6.6

5.0-8.0 if not 5.0-8.0 if not at A1c targetat A1c target

Clinical assessment and initiation of nutrition and physical activity

A1C <9% A1C ≥9%

BMI ≥25 BMI <25

Metformin (first-line)incretin

TZDSecretagogue

Insulinacarbose

Metforminincretin

TZDSecretagogue

Insulinacarbose

2 agents:Metformin

incretinTZD

SecretagogueInsulin

acarbose

Insulin

Achieve Target A1C Achieve Target A1C within 6within 6––12 Months12 Months

Timely adjustments/additions should be made to attain target A1C within 6–12 months.

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2003;27(Suppl 2):S1–152.

Oral Medications Oral Medications to Treat Type 2 to Treat Type 2

DiabetesDiabetes

Major Classes of Major Classes of MedicationsMedications

1. Drugs that sensitize 1. Drugs that sensitize the body to insulin the body to insulin and/or control hepatic and/or control hepatic glucose productionglucose production

2. Drugs that stimulate 2. Drugs that stimulate the pancreas to make the pancreas to make more insulinmore insulin

3. Drugs that slow the3. Drugs that slow the absorption of starchesabsorption of starches

ThiazolidinedioneThiazolidinedioness

BiguanidesBiguanides

SulfonylureasSulfonylureasMeglitinidesMeglitinides

Alpha-glucosidase Alpha-glucosidase inhibitorsinhibitors

New Class of New Class of MedicationsMedications

IncretinsIncretins Derived from gut hormone GLP-1 Derived from gut hormone GLP-1 Glucagon like peptide 1Glucagon like peptide 1

GLP-1 Effects in Humans: GLP-1 Effects in Humans: Understanding Glucoregulatory Understanding Glucoregulatory

Role of IncretinsRole of Incretins

Adapted from Flint A, et al. J Chin Invest. 1998;101:515-520; Larsson H, et al. Acta Physiol Scand. 1997;160:413-422; Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Drucker DJ. Diabetes. 1998;47:159-169.

ThiazolidinedionesThiazolidinediones Thiazolidinediones decrease insulin resistance by Thiazolidinediones decrease insulin resistance by

making muscle and adipose cells more sensitive to making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose insulin. They also suppress hepatic glucose production.production.

EfficacyEfficacy Decrease fasting plasma glucose ~1.9-2.2 mmol/LDecrease fasting plasma glucose ~1.9-2.2 mmol/L Reduce A1C ~0.5-1.0%Reduce A1C ~0.5-1.0% 6 weeks for maximum effect6 weeks for maximum effect

Other EffectsOther Effects Weight gain, edema Weight gain, edema Hypoglycemia (if taken with insulin or agents that stimulate Hypoglycemia (if taken with insulin or agents that stimulate

insulin release)insulin release) Contraindicated in patients with abnormal liver function or Contraindicated in patients with abnormal liver function or

CHFCHF Improves HDL cholesterol and plasma triglycerides; usually Improves HDL cholesterol and plasma triglycerides; usually

LDL neutralLDL neutral Medications in this Class: pioglitazone (Actos), Medications in this Class: pioglitazone (Actos),

rosiglitazone (Avandia), rosiglitazone (Avandia),

BiguanidesBiguanides Biguanides decrease hepatic glucose production and Biguanides decrease hepatic glucose production and

increase insulin-mediated peripheral glucose uptake.increase insulin-mediated peripheral glucose uptake. EfficacyEfficacy

Decrease fasting plasma glucose 3.3-3.9 mmol/LDecrease fasting plasma glucose 3.3-3.9 mmol/L Reduce A1C 1.0-2.0%Reduce A1C 1.0-2.0%

Other EffectsOther Effects Diarrhea and abdominal discomfortDiarrhea and abdominal discomfort Risk of Lactic acidosis in those at risk (renal failure, CHF)Risk of Lactic acidosis in those at risk (renal failure, CHF) Cause small decrease in LDL cholesterol level and triglyceridesCause small decrease in LDL cholesterol level and triglycerides No specific effect on blood pressureNo specific effect on blood pressure No weight gain, with possible modest weight lossNo weight gain, with possible modest weight loss Contraindicated in patients with impaired renal function Contraindicated in patients with impaired renal function

(eGFR<33 ml/min)(eGFR<33 ml/min) Medications in this Class: metformin (Glucophage), Medications in this Class: metformin (Glucophage),

metformin hydrochloride extended release metformin hydrochloride extended release (Glumetza)(Glumetza)

SulfonylureasSulfonylureas Sulfonylureas increase endogenous insulin Sulfonylureas increase endogenous insulin

secretionsecretion EfficacyEfficacy

Decrease fasting plasma glucose 3.3-3.9 mmol/LDecrease fasting plasma glucose 3.3-3.9 mmol/L Reduce A1C by 1.0-2.0%Reduce A1C by 1.0-2.0%

Other EffectsOther Effects HypoglycemiaHypoglycemia Weight gain Weight gain No specific effect on plasma lipids or blood pressureNo specific effect on plasma lipids or blood pressure Generally the least expensive class of medicationGenerally the least expensive class of medication

Medications in this Class:Medications in this Class: glyburide (DiaBeta), glimepiride (Amaryl), gliclizide glyburide (DiaBeta), glimepiride (Amaryl), gliclizide

(Diamicron)(Diamicron)

MeglitinidesMeglitinides Meglitinides stimulate insulin secretion Meglitinides stimulate insulin secretion

(rapidly and for a short duration) in the (rapidly and for a short duration) in the presence of glucose.presence of glucose.

EfficacyEfficacy Decreases peak postprandial glucoseDecreases peak postprandial glucose Decreases plasma glucose 3.3-3.9 mmol/LDecreases plasma glucose 3.3-3.9 mmol/L Reduce A1C 1.0-2.0%Reduce A1C 1.0-2.0%

Other EffectsOther Effects Hypoglycemia (although may be less than with Hypoglycemia (although may be less than with

sulfonylureas if patient has a variable eating schedule)sulfonylureas if patient has a variable eating schedule) Weight gain Weight gain No significant effect on plasma lipid levelsNo significant effect on plasma lipid levels Safe at higher levels of serum Cr than sulfonylureasSafe at higher levels of serum Cr than sulfonylureas

Medications in this Class: repaglinide Medications in this Class: repaglinide (Gluconorm), nateglinide (Starlix)(Gluconorm), nateglinide (Starlix)

Alpha-glucosidase Alpha-glucosidase InhibitorsInhibitors Alpha-glucosidase inhibitors block the Alpha-glucosidase inhibitors block the

enzymes that digest starches in the small enzymes that digest starches in the small intestineintestine

EfficacyEfficacy Decrease peak postprandial glucose 2.2-2.8 mmol/LDecrease peak postprandial glucose 2.2-2.8 mmol/L Decrease fasting plasma glucose 1.4-1.7 mmol/LDecrease fasting plasma glucose 1.4-1.7 mmol/L Decrease A1C 0.5-1.0%Decrease A1C 0.5-1.0%

Other EffectsOther Effects Flatulence or abdominal discomfort Flatulence or abdominal discomfort No specific effect on lipids or blood pressureNo specific effect on lipids or blood pressure No weight gainNo weight gain Contraindicated in patients with inflammatory bowel Contraindicated in patients with inflammatory bowel

disease or cirrhosisdisease or cirrhosis Medications in this Class: acarbose Medications in this Class: acarbose

(Glucobay)(Glucobay)

Treatment of Type 2 Treatment of Type 2 DiabetesDiabetes

DiagnosisDiagnosis

Therapeutic Lifestyle ChangeTherapeutic Lifestyle Change

Combination Therapy - Oral Drug with InsulinCombination Therapy - Oral Drug with Insulin

Combination Therapy - Oral Drugs OnlyCombination Therapy - Oral Drugs Only

MonotherapyMonotherapy

Insulin TherapyInsulin Therapy

Normal Pancreatic Normal Pancreatic FunctionFunction

Meal Meal Meal

Bolus: At mealtime, insulin is rapidly released

in response to food.

Basal: Beta cells secrete small amounts of insulinthroughout the day.

Basal Insulin

Bolus Insulin

• Expected insulin changes during the day Expected insulin changes during the day for individuals with a healthy pancreasfor individuals with a healthy pancreas..

*Insulin effect images are theoretical representations and are not derived from clinical trial data.

Action Profiles of Bolus Action Profiles of Bolus & Basal Insulins& Basal Insulins

Pla

sm

a In

sulin

lev

els

HoursNote: action curves are approximations for illustrative purposes. Actual patient response will vary.

regular 6-10 hours

NPH 12–20 hours

lispro/aspart 4–6 hours

BASAL INSULINS

detemir ~ 6-23 hours (dose dependant)

glargine ~ 20-26 hours

Mayfield, JA.. et al, Amer. Fam. Phys.; Aug. 2004, 70(3): 491 Plank, J. et.al. Diabetes Care, May 2005; 28(5): 1107-12

BOLUS INSULINS

• Expected insulin changes during the day Expected insulin changes during the day • for individuals with a healthy pancreas.for individuals with a healthy pancreas.

*Insulin effect images are theoretical representations and are not derived from clinical trial data

Mayfield, JA. et al., Amer. Fam. Phys.; Aug. 2004, 70(3): 489-500

BID NPH and Regular BID NPH and Regular Insulin Therapy - Insulin Therapy -

Compared to Normal Compared to Normal PhysiologyPhysiology

Bolus needs: Regular

Basal needs: NPH

Meal Meal Meal

• Expected insulin changes during the day Expected insulin changes during the day • for individuals with a healthy pancreas.for individuals with a healthy pancreas.

*Insulin effect images are theoretical representations and are not derived from clinical trial data.

Multiple Daily Injections Multiple Daily Injections (MDI) – (MDI) –

Strive to Mimic Normal Strive to Mimic Normal PhysiologyPhysiology

MDI insulin therapy addresses:

Bolus needs: Lispro, Aspart Basal needs: Glargine, Detemir

Meal Meal Meal

Insulin RegimensInsulin RegimensType 2Type 2

Usually – a single bedtime injection Usually – a single bedtime injection of basal insulin added to OAD. of basal insulin added to OAD.

Occasionally - twice daily injections Occasionally - twice daily injections of basal insulin with OAD.of basal insulin with OAD.

Twice daily injection of “pre-mixed” Twice daily injection of “pre-mixed” insulin (split mix without mixing).insulin (split mix without mixing).

Intensive insulin – basal/bolusIntensive insulin – basal/bolus 40% basal/20% mealtime with each meal40% basal/20% mealtime with each meal

Case 1Case 1

Breakfast Lunch Dinner Bedtime

9.5 7.5 7.1 7.0

Is this patient well controlled? Does this patient require insulin?

55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5% 55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5% On metformin, glyburide, On metformin, glyburide,

Case 1 - Bedtime InsulinCase 1 - Bedtime Insulin

Breakfast Lunch Dinner Bedtime

Start with 10 units1, or use 0.1- 0.2 units/kg and titrate2 Ex. 84 kg X 0.1 = 8 units OR 84 kg X 0.2 = 17 units Continue metformin, glyburide. Continuing TZD would be

off-label in Canada

NPH, Glargine or Detemir - 10 units

55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5% 8.5% On metformin, glyburide, On metformin, glyburide,

- - -

1 Riddle et.al., Diabetes Care, 2003, 26(11):3080-862 CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S135

Hypoglycemia – Hypoglycemia – RecognitionRecognition

Hypoglycemia = development of symptoms or a plasma Hypoglycemia = development of symptoms or a plasma glucose <4.0 mmol/L.glucose <4.0 mmol/L.

Symptoms of hypoglycemiaSymptoms of hypoglycemia

AutonomicAutonomic NeuroglycopenicNeuroglycopenicTremblingTremblingPalpitationsPalpitationsSweatingSweatingAnxietyAnxiety

HungerHungerNauseaNauseaTinglingTingling

Difficulty Difficulty concentrating concentrating Vision changesVision changesDifficulty speakingDifficulty speakingHeadacheHeadacheDizzinessDizziness

ConfusionConfusionWeaknessWeaknessDrowsinessDrowsinessTirednessTiredness

Severity of hypoglycemiaSeverity of hypoglycemiaMild: Mild: Autonomic symptoms are present. The individual is Autonomic symptoms are present. The individual is able to self-treat.able to self-treat.Moderate: Moderate: Autonomic and neuroglycopenic symptoms are Autonomic and neuroglycopenic symptoms are present. The individual is able to self-treat.present. The individual is able to self-treat.Severe: Severe: Individual requires assistance of another person. Individual requires assistance of another person. Unconsciousness may occur. Plasma glucose is typically Unconsciousness may occur. Plasma glucose is typically <2.8 mmol/L. <2.8 mmol/L.

CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S43

Diabetic Diabetic ketoacidosisketoacidosis

Diagnostic criteriaDiagnostic criteria

HyperglycemiaHyperglycemia Glucose >11.1 mmol/l; usually > 15 mmol/lGlucose >11.1 mmol/l; usually > 15 mmol/l

metabolic acidosis (increased anion gap)metabolic acidosis (increased anion gap) pH < 7.35pH < 7.35 decreased bicarbonate <15 (best estimation decreased bicarbonate <15 (best estimation

with venous)with venous) positive serum ketonespositive serum ketones

Urine ketones: may be absent in early stagesUrine ketones: may be absent in early stages

Insulin deficiencyInsulin deficiency

Decreased peripheral glucose Decreased peripheral glucose utilizationutilization

increased glucose productionincreased glucose production liver - gluconeogenesis (from liver - gluconeogenesis (from

aminoacids, glycerol), glycogenolysisaminoacids, glycerol), glycogenolysis increased ketogenesisincreased ketogenesis

increased lipolysis in adipocytes - increased lipolysis in adipocytes - provides free fatty acids for ketones and provides free fatty acids for ketones and glycerol for gluconeogenesisglycerol for gluconeogenesis

Clinical featuresClinical features

Hyperglycemia: thirst, polyuria, Hyperglycemia: thirst, polyuria, circulatory collapsecirculatory collapse

Ketosis: “acetone breath’Ketosis: “acetone breath’ Acidosis/ compensatory respiratory Acidosis/ compensatory respiratory

alkalosis: tachypneaalkalosis: tachypnea

DKA: Precipitating Causes

Consequences of DKAConsequences of DKA

HyperglycemiaHyperglycemia osmotic diuresisosmotic diuresis

dehydrationdehydration loss of K, Na, HCO3 in urineloss of K, Na, HCO3 in urine

hyperosmolar state hyperosmolar state increase free water into blood increase free water into blood hyponatremia, hyponatremia,

cerebral dehydration cerebral dehydration decreased level of decreased level of consciousnessconsciousness

acidosisacidosis compensatory respiratory alkalosiscompensatory respiratory alkalosis K shifts (hyperkalemia)K shifts (hyperkalemia)

Laboratory Calculations Laboratory Calculations for diagnosis and for diagnosis and

treatmenttreatment Serum osmolalitySerum osmolality 2(Na + K) + glucose +BUN2(Na + K) + glucose +BUN

serum Naserum Na for each 3-4 mmol/l increase in glucose, Na for each 3-4 mmol/l increase in glucose, Na

should decrease by 1should decrease by 1 anion gapanion gap

Na -(Cl+HCO3)Na -(Cl+HCO3) compensation for metabolic acidosiscompensation for metabolic acidosis If suspect other causes for acidosis; If suspect other causes for acidosis;

meausre serum lactate and salicylatemeausre serum lactate and salicylate

TreatmentTreatment

GOAL: GOAL: replace volume loss (with normal replace volume loss (with normal

saline)saline) stop ketone production (with insulin)stop ketone production (with insulin) replace K loss (K initially high but falls replace K loss (K initially high but falls

rapidly with treatment)rapidly with treatment) lower serum glucoselower serum glucose

**Need to correct INSULIN DEFICIENCYNeed to correct INSULIN DEFICIENCY

*Look for precipitating cause and treat*Look for precipitating cause and treat

FluidFluid NS 1L per hour first 2 hours, then 1L over 4 hrsNS 1L per hour first 2 hours, then 1L over 4 hrs NS until glucose < 15 NS until glucose < 15 then D5/NS or D5 depending if still replacing then D5/NS or D5 depending if still replacing

volumevolume insulininsulin

intravenousintravenous 50 units regular in 500 normal saline (0.1U/ml)50 units regular in 500 normal saline (0.1U/ml) Bolus 0.1 unit per kg body weight (IM/IV)Bolus 0.1 unit per kg body weight (IM/IV) Infusion 0.1 unit/kg/hourInfusion 0.1 unit/kg/hour Glucoscans q1h, adjust IV rate and IV D5Glucoscans q1h, adjust IV rate and IV D5* Do not stop insulin infusion until acidosis/ AG * Do not stop insulin infusion until acidosis/ AG

correctedcorrected bicarbonate generally avoidedbicarbonate generally avoided potassiumpotassium

start when K 3.3-5.5, 20 mmol/L (hold insulin if K start when K 3.3-5.5, 20 mmol/L (hold insulin if K is <3.3 and give 40 meq/his <3.3 and give 40 meq/h

Hyperosmolar non-Hyperosmolar non-ketotic stateketotic state

Severe hyperglycemia generally in DM Severe hyperglycemia generally in DM type 2type 2

dehydrationdehydration serum hyperosmolalityserum hyperosmolality lack of significant ketosis (still some lack of significant ketosis (still some

circulating insulin)circulating insulin)

* takes less insulin to prevent ketosis than * takes less insulin to prevent ketosis than to stop hyperglycemiato stop hyperglycemia

Stressor - increased insulin Stressor - increased insulin resistanceresistance

relative insulin deficiencyrelative insulin deficiency increased glucose production, increased glucose production,

decreased utilizationdecreased utilization reduced renal excretion of glucose reduced renal excretion of glucose

secondary to renal disease, aging secondary to renal disease, aging kidneyskidneys

Treatment of HONKTreatment of HONK

Correct increased serum osmolality Correct increased serum osmolality Blood glucose will fall in response to Blood glucose will fall in response to

fluid repletionfluid repletion If Na>155 mmol/L, start 0.45% NS If Na>155 mmol/L, start 0.45% NS

as initial fluidas initial fluid Insulin infusion only if persistent Insulin infusion only if persistent

hyperglycemia after fluid repletehyperglycemia after fluid replete

Screening and prevention of Screening and prevention of complicationscomplications

Target Lipid LevelsTarget Lipid Levels

Risk categories and target lipid levels

III-9

Reduce LDL-C to target for high risk patients Reduce LDL-C to target for high risk patients (< 2.0 mmol/L)(< 2.0 mmol/L)

Combinations of lipid-lowering medications can Combinations of lipid-lowering medications can and should be used to achieve lipid targetsand should be used to achieve lipid targets

Statin + cholesterol absorption inhibitorsStatin + cholesterol absorption inhibitors

Statin + fibratesStatin + fibrates

Statin + niacinStatin + niacin

Cholesterol absorption inhibitors + fibratesCholesterol absorption inhibitors + fibrates

Treatment optionsTreatment options

Vascular Protection Through Vascular Protection Through a a

Multifaceted ApproachMultifaceted Approach For ALL High-risk Patients with Diabetes • ACEI• ASA (clopidogrel if intolerance)• Lifestyle management: No smoking, healthy diet / weight, physical activity

Blood Pressure Control

Aim for BP < 130/80 mm Hg

If BP >130/80 mm Hg despite ACEI:Treat as per hypertension recommendations (CHEP/CHS)

Glycemic Control

Aim for A1C < 7.0%(< 6.0% if achievable safely)

If AIC > 7%: Treat as per glycemiarecommendations (CDA)

High CV risk

Renal Protection•Treat as per nephropathy recommendations (CDA)

Lipid Control

Adapted from Can J Diabetes. 2003;27:S58-S65.

When monotherapy fails to achieve lipid targets, the addition of a second drug from another class should be considered

Aim forLDL ≤ 2.0 andTC:HDL < 4.0

Smoking Cessation advice.

Diabetic Diabetic NephropathyNephropathy

Diabetic NephropathyDiabetic Nephropathy Over 40% of new cases of Over 40% of new cases of

end-stage renal disease end-stage renal disease (ESRD) are attributed to (ESRD) are attributed to diabetes. diabetes.

In 2001, 41,312 people In 2001, 41,312 people with diabetes began with diabetes began treatment for end-stage treatment for end-stage renal disease in U.S.renal disease in U.S.

In 2001, it cost $22.8 In 2001, it cost $22.8 billion in public and billion in public and private funds to treat private funds to treat patients with kidney patients with kidney failure.failure.

Minorities experience Minorities experience higher than average rates higher than average rates of nephropathy and kidney of nephropathy and kidney diseasedisease

Incidence of ESRD Resulting from Primary

Diseases (1998)

43%

23%

12%

3%

19%

Diabetes

Hypertension

Glomerulonephritis

Cystic Kidney

Other Causes

Screening for Diabetic Screening for Diabetic NephropathyNephropathy

Test When Normal Range

Blood Pressure1

Each office visit <130/80 mm/Hg

Urinary Albumin1

Type 2: Annually beginning at diagnosis Type 1: Annually, 5-years post-diagnosis

<30 mg/day 30 g/mgcreatinine

1American Diabetes Association: Nephropathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S79-S83, 2004

ACR </= 2.8 for womenACR </= 2.0 for men

Treatment of Diabetic Treatment of Diabetic NephropathyNephropathy

Hypertension Control -Hypertension Control - Goal: lower Goal: lower blood pressure to <130/80 mmHg blood pressure to <130/80 mmHg Antihypertensive agentsAntihypertensive agents

Angiotensin-converting enzyme (ACE) Angiotensin-converting enzyme (ACE) inhibitorsinhibitors

captopril, enalapril, lisinopril, benazepril, captopril, enalapril, lisinopril, benazepril, fosinopril, ramipril, quinapril, perindopril, fosinopril, ramipril, quinapril, perindopril, trandolapril, moexipriltrandolapril, moexipril

Angiotensin receptor blocker (ARB) therapy Angiotensin receptor blocker (ARB) therapy candesartan cilexetil, irbesartan, losartan candesartan cilexetil, irbesartan, losartan

potassium, telmisartan, valsartan, esprosartan potassium, telmisartan, valsartan, esprosartan

Beta-blockersBeta-blockers

Glycemic Control Glycemic Control Preprandial plasma glucose 90-130 mg/dlPreprandial plasma glucose 90-130 mg/dl A1C <7.0%A1C <7.0% Peak postprandial plasma glucose <180 Peak postprandial plasma glucose <180

mg/dlmg/dl Self-monitoring of blood glucose (SMBG)Self-monitoring of blood glucose (SMBG) Medical Nutrition TherapyMedical Nutrition Therapy

Restrict dietary protein to RDA of 0.8 Restrict dietary protein to RDA of 0.8 g/kg body weight per day g/kg body weight per day

Treatment of Diabetic Treatment of Diabetic Nephropathy (cont.)Nephropathy (cont.)

Treatment of Diabetic Treatment of Diabetic Nephropathy (cont.)Nephropathy (cont.)

Treatment of End-Stage Treatment of End-Stage Renal Disease (ESRD)Renal Disease (ESRD)

There are three primary treatment There are three primary treatment options for individuals who options for individuals who experience ESRD:experience ESRD:

1. Hemodialysis1. Hemodialysis

2. Peritoneal Dialysis2. Peritoneal Dialysis

3. Kidney Transplantation3. Kidney Transplantation

How Can You Prevent How Can You Prevent Diabetic Kidney Diabetic Kidney

Disease?Disease? Maintain blood pressure <130/80 Maintain blood pressure <130/80

mm/Hgmm/Hg Maintain preprandial plasma glucose 4-Maintain preprandial plasma glucose 4-

7 mmol/L7 mmol/L Maintain postprandial plasma glucose Maintain postprandial plasma glucose

<10 mmol/L<10 mmol/L Maintain A1C <7.0%Maintain A1C <7.0% Use ACE inhib or ARB if ACR is Use ACE inhib or ARB if ACR is

elevated even if normotensiveelevated even if normotensive Use antiplatelet therapyUse antiplatelet therapy

Diabetic Diabetic RetinopathyRetinopathy

Diabetic RetinopathyDiabetic Retinopathy

• Diabetic retinopathy is the most common cause of new cases of blindness among adults 20-74 years of age.

• During the first two decades of disease, nearly all patients with type 1 diabetes and over 60% of patients with type 2 diabetes have retinopathy

Risks of Diabetic Risks of Diabetic Retinopathy Related Retinopathy Related

Vision LossVision Loss Duration of diabetes diseaseDuration of diabetes disease type 1 patients experience a 25% rate of type 1 patients experience a 25% rate of

retinopathy after 5 years of disease, and 80% at retinopathy after 5 years of disease, and 80% at 15 years of disease15 years of disease11

Up to 21% of newly diagnosed type 2 patients Up to 21% of newly diagnosed type 2 patients have some degree of retinopathy at time of have some degree of retinopathy at time of diagnosisdiagnosis11

PubertyPuberty PregnancyPregnancy Lack of appropriate ophthalmic examinationLack of appropriate ophthalmic examination

1American Diabetes Association: Retinopathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S84-S87, 2004

Retinopathy ScreeningRetinopathy Screening Type 1 diabetes - screen within 3-5 Type 1 diabetes - screen within 3-5

years of diagnosis after age 10years of diagnosis after age 1011

Type 2 diabetes - screen at time of Type 2 diabetes - screen at time of diagnosisdiagnosis11

Pregnancy - women with preexisting Pregnancy - women with preexisting diabetes should be screened prior to diabetes should be screened prior to conception and during first trimesterconception and during first trimester11

Follow-up annually; less frequent Follow-up annually; less frequent exams (2-3 yrs) may be consideredexams (2-3 yrs) may be considered11

Examination Methods - Dilated indirect Examination Methods - Dilated indirect ophthalmoscopy coupled with ophthalmoscopy coupled with biomicroscopy and seven-standard field biomicroscopy and seven-standard field steroscopic 30° fundus photographysteroscopic 30° fundus photography11

1American Diabetes Association: Retinopathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S84-S87, 2004

Natural History of Natural History of Diabetic RetinopathyDiabetic Retinopathy

Mild nonproliferative Mild nonproliferative diabetic retinopathy diabetic retinopathy (NPDR)(NPDR)

Moderate NPDRModerate NPDR Severe NPDRSevere NPDR Very Severe NPDRVery Severe NPDR Proliferative diabetic Proliferative diabetic

retinopathy (PDR)retinopathy (PDR)

Diabetic Diabetic ketoacidosisketoacidosis

Diagnostic criteriaDiagnostic criteria

HyperglycemiaHyperglycemia Glucose >11.1 mmol/l; usually > 15 mmol/lGlucose >11.1 mmol/l; usually > 15 mmol/l

metabolic acidosis (increased anion gap)metabolic acidosis (increased anion gap) pH < 7.35pH < 7.35 decreased bicarbonate <15 (best estimation decreased bicarbonate <15 (best estimation

with venous)with venous) positive serum ketonespositive serum ketones

Urine ketones: may be absent in early stagesUrine ketones: may be absent in early stages

Insulin deficiencyInsulin deficiency

Decreased peripheral glucose Decreased peripheral glucose utilizationutilization

increased glucose productionincreased glucose production liver - gluconeogenesis (from liver - gluconeogenesis (from

aminoacids, glycerol), glycogenolysisaminoacids, glycerol), glycogenolysis increased ketogenesisincreased ketogenesis

increased lipolysis in adipocytes - increased lipolysis in adipocytes - provides free fatty acids for ketones and provides free fatty acids for ketones and glycerol for gluconeogenesisglycerol for gluconeogenesis

Clinical featuresClinical features

Hyperglycemia: thirst, polyuria, Hyperglycemia: thirst, polyuria, circulatory collapsecirculatory collapse

Ketosis: “acetone breath’Ketosis: “acetone breath’ Acidosis/ compensatory respiratory Acidosis/ compensatory respiratory

alkalosis: tachypneaalkalosis: tachypnea

DKA: Precipitating Causes

Consequences of DKAConsequences of DKA

HyperglycemiaHyperglycemia osmotic diuresisosmotic diuresis

dehydrationdehydration loss of K, Na, HCO3 in urineloss of K, Na, HCO3 in urine

hyperosmolar state hyperosmolar state increase free water into blood increase free water into blood hyponatremia, hyponatremia,

cerebral dehydration cerebral dehydration decreased level of decreased level of consciousnessconsciousness

acidosisacidosis compensatory respiratory alkalosiscompensatory respiratory alkalosis K shifts (hyperkalemia)K shifts (hyperkalemia)

Laboratory Calculations Laboratory Calculations for diagnosis and for diagnosis and

treatmenttreatment Serum osmolalitySerum osmolality 2(Na + K) + glucose +BUN2(Na + K) + glucose +BUN

serum Naserum Na for each 3-4 mmol/l increase in glucose, Na for each 3-4 mmol/l increase in glucose, Na

should decrease by 1should decrease by 1 anion gapanion gap

Na -(Cl+HCO3)Na -(Cl+HCO3) compensation for metabolic acidosiscompensation for metabolic acidosis If suspect other causes for acidosis; If suspect other causes for acidosis;

meausre serum lactate and salicylatemeausre serum lactate and salicylate

TreatmentTreatment

GOAL: GOAL: replace volume lossreplace volume loss stop ketone productionstop ketone production replace K loss (K initially high but falls replace K loss (K initially high but falls

rapidly with treatment)rapidly with treatment) lower serum glucoselower serum glucose

**Need to correct INSULIN DEFICIENCYNeed to correct INSULIN DEFICIENCY

*Look for precipitating cause and treat*Look for precipitating cause and treat

FluidFluid NS 1L per hour first 2 hours, then 1L over 4 hrsNS 1L per hour first 2 hours, then 1L over 4 hrs NS until glucose < 15 NS until glucose < 15 then D5/NS or D5 depending if still replacing then D5/NS or D5 depending if still replacing

volumevolume insulininsulin

intravenousintravenous 50 units regular in 500 normal saline (0.1U/ml)50 units regular in 500 normal saline (0.1U/ml) Bolus 0.1 unit per kg body weight (IM/IV)Bolus 0.1 unit per kg body weight (IM/IV) Infusion 0.1 unit/kg/hourInfusion 0.1 unit/kg/hour Glucoscans q1h, adjust IV rate and IV D5Glucoscans q1h, adjust IV rate and IV D5* Do not stop insulin infusion until acidosis/ AG * Do not stop insulin infusion until acidosis/ AG

correctedcorrected bicarbonate generally avoidedbicarbonate generally avoided potassiumpotassium

start when K 4.5-5.0, 20 mmol/Lstart when K 4.5-5.0, 20 mmol/L

Hyperosmolar non-Hyperosmolar non-ketotic stateketotic state

Severe hyperglycemia generally in DM Severe hyperglycemia generally in DM type 2type 2

dehydrationdehydration serum hyperosmolalityserum hyperosmolality lack of significant ketosis (still some lack of significant ketosis (still some

circulating insulin)circulating insulin)

* takes less insulin to prevent ketosis than * takes less insulin to prevent ketosis than to stop hyperglycemiato stop hyperglycemia

Stressor - increased insulin Stressor - increased insulin resistanceresistance

relative insulin deficiencyrelative insulin deficiency increased glucose production, increased glucose production,

decreased utilizationdecreased utilization reduced renal excretion of glucose reduced renal excretion of glucose

secondary to renal disease, aging secondary to renal disease, aging kidneyskidneys

Treatment of HONKTreatment of HONK

Correct increased serum osmolality Correct increased serum osmolality Blood glucose will fall in response to Blood glucose will fall in response to

fluid repletionfluid repletion If Na>155 mmol/L, start 0.45% NS If Na>155 mmol/L, start 0.45% NS

as initial fluidas initial fluid Insulin infusion only if persistent Insulin infusion only if persistent

hyperglycemia after fluid repletehyperglycemia after fluid replete