DIABETES MELLITUS

References:

Harrison’s Principles of Internal Medicine 17th edition

http://cadre-diabetes.org/r_treatment_guidelines.asp

http://care.diabetesjournals.org/cgi/reprint/31/Supplement_1/S12

http://www.aace.com/meetings/consensus/dcc/pdf/dccwhitepaper.pdf

ANATOMY

Endocrine pancreas (islet cells)

Beta cells: insulin

Alpha cells: glucagon

Undiagnosed diabetes

5.9 million

Prevalence of Glycemic Abnormalities in the United States

Additional 24.6 million

with IGT

Diagnosed type 2 diabetes

10 million

Diagnosed type 1 diabetes

~1.0 million

Centers for Disease Control. Available at: http://www.cdc.gov/diabetes/pubs/estimates.htm; Harris MI. In: National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: NIDDK; 1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001

US Population: 275 Million in 2000

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What happens when insulin production and secretion fails? 

destruction of Islet beta cells (diabetes type 1)

or loss of response to insulin (diabetes type 2/insulin resistance)

INSULIN ACTION IN MUSCLE AND FAT CELLS

1. Insulin finds and docks onto its receptor.

2. A signal is sent to a pool of glucose transport proteins (Glut 4 Protein) located inside the cell.

3. These Glut 4 proteins move rapidly up to the cell membrane and cause glucose channels to open.

4. Glucose is "escorted " to the interior of the cell where enzymes will begin to break it down to fuel the work of the cell.

Overall Effects of Insulin on Muscle and Fat

MUSCLE blood glucose levels and availability of

energy for muscle contraction Conversion of glucose into glycogen entry of amino acids from the blood breakdown of existing muscle proteins

into glucose

Overall Effects of Insulin on Muscle

What is the effect of diabetes on muscle? lack quick fuel to do their work. Muscle cells then begin to convert glycogen

stores to glucose Muscle cells turn to fat and protein as fuel

sources The result is elevated blood glucose, loss of

muscle mass, weight loss, weakness and fatigue.

Overall Effects of Insulin on FAT

Storage of both excess blood glucose and blood fats inside the fat cell.

provides the body with an energy reserve that can be utilized during prolonged exercise or fasting.

Depositing of blood fats (triglycerides) into fat cells is increased

What is the effect of diabetes on fat? Glucose cannot get in to the fat cell to be

converted to fat. Fat is then broken down for energyproduces ketoacidosis in persons with

Type I diabetes and gestational diabetes

Factors that can contribute

1. Reduced insulin secretion

2. Decreased glucose utilization

3. Increased hepatic glucose production

Figure 338-1

Type NormalPrediabetes DMIFG or IGT + Insulin

Type 1Type 2GDM

FPG<5.6 mmol/L(100 mg/dL)

5.6-6.9 mmol/L(100-125 mg/dL)

>7 mmol/L(126 mg/dL)

2hPG<7.8 (140 mg)

7.8-11.1 (140-199 mg)

>11.1 (200 mg)

Criteria for Diagnosis

1. Symptoms of diabetes (3 P’s, etc) plus RBS >11.1 mmol/L (200 mg/dL) or

2. FBS>7 mmol/L (126 mg/dL) or3. 2 hour PG>11.1 mmol/L (200 mg/dL)

during OGTT (75 gm glucose)

Screening for people >45 yrs. every 3 yrs

• A meal contains 6 to 20 times the glucose content of the blood

• Normally, postprandial hyperglycemia is regulated by• Clearance of ingested glucose by

the liver• Suppression of hepatic glucose

production• Peripheral clearance of glucose

Regulation of Postprandial Glucose

• In impaired glucose tolerance or diabetes, glucose regulation is impaired by • Delayed and reduced insulin secretion• Lack of suppression of glucagon • Hepatic and peripheral insulin

resistance

• Postprandial hyperglycemia results

Impaired Regulation ofPostprandial Glucose

Who Should Be Tested for Diabetes?

Symptoms suggesting diabetes: weight loss, hunger, urinary frequency, blurred vision

Age >45 (>30 if patient has other risk factors) Prior IGT or IFG or family history of diabetes Prior gestational diabetes or baby weighing >9 lb Women with polycystic ovarian syndrome (PCOS) Obesity (BMI 25 kg/m2), especially adolescents African, Latino, Asian, or Native American ancestry History of vascular disease or hypertension

American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S11-S14;AACE/ACE medical guidelines. Endocr Pract. 2002;8(suppl 1):40-82 19

Classification of Diabetes Mellitusby Etiology

Type 1 -cell destruction—complete lack of insulin

Type 2 -cell dysfunction and insulin resistance

Gestational -cell dysfunction and insulin resistance during pregnancy

Other specific types • Genetic defects of -cell function• Exocrine pancreatic diseases• Endocrinopathies• Drug- or chemical-induced• Other rare forms

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Type 1

injury to β-cells of the pancreas, leading to complete β-cell destruction and total insulin deficiency

5% to 10% of all cases of diabetes and is most frequently diagnosed in children and adolescents

Islet destruction mediated by T lymphocytes Genetic susceptibility (islet cell autoantibodies-

GAD 65)

Type 1

unrestrained glucose production by the liver and impaired uptake of glucose by peripheral target tissue

Environmental factorsViruses (coxsackie, rubella)Bovine milk proteinsNitrosourea compounds (cured meat, cheese)

Putativetrigger

Circulating autoantibodies (ICA, GAD65)

Cellular autoimmunityCellular autoimmunity

Loss of first-phase insulin response (IVGTT)

Glucose intolerance (OGTT)

Clinicalonset—

only 10% of-cells remain

Time

-Cell mass 100%

“Pre”-diabetes

Geneticpredisposition

Insulitis-Cell injury

Eisenbarth GS. N Engl J Med. 1986;314:1360-1368

Diabetes

Natural History Of “Pre”–Type 1 Diabetes

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Type 2 Pathophysiology

Impaired insulin secretion Insulin resistance Excessive hepatic glucose production Abnormal fat metabolism

Pathogenesis of Type 2 DiabetesTwo Defects

Excessiveglucose production

Impaired glucoseclearance

Hepaticinsulin

resistance

Muscle/fatinsulin

resistance

Impairedinsulin

secretion

Hyperglycemia

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More glucose entersthe blood stream

Less glucose entersperipheral tissues

Glycosuria

Etiology of Type 2 Diabetes Impaired Insulin Secretion and Insulin Resistance

Genes and environment

Type 2 diabetes

Impaired glucose tolerance

Impaired insulin secretion

Insulin resistance+

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

Natural History of Type 2 Diabetes

Macrovascular complicationsMicrovascular complications

Insulin resistanceInsulin resistance

ImpairedImpairedglucose toleranceglucose tolerance

UndiagnosedUndiagnoseddiabetesdiabetes Known diabetesKnown diabetes

Insulin secretionInsulin secretion Postprandial glucose

Fasting glucoseFasting glucose

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Acute Complications

Absolute/relative insulin deficiency

Volume depletion Acid-base

abnormalities Hyperglycemia +

Ketosis

Hyperglycemic Hyperosmolar State Type 2

DKA

Signs and symptoms of dehydrationNausea, vomiting, abdominal pain, thirst,

polyuriaTrigger: infection, inadequate insulin,

cocaine, pregnancy

DKA

Hyperglycemia Ketosis Increased anion gap

metabolic acidosis Bicarbonate <10

mmol/L Arterial pH 6.8-7.3

Low sodium Leukocytosis Serum ketones > 1:8

β-hydroxybutyrate

Kidney function tests Fluid deficit 3-5 liters

Goals of Treatment

Hydration: 2-3 L 0.9 saline over the first 3 hours 0.45 saline at 150-300 ml/hr

Short acting Insulin (IV 0.1 units/kg) then 0.1 units/kg/hr by continuous IV infusion

K supplement Monitor anion gap, serum electrolytes, VS, I & O Glucose level: 150-250 mg

Hyperosmolar Hyperglycemic State Elderly type 2 diabetic Trigger: other illness, sepsis, pneumonia,

stroke, AMI Causes: inadequate fluid intake, relative

insulin deficiency Absence of nausea, vomiting, abdominal

pain, Kussmaul breathing

HyperglycemiaHyperosmolar >350Prerenal azotemiaModerate ketonuria (sec. to starvation)

Mechanisms of Complications

4 theories Exact mechanism???

Microvascular Complications of Diabetes

Retinopathy (proliferative and non-proliferative)Leading cause of blindness for ages 20-74

in the USANeovascularization (hallmark -

proliferative)

Nephropathy

-Annual urinary microalbumin screen (normal <30 mg/g creatinine)

-leading cause of ESRD (USA)

-Microalbuminuria 30-300 µg/mg (spot collection)

Neuropathy

-Annual foot exam with 10-g monofilament test

- 50% of patients

- poly, mono, autonomic

- Distal symmetric neuropathy (most common)

GastointestinalGastroparesis (most prominent)

GUTErectile dysfunction

Lower Extremity ComplicationsDM – leading cause of nontraumatic

lower extremity amputation

Macrovascular Complications

CAD PAD CVD

Enhanced coagulation process and impaired fibrinolysis (development of thrombosis)

Identifying Cardiovascular Complications of DiabetesAssess CV risk factors annually and screen for coronary artery disease

Perform stress ECG testing if Cardiac symptoms or abnormal ECG Peripheral or carotid vascular disease Multiple risk factors Plans to begin vigorous exercise program

Refer to cardiologist if Positive exercise ECG test Unable to perform exercise test

RISK FACTORS

Dyslipidemia Hypertension

300

200

100

0

Plasma glucose (mg/dL)

Postprandialhyperglycemia

Normal

Fasting hyperglycemia

Riddle MC. Diabetes Care. 1990;13:676-686

Time of day

0600 1200 1800 2400 0600

A1C Reflects Both Fasting and Postprandial Hyperglycemia

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Glycated hemoglobin

hemoglobin A1C, HbA1c, or A1C

reflects the glycemic exposure of a patient’s red blood cells over a 60- to 90-day period and has become the standard indicator of glycemic control in diabetes

The CADRE Recommended A1C

 Normal A1C (nondiabetes): 4.0% - 6.0%  Target A1C in diabetes: Lowest A1C

possible without unacceptable hypoglycemia*  Action recommended: A1C >7.0%

ADA Treatment Goals Table 338-8

A1c <7% Premeal 90-130 mg/dL Peak postmeal <180 mg/dL

BP < 130/80 Lipids

LDL <100 mg/dL HDL >40 mg/dL TG <150 mg/dL

Nutrition Table 338-9

Fat 20-35% Saturated<7% <200 mg/day of dietary

cholesterol 2 or more servings of

fish/week

Carbohydrate 45-65%

Protein 10-35%

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Antihyperglycemic AgentsMajor Sites of Action

Carbohydrate absorption

Glucose production

Insulin secretion

Secretagogues

Glucose uptake

Injected insulin

Glitazones-Glucosidase inhibitors

–

+

+

+

Pancreas

Metformin

Muscle/Fat

–

–

–

+

GI tract

Liver

Plasma glucose

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Oral Antihyperglycemic Agentsfor Type 2 Diabetes

Class Agents

Secretagogue SulfonylureasRepaglinide, nateglinide

Biguanide Metformin

α-Glucosidase inhibitor Acarbose, miglitol

Glitazone (TZD) Pioglitazone, rosiglitazone

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Insulin Secretagogues Sulfonylureas, Repaglinide, and Nateglinide

Mechanism of action Increase basal and/or postprandialinsulin secretion

Efficacy depends upon Functioning -cells

Power Sulfonylureas, repaglinide: decrease A1C 1%–2%

Nateglinide: decreases A1C 0.5%–1%

Dosing Sulfonylureas: 1 or 2 times daily Repaglinide, nateglinide:

3 or 4 times daily with meals

Side effects Weight gain, allergy (rare)

Main risk Hypoglycemia

48

BiguanidesMetformin

Primary mechanism Decreases hepatic glucose of action production

Efficacy depends upon Presence of insulin

Power Decreases A1C 1%–2%Dosing 2 or 3 times daily

(metformin)1 or 2 times daily (metformin

XR)

Side effects Diarrhea, nausea

Main risk Lactic acidosis

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α-Glucosidase InhibitorsAcarbose and Miglitol

Mechanism of action Delay carbohydrate

absorption

Efficacy depends upon Postprandial hyperglycemia

Power Decrease A1C 0.5%–1%

Dosing 3 times daily

Side effects Flatulence

Main risk Liver enzyme elevation

(rare)Riddle MC. Am Fam Physician. 1999;60:2613-2620; Lebovitz HE. Endocrinol Metab Clin North Am. 1997;26:539-551

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Glitazones (TZDs)Pioglitazone and Rosiglitazone

Mechanism of action Enhance tissue response to insulinEfficacy depends upon Presence of insulin and resistance

to its action

Power Decrease A1C 0.9%–1.6%

Dosing Once daily

Side effects Edema, weight gain, anemia

Main risk Congestive heart failure

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Treatment of Postprandial GlycemiaConclusions From Studies

• Most oral agents control mainly fasting (basal)

hyperglycemia

• Acarbose, miglitol, and nateglinide have the greatest

effect on postprandial increments and the least ability

to reduce A1C

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Efficacy of Oral AntihyperglycemicsDeclines With Time

• A1C rises at ~0.2% to 0.3% yearly on stable therapy

• This rate is the same as for diet alone, sulfonylureas, and metformin

-Cell function declines at the same rate with all these treatments

• Combination treatments are routinely needed

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Summary of Oral Antihyperglycemic Agents• Four major classes of oral agents acting at different sites

are available• Fasting and preprandial glucose are reduced by

sulfonylureas, repaglinide, metformin, and glitazones (TZDs), with lesser effects on postprandial increments

• Postprandial glucose increments are reduced best by -glucosidase inhibitors and nateglinide

• A1C reductions are similar using sulfonylureas, metformin, and glitazones

• Secondary failure to monotherapy routinely occurs

INSULIN THERAPY?

Types

Onset

Peak

Duration of Action