DIABETES MELLITUS

References: Harrisons 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) Alpha cells: glucagon Beta cells: insulin

Prevalence of Glycemic Abnormalities in the United States

US Population: 275 Million in 2000
Undiagnosed diabetes 5.9 million

Diagnosed type 1 diabetes ~1.0 million

Additional 24.6 million with IGT

Diagnosed type 2 diabetes 10 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

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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 energy produces ketoacidosis in persons with Type I diabetes and gestational diabetes

Factors that can contribute

1. 2. 3.

Reduced insulin secretion Decreased glucose utilization Increased hepatic glucose production

Figure 338-1
Type Type 1 Type 2 GDM FPG 2hPG
<5.6 mmol/L 5.6-6.9 mmol/L >7 mmol/L (100 mg/dL) (100-125 mg/dL) (126 mg/dL) <7.8 (140 mg) 7.8-11.1 (140-199 mg) >11.1 (200 mg)

Normal

Prediabetes

IFG or IGT

DM + Insulin

Criteria for Diagnosis

1. Symptoms of diabetes (3 Ps, etc) plus RBS >11.1 mmol/L (200 mg/dL) or 2. FBS>7 mmol/L (126 mg/dL) or 3. 2 hour PG>11.1 mmol/L (200 mg/dL) during OGTT (75 gm glucose) Screening for people >45 yrs. every 3 yrs

Regulation of Postprandial Glucose 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

Impaired 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

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

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Classification of Diabetes Mellitus by Etiology

Type 1 insulin
Type 2

-cell destructioncomplete lack of

-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 -cells of the pancreas, leading to complete -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 autoantibodiesGAD 65)

Type 1
unrestrained glucose production by the liver and impaired uptake of glucose by peripheral target tissue Environmental factors

Viruses

(coxsackie, rubella) Bovine milk proteins Nitrosourea compounds (cured meat, cheese)

Natural History Of PreType 1 Diabetes

-Cell mass 100%
Putative trigger
Cellular autoimmunity Circulating autoantibodies (ICA, GAD65) Loss of first-phase insulin response (IVGTT)

Genetic predisposition

Insulitis -Cell injury

Prediabetes

Clinical Glucose intolerance onset (OGTT) only 10% of -cells remain

Diabetes

Time
Eisenbarth GS. N Engl J Med. 1986;314:1360-1368
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Type 2 Pathophysiology
Impaired insulin secretion Insulin resistance Excessive hepatic glucose production Abnormal fat metabolism

Pathogenesis of Type 2 Diabetes Two Defects

Impaired insulin secretion

Hepatic insulin resistance

Excessive glucose production

Muscle/fat insulin resistance

Impaired glucose clearance

Hyperglycemia

More glucose enters the blood stream

Glycosuria

Less glucose enters peripheral tissues

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Etiology of Type 2 Diabetes Impaired Insulin Secretion and Insulin Resistance

Genes and environment
Impaired insulin secretion

Insulin resistance

Impaired glucose tolerance

Type 2 diabetes

Natural History of Type 2 Diabetes Impaired

glucose tolerance Undiagnosed Known diabetes diabetes

Insulin resistance

Insulin secretion Postprandial glucose Fasting glucose

Microvascular complications Macrovascular complications

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

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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 dehydration Nausea, vomiting, abdominal pain, thirst, polyuria Trigger: 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

-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

Hyperglycemia Hyperosmolar >350 Prerenal azotemia Moderate 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 USA Neovascularization (hallmark proliferative)

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

-leading cause of ESRD (USA)

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

Neuropathy -Annual foot exam with 10-g monofilament test - 50% of patients - poly, mono, autonomic - Distal symmetric neuropathy (most common)

Gastointestinal
Gastroparesis

(most prominent)

GUT
Erectile

dysfunction

Lower Extremity Complications DM 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 Diabetes

Assess 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

Plasma glucose (mg/dL)

A1C Reflects Both Fasting and Postprandial Hyperglycemia

300

200

Postprandial hyperglycemia Fasting hyperglycemia Normal

100

0600

1200

1800

2400

0600

Time of day
Riddle MC. Diabetes Care. 1990;13:676-686
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Glycated hemoglobin

hemoglobin A1C, HbA1c, or A1C

reflects the glycemic exposure of a patients 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
Premeal Peak

<7%
postmeal 90-130 mg/dL <180 mg/dL

BP Lipids
LDL HDL TG

< 130/80
<100 mg/dL >40 mg/dL <150 mg/dL

Nutrition Table 338-9

Fat 20-35%
Saturated<7% <200

Carbohydrate
45-65%

mg/day of dietary cholesterol 2 or more servings of fish/week

Protein
10-35%

Antihyperglycemic Agents
Major Sites of Action
-Glucosidase inhibitors

Carbohydrate absorption

Glitazones
+ Glucose uptake

Plasma glucose

GI tract

Glucose production

Muscle/Fat +

Metformin

Liver
Insulin secretion

Injected insulin

Secretagogues

Pancreas
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Oral Antihyperglycemic Agents for Type 2 Diabetes

Class Agents

Secretagogue
Biguanide -Glucosidase inhibitor Glitazone (TZD)

Sulfonylureas Repaglinide, nateglinide

Metformin Acarbose, miglitol Pioglitazone, rosiglitazone

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Insulin Secretagogues
Sulfonylureas, Repaglinide, and Nateglinide
Mechanism of action Efficacy depends upon Power Increase basal and/or postprandial insulin secretion Functioning -cells 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

Weight gain, allergy (rare)

Side effects

Main risk

Hypoglycemia
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Biguanides
Metformin
Primary mechanism of action Decreases hepatic glucose production

Efficacy depends upon

Power Dosing XR) Side effects

Presence of insulin
Decreases A1C 1%2% 2 or 3 times daily (metformin) 1 or 2 times daily (metformin Diarrhea, nausea

Main risk

Lactic acidosis
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-Glucosidase Inhibitors
Acarbose and Miglitol
Mechanism of action Efficacy depends upon Power
Delay carbohydrate absorption

Postprandial hyperglycemia Decrease A1C 0.5%1%

Dosing
Side effects

3 times daily
Flatulence

Main risk

Liver enzyme elevation

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

(rare)

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Glitazones (TZDs)
Pioglitazone and Rosiglitazone
Mechanism of action
Efficacy depends upon Power Dosing Enhance tissue response to insulin Presence of insulin and resistance to its action Decrease A1C 0.9%1.6% Once daily

Side effects
Main risk

Edema, weight gain, anemia

Congestive heart failure

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Treatment of Postprandial Glycemia

Conclusions 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 Antihyperglycemics Declines 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

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INSULIN THERAPY?

Types Onset Peak Duration of Action