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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
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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
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
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
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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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)
Genetic predisposition
Prediabetes
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
Hyperglycemia
Glycosuria
Insulin resistance
Type 2 diabetes
Insulin resistance
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Acute Complications
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
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
Mechanisms of Complications
4 theories Exact mechanism???
Nephropathy
-Annual urinary microalbumin screen (normal <30 mg/g creatinine)
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
Macrovascular Complications
CAD PAD CVD
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
200
100
0600
1200
1800
2400
0600
Time of day
Riddle MC. Diabetes Care. 1990;13:676-686
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Glycated hemoglobin
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
Normal A1C (nondiabetes): 4.0% - 6.0% Target A1C in diabetes: Lowest A1C possible without unacceptable hypoglycemia* Action recommended: A1C >7.0%
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
Fat 20-35%
Saturated<7% <200
Carbohydrate
45-65%
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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Secretagogue
Biguanide -Glucosidase inhibitor Glitazone (TZD)
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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
Side effects
Main risk
Hypoglycemia
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Biguanides
Metformin
Primary mechanism of action Decreases hepatic glucose production
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
Dosing
Side effects
3 times daily
Flatulence
Main risk
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
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-Cell function declines at the same rate with all these treatments
Combination treatments are routinely needed
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INSULIN THERAPY?