DIABETES MELLITUS

**DEFINITIONS
Type 1 DM: All causes of diabetes resulting from destruction (>80-90%) of pancreatic beta cells. Classified as autoimmune (type 1A), which is most common, or idiopathic (1B). Antibodies to the cytoplasm of islet cells, glutamic acid decarboxylase (GAD65), insulin, and tyrosine phosphatase-like protein (IA-2 or IA-2B), which appear before the clinical onset of diabetes, are good markers of the autoimmune process. However, most antibody-positive relatives of patients do not develop diabetes. Up to 10% of patients newly diagnosed with T1 DM have no diabetes-related antibodies.

Type 2 DM: All forms of diabetes characterized by combination of insulin resistance and deficient (relative to the insulin resistance - absolute levels may be supranormal early on, later absolute insulin deficit develops as beta cell function deteriorates) secretion of insulin. T2 DM is the most common form of diabetes, and has a strong genetic predisposition (twin concordance rate 90%, cf. T1 DM twin concordance 50%). Majority of patients are obese, and have features of the insulin resistance syndrome (dyslipidemia, hypertension, atherosclerotic cardiovascular disease). The prevalence of T2 DM is increasing worldwide. About 15.6 million T2 diabetics in U.S. (1997).

Gestational DM: Onset of DM during pregnancy, usually during the 3rd trimester; characterized by insulin resistance and deficient secretion, complicates ~4% of pregnancies in the U.S. (~135,000 cases/yr). 3/4 of these patients have a family history of T2 DM and they are at high risk (17-63% within 5-16 years of the index pregnancy) of subsequent development of T2 DM and require frequent long-term monitoring (6 weeks post partum and afterward at least every 3 years).

Impaired glucose tolerance (~13.4 million in U.S.) and impaired fasting glucose: Patients with values on testing which are intermediate between normal and diabetic; they are at risk for developing T2 DM and at high risk of developing atherosclerotic cardiovascular disease.

Some causes of secondary diabetes: hemochromatosis, pancreatic disease, acromegaly, pheochromocytoma, Cushing's syndrome, drug-induced (e.g. pentamidine).

**DIAGNOSIS
Diagnosis of diabetes mellitus (confirm with a repeat test):
1. Symptoms of DM (polyuria, polydipsia, unexplained weight loss with glucosuria and ketonuria) plus a random plasma glucose >= 200 mg/dl. [Whole blood values are lower by 10-15 mg/dl].
2. Fasting plasma glucose >= 126 mg/dl. Fasting value determined in the morning after absence of caloric intake for at least 8 hours.
3. OGTT (oral glucose tolerance test): Plasma glucose >= 200 mg/dl at 2 hours during a 75-g OGTT (equivalent of 75-g anhydrous glucose dissolved in water). OGTT can be abnormal before elevation of fasting plasma glucose to diabetic range is seen.

Diagnosis of gestational diabetes mellitus: Screening done during weeks 24-28 (and also at initial visit if high risk: obese, previous macrosomic infant, DM in 1st degree relative, history of glucose intolerance, glycosuria, Hispanic, Native American, Asian American, African-American, Pacific Islander) with a 50-g oral glucose load followed by plasma glucose determination at 1 hour; if this is >= 140 mg/dl, a 3 hour 100-g OGTT is done, with GDM diagnosed if two or more values are exceeded: fasting 95; 1 hr 180; 2 hr 155; 3 hr 140 mg/dl.

Impaired glucose tolerance: fasting plasma glucose < 126 mg/dl plus 2-hr plasma glucose during 75-g OGTT >= 140 and < 200 mg/dl.

Impaired fasting glucose: fasting plasma glucose >= 110 and < 126 mg/dl.

Screening for DM should be done every 3 years in people > 45 years old. Earlier and more frequently if obese (ƒE120% desirable weight or BMI ƒE>= 27), 1st degree relative with DM, high-risk ethnic group, have delivered a baby > 9 lb or history of GDM, hypertension (>= 140/90), dyslipidemic (HDL <= 35 mg/dl and/or TG >= 250 mg/dl), or history of IGT or IFG.

**CLINICAL FEATURES
Classic symptoms: polyuria, polydipsia, polyphagia, weakness & unexplained weight loss. Regarding polyuria, renal threshold for glucose reabsorption is ~180 mg/dl (higher in older patients), so may not see polyuria (if plasma glucose 126-180 mg/dl).

Diabetes can also present with other signs and symptoms: frequent vaginal infections, other infections, blurry vision, numbness and tingling in the feet, obesity, family history of diabetes, erectile dysfunction, non-healing sores on the feet, gastroparesis, orthostasis.

Microvascular complications (neuropathy, retinopathy, nephropathy) can be delayed by strict glycemic control. Of note, four years after the DCCT, the intensive control group still had reduced onset and progression of nephropathy and retinopathy despite convergence of their glycosylated hemoglobins with those of the conventional group. Macrovascular complications (atherosclerotic cardiovascular disease, stroke, peripheral vascular disease) have not been shown definitively to benefit from good glycemic control. Diabetes and its complications result in the deaths of > 160,000 Americans annually; at least 70% of these deaths are caused by cardiovascular disease.

**MEDICATIONS
Category
Mechanism of action
Efficacy
Side effects & contraindications

**Sulfonylureas
glyburide (Micronase, Diabeta 2.5-20 mg/d; Glynase, 1.5-12 mg/d); glipizide (Glucotrol, 5-40 mg/d; Glucotrol XL 5-20 mg/d); chlorpropamide (Diabinese, 100-500 mg/d); glimepiride (Amaryl, 1-8 mg qd); tolazamide (Tolinase, 100-1000 mg/d); tolbutamide (Orinase, 500-2500 mg/d); acetohexamide (Dymelor, 250-1500 mg/d)

Direct stimulation of insulin release by beta cells. [Via closure of ATP-sensitive K+ channels, causing influx of Ca++ which stimulates insulin release).

Predictors of response: age > 40, weight 110-160% of IBW, DM duration < 5 yrs, no prior insulin rx or control with < 40U/d, FPG < 220 mg/dl, good beta cell function (high fasting C-peptide), absence of anti-islet cell ab or anti-glutamic acid decarboxylase ab. Secondary failure rate up to 10%/yr. Average reduction FPG 60-70 mg/dl, reduction HbA1c 1.5-2%.

Major: hypoglycemia & weight gain (1.8-2.8 kg). Hypoglycemia more common with longer acting agents (chlorpropamide, glyburide).
Rare: dermatological reactions, hematological reactions, GI disturbances. Disulfiram reaction & hyponatremia with chlorpropamide. All are hepatically cleared; renal metabolite clearance important with chlorpropamide, acetohexamide, tolazamide, glyburide, glimepiride. Glipizide (shorter half life) is preferred in those with moderate renal dysfunction.

**Meglitinides
repaglinide (Prandin, start 0.5-1 mg tid with meals (15 min pre-meal), maintenance 0.5-4 mg tid, max 16 mg/d). 1 mg tid produces 90% of maximum glucose lowering effect.

A nonsulfonylurea benzoic acid derivative which stimulates insulin release by beta cells by same mechanism.

Unlike sulfonylureas, agent is rapidly absorbed (Cmax in 1 hr) and rapidly eliminated (t 1/2 < 1 hr). Best taken tid before meals. Original reductions: FPG 31, PPG 48 mg/dl, HbA1c 0.6% less than baseline. Recently, found equivalent efficacy (lower FPG 60-70, HbA1c 1.5-2%) to sulfonylurea.

Hypoglycemia & weight gain. Administer with food to reduce risk of hypoglycemia. Overall less likely to cause serious hypoglycemia than sulfonylurea.
Rare: thrombocytopenia, leukopenia, elevated transaminases, anaphylaxis. 90% excreted in stool; not contraindicated in renal insufficiency. If patient has liver disease, use slower titration schedule (some hepatic metabolism).

**Alpha-glucosidase inhibitors
acarbose (Precose, start 25 mg tid with meals, titrate to 50-100 mg tid); miglitol (Glyset, start at 25 mg before dinner & titrate to 50-100 mg tid)

Competitive inhibition of a-glucosidase enzymes (e.g. maltase, sucrase) in brush border of small intestine, which hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose. Also inhibits a-amylase, which hydrolyzes complex starches to oligosaccharides.

Delays complex carbohydrate digestion and subsequent absorption (shifts it to distal small intestine and colon), lowering postprandial glucose excursions. Reduction from baseline: FPG 20-30 mg/dl, PPG 50 mg/dl, HbA1c 0.5-1.0 %. Miglitol may cause modest weight loss. Drug given tid with meals.

Dose-related GI effects: flatulence (40%), diarrhea (20-30%), bloating, abdominal pain (12%), which often abate with continued administration. Minimize GI effects by dose titration. Acarbose associated with elevated transaminases at highest (> 200 mg tid) doses. Miglitol, unlike acarbose, which is a much bigger molecule, is absorbed and excreted unchanged in urine. Does not cause hypoglycemia, but if being used in combination with hypoglycemic agent, must use glucose gel or tablets to treat hypoglycemia. Avoid in inflammatory bowel disease, colonic ulceration, obstructive bowel disorders, malabsorptive diseases. Avoid if creatinine > 2 mg/dl or cirrhosis. Glyset may interfere with absorption of other drugs, including propranolol and ranitidine.

**Thiazolidinediones
troglitazone (Rezulin, withdrawn from market, start 200 mg qd, max 600 mg qd, taken with food); rosiglitazone (Avandia, start 4 mg qd (or 2 mg bid), then increase to 8 mg qd (or 4 mg bid), with or without food); pioglitazone (Actos, 15-45 mg qd)

Insulin sensitizing agent, acts by activating PPAR-g (peroxisome proliferator-activated receptors) which alters gene transcription, leading to increases in insulin-dependent glucose disposal in skeletal muscle and, at higher doses, reduction in hepatic glucose production.

Reduction compared to baseline: FPG 35-40 mg/dl, HbA1c 1-1.2%. May take several weeks to see maximal effect. Associated with increases in both LDL and HDL (no change in LDL:HDL ratio) with increase in LDL particle size. Troglitazone and pioglitazone associated with decrease in triglycerides. In premenopausal anovulatory women with insulin resistance (PCOS), these agents may result in pregnancy. Found to retard atherosclerosis in mouse model of hyperlipidemia.

Troglitazone associated with rare idiosyncratic hepatocellular injury, which has resulted in death (mortality rate ~1 in 60,000, compare with 1 in 30,000 for sulfonylurea or metformin) or liver transplant but usually resolves after discontinuation of the drug. 2% of patients on troglitazone develop elevated ALT; incidence with rosiglitazone and pioglitazone (0.2%) similar to placebo. 2 cases of liver failure with rosiglitazone recently reported. Transaminases must be monitored regularly: every month x 1 yr, then every 3 months for troglitazone, monitor weekly if ALT 1.5-2 x ULN, discontinue if ALT >= 3 x ULN; other agents monitor ALT every other month x 1 year. Also associated with weight gain (~3 kg), dilutional anemia, edema formation (caution in class III, IV CHF patients), headache, dizziness. No dose adjustment for renal insufficiency or elderly.

**Biguanides
metformin (Glucophage, start 500 mg qd/bid with meals, increase by 500 mg/d every 2 weeks, max 2550 mg/d). 80-85% of maximum glucose lowering effect at 1500 mg/d.

Primarily reduces hepatic glucose production. Also enhances insulin-stimulated glucose transport in muscle.

Reduction compared to baseline: FPG 60-70 mg/dl, HbA1c 1.5-2%. Also reduces triglycerides, LDL (10-15%), total cholesterol; and increases HDL slightly. Associated with weight loss (2-3 kg). In premenopausal anovulatory women with insulin resistance (PCOS), these agents may result in pregnancy.

20-30% report abdominal bloating, nausea, cramping, fullness, diarrhea, often self-limited and helped by dose titration and taking drug with food. Rare: metallic taste, reduction in B12 absorption, lactic acidosis (0.03/1,000 patient-yrs, mainly in renal dysfunction). Avoid if creatinine > 1.5 in men and > 1.4 mg/dl in women [use CrCl in elderly], and in conditions predisposing to acidosis: hepatic failure, alcoholism, CHF, MI, severe infection, hypoxia, surgery. Should be discontinued prior to administration of iodinated contrast & not restarted until normal renal function documented 48 hr later.

**Insulin
human recombinant (Humulin, Novolin) or lispro insulin (Humalog). Given subcutaneously, vehicle determines release. Most type 2 diabetics require 80-100 U/d.

Binds to a-subunit of receptor which activates tyrosine kinase activity of beta-subunit. Insulin inhibits hepatic glucose production, stimulates muscle glucose uptake, inhibits lipolysis in adipose tissue.

Degree of glucose lowering is dose-related; FPG can be lowered up to 190 mg/dl.

Hypoglycemia (particularly with intensive therapy), weight gain (as high as 6 kg), potential for accelerated macrovascular disease (controversial)

FPG = fasting plasma glucose; PPG = postprandial glucose.

**Notes
Care of all type 2 diabetics should include nutrition therapy, lifestyle modification (exercise, weight loss, smoking cessation), assessment of cardiac risk factors (hypertension, lipids), and self monitoring of blood glucose. This may result in achievement of glycemic goals (HbA1c < 7% and fasting and preprandial glucose 80-120 mg/dl). If not, these measures should be continued and oral agents begun. Absence of nutrition/weight management jeopardizes the success of drug treatment.

Stepped care approach: begins with oral agent monotherapy; if this fails, proceed to oral agent combination therapy, then combination therapy with oral agents and insulin, and ultimately, once beta cell failure has occurred, insulin therapy only.

Newly diagnosed T2 DM (positive C-peptide): Guidelines for oral monotherapy:
1. With moderate fasting plasma glucose elevation (150-250 mg/dl), begin with insulin sensitizers, using metformin (or thiazolidinediones) in obesity, dyslipidemia, hypertension, short duration of diabetes, no renal, cardiac, hepatic or pulmonary insufficiency. Use thiazolidinediones in obese patients with renal insufficiency and normal hepatic and cardiac function.
2. If initial FPG are more severely elevated (200-280 mg/dl), use insulin secretagogues. Sulfonylureas or repaglinide for lean patients with normal renal and hepatic function. Use repaglinide in lean, elderly patients with mild renal insufficiency, sulfa allergy, postprandial hyperglycemia.

Sulfonylureas and repaglinide increase insulin levels. Alpha-glucosidase inhibitors do not change insulin levels. Insulin levels decrease with metformin or thiazolidinediones.

Sulfonylureas: Initiate at lowest dose and titrate up every 1-2 weeks to achieve goal. Most (75%) of hypoglycemic action is seen with a daily dose equivalent to half of the maximum effective dose [considered 20 mg/d for glipizide]. If no effect is seen at half of maximum dose, unlikely to benefit from further dose increase. One study showed increased CAD with sulfonylurea use, this was not confirmed in repeat studies, and is not considered in choosing sulfonylurea as therapy.

In the UKPDS, metformin decreased MI and stroke compared to placebo & decreased all cause mortality and total DM endpoints compared to insulin or sulfonylurea. Its effects on lipids and weight make it an ideal initial choice for obese diabetics. One study showed maximum efficacy of metformin at 2 g/d (best given as 1 g bid for compliance) with no additional benefit from higher doses.

Preliminary studies suggest pioglitazone is better regarding lipids (decrease TG by 50 mg/dl, increase LDL by 5 mg/dL, increase HDL by 7-8 mg/dl) than rosiglitazone (no effect on TG, increased LDL by 10-15 mg/dl). However, rosiglitazone seems better regarding edema (2-3 kg weight gain vs. 3-4.6 kg weight gain with pioglitazone). This may influence choice of agent. Allow a 7-14 day washout of troglitazone before starting on a newer thiazolidinedione.

Indications to initiate T2 therapy with insulin: Severe (> 280 mg/dl) hyperglycemia with ketonuria, ketonemia, or symptoms. After 6-8 weeks of good control with insulin, patient may be switched to oral agent; benefit is in reversal of glucose toxicity, which worsens insulin sensitivity and insulin secretion. Must use insulin in all pregnant diabetics.

Only 25% of patients will achieve initial control (FPG <= 140 mg/dl) on monotherapy with sulfonylurea or metformin (the most effective agents). T2 DM is a progressive disorder; with time majority of patients will require combination therapy, often including insulin.

Many combinations are possible and result in additive glucose-lowering effects (e.g. metformin + sulfonylurea (most common); sulfonylurea + a-glucosidase inhibitor; metformin + Prandin; rosiglitazone + metformin). Patients currently on insulin may be able to obtain equivalent or superior glycemic control and significant weight loss with addition of oral therapy (especially metformin or troglitazone) which allows reduction of insulin dose.

**INSULIN THERAPY
Subcutaneous

Regular
Onset 30 min - 1 hour
Peak 2 - 4 hr
Duration 4 - 6 hr

Lispro insulin
Onset 15 min - 30 min
Peak 1 -2 hr
Duration 3 - 5 hr

NPH
Onset 1 - 4 hr
Peak 8 - 10 hr
Duration 12 - 20 hr

Ultralente
Onset 3 - 5 hr
Peak 10 - 16 hr
Duration 18 - 24 hr

IV insulin bolus
Onset immediate
Peak 20 - 30 min
Duration 2 - 3 hr

Insulin secretion: basal (0.5-1 U/hr) and meal peaks (1 U per 10 g carbohydrate). How to simulate this? Intensive therapy: Usually takes four injections or continuous subcutaneous insulin infusion (CSII):

1. NPH at bedtime, regular before each meal.
2. NPH + regular in AM, regular before lunch, regular pre-dinner, NPH qhs.
3. Ultralente in AM, 3 regular (can't mix regular with ultralente) before each meal.
4. CSII: Pump gives basal & you hit button pre-meal.

One insulin method: Weight in kg x 0.5 (a good start is 30U, it is conservative to avoid hypoglycemia). Divide AM, PM by 2:1 (need more insulin in AM since eating). Then divide NPH, Reg by 2:1. E.g. 30 U total: AM 14 U NPH, 6 Reg; PM 7 NPH, 3 Reg.

Monitoring: pre-breakfast BG reflects last PM NPH; pre-lunch BG reflects AM Reg; pre-dinner BG reflects AM NPH, bedtime BG reflects PM reg.

Benefits of bedtime NPH: Dawn effect: At night one is more sensitive to insulin (2-4 hours after sleep), as dawn approaches resistance increases. Thus, want more insulin around when waking up. Nice to give before bed NPH so peaks in morning. NPH at supper is not as good: peaks at night & not around in AM. Bedtime NPH avoids nocturnal hypoglycemia & is there in morning to prevent hyperglycemia & keep tissues sensitive. BIDS = bedtime insulin, daytime sulfonylurea. Can start qhs NPH at weight kg/4 and titrate to normalize fasting glucose.

Lispro: a faster acting insulin [LYS(B28), PRO(B29)]. Recombinant, it is identical to human insulin except for transposition of proline & lysine at position 28, 29 in C terminus of B chain. Lispro injected SC does not form hexamers (which dissociate slowly) as does regular insulin, which is why it is absorbed so rapidly. Benefit is that it can be given right before a meal, as compared with regular insulin, which must be given 30-60 minutes before a meal.

Intensive control in T1 DM is associated with a 3-fold increased risk of hypoglycemia, with 2-4% mortality. These patients are at risk because they cannot decrease insulin levels in response to hypoglycemia and early on lose glucagon responsiveness, making them dependent on epinephrine, the secretion of which is also often attenuated. Avoidance of hypoglycemia for 2-3 weeks can restore hypoglycemic symptoms and epinephrine (not glucagon) responsiveness.

Rate of insulin absorption can vary by site (abdomen > arm > thigh > buttock) and route (IV > IM > SC > intradermal). Variability of absorption is affected by volume (larger injections have more variable absorption) and type (lispro < regular < lente < ultralente). As SC dose of regular (but not lispro) insulin increases, duration tends to increase.

**TREATMENT GUIDELINES

HbA1c (normal range: 4-6%)
-Frequency - Quarterly if treatment changes or patient is not meeting goals. Twice per year if stable.
-Treatment Goal: Optimal < 6%; goal < 7%; action level >= 8%

Fasting lipid profile (LDL, HDL, TC, TG)
-Frequency - Patients on Insulin: Initially - subsequent frequency depends on results and treatment. At least yearly if not normal.
-Treatment Goal: TC < 200 mg/dl; LDL <= 100 mg/dl; HDL > 45 (men) > 55 mg/dl (women); TG < 200 mg/dl.

Determination for microalbuminuria
-Frequency - Patients on Insulin: Yearly (if urine protein dipstick negative)
-Treatment Goal: Normal

Office visit for diabetes - includes weight, BP, foot examination
-Frequency - Daily for initiation of insulin; weekly for initiation or oral glucose-lowering agent. Routine visit: quarterly if patient not meeting goals; semiannually for other patients
-Treatment Goal: Education, management of DM and lipid disorders, early detection and treatment of complications

Dilated retinal exam
-Frequency - Yearly
-Treatment Goal: Early detection and treatment of diabetic retinopathy

Due to predisposition to infection (hyperglycemia impairs macrophage migration and phagocytosis), all diabetics should receive pneumovax and yearly influenza vaccinations.

Blood pressure goal is < 130/85 in adults. In those with isolated systolic hypertension >= 180 mm Hg, the goal is SBP < 160 mm Hg. If SBP is 160-179, the goal is a reduction of 20 mm Hg. If these goals are achieved and well tolerated, further lowering to 140 mm Hg is prudent.

Patients with diabetes and macrovascular disease (CAD, CVA, PVD), in whom aspirin is not contraindicated [allergy, bleeding tendency, anticoagulant therapy, recent GI bleeding, clinically active hepatic disease], should take 81-325 mg of enteric-coated aspirin per day as secondary prevention.

Consider aspirin therapy as primary prevention in high-risk men and women with T1 or T2 diabetes: family history of CAD, smoking, hypertension, obesity (> 120% desirable weight, BMI > 27.3 in women, > 28 in men), albuminuria (micro or macro), dyslipidemia (cholesterol > 200 mg/dl, LDL > 100 mg/dl, HDL < 45 mg/dl in men, HDL < 55 in women, triglycerides > 250 mg/dl). Do not use if age < 21 due to risk of Reye's syndrome.

Pancreas transplant normalizes glycemia. Should be routine for DM patients undergoing kidney transplant (will be immunosuppressed anyway). Islet cell transplantation has not been very successful.

**SELF-MONITORING OF BLOOD GLUCOSE (SMBG)
Particularly important in patients using insulin. Ideally, capillary blood glucose should be checked preprandially and before bedtime snack (actual regimen will depend on patient's needs). The following goals are for non-pregnant adults:

Whole blood values = capillary blood glucose
Average fasting/preprandial glucose
Normal: < 100 mg/dl
Goal: 80-120 mg/dl
Additional Action*: < 80 or > 140 mg/dl

Average bedtime glucose
Normal: < 110 mg/dl
Goal: 100-140 mg/dl
Additional Action: < 100 or > 160 mg/dl

Plasma values - some monitors measure plasma glucose, which is 10-15% higher than whole blood values
Average fasting/preprandial glucose
Normal: < 110 mg/dl
Goal: 90-130 mg/dl
Additional Action*: < 90 or > 150 mg/dl

Average bedtime glucose
Normal: < 120 mg/dl
Goal: 110-150 mg/dl
Additional Action: < 110 or > 180 mg/dl

*Additional action may include enhanced diabetes self-management education, co-management with a diabetes team, referral to an endocrinologist, change in pharmacological therapy, initiation or increased SMBG, or more frequent contact with the patient.

Postprandial glucose (2 hour) should be <= 180 mg/dl.

Blood glucose goals in gestational diabetes are much more strict: preprandial glucose < 95 mg/dl, 1 hour postprandial glucose < 140 mg/dl, 2 hour postprandial glucose < 120 mg/dl. If medical nutrition therapy fails to achieve these goals, insulin is used.

**NUTRITIONAL GUIDELINES
Provide regular meal-planning advice and guidelines
Balance food intake with drug therapy and exercise
Maintain reasonable weight by monitoring calorie consumption

10-20% of calories from protein
< 10% of calories from saturated fat
<= 10% of calories from polyunsaturated fat
60-70% of calories from monounsaturated fat and carbohydrate
< 300 mg cholesterol per day.

Patients benefit from eating consistent carbohydrates, eating at consistent times, and controlling portion size. Portion of daily calories from carbohydrate varies with treatment goal and is generally the difference between daily caloric goal and goal calories from fat and protein. Patient should have consistency in number of servings of carb each day. 15 g carb portion size is important to learn (e.g. 1 cup milk, 1 slice bread). Total carb is more important than source (simple vs. starch); one gets the same glycemic excursions from a given amount of total carb, regardless of % simple.

For planned exercise, patients should adjust their insulin dose. For unplanned exercise, they should eat a carbohydrate snack (15 g carb/hr for moderate exercise, 30 g/hr for strenuous). Remember that exercise can have a hypoglycemic effect even 6-15 (up to 24) hours after the activity is completed (lag effect). Injection site is also important due to increased blood flow to exercised limbs.

** References (v1.6)
American Diabetes Association. Aspirin therapy in diabetes. Diab Care 2000;23 (suppl 1):S61-S62.
American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diab Care 2000;23 (suppl 1):S32-S42.
DCCT/EDIC. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000;342:381-9.
DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281-303.
Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y. A novel subtype of type I diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. N Engl J Med 2000;342:301-7.
Kjos SL, Buchanan TA. Gestational diabetes mellitus. N Engl J Med 1999;341:1749-56.
White JR. The pharmacological reduction of blood glucose in patients with type 2 diabetes mellitus. Clin Diab 1998;16:58-67.

The above review is a synthesis of the papers listed in the references section. Every effort has been made to ensure accuracy, but I make no warranty regarding errors and omissions and assume no responsibility or liability for loss or damage resulting from the information contained within. For detailed information the reader should refer to the original text of the references. Use of the above information for patient care purposes is done at the discretion of the clinician.

Please email me with any comments or suggestions.
Mark Goodarzi, M.D.
mgoodarzi@mednet.ucla.edu

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