Mark Goodarzi, M.D.
 | Type 1 DM: All causes of diabetes resulting from destruction (>80-90%) of pancreatic beta cells. Can occur at any age (highest incidence in Caucasians age 10-14); rate of beta cell destruction tends to be rapid in children, slow in adults (may occur over years, called latent autoimmune diabetes in adults, LADA). Classified as autoimmune (type 1A, 90% have HLA DR3 and/or DR4), which is most common, or idiopathic (1B). Antibodies to the cytoplasm of islet cells (60-70% sensitive), glutamic acid decarboxylase (GAD65, 85-90% sensitive, longest lasting), insulin (50% sensitive), 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 (islets destroyed by T cells [Th1]). However, most antibody-positive relatives of patients do not develop diabetes (those with highest titers have lower disease risk). Estimated risk of T1 DM is 0.1% if no relatives with T1 DM, 6% if father with T1 DM, 4% if mother < 25 y.o at child's birth, 1% if mother ≥ 25 y.o at child's birth; risk 2-fold higher if parent diagnosed with T1 DM before age 11. Up to 10% of patients newly diagnosed with T1 DM have no diabetes-related antibodies. Idiopathic T1 DM: many African or Asian in origin, strongly inherited, no HLA association. |
| Type 2 DM: All forms of diabetes characterized by combination of insulin resistance and deficient insulin secretion (relative to the insulin resistance - absolute levels may be supranormal early on, later absolute insulin deficit develops as beta cell function deteriorates). Others claim that impaired beta cell function occurs first. T2 DM is the most common form (90%) of diabetes, and has a strong genetic predisposition (twin concordance rate 90%, cf. T1 DM twin concordance 33-50%). Risk of T2 DM in offspring of patients is 40% if one parent is affected; if two parents affected, risk is 70%. Majority (75%) 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. ~18 million diabetics in the U.S. (6% of population), 1 million with T1 DM, 17 million with T2 DM, of the latter, 10 million diagnosed, 7 million undiagnosed. |
| Gestational DM: Onset of DM during pregnancy, usually during the 3rd trimester; characterized by insulin resistance and deficient secretion, complicates 3-5% 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., 5-11% of people aged 20-74) and impaired fasting glucose: Patients with values on testing which are intermediate between normal and diabetic; they are at risk (6-10%/yr) for developing T2 DM and at high risk of developing atherosclerotic cardiovascular disease (especially IGT). IGT/IFG may precede T1 DM, especially in adults. A study of patients with IGT found that supervised lifestyle intervention (goals: ≥ 5% weight loss, reduction of fat to 30% of total calories, saturated fat to 10%, increase fiber ≥ 15 g/1000 kcal, increase exercise ≥ 30 min/d) resulted in a 58% lower risk of developing T2 DM with only a 3-5 kg weight loss over a mean of 3.2 years. No subject meeting 4-5 of the goals developed diabetes. The Diabetes Prevention Program confirmed this and also showed metformin 850 mg bid in IGT reduced risk of T2 DM by 31% (less effective in older or less overweight patients). |
| Other specific types: disease of exocrine pancreas (hemochromatosis, pancreatitis, cystic fibrosis), acromegaly, pheochromocytoma, Cushing’s syndrome, drug-induced (e.g. pentamidine, thiazides, HIV protease inhibitors, tacrolimus > cyclosporine), infections (congenital rubella, CMV), Stiff man syndrome, genetic syndromes associated with DM (Down syndrome, Klinefelter's, Wolfram), genetic defects of beta cell function (MODY), genetic defects in insulin action (type A insulin resistance). |
DIAGNOSIS
| Diagnosis of diabetes mellitus (confirm with a repeat test): |
- 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].
- Fasting plasma glucose ≥ 126 mg/dL. Fasting value determined in the morning after absence of caloric intake for at least 8 hours.
- 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 (≥120% desirable weight or BMI ≥ 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, acanthosis nigricans. |
| 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. The UKPDS showed that for every 1% lowering in HbA1c, microvascular complications are lowered by 35%. |
| Macrovascular complications (at least 3-fold risk; atherosclerotic cardiovascular disease, stroke, peripheral vascular disease) have not been shown definitively to benefit from good glycemic control. Diabetes is the fourth leading cause of death by disease; at least 70% of these deaths are caused by cardiovascular disease (silent ischemia is common). T2 DM annually accounts for 200,000 deaths, 400,000 myocardial infarctions, and 130,000 strokes. |
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 < 40 U/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 mg tid if new patient or HbA1c < 8, 1-2 mg tid if HbA1c > 8, with meals (15 min pre-meal), maintenance 0.5-4 mg tid, max 16 mg/d). 1 mg tid produces 90% of maximum effect. Nateglinide (Starlix, 120 mg tid 30 min pre-meal, 60 mg tid if lower HbA1c) |
Nonsulfonylurea benzoic acid derivative (repaglinide) and phenylalanine derivative (nateglinide) that stimulate insulin release by beta cells by same mechanism as sulfonylurea. |
Unlike sulfonylureas, agent is rapidly absorbed (Cmax in 1 hr) and rapidly eliminated (t 1/2 < 1 hr). Repaglinide reductions: FPG 31, PPG 48 mg/dL, HbA1c 0.6-2% less than baseline. Nateglinide: 0.6-0.9% lower HbA1c compared to placebo. Nateglinide may have earlier onset and shorter duration. |
Hypoglycemia & weight gain. Must administer with food to reduce risk of hypoglycemia. Overall less likely to cause serious hypoglycemia than sulfonylurea. Repaglinide: rare: leukopenia, thrombocytopenia, elevated transaminases, anaphylaxis. 90% excreted in stool; not contraindicated in renal insufficiency. If patient has liver disease, use slower titration schedule (some hepatic metabolism). Nateglinide: metabolized in liver, excreted in urine. |
|
Alpha-glucosidase inhibitors : acarbose (Precose, start 25 mg tid with meals, titrate every 2-4 wks 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 the 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 (up to 26%). In PCOS, these agents may result in pregnancy. Found to retard atherosclerosis in mouse model of hyperlipidemia. Also reduce BP, PAI-1, platelet aggregation, vascular contraction, vascular smooth muscle migration and seem to redistribute fat from visceral to subcutaneous. |
Troglitazone was associated with rare idiosyncratic hepatocellular injury, which resulted in death (mortality rate ~1 in 60,000, compare with 1 in 30,000 for sulfonylurea or metformin) or liver transplant but usually resolved after discontinuation of the drug. 2% of patients on troglitazone developed elevated ALT; incidence with rosiglitazone and pioglitazone (0.2%) similar to placebo. 2 cases of liver failure with rosiglitazone 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, then periodically thereafter. 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. New: Glucophage XR (500 mg tab), Glucovance (glyburide + metformin, 1.25/250 (initial therapy qd or bid), 2.5/500, 5/500 (previously treated, bid)) |
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, vehicle determines release: soluble zinc-insulin (regular), protamine in phosphate (NPH), zinc in acetate (lente, ultralente). Analogs: lispro insulin (Humalog), aspart (Novolog), glargine (Lantus). Given subcutaneously, comes in 10 mL vials of 100 U/mL. Many type 2 diabetics require 80-100 U/d. |
Binds to a -subunit of receptor which activates tyrosine kinase activity of b -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). Allergic reactions are rare with human insulin. Lipodystrophy is avoided by rotating injection sites. Sodium and water retention can occur, especially if previously poor metabolic control is being improved. |
FPG = fasting plasma glucose; PPG = postprandial glucose.
| 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: |
- 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.
- 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 meglitinides 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. |
| Possibly, glyburide potentiates basal insulin more (good for fasting hyperglycemia), and glipizide potentiates postprandial insulin more (good for postprandial hyperglycemia). |
| 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); no additional benefit from higher doses. It has also been shown to improve endothelium-dependent vasodilation in T2 DM. |
| 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 (especially if able to use < 0.3-0.4 U/kg/d), 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, also during acute injury/infection, stress, surgery, myocardial infarction. |
| 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. In the UKPDS, mean HbA1c (on treatment) rose by 0.2-0.3% yearly. One can use this rate to predict secondary failure. In general, monotherapy is rarely effective more than 5 years. |
| Many combinations are possible and result in additive glucose-lowering effects (e.g. metformin + sulfonylurea (most common); sulfonylurea + a -glucosidase inhibitor; metformin + repaglinide; 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) which allows reduction of insulin dose. |
INSULIN THERAPY
|
Onset |
Peak |
Duration |
||
|
Regular |
30 min - 1 hour |
2 - 4 hr |
4 - 6 hr |
||
|
Lispro/Aspart |
15 min - 30 min |
1 - 2 hr |
3 - 5 hr |
||
|
NPH |
1 - 4 hr |
8 - 10 hr |
12 - 20 hr |
||
|
Ultralente |
3 - 5 hr |
10 - 16 hr |
18 - 36 hr |
||
|
Glargine |
2 - 4 hr |
None |
~24 hr |
||
|
IV insulin bolus |
immediate |
20 - 30 min |
2 - 3 hr |
| Also available: Premixed 70% NPH, 30% regular; 50% NPH, 50% regular; 75% NPL, 25% lispro. If mixing separate insulins, fast-acting insulin should be drawn into syringe first. Lente and ultralente retard regular insulin action. |
| Insulin requirements: Starting total daily dose = 0.2 x weight in lbs; average dose (T1 DM) 0.3 x weight in lbs (T2 DM may require more, especially initially if glucose toxicity present). |
|
|
- NPH (or UL, glargine) at bedtime, regular or lispro before each meal. Initially, of total daily dose, 20-25% before each meal, 25-40% at bedtime. Limitation is that meals are required at no more than 5 hour intervals.
- NPH + regular in AM, regular before lunch, regular pre-dinner, NPH qhs. Basal NPH given as equal AM & qhs doses, adjusted simulataneously. Such a regimen often needed when using lispro.
- Ultralente in AM, 3 regular (can’t mix regular with ultralente) before each meal.
- CSII: Pump gives basal & you hit button pre-meal. Best reproduction of normal insulin secretion, most reproducible insulin absorption (2.8% variability, compare with 10-52% with SC), and better glycemic control and less hypoglycemia.
| Insulin adjustments are based on daily BG and peak effect of insulin dose. Adjust in 20% increments (e.g. 2 U for dose of 10 U). Downward should be done next day to avoid repeat hypoglycemia. Upward should be delayed 2 days to establish a pattern. Each dose of regular or lispro should be adjusted for current BG level. Supplement is added to or subtracted from planned dose. Supplement = (actual BG - goal BG)/(1500/total daily dose). Goal is 100 mg/dL if normal counterregulation, 120 if impaired counterregulation, 80 if pregnant. |
| Conventional insulin method: Weight in kg x 0.5 (a good start is 30 U, it is conservative to avoid hypoglycemia). Divide AM, PM by 2:1 (need more insulin in AM since eating). Then divide NPH, Reg (or lispro) by 2:1. E.g. 30 U total: AM 14 U NPH, 6 Reg; PM 7 NPH, 3 Reg. Or, AM: 40% NPH, 15% regular; PM: 30% NPH, 15% regular. Or, AM: 55% 70/30, PM: 45% 70/30. Problem of poor peaking of noon insulin and excess insulin during night. Solution is to limit size of noon meal and eat bedtime snack. Moving PM NPH to bedtime is indicated if nighttime hypoglycemia or persistent AM hyperglycemia. |
| Conventional 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. |
| T2 DM: Benefits of bedtime NPH (or glargine): 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. Can start qhs NPH at weight kg/4 (if patient is > 150% ideal body weight, consider weight in lbs x 0.1 = units of 50/50 or 70/30 given before evening meal) and titrate to normalize fasting glucose (< 120 mg/dL). If BG does not normalize, consider insulin + oral agents. BIDS = bedtime insulin, daytime sulfonylurea. If this fails, proceed with conventional insulin regimen (start total daily dose 0.2 x weight in lbs). |
| 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. If mixed with NPH or UL, must give immediately. |
| 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. |
| Hypoglycemia: If conscious, treat with 15 g oral glucose (3 glucose tabs, 6 Lifesavers, 4 oz. juice, 1/2 can soda, 1 tablespoon table sugar or honey); repeat in 15 minutes if hypoglycemia persists. If next meal is > 1-2 hours away, eat extra snack. If cannot swallow, give 1 mg SC or IM glucagon. If an IV is in place, treat with 25 mL of D50. |
| 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. |
| Glargine is a long-lasting analog with 24 hour duration and no significant peak. Compared to NPH, it caused less hypoglycemia (10% vs. 24%), less nocturnal hypoglycemia, and less weight gain (0.9 lb vs. 3.1 lb). A once daily NPH or ultralente can be directly converted to glargine; if twice daily, the dose should be reduced by 20% first. If new to insulin, start 10 U qhs and titrate. Glargine comes in a clear acidic (may cause pain) formulation that precipitates at neutral pH subcutaneously. It cannot be mixed with any other insulin and should not be confused with regular or lispro which are also clear. |
| IV insulin is given for DKA, HHNK, acute MI, surgery, delivery, parenteral alimentation, gastroparesis, NPO. Vary infusion rate with hourly monitoring. Rate (U/hr) = (BG - 60) x SF. Start with SF = 0.02 or 0.03. Adjust SF by 0.01 increments until BG 100-140: if BG > 140 mg/dL, increase SF by 0.01; if BG 100-140, no change; if BG < 100, decrease SF by 0.01; if BG < 60, give 25 mL 50% glucose. The IV insulin should be continued until 2 hours after first SC injection is given. |
| Perioperatively, maintain BG 100-180 mg/dL to prevent dehydration/ketosis, promote wound healing, optimize leukocyte function, avoid hypoglycemia. Start 5 g/h glucose infusion (e.g. D5 1/2 NS + 20 mEq KCl @ 100 mL/h). Can start IV insulin (1 U/h) and adjust for goal or, if surgery is minor and patient's glucose is well-controlled, give 50% of usual SC insulin in the AM of surgery and supplement with regular insulin q4-6 hr to achieve goal. |
TREATMENT GUIDELINES
| HbA1c (mean BG control for prior 6-10 weeks) is affected by hemoglobinopathies and rapid turnover of RBC (blood loss, hemolytic anemia). Usual goal is within 1% of normal. |
| Citing the lack of a threshold HbA1c over which complications occur, the 2001 AACE recommended that the HbA1c goal should be < 6.5, fasting plasma glucose < 110 mg/dL, and 2-hr postprandial glucose < 140 mg/dL. |
| Due to predisposition to infection (hyperglycemia impairs macrophage migration and phagocytosis), all diabetics should receive pneumovax and yearly influenza vaccinations. Diabetics are at risk for unique infections such as rhinocerebral mucormycosis, malignant otitis externa, emphysematous cholecystitis, and emphysematous pyelonephritis. |
|
Measure |
Frequency |
Treatment Goal |
|
HbA1c (normal range: 4-6%) |
Quarterly if treatment changes or patient is not meeting goals. Twice per year if stable. |
Optimal < 6%. Goal < 7%. Additional action at ≥ 8% |
|
Fasting lipid profile (LDL, HDL, TC, TG) |
Initially - subsequent frequency depends on results and treatment. At least yearly if not normal. |
TC < 200 mg/dL; LDL ≤ 100 mg/dL; HDL > 45 (men), HDL > 55 mg/dL (women); TG < 150 mg/dL |
|
Determination for microalbuminuria |
Yearly (if urine protein dipstick negative) |
Normal (< 30 mg/d or < 30 μg/mg creatinine) |
|
Office visit for diabetes - always includes weight, BP, foot examination |
Daily for initiation of insulin; weekly for initiation of oral glucose-lowering agent. Routine visit: quarterly if patient not meeting goals; semiannually for other patients |
Education, management of DM and lipid disorders, early detection and treatment of complications |
|
Dilated retinal exam |
Yearly |
Early detection and treatment of diabetic retinopathy |
| Blood pressure goal is < 130/80-85 in adults (requires an average of 3.2 antihypertensives, even up to 5). 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. If renal insufficiency or > 1 g/d proteinuria is present, the blood pressure goal is 120/75. |
| 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 2° 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 for 3 years in 70-80% of patients. Should be routine for DM patients undergoing kidney transplant (will be immunosuppressed anyway). Islet cell transplantation up to 1996 was not very successful. Recently, 7 out of 7 patients had normoglycemia for a mean of one year, with islets harvested from 2 pancreas for each patient, transplantation as soon as possible after harvest (delivered to liver via portal vein), and less toxic immunosuppression consisting of sirolimus, daclizumab, and low-dose tacrolimus, with no glucocorticoid or cyclosporine. |
SELF-MONITORING OF BLOOD GLUCOSE (SMBG)
| SMBG is particularly important in patients using insulin. Ideally, capillary blood glucose should be checked preprandially and before bedtime snack and periodically at 3 AM (actual regimen will depend on patient’s needs). 2 hour post-prandial BG should be checked for lispro programs, pregnancy, or in patients with elevated HbA1c but normal pre-meal BG. The following goals are for non-pregnant adults: |
|
Measure |
Normal |
Goal |
Additional Action* |
|
Whole blood values = capillary blood glucose |
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Average fasting/preprandial glucose |
< 100 mg/dL |
80-120 mg/dL |
< 80 or > 140 mg/dL |
|
Average bedtime glucose |
< 110 mg/dL |
100-140 mg/dL |
< 100 or > 160 mg/dL |
|
Plasma values - some monitors measure plasma glucose, which is 10-15% higher than whole blood values |
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|
Average preprandial glucose |
< 110 mg/dL |
90-130 mg/dL |
< 90 or > 150 mg/dL |
|
Average bedtime glucose |
< 120 mg/dL |
110-150 mg/dL |
< 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 of or increased SMBG, or more frequent contact with the patient.
| Postprandial glucose (2 hour) should be ≤ 180 mg/dL. 3 AM should be > 90 mg/dL. |
| Some studies suggest postprandial SMBG correlates better with HbA1c and its control gives lower HbA1c. Also, postprandial blood sugars have been correlated with increased cardiovascular risk. |
| 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. |
| Pregnant patients with T1 DM: Goals: 60-90 mg/dL pre-meal; < 120 mg/dL 1-2 hr post-meal; HbA1c in normal range (lower goal since increased erythropoiesis); ketones checked every morning. If ketones positive and BG elevated, insulin is insufficient. If ketones positive and BG normal, calorie intake is insufficient. Insulin need can rise dramatically in 3rd trimester. DKA is associated with up to 50% intrauterine mortality. |
| Impaired counterregulation or history of severe hypoglycemia or significant macrovascular disease: Goals: 100-160 mg/dL pre-meal; 100-200 mg/dL bedtime; HbA1c within 2% of normal. |
| Meters with memory exist but patients should still write their sugars in a log book. Studies have shown that this practice leads to better glycemic control. |
| CGMS: continuous glucose monitoring system measures interstitial glucose every 10 seconds for 3 days; use of this information improves glycemic control and reduces hypoglycemia. |
NUTRITIONAL GUIDELINES
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| 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); the classic concept that simple sugars give higher glycemic excursions than starches is largely unfounded. Patients should be taught to focus on total carb rather than glycemic index (increase in blood glucose in 3 hours after the consumption of a test food containing 50 g of available carbohydrate relative to white bread with 50 g carb), although highly motivated patients may do so. |
| Carb counting can replace fixed meals. To determine insulin to carb ratio, insulin is first adjusted to a fixed carb meal; once BG (pre and post-meal) is in goal range, a ratio can be calculated (g carb/U insulin). Patient is then free to take insulin based on carb consumed. On average, 1 U covers 15 g (7-20 g) carb. Alternatively, can use the rule of 500. 500/total daily dose = X g, give 1 U insulin for every X g carb. |
| Conversion of food to blood sugar: Carbohydrates 100% to BG in 1-1.5 hours (slowed if much fat in meal); protein 60% to BG in 3-4 hours; fat 10% to BG in several hours. A bolus dose has the right ratio of g carb to U insulin needed to utilize it if post-meal BG increases by 30-50 mg/dL. Ratio can be different for different meals (dawn effect). |
| A randomized trial showed that a high intake of dietary fiber, particularly soluble fiber (50 g day, with 25 g of soluble fiber), improved glycemic control and decreased hyperinsulinemia and hyperlipidema. Foods with a low glycemic index and high fiber content may improve postprandial glycemia by delaying the absorption of glucose, permitting a better match between the timing of insulin release (deficient early phase insulin release after meals, even in hyperinsulinemic T2 diabetics) and peak glucose concentrations. In addition, the production of free fatty acids, which promote insulin resistance, is lower after a meal with a low glycemic index. |
| For planned exercise, patients should adjust their insulin dose. For unplanned exercise, they should eat a carbohydrate snack (10-15 g carb/hr for moderate exercise, 30-50 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. Delay exercise if BG < 80 or > 250 mg/dL or if urine ketones present. If proliferative retinopathy is present, exercise carries a risk of vitreous hemorrhage. |
References (v1.7.7)
- 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.
- Bode BW, Davidson PC, Steed RD, Robertson DG. DiabetesDek: Professional Edition. Skyler JS, Ed. Infodek: Atlanta, GA 2000.
- Chandalia M, Garg A, Lutjohann D, et al. Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus. N Engl J Med 2000;342:1392-8.
- 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.
- Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol 2001;37:1344-50.
- Parulkar AA, Pendergrass ML, et al. Nonhypoglycemic effect of thiazolidinediones. Ann Intern Med 2001;134:61-71.
- Tuomilehto J, Lindstrom J, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. NEJM 2001;344:1343-50.
- White JR. The pharmacological reduction of blood glucose in patients with type 2 diabetes mellitus. Clin Diab 1998;16:58-67.