Basics
Description
Diabetes mellitus (DM) is a syndrome that results from an absolute or relative insulin deficiency.
Epidemiology
- Prevalence of diabetes in the US is 7.2% (80% Type 2, 10% Type 1, and 10% other).
- Gestational DM (GDM) occurs in 3% pregnancies; 50% develop Type 2 DM in 20 years.
- Increased risk of coronary artery disease (CAD) (2- to 5-fold), stroke (2- to 3-fold), blindness (20-fold), kidney failure (25-fold), and amputation (40-fold). Fifth leading cause of death in the US.
Etiology
- Type 1 DM: Destruction of pancreatic beta cells leading to absolute insulin deficiency. Requires insulin therapy and at risk for diabetic ketoacidosis (DKA). Genetic factors (HLA-D and 50% concordance in identical twins) and environmental inducers (mumps and rubella) also associated.
- Type 2 DM: Combined insulin resistance and relative insulin deficiency results. Usually present with nonketotic hyperglycemia.
- Under stress (i.e., infection, surgery) may develop DKA secondary to partial insulin deficiency.
- Genetic factors (e.g., 90-100% concordance in twins) and environmental inducers (e.g., obesity) are associated with risk for Type 2 DM.
- Genetic defects
- Maturity-onset diabetes of the young: 6 genetic abnormalities have been identified. Presents in childhood and is responsive to oral agents and insulin.
- Other rare genetic defects, including abnormalities in insulin action, mutation in the sulfonylurea receptor, Wolfram, and Prader-Willi, can cause diabetes.
- Disease of the pancreas: Includes surgery, cystic fibrosis, hemochromatosis, and pancreatitis. Associated with loss of both alpha and beta cells resulting in insulin and glucagon deficiency. Requires insulin therapy.
- Endocrinopathies: Cushing's syndrome, acromegaly, pheochromocytoma, and glucagonomas increase hormones that antagonize the action of insulin and can lead to glucose intolerance and DM.
- Medications: Glucocorticoids, protease inhibitors, thiazides, niacin, beta blockers, calcium blockers, clonidine, anti-psychotics, and alcohol can cause glucose intolerance.
- Immune-mediated diabetes:
- Stiff-man syndrome: Autoimmune (anti-GAD) disorder of the CNS characterized by progressive axial muscle stiffness leading to impaired ambulation.
- Insulin receptor antibodies: Causes DM by blocking the binding of insulin to its receptor.
- GDM: Insulin resistance and glucose intolerance develop in the second or third trimester due to secretion of counter-regulatory hormones such as human chorionic somatomammotropin. Usually resolves after delivery.
Associated Conditions
Evaluation of other autoimmune conditions should be considered in Type 1 diabetes, such as celiac disease, hypothyroidism, and pernicious anemia.
Diagnosis
History
Signs and symptoms:
- High glucose levels: Initially asymptomatic, but can cause polyuria, polydipsia, weight loss, and blurred vision.
- Diabetic complications: Asymptomatic initially, but develop as diabetes progresses. Assess complications 3-5 years after initial presentation in Type 1 and at the time of presentation in Type 2.
- Diabetic eye complications:
- Nonproliferative retinopathy: Microaneurysm, hemorrhages, hard exudates, macular edema, cotton wool exudates, and arteriovenous shunts
- Proliferative retinopathy: Neovascularization, vitreous hemorrhage, and retinal detachment
- Cataract and glaucoma
- Diabetic nephropathy: Hypertension (HTN), pedal edema, uremic appearance
- Diabetic neuropathy:
- Autonomic: Gastroparesis, constipation, diarrhea, neurogenic bladder, impotence, orthostatic hypotension, gustatory sweating
- Peripheral:
- Symmetrical polyneuropathy: Characterized by paresthesias, burning and gnawing pain sensation. On exam, decreased pinprick, light touch, pain, vibration, and deep tendon reflexes
- Asymmetric mononeuropathies: Cranial neuropathy, mononeuropathy, mononeuritis multiplex, and entrapment neuropathy
- Complications: Foot ulcers and Charcot's arthropathy
- Macrovascular disease: Coronary artery, cerebrovascular or peripheral arterial disease
- Infections: Rhinocerebral mucormycosis, malignant otitis externa (pseudomonas), and emphysematous cholecystitis (clostridia)
Tests
Lab
- Diagnosis of diabetes (1)[A]:
- Random plasma glucose: Level ≥200 mg/dL, confirmed on a second occasion, with symptoms of polyuria, polydipsia, or weight loss, suggests diabetes.
- Fasting plasma glucose (8-hour fast): Level ≥126 mg/dL suggests diabetes.
- Oral glucose tolerance test: Level ≥200 mg/dL 2 hours after a 75 g glucose load suggests diabetes.
- Hemoglobin A1C (HgA1C): Level ≥6.5%, which correlates with an estimated average glucose of ≥140 mg/dL, suggests diabetes.
- Assess etiology of diabetes:
- Antibodies to islet cells (ICA), glutamic acid dehydrogenase (anti-GAD), and insulin can confirm the diagnosis of Type 1.
- Serum C-peptide reflects endogenous insulin secretion. Elevated level suggests conditions associated with insulin resistance, such as Type 2 diabetes.
- Monitor diabetes and its complications:
- HgA1C: Correlates with mean blood glucose over the previous 8-12 weeks. HgA1C of 7% and 9% represent a mean blood glucose value of about 150 and 210 mg/dL, respectively. Treatment goals aim for HgA1C <7%.
- Self-monitoring blood glucose and plasma glucose: Whole blood glucose measurements with a glucose meter vary by as much as 15% from plasma glucose measurement.
- Urine ketones: Test urine for ketones during periods of illness or stress in patients at risk for ketoacidosis.
- Test urine for microalbuminuria
- Microalbuminuria: 30-300 mg albumin per 24 hours or 30-300 mg of albumin per gram of creatinine in spot urine sample.
- Macroalbuminuria or nephropathy: >300 mg albumin per 24 hours or >300 mg of albumin per gram of creatinine.
- Fasting lipid panel: In patients without a known history of macrovascular disease, target goal for serum LDL cholesterol is <100 mg/dL, TG"‚<150 mg/dL and HDL >40 mg/dL in men and >50 mg/dL in women. LDL <70 mg/dL is recommended for individuals with established CAD.
- At 24-28 weeks gestation, screening with 75 g glucose tolerance test is recommended.
- Diagnosis of gestational diabetes requires one abnormal value: Fasting ≥92 mg/dL; 1 hour ≥180 mg/dL and 2 hours ≥153 mg/dL. Fasting ≥126 mg/dL, random ≥200 mg/dL or HgA1C >6.5% confirms overt diabetes (1)[A].
- Earlier screening is recommended for high-risk individuals. Fetal ultrasound surveillance is recommended for all diabetics.
Differential Diagnosis
Individual with impaired glucose intolerance are at risk for developing diabetes and cardiovascular disease (CVD) (1)[A]. Diagnostic criteria:
- Fasting plasma glucose: 100-125 mg/dL
- 2-hour postload glucose: 140-199 mg/dL
- HgA1C: 5.7-6.4%
Treatment
Medication
- Sulfonylureas: Lower blood glucose by increasing insulin secretion. Lower HgA1C by 1-2%. Efficacy wanes over time due to beta cell failure. Metabolized by the liver and cleared by the kidney. Side effects: Hypoglycemia, weight gain, and potential increase in CV mortality because of its effect of K+ ATP channels. Dosed daily or b.i.d. in Type 2 DM.
- First generation: Chlorpropamide, tolbutamide, acetohexamide, tolazamide
- Second generation: Glipizide, glyburide, and glimepiride are the preferred agents.
- Meglitinides (nateglinide and repaglinide): Short-acting secretagogues given to lower postprandial blood glucose by increasing insulin secretion. Lower HgA1C by 1.0-1.5%. Metabolized by the liver and cleared by the kidney. Side effects include hypoglycemia and weight gain. Dosed t.i.d. with meals in Type 2 DM.
- Biguanides (Metformin): Lower blood glucose by decreasing hepatic glucose output and increasing insulin action. Metformin lowers HgA1C by 1.0-2.0%. Associated with modest weight reductions and decreased risk of all-cause mortality in obese individuals. Side effects: GI distress and lactic acidosis (avoid in renal dysfunction, hepatic dysfunction, cardiac disease, excess alcohol, IV iodinated contrast or surgical procedure). Dosed b.i.d. or t.i.d. in Type 2 DM.
- Thiazolidinediones (rosiglitazone and pioglitazone): Lower blood glucose by increasing insulin sensitivity. Lower A1C by 1.0-2.0%. Metabolized and cleared by the liver. Side effects: Hepatotoxicity, fluid retention, congestive heart failure, bladder cancer and weight gain. Dosed daily or b.i.d. in Type 2 DM.
- Alpha-glucosidase inhibitors (acarbose and miglitol): Interfere with digestion and absorption of complex carbohydrates. Lower HgA1C by 0.5-1.0%. Side effects: Flatulence, diarrhea, and abdominal discomfort. Dosed t.i.d. with meals in Type 2 DM.
- Amylin analogs (pramlintide): Decrease gastric emptying and suppress glucagon secretion and hepatic glucose production. Side effects: Nausea and hypoglycemia. Subcutaneous injections t.i.d. with meals for Type 1 and insulin-treated Type 2 DM.
- GLP-1 therapies (exenatide and laraglutide): Stimulate glucose-dependent insulin release from the pancreatic islets, slow gastric emptying, inhibit inappropriate postmeal glucagon release, and reduce food intake. Side effects: Nausea, hypoglycemia with sulfonylurea and pancreatitis. Contraindicated in Medullary thyroid cancer or MEN 2. Subcutaneous injection of exenatide is dosed daily within 1 hour of morning and evening meals. Weekly extended release preparation is now available. Laraglutide is a daily injection.
- Dipeptidyl peptidase IV (DPP-IV) Inhibitors (sitagliptin, saxagliptin and linagliptin): Inhibits DPP-IV, an enzyme that deactivates GLP-1. Glucose regulation similar to GLP-1 therapies. Administered orally. Lower doses recommended in renal failure. Side effect: Skin reaction, severe hypersensitivity and pancreatitis.
- Insulin: For all Type 1 and in Type 2 with inadequate blood glucose control on oral agents. Side effects: Hypoglycemia and weight gain.
- Rapid-acting (lispro, aspart, and glulisine): Onset of action 30 minutes and duration of action 2-4 hours
- Short-acting (regular): Peak at 2-4 hours and duration of action 6-8 hours
- Intermediate-acting (NPH): Peak at 4-10 hours and duration of action 12-18 hours
- Long-acting (glargine and detemir): Onset 1-2 hours and duration of action up to 24 hours. Once or twice a day dosing.
- Combine long-acting insulin with short-acting insulin to achieve glycemic control: Common regimens include glargine at bedtime with lispro/aspart/glulisine for meal time coverage or NPH/regular before morning and evening meals. Insulin pump infuses continuous subcutaneous short- or rapid-acting insulin in Type 1 DM.
- Side effects: Hypoglycemia and weight gain
- GDM, Type 1 or Type 2 DM: Insulin (NPH, regular, and lispro) is recommended (1)[A].
- Target plasma glucose in pregnancy: Fasting <95 mg/dL, 1-hour postprandial <140 mg/dL or 2-hour postprandial <120 mg/dL. During labor and delivery, insulin drip and glucose infusion are used to maintain maternal blood glucose concentration between 70 and 90 mg/dL.
- Insulin requirements decrease after delivery due to a drop in counter-regulatory hormones.
Additional Treatment
General Measures
- Exercise, diet, and weight management are critical to blood glucose control (1)[A].
- Recommend 30-45 minutes of moderate aerobic activity for 3-5 days/week and a balanced diet (40-50% carbohydrate, 20% protein, and 30-40% fat).
- Weight loss is achieved by reducing caloric intake and increasing physical activity. A decrease of 500 kcal/day results in a 1-2 lbs/week weight loss.
In-Patient Considerations
Admission Criteria
DKA (hyperglycemia <800 mg/dL, ketone bodies, anion gap acidosis) and nonketotic hyperglycemia (hyperglycemia >800 mg/dL and plasma osmolality >320 mosmol/kg) require ICU admission for IV fluids, insulin drip, potassium replacement, and evaluation of precipitating event. Bicarbonate therapy reserved for severe acidosis.
Ongoing Care
Complications
- Glucose control decreases microvascular and macrovascular complications in Type 1 diabetics and newly diagnosed Type 2 diabetics. Glucose control also decreases microvascular complications in long-standing Type 2 diabetics. No randomized controlled trial has shown that tight glycemic control (HgA1C <7%) decreases macrovascular complications in long-standing Type 2 diabetics (1)[A].
- Other preventative measures include:
- Macrovascular disease:
- Aspirin therapy: Recommended in all individuals with CVD or in men >50 and women >60 years with CVD risk factors. CVD risk factors include smoking, hypertension, obesity, albuminuria, dyslipidemia or family history.
- Lipid management: Statin (3050% LDL reduction) and fibrates (3550% TG reduction) are first line in management. Statin are recommended in any individual with CVD or >40 years of age with CVD risk factors. For individuals <40 yrs, statins are considered only if LDL >100mg/dL. TG (<150 mg/dL) and HDL (>40 mg/dL in men and >50 mg/dL in women) target goals are also recommended.
- Blood pressure control: Goal <130/80 mmHg. ACE inhibitors and ARB are first line.
- Smoking cessation
- Neuropathy: Regular foot exam with referral to podiatry for foot care. Consider antidepressants (e.g., amitriptyline) and anticonvulsants (e.g., gabapentin) for pain control; metoclopramide for gastroparesis.
- Retinopathy: Regular dilated eye exam by an ophthalmologist; consider photocoagulation and vitrectomy in symptomatic individuals.
- Nephropathy: ACE inhibitors and ARB decrease progression in individuals with microalbuminuria.
- Vaccines: Flu vaccine every year and pneumococcal vaccine per recommendations.
- Hyperglycemia in pregnancy is associated with preeclampsia, polyhydramnios, macrosomia, intrauterine growth restriction, congenital anomalies, perinatal mortality, neonatal complications (e.g., hypoglycemia, hyperbilirubinemia), and childhood complications (e.g., DM, obesity). Normalizing glucose can reduce risk of complication.
- Several agents widely used are contraindicated during pregnancy, including ACE inhibitors, ARBs, statins, and oral antidiabetic agents. Assessment of medications, glycemic control, and complications (e.g., blood pressure, retinopathy progression) is recommended prior to and during pregnancy.
References
1 Standards of medical care in diabetes. Diabetes Care. 2011;34(Suppl 1):S11-S61.
Additional Reading
1Nathan DM, Buse JB, Davidson MB. Medical management of hyperglycemia in Type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203. [View Abstract]
Codes
ICD9
- 250.00 Diabetes mellitus without mention of complication, type II or unspecified type, not stated as uncontrolled
- 250.01 Diabetes mellitus without mention of complication, type I [juvenile type], not stated as uncontrolled
- 250.80 Diabetes mellitus with other specified manifestation
- 648.80 Abnormal glucose tolerance of mother, unspecified as to episode of care or not applicable
- 250.10 Diabetes with ketoacidosis, type II or unspecified type, not stated as uncontrolled
- 250.11 Diabetes with ketoacidosis, type I [juvenile type], not stated as uncontrolled
- 250.40 Diabetes with renal manifestations, type II or unspecified type, not stated as uncontrolled
- 250.50 Diabetes with ophthalmic manifestations, type II or unspecified type, not stated as uncontrolled
- 250.60 Diabetes with neurological manifestations, type II or unspecified type, not stated as uncontrolled
- 250.70 Diabetes with peripheral circulatory disorders, type II or unspecified type, not stated as uncontrolled
ICD10
- E10.9 Type 1 diabetes mellitus without complications
- E11.9 Type 2 diabetes mellitus without complications
- O24.419 Gestational diabetes mellitus in pregnancy, unsp control
- E10.10 Type 1 diabetes mellitus with ketoacidosis without coma
- E11.29 Type 2 diabetes mellitus w oth diabetic kidney complication
- E11.319 Type 2 diabetes w unsp diabetic rtnop w/o macular edema
- E11.21 Type 2 diabetes mellitus with diabetic nephropathy
- E11.51 Type 2 diabetes w diabetic peripheral angiopath w/o gangrene
SNOMED
- 73211009 diabetes mellitus (disorder)
- 46635009 diabetes mellitus type 1 (disorder)
- 11687002 gestational diabetes mellitus (disorder)
- 420422005 ketoacidosis in diabetes mellitus (disorder)
- 420270002 ketoacidosis in type I diabetes mellitus (disorder)
- 127013003 diabetic renal disease (disorder)
- 4855003 diabetic retinopathy (disorder)
- 230572002 diabetic neuropathy (disorder)
- 127014009 diabetic peripheral angiopathy (disorder)
Clinical Pearls
- Diabetes mellitus (DM) results from an absolute or relative insulin deficiency.
- DM: Fasting plasma glucose ≥126 mg/dL, postprandial plasma glucose ≥200 mg/dL, or HgA1C ≥6.5%.
- Absolute insulin deficiency (e.g., Type 1 DM or pancreatitis) requires insulin therapy. Oral agents and insulin can lower glucose in conditions associated with insulin resistance and relative deficiency (e.g., Type 2 DM).
- In pregnant women, diabetes needs to be treated aggressively with insulin.