History

• Patients with T2DM are almost always overweight
• Patients often present with no symptoms and may go undiagnosed for many years. Symptomatic patients may have polyuria, polydipsia, polyphagia, and unintentional weight loss
• Other symptoms suggesting hyperglycemia are blurred vision, paresthesias (usually in the feet), and yeast infection (commonly vaginal, penile foreskin, or skin-fold candidiasis)
• Patients may also present with fatigue or slowly resolving infections, such as urinary tract infections (cystitis or pyelonephritis), skin infections (such as cellulitis or abscesses), or other infections

Physical findings on examination

• Acanthosis nigricans
• Central obesity
• Dry feet, muscular atrophy, claw toes and ulcers
• Hirsutism
• Hypertension
• Neuropathy, especiallydecreased sensation to the feet and loss of tendon reflexes at the ankle
• Paresthesias (particularly lower extremities)
• Poor wound healing
• Retinopathy (retinal hemorrhages, exudates, neovascularization)
• Yeast infection (vaginal, penile, or in skin folds)

Blood test findings

Criteria for diagnosis of T2DM:

• Glycosylated hemoglobin (HbA1c): 6.5% or greater on 2 or more occasions is diagnostic; HbA1c between 5.7–6.4% is pre-diabetes
• Fasting plasma glucose: 126 mg/dL (6.9 mmol/L) on 2 occasions, OR
• 2-hours after a glucose load of 75 g orally: 200 mg/dL (11.1 mmol/L), OR
• Random glucose level 200 mg/dL (11.1 mmol/L) along with classic symptoms such as polyuria, polydipsia, or weight loss

• Fasting lipid profile: Dyslipidemia is common in T2DM patients with elevated total cholesterol, LDL, and triglycerides, and low HDL levels
• Urine microalbumin: Patients may have microalbuminuria, which is suggestive of end-organ damage and is a marker of early renal disease. Annual screening is recommended for all patients with T2DM
• Serum creatinine and estimated GFR: May show renal insufficiency
• Metabolic studies: Elevated levels of plasma gamma glutamyl transferase (GGT) and alanine aminotransferase (ALT) may serve as biomarkers for insulin resistance
• C-peptide insulin level: High levels of C-peptide indicate high levels of insulin, consistent with T2DM and insulin resistance
• AHA criteria for ketoacidosis (all 5 must be present):
• Plasma glucose concentration: >250mg/dL (13.9mmol/L)
• pH: <7.30
• Serum bicarbonate: 18meq/L (18 mmol/L)
• Beta-hydroxybutyrate or ketones in urine or blood
• Anion gap >10mEq/L (10 mmol/L)
• Note that ketoacidosis is only occasionally seen in patients with T2DM

• Diabetes Mellitus Type 1 (T1DM)
• Endocrine disorders (e.g. Cushing's syndrome, acromegaly)
• Gestational diabetes
• Pre-diabetes
• Maturity onset diabetes of the young (MODY)
• Metabolic syndrome (also called Syndrome X or insulin-resistance syndrome)

General treatment items

• Treatment of T2DM focuses on 3 important items:
  • Decreasing cardiovascular disease risk factors
  • Lifestyle changes (diet/exercise)
  • Management of blood glucose levels
• Patients receive education on healthy lifestyle choices such as:
  • Dietary counseling by a dietician or diabetic educator on healthy food choices and limiting simple carbohydrate consumption
  • Weight loss and increased physical activity
• Most patients require one or more medications to achieve glycemic control. These include a range of oral and injectable medications, including insulin
• Aggressive lifestyle changes may be tried before initiating medications. Medications can sometimes be avoided when the patient achieves substantial weight loss, makes dietary changes, and becomes physically active
• Early detection through screening (at intervals recommended by national and international guidelines) to treat complications. Patient care includes eye examination, urine for microalbumin, foot care, blood pressure monitoring, and specialist referrals
• Patient self-monitoring for signs/symptoms of hypoglycemia (such as drowsiness, shakiness, diaphoresis, hunger, and dizziness) and for hyperglycemia
• Patients should be provided with detailed education on the importance of foot care
• Management of cardiovascular disease risk factors:
  • Daily low-dose aspirin is recommended for patients with T2DM and coronary artery disease (CAD), those older than 40 years of age, and those who have additional risk factors for cardiovascular disease (e.g., family history of albuminuria, cardiovascular disease, hypertension, lipid disorders, or smoking)
  • Statins are recommended for patients with T2DM and CAD, and for patients with diabetes without CAD who are older than 40 years of age, who have one other cardiovascular disease risk factor
  • Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the mainstays of treatment for patients with micro or macro-albuminuria (and also for T2DM patients who have hypertension)
• Management of blood glucose levels: Medications used to manage blood glucose in patients with T2DM, listed by route & class:
• Oral antidiabetic drugs:
  • Alpha-Glucosidase Inhibitors:
    • Acarbose: Inhibits intestinal alpha-glucoside hydrolase and pancreatic alpha-amylase and delays glucose absorption
    • Miglitol: Inhibits intestinal alpha-glucoside hydrolase and delays glucose absorption
  • Amylin analog:
    • Pramlintide: By augmenting endogenous amylin, pramlintide aids in reducing postprandial hyperglycemia by slowing gastric emptying. This agent also promotes satiety via hypothalamic receptors (different receptors than for GLP-1), inhibits inappropriate secretion of glucagon, and decreases caloric intake by decreasing appetite
  • Biguanides: Inhibit hepatic gluconeogenesis, and decrease triglyceride levels
    • Metformin: Inhibits hepatic gluconeogenesis and increases insulin sensitivity
    • Thiazolidinediones: Increases insulin sensitivity in adipose tissue, skeletal muscle, and liver
      • Pioglitazone
      • Rosiglitazone
  • Incretins: Act on gastrointestinal cells, with release of GLIP (glucose linked insulinogenic peptide) hormone
    • Gliptins: Dipeptidyl peptidase IV (DPP-IV) inhibitors which slow inactivation of incretin hormones, resulting in increased glucose-stimulated insulin secretion and decreased glucagon secretion
      • Linagliptin
      • Saxagliptin
      • Sitagliptin
    • GLP-1 agonists: Incretin analog that reduces fasting and postprandial glucose by increasing glucose-stimulated insulin secretion, decreasing glucagon secretion, slowing gastric emptying, and reducing appetite
      • Exenatide
      • Liraglutide
  • Meglitinides: Stimulate pancreatic beta-cell insulin release
    • Nateglinide
    • Repaglinide
  • Sulfonylureas: 1st generation: Stimulate pancreatic beta-cell insulin release
    • Chlorpropamide
    • Tolazamide
    • Tolbutamide
  • 2nd generation: Stimulate pancreatic beta-cell insulin release
    • Gliclazide
    • Glimepiride
    • Glipizide
    • Glyburide
• Insulin:
  • Rapid/ultra short acting: Stimulates peripheral glucose uptake, and inhibits hepatic gluconeogenesis
    • Aspart (Novolog/Novorapid)
    • Glulisine (Apidra)
    • Lispro (Humalog)
  • Short-acting: Stimulates peripheral glucose uptake, and inhibits hepatic gluconeogenesis
    • Regular Insulin (Novolin R, Humulin R)
  • Intermediate-acting: Stimulates peripheral glucose uptake, and inhibits hepatic gluconeogenesis
    • NPH (Novolin N, Humulin N)
  • Long acting: Stimulates peripheral glucose uptake, and inhibits hepatic gluconeogenesis
    • Detemir (Levemir)
    • Glargine (Lantus)
• Initial management:
  • First line therapy
    • Metformin: Preferred first-line medication because of its beneficial effect on weight and insulin resistance
    • Additional agents include sulfonylureas, non-sulfonylurea secretagogues, thiazolidinediones, and alpha-glucosidase inhibitors, which can be combined with other drugs
    • When maximal benefit is achieved from first-line medications, the addition of other agents is often required. Agents such as exenatide (approved for use with metformin or sulfonylureas) and sitagliptin (approved for use with metformin or thiazolidinediones) may be added
    • Carefully consider the patient with addition of agents to metformin as each has risks and benefits
• Initiating insulin therapy:
  • Second line therapy
    • Insulin: Rapid (Aspart, Lispro, Glulisine), short (regular insulin), intermediate (NPH, Lente), and long/peakless (Glargine) or long/peak (Detemir)
    • While adding insulin to an oral medication regimen, it is recommended that the oral agents should be continued, as minimizing insulin dose probably has benefits in regard to minimizing weight gain
    • When insulin is prescribed, long acting insulin is generally the initial agent of choice. Typical adult starting dose is 10 units per day, with final dosing range being 0.17-0.5 units/kg/day. Titration is typically in increments of two units every three days, with close monitoring
    • Rapid-acting or premixed insulin preparations can be added in cases where fasting blood glucose levels or HbA1C is persistently high (HbA1C>7.5%), as this indicates high postprandial glucose levels
    • Sliding-scale doses are assigned by counting carbohydrate grams or by utilizing a preset scale which is based upon pre-prandial blood glucose levels
• Children/Adolescents:
  • Metformin (approved for use) in children 10 years and sustained-release preparations (approved for use) in persons 17 years who cannot maintain glycemic control with diet and exercise
  • Insulin approved for use in children 2 years of age
  • Other agents increasingly used if needed in children/adolescents with T2DM

Medications indicated with specific doses

Alpha-Glucosidase Inhibitors

• Acarbose
  • Adult Dosing
• Miglitol
  • Adult Dosing

• Pramlintide [SC]
  • Adult Dosing

• Metformin
  • Adult Dosing
  • Pediatric Dosing

• Pioglitazone
  • Adult Dosing
• Rosiglitazone
  • Adult Dosing

• Linagliptin
  • Adult Dosing
• Saxagliptin
  • Adult Dosing
• Sitagliptin
  • Adult Dosing

• Exenatide
  • Adult Dosing
• Liraglutide
  • Adult Dosing

• Nateglinide
  • Adult Dosing
• Repaglinide
  • Adult Dosing

• Chlorpropamide
  • Adult Dosing
• Tolazamide
  • Adult Dosing
• Tolbutamide
  • Adult Dosing

• Gliclazide
  • Adult Dosing
• Glimepiride
  • Adult Dosing
• Glipizide
  • Adult Dosing
• Glyburide
  • Adult Dosing

• Insulin aspart [IV/SC]
  • Adult Dosing
  • Pediatric Dosing
• Insulin glulisine [IV/SC]
  • Adult Dosing
  • Pediatric Dosing
• Insulin lispro [SC]
  • Adult Dosing
  • Pediatric Dosing

Short-acting insulins

• Insulin regular [IV/SC]
  • Adult Dosing
  • Pediatric Dosing

• Insulin nph [SC]
  • Adult Dosing
  • Pediatric Dosing

• Insulin detemir (rDNA origin) [SC]
  • Adult Dosing
  • Pediatric Dosing
• Insulin glargine [SC]
  • Adult Dosing
  • Pediatric Dosing

Dietary or Activity restrictions

• Diet should be directed toward healthy distribution and matching of carbohydrate intake with insulin action. Carbohydrates shouldcomprise 55% of caloric intake, fats should be 30%, and protein should be 15%
• Fiber 50 grams/day is recommended (adult recommendation)
• Low glycemic index (GI) foods should comprise the majority of carbohydrate intake
• Calorie counting is helpful in flexible insulin regimens while evenly spaced meals or snacks are essential for fixed insulin regimens
• Reduction of saturated and trans fats may be beneficial
• Regular aerobic exercise recommended. Frequent exercise reduces blood glucose and insulin requirements
• In the event of excessive caloric intake (large consumption of high carbohydrate meal), additional short-acting insulin will be required
• Patients are advised to adjust their insulin dose according to their daily food intake and activity level. Regular eating on a fixed regimen is important
• To avoid hypoglycemia, patients may need to decrease medications in the event of illness affecting ability to eat, voluntary fasting for procedures or personal reasons, excessive physical activity or exercise
• Exercise may require additional eating or reduced insulin to prevent hypoglycemia
• Patients need to be educated on glycemic index of food to understand which foods elevate blood sugar easily versus those that have less effect on blood sugar. Consuming pure glucose is given a ranking of 100; therefore, a food with a glycemic index close to 100 is similar to consuming glucose directly. Food which raises the glycemic index by 20-30 hardly contributes to the rise in blood sugar. Patients should be aware that no two apples are the same and thus glycemic index may vary. Numbers given are an average calculated after trials on people with different sensitivities. Given the variation between foods and individuals, 5 or 10 points on the glycemic scale is of little consequence
• Regular aerobic exercise at least 150 min/week can improve glucose tolerance and decrease medication requirements

Monitoring

• Diabetes assessments should be carried out every 3-4 months in most patients
• Regular monitoring and control of blood pressure (goal<130/80mmHg); lipids (LDL <100 mg/dL[2.59 mmol/L], HDL >50 mg/dL [1.29 mmol/L], triglycerides <150 mg/dL[2.31 mmol/L]), HbA1c (<7%). Tobacco use should be avoided; aspirin use is recommended
• HbA1c should be tested twice yearly for patients with glycemic control; quarterly for patients who are uncontrolled or who have a change in therapy
• Dilated eye examination(fundoscopy) is recommended every 1 to 2 years
• Assessment of renal function including microalbuminuria, serum creatinine, and estimated creatinine clearance should be performed annually
• Proper foot care, and annual or more frequent foot examinations are recommended and should include ankle reflexes, dorsalis pedis pulse, vibratory sensation, and monofilament touch sensation

Complications

• Abducens nerve palsy
• Autonomic neuropathy
• Cardiovascular disease
• Cataracts
• Charcot joints
• Chronic renal failure
• Congestive heart failure
• Dawn phenomenon (an abnormal early-morning rise in blood sugar)
• Dermatopathy (necrobiosis lipidoica diabeticorum, acanthosis nigricans)
• Diabetic coma
• Diabetic ketoacidosis
• Gangrene of extremities resulting in possible amputation
• Glaucoma
• Infections (Bacterial & Fungal)
• Macro and microvascular arterial cell wall damage
• Nephropathy
• Non-ketotic hyperosmolar state
• Periodontal disease
• Peripheral neuropathy
• Retinopathy/Blindness
• Skin ulceration
• Stroke
• Treatment-related hypoglycemia
• Water intoxication (cerebral edema, convulsions)