Type 2 Diabetes Mellitus

See Also

Epidemiology

Represents 90% of all Diabetes Mellitus
Typically occurs over age 40 years in obese patients
Type II Diabetes Mellitus Prevalence is rapidly increasing in the United States
1. Prevalence: 22 Million in 2014 (was 5.5 Million in 1980)
2. More than 8 Million are estimated to be undiagnosed (27%)
3. Over 29 Million people with Type II Diabetes represents over 9% of the U.S. population
4. Total cost of Type II Diabetes: $245 Billion in 2012 (includes $69B indirect costs such as Disability, work loss)
5. Estimated to rise to 44 Million with Type II Diabetes in U.S. by 2035
6. http://www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm
7. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf

Pathophysiology

Triad of factors contributing to Diabetes Mellitus
1. Impairment of pancreatic beta-cell function
  1. Decreased beta cell response to Glucose
    1. Abnormal Glucagon secretion
  2. Amyloidosis of islet cells (40% of patients)
  3. Pancreatic fibrosis (66% of patients)
    1. Associated fatty infiltration, vessel sclerosis
2. Decreased Insulin sensitivity (60-80% of patients)
  1. See Insulin Resistance
  2. Obesity
3. Incretin Deficiency
Course
1. 12 years before diagnosis: Impaired Glucose Tolerance
  1. Insulin Resistance starts
  2. Insulin levels start to rise
  3. Fasting and post-meal Glucose normal
2. 8 years before diagnosis: Postprandial Hyperglycemia
  1. Beta cell function at 75%
  2. Insulin levels increase to 150% of normal
  3. Fasting and post-meal Glucose normal
3. 2 years before diagnosis: Type 2 diabetes phase I
  1. Beta cell function at 50%
  2. Insulin levels increase to 200% of normal (peak)
  3. Post-prandial Glucose 150-200 mg/dl
  4. Normal Fasting Glucose
4. 2 years after diagnosis: Type 2 diabetes phase II
  1. Insulin levels fall to 150% of normal
  2. Post-prandial Glucose 200 mg/dl
  3. Fasting Glucose >140-150 mg/dl
5. 8 years after diagnosis: Type 2 diabetes phase III
  1. Beta cell function at 25%
  2. Insulin levels fall to 100% of normal
6. 14 years after diagnosis
  1. Beta cell function approaches 0%
  2. Insulin levels fall below 50% and approach 0

Risk Factors

Obesity (especially Apple Obesity)
Previous Gestational Diabetes (GDM)
Family History of Type II Diabetes Mellitus
1. Autosomal Recessive inheritance
Age over 40 years (risk increases with age)
1. Type II Diabetes Mellitus does occur in children
Sedentary lifestyle (decreased Physical Activity)
Previously Impaired Glucose Tolerance (IGT)
Polycystic Ovary Syndrome
Western diet
1. Red meats and processed meats
2. High fat foods (french fries, high fat dairy, eggs)
3. High sugar foods, desserts and drinks
4. Van Dam (2002) Ann Intern Med 136:201-9 [PubMed]
Ethnicity
1. Native American
2. African American or Black
3. Asian Type II Diabetics may be thin
4. Hispanic
Cigarette smoking decreases Insulin sensitivity
1. Targher (1997) Clin Endocrinol Metab 82:3619-23 [PubMed]

Risk Factors
Protective Factors (based on initial study findings)

See Insulin Resistance

Symptoms and Signs

See Diabetes Mellitus

Diagnostic Criteria

See Diabetes Mellitus

Associated Conditions

Labs

Urine Ketones: Usually negative
1. Exception: Children with Type II Diabetes
See Diabetes Mellitus

Precautions

Accord Trial and Ideal A1C Target <8%
1. Suggests higher risk of aggressively lowering Blood Glucose in Type II Diabetes
2. Risk increased with Hemoglobin A1C of 6.4% compared with 7.5%
3. Mortality was higher in the 6.4% A1C group by 3 per thousand patients
4. Endocrinologists still recommend goal of <7.0% and await larger trial (Advance)
5. References: NHLBI Questions and Answers regarding Accord Study
  1. http://www.nhlbi.nih.gov/health/prof/heart/other/accord/q_a.htm
Glucose Monitoring
1. Self monitoring of Glucose in non-Insulin dependent diabetes does not improve Hemoglobin A1C at one year
2. Multiple professional organizations (AAFP, SGIM) recommend against daily Glucose checks in Diabetes Mellitus not on Insulin
3. Regular Glucose monitoring is optional in patients in non-Insulin dependent Type 2 diabetes
4. However, certain agents may predispose to Hypoglycemia (e.g. Sulfonylureas), and symptomatic patients should check Glucose as needed
5. References

Management
General

Intensive Diabetic Education
1. Goal Hemoglobin A1C <7.0 to 8.0%
  1. Goal relaxed to 8% in 2009 based on ACCORD and ADVANCE results
  2. Goal 6.5 to 7% is ideal for young, otherwise healthy patients without Hypoglycemia risk
  3. Tight control in the elderly significantly increases severe Hypoglycemia and hospitalization risk
    1. Ling (2021) Diabetes Care 44(4):915-24 [PubMed]
2. Fasting plasma Glucose: 70 to 140 mg/dl (ideal <105)
  1. New guidelines may suggest 70 to 120 mg/dl
3. 2 hour postprandial Glucose: <160 mg/dl (ideal <135)
  1. Ideally, only 20-40 mg/dl rise over pre-meal
4. Bedtime Glucose: 100-140 mg/dl
Intensive lifestyle intervention (Look Ahead Study)
1. Results in up to 5% weight loss and improved glycemic control (or in up to 20%, diabetes remission)
2. Best outcomes are for early intervention (<2 years of type 2 diabetes)
3. Gregg (2012) JAMA 308(23): 2489-96 [PubMed]
Weight loss (if Overweight)
1. Recommend 10-20 pound weight loss or 7% of body weight
2. Lower Caloric Intake by 250-500 calories per day, including reduced Dietary Fat
3. Low Carbohydrate Diet does not result in longterm Blood Sugar control (at >= 6 months)
Regular Exercise
1. Regular aerobic Exercise (150 min/week moderate, or 75 min/week vigorous)
2. Resistance Training
Cardiovascular Disease Prevention
1. Lower LDL Cholesterol <80-100 (Statin)
2. Lower Blood Pressure <130/80 (ACE Inhibitor or ARB as first line medication)
  1. Keep systolic Blood Pressure between 120 and 130 mmHg
3. Aspirin 81-160 mg PO qd
4. ACE Inhibitor (Indicated in Proteinuria)

Management
Oral Glycemic Protocol

See Diabetes Mellitus Glucose Management
See Oral Hypoglycemic agents
Sample Initial Protocol based on Glucose
1. Fasting Blood Sugar <200 or random Glucose <250
  1. Consider trial of diet and Exercise for 1-2 months
  2. Strongly consider concurrent Oral Hypoglycemic
2. Fasting Blood Sugar <300 or random Glucose <350
  1. Start Oral Hypoglycemic agent (see above)
3. Fasting Blood Glucose >250 mg/dl and Glucose toxicity
  1. Start Insulin replacement protocol (see above)
  2. Concurrently start Oral Hypoglycemic (Metformin)
4. Fasting Blood Sugar >300 or random Glucose >350
  1. Start Insulin replacement protocol (see above)
  2. Concurrently start Oral Hypoglycemic (Metformin)
Medical nutrition therapy (adjunct to all other management)
1. Efficacy: A1C decrease 1%
2. Obese patients (Fasting Glucose high)
  1. Insulin Resistance primary problem in early phase
  2. Focus on weight loss and activity
3. Lean patients (Postprandial Glucose high)
  1. Insulin deficiency is primary problem
  2. Focus on Carbohydrate Counting
Single Oral Agents
1. See Oral Hypoglycemic (reviews all non-Insulin agents)
2. Indications to start at presentation
  1. Hemoglobin A1C >6.5% or
  2. Fasting Blood Glucose >126 mg/dl or
  3. Random Blood Glucose >250 mg/dl or
  4. Glucose Tolerance Test 2 hour >200 mg/dl
3. Efficacy: A1C decrease 1-2% (combined with above)
4. First-Line agents
  1. Metformin (Glucophage)
    1. First-line (regardless of weight) unless otherwise contraindicated
    2. Contraindicated if GFR <30 ml/min/kg
5. Second-Line agents
  1. See SGLT2 Inhibitor and GLP-1 Receptor Agonist indications as below
  2. SGLT2 and GLP-1 agents improve patient oriented outcomes
    1. In contrast, older agents improve Glucose control (e.g. Sulfonylureas) and may not alter outcomes
    2. Shi (2023) BMJ 381:e074068 [PubMed]
6. Other agents that have historically been second-line
  1. Glitazone (e.g. Pioglitazone, Rosiglitazone)
    1. Especially obese patients with Insulin Resistance (Fasting Glucose high)
  2. Oral secretagogue (e.g. Sulfonylurea)
    1. Especially lean patients (Postprandial Glucose high)
Dual Drug Therapy
1. Indications to add a second agent
  1. Inadequate Glucose control after 3 months on single oral agent (as above)
2. Indications to start two agents at presentation
  1. Hemoglobin A1C 9-11%
  2. Fasting BG 251-300 mg/dl
  3. Random or casual BG 301-350 mg/dl
3. Efficacy: A1C decrease 2-4% (combined with above)
4. First-line combinations: Metformin AND
  1. Sulfonylurea (esp. lean patients) or
  2. Glitazone (esp. obese patients) or
  3. Incretin (choose only 1)
    1. Gliptin or DPP-4 Inhibitor (e.g.Sitagliptin or Januvia)
    2. GLP-1 Agonist (e.g. Exenatide or Byetta)
    3. Avoid using 2 Incretins in combination (raises cost, Pancreatitis risk, no significant benefit)
      1. (2012) Presc Lett 19(8): 45
5. Second-Line combinations (with something other than Metformin)
  1. Insulin Secretagogue with Glitazone
  2. Incretin with Sulfonylurea (use caution)
  3. Basal insulin (e.g. Lantus) with Sulfonylurea, Glitazone, Gliptin or Incretin
6. Other indications to add SGLT2 Inhibitor or GLP-1 Receptor Agonist (associated with lower mortality)
  1. Established cardiovascular disease or Chronic Kidney Disease (esp. SGLT Inhibitor)
  2. Four or more Cardiovascular Risk Factors
  3. Li (2021) BMJ 373: n1091 [PubMed]
Triple Drug Therapy
1. Add a third drug from the agents listed above if inadequate control on dual agents
Insulin Therapy
1. Indications to start at presentation
  1. Hemoglobin A1C >10-11%
  2. Fasting BG >300 mg/dl (or >250 mg/dl and Glucose toxicity)
  3. Random or casual BG >350 mg/dl
2. Protocol: Options
  1. See below
  2. Basal insulin
  3. Basal with Bolus Insulin
  4. Mixed Insulin

Management
Insulin Protocol

Indications
1. Glucose toxicity
  1. Fasting Blood Glucose >250 mg/dl and
  2. Ketosis or weight loss
2. Hemoglobin A1C > 10% or random Blood Glucose consistently >300 mg/dl
3. Inadequate Blood Sugar control on oral agents and Hemoglobin A1C >9%
4. Late stage Type II Diabetes (>5-10 years)
5. Perioperative Diabetes Management
6. Chronic Renal Failure
7. Pregnancy
8. Acute illness
Protocol
1. See Insulin Dosing
2. See Insulin Dosing in Type II Diabetes
3. Option 1: Insulin augmentation
  1. Start Dose: 0.15 to 0.20 units/kg daily (10-14 units/day)
  2. Titrate Dose: Increase by 2 units every 3 days
  3. Preparations
    1. Insulin Glargine (Lantus) daily or
    2. NPH (Novolin N, Humulin N) at bedtime or twice daily
4. Option 2: Insulin replacement
  1. Titrate dose up to 0.5 units/kg daily
  2. Long-acting Basal insulin (NPH or Lantus) and Short-acting Bolus Insulin (Lispro, Aspart, Reg) OR
  3. Premixed Insulin 70/30 (may be less expensive)
Efficacy
1. Insulin therapy does not reduce quality of life
2. No increase in hypoglycemic episodes
3. Significant improvement in glycemic control
4. De Grauw (2001) Br J Gen Pract 51:527-32 [PubMed]

Management
Follow-up Adjustment Phase

Weekly phone call to review Blood Glucose log
Monthly clinic visits
Dietician or nutritionist every 2-4 weeks
Goal Blood Glucose not met (Hemoglobin A1C >7.0 to 8.0)
1. Oral Hypoglycemics
  1. Advance from single therapy to dual therapy to triple therapy every 3 months as needed
  2. See Oral Hypoglycemic for protocol (also described above)
2. Oral Hypoglycemics maximized or contraindicated
  1. Start Insulin augmentation (see above)
3. Insulin augmentation has already been started
  1. Start Insulin replacement (see above)

Management
Follow-up Maintenance Phase

Clinic visits every 3-4 months
1. Review Blood Sugar log and Hypoglycemic episodes
2. Review medication dosages
3. Evaluate comorbid conditions
  1. Evaluate weight or BMI
  2. Check Blood Pressure
4. Clean and check Glucometer
5. Diabetic Foot Exam (examine feet at every visit or at a minimum annually)
Education
Examination
1. Annual Health Maintenance Exam
2. Annual Eye Examination with Pupil Dilation
3. Annual Dental Exam
Labs
1. Daily
  1. Home Glucose monitoring before meals and bedtime
  2. Postprandial Glucose (2 hours after meal)
    1. May be better marker for control
2. Every 3 months
  1. Hemoglobin A1C
3. Annual
  1. Fasting Lipid Profile
  2. Renal Function tests (BUN and Creatinine)
  3. Urinalysis
  4. Urine Microalbumin

Complications

See Diabetes Mellitus Complications

Prevention

References