TYPE 2 DIABETES MELLITUS

Pathogenesis

Type 1 Diabetes—Autoimmune destruction of pancreatic b cells in genetically susceptible individuals causing insulin deficiency

Type II Diabetes

1)   Insulin resistance leads to hyperinsulinism to compensate, occurs long before diagnosis

a.     Hyperinsulinism is associated with hypertension, lipid abnormalities, and acanthosis nigricans.

2)   Concurrent decrease in glucose uptake by muscle tissue, increased liver gluconeogenesis

3)   Eventually pancreatic beta cells become unable to produce sufficient insulin to maintain normal glucose levels.

4)   Obesity strongly associated with an increased insulin resistance because adipose tissue release increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that promote insulin resistance.

5)   Insulin levels remain normal-high, and there is ‘relative’ insulin deficiency

6)   Increased circulating glucose causes glycation of RBCs, platelets, and endothelial cells, neuronal injury, and impaired immune function leading to macrovascular and microvascular complications

7)   Hyperinsulinemia and T2DM often accompanied by hypertension, dyslipidemia (high LDL, cholesterol, low HDL), leading to macrovascular complications

Epidemiology: worldwide rise in childhood type 2 diabetes in parallel with increase in obesity

Risk Factors:

1)   Obesity —most important risk factor for the development of T2DM

2)   Genetic susceptilbity—1 parent with T2DM confers 40% risk, 2 parents confer 60% risk

3)   Ethnicity—Native American, African American, Hispanic, Asian-American, Pacific Island

4)   Gender — females more likely than males to develop childhood T2DM

5)   Conditions with insulin resistance—PCOS, maternal gestational diabetes, SGA birth weight

Clinical Symptoms

1)    progression of symptoms more indolent than Type 1, increased levels of glucose may be picked up on routine screening of blood sugar levels or with the presence of glucosuria.

a.     mild polyuria and polydypsia

b.     fatigue

c.     weight loss

d.     blurred vision

e.     increased fungal infections

f.      increased periodontal disease

g.     numbness and tingling of hands and feet

2)    Uncommonly may present with ketoacidosis (10-15%)

Screening and Diagnosis

1)    Screen children every 3 years beginning at 10 years of age or at onset of puberty if overweight or obese (BMI ≥85th percentile) with ≥ 2 of the following risk factors:

a.     Type 2 DM in a 1^st or 2^nd degree relative

b.     Native American, non-Hispanic black, Hispanic, Asian American, or Pacific islander

c.     Signs of insulin resistance or conditions associated with insulin resistance (hypertension, dyslipidemia, acanthosis nigricans, and polycystic ovary syndrome, or small for gestational age birth weight)

d.     Maternal history of gestational diabetes during the child's gestation

2)    Diagnosis of diabetes mellitus in a child or adolescent can be done in one of four ways

a.     Hemoglobin A1C ≥ 6.5% (current recommended screening test)

b.     Fasting plasma glucose ≥126 mg/dL 

c.     Oral glucose tolerance test (OGTT) plasma glucose ≥200 mg/dL (2 hrs after a glucose challenge of 1.75 g/kg or maximum dose of 75 g)

d.     Symptoms of hyperglycemia and a random venous plasma glucose ≥200 mg/dL

3)    Pre-diabetes/impaired glucose tolerance if A1C 5.7-6.4 % of fasting plasma glucose 100 mg/dL – 125 mg/dL, OGTT 140-200mg/dl, these patients should undergo repeat testing

4)    Evaluate serum lipids and cholesterol

Co-morbidities

1)    Hypertension

2)    Dyslipidemia (high LDL, cholesterol and low HDL)

a.     hypertension and dyslipidemia lead to increased atherosclerosis and adulthood macrovascular complications (stroke, CAD, MI, peripheral vascular disease).

3)    nonalcoholic fatty liver disease

a.     elevated ALT (twice normal) in 20% of patients

b.     steatosis (increased liver fat without inflammation) or nonalcoholic steatohepatitis (NASH, increased liver fat with inflammation) can occur

c.     NASH may lead to fibrosis, cirrhosis, and ultimate liver failure if not treated

Complications—Microvascular complications include retinopathy, nephropathy, and neuropathy, causing adulthood:

1)    Visual loss

2)    Renal failure

3)    Neuropathy (peripheral, central/mononeuropathy, autonomic)

4)    Cardiovascular disease

Management

1)    Nonpharmacologic therapy: weight loss, increase physical activity, improved diet

2)    Pharamacologic therapy: insulin, metformin, sulfonylurea, thiazolidenediones

3)    Asymptomatic patients treated only with nonpharmacologic therapy

4)    Symptomatic patients (polyuria, polydipsia) with mild hyperglycemia w/o ketosis are treated with metformin and nonpharmacologic therapy

5)    Patients with severe hyperglycemia (plasma glucose ≥200 mg/dL and/or A1C >8.5%) and/or ketosis are treated with insulin and nonpharmacologic therapy

Goals of Therapy

1)    Improvement of glycemic control through weight reduction and increased activity has been associated with decreased insulin resistance and reversal of complications.

2)    Glycemic control:

a.     HbA1C < 7%

b.     Fasting glucose 90-130 mg/dL

c.     OGTT < 180mg/dL

3)    Monitor and control hypertension

a.     Prehypertension (systolic and/or diastolic between 90^th and 95^th percentiles) treated with nonpharmacologic therapy

b.     Hypertension (systolic and/or diastolic BP ≥95th percentile) treated with pharmacologic therapy–ACE inhibitor

4)    Monitor and treat hyperlipedemias

a.     goal LDL<100 mg/dL

b.     non-pharmacologic therapy initially to manage dyslipidemia

c.     pharmacologic therapy (statins) for older children (>10yrs) and children who fail non-pharmacologic therapy, have extreme dyslipidemia, or cardiovascular risk factors

5)    Monitor Neuropathy, Retinopathy, Nephropathy

a.     Yearly Retinal Fundoscopic exam, foot microfilament exam, UA and microalbumin

b.     Yearly Influenza vaccine

References

1. Pinhas-Hamiel, O, Zeitler, P. The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr 2005; 146:693.2.

2. Kahn, S.E., Hull, R. L., Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444: 840-846

3. Pinhas-Hamiel, O, Zeitler, P. Acute and chronic complications of type 2 diabetes mellitus in children and adolescents. Lancet 2007; 369:1823.

4. American Diabetes Association. Standards of medical care in diabetes--2010. Diabetes Care 2010; 33 Suppl 1:S11.

5. American Diabetes Association. Type 2 Diabetes in Children and Adolescents. Pediatrics Vol. 105 No. 3 March 2000