DIABETES MELLITUS

TYPE 2

INTRODUCTION AND DEFINITION

Type 2 DM is a chronic disease characterized by hyperglycemia

Results from a combination of:

• resistance to insulin • inadequate insulin secretion• Dysfunctional glucagon secretion

Poorly controlled type 2 diabetes an array of microvascular, macrovascular, and neuropathic complications.

CLASSIFICATIONType 2 DM patients are not absolutely dependent on insulin for life and are ty pically older than 40 years, hence the older terms “non–insulin dependent diabetes” and “adult-onset diabetes”.

However; many patients with type 2 diabetes are ultimately treated with

insulin type 2 diabetes mellitus is occurring at younger ages due to

the epidemic of obesity and inactivity in children and in case of a family history of diabetes

SYMPTOMS Many patients with type 2 diabetes are asymptomatic

Clinical manifestations include the following:• Polyuria, polydipsia, polyphagia, and weight loss • Blurred vision • Lower-extremity paresthesias • Yeast infections (eg, balanitis in men)

RISK FACTORS AND CAUSES

Causes: • Peripheral insulin resistance

(attributed to elevated levels of free fatty acids and proinflammatory cytokines in plasma)

• Beta-cell dysfunction:inadequate insulin secretion by pancreatic beta cells

• Hyperglucagonemia and the consequent hyperglycemia

Diabetogenic lifestyle + Susceptible genotype

CONT. CAUSES AND RISK FACTORS• Obesity

• Age >45

• Family history

• Hispanic, Native American, African American, Asian American, or Pacific Islander descent

• History of previous impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)

• Hypertension or dyslipidemia

• History of gestational diabetes

• Polycystic ovarian syndrome

• Genetic influences

• High fasting plasma concentrations of 3 amino acids (isoleucine, phenylalanine, and tyrosine).

DIAGNOSIS AND TESTSDiagnostic criteria by the American Diabetes Association (ADA):• Fasting plasma glucose (FPG) level of 126 mg/dL (7.0 mmol/L) or

higher

• 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT)

• A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis

• Optional: Hemoglobin A1c (HbA1c) level of 6.5% or higher

COMPLICATIONSCardiovascular risk * *2-4 times greater in patients with diabetes* *1. Lipid abnormalities:

• small, dense low-density lipoprotein (LDL) cholesterol• high-density lipoprotein (HDL) cholesterol • triglyceride-rich remnant lipoproteins

2. Thrombotic abnormalities:

• type-1 plasminogen activator inhibitor [PAI-1]• fibrinogen

3. Hypertension

Cognitive decline• Hippocampal atrophy• Temporal, frontal, and limbic gray-matter atrophy• Frontal and temporal white-matter atrophy

Diabetic retinopathy

End-stage renal disease

Neuropathy and vasculopathy (non-traumatic lower limb amputations )

Cancer (higher risk for bladder cancer )

DRUGS AND TREATMENTDrug class

• Biguanides

• Sulfonylureas

• Meglitinide derivatives

• Alpha-glucosidase inhibitors

• Thiazolidinediones (TZDs)

• Glucagonlike peptide–1 (GLP-1) agonists

• Dipeptidyl peptidase IV (DPP-4) inhibitors

• Selective sodium-glucose transporter-2 (SGLT-2) inhibitors

• Amylinomimetics

• Bile acid sequestrants

• Dopamine agonists

• Rapid-acting Insulins• Short-Acting Insulins• Intermediate-Acting Insulins• Long-Acting Insulins

Example

• Metformin

• Glimepiride

• Repaglinide

• Acarbose

• Rosiglitazone

• Exenatide

• Sitagliptin

• Canagliflozin

• Pramlintide

• Colesevelam

• Bromocriptine

• Insulin aspart• Regular insulin• Insulin NPH• Insulin detemir

Brand name

• Glucophage

• Amaryl

• Prandin

• Precose

• Avandia

• Byetta

• Januvia

• Invokana

• Symlin

• WelChol

• Cycloset

• NovoLog• Humulin R• Humulin N• Levemir

TREATMENT REGIMEN AND GOALSThe goals with diabetes mellitus are to

• eliminate symptoms • prevent or slow development of complications

Glycemic goals: Premeal glucose 80-120 mg/dL,or 100-140 mg/dL for

patients with less stringent glycemic goals Therapy should normalize preprandial and postprandial

glycemia

Glycemic monitoring is based on HbA1c + self-monitoring of blood glucose (SMBG).

The ACP recommends HbA1c < 7% Some organizations recommend HbA1c <6.5%

Monotherapy: Metformin is the preferred initial agent for monotherapy and is a standard part of combination treatments.

Dual-drug therapy: If the patient fails to safely achieve or sustain glycemic goals within 2-3 months

Triple-drug therapy: If 2 drugs prove unsuccessful after 2-3 months

NON-PHARMACOLOGICAL TREATMENT• Dietary Modifications and Weight loss

• Caloric restriction• Modest restriction of saturated fats and simple sugars• Weight loss has been associated with significant improvements in

cardiovascular disease risk factors

Activity Modifications• Aerobic exercise improves insulin sensitivity and may improve

glycemia markedly in some patients.• physical activity +dietary modificaions lower HbA1c

Bariatric SurgeryIn morbidly obese patients to:• improve diabetes control • in some situations, normalize glucose tolerance.

PREVENTION To prevent type 2 diabetes mellitus in patients at risk:

• Weight reduction • Proper nutrition• Regular physical activity • Cardiovascular risk factor reduction • Aggressive treatment of hypertension and dyslipidemia• Pharmacologic prevention using drugs e.g. Metformin,

Thiazolidinediones, Acarbose

Stroke Prevention in Diabetes• Regular blood pressure screening • Physical activity • Low-sodium, high-potassium diet• Blood pressure <130/80 mm Hg • Drug therapy with ACE inhibitors or ARBs • Statin therapy

BIGUANIDES (METFORMIN)Mechanism of actionIt lowers basal and postprandial plasma glucose levels by:

• decreasing hepatic gluconeogenesis production

• decreasing intestinal absorption of glucose

• improving insulin sensitivity by increasing peripheral glucose uptake and utilization

The only oral diabetes drug that reliably facilitates modest weight loss

CONT. BIGUANIDES (METFORMIN)Side effects, drug interaction, contraindications

• Taken with food to minimize adverse GI effects. • Contraindicated in patients with impaired renal function (risk

of lactic acidosis)• Not be used within 48 hours of IV iodinated contrast medium.

Dose and duration of treatment• Metformin is available in immediate-release and extended-

release formulations, as well as in combination with other antidiabetic drugs.

• The dose is titrated over 1-2 months to at least 2000 mg daily, administered in divided doses

SULFONYLUREASMechanism of action• Insulin secretagogues that stimulate insulin release from pancreatic

beta cells and probably

• greatest efficacy for glycemic lowering but effect is only short-term

• May also enhance peripheral sensitivity to insulin secondary to an increase in insulin receptors or to changes in the events following insulin-receptor binding.

can usually reduce HbA1c by 1-2% and blood glucose concentrations by about 20%.

CONT. SULFONYLUREASSide effects, drug interaction, contraindications• One study sulfonylureas were found to be the chief cause of

cardiovascular death in diabetic patients admitted with acute myocardial infarction

• Induction of weight gain

Dose and duration of treatment

MEGLITINIDE DERIVATIVESMechanism of action

• much shorter-acting insulin secretagogues than sulfonylureas

Side effects, drug interaction, contraindications• inducing weight gain as sulfonylureas• less risk for hypoglycemia than sulfonylureas

Dose and duration of treatment

ALPHA-GLUCOSIDASE INHIBITORSMechanism of action

• prolong the absorption of carbohydrates• Thus help prevent postprandial glucose surges.

Side effects, drug interaction, contraindicationsinduction of flatulence

Dose and duration of treatment