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Type I Diabetes Mellitus

Complex and chronic metabolic disorders characterized by symptomatic glucose intolerance

Abnormalities of insulin secretion and complication of the disease

Insulin Biosynthesis, Secretion and Action

Insulin is produced in the beta cell of pancreatic islets

Glucose is a key regulator of insulin secretion by the pancreatic beta cell

Insulin inhibit glucose production from the liver, and increase glucose uptake at peripheral tissue

Type 1 Diabetes

Destruction of pancreatic islet B-cell

Prone to develop DKA if no insulin is given

Symptom:

Polyurea, polydipsia, and polyphagia

Weight loss, weakness, dry skin

Type 2 Diabetes

Results from insulin resistance with a relative defect in the secretion of insulin

Symptom:

Obesity, weight changes

Polyuria, fatigue

Gestational Diabetes

During pregnancy

Body increases insulin requirement because of metabolic change

Lead to hyperglycemia or impair glucose tolerance

Incidence 4% -- 30-60% prone to DM later in life

Type 1 Diabetes

Usually develops in childhood or early adulthood

Accounts for 10% of all diabetes patients

Presented very thin

Absolute lack of insulin

Prone to develop diabetic ketoacidosis if insulin is withheld

Onset is usually rapid

Pathogenesis

Etiology is unknown

Heredity

Viral infection

Autoimmune disease

Environmental

Normal Lab

Fasting plasma glucose <110

Postprandial plasma glucose <140

Casual plasma glucose<200

Hb A1c < 6%

1%=30mg/dl

Diagnosis

American Diabetes Association, 2000

Symptoms of diabetes plus random blood glucose concentration >11.1mmol/L (200mg/dl)

Fasting plasma glucose >7.0 mmol/L (120 mg/dl)

2 hour plasma glucose >11.1 mmol/L (200mg/dl) during an glucose tolerance test (75g)

Complications

Macrovascular Disease

Coronary heart disease

Hyperlipidemia

HTN

Stroke

Peripheral vascular disease

Microvascular Disease

Retinopathy

Nephropathy

neuropathy

Goals

Eliminate symptoms related to hyperglycemia

Tighter management of glucose control is beneficial

Harrison’s IM: "Comprehensive Diabetes care" to emphasize the fact that optimal diabetes therapy involve more than just glucose control

Reduce or eliminate long time microvascular or macrovascular complication

Allow patient to achieve a normal life style

Non-pharmacological Treatment

Type 1 Diabetes

Healthy daily nutrition to allow flexibility in insulin therapy and home monitoring

Na: <3g/d

Saturated fat to provide <10% kcal/d

Exercise

Improve insulin sensitivity

Lower plasma glucose during and after exercise

Insulin

Rapid acting Onset Duration

Lispro 0.25 5

Short acting

Regular 0.5 7

Intermediate acting

NPH 3 18

Lente 3 18

Long acting

Glargine 4 >24

Ultralente 8 22

Treatment in Type 1

In all regimen, long-acting insulin supplies basal insulin

Postprandial insulin provide by regular or lispro

Lispro : inject before meal

Reg: inject 30-45min before meal

Insulin Glargine Injection

Recombinant human insulin analog

Long Acting up to 24 hour duration

Constant concentration/time profile

No pronounce peak

QD Dosing

Indication and Usage

Once daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus

Adult patient with type 2 diabetes mellitus who require basal insulin for the control of hyperglycemia

Mechanism of Action

Regulation of glucose metabolism

Enhances protein synthesis

Lower blood glucose levels

Stimulating peripheral glucose uptake

Skeletal muscle and fat

Inh hepatic glucose production

How does Insulin Glargine Work?

Low aqueous solubility at neutral pH

At pH4, solution is completely soluble

After injection into the tissue, the acidic solution is neutralized

It forms micro precipitates

Small amounts of insulin glargine are slowly released

Continue

Resulting in a relatively constant concentration/time profile over 24 hours with no pronounce peak

Allows once-daily dosing as a patients basal insulin

Adverse Reaction

Allergic reaction

hypoglycemia

Injection site

Pruritus, rash

Drug Interaction

Drugs increases the blood glucose-lowering effect

ACE Inhibitor, fluoxetine, MAOI…

Drugs reduce the blood glucose-lowering effect

Corticosteroids, diuretics, sympathomimetic agents(albuterol, terbutaline, epinephrine)

Provides effective once daily bedtime dosing

Clinical Study

Type 1 diabetes mellitus – NPH

Pharmacokinetics and pharmacodynamics

Type 1 Study

Less hypoglycemia with insulin Glargine in intensive insulin therapy for type 1 diabetes

Author: Dr. Robert Retna

Journal: Diabetes Care, volume 23, number 5, May 2000

Type 1 Study:Objective

Purpose of Study

Compare insulin glargine with NPH human insulin in subjects with type 1 diabetes.

Examines the safety and efficacy of once-daily insulin glargine versus once or twice-daily NPH insulin as part of basal bolus insulin regimen in type 1 diabetes.

Type 1 Study: Design

N=534

Study Design

Multicenter randomized parallel-group study

Subjects were to receive premeal regular insulin

Subjects were randomized to received Glargine or NPH at bedtime

Duration of 28 weeks

Type 1 Study:Efficacy

Efficacy measure

Base line FBG, mean change from baseline

Base line Hgb A1c, mean change from baseline

Incidence of hypoglycemia with blood glucose level of <36mg/dl

All events

Severe hypoglycemia

Nocturnal hypoglycemia

Type 1 Study:Result

FBG

Significant reduction in median FPG levels from baseline

Glargine (-30.6) Vs NPH (-5.94)

Hgb A1c

Both Glargine(-0.16%) and NPH(-0.21%) have show decrease

Hypoglycemia event

Conclusion

Glargine significantly reduced morning FPG levels compared with NPH

Because hypoglycemia is the limiting factor in achieving normoglycemia, Glargine may be advantageous for improving glycemia control in the type 1 diabetic population

Kinetics and Dynamics Study

Pharmacokinetics and pharmacodynamics of subcutaneous injection fo long acting human insulin analog Glargine, NPH insulin, and Ultralente human insulin and continuous subcutaneous infusion of insulin lispro

By Dr. Geremia Bolli

Journal: Diabetes, vol 49, December 2000

Objective

Purpose of study

To establish the pahrmacokinetic and pharmacodynamic effects of an SC injection of a therapeutic dose of glargine, compared with NPH, ultralenteand CSII in type 1 diabetic patients.

Design

N=20

Study design:

The patients were initially studied on two occasions after SC injection of glargine or NPH, random sequence, crossover design

6-9 month later

Restudied on two additional occasions after SC injection of ultralente or CSII of Lispro, random sequence, crossover design

Conclusion

Guidelines for Ongoing Medical Care for Patients with Diabetes

Self monitoring of blood glucose

HbA1c testing

Patient education in diabetes management

Medical nutrition therapy and education

Eye examination

Foot examination