Diabetes Mellitus(Lecture 2)

Type 2 DM• 90% of diabetics (in USA)• Develops gradually • may be without obvious symptoms• may be detected by routine screening tests• BUT: many type 2 diabetics have symptoms of polyuria & polydepsia • Polyphagia is less common• In type 2 DM: a combination of insulin resistance & dysfunctional -cells

• Metabolic changes in type 2: are milder than type 1 as insulin secretion restrain ketoacidiosis (although not adequate)• Diagnosis: blood glucose concentration equal or more than 126 mg/dl

• Treatment : no requirement for insulin to sustain life BUT: insulin may be required to control hypoglycemia in some

Insulin resistance

• is the decreased ability of target tissues, such as liver, adipose tissue & muscle to respond properly to normal circulating insulin

• Examples of metabolic effects of insulin resistance:

- increased gluconeogenesis (liver synthesis of glucose) - decreased glucose uptake by muscles & adipose tissues

Causes of insulin resistance

• Insulin resistance increases with weight gain & diminishes with weight loss

• So, fat accumulation (OBESITY) causes insulin resistance as:

- substances produced by fat cells as leptin and resistin may contribute to development of insulin resistance - Free fatty acids elevated in obesity is involved in insulin resistance

Insulin resistance & obesity

• Obesity is the most common cause of insulin resistance

• However, most people with obesity & insulin resistance do not develop DM ??

in the absence of defect in -cell function, nondiabetic , obese

individuals can compensate for insulin resistance by: increasing levels of secretion of insulin from -cells

So, glucose levels in blood remain within normal range

Insulin resistance & type 2 DM

• Insulin resistance alone will not lead to type 2 DM.• BUT: type 2 DM will develop in individuals with: insulin resistance + impaired -cells function

• This is common to occur in: - elderly - obese - physically inactive - 3-5% of pregnant women (develop gestational DM)

All these are unable to sufficiently compensate by increasing insulin release

Dysfunctional -cells

In type 2 DMInitially (In early stages)

the pancreas retains -cell capacity

insulin is secreted (may be higher than normal)

normal blood glucose levels________________________________________________

With time (late stages)-cells become dysfunctional (fat cells substances , FFA & hyperglycemia)

-cells fail to secrete enough insulin

Increased blood glucose levels (hyperglycemia)

Progression of type 2 DM

Metabolic changes in type 2 DM

metabolic abnormalities of type 2 DM are the results

of insulin resistance (in liver, muscle & adipose tissue)

1- hyperglycemia (BUT: ketosis is minimal or absent) 2- hypertriacylglyceridemia

Metabolic changes in type 2 DM

Hyperglycemia in type 2 DM

• Causes: as a result of insulin resistance

1- increased gluconeogenesis (glucose production) by liver 2- diminished peripheral use of glucose _______________________________________________

Ketosis: usually minimal or absent because of the presence of insulin (even with resistance) is sufficient to prevent liver ketogenesis

Metabolic changes in type 2 DM

Hypertriacylglyceridemia in type 2 DM

insulin resistance (in adipose tissues)

active hormone sensitive lipase

Lipolysis

free fatty acids in liver

VLDL synthesis in liver

hypertriacylglyceridemia

Treatment of type 2 DM

• AIM:

1- to maintain blood glucose concentrations within normal limits 2- to prevent the development of long-term complications occurring due to prolonged hyperglycemia

• Lines of treatment: 1- weight reduction (to control insulin resistance) 2- exercise 3- dietary modification 4- hypoglycemic agents 5- insulin (required in some cases)

Chronic effects of DM

• The long-standing elevation of blood glucose (hyperglycemia) causes the chronic complications of DM

some complications of DM for long durations: 1- Atherosclerosis : retinopathy nephropathy neuropathy cardiovascular diseases & stroke 2- Sorbitol accumulation in certain cells ----- complications 3- Glycated proteins formation---- microvascular

complications

Chronic effects of DM (cont.)

in cells where entry of glucose is not dependent on insulin (eye lens, retina, kidney, neurones)

intracelluar levels of glucose

SORBITOL

Cataract diabetic retinopathy

diabetic nephropathy diabetic neuropathy

Chronic effects of DM (cont.)

Cellular glycated proteins formation:

• Hyperglycemia promotes condensation of glucose with many cellular proteins

• Glycated prioteins mediate some early microvacular changes of DM

Prevention of DM

For prevention of DM occurrence 1- type 1: no preventive measures available

2- type 2: combined regimen of medical nutritional therapy & exercise

For prevention of occurrence complications type 1 DM: tight control of may prevent complications (may prevent complications in DM type 2 also)