Human Physiology, 14th edition (2016)

682 Chapter 19

In addition to the lack of insulin, people with type 1 dia-

betes have an abnormally high secretion of glucagon from the

alpha cells of the islets. Glucagon stimulates glycogenolysis in

the liver and thus helps to raise the blood glucose concentra-

tion. Glucagon also stimulates the production of enzymes in

the liver that convert fatty acids into ketone bodies. The full

range of symptoms of diabetes may result from high glucagon

secretion as well as from the absence of insulin. The lack of

insulin may be largely responsible for hyperglycemia and for

the release of large amounts of fatty acids into the blood. The

high glucagon secretion may contribute to the hyperglycemia

and be largely responsible for the development of ketoacidosis.

Type 2 Diabetes Mellitus

The effects produced by insulin, or any hormone, depend on

the concentration of that hormone in the blood and on the sen-

sitivity of the target tissue to given amounts of the hormone.

Tissue responsiveness to insulin, for example, varies under

normal conditions. Exercise increases insulin sensitivity and

obesity decreases insulin sensitivity of the target tissues. The

islets of a nondiabetic obese person must therefore secrete high

amounts of insulin to maintain the blood glucose concentration

in the normal range. Conversely, nondiabetic people who are

thin and who exercise regularly require lower amounts of insu-

lin to maintain the proper blood glucose concentration.

Insulin resistance refers to a reduction in the target tis-

sue sensitivity to insulin. As long as a person’s pancreatic islets

secrete sufficient insulin, their insulin resistance can be over-

come and a normal plasma glucose level can be maintained. In

people with type 2 diabetes, however, the number and secretory

ability of beta cells diminish, resulting in failure to overcome the

insulin resistance. This indicates that type 2 diabetes involves

defects in beta cell function as well as an insulin resistance of

the target tissue. There is a strong heritable component: the con-

cordance of identical twins with type 2 diabetes is 70%. Also,

the risk of type 2 diabetes is almost 70% if both parents have it.

The expression of this genetic tendency toward diabetes

is increased by obesity. This is particularly true if the obesity

involves an “apple shape,” with large adipocytes in the greater

omentum (visceral fat). Visceral obesity, and the accumulation

of ectopic fat (fat deposited in skeletal muscles and the liver, as

opposed to subcutaneous adipose cells) are associated with insu-

lin resistance, type 2 diabetes, and metabolic syndrome (discussed

in section 19.2). Insulin resistance is promoted by fatty acids

and diacylglycerol from ectopic fat, and by adipokines released

by adipocytes. There is also a chronic, low-grade inflammation

produced by excessive fat within muscles, the greater omentum,

and the liver that promotes insulin resistance. As a result, mac-

rophages within these organs release pro-inflammatory cytokines

that promote insulin resistance.

In type 2 diabetes, insulin resistance prevents the alpha cells

of the pancreatic islets from being inhibited by the higher blood

glucose. The alpha cells thereby secrete more glucagon than

they normally would, which stimulates hepatic glycogenolysis

and gluconeogenesis. These processes provide free glucose that

twins. Because the incidence of type 1 diabetes is increasing
faster than can be accounted for by genetics, it appears that envi-
ronmental factors play a triggering role in genetically susceptible
people. Viruses are prominent among the environmental factors
that may trigger an autoimmune attack of the islet beta cells.
Autoreactive T lymphocytes—helper and killer T cells—are
believed to be most important in the progressive destruction of
the insulin-secreting beta cells, although autoantibodies appear
early in the course of the disease and aid diagnosis.
Removal of the insulin-secreting beta cells causes hyper-
glycemia and the appearance of glucose in the urine. Without
insulin, glucose cannot enter the adipose cells; the rate of fat
synthesis thus lags behind the rate of fat breakdown and large
amounts of free fatty acids are released from the adipose cells.
In a person with uncontrolled type 1 diabetes, many of the
fatty acids released from adipose cells are converted into ketone
bodies in the liver. This may result in an elevated ketone body
concentration in the blood (ketosis), and if the buffer reserve
of bicarbonate is neutralized, it may also result in ketoacidosis.
During this time, the glucose and excess ketone bodies that are
excreted in the urine act as osmotic diuretics and cause the exces-
sive excretion of water in the urine (chapter 17, section 17.6).
This can produce severe dehydration, which, together with keto-
acidosis and associated disturbances in electrolyte balance, may
lead to coma and death ( fig. 19.11 ).

Table 19.5 | Comparison of Type 1 and
Type 2 Diabetes Mellitus

Feature Type 1 Type 2

Usual age at onset Under 20 years Over 40 years

Development

of symptoms

Rapid Slow

Percentage of

diabetic population

About 5% About 95%

Development

of ketoacidosis

Common Rare

Association with

obesity

Rare Common

Beta cells of islets

(at onset of disease)

Destroyed Not destroyed

Insulin secretion Decreased Normal or increased

Autoantibodies

to islet cells

Present Absent

Associated with

particular MHC

antigens*

Yes Unclear

Treatment Insulin injections Diet and exercise;

oral stimulators of

insulin sensitivity

*Discussed in chapter 15, section 15.3.