Human Physiology, 14th edition (2016)

Regulation of Metabolism 685

CLINICAL APPLICATION

Metformin ( Glucophage ) is the most widely used drug for

treating type 2 diabetes and is effective in reducing glycated

hemoglobin levels. Metformin lowers blood glucose primarily

by inhibiting hepatic gluconeogenesis, reducing the ability of

the liver to generate and secrete glucose. Another antidia-

betic drug is sulfonylurea, which closes the ATP-gated K^1

channels on pancreatic islet beta cells. This depolarizes them

and opens the voltage-gated Ca^2 1 channels in the plasma

membrane, which stimulates insulin secretion as previously

described. The thiazolidinediones ( pioglitazone and rosi-

glitazone ) are a newer class of antidiabetic drugs that act to

reduce the insulin resistance of the target cells.

Inflammatory pathways within adipose tissue, liver, and

muscles contribute to insulin resistance. The thiazolidinedio-

nes increase the sensitivity of target tissues to insulin by acti-

vating the PPAR g nuclear receptors in both adipocytes and

macrophages. This can alter the secretion of pro-inflammatory

cytokines from macrophages and the secretion of adipokines

from adipocytes in a way that decreases insulin resistance.

Specifically, the secretion of TNF a , interleukin-1, and resistin

(which promote insulin resistance) are decreased, while the

secretion of adiponectin (which reduces insulin resistance) is

increased.

after a carbohydrate meal. This reactive hypoglycemia, caused

by an exaggerated response of the beta cells to a rise in blood

glucose, is most commonly seen in adults who are genetically

predisposed to type 2 diabetes. For this reason, people with reac-

tive hypoglycemia must limit their intake of carbohydrates and

eat small meals at frequent intervals, rather than two or three

meals per day.

The symptoms of reactive hypoglycemia include tremor, hun-

ger, weakness, blurred vision, and mental confusion. The appear-

ance of some of these symptoms, however, does not necessarily

indicate reactive hypoglycemia, and a given level of blood glucose

does not always produce these symptoms. Diagnosis of reactive

hypoglycemia is controversial, but an accepted criterion is a blood

glucose concentration of less than 70 mg/dl when a person is expe-

riencing hypoglycemic symptoms and a relief from these symp-

toms by a rise in blood glucose following a carbohydrate meal. In

the oral glucose tolerance test, for example, reactive hypoglycemia

is shown when the initial rise in blood glucose produced by the

ingestion of a glucose solution triggers excessive insulin secretion,

so that the blood glucose levels fall below normal within five hours

( fig. 19.13 ). This test is no longer used because of the danger that it

can trigger hypoglycemic symptoms.

Clinical Investigation CLUES

The physician told Marty that he needed to lose weight

and exercise, and that he had a fasting plasma glucose

concentration of 120 mg/dL.

• What does Marty’s fasting plasma glucose
  concentration indicate?


• How could weight loss and exercise help?


• What type of diabetes might Marty get, and what
  are its characteristics?


• What types of medications might Marty have to take
  if he gets diabetes?

Figure 19.13 Reactive hypoglycemia. An

idealized oral glucose tolerance test on a person with reactive

hypoglycemia. The blood glucose concentration falls below the

normal range within five hours of glucose ingestion as a result

of excessive insulin secretion. Because this can be dangerous,

the oral glucose tolerance test is no longer used for diagnosis of

reactive hypoglycemia.

Normal range

Hypoglycemia

Hours after oral glucose

12345

Blood glucose(mg/100 ml)

150

100

50

Hypoglycemia

A person with type 1 diabetes mellitus depends on insulin injec-
tions to prevent hyperglycemia and ketoacidosis. If inadequate
insulin is injected, the person may enter a coma as a result of the
ketoacidosis, electrolyte imbalance, and dehydration that develop.
An overdose of insulin ( insulin shock ), however, can also produce
a coma as a result of the hypoglycemia (abnormally low blood
glucose levels) produced. The physical signs and symptoms of
diabetic and hypoglycemic coma are sufficiently different to allow
hospital personnel to distinguish between these two types.
Less severe symptoms of hypoglycemia are usually pro-
duced by an oversecretion of insulin from the islets of Langerhans

| CHECKPOINT

10a. Explain how ketoacidosis and dehydration are

produced in a person with type 1 diabetes mellitus.

10b. Describe the causes of hyperglycemia in a person

with type 2 diabetes. How may weight loss help to

control this condition?

11. Explain the meaning of the terms insulin resistance,
    impaired glucose tolerance, and reactive
    hypoglycemia.