1.

PATOFISIOLOGI

DM Tipe 1

Type 1 DM is characterized by an absolute deficiency of pancreatic -cell function. Most often this is the
result of an immunemediated destruction of pancreatic cells, but rare unknown or idiopathic processes
may contribute. In immune mediated, a potential disruption of the T-helper 1/T-helper 2 balance may
lead to higher T-helper 1 activity, with subsequent activation of the immune system and eventual
destruction of pancreatic cell. What is evident are four main features: (1) a long preclinical period
marked by the presence of immune markers when cell destruction is thought to occur; (2)
hyperglycemia when 80% to 90% of cells are destroyed; (3) transient remission (the so-called
honeymoon phase); and (4) established disease with associated risks for complications and death.
Unknown is whether there is one or more inciting factors (e.g., cows milk, or viral, dietary, or other
environmental exposure) that initiate the autoimmune process 2 ( Fig. 834 ). Vitamin D deficiency has
been observed to be more prevalent in patients who develop type 1 DM, and

potential mechanisms, including a role of vitamin D in reduction of interferon- and several interleukins,
have been proposed. Observational data supports a potential role, but further study is needed.

The autoimmune process is mediated by macrophages and T lymphocytes with circulating

autoantibodies to various cell antigens. The most commonly detected antibody associated with type 1
DM is the islet cell antibody. The test for islet cell antibody, however, is difficult to standardize across
laboratories. Other more readily measured circulating antibodies include insulin autoantibodies,
antibodies directed against glutamic acid decarboxylase, insulin antibodies against islet tyrosine
phosphatase, and several others. More than 90% of newly diagnosed persons with type 1 DM have one
or another of these antibodies, as will 3.5% to 4% of unaffected first-degree relatives. Preclinical -cell
autoimmunity precedes the diagnosis of type 1 DM by up to 9 to 13 years. Autoimmunity may remit in
some perhaps less-susceptible persons, or can progress to -cell failure in others. These antibodies are
generally considered markers of disease rather than mediators

of -cell destruction. They have been used to identify individuals at risk for type 1 DM in evaluating
disease prevention strategies. Other nonpancreatic autoimmune disorders are associated with type 1
DM, most commonly Hashimoto thyroiditis, but the extent of organ involvement can range from no
other organs to polyglandular failure.

There are strong genetic linkages to the DQA and B genes and certain human leukocyte antigens (HLAs)
may be predisposing ( DR3 and DR4 ) or protective ( DRB1*04008-DQB1*0302 and DRB1*0411-
DQB1*0302 ) on chromosome 6. 18 Other candidate gene regions have been identified on several other
chromosomes as well. Because twin studies do not show 100% concordance, environmental factors such
as infectious agents, chemical agents, and dietary agents are likely contributing factors in the expression
of the disease.

Destruction of pancreatic -cell function causes hyperglycemia due to an absolute deficiency of both
insulin and amylin. Insulin lowers blood glucose by a variety of mechanisms, including stimulation of
tissue glucose uptake, suppression of glucose production by the liver, and suppression of free fatty acid
(FFA) release from fat cells. The suppression of free fatty acids plays an important role in glucose
homeostasis. Increased levels of free fatty acids inhibit the uptake of glucose by muscle and stimulate
hepatic gluconeogenesis. Amylin, a glucoregulatory peptide hormone cosecreted with insulin, plays a
role in lowering blood glucose by slowing gastric emptying, suppressing glucagon output from pancreatic
alpha cells, and increasing satiety. In type 1 DM, amylin production, due to -cell destruction, is very
low.