Genetics
NIDDM is known to occur more often in some families than others. Recent
advances have led to a better understanding of how insulin is produced
and released have led to the discovery of several genes that cause diabetes
in a small proportion of affected families. A major effort is now underway
to discover the other genes that cause diabetes in the majority of patients.
Researchers have announced that they have identified mutations in at
least 3 genes involved in the subset of Type 2 called MODY (Maturity -
Onset - Diabetes of the Young), which tends to be diagnosed prior to age
25, and there are some mitochondrial disorders implicated in some types
of Type 2 diabetes, but the cause for the majority of people with Type
2 diabetes does not seem well-understood.
Aging and obesity are commonly identified risk factors for diagnosis
of Type 2 diabetes but these are correlations not causes; we do know that
it is a genetically- or congenitally-based disease and that predisposing
genes are necessary. In fact, the correlation among identical twins for
Type 2 diabetes is virtually 100%.
An abstract of a report entitled "Epidemiologic studies on the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM)" by M.I. Harris of the National Diabetes Data Group, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, published in Clin Invest Med, 1995Aug, 18:4, 231-9 stated:
"The diagnostic criteria of the US National Diabetes Data Group and the World Health Organization have stimulated a major increase throughout the world in epidemiologic studies on the pathogenesis of non-insulin- dependent diabetes mellitus (NIDDM). They have established that much of NIDDM is undiagnosed, that onset of NIDDM occurs at least 7 years before its diagnosis, and that significant morbidity and premature mortality occur in subjects with undiagnosed diabetes. New studies have shown that rural or traditional-living populations are experiencing a major increase in the burden of NIDDM as they move to urban or nontraditional situations, often with 5- to 10-fold increases in NIDDM prevalence. Epidemiologic studies have documented that major risk factors for NIDDM include increasing age, greater obesity, longer duration of obesity, unfavourable body fat distribution, physical inactivity, and hyperinsulinemia. All these factors interact with unknown genetic factors to produce NIDDM. Studies have shown that genes for diabetes, as yet undetermined, are a necessary cause of NIDDM"
For more information on the genetic causes to Type II Diabetes, check
out Diabetes
& Hypoglycemia Forum
Diet
Hyperinsulinemia exists in childhood in populations at high risk for
NIDDM. Stimulated by obesity, upper body obesity, and physical inactivity,
insulin resistance develops, accompanied by impaired glucose tolerance.
The pressure of the NIDDM risk factors continues this process of insulin
resistance/hyperinsulinemia/hyperglycemia, until glucose toxicity to the
beta cell results in inability to secrete sufficient insulin, resulting
in decompensated fasting hyperglycemia."
The March 21, '96 issue of the New England Journal of Medicine had an article by Kenneth Polonsky, M.D.,J Sturis, PhD., & G Bell, PhD., entitled "Non-Insulin-Dependent Diabetes Mellitus -- A Genetically Programmed Failure of the Beta Cell to Compensate for Insulin Resistance." In this article, the authors noted that, although "the majority of people with insulin resistance do not become diabetic," it is "the failure of the beta cell to continue to hypersecrete insulin thus underlies the transition from insulin resistance with compensatory hyperinsulinemia to impaired glucose tolerance...and then to clinical diabetes with overt hyperglycemia. Whether there is a causal relation between insulin resistance and beta failure in persons predisposed to NIDDM or whether these variables are independent are unknown."
They note that a number of molecular defects have been associated with insulin resistance, including "reduced expression of insulin receptors on the surface of insulin-responsive cells, alterations in the signal-transduction pathways that become activated after insulin binds to the receptor, and abnormalities in biological pathways normally stimulated by insulin, including glucose transport and glycogen synthesis." They add that, "Mutations in the insulin-receptor gene are responsible for insulin resistance in a limited number of persons, but the molecular basis of insulin resistance in the vast majority of persons with NIDDM remains unknown."
They write, ""Abnormalities of insulin secretion in persons with overt NIDDM include reduced or absent first-phase responses to intravenous glucose, delayed and blunted secretory responses to ingestion of a mixed meal, alterations in the rapid pulses and ultradian oscillations of insulin secretion, and increases in the plasma concentrations of proinsulin-like peptides relative to those of insulin." Dr. Polonsky also explained that "...we believe that by the time overt hyperglycemia develops, severe and diffuse defects are present in the beta cell. Although some improvements in beta-cell function is still possible at this stage with improvement in glucose control, the process is probably largely irreversible."
Other
Environmental Factors
A number of researchers, particularly those in the U.K., have been
reporting on interesting epidemiological studies of Type 2 diabetics, which
suggest that prenatal environment may have a significant role in the causation
of Type 2 diabetes, as well as hypertension. More than 20 studies have
shown that lightweight babies, babies who are long and thin at birth, or
those who are short and have disproportionately small bellies grow into
adults with high blood pressure, elevated cholesterol, high blood sugar
levels, and increased risk of dying from cardiovascular disease. In one
study of 15,000 adults in Hertfordshire, men who weighed less than 2.5
kg (5.5 lbs) at birth were found to have 3 times the incidence of Type
2 diabetes than men born weighing more than 4.5 kg (9.9 lbs). Several hypotheses
have been developed about this idea, including that maternal glucocorticoids
reprogram the fetal hormone system, or that maternal deprivation at the
end of pregnancy when the liver is forming affects its development and
leads to NIDDM.
