Prediction of type 2 diabetes: A

natural history perspective

Bulanga L. Nyomba
Department of Internal Medicine, Facutly of Medicine and Health Sciences, UAE
University, Al Ain, United Arab Emirates.
Introduction
Type 2, non-insulin dependent diabetes mellitus (NIDDM) is the most common form
of diabetes and one of the most frequent metabolic disorders worldwide. About 5% of
individuals of European ancestry are affected, while epidemics of NIDDM have
recently appeared among non-white populations that have traditionally lived in harsh
environmental conditions, once they had adopted a modern lifestyle.
1
In such
populations, which may soon include many rapidly developing middle eastern
countries. the prevalence of NIDDM may be as high as 50% among the adults. In the
relatively lower risk of Caucasian populations, the plasma glucose concentrations
display a near-normal distribution.2 In high-risk populations such as Pima Indians of
South-Western Arizona, USA, and the Mrcronesians of the South Pacific Island of
Nauru, the frequency distribution of plasma glucose concentrations is bimodal, and
the intersection of the two modes occurs near a plasma glucose concentration of 7.8
mmol/l fasting or 11.1 mmol/ 1 2 hours after an oral glucose tolerance test (OGTT).
Furthermore, there is an increased frequency of microvascular diseases in the second
mode, justifying the choice of these cut-off points for the diagnosis of diabetes.
The bimodal distribution of the plasma glucose concentration also means that diabetes
in these populations might be caused by a major gene with a high frequency in the
populations.3,4 This disorder is clearly becoming a burden to the public health
systems of developing countries, causing an excess morbidity and mortality mainly
through cardiovascular and cerebrovascular complications. NIDDM is believed to be
a genetic disorder, whose expression is greatly affected by environmental factors.5
This disorder has an insidious onset and its characteristic over hyperglycaemia is
preceded by a period of normoglycaemia associated with hyperinsulinaemia,6 which
in itself is associated with macrovascular complications.7 Hyperglycaemia results
from a combination of insulin resistance (decreased effectiveness of insulin on its
target tissues) and impaired glucose secretion. 6,8 Predicting this disorder at an early
stage would help to initiative preventive measures, thus avoiding the morbidity and
mortality associated with chronic hyperinsulinaemia and hyperglycaemia.
Abnormalities found in both clinically overt disease and its prodromal phase could be
used to identify those subjects who are likely to manifest overt hyperglycaemia during
their lifetime. It would be most beneficial, however, to identify genetic carriers when
no physiological alterations are present, i.e. at the time when environmental triggers
can be avoided. In this paper, I will discuss the possibility of predicting NIDDM in
the light of its natural history.
Natural history of Type 2 Diabetes
Cross-sectional and longitudinal studies in Pima Indians, Nauruans, and other
populations have all found that type 2 diabetes progresses to overt hyperglycaemia
through a series of characteristic stages. 6,8-10. A plot of plasma insulin levels versus
glucose concentrations shows an inverted U relationship. Within the normoglycaemic
range increasing plasma glucose levels are associated with increasing insulin
concentrations. In the diabetic range, however, increasing glucose levels are
associated with a progressive decrease in the plasma insulin concentrations. Maximal
insulin concentrations typically correspond to glucose levels that define a category of
glucose intolerance intermediate between normal and diabetic, viz. Impaired Glucose
Tolerance (IGT). Plasma glucose level in IGT is below 7.8 mmol/1 fasting, but
between 7.8 and 11.1 two hours after ingestion of 75 grams of glucose.11 Studies
using euglycemic hyperinsulinaemic clamp techniques to measure insulin sensitivity
have demonstrated that the ascending, hyuperinsulinaemic limb of the inverted U-
curve is caused by the development of tissue insulin resistance, mainly in the skeletal
muscle, and that hyperinsulinaemia at this stage is very compensatory response to
preserve normoglycaemia.. 6,12 Insulin resistant subjects also have low metabolic
rate,13 in spite of their hyperinsulinaemia probably because of the insulin resistance
of muscle, the metabolically most active tissue. As a result, the development of IGT is
usually associated with increasing body weight.
Insulin resistance in type 2 diabetes.
The total amount of glucose metabolized by the whole body in response to insulin
(insulin-mediated glucose metabolism) is reduced by about 40% in NIDDM
compared with normal subjects.6,8 Insulin mediated glucose metabolism is also
reduced in normoglycaemic subjects at high risk for developing diabetes, eg. first-
degree relatives of NIDDM patients, indicating pre-diabetic insulin resistance. 14,15
In a longitudinal study of Pima Indians the development of IGT was associated with a
worsening of insulin resistance, but the same degree of insulin resistance was present
during the transition from IGT to NIDDM.6 In addition, insulin resistance in this
population may be genetically determined.16-18
The whole body glucose metabolism is mainly explained by its metabolism in skeletal
muscle.19 Cellular pathways of glucose metabolism in this tissue have therefore been
explored. In normal target cells, insulin action is initiated by insulin binding to its
receptor in the plasma membrane. This is followed by activation of receptor-
associated tyrosine kinase, which then initiates a cascade of reactions ending in
glucose metabolism. 20,21 Under the influence of insulin a glucose transporter
(GLUT4) present in muscle and fat cells facilitates glucose entry in to the cells, 22
while glycogen synthetase present in muscle and liver synthesizes glycogen from the
glucose.23,24. In muscle, the insulin receptor tyrosine kinase has a low activity in
NIDDM, but not in prediabetic insulin resistance, indicating that the kinase defect is
secondary to the diabetic state.25,26 The stimulation of glycogen synthetase by
insulin is defective in NIDDM as well as in prediabetic insulin resistance. 27-29
Moreover, our more recent studies in Pima Indians show a reduced activity of muscle
type-1 protein phosphatase, an enzyme that activates glycogen synthetase upon
insulin stimulation.
Insulin secretion in Type 2 Diabetes
In most NIDDM patients the plasma concentrations of insulin in the fasting state and
in response to glucose are usually in the normal range when considered in terms of
absolute values.8,32 In fact, these insulin values are low for the prevailing glucose
levels, and the inverted U-curve clearly shows a loss of the normal positive
relationship between plasma glucose levels and insulin concentrations. Moreover, the
insulin values in NIDDM are clearly subnormal when corrected for the cross-
reactivity of proinsulin in the insulin assay. The early phase of insulin release during
both the OGTT and intravenous glucose tolerance test (IVGTT) is reduced and the
overall insulin release is delayed, which may contribute to the delay in post-prandial
glucose metabolism in NIDDM. The early insulin response to non glucose
secretagogues is not affected, but the glucose potentiation of the pancreatic response
to these secretagogues is impaired.33 This selective glucose insensitivity is thought
to result from the down-regulation of the beta-cell glucose-transporter (GLUT 2) by
hyperglycemia ( a mechanism known as glucose toxicity). GLUT2 constitutes with
the enzyme glukokinase the so called pancreatic glucose sensor system. 22,34 A
new dimension of the pancreatic function was introduced by studies of the pulsatility
of insulin secretion. Normal insulin secretion displays a pattern of rapid oscillations
occurring every 10-15 minutes, and large-amplitude pulses released every 1-3 hours
mostly during the post-prandial period. Subjects with NIDDM do not have this
normal pattern of insulin delivery, which is thought to maximize insulin effectiveness:
the rapid oscillations are gone and the post-prandial pulses are small and
irregular.35,36
Whether the pancreatic beta-cell function is normal in prediabetes is still
controversial. In most subjects with prediabetic insulin resistance neither the first not
the second phase of insulin secretion is reduced, there is a charecteristic
hyperinsulinaemia both in the fasting state and after glucose stimulation. 6,14
Recently, however, Mitrakou et al37 reported reduced insulin levels 30 minutes after
the ingestion of glucose in subjects with IGT. In fact, many of these subjects had a 2-
hour plasma glucose of more than 11.1 mmol/l, i.e. diagnostic of diabetes.11 Also
ORahilly et al 35 reported abnormal pulsatile insulin secretion in first-degree
relatives of patients with NIDDM at a time when their first-phase insulin response to
intravenous glucose was still normal. Insulin sensitivity was not measured in this
study. Since these subjects had (mild) glucose intolerance, they were probably also
insulin resistant.
Predictor of Type 2 diabetes
It appears from the above discussion that the natural history of type 2 diabetes evolves
in 4 main stages: genetic susceptibility, insulin resistance, IGT and overt diabetes.
The temporal profile of insulin secretion in NIDDM, on the other hand, exhibits 3
main features: loss of pulsatility, disappearance the first phase, and diminished
responsiveness to glucose. Eriksson et al14 have shown that insulin resistance
precedes the alterations of the first-phase insulin secretion, leaving insulin resistance
and loss of insulin secretion pulsatility as the earliest functional lesions in the course
of type 2 diabetes. Which comes first, the loss of beta-cell pulsatility or insulin
resistance, is still uncertain. Also whether only insulin resistance or beta-cell
dysfunction or both abnormalities are genetically determined is still debated.
A.Clinical and Physiological Predictors of NIDDM
Since the period preceding overt hyperglycemia is accompanied by physiological
alterations (obesity, hyperinsulinemia, impaired glucose tolerance), these have been
used as predictors of NIDDM in a few studies. It is a common belief that obesity,
especially central or truncal obesity, predisposes to NIDDM. Studies in high risk
populations have found that the predictive power of obesity for diabetes becomes
negligible when other predictors such as plasma glucose and insulin, i.e. metabolic
factors related to insulin resistance, are taken in to account. 38,39
Insulin secretion pulsatility has not been used in predicting type 2 diabetes. However,
Warram et al 40 found that, in contrast with glucose disposal rate (a measure of
insulin action), the acute insulin response does not predict diabetes in glucose tolerant
offspring of diabetic parents. In contrast, in individuals who already have IGT,
hypoinsulinaemia predicts the development of NIDDM, as shown in Pima Indians,
Nauruans, Japanese and Caucasians.32 In other studies, hypoinsulinaemia was less
powerful predictor than insulin resistance, 41 offering support for the hypothesis that
it is insulin resistance that remains the most important determinant of the development
of type 2 diabetes. Plasma glucose concentration is a predictor of diabetes; the higher
the glucose concentration the higher the risk of developing diabetes. In particular, IGT
individuals have about a 6-fold increased risk of developing diabetes compared with
individuals with normal glucose tolerance.3,4,39
Fasting plasma insulin levels have been found to predict the development of diabetes
in Pima Indians, 41 Pacific Islanders3 and Mexican Americans.39 Subjects with
fasting hyperinsulinaemia have about a 7-fold increased risk of developing diabetes.
The predictive power of hyper insulinaemia is no longer statistically significant when
insulin resistance, as measured in vivo by clamp techniques, is taken into account.
Studies using clam s in Pima Indians have demonstrated that insulin resistance per se
is an independent predictor of the development of NIDDM.41 Clamp techniques are
still considered too specialized and time consuming for clinical use. The simpler
modified IVGTT may be an earlier substitute in the clinical setting, as it measures
insulin sensitivity with a comparable accuracy.42 Assay of enzymes of the insulin
action pathways may soon become available for the detection of insulin resistance.
B. Genetic predictors of type 2 diabetes
Genetic factors significantly contribute to the development of type 2 diabetes. The
disorder shows a strong familial aggregation and 10 to 30% of first degree relatives of
diabetic individuals are affected. The prevalence of this disorder varies among
different ethnic groups living in the same environment. More importantly, its
concordance rate has been found to be about 100% among monzygotic twins, whid 10
to 30% in dizygotic twins. 43,44 A recent population survey in Finland, however,
suggests that the concordance rate of NIDDM in identical twins may be much lower
than previously thought.45 Thus, although NIDDM is believed to be caused by a
major gene in some populations, this may not be universal, and its mode of
inheritance remains unknown. There is no clear association with the HLA system as
in type 1 diabetes.44
Analysis of molecular genetic materials has been pursued in recent years, mainly
based on genes that code for known pathways of insulin secretion (insulin, GLUT2,
glukokinase) and insulin action (insulin receptor, GLUT4, glycogen synthase), the
so-called candidate genes. Polymorphism or mutations were rarely found in most
go these genes in NIDDM subjects.43,44,46 Recently, polymorphisms in the
glycogen synthetase47 and the glukokinase 48-50 genes were reported in subsets of
NIDDM subjects but for the majority of the patients no genetic information is
available.
Conclusion
For the clinicians, early prediction of NIDDM is based on historical data such as
obesity and parental diabetes. The predictive power could be increased by additional
diagnostic techniques such as OGTT or modified IVGTT with a determination of
plasma insulin. IGT with its associated hyperglycaemia and hyperinsulinaemia is
currently the best predictor of NIDDM. Future developments may allow routine
assays of insulin-responsive enzymes such as glycogen synthase and type-1 protein
phosphatase, whose biochemical defects are demonstrated early in the course of type
2 diabetes.
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