The development of late onset
non-insulin dependent diabetes mellitus (
NIDDM) is due to a complicated interplay between genes and environment on one side, and the interaction between metabolic defects in various tissues including the pancreatic beta cell (decreased insulin secretion), skeletal muscle (
insulin resistance), liver (increased gluconeogenesis), adipose tissue (increased lipolysis) and possibly gut
incretin hormones (defective
glucagon like peptide 1 (GLP1) secretion) on the other side. Evidence for a genetic component includes the finding of a variety of metabolic defects in various tissues in non-diabetic subjects with a
genetic predisposition to
NIDDM, higher concordance rates for abnormal
glucose tolerance including
NIDDM in monozygotic compared with dizygotic twins, and the more recent demonstration of different
NIDDM susceptibility genes at the sites of
Insulin Receptor Substrate 1 (IRS1), the beta-3
adrenergic receptor, and the
sulfonylurea receptor. However, the latter susceptibility genes only explain a minor proportion of
NIDDM in the general population, and the quantitative extent to which genetic versus non-genetic factors contribute to
NIDDM is presently unsolved. Environmental components include both an early intrauterine component associated with low birth weight, and later postnatal components including low physical activity, high fat diet, and the subsequent development of
obesity and elevated plasma and tissue
free fatty acid levels. Our finding of lower
birth weights in monozygotic twins compared with their non-diabetic genetically identical co-twins excludes the possibility that the association between
NIDDM and low birth weight as demonstrated in several studies may solely be explained by a coincidence between a certain gene causing both a low birth weight and an increased risk of
NIDDM. Young first degree relatives of patients with
NIDDM are characterized by hyperinsulinaemia and peripheral
insulin resistance, which in turn may be explained by a decreased
insulin activation of the
enzyme glycogen synthase in skeletal muscle. Therefore, a defective skeletal muscle
glycogen synthase activation may represent an early phenotypic expression of a genetic defect contributing to an increased risk of later development of
NIDDM. However, elderly
insulin resistant non-diabetic co-twins (64 years old) of twins with overt
NIDDM does not--in contrast to their
NIDDM co-twins--have a significantly decreased
insulin activation of
glycogen synthase in skeletal muscle. This demonstrates that the defective muscle
glycogen synthase insulin activation has an apparent non-genetic component, and that this key defect of metabolism can be escaped or postponed even in non-diabetic subjects with a presumably 100%
genetic predisposition to
NIDDM. The
insulin activation of
glycogen synthase in skeletal muscle is compensated or apparently normalised in
NIDDM patients when studied during their ambient fasting hyperglycaemia and a subsequent isoglycaemic (hyperglycaemic) physiologic
insulin infusion. This indicates that the prevailing hyperglycaemia in
NIDDM subjects compensates for the defective
insulin activation of
glycogen synthase present in those subjects when studied during eulycaemia. Our data and those of others also indicates that hyperglycaemia in
NIDDM compensates for the defects in insulin secretion, the disproportionately elevated hepatic
glucose production, and to some extent for the increased
lipid oxidation and the decreased
glucose oxidation present in
NIDDM patients. Accordingly,
NIDDM subjects exhibit all of those defects of metabolism when studied during "experimental decompensation" when the ambient hyperglycaemia is normalized by a prior and later withdrawn intravenous
insulin infusion. However, shortly after the withdrawal of the intravenous
insulin infusion, the plasma
glucose concentration increased spontaneously in the
NIDDM patients. (ABSTRACT TRUNCATED)