Pathophysiology of type 2 DM
Type 2 diabetes is a heterogeneous condition resulting from a combination of reduced insulin secretion and increased requirement for insulin: the relative contribution of each varies from one individual to another. Insulin secretion tends to decline with increasing age, and this may reflect the role of diabetes-associated genes, most of which influence beta cell function rather than tissue sensitivity to insulin. Possible added factors include a reduced incretin effect and deposition of IAPP (islet-associated amyloid peptide) in and around the islets. Diabetes does not develop in individuals with healthy insulin secretory capacity. Insulin resistance - an increased threshold for response to insulin in cells and tissues - is mainly located within skeletal muscle, liver, and fat. The proximate cause of hyperglycaemia is overproduction of glucose by the liver and reduced glucose uptake in peripheral tissues due to insulin resistance. Insulin secretion is increased in the earlier stages of diabetes, but declines with increasing duration as a consequence of progressive beta cell failure. Other potentially important mechanisms associated with type 2 diabetes and insulin resistance include an increase in circulating glucagon, abnormalities of lipid metabolism including increased deposition within cells, and effects mediated by the central nervous system.
The beta cell is derived from neural crest tissue and resembles a neuron in may respects including, for example, release of stored granules in response to depolarization of the membrane. The capacity for beta cell regeneration is reduced or lost in adults, and a decline in beta cell mass is seen with increasing age in parallel with the increasing risk of diabetes. This decline might be influenced by diabetes-associated genes which play a role in beta cell maintenance and function.
Pattern of insulin secretion in type 2 diabetes:
The altered homeostasis of type 2 diabetes is reflected in the parallel increase of fasting plasma glucose and insulin. For whatever reason, the increase in insulin secretion seen in the early stages of type 2 diabetes lags behind the amount needed to normalize glucose levels, and it has been suggested that the increased glucose drive is necessary to maintain insulin secretion.
Insulin output by the pancreas increases to a peak as diabetes develops, but fails progressively thereafter; the timescale can vary markedly from one person to another. This sometimes referred to as "the Starling curve of the pancreas".
Insulin is released from the beta call mass in synchronized packets rather than continuously, and has greater effect upon the liver when delivered in this manner. Loss of synchronized insulin release occurs at an early stage in the development of hyperglycaemia and may be one of the factors contributing to so-called glucose toxicity.
A further change in the pattern of insulin secretion is in that the physiological first phase of insulin release observed in response to the intravenous glucose tolerance test (IVGTT) is blunted at prevailing glucose levels greater than ~6 mmol/l (110 mg/dl). A corresponding change occurs in the second phase insulin response, which becomes progressively exaggerated and delayed, in response to a glucose challenge.
GLP-1 and GIP are insulin secretagogues released from intestinal cells in response to feeding. They potentiate insulin release from pancreatic beta cells, and their release is impaired in type 2 diabetes, although this may be a consequence rather than a cause of the condition. See Incretins.
IAPP (insulin-associated amyloid polypeptide):
It was noted early in the 20th century that hyaline material accumulates in and around the islets of people with type 2 diabetes. This was later shown to be associated with precipitation of insoluble polymers of IAPP, which appear to be harmful and may compromise beta cell function.
Insulin resistance is sometimes described as if it were a physiological condition rather than a relative term which only has real meaning when applied to a specific experimental situation. Thus, for example, the term can be applied to the behaviour of isolated cells, of specific organs, or of the whole body. Its causes range from hormonal antagonism (glucagon, cortisol etc), increased levels of NEFA, sympathetic drive, cytokine release, tissue inflammation, and ectopic fat accumulation. These are briefly summarized below.
Insulin is the leader of the endocrine orchestra; almost all other hormones with a metabolic effect achieve this by modulating insulin's spectrum of action. This is why they are often referred to as counter-regulatory hormones. Glucagon is the partner hormone of insulin regulating the hepatic release of glucose, and increased glucagon release plays an important role in the pathophysiology of type 2 diabetes.
Increased secretion of counter-regulatory hormones is a major feature of tissue injury, and is largely responsible for the increased insulin resistance and transient hyperglycaemia associated with physical stress.
Low grade tissue inflammation is recognised as a consequence of obesity, and causes the release of inflammatory cytokines including tumour necrosis factor-α (TNFα) and resistin which antagonize the effect of insulin.
NEFA (non-esterified fatty acids)
Skeletal muscle takes up NEFA in preference to glucose via the Randle glucose-fatty acid cycle, and as a result glucose uptake into muscle is inhibited in the presence of high circulating levels of NEFA, resulting in insulin resistance. NEFA output is increased in obesity, thus contributing to the insulin resistance seen in this condition.
In experimental animals, enhanced activation of the sympathetic nervous system results in activation of brown adipose tissue and increased thermogenesis, tending to counterbalance increased adiposity. Low sympathetic drive is found in animal models of obesity and diabetes.
Sympathetic activation is increased in human obesity, and may be inversely associated with the propensity to gain weight. Enhanced sympathetic activity is a driver for lipolysis and hence release of NEFA into the circulation, and may contribute to insulin resistance in other ways.
Body fat distribution
Central adiposity is a powerful predictor of diabetes risk, independent of BMI, and visceral fat is a major component of this risk, together with other associated features such as dyslipidaemia and increased cardiovascular risk.
Intramyocellular fat accumulation
Obese insulin-resistant individuals are prone to accumulate triglycerides and NEFA with skeletal muscle cells, and the degree to which this occurs correlates with the degree of insulin resistance. Intracellular fat interferes with insulin sigalling and (possibly) glucose transport, thereby contributing to insulin resistance.