Pathophysiology of Type diabetes

Konstantinos Makrilakis

What are the main pathophysiologic characteristics of Type 2 diabetes mellitus?

Type 2 diabetes mellitus is a heterogeneous syndrome, with a complex interaction of genetic and environmental factors, which affect multiple phenotypic manifestations in the body, such as insulin secretion and action, pancreatic b-cell mass, distribution of body fat and development of obesity. Type 2 DM is generally characterized by two main pathophysiologic entities: i) resistance to the action of insulin; and ii) insufficient secretion of insulin from the b-cells of the pancreas. Both of these pathophysiologic disturbances (insufficient secretion and peripheral insulin resistance) are thought to be necessary for the development of the disease.

What are the physiologic effects of insulin in the body?

Insulin has multiple and varied metabolic and vascular effects. Traditionally, it has been associated with regulation of glucose metabolism, but in fact it also, equally significantly, affects lipid and protein metabolism and has important effects on the vascular function, on the platelets, the nervous system and the electrolyte equilibrium of the body.

Specifically, insulin regulates glucose metabolism, by promoting glucose intake through insulin-sensitive tissues (muscle cells and cells of the adipose tissue) and by inhibiting hepatic glucose production (it

Diabetes in Clinical Practice: Questions and Answers from Case Studies. Nicholas Katsilambros et al. © 2006 John Wiley & Sons, Ltd. ISBN: 0-470-03522-6

inhibits glycogenolysis and gluconeogenesis and promotes glycogen-synthesis in the liver). Insulin secretion from pancreatic b-cells is under the direct control of the plasma glucose concentration, which is the main regulator of its secretion: increase in plasma glucose (for example, after a meal) causes an increase in the secretion of insulin and vice versa. The fact that insulin secretion from the pancreas occurs directly into the portal vein and therefore is transferred initially to the liver is very important for the initial decrease/inhibition of glycogenolysis and gluconeogenesis and promotion of glycogen synthesis in the liver after a meal. It is estimated that about 25-50 percent of an oral glucose load is taken up by the liver (and stored as glycogen), while the rest is distributed mainly in the muscle (80-85 percent) and adipose tissue (10-25 percent). Furthermore, b-cells have various cellular receptors for different peptides, hormones and neurotransmitters that can affect insulin secretion, as do various substances inside them (for example, hepatocyte nuclear factors 4-a, 1-a and 1-b, mutations of which are responsible for some of the inherited syndromes of MODY [Maturity Onset Diabetes of the Young]). But even insulin itself, through special insulin receptors on the surface of the b-cells, affects its glucose-dependent secretion (at least in experiments in animals).

The effects of insulin on lipid metabolism are very important: they include stimulation of intravascular lipolysis (through an increase of endothelial lipoprotein lipase activity), promotion of lipogenesis, and inhibition of lipolysis in adipose tissue and inhibition of very-low-density lipoprotein (VLDL) synthesis in the liver.

Insulin also stimulates protein synthesis and transfer of amino-acids into muscle and liver cells. The final effect of all these actions is a decrease in the plasma levels of glucose, triglycerides and free-fatty acids after a meal.

Furthermore, apart from these actions, insulin has significant effects on vascular function and overall body metabolism. It decreases rigidity and stiffness of the large arteries and causes vasodilatation in the smaller peripheral vessels. It inhibits platelet aggregation and their interaction with collagen and regulates autonomic nervous system tone, acting centrally on special receptors in the brain to stimulate sympathetic cardiovascular activity. All of these effects are potentially anti-atherogenic and protective as regards hypertension development. There are, however, also conflicting observations regarding vascular effects of insulin: in experimental studies it was shown that insulin promotes sodium and uric acid re-absorption from the kidneys (contributing to hypertension development), promotes endothelin secretion and secretion of both plasminogen activator as well as plasminogen activator inhibitor-1 (PAI-1). It is believed that the varied degrees of hyperinsulinaemia and insulin resistance in these studies are responsible for these conflicting results.

What is insulin resistance and how is it measured?

Insulin resistance is the inability of insulin to produce its usual biologic effects, at circulating plasma levels that are effective in normal subjects. Insulin resistance is not easy to measure in daily clinical practice. It is estimated clinically only as regards the effects of insulin on carbohydrate metabolism, without taking into consideration its other activities. It is theoretically expressed as the insufficient intake of glucose by the muscles and adipose tissue and by the inability of insulin to suppress hepatic glucose production. Given the fact, as mentioned before, that insulin has multiple and varied effects on whole body metabolism (carbohydrates, lipids, proteins, etc.), and that insulin resistance can develop towards all of these effects (in a degree that varies from person to person, or even occasionally in the same person, it can be seen that it is not correct to focus only on carbohydrate metabolism for the expression of insulin resistance. It is also very possible that many of the phenotypic manifestations of DM can be due both to the presence of insulin resistance to some of its actions (e.g., glucose metabolism) as well as to the increased, unopposed effects of the initial compensatory hyper-insulinaemia on unaffected pathways, where no resistance exists (e.g., protein metabolism, proliferative vascular effects, etc.).

In general, the euglycaemic hyperlnsullnaemlc clamp technique is considered the best for measuring insulin resistance, even though it is technically relatively difficult and demanding. According to its methodology, the rate of intravenous glucose infusion that is necessary to maintain normoglycaemia is measured, while insulin is simultaneously infused intravenously, so that steadily high concentrations of insulin are maintained in the plasma. In this case, the need for a low exogenous glucose infusion rate denotes increased resistance (low sensitivity) to insulin action.

Another method of measuring insulin resistance is the Homeostasis Model Assessment (HOMA) technique, where a specific mathematical formula is used, taking into consideration both fasting insulin and plasma glucose levels:

HOMA-R = [plasma insulin (mU/L)x plasma glucose (mmol/L)]/22.5

This method is much easier, but less reliable, than the first, and is widely used in population studies. Its normal reference values are not precisely established (normal values for HOMA: around 2-3).

There are also some other methods for measuring insulin resistance (intravenous glucose tolerance test, insulin-suppression test, etc.), which are mostly used in research settings.

Which pathophysiologic defect first, but temporally, precedes development of Type 2 DM, insulin resistance or impairment of b-cell secretion?

The natural history of Type 2 DM development is usually characterized by three general stages: i) 'normal glucose tolerance'; ii) 'impaired glucose tolerance'; and iii) 'clinical manifestation of DM'. Plasma insulin levels are generally increased long before clinical development of DM. The fact that this hyperinsulinaemia is observed long before impaired glucose tolerance is manifested, led initially to the belief that impaired insulin secretion develops later, secondary to the existence of resistance to the peripheral action of insulin. It was consequently concluded that insulin resistance always precedes b-cell failure. On the other hand, however, it was observed that many obese, non-diabetic people, with insulin resistance, never develop DM; in addition, many of them never develop impaired glucose tolerance. This clearly shows that the pancreas of these people is able to secrete enough insulin to overcome peripheral resistance. Consequently, insulin resistance is not sufficient in itself to lead to dysfunction, insufficient secretion of the b-cell, and later to DM. The acceptance of this view has been facilitated by experimental studies in animals, where mice with induced disruption of certain genes that caused marked insulin resistance to them, never developed diabetes, in the absence of a simultaneous independent insulin secretory b-cell defect.

It seems, therefore, that both of these pathophysiologic disturbances act simultaneously and separately, both on peripheral tissues and the pancreas and are, in most cases, both necessary for diabetes development.

Type 2 DM can thus be considered a consequence of an inability of the pancreatic b-cells adequately to increase their insulin output in order to compensate for the resistance of the peripheral tissues to its actions. It is deemed certain today that these two pathophysiologic defects are subject to both genetic (mainly) and environmental (obesity - intracellular lipid accumulation) influences, which sometimes renders the exact determination of the aetiology of diabetes in a certain person extremely difficult. About 10 percent of the patients who initially seem to be suffering from Type 2 DM, have in fact a delayed form of autoimmune Type 1 DM (called Type 1.5 diabetes or LADA [Latent Autoimmune Diabetes in Adults]). This type is characterized by the presence of auto-antibodies against the pancreas and a faster failure of its insulin secretory capacity, compared to the classic Type 2 DM. Furthermore, an additional proportion (up to 5 percent) of the phenotypically evident Type 2 DM patients, actually have some kind of the dominantly, autosomally inherited, monogenic syndromes MODY (Maturity Onset Diabetes of the Young). Another approximately 1 percent have some rare genetic mutation of the insulin receptor or of one of the components of the cataract of reactions that insulin binding to its receptor on the cell surface activates. The rest (about 85 percent of the patients) have what we call classical Type 2 DM, with the two pathophysiologic disturbances, already mentioned above. Impaired insulin secretion from the b-cell is considered by many investigators to be the primary genetic disturbance leading to Type 2 DM, and insulin resistance to be the primary acquired defect. In general, the available evidence today favours the view that impaired insulin secretion precedes insulin resistance in those people who finally develop Type 2 DM.

What is the cause of peripheral insulin resistance?

Insulin resistance is strongly related to obesity, especially the central distribution of body fat (abdominal or visceral obesity). The fact that more than 80 percent of diabetics are obese led to the opinion that obesity is most likely the main cause of insulin resistance in DM. Studies, however, both in humans and animals, have shown that insulin resistance is basically associated with intramyocellular triglyceride concentration (as assessed by muscle biopsies or nuclear magnetic spectroscopy) and not that well associated with the degree of obesity, as determined by body mass index. 'Shifting' of lipid deposition from adipose tissue (where it should normally be) to other non-adipose areas (muscle cells, liver, etc), therefore seems to play a very important role in the development of insulin resistance. The role of the central (visceral) distribution of fat is probably related to the increased lipolytic activity of the visceral fat (due to its enhanced adrenergic activity and increased insulin resistance compared to peripheral fat), which leads to increased availability of free fatty acids in the periphery for deposition in non-adipose tissues. The exact molecular mechanism that leads to this result has not been completely elucidated; it seems to be complex and multivariable, and involves multiple sites in the cataract of intracellular reactions that binding of insulin to its cell-surface receptor causes (decreased activation of insulin receptor substrate-1 [IRS-1], phosphati-dylinositol kinase-3 [PI-3 kinase], translocation of glucose transporters-4 [Glut-4] to the cellular membrane, etc.). Recent studies in insulin resistant offspring of diabetic patients show that this defect of intramyo-cellular fatty acid metabolism is probably due to an inherited mitochondrial dysfunction of oxidative phosphorylation in these people. Disturbances in the recently discovered adipose tissue hormones (resis-tin, adiponectin, tumour necrosis factor-a [TNF-a]) seem to be involved in the development of insulin resistance as well.

Is insulin resistance genetically predetermined or is it due to environmental influences?

Studies in populations at high risk for the development of Type 2 DM have shown that a strong genetic predisposition exists for the development of insulin resistance, as is the case for the development of Type 2 DM in general, as well. It seems that heritable differences in insulin sensitivity may be one element of the 'susceptibility genotype' predisposing members of these high-risk populations to Type 2 DM. Further evidence for genetic influences in the development of insulin resistance is derived from twin studies, demonstrating hereditary effects, estimated to range from 47-66 percent. Whether this heritability depends on obesity, however, is unclear. Type 2 DM is considered to be a polygenic disorder and heritable influences are likely to involve alterations in several genes. To date, no genetic defect has been found in patients with typical Type 2 DM that might cause their diabetes to be due solely to insulin resistance. Cases of monogenic heritable Type 2 DM syndromes involve mutations in genes that cause decreased secretion of the b-cell (MODY syndromes), whereas mutations involving the insulin receptor are exceptionally rare causes of DM. Nevertheless, research in this field of molecular biology-genetics continues intensely in large research centres worldwide, and there are already several studies for some candidate genes (for example, the nuclear receptor PPARg, insulin receptor substrates, PPARg coactivator-1 [PGC-1], etc.), which may finally demonstrate existence of a genetic defect in the development of insulin resistance.

Furthermore, the epidemiologic correlation of insulin resistance development with environmental factors, mainly intra-abdominal obesity (a consequence of a modern high-fat, high-energy diet and sedentary lifestyle) is very strong. Central adiposity appears to be a major determinant of insulin resistance, not only in obese individuals, but also in apparently healthy, non-obese persons who have evidence of increased abdominal fat, as assessed by special techniques (NMR spectroscopy, etc.). In obese patients with Type 2 DM, weight loss alone is able, in many cases, to normalize insulin sensitivity and improve glycaemic control. Moreover, it can prevent the progression to DM in high-risk populations (including patients with impaired glucose tolerance), proving the significant contribution of this environmental factor to the development of insulin resistance/diabetes. These observations suggest therefore that insulin resistance is most likely not to be the result of specific gene defects (at least there is no strong genetic influence) but rather is simply due to obesity (with the reservation, of course, of possible hereditary predisposition for obesity development, an issue not yet completely clarified).

What is the role of impaired p-cell insulin secretion in Type 2 DM development?

Although the majority of Type 2 diabetics manifest insulin resistance (around 90-92 percent), Type 2 DM can actually occur even in the absence of insulin resistance. Furthermore, as already mentioned, many people with insulin resistance never develop DM, because their pancreatic b-cells are able to secrete enough insulin to compensate for the peripheral resistance to its action. Consequently, insulin resistance is insufficient, by itself, to cause diabetes. Type 2 DM development necessarily requires the existence of impaired insulin secretion from the ß-cell. This impaired insulin secretory ability is present for many years before the clinical manifestation of DM. Even diabetics with insulin resistance who, at the early stages of the course of the disease (before DM develops), manifest compensatory hyperinsulinaemia to overcome increased peripheral resistance, have actually been shown to have decreased insulin secretion relative to the degree of peripheral insulin resistance.

How does insulin secretion from the b-cell occur?

Insulin is a peptide hormone, composed of two chains, a and b (with a total of 51 amino-acid residues - 30 and 21 in each chain, respectively). It is produced in the pancreatic b-cells - specialized cells inside special cellular aggregates in the pancreas, called islets of Langerhans. These islets also contain other types of cells that produce various hormones, such as glucagon (a-cells), somatostatin (S-cells) and pancreatic polypeptide (PP cells), which communicate with each other via a neurovascular net of arterioles and autonomous nerves. Initially, insulin is composed of pre-pro-insulin (Figure 3.1) in the ribosomes of the rough endoplasmic reticulum, to be quickly converted to pro-insulin (a mixture of insulin and C-peptide), after the splitting of a small part from the molecule. Pro-insulin is transferred to the Golgi apparatus of the cell, where it is stored in special secretory granules and remains in this form inside the cytoplasm of the cell until a stimulus for secretion is applied to the granules. It is then split into equimolar quantities of insulin and C-peptide (connecting peptide) and is excreted from the cell (via exocytosis), with only a small quantity (around 10-15 percent) normally secreted as pro-insulin. The Pancreas produces and secretes insulin constantly, the whole 24 hours (basal, non-stimulated secretion), in a pulsatile way, every about 9-14 minutes. This basal secretion aims at regulating hepatic glucose production (glycogenolysis -gluconeogenesis), which in the case of insulin shortage (total or partial) remains unopposed (it is the main cause of fasting hyperglycaemia in DM). The basic stimulus for insulin secretion, however, is plasma glucose concentration after a meal. The b-cell is able to 'measure' plasma glucose concentration constantly and change insulin secretion accordingly. This coupling of

Ca2+ channel

Ca2+ channel

Figure 3.1. Coupling of blood glucose with insulin secretion from the pancreatic b-cell (Reprinted from Textbook of Diabetes, 3rd edn., J. Pickup & G. Williams, Copyright 2003, with permission from Blackwell Science Ltd.)

plasma glucose concentration with insulin secretion is achieved through the ability of glucose to enter the b-cell freely (with the help of special glucose-transporters [GLUT2]), subsequently oxidize itself in the mitochondria and produce energy in the form of ATP. The increased intracellular concentration of ATP causes special potassium channels on the cell-surface to close, which leads to depolarization of the cellmembrane and opening of special calcium channels of the cell-membrane. Intracellular calcium concentration increases (because of the entry of calcium into the cell) and causes exocytosis of the vesicles with the stored insulin (Figure 3.1).

Various substances that are secreted by the intestine after the entry of food in it, the so-called incretins (glucagon like peptide-1 [GLP-1] and gastric inhibitory polypeptide or glucose-dependent insulinotropic peptide [GIP]) also seem to play a very significant role in post-prandial production and secretion of insulin. These substances, in a sense, notify the pancreas about the forthcoming entry of glucose into the circulation after a meal and promote both production and secretion of insulin. Since it was discovered that mainly GLP-1 is decreased in Type 2 DM, there is currently enormous research interest for this substance, or analogues of it, for therapeutic use in DM (see also Chapter 29 'New therapies in diabetes').

After a meal, insulin secretion from the b-cell is biphasic: there is an acute, quick (around 5-6 minutes) first phase (which intends to suppress hepatic glucose production) and a second phase, more prolonged, but of lower intensity, which promotes entry of plasma glucose into the insulinsensitive cells, mainly muscle cells and adipocytes. The first phase of insulin secretion comes from insulin stored in vesicles found near or in contact with the b-cell membrane, whereas the second phase is derived from newly synthesized insulin or insulin stored in vesicles that are deeper in the cytoplasm. The first phase of insulin release is the one that is initially disrupted during the early phases of the natural history of DM (from impaired glucose tolerance to overt diabetes). Furthermore, the proportion of pro-insulin that is secreted from the pancreas rises in DM (up to 30-40 percent), which implies that there is possibly a disturbance either in the secretion or in the process of insulin inside the b-cell.

Apart from glucose, which as mentioned is the most significant stimulus for insulin secretion, an increase in circulating levels of amino-acids, free fatty acids and the gastrointestinal hormones GLP-1 and GIP also promote insulin secretion. In contrast, an increase of other factors, such as catecholamines, cortisol, growth hormone, leptin and tumour necrosis factor-a, decreases insulin secretion.

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