Pathophysiology of type 2 diabetes mellitus
Insulin resistance, largely caused by obesity and physical inactivity, both precedes and predicts type 2 diabetes. This insulin resistance is commonly referred to as the metabolic syndrome (MetS, see Chapter 13.3.6). The latter condition consists of a cluster of risk factors, which are thought to be either causes or consequences of insulin resistance.
In addition to type 2 diabetes, the metabolic syndrome is associated with an increased risk of cardiovascular disease, the main complication of type 2 diabetes (see Chapter 13.6.1). The development of type 2 diabetes, overt hyperglycaemia, also requires the presence of a relative defect in insulin secretion. This defect appears, at least in part, genetically determined (see Chapter 13.3.1).
Excess glucagon secretion may also contribute to the development of hyperglycaemia. Chronic hyperglycaemia and hypertension both contribute to the development of microvascular complications (see Chapter 13.5).
The ensuing discussion is focused on defining and characterizing defects in insulin action and in insulin and glucagon secretion in patients with type 2 diabetes. This discussion includes an overview of the metabolic syndrome and of nonalcoholic fatty liver disease (NAFLD), which can be viewed as the hepatic manifestation of insulin resistance in type 2 diabetes.
Current definitions of type 2 diabetes and the metabolic syndrome are described in Chapter 13.1. Diagnosis of conditions resembling type 2 diabetes (Chapters 13.3.4 and 13.3.5) and the pathophysiology of hypertension, macro- and microvascular disease (Chapters 13.5, 13.6.1, and 13.6.4), and the role of genetic factors in the aetiology of type 2 diabetes (Chapter 13.3.1) are described in detail elsewhere.
Diagnostic criteria and definitions
Diagnosis of type 2 diabetes
The diagnostic criteria of type 2 diabetes are reviewed in Chapter 13.1.
Insulin resistance and the metabolic syndrome
Insulin resistance can be defined as the inability of insulin to produce its usual biological actions at circulating concentrations that are effective in normal subjects. Insulin resistance in the context of glucose metabolism leads to impaired suppression of endogenous glucose production, under basal conditions as well as after eating, when the physiological rise in insulin in response to glucose entry from the gut normally shuts down glucose production by the liver, and to reduced peripheral uptake of glucose. These alterations result in hyperglycaemia and a compensatory increase in insulin secretion. Resistance to the ability of insulin to suppress very-low-density lipoprotein (VLDL) production from the liver increases circulating serum triglycerides, which, in turn, leads to a decrease in high-density lipoprotein (HDL) cholesterol and formation of atherogenic, small, dense, low-density lipoprotein (LDL) particles. Resistance in adipose tissue increases the flux of non-esterified fatty acids (NEFA) both to the liver and skeletal muscle, and impairs the action of insulin on glucose metabolism in these tissues (1). Resistance to other actions of insulin, such as its vasodilator and antiplatelet aggregation effects, also characterize insulin resistance in patients with type 2 diabetes.
Although obesity and physical inactivity are the main causes of insulin resistance, and have precipitated the present epidemic of type 2 diabetes (see Chapter 13.3.3), these factors are poorer predictors of cardiovascular disease than the combination of risk factors that define the metabolic syndrome. Diagnosis of the metabolic syndrome provides a tool to diagnose insulin resistance in the clinic. According to the definition proposed by the International Diabetes Federation (2), it requires measurement of waist circumference, blood pressure, and the concentrations of glucose, triglycerides, and HDL cholesterol, as reviewed in Chapter 13.1. A person has the metabolic syndrome if they have any three of the following: central obesity (defined with ethnicity-specific values); raised triglycerides; reduced HDL cholesterol; increased blood pressure; and/or raised fasting plasma glucose. As discussed in detail in Chapter 13.1, using these criteria, 20–25% of the world’s adult population have the metabolic syndrome. The risk of death from cardiovascular disease is increased approximately two-fold in subjects with the metabolic syndrome, as compared to those not meeting these criteria. In addition, subjects with the metabolic syndrome have a five-fold greater risk of developing type 2 diabetes (2).
Not all obese individuals have the metabolic syndrome, and the syndrome may occur in normal-weight individuals. Subjects who develop the metabolic syndrome commonly have, however, excess fat deposited in ectopic locations, especially in the liver, which is the site of production of endogenous glucose, VLDL, as well as some other circulating markers of cardiovascular risk, such as C-reactive protein (3). The insulin resistance-associated steatosis is known by gastroenterologists as ‘non-alcoholic fatty liver disease’ (NAFLD).
Non-alcoholic fatty liver disease
Subjects with the metabolic syndrome frequently have an increase in fat accumulation in the liver and hepatic insulin resistance, even independent of obesity and body fat distribution (4). Formally, NAFLD is defined as excess fat in the liver (more than 5–10% fat, histologically), which is not due to excess alcohol use (more than 20 g/day), effects of other toxins, autoimmune, viral, or other causes of steatosis (5). NAFLD has been shown to predict both type 2 diabetes and cardiovascular disease in multiple prospective studies, independent of obesity (3).
NAFLD covers a spectrum of liver disease, including not only steatosis, but also non-alcoholic steatohepatitis (NASH) and cirrhosis (5) (Fig. 188.8.131.52). The reasons why the liver develops inflammatory changes, as in NASH, in some individuals is unclear. The prevalence of NAFLD and NASH is increased in type 2 diabetes (6). The mechanisms linking components of the metabolic syndrome to a fatty liver are discussed below.
Role of defects in insulin action and secretion in the natural history of type 2 diabetes
There has been much debate as to whether insulin resistance is the primary defect that precedes any defect in insulin secretion in the evolution of hyperglycaemia in type 2 diabetes, or vice versa. There is a linear decrease in both first-phase insulin release and insulin sensitivity in individuals who progress from normal to impaired glucose tolerance (Fig. 184.108.40.206). Once the plasma glucose concentration 2 h after an oral glucose challenge (75 g) reaches the upper limit for impaired glucose tolerance (11.1 mmol/l (200 mg/dl)), post-glucose insulin concentrations fall and glucose then rises into the diabetic range (Fig. 220.127.116.11). Similar relationships have emerged from prospective studies. Thus, low insulin sensitivity and impaired first-phase insulin release both predict type 2 diabetes (7). These data imply that development of overt hyperglycaemia requires a relative decrease in insulin secretion as depicted in Fig. 18.104.22.168.
Insulin resistance in type 2 diabetes
Insulin resistance in the liver
Insulin action on glucose metabolism in the fasting state
After an overnight fast, insulin restrains endogenous glucose production. Endogenous glucose production is closely correlated with the fasting plasma glucose concentration, and is its main determinant in patients with type 2 diabetes (8). This is because glucose utilization occurs largely independent of insulin in tissues such as the brain (which accounts for approximately 50% of whole body-glucose utilization in the fasting state), and because hyperglycaemia, via the mass-action effect of glucose, maintains glucose utilization at a normal or even increased rate. The relationship between endogenous glucose production and fasting glucose is observed despite hyper-glycaemia, normo- or hyper-glucagonaemia, and normo- or hyperinsulinaemia. Since hyperglycaemia and hyperinsulinaemia normally inhibit endogenous glucose production (Fig. 22.214.171.124), this implies that insulin resistance contributes to the increase in basal endogenous glucose production (9). Normal or raised glucagon levels in the face of hyperglycaemia also contribute to increased glucose production (10). This hepatic insulin resistance is associated with excess fat accumulation in the liver (11, 12). The clinical implication of these findings is that strategies designed to lower fasting glucose should aim at inhibiting overproduction of glucose from the liver, rather than at further increasing glucose uptake in type 2 diabetes. Also, the greater the resistance at the liver, the greater the need for endogenous and exogenous insulin (11).
Insulin action on glucose metabolism in the postprandial state
After a meal, increases in insulin and glucose concentrations and a concomitant decrease in glucagon almost completely suppress endogenous glucose production under normal conditions (13). In patients with type 2 diabetes, this suppression is incomplete because of hepatic insulin resistance, deficient insulin, and excessive glucagon secretion (10). Persistent hepatic glucose production after eating is the main reason for sustained post-meal hyperglycaemia (13). Under postprandial conditions, approximately one-third of glucose is utilized in skeletal muscle, one-third is oxidized in the brain, and the remaining third is stored in the liver (14). In patients with type 2 diabetes, the overall rate of glucose utilization is quantitatively normal, because hyperglycaemia per se, due to the mass-action effect of glucose, acts to compensates for impaired insulin stimulation of glucose uptake into peripheral tissues (13). The ability of the liver to store glucose during a meal appears intact or is only slightly diminished (10). The brain utilizes similar amounts of glucose in both normal subjects and patients with type 2 diabetes. Thus, postprandial hyperglycaemia must be due to the incomplete suppression of endogenous glucose production.
Evidence from both in vitro (15, 16) and in vivo (17) studies has suggested that insulin normally suppresses the production of VLDL, especially VLDL1 apoB (apolipoprotein B) particles, from the liver (see Chapter 13.6.3). This effect is due to decreases in NEFA availability following inhibition of lipolysis in fat tissue, and to a direct hepatic effect of insulin, inhibiting the assembly and production of VLDL particles (17). In contrast to normal, insulin fails to suppress VLDL apoB production in type 2 diabetes (18). Overproduction of VLDL (19) and the defect in insulin suppression of VLDL production (20) correlates with the amount of fat in the liver and appears to be one major contributory mechanism underlying the increase in serum triglycerides in insulin-resistant type 2 diabetic patients (21). (Fig. 126.96.36.199b).
HDL concentrations are reduced in insulin-resistant patients with high serum triglycerides. Under hypertriglyceridaemic conditions, there is excessive exchange of cholesterol esters and triglycerides between HDL and the expanded pool of triglyceride-rich lipoproteins, mediated by cholesterol ester transfer protein (CETP) (22). HDL separating particles become enriched with triglycerides (predominantly in the lighter HDL3 density range), rendering them a good substrate for hepatic lipase, which removes HDL particles from the circulation at an accelerated rate. Subnormal activity of lipoprotein lipase (LPL) may further decrease levels of HDL cholesterol by decreasing the conversion of HDL3 to HDL2 particles (22). Elevated concentrations of VLDL particles in the serum of patients with type 2 diabetes also increase the CETP-mediated exchange of cholesterol ester and triglyceride between VLDL and LDL particles (23). This increases the triglyceride content of LDL particles and makes them a better substrate for hepatic lipase (24), which hydrolyses triglycerides in the LDL particles and increases their density. This sequence of events at least partly explains why patients with type 2 diabetes have smaller and more dense LDL particles than nondiabetic individuals (25, 26). The small, dense LDL particles are known to be highly atherogenic and provide a plausible link between insulin resistance and cardiovascular disease (27).
Pathogenesis of hepatic insulin resistance and NAFLD
Hepatic insulin resistance in type 2 diabetes correlates with liver fat content (11, 28). Although triglycerides themselves are inert, their accumulation serves as a marker of hepatic insulin resistance in humans. The amount of liver resistance can be predicted based on simple, clinically available parameters such as the liver enzymes, fasting glucose concentrations, and the presence and absence of the metabolic syndrome and type 2 diabetes (29).
Fatty acids in hepatocytes can be derived from dietary chylomicron remnants; NEFAs released from adipose tissue; from postprandial lipolysis of chylomicrons, which can occur at a rate in excess of that which can be taken up by tissues (spillover) and from de novo lipogenesis (30). In vivo studies have shown that, after an overnight fast as well as postprandially, the majority of hepatic fatty acids originate from subcutaneous adipose tissue lipolysis (31). The contribution of splanchnic lipolysis to hepatic NEFA delivery averages 5–10% in normal-weight subjects, and increases to 30% in men and women with visceral obesity (32). De novo lipogenesis accounts for less than 5% of hepatic NEFA in normal subjects postprandially (33). However, in subjects with fatty liver, rates of de novo lipogenesis are significantly elevated (31). This may result from excess carbohydrate intake in the form of simple sugars, such as fructose and soft drinks sweetened with corn syrup (34–36).
Causes of variation in hepatic insulin sensitivity and liver fat content
Obesity is related to insulin resistance, although, at any given body mass index (BMI), insulin sensitivity—measured as the amount of glucose required to maintain normoglycaemia during experimental hyperinsulinaemia (a measure of whole body insulin resistance, which could be both hepatic and peripheral)—varies considerably (4). Obesity impairs insulin stimulation of glucose uptake and insulin inhibition of endogenous glucose production. Liver fat content and hepatic insulin resistance are related to BMI and waist circumference; however, the variation at any given BMI is large (Fig. 188.8.131.52).
Weight loss induces rapid and substantial changes in liver fat content and hepatic insulin sensitivity. In a study where obese women lost 8% of their body weight over 18 weeks, liver fat content decreased by 39% (37). In another study, 7% weight loss decreased liver fat content by approximately 40% over 7 weeks (38). In this study, a 30% decrease in liver fat was observed as early as 2 days into a low-carbohydrate diet (–1000 kcal, c.10% carbohydrate). Conversely, weight gain, such as that induced by fast food, increases liver fat (39).
More than 50 years ago, Jean Vague classified obese subjects, according to the degree of ‘masculine differentiation’ (40), into those with ‘gynaecoid’ and those with ‘android’ obesity. Gynaecoid obesity was characterized by lower-body deposition of fat (around the thighs and buttocks) and relative underdevelopment of the musculature, while android obesity defined upper-body (truncal) adiposity, greater overall muscular development and a tendency to develop hypertension, diabetes, atherosclerosis, and gout. These phenotypic observations have subsequently been confirmed in prospective studies (41–43). The mechanisms by which various fat depots may be harmful are discussed in Chapter 12.1.
Human data are sparse regarding the effects of changes in diet composition on hepatic insulin sensitivity and liver fat content. It is possible that both high saturated fat and high intake of refined carbohydrates, e.g. the simple sugars such as fructose used in soft drinks, promote fat accumulation (35, 36).
Adiponectin is an insulin-sensitizing hormone produced by adipose tissue, which is likely to reduce liver fat content (see below) (44).
Recently, a genome-wide association scan of non-synonymous sequence variations in a population comprising Hispanic, African-American, and European-American individuals identified an allele in the PNPLA3 (adiponutrin) gene to be strongly associated with increased liver fat. The finding that hepatic fat content was more than two-fold higher in PNPLA3 rs738409[G] homozygotes than in non-carriers has been confirmed (45, 46). The polymorphism influences liver fat, but not hepatic insulin sensitivity.
Insulin resistance in adipose tissue
Resistance to the antilipolytic action of insulin
Lipolysis in adipose tissue is exquisitely insulin sensitive: in normal subjects, rates of glycerol production are half-maximally suppressed at a plasma insulin concentration just exceeding fasting concentrations. Triglyceride breakdown is increased and plasma NEFA concentrations are higher in patients with type 2 diabetes than in normal subjects studied at comparable insulin levels, suggesting that adipose tissue is also affected by insulin resistance (47, 48). However, unrestrained lipolysis to a degree that could lead to ketoacidosis does not occur spontaneously in type 2 diabetes, because insulin deficiency is not sufficiently profound.
Increased NEFA concentrations may contribute to worsening of hyperglycaemia because of multiple interactions between NEFA and glucose metabolism. Increased concentration of NEFA reflects increased NEFA turnover, which increases delivery to the liver, where NEFA can be deposited as triglycerides (see above). In the liver, NEFA also stimulate glucose production, especially via gluconeogenesis. A large increase in plasma NEFA concentrations can decrease insulin-stimulated glucose uptake (49) and NEFA may be deposited as triglycerides in skeletal muscle (50).
Regarding the reasons for adipose tissue insulin resistance, in obese subjects (51) and in subjects with a fatty liver independent of obesity (52), adipose tissue is inflamed. This inflammation is characterized by macrophage infiltration and increased expression of proinflammatory molecules antagonizing insulin action, such as tumour necrosis factor α (TNFα) and interleukin-6 (IL-6), and of chemokines such as monocyte chemoattractant protein-1 (MCP-1) (51, 53, 54]). The initial trigger of the inflammatory changes is unknown. Macrophage accumulation in human adipose tissue is, at least in part, reversible as weight loss can reduce both macrophage infiltration and expression of genes involved in macrophage recruitment (55).
Adiponectin is a hormone exclusively produced in adipose tissue. In animals, its main target is the liver, where it has both anti-inflammatory and insulin-sensitizing effects and decreases liver fat content (44). The marked increase in serum adiponectin observed during treatment with peroxisome proliferator-activated receptor γ (PPARγ) agonists and the close correlation between changes in liver fat and serum adiponectin concentrations (56) support the possibility that adiponectin regulates liver fat content in humans. Serum adiponectin levels have consistently been decreased in obese, as compared to non-obese, subjects and in subjects with the metabolic syndrome compared to those without.
Insulin resistance in skeletal muscle
There is abundant evidence that the ability of insulin to stimulate in-vivo glucose disposal is decreased in skeletal muscle of patients with type 2 diabetes when measured under similar conditions in age-, gender-, and weight- matched nondiabetic subjects (57). Insulin stimulation of glucose oxidation and of glycogen synthesis are both diminished under such conditions. However, under real-life conditions, hyperglycaemia compensates, via the mass-action effect of glucose, for the defect in insulin-stimulated glucose uptake, and maintains the rate of absolute glucose utilization at a normal level in type 2 diabetic patients, compared to healthy subjects (58).
The defects in insulin action in skeletal muscle are generally more severe than in equally obese, non-diabetic subjects of the same age, gender, and body fat distribution. This may be because of an additional genetic defect (discussed in Chapter 13.3.1), or, perhaps more likely, because of metabolic disturbances, such as chronic hyperglycaemia (‘glucose toxicity’, see below), or extracellular NEFA or lipid accumulation within the myocytes (‘lipotoxicity’) (59).
Causes of insulin resistance in muscle
Obesity decreases insulin-stimulated glucose uptake in skeletal muscle independent of changes in physical fitness (see Chapter 12.1.3). This decrease may be partly due to increased NEFA produced by adipose tissue and fat accumulation in myocytes (50).
Insulin resistance in skeletal muscle is more severe in subjects with android, as compared to gynaecoid, obesity (60). Histologically, abdominally obese subjects have a decreased capillary density and an insulin-resistant fibre type in their skeletal muscle (61).
The sedentary lifestyle that characterizes Westernized societies is an important contributor to obesity and to type 2 diabetes (see Chapter 13.3.3). Data from several prospective epidemiological studies, such the Nurse’s Health Study (62), have shown an inverse association between physical activity and the incidence of type 2 diabetes. Insulin sensitivity of glucose uptake by skeletal muscle is directly proportional to physical fitness measured by maximal oxygen uptake (VO2 max) (63). Decreased physical fitness (or maximal aerobic power) in muscle in patients with type 2 diabetes is characterized by decreased capillary density and impaired mitochondrial oxidative phosphorylation (64). Glucose tolerance and insulin-stimulated glucose uptake are also enhanced by resistive training, which increases total muscle mass without influencing glucose uptake per unit muscle mass (63).
Hyperglycaemia itself—independent of insulin, NEFA, or counterregulatory hormones—can induce insulin resistance in human skeletal muscle (65). This ‘glucose toxicity’-induced insulin resistance may contribute to the lower rates of insulin-stimulated glucose uptake in patients with type 2 diabetes, compared with weight-, age-, and gender- matched nondiabetic subjects and measured during maintenance of similar levels of glycaemia and insulinaemia (66). However, although chronic hyperglycaemia induces insulin resistance, glucose utilization is stimulated acutely via the mass-action effects of glucose, even in diabetic patients. This effect explains why hyperglycaemic type 2 diabetic patients are able to utilize as much glucose as normal subjects at normo glycaemia, in spite of their insulin resistance (65, 67).
Defects in insulin secretion
The insulin response to intravenous glucose is biphasic, with an early first-phase burst (the acute insulin response) followed by a second, sustained phase. When glucose tolerance deteriorates from normal to impaired, there is a progressive decrease in the acute insulin response to glucose, and an increase in the total insulin response during an oral glucose tolerance test (OGTT), as determined by both longitudinal and cross-sectional studies (Fig. 184.108.40.206). The acute insulin response to glucose is lost at a fasting plasma glucose concentration of around 6.4 mmol/l. Thus, insulin secretion decreases prior to the onset of diabetic hyperglycaemia. Despite this, as discussed below, if insulin secretion is assessed by measuring fasting insulin or C-peptide concentrations, most type 2 diabetic are hyperinsulinaemic. The insulin-secretory response to non-glucose secretagogues such as arginine in type 2 diabetes are reduced, but not absent (59). The disappearance of the first-phase insulin response is predominantly a functional alteration independent of β cell mass. However, autopsy studies have shown that, in addition to a functional defect, there is also a decrease in β cell mass both in type 2 diabetes and even in subjects with impaired fasting glucose (68).
The increase in total insulin concentrations reflects an attempt of β cells to maintain glucose tolerance in the non-diabetic range, despite worsening insulin resistance (Fig. 220.127.116.11). Once the 2-h plasma glucose in an OGTT exceeds 11.0 mmol/l, insulin secretion starts to decrease relative to insulin resistance and hyperglycaemia (Fig. 18.104.22.168). This decrease in insulin secretion is a hallmark of the onset of type 2 diabetes. There is thus absolute hyperinsulinaemia, but relative deficiency of insulin in type 2 diabetic patients. Thus, both fasting and postprandial insulin concentrations can be markedly increased, despite hyperglycaemia. This relative hyperinsulinaemia reflects not only insulin resistance, but also, in many patients, impaired insulin clearance due to increased liver fat content (28). However, even if insulin concentrations are corrected for impaired insulin clearance, hyperinsulinaemia characterizes many type 2 diabetic patients. C-peptide is not cleared by the liver and, therefore, provides a better measure of endogenous insulin secretion.
The degree to which defects in insulin secretion are familial or inherited is discussed in detail in Chapter 13.3.1. Recent genome-wide scans have found polymorphisms in genes involved in insulin secretion to be more common in patients with type 2 diabetes than in nondiabetic subjects. Identification of these genetic markers has not, however, helped in identification of subjects at risk of developing type 2 diabetes. Acquired factors may also contribute to defects in insulin secretion, although most data rely on animal experiments and their relevance for human disease is uncertain. Such causes may include insulin-resistance induced β-cell exhaustion, gluco- and lipo-toxicity, and amyloid deposition (59).
In response to ingestion of a large carbohydrate meal, glucose and insulin levels increase and there is suppression of glucagon secretion. Each of these changes serves to inhibit the production of endogenous glucose when exogenous glucose appears in the circulation. Specifically, selective glucagon deficiency in healthy subjects produces a marked and sustained decrease in glucose production (69).
In patients with type 2 diabetes, absolute fasting plasma concentrations of glucagon may or may not be increased, compared with non-diabetic subjects (10). However, fasting plasma plasma glucagon levels are inappropriate in the context of hyperglycaemia and hyperinsulinaemia in type 2 diabetes, and contribute to the increased rate of hepatic glucose output characteristic of type 2 diabetes (10). Normal suppression of glucagon following a carbohydrate or mixed meal is blunted in patients with type 2 diabetes (10). Thus, excessive hyperglucagonaemia contributes to postprandial hyperglycaemia in type 2 diabetes.
Incretins and type 2 diabetes
Incretins are hormones secreted from gut endocrine cells in response to meals. The most important incretin hormones include glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (glucose-dependent insulinotropic polypeptide; GIP). GIP is produced by duodenal and jejunal enteroendocrine K cells in the proximal small bowel, while GLP-1 is made by enteroendocrine L-cells in the distal ileum and colon. Incretin hormones stimulate insulin secretion, suppress glucagon secretion, inhibit gastric emptying, and reduce appetite and food intake (70, 71). The ‘incretin effect’ refers to amplification of insulin secretion by hormones secreted from the gastrointestinal tract. Oral, as compared to intravenously, administered glucose (50–100 g) is associated with a two- to four-fold enhanced insulin secretory response when comparable circulating glucose levels are maintained. This incretin effect is significantly diminished in type 2 diabetic patients. The defect appears, at least in part, due to decreased sensitivity of islet of type 2 diabetic patients to GIP and GLP-1 (71). This defect is not a primary cause of type 2 diabetes since it can be partly restored by improved glycaemic control and is only observed in the diabetic twin of identical twins discordant for type 2 diabetes (71). Therapeutic approaches for enhancing incretin action include degradation resistant GLP-agonists (incretin mimetics) and inhibitors of dipeptidyl peptidase 4 (DPP4) activity (DPP4 inhibitors) (70, 71). Their therapeutic potential is discussed in Chapter 13.4.2.
Although obesity and physical inactivity have precipitated the epidemic of type 2 diabetes, not all obese subjects suffer similarly from the consequences of an unhealthy lifestyle. Individuals who develop its adverse metabolic consequences appear to be those whose liver becomes insulin resistant, although insulin resistance also characterizes skeletal muscle and adipose tissue. The insulin resistance is coupled with accumulation of fat in the liver, a condition known by gastroenterologists as NAFLD, and, by endocrinologists, as the metabolic syndrome (see Chapter 13.3.6). Once insulin resistant, the normal actions of insulin to inhibit glucose and VLDL production are impaired, resulting in mild hyperglycaemia, hyperinsulinaemia, and hypertriglyceridaemia. The latter is the main cause of a low HDL-cholesterol concentration and leads to the generation of small, dense, and atherogenic LDL particles. Such individuals are often also hypertensive and have an increased waist circumference.
This metabolic syndrome is important to recognize clinically, as it is associated with many components that can potentially be modified to prevent premature atherosclerosis and cardiovascular disease, the main cause of the excess mortality in type 2 diabetes. The hidden fat in the liver is difficult to detect in the clinic, but plays an important pathogenetic role as evidenced by multiple studies showing NAFLD to predict, independent of obesity, both type 2 diabetes and cardiovascular disease in multiple prospective epidemiological studies. This may explain the role of obesity, which clearly increases the risk of NAFLD. The fatty liver may become inflamed (NASH) and even cirrhotic.
Once the β cell no longer can sustain increased insulin secretion to compensate for insulin resistance, overt hyperglycaemia develops. This abrupt decrease in the post-glucose insulin secretion relative to plasma glucose marks the onset of type 2 diabetes (Fig. 22.214.171.124). Overt hyperglycaemia is associated with an increased risk of microvascular disease. In addition to defective insulin secretion, hyperglucagonaemia and an incretin defect characterizes type 2 diabetes. Family history and genetic factors appear to play a significant role in determining the susceptibility to overt type 2 diabetes. The exact causes of the defects in insulin and glucagon secretion remain speculative. Perhaps the only certain aspect of the aetiology and pathogenesis of type 2 diabetes is that its incidence can very significantly be reduced by increasing physical activity and avoiding obesity.
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