Glucose homeostasis

The plasma glucose concentration is normally maintained within a relatively narrow range, between 3.3 and 8.8 mmol/l (multiply by 18 to convert to mg/dl) despite wide variations in glucose levels after meals and exercise. This normoglycaemia is maintained through an intricate regulatory and counter-regulatory neuro-hormonal system. Both insulin-dependent and insulin-independent processes contribute to fasting and postprandial plasma glucose regulation.

Plasma glucose is the predominant metabolic fuel used by the central nervous system (CNS). The CNS cannot synthesise glucose, store more than a few minutes’ supply, or concentrate glucose from the circulation. Brief hypoglycaemia can cause profound CNS dysfunction, and prolonged severe hypoglycaemia can cause cellular death. Glucose regulatory systems have evolved to prevent or correct hypoglycaemia.

The brain and nervous system are insulin independent; they autonomously regulate their use of glucose as a metabolic fuel.

Glucose transport is mediated by protein called glucose transporter 1 (GLUT-1) that actively transports glucose across the cell membrane of nervous tissue in the presence of low or high plasma glucose levels and in the presence or absence of insulin.

Muscle and adipose tissue are responsive to insulin. Both can use either glucose or ketones and free fatty acids as their primary metabolic fuel. Which fuel the cell uses is determined primarily by the amount of insulin bound to its cell-surface insulin receptors. In the presence of large amounts of insulin, the cell preferentially uses glucose, by actively taking it up and metabolising it or storing it as glycogen in the muscle or as fat in the adipose tissue, effectively lowering postprandial plasma glucose. When insulin levels are low, the cell switches to ketone/free fatty acid metabolism, reducing uptake of glucose and instead using circulating free fatty acids for energy.

Glucose in plasma is derived from three sources: intestinal absorption from diet; glycogenolysis the breakdown of glycogen in liver, and gluconeogenesis the formation of glucose in liver and kidney from other carbons, including lactate, pyruvate, amino acids, and glycerol.

Glucose removed from plasma is disposed through different but limited pathways. It may be stored as glycogen or may undergo glycolysis. The process of glycolysis can be ‘non-oxidative’ producing pyruvate that can be reduced to lactate or transaminated to form alanine. It can be ‘oxidative’ through conversion to acetyl CoA that is further oxidised through the tricarboxylic acid cycle to form carbon dioxide and water. Non-oxidative glycolysis carbons undergo gluconeogenesis, and the newly formed glucose is either stored as glycogen or released back into plasma.

The important factors that regulate the glucose concentration are: (1) the immediate response hormones: insulin, glucagon, and catecholamines; (2) the sympathetic nervous system activity; (3) the concentration of free fatty acids (FFA); (4) the prolonged response hormones: cortisol and growth hormone; and (5) the nutritional factors, exercise and physical fitness. Cortisol, growth hormone, and catecholamines affect glucose homeostasis by altering insulin sensitivity and also by changes in the availability of alternative substrates, along with concomitant changes in the sensitivity.

Insulin

Insulin regulates glucose metabolism by direct and indirect actions. Through binding to its receptors in the liver, kidney, muscle, and adipose tissue, insulin activates its signalling pathway, which involves a complex cascade of protein kinases and regulatory proteins the insulin receptor substrate (IRS), of which IRS-1 and IRS-2 are the most important. This leads to: (1) suppression of glucose release from liver and kidney; (2) translocation of glucose transporters in muscle and adipose tissue to increase their glucose uptake; and (3) inhibition of release of FFA into the circulation owing to suppression of the activity of ‘hormone-sensitive lipase’ and a simultaneous increase in their clearance from the circulation.

Although insulin does not increase glucose transport into liver, it promotes glycogen accumulation by inhibiting glucose-6-phosphatase and phosphorylase (glycogenolysis enzymes) while stimulating glycogen synthase.

The effect of insulin on circulating FFA levels indirectly reduces glucose release into circulation and promotes glucose removal as FFA stimulate gluconeogenesis and reduce glucose transport into cells.

The main regulator of insulin secretion is the plasma glucose concentration: increased plasma glucose after meal ingestion results in three-to four-fold increase in plasma insulin within 30–60 min. Acute increases in amino acids, and to a lesser extent, FFA also increase insulin secretion.

After meal ingestion, intestinal factors called incretins (e.g. gastrointestinal-inhibitory peptide and glucagon-like peptide [GLP-1]) augment insulin secretion. This is the reason that plasma insulin concentrations increase to a greater extent after oral glucose load than after intravenous glucose, despite identical plasma glucose concentrations.

Insulin

Insulin regulates glucose metabolism by direct and indirect actions. Through binding to its receptors in the liver, kidney, muscle, and adipose tissue, insulin activates its signalling pathway, which involves a complex cascade of protein kinases and regulatory proteins the insulin receptor substrate (IRS), of which IRS-1 and IRS-2 are the most important. This leads to: (1) suppression of glucose release from liver and kidney; (2) translocation of glucose transporters in muscle and adipose tissue to increase their glucose uptake; and (3) inhibition of release of FFA into the circulation owing to suppression of the activity of ‘hormone-sensitive lipase’ and a simultaneous increase in their clearance from the circulation.

Although insulin does not increase glucose transport into liver, it promotes glycogen accumulation by inhibiting glucose-6-phosphatase and phosphorylase (glycogenolysis enzymes) while stimulating glycogen synthase.

The effect of insulin on circulating FFA levels indirectly reduces glucose release into circulation and promotes glucose removal as FFA stimulate gluconeogenesis and reduce glucose transport into cells.

The main regulator of insulin secretion is the plasma glucose concentration: increased plasma glucose after meal ingestion results in three-to four-fold increase in plasma insulin within 30–60 min. Acute increases in amino acids, and to a lesser extent, FFA also increase insulin secretion.

After meal ingestion, intestinal factors called incretins (e.g. gastrointestinal-inhibitory peptide and glucagon-like peptide [GLP-1]) augment insulin secretion. This is the reason that plasma insulin concentrations increase to a greater extent after oral glucose load than after intravenous glucose, despite identical plasma glucose concentrations.

Glucagon

Glucagon is secreted from the alpha cells of the pancreas. This is the major counter-regulatory hormone to insulin. Glucagon secretion is inhibited by hyperglycaemia and stimulated by hypoglycaemia. Glucagon acts exclusively on the liver where it binds to its receptors and activates adenylate cyclase. The immediate action of glucagon to increase plasma glucose level is through stimulation of hepatic glycogenolysis. As a result, intracellular cyclic adenosine monophosphate level increases, enhancing glycogenolysis.

Catecholamines

Catecholamine release is mediated through changes in sympathetic nervous system. The release is increased during stress and hypoglycaemia. Metabolic actions of catecholamines are mainly mediated through beta-2 adrenergic receptors: catecholamines inhibit insulin secretion while decreasing insulin action. They act as both hormones (epinephrine) and neurotransmitters (norepinephrine), and potentiate hyperglycemic factors that affect both glucose release and glucose removal. At the liver, they directly increase glycogenolysis and, to a lesser extent, augment, gluconeogenesis indirectly through increasing gluconeogenic substrate availability and plasma FFA.

At the kidney level, they are potent stimulators of gluconeogenesis, and result in renal glucose release both directly and indirectly. In skeletal muscles, they reduce glucose uptake and stimulate glycogenolysis, which causes an increase in lactate, the major gluconeogenic precursor. In adipose tissue, catecholamines stimulate lipolysis that results in an increase in the release of FFA and glycerol, another key gluconeogenic precursor.

Growth hormone and cortisol

The metabolic actions of growth hormone and cortisol generally take several hours to become evident. Their actions are antagonistic to the action of insulin. They reduce the ability of insulin to suppress glucose release, stimulate glucose uptake, and inhibit lipolysis. Both hormones increase the synthesis of gluconeogenic enzymes and reduce glucose transport. In addition, cortisol can impair insulin secretion by insulin resistance.

Free fatty acids

Free fatty acids are the predominant fuel used by most tissues of the body, except brain, renal medulla, and blood cells. Increases in plasma FFA causes stimulation of hepatic and renal gluconeogenesis, inhibition of muscle glucose transport, and competition with glucose as an oxidative fuel.

The major regulators of circulating FFA levels are the sympathetic nervous system and growth hormone. These increased plasma FFA levels and insulin h reduces plasma FFA levels by suppressing lipolysis and increasing FFA clearance and hyperglycaemia.

Incretins

Incretins are the factors secreted from the intestinal mucosa in response to nutrients that can stimulate the pancreas to release insulin. Two such peptides have been identified: gastric inhibitory polypeptide and GLP-1. Both peptides are secreted from intestinal endocrine mucosa (L and K cells) within minutes of nutrient ingestion, and have a short half-life owing to the rapid inactivation by a proteolytic enzyme called dipeptidyl peptidase-4 (DPP-4).

Peptide GLP-1 also delays gastric emptying and, through a neural mechanism, promotes satiety, decreasing food intake and leading to weight loss.

Glucose transport pathways

Glucose needs specific transporter proteins to facilitate its entry into cells.

Two distinct families of transport proteins exist: GLUT and sodium glucose transporter (SGLT).

Glucose production

The liver is responsible for about 80% of glucose release into the circulation in the postabsorptive state. Fifty per-cent of the glucose entering the circulation is caused by glycogenolysis, and the reminder (5.0 μmol/kg/min) is caused by gluconeogenesis. The proportion caused by gluconeogenesis rapidly increases with the duration of fasting, as glycogen stores become depleted (by 24 h from the last meal). Gluconeogenesis accounts for about 70% of all glucose released into the circulation and, by 48 h, it accounts for over 90% of all glucose released into the circulation.

The kidney normally contains little glycogen, so all the glucose released by the kidney is the result of gluconeogenesis.

Glucose utilisation

Glucose is mainly used by six tissues in the body. These include the brain (45–60%), skeletal muscle (15–20%), kidney (10–15%), blood cells (5–10%), splanchnic organs (3–6%), and adipose tissue (2–4%).

Obesity

Obesity can be described as the accumulation of adipose tissue. The definition of obesity is based on the body mass index (BMI), which is calculated as weight in kilograms divided by height in meters squared (kg/m ² ). Obesity is defined as a BMI greater than 30 kg/m ² , and overweight is defined as a BMI from 25–30 kg/m ² . It is important to remember that, although BMI correlates with the amount of body fat, BMI does not directly measure body fat. The main limitation with using BMI as a calculation is that it does not differentiate fat mass from lean mass. Other methods of estimating body fat and body fat distribution include measurements of skinfold thickness and waist circumference, calculation of waist-to-hip circumference ratios, and techniques such as ultrasound, computed tomography, and magnetic resonance imaging. Measurement of waist circumference as an indicator of excess visceral (or intra-abdominal) fat, which is also known as ‘central obesity’, is regarded as a more accurate indicator of risk than BMI in considering associated health risks. It is carried out by locating the point halfway between the crest of the hip (iliac crest) and the lowest rib at the side, passing the tape measure around the waist parallel to the floor, whilst the person is in expiration (breathing out) with a relaxed abdomen.

A healthy waist measurement is below 37 inches (94 cm) for men and 32 inches (80 cm) for women. The greatest health complications occur with a waist measurement of greater than 40 inches (102 cm) for men and 35 inches (88 cm) for women, although risk increases with increasing waist circumference even at lower levels. An alternative is waist/hip ratio (dividing the waist measurement by the hip measurement). If the waist/hip ratio exceeds 1.0 in men or 0.9 in women, central obesity is diagnosed.

In South Asians and other ethnic groups, lower thresholds are appropriate. On the basis of the available data in Asia, the World Health Organization (WHO) expert consultation concluded that Asians generally have a higher percentage of body fat than white people of the same age, sex, and BMI. Also, the proportion of Asian people with risk factors for type 2 diabetes and cardiovascular disease is substantial even below the existing WHO BMI cut-off point of 25 kg/m ² . Thus, current WHO cut-off points do not provide an adequate basis for taking action on risks related to overweight and obesity in many populations in Asia. The available data, however, do not necessarily indicate one clear BMI cut-off point for all Asians for overweight or obesity. The BMI cut-off point for observed risk in different Asian populations varies from 22 kg/m ² to 25 kg/m ² ; for high risk it varies from 26 kg/m ² to 31 kg/m ² .

In Europe, the prevalence of obesity in men ranges from 4–28% and in women from 6–36%, with a considerable geographic variation. In the USA, it is estimated that about one-third of the adult population are obese. The metabolic syndrome (MetS) is a term that refers to a collection of obesity-related metabolic abnormalities and risk factors that often co-occur in the same individuals. The essential components of MetS are obesity, glucose intolerance, insulin resistance, lipid disturbances, and hypertension, all well documented risk factors for cardiovascular disease.

Genetics of obesity

Unlimited access to food combined with a sedentary life style has contributed to the increase in the incidence of obesity over time. Marked differences in adiposity between individuals, however, seem to be explained mainly by our genes. Heritability estimates from twin studies show that as much as 70% of the individual variation in adiposity between people may be due to genetic factors.

Compelling evidence exists of a genetic variability in the response to changes in energy balance, with strikingly similar weight changes in response to overfeeding or exercise between identical twins, compared with marked differences between unrelated individuals.

Genes that cause rare, monogenic forms of obesity were identified a decade ago. Common for most of these genes is their involvement in hypothalamic regulation of feeding behaviour, including the leptin gene, the pro-opiomelanocortin (POMC) gene, and the melanocortin 4 receptor gene (MC4R). Individuals with defects in these genes typically present with an increased drive to eat and early onset obesity. Research has also revealed some of the low penetrance genes of obesity. There are many examples of genetic polymorphisms (i.e. genetic variants that appear in at least 1% of the population that have been reported to be associated with obesity). To date, however, only a few genes have been identified in which common variants have been consistently associated with BMI in humans, such as the fat mass- and obesity associated (FTO) gene and the MC4R gene.

Adipose tissue

Adipose tissue plays a key role in the development of obesity and metabolic complications. This tissue functions both as an energy store and as a major endocrine organ.

The adipocyte is the main cell type in adipose tissue, but the tissue is also composed of adipocyte precursor cells, stromal-vascular cells, immune cells, and nerve cells.

In mammals, two types of adipose tissues are present: white adipose tissue, which mainly serves as an energy storing tissue, and brown adipose tissue, which is mainly a thermogenic tissue. White adipocytes are characterised by large lipid droplets that occupy the major part of the cytoplasmic space, whereas brown adipocytes contain multiple and relatively smaller lipid droplets and a large number of mitochondria. Brown adipose tissue is abundant in small mammals and in newborns of larger mammals, including humans. In contrast to what was previously believed, a substantial fraction of adult humans possess some amount of active brown adipose.

The core function of the white adipocyte is to store excess energy and to provide other tissues with energy during periods of negative energy balance, by releasing fatty acids and glycerol from lipolysis of triglycerides stored in the adipocyte lipid droplet. The storage function of adipose tissue seems to be an important factor in obesity-related metabolic disorders.

Type 2 diabetes

The risk of type 2 diabetes increases exponentially as BMI increases above about 25 kg/m ² . Compared with a normal BMI of 22 kg/m ² , the risk of type 2 diabetes is increased by two to eight-fold at BMI 25, 10–40-fold at a BMI greater than 30, and over 40-fold at a BMI greater than 35, depending on age, gender, duration and distribution of adiposity and ethnicity. For example, a BMI of 30–35 increased the occurrence of type 2 diabetes by over 20-fold in women and over 10-fold in men.

Excess weight is an established risk factor for abnormal glucose homeostasis and type 2diabetes. Most of the patients with type 2diabetes are obese. The global epidemic of obesity largely explains the dramatic increase in the incidence and prevalence of type 2diabetes over the past 20 years. Currently, over one-third (34%) of US adults are obese (defined as BMI greater than 30 kg/m ² ), and over 11% of people aged 20 years or over have diabetes. This prevalence is projected to increase to 21% by 2050. The precise mechanisms linking the two conditions remain unclear, as most obese individuals do not develop type 2 diabetes. Recent studies have identified ‘links’ between obesity and type 2 diabetes involving proinflammatory cytokines (tumour necrosis factor and interleukin-6), insulin resistance, deranged fatty acid metabolism, and cellular processes, such as mitochondrial dysfunction and endoplasmic reticulum stress. These interactions are complex and not clearly defined. Accumulating evidence shows that even modest weight reduction can improve glycaemic control and reduce diabetes risk.

Mechanisms of obesity-associated insulin resistance

The influence of obesity on type 2 diabetes risk is determined by the degree of obesity and also by where fat accumulates. Increased upper body fat, including visceral adiposity as reflected in increased abdominal girth or waist-to-hip ratio, is associated with the metabolic syndrome, type 2diabetes, and cardiovascular disease.

Visceral adipose tissue displays intrinsic properties that are different from subcutaneous adipose tissue. For example, the rate of lipolysis is higher in visceral than in subcutaneous fat depots, which may be explained by site variations in the function of receptors for insulin, catecholamines and adenosine. One suggested explanation for the adverse effects of visceral obesity is an increased delivery of fatty acids from the visceral depot to the liver via the portal vein, leading to elevated hepatic triglyceride and glucose production and hyperinsulinemia. Another important feature of visceral fat depots is the presence of lymphoid tissue, such as lymph nodes in the mesenteric adipose tissue and milky spots in the omentum. Compared with subcutaneous depots, visceral adipose tissue expresses higher levels of many cytokines, immunoglobulins and complement factors, suggesting a more active role in immune defence. Furthermore, omental and mesenteric adipocytes interact strongly with immune cells, such as dendritic cells and macrophages.

The subcutaneous fat may lack the pathological effects of visceral fat and represent a more neutral storage location. Emerging evidence also suggests that different subtypes of adipose tissue may be functionally distinct and affect glucose homeostasis differentially. Adult humans have limited and variable numbers of brown fat cells, which play a role in thermogenesis and potentially influence energy expenditure and obesity susceptibility. Adipose tissue is composed of heterogeneous cell types. Immune cells within adipose tissue also likely contribute to systemic metabolic processes. At least three distinct mechanisms have been proposed to link obesity to insulin resistance and predispose to type 2diabetes: (1) increased production of adipokines and cytokines, including tumour necrosis factor-alpha, resistin, and retinol-binding protein 4, that contribute to insulin resistance as well as reduced levels of adiponectin ; (2) ectopic fat deposition, particularly in the liver and perhaps also in skeletal muscle, and the dysmetabolic sequelae ; (3) mitochondrial dysfunction, evident by decreased mitochondrial mass, function, or both. Mitochondrial dysfunction can link obesity to diabetes, both by decreasing insulin sensitivity and by compromising beta-cell function.