This section reviews the consequences of insulin deficiency resulting from loss of beta cell mass and function. The earliest abnormalities of beta cell function, detectable before clinical onset, include loss of pulsatile insulin secretion and loss of the first-phase insulin response (FPIR) to intravenous glucose. Insulin secretion declines rapidly before and following onset of symptoms, and reduced insulin action results in increased glucose output by the liver and reduced glucose uptake by insulin sensitive tissues including muscle and fat. Blood glucose rises and spills into the urine, producing an osmotic diuresis. Glucose deprivation in other tissues triggers breakdown of fat and structural proteins, causing rapid weight loss. These changes account for the three leading symptoms of uncontrolled diabetes: thirst, polyuria and weight loss. The underlying metabolic abnormalities are largely − but incompletely − reversed by standard insulin therapy. In the absence of insulin, the 'accelerated starvation' of uncontrolled diabetes is followed by overproduction of acidic ketone bodies, and culminates in the metabolic emergency of diabetic ketoacidosis, the hallmark of type 1 diabetes.

Changes in insulin secretion

The beta cells within each islet are linked into a single functional mass by junctions between the membrane of one cell and the next. This allows depolarization of the cell membrane to propagate throughout the beta cell mass such that the beta cells of each islet release insulin in unison. A neural network links the million or so islets scattered though the pancreas to a putative 'pancreatic pacemaker', enabling them to secrete insulin in synchronous pulses. These pulses, which account for ~70% of insulin production by the liver, were initially believed to occur every 11–13 minutes,[1] but more recent work suggests a 4-minute cycle,[2] potentially regulated by a 'pancreatic pacemaker'. Insulin leaving the pancreas passes into the portal vein via the pancreatic vein, and some 75–85% of insulin secreted by the human pancreas is bound to insulin receptors and cleared on its first passage through the liver.[3] Portal insulin levels are therefore two to three times greater than those in the systemic circulation. Insulin pulses, although greatly 'damped' in the systemic circulation, are still detectable by sophisticated sampling methods, but represent only about 1% of the amplitude seen by the liver. Insulin action upon the liver is regulated by the amplitude, rather than the frequency of secretory pulses, and the amount secreted is determined by the level of glucose and other fuels in blood reaching the beta cell. Experimental delivery of constant as against pulsed levels of insulin causes both loss of insulin sensitivity and decreased insulin clearance by the liver. These observations suggest that (1) pulsed delivery avoids downregulation of insulin receptors on liver cells and (2) that hepatic insulin receptors bind and clear insulin more avidly at the higher concentrations seen at the height of each pulse, thereby regulating the amount reaching the systemic circulation. Partial pancreatectomy demonstrates that pulsatile secretion is lost in proportion to the decrease in beta cell mass, that this results in loss of hepatic insulin sensitivity (restored by pulsatile insulin delivery), and an increase in the proportion of insulin reaching the systemic circulation. The studies described above mainly relate to experimental diabetes in animals and type 2 diabetes in man, but loss of pulsatility has been described in the prodrome to type 1 diabetes.

First-phase insulin response (FPIR)

In contrast to oral administration, glucose injection into the circulation produces a biphasic insulin response, with an immediate first phase lasting ~10 minutes followed by a delayed second phase which peaks after 2–3 hours (Figure). Both phases are reduced prior to the onset of either type 1 or type 2 diabetes, but the focus has been upon FPIR, which is much easier to measure. Loss of the FPIR can be induced by partial pancreatectomy in experimental animals, suggesting that this is a useful index of beta cell mass in humans, although family studies have provided some evidence for a hereditary component in type 2 diabetes.[4] Prospective studies do however suggest that this is an acquired defect in the prodrome to type 1 diabetes and, as such, highly predictive of early clinical onset. As noted above, loss of FPIR is associated with loss of pulsatile insulin secretion, impaired hepatic sensitivity to insulin, and decreased hepatic clearance of insulin.

An overview of intermediary metabolism

The liver is the organ mainly responsible for maintaining glucose homeostasis in the circulation. It achieves this by absorbing and storing surplus glucose following meals, and releasing it in controlled amounts between meals; both functions are regulated by insulin. Glucose may be stored as liver glycogen, which provides a rapid-response source of circulating glucose, although with a storage capacity limited to about 50 g. Most of the glucose produced by the liver is derived from gluconeogenesis, a process by which 3-carbon molecules reaching the liver such as lactate, alanine and glycerol are synthesised into the 6-carbon glucose molecule. Gluconeogenesis also occurs in the renal cortex, which accounts for ~10% of total glucose production.

High insulin concentrations promote the formation of glycogen and suppress glucose production by gluconeogenesis. Glucose output is regulated by the reciprocal balance between insulin and glucagon; low insulin and high glucagon promote glucose release and high insulin and low glucagon promote glucose uptake. Counter-regulatory or 'stress' hormones such as adrenaline (epinephrine) and cortisol also promote glucose output. The liver produces about 140 g of glucose each day, of which 40–50% is metabolised aerobically to carbon dioxide and water by the brain, which is an obligate glucose consumer under normal physiological conditions. The energy it derives from glucose is mainly required to drive the membrane pumps which maintain the potential difference across nerve membranes. Glucose not required by the brain is consumed by other glucose-requiring tissues such as red blood cells or the brush border of the intestine, or taken up into muscle of fat under the influence of increased insulin levels, which promote glucose entry by activation of glucose-transporter-4 (GLUT-4). Glucose is phosphorylated within the cell, and stored as glycogen in muscle or triacylglycerol within fat cells.

Consequences of insulin deficiency

Insulin deficiency results in reduced inhibition of gluconeogenesis and overproduction of glucose by the liver. Glucose can still enter nervous tissue and other tissues whose glucose transporters are unaffected by insulin, but glucose entry into insulin responsive tissues such as muscle and fat is reduced. Plasma glucose rises, and exceeds the ability of glucose transporters located in the proximal renal tubules to reabsorb glucose before it enters the urine, otherwise known as the renal threshold for glucose. As glucose passes through the renal tubules it established an osmotic gradient which takes with it salt and other electrolytes which are thus lost to the body. Excessive urination (which gave rise to the Greek name 'diabetes') results and leads to an intense thirst. Insulin levels fall in healthy individuals during prolonged fasts, allowing catabolism (breakdown) of fat and non-essential proteins which serve as reserve fuels. The insulin deficiency of diabetes creates a state resembling an accelerated fast, and rapid weight loss results from the combined loss of tissue mass and fluid.

Ketone bodies are organic acids formed within the liver mitochondria as the result of fatty acid breakdown, a process readily inhibited by insulin at low concentrations. Extreme insulin deficiency, as encountered in type 1 but not type 2 diabetes, results in loss of this inhibition and overproduction of ketones. The resulting metabolic acidosis is associated with nausea and profuse vomiting, which exacerbates the loss of fluid and electrolytes via the kidney. This sequence of events culminates in the metabolic emergency of diabetic ketoacidosis which (as the name implies) represents the combination of hyperglycaemia, ketosis and acidosis, a condition that was invariably fatal prior to the introduction of insulin.


  1. ^ Lang DA et al. Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man. Diabetes 1981;30:435–9

  2. ^ Song SH et al. Direct measurement of pulsatile insulin secretion from the portal vein in human subjects. J Clin Endocrinol Metab 2000;85:4491–9

  3. ^ Meier JJ et al. Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. Diabetes 2005;54:1649–56

  4. ^ Gerich JE. Is reduced first phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes? Diabetes 2002;51(Suppl 1):S117–S121


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