Physiology1

The adult human pancreas is made up of numerous collections of cells called islets of Langerhans. There are about 1–2 million islets and it makes up only about 2% volume of the pancreas, while the rest constitutes ducts, blood vessels and the larger exocrine portion of the pancreas made of acini which secrete digestive juice.

α cells: Produce glucagon. It increases plasma glucose by increasing hepatic glycogenolysis and gluconeogenesis; increases lipolysis.

β cells: The majority of cells in the islets of Langerhans are β cells, i.e. about 60–70%. They produce insulin, which is anabolic in nature. The effects of insulin are discussed further along in this chapter.

Δ cells: Produce somatostatin, which acts locally in a paracrine manner and inhibits secretion of pancreatic polypeptide, insulin and glucagon.

F (or PP) cells: Produce pancreatic polypeptide, which slows absorption of food, but its physiological significance is uncertain.

Insulin is synthesized in the rough endoplasmic reticulum of the β cells. It is then packed into secretory granules in the golgi apparatus and released by exocytosis.

Insulin receptors are present in almost all cells of the body. It is a glycoprotein made of 2 α and 2 β subunits linked by disulfide bridges (Fig. 1.3).

Insulin binds to the α subunit of its receptor. This binding triggers tyrosine kinase activity in the β subunit and causes autophosphorylation of the β subunit. This in turn causes either phosphorylation or dephosphorylation of certain proteins and enzymes in the cytoplasm, activating some and inactivating some, thus bringing about the actions of insulin. One of the cytoplasmic substrates for insulin action is the insulin receptor substrate or IRS-1. Protein synthesis and growth promoting actions of insulin are mediated through phosphoinositol 3-kinase (PI3K) pathway.

Insulin increases movement of potassium into cells which is probably due to activation of sodium potassium ATPase. The sodium potassium ATPase, which is present on the cell membrane, pumps out sodium and pumps potassium into the cells. Diabetic ketoacidosis, when treated vigorously with insulin can cause hypokalemia due to movement of potassium into cells. Thus, potassium levels need to be monitored in addition to the blood glucose levels, and potassium supplements should be given, if necessary. Insulin is used in the treatment of hyperkalemia but glucose needs to be supplemented simultaneously due to the hypoglycemic effect of insulin.

The effects of insulin can occur within seconds to several hours

The entry of glucose into cells is by the process of facilitated diffusion, with the help of glucose transporters, GLUT 1 to GLUT 7. The glucose transporter in muscle and adipose tissue which is stimulated by insulin is GLUT 4 (Fig. 1.5). Glucose transportation into the intestines and kidneys is by secondary active transport via SGLT 1 and SGLT 2 (sodium dependent glucose transporters).

The most important regulator of insulin secretion is the direct feedback of plasma glucose on the β cells.

6Metformin reduces blood glucose by reducing hepatic gluconeogenesis and thus reduces glucose output from the liver. Thiazolidinediones (Rosiglitasone, Pioglitazone) reduce the insulin resistance or increase the insulin sensitivity (insulin stimulated glucose uptake) by activating peroxisome proliferator-activated receptors (PPARγ) in the cell nucleus.

Glucagon-like peptide (GLP)-1 is a gut hormone that stimulates insulin secretion, gene expression, and β-cell growth. Together with the related hormone, glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect- the augmentation of insulin secretion by oral as opposed to intravenous administration of glucose.

GIP is a peptide of 42 amino acids belonging to the glucagon-secretin family of peptides, the members of which have pronounced sequence homology, particularly in the NH₂-terminus. It is processed from a 153 amino acids precursor, but specific functions for other fragments of the precursor have not been identified. It is expressed in the islets and also in the gut, adipose tissue, heart, pituitary, adrenal cortex, and several regions of the brain. GIP is secreted from specific endocrine cells called K cells, with highest density in the duodenum but also found in the entire small intestinal mucosa. Secretion is stimulated by absorbable carbohydrates and by lipids. GIP secretion is, therefore, greatly increased in response to meals, resulting in,10–20 fold elevations of the plasma concentration.

Glucagon-like peptide (GLP-1) is one of the most potent incretin hormone produced by the L-cells of the intestinal mucosa. Its insulin-releasing property exceeds that of GIP. It is produced by tissue-specific post-transational processing of the glucagon gene which is expressed not only in the islet cells but also in the L-cells, one of the most abundant endocrine cells of the gut. Unlike in the islets where proglucagon is cleaved to form glucagon (Fig. 1.8), in the L-cells, the COOH – terminal part is cleaved to give rise to GLP-1 and GLP-2, both showing 50% sequence homology with glucagon.

GLP-1 rapidly and potently stimulates insulin secretion. GLP-1 also stimulates insulin gene transcription, islet cell growth and neogenesis, additional potentially important functions that may be clinically relevant for the treatment of diabetes.9

GLP-1 decreases gastric motility via direct effects on gastric smooth muscle and also inhibits postprandial acid secretion. It also decreases small intestinal movement through inhibition of smooth muscle activity, resulting in an overall reduction in the absorption of nutrients from the GI tract. It is more likely that reduced motility causes less severe postprandial glucose fluctuations and reduces the need for a large and rapid postprandial insulin response.

GLP-1 has profound effects on feeding behavior. Although these actions of GLP-1 could be partly related to its effects on intestinal motility, they also appear to directly affect the hypothalamic feeding centers as GLP-1 receptors are found in specific nuclei within the hypothalamus. Studies have shown that acute administration of GLP-1 induces satiety and decreases calorie intake. In humans with type 2 diabetes, short-term GLP-1 or exendin-4 administration curbs appetite and food intake in addition to its insulinotropic actions, suggesting in long-term this will promote weight loss in these patients. The ability of GLP-1 analogs to promote weight loss and improve ß cell function has made these agents useful for the treatment of type 2 diabetes.

In a nutshell, anti-diabetic potential of GLP-1 is mediated by the following mechanisms:

Substances with insulin-like activity include IGF I and IGF II (insulin like growth factors) also called somatomedins. They are synthesized and secreted by liver, cartilage and other tissues in response to growth hormone. The IGF receptor and the insulin receptor are very similar. Their activity is weak when compared with insulin and cannot replace insulin. The insulin like growth factors are mainly concerned with growth.

Diabetes mellitus (DM) is a chronic disorder characterized by fasting and/or postprandial hyperglycemia with plasma glucose levels that are above defined limits during oral glucose tolerance testing or random blood glucose measurements, as defined by established criteria.

There is absolute insulin deficiencydue to autoimmune destruction of β cells. There is also a genetic susceptibility to the disease. The main genetic abnormality is in the major histocompatability complex on chromosome 6. This usually presents at a younger age.10

This occurs due to insulin resistance or insensitivity of tissues to insulin and relative insulin deficiency (and may later lead to absolute insulin deficiency).

Decreased entry of glucose into insulin-sensitive cells and also increased release of glucose from the liver leads to hyperglycemia. Glucose is a major source of energy in the cell and due to deficient intracellular glucose, protein and fat reserves are used for energy. The increased breakdown of fat leads to ketosis. Polyuria, polydypsia and polyphagia are seen in some diabetic patients. The renal threshold for glucose is 180 mg%, i.e. if the plasma glucose value is raised above 180 mg%, the ability of the kidney to reabsorb glucose is exceeded and glucose will start appearing in urine (glycosuria). Thus, as glucose is lost in the urine, water is osmotically dragged along with it (osmotic diuresis), leading to an increased urine output (polyuria). Since lot of water is lost in the urine, it leads to dehydration and this triggers the processes regulating water intake and causes increased thirst (polydypsia). Electrolytes are also lost in the urine. The quantity of glucose lost in urine is enormous and thus to maintain energy balance the patient takes in large quantities of food. Reduced glucose utilization by the ventromedial nucleus of hypothalamus (satiety center) is also possibly the cause for the polyphagia.

There is increased breakdown of lipids and decreased formation of fatty acids and triglycerides. Increased fat breakdown leads to increased formation of ketone bodies, which leads to ketosis and acidosis. The ketone bodies include acetoacetate, acetone and β-hydroxybutyrate. The hydrogen ions formed from acetoacetate and β-hydroxybutyrate are buffered to a great extent, beyond which metabolic acidosis occurs. The pH drops due to the acidosis and the increased hydrogen ion concentration stimulates the respiratory center causing the characteristic rapid and regular deep breathing called Kussmaul breathing.

There is decreased protein synthesis and increased protein breakdown leading to protein catabolism and muscle wasting. There is increased plasma amino acids and nitrogen loss in urine. All this leads to negative nitrogen balance and protein depletion. Protein depletion causes poor resistance to infections. There is increased gluconeogenesis in the liver since the amino acids are converted to glucose.

Diabetics are more prone for myocardial infarctions and stroke because the cholesterol levels are elevated causing atherosclerosis. This is due to an increase in LDL (low-density lipoprotein) and VLDL (very 11low-density lipoprotein) levels in the plasma, probably because of either augmented production of VLDL in the liver or decreased removal of LDL and VLDL from the blood stream (Table 1.1).

Long standing uncontrolled diabetes can lead to

Causes for delay in wound healing and gangrene in diabetes include: