Diabetes Mellitus

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Questions Received:

  1. Is diabetes mellitus hereditary?

  2. Can you tell me more about diabetes or a web site where I can find more out?

  3. Could you possibly send me any info u may have regarding insulin glargine and it's implications regarding the pre and post op care of the general surgical patient.

Responses:

Is diabetes mellitus hereditary?

23rd March 2000, updated 18th January 2001

Yes, there is a hereditary link. There are two main types of diabetes mellitus:

Type 1 This accounts for about 20% of cases of diabetes mellitus. It tends to have an early onset. It is the result of an autoimmune destruction of the insulin-producing beta cells in the pancreas, and is carried out by T cells of the immune system.

Also known as insulin-dependent diabetes mellitus.

Type 2

 This is the more common type of diabetes: approximately 80% of cases. It tends to have a later onset. 90% of those affected are overweight. In most cases the tissues of the body become insensitive to insulin.

Also known as non-insulin-dependent diabetes mellitus.

The causation of diabetes mellitus is complex and involves both genetic and environmental influences (Davies et al, 1994). Some families are more at risk: if a parent has type 1 diabetes, the risk that their children will be affected is 25% to 40% (Valentine, 1992). In the case of type 1 diabetes, several genes have been implicated. These include genes in the major histocompatibility complex on chromosome 6 and in the insulin region on chromosome 11 (Hashimoto et al, 1994). There is some evidence that a viral infection may be involved in setting off the autoimmune destruction (Benoist and Mathis, 1997).

In the case of type 2 diabetes, the genetic factors linked with insulin resistance are unclear (Kahn, 1995). Although genetic defects in the insulin receptor have been found in a few severe cases of type 2 diabetes, these are thought to be uncommon and it is possible that the fault lies in the signalling process within cells downstream of the insulin receptors. Insulin-receptor substrate proteins (eg: IRS-1 and IRS-2) mediate signals initiated by receptors for insulin and other cytokines and genetic variants of these may contribute to type 2 diabetes (Withers et al, 1998). There is also a suggestion that a newly-identified hormone resistin that is produced by fat cells may provide a link between obesity and type 2 diabetes by increasing insulin resistance (Steppan et al, 2001).

Maturity-onset diabetes of the young (MODY) is an inherited form of type 2 diabetes that appears usually before age 25. Genetic mutations linked with three variants of this disorder have been mapped to chromosomes 20, 7, and 12 (Todd, 1996).

Genetic Factors Linked with Diabetes Mellitus
Type of Diabetes Gene/Molecule Function Effect of Mutation
MODY1 (maturity-onset diabetes of the young type 1) TCF14/HNF-4alpha Hormone Receptor Reduces beta cells' insulin response to glucose
MODY2 GCK/Glucokinase Beta Cell Glucose Sensor - " -
MODY3 TCF1/HNF-1alpha Transcription Factor - " -
Diabetes and Deafness /Transfer RNA Protein Synthesis in Mitochondria Reduces insulin production
Insulin Resistance /Insulin Receptor Detects Insulin and Signals to Cell Insulin resistance
IDDM1 HLA/immune response receptors T-cell activation Autoimmune destruction of beta cells in pancreas
IDDM2 Insulin VNTR/ promoter for insulin gene Affects transcription of insulin gene unknown
Modified from Todd, 1996

References

Can you tell me more about diabetes or a web site where I can find more out?

19th June 2000

Diabetes - derived from the Greek word diabainein, meaning to ‘pass through’

There are two main types of diabetes: diabetes mellitus and diabetes insipidus. Both are associated with increased thirst and the production of more urine than usual. In days gone by the two types of diabetes were distinguished by tasting the urine: in the case of diabetes mellitus the urine had a sweetish taste (mellitus means honey-like) because it contained sugar, while in the case of diabetes insipidus the urine had only a dilute, watery taste. Usually, when people say diabetes they mean diabetes mellitus.

Diabetes Mellitus

< Testing blood sugar level

Most cells in the body require a supply of glucose to meet their energy needs. Diabetes mellitus is a metabolic disorder in which the glucose in the blood cannot be taken up by the cells which need it. As a consequence, cells have to switch over to different energy sources such as fats and protein, and this can give rise to increasing metabolic imbalances. The level of glucose in the blood continues to rise - hyperglycaemia - and this can affect the functioning of vital organs such as the brain. The underlying problem in diabetes mellitus is usually either an inadequate secretion of insulin (the hormone that enables cells to take in the glucose that they need) or a reduction in the responsiveness of tissues to insulin. The long-term effects of diabetes mellitus can be serious if it is not properly controlled and include damage to blood vessels and the structures they supply, damage to the nervous system, skin problems, and problems during pregnancy

 

Diagram showing the main features of diabetes mellitus



Diagram showing the main features of diabetes mellitus

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The main symptoms of diabetes mellitus are increased thirst, the production of more urine than usual, glucose in the urine, blurring of vision, and weight loss. In its most severe form, the person can become comatose and in the absence of effective treatment will die.

Two sub-categories of diabetes mellitus are recognised, together with a number of less-common variants. Diabetes mellitus that is due to inadequate production of insulin by the pancreas as a result of autoimmune destruction of beta cells is called Type 1 diabetes, and is treated by the administration of insulin. Diabetes mellitus that is predominantly due to a reduced responsiveness of cells to insulin, but which might also involve reduced insulin secretion for non-autoimmune reasons, is called Type 2 diabetes. Generally insulin is not required for treatment of Type 2 diabetes.

Type 1 diabetes mellitus

This occurs in about 20% of cases of diabetes mellitus. The incidence of Type 1 onset is highest in young people up to the age of 20, and arises less frequently in adults. The rate of autoimmune destruction of beta cells is quite variable, being rapid in some individuals and slower in others. Type 1 diabetes is usually characterized by the presence in the blood of antibodies against constituents of beta cells.

When insufficient insulin is being released, the uptake of glucose by cells is reduced and blood sugar continues to rise. When the blood sugar level crosses the renal threshold of about 10-12 mmol/L, the excess glucose passes into the urine. The high concentration of glucose in urine increases its osmotic pressure and inhibits the reabsorption of water, resulting in the excretion of large quatities of urine (polyuria). As a result of fluid loss the person with diabetes mellitus may feel continuously thirsty - polydipsia - and will be at risk of dehydration and electrolyte imbalances. Since glucose is being excreted rather than providing energy for the cells, the person may feel tired and lethargic. As fats and proteins are used to meet energy requirements, there may be loss of weight and muscle wasting.

Fat metabolism in the absence of carbohydrate metabolism produces chemicals known as ketones. If these are produced more rapidly than they can be metabolised they accumulate and cause ketoacidosis: the pH of the blood falls (metabolic acidosis), stimulating the respiratory centre so that the respiratory rate rises. The deep sighing inspirations blow off carbon dioxide and hence raise blood pH. The patient's urine and breath smell of pear-drops (acetone) formed during this change in energy metabolism. Ketones are toxic for the central nervous system and lead to depression of activity, drowsiness, and ultimately diabetic coma.

Several beta cell proteins have been identified as autoantigens that may be involved in initiating the autoimmune response. In diabetic mice, the earliest detectable response by the immune system is against a substance called glutamic acid decarboxylase (GAD) which is produced by the beta-cells soon after birth (Kaufman et al, 1993; Tisch et al, 1993). Injection of GAD into susceptible mice before the appearance of diabetes produced tolerance in T-lymphocytes and the disease was prevented in 75% of cases (Kaufman et al, 1993). GAD is an enzyme involved in the synthesis of a signalling molecule - GABA - used by pancreatic beta cells. (GABA is also used as an inhibitory neurotransmitter in the brain.) Antibodies against this protein were found in most newly-diagnosed diabetic patients, and in pre-diabetic patients before the appearance of symptoms.

Type 2 diabetes mellitus

Type 2 occurs in about 80% of cases of diabetes mellitus and is characterized by disorders of insulin action and insulin secretion, either of which may be the predominant feature. At least initially, and often throughout their lifetime, people with Type 2 diabetes do not need insulin treatment. Although the specific cause of this type of diabetes is not known, autoimmune destruction of the pancreas is not involved. The majority of patients with this form of diabetes are obese, and obesity itself causes or aggravates insulin resistance. The effects are not necessarily less serious than those seen in Type 1, although the onset tends to be later in life and slower.

A polypeptide called amylin is deposited in the pancreatic islets of patients who develop Type 2 diabetes. This substance is toxic to pancreatic beta cells and induces apoptosis (Lorenzo et al, 1994). Amylin has a similar composition to the amyloid protein seen in the brains of people with Alzheimer's disease, and is also similar to the prion protein that is linked with the Jakob-Creutzfeldt disease of the brain. Thus, the toxic effects of amyloid materials seem to be involved with several degenerative disorders in humans.

Gestational Diabetes

Gestational diabetes is a form of carbohydrate intolerance that first becomes recognised during pregnancy, and results in hyperglycaemia to different degrees. It is possible that glucose intolerance predates the pregnancy in some cases and then symptoms emerge as the pregnancy progresses.

Diabetes Insipidus

Diabetes insipidus is an uncommon form of diabetes which results either from a failure of the pituitary gland to secrete enough antidiuretic hormone (ADH) or from a failure of the kidneys to respond to ADH. The main symptoms are excessive thirst and the passing of large quantities of dilute urine. If water is unobtainable or witheld, the affected person becomes dehydrated and will eventually become comatose. The condition is treated by giving analogues of ADH such as lypressin or desmopressin.

ADH is a small peptide formed from only 9 amino acids. It is synthesised in the hypothalamus and released from the posterior lobe of the pituitary. The output of ADH is influenced by the osmolarity of the blood and information coming to the hypothalamus from baroreceptors monitoring blood pressure. ADH increases the permeability of the collecting ducts in the kidney to water and urea. It also stimulates the active resoption of sodium chloride by the ascending limb of the loop of Henle and the collecting ducts. The production of ADH is linked with the neurological processes involved in thirst. Diabetes insipidus can be inherited, but this is rare. Usually it is caused by head injuries, brain tumours, or infections of the brain.

References

Useful Websites

There are many excellent websites which cover all aspects of diabetes, including treatment. Here are two from which to begin:

(Clicking on these links will open a new browser window.)

Could you possibly send me any info u may have regarding insulin glargine and it's implications regarding the pre and post op care of the general surgical patient.

18th October 2002

Insulin Glargine

Insulin glargine (GlyA21, ArgB31, ArgB32 - previously known as HOE 901) is a long-acting analogue of human insulin. After injection into the body as an acidic solution, it precipitates in the pH-neutral tissues and is released slowly and evenly into the blood stream over a period of 24 to 36 hours. Small amounts of zinc can be added to the formulation to further delay absorption. Insulin glargine provides a better basal insulin level than traditional extended-action insulins such as NPH (Neutral Protamine Hagedorn) insulin. Clinical trials comparing insulin glargine with NPH insulin show less nocturnal hypoglycaemia, and so far there are no reports of harmful side effects when insulin glargine is used (Gillies, Figgitt, and Lamb, 2000; Home and Ashwell, 2002).

Development of Insulins

For about half a century, animal-derived insulins were used in the treatment of diabetes mellitus, and then in the early 1980s recombinant DNA techniques made human insulin widely available. Over the last decade, insulin analogs have been constructed by changing the structure of the human insulin protein to improve therapeutic activity. The first clinically available insulin analogue, lispro, achieved faster absorption and reached higher blood levels, and was followed by another fast-acting analogue insulin aspart. Then insulin glargine and determir with their long-lasting effects were cleared for clinical use. Several other insulin analogues are now being tested (Vajo, Fawcett, and Duckworth, 2001). It is probable that combinations of both quick and long-acting analogues will lead to better overall glycaemic control (Bolli, 2002; Gerich, 2002; Heller, 2002; Liebl, 2002; Owens and Griffiths, 2002). The Diabetes Treatment Satisfaction Questionnaire has demonstrated improved patient satisfaction with regimens that incorporate the new insulin analogues (Bradley and Speight, 2002). There is also research into new routes of administration of insulin, for example by inhalation of insulin powder and orally, both for treatment and prevention (Gualandi-Signorini and Giorgi, 2001).

Diabetes Mellitus

Diabetes mellitus is broadly classified as type 1, type 2, secondary (eg, due to glucocorticoid administration, Cushing’s syndrome, hemochromatosis, or pancreatectomy), or gestational diabetes (transiently during pregnancy). People with type 1 diabetes comprise approximately 10% of the population with diabetes.They develop hyperglycemia as a result of a loss of beta cell function in the pancreas and need insulin for glucose management. Those with type 2 diabetes develop hyperglycemia as a result of insulin resistance (often associated with obesity), increased hepatic glucose production, and varying degrees of relative or absolute insulinopenia. Secondary forms of diabetes mellitus may mimic features of type 1 diabetes if they result from insulinopenia (eg, pancreatectomy) or type 2 diabetes if they result from insulin resistance (eg, endogenous/exogenous glucocorticoids). Gestational diabetes is most closely related to type 2 diabetes.

Role of Insulin Glargine in Operative Care

Reports on the use of insulin glargine in operative care currently focus on patients with pre-existing diabetes mellitus. Management begins in the preoperative period and extends throughout hospitalization into the postdischarge period (Hirsch et al, 1991; Gavin, 1992; Hoogwerf, 1992; Hirsch, Paauw, and Brunzell, 1995; Peters and Kerner, 1995; Jacober and Sowers, 1999; Gillies, Figgitt, and Lamb, 2000; Hoogwerf, 2001). Glycemic control during hospitalization often requires insulin therapy, and insulin glargine can form a part of this. Complications of diabetes mellitus, including coronary disease, diminished vision, renal impairment, and neuropathy, may have a significant impact on education, recovery times, and risk for adverse outcomes.

Pre-Operative Care

Although evidence is limited, good preoperative glycemic control can improve postoperative outcomes. Patients managed with diet and exercise alone may not need any additional medications preoperatively, but if there is evidence of acute glucose imbalances triggered by medications or underlying disease (eg: infections), some pre-operative insulin preparations (typically intermediate- and short-acting) will be required. Patients with reasonable glycemic control on oral agents should have these agents continued up to the time of surgery. Those on insulin therapy should be continued in the preoperative period. Most individuals require approximately half their normal maintenance dose of insulin even if not allowed preoperatively to consume anything orally. This ‘basal’ insulin can be given in the form of intermediate-acting insulins (isophane, lente, ultralente) or long-acting insulin glargine.

Intraoperative Care

Insulin drips are commonly used during major surgical procedures and are usually maintained by the anaesthesia team.

Post-Operative Care

Postoperative management of diabetes mellitus requires an understanding of disease type, the variables that affect hyperglycemia in the perioperative period, the management strategies for hyperglycemia, and the impact of disease complications. Numerous variables affect glucose control in the postoperative period. Most important are nutrient intake and the type and dose of antihyperglycemic medications. Nutrient intake in the form of intravenous fluids and oral nutrients is often widely variable in the postoperative state. Stress hormone levels in the postoperative state predispose to hyperglycemia. Changes in activity level, infection, and some medications may also increase risk of hyperglycemia. Each must be considered in the perioperative management of the individual with this condition. Adequate postoperative glycemic control is important in people with diabetes to improve wound healing, reduce the risk for wound infections, and improve overall outcomes.

References

Online Resource

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