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Anaesthetic management of patients with diabetes mellitus

2000; Elsevier BV; Volume: 85; Issue: 1 Linguagem: Inglês

10.1093/bja/85.1.80

1471-6771

Greg McAnulty, Heidi Robertshaw, G. M. Hall,

Cardiac, Anesthesia and Surgical Outcomes

Br J Anaesth 2000; 85: 80–90 The prevalence of diabetes mellitus in both adults and children has been steadily rising throughout the world for the past 20–30 yr.29Gardner SG Bingley PJ Sawtell PA Weeks S Gale EAM Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford region: time trend analysis.Br Med J. 1997; 315: 713-717Crossref PubMed Google Scholar 55King H Rewers M Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults.Diabetes Care. 1993; 16: 157-177Crossref PubMed Google Scholar 97Ruwaard D Hirasing RA Reeser HM et al.Increasing incidence of type I diabetes in The Netherlands. The second nationwide study among children under 20 years of age.Diabetes Care. 1994; 17: 599-601Crossref PubMed Google Scholar Recent changes in diagnostic criteria, if widely adopted, will probably also lead to more patients being classified as having diabetes.16DECODE Study Group, on behalf of the European Diabetes Epidemiology Study Group Will new diagnostic criteria for diabetes mellitus change phenotype of patients with diabetes? Reanalysis of European epidemiological data.Br Med J. 1998; 317: 371-375Crossref PubMed Google Scholar Inevitably, diabetic patients presenting for incidental surgery, or surgery related to their disease, will place an increasing burden on anaesthetic services. Conflict will occur between an economic need to minimize hospital stay and traditional approaches to managing perioperative diabetic patients that rely on a period of inpatient preoperative 'stabilization'. Better glycaemic control in diabetic patients undergoing major surgery has been shown to improve perioperative mortality and morbidity.44Hickman MS Schwesinger WH Page CP Acute cholecystitis in the diabetic. A case–control study of outcome.Arch Surg. 1988; 123: 409-411Crossref PubMed Google Scholar 90Risum O Abdelnoor M Svennevig JL et al.Diabetes mellitus and morbidity and mortality risks after coronary artery bypass surgery.Scand J Thorac Cardiovasc Surg. 1996; 30: 71-75Crossref PubMed Google Scholar Simple avoidance of hypoglycaemia and gross hyperglycaemia are no longer adequate in the light of this knowledge. While there can be little argument about the management of diabetic patients undergoing major procedures, their management for minor surgery is an increasing dilemma. Under what circumstances are day-case anaesthesia and surgery appropriate? Does admission on the day of surgery add to the risk for the diabetic patient? What investigations, if any, are needed to assess the cardiovascular system of an asymptomatic diabetic who presents for major surgery? Unfortunately, there are few data to provide answers to these questions. An understanding of the pathophysiology of diabetes and of the importance of recent research should improve the perioperative care of diabetic surgical patients. This review will discuss some recent developments in the field. It will not provide 'recipes' or algorithms for management. These can be found in any of the standard texts. Recently, both the American Diabetes Association (ADA) and the World Health Organization (WHO) published recommendations for new diagnostic criteria for diabetes mellitus.1Alberti KGMM Zimmet PZ for the WHO Consultation Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation.Diabet Med. 1998; 15: 539-553Crossref PubMed Scopus (0) Google Scholar 106The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus.Diabetes Care. 1997; 20: 1183-1197Crossref PubMed Google Scholar Both bodies advise a reduction in the threshold limit for fasting plasma glucose concentrations and reaffirm a more aetiologically based nomenclature. The terms type 1 (pancreatic B-cell destruction) and type 2 (defective insulin secretion and, usually, insulin resistance) diabetes are recommended to replace completely the frequently misleading terms 'insulin-dependent' and 'non-insulin-dependent' diabetes. The ADA has specified that the diagnosis of diabetes mellitus should be made if a 'casual' (random) plasma glucose value in an asymptomatic individual is >11.1 mmol litre−1. If a fasting plasma glucose is >7.0 mmol litre−1 (6.1 mmol litre−1 blood glucose) in an asymptomatic individual, the test should be repeated on a different day and a diagnosis made if the value remains above this limit. The ADA defines fasting plasma glucose concentrations between 6.1 and 7.0 mmol litre−1 (5.6–6.1 mmol litre−1 blood glucose) as representing 'impaired fasting glycaemia'. The WHO also recommends that a diagnosis of diabetes mellitus be made if a random plasma glucose concentration is >11.1 mmol litre−1 (venous whole blood >10.0 mmol litre−1). It can also be diagnosed with a fasting plasma glucose concentration of >7.0 mmol litre−1 and a second similar test or an oral glucose tolerance test producing a result in the diabetic range. The change in the fasting plasma glucose concentrations used to define diabetes and the role of a standard oral glucose tolerance test may make it difficult to compare epidemiological studies using these new criteria with those using previous ones. Inevitably, some individuals will be diagnosed as having diabetes using criteria based solely on (lower) fasting plasma glucose concentrations who would not have been so diagnosed under the earlier definitions. There will be others who would have fulfilled the definition using an oral glucose tolerance test but who will have acceptable fasting values. Thus it is likely that the new definitions will define as diabetic a group of glucose intolerant individuals.52Keen H Impact of new criteria for diabetes on pattern of disease.Lancet. 1998; 352: 1000-1001Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In addition to the two common types of diabetes, a number of causes of glucose intolerance can be defined according to a specific causal or pathological process. Gestational diabetes is glucose intolerance which has its onset in, or is first diagnosed during, pregnancy. The severity varies and the definition applies whether or not insulin is administered in treatment. Women with diabetes diagnosed before pregnancy are defined as having 'diabetes mellitus and pregnancy', not gestational diabetes.1Alberti KGMM Zimmet PZ for the WHO Consultation Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation.Diabet Med. 1998; 15: 539-553Crossref PubMed Scopus (0) Google Scholar The neonatal outcome of type 1 diabetic women who become pregnant is poor. Their infants are approximately five times more likely to be stillborn and 10 times more likely to have congenital malformations than those born to non-diabetic mothers.10Casson IF Clarke CA Howard CV et al.Outcomes of pregnancy in insulin dependent diabetic women: results of a five year population cohort study.Br Med J. 1997; 315: 275-278Crossref PubMed Google Scholar Management in a specialist centre may improve the incidence of perinatal mortality.34Hadden DR How to improve prognosis in type 1 diabetic pregnancy. Old problems, new concepts.Diabetes Care. 1999; 22: B104-B108PubMed Google Scholar Abnormally increased membrane transport of glucose, even in mothers whose diabetes is well controlled, may explain the continuing high rates of congenital malformations (particularly macrosomia) despite improved treatment.48Jansson T Wennergren M Powell TL Placental glucose transport and GLUT 1 expression in insulin-dependent diabetes.Am J Obstet Gynaecol. 1999; 180: 163-168Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Increasing the frequency of insulin administration from two to four times daily during pregnancy can lead to better maternal glycaemic control with a lower incidence of neonatal hypoglycaemia and hyperbilirubinaemia without increasing the risk of maternal hypoglycaemia.73Nachum Z Ben-Shlomo I Weiner E Shalev E Twice daily versus four times daily insulin regimens for diabetes in pregnancy: randomised controlled trial.Br Med J. 1999; 319: 1223-1227Crossref PubMed Google Scholar There is a number of rare genetic causes of glucose intolerance. Among these are defects of B-cell function (formerly called maturity-onset diabetes of the young, or MODY) and defects in insulin action (formerly called type A insulin resistance). Diffuse diseases of the exocrine pancreas (such as pancreatitis), specific viral infections which destroy pancreatic B cells (rubella, Coxsackie B, cytomegalovirus, mumps and others) and immune-mediated processes (insulin autoantibodies or insulin receptor antibodies) can also lead to a 'diabetic state'.1Alberti KGMM Zimmet PZ for the WHO Consultation Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation.Diabet Med. 1998; 15: 539-553Crossref PubMed Scopus (0) Google Scholar Endocrinopathies associated with excess secretion of counter-regulatory hormones (such as growth hormone, cortisol, glucagon and epinephrine) can lead to hyperglycaemia. A number of drugs can induce glucose intolerance either by inhibiting the secretion of insulin or by interfering with the peripheral action of insulin.1Alberti KGMM Zimmet PZ for the WHO Consultation Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation.Diabet Med. 1998; 15: 539-553Crossref PubMed Scopus (0) Google Scholar In anaesthesia, glucocorticoids and adrenergic agonists are most frequently implicated. The new oral corticosteroid, deflazacort, may be less 'diabetogenic' than prednisolone or betamethasone.2Anon Deflazacort—an alternative to prednisolone?.Drug Ther Bull. 1999; 37: 57-58Crossref PubMed Google Scholar 'Metabolic syndrome' (also called syndrome X or insulin resistance syndrome) is a non-causally linked cluster of symptoms which carry a high risk of macrovascular disease. The cluster includes impaired glucose tolerance or diabetes, insulin resistance, raised arterial pressure, raised plasma triglycerides, central obesity and microalbuminuria.1Alberti KGMM Zimmet PZ for the WHO Consultation Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation.Diabet Med. 1998; 15: 539-553Crossref PubMed Scopus (0) Google Scholar Type 1 diabetics completely lack insulin secretion, making them prone to lipolysis, proteolysis and ketogenesis. These processes are inhibited by minimal levels of insulin secretion and are rare in type 2 diabetics unless there is an additional stress such as sepsis or dehydration.122Westphal SA The occurrence of diabetic ketoacidosis in non-insulin-dependent diabetics and newly diagnosed diabetic adults.Am J Med. 1996; 101: 19-24Abstract Full Text PDF PubMed Scopus (0) Google Scholar Obviously, both groups are subject to the effects of hyperglycaemia. Diabetics are at increased risk of myocardial ischaemia, cerebrovascular infarction and renal ischaemia because of their increased incidence of coronary artery disease,94Rodriguez BL Lau N Burchfiel CM et al.Glucose intolerance and 23-year risk of coronary heart disease and total mortality: the Honolulu Heart Program.Diabetes Care. 1999; 22: 1262-1265Crossref PubMed Scopus (0) Google Scholar arterial atheroma51Keen H Jarrett RJ Fuller JH McCartney P Hyperglycemia and arterial disease.Diabetes. 1981; 30: 49-53Crossref PubMed Google Scholar and renal parenchymal disease.14Culleton BF Larson MG Evans JC et al.Prevalence and correlates of elevated serum creatinine levels: the Framingham Heart Study.Arch Intern Med. 1999; 159: 1785-1790Crossref PubMed Scopus (161) Google Scholar Increased mortality is found in all diabetics undergoing surgery44Hickman MS Schwesinger WH Page CP Acute cholecystitis in the diabetic. A case–control study of outcome.Arch Surg. 1988; 123: 409-411Crossref PubMed Google Scholar 90Risum O Abdelnoor M Svennevig JL et al.Diabetes mellitus and morbidity and mortality risks after coronary artery bypass surgery.Scand J Thorac Cardiovasc Surg. 1996; 30: 71-75Crossref PubMed Google Scholar and type 1 diabetics are particularly at risk of post-operative complications.111Treiman GS Treiman RL Foran RF et al.The influence of diabetes mellitus on the risk of abdominal aortic surgery.Am Surg. 1994; 60: 436-440PubMed Google Scholar Increased wound complications are associated with diabetes24Folk JW Starr AJ Early JS Early wound complications of operative treatment of calcaneus fractures: analysis of 190 fractures.J Orthop Trauma. 1999; 13: 369-372Crossref PubMed Scopus (200) Google Scholar 64Maher M Singh HP Dias S Street J Aherne T Coronary artery bypass surgery in the diabetic patient.Ir J Med Sci. 1995; 164: 136-138Crossref PubMed Google Scholar 72Mossad SB Serkey JM Longworth DL Cosgrove DM Gordon SM Coagulase-negative staphylococcal sternal wound infections after open-heart operations.Ann Thorac Surg. 1997; 63: 395-401Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar 126Zacharias AZ Habib RH Factors predisposing to median sternotomy complications.Chest. 1996; 110: 1173-1178Abstract Full Text Full Text PDF PubMed Google Scholar and anastomotic healing is severely impaired when glycaemic control is poor.118Verhofstad HJ Hendriks T Complete prevention of impaired anastomotic healing in diabetic rats requires preoperative blood glucose control.Br J Surg. 1996; 83: 1717-1721Crossref PubMed Google Scholar The 'stress response' to surgery is associated with hyperglycaemia in non-diabetic patients as a result of increased secretion of catabolic hormones in the presence of a relative insulin deficiency. This deficiency arises from a combination of reduced insulin secretion41Halter JB Pflug AE Effects of anesthesia and surgical stress on insulin secretion in man.Metabolism. 1980; 29: 1124-1127Abstract Full Text PDF PubMed Google Scholar and insulin resistance.109Thorell A Nygren J Hirshman MF et al.Surgery-induced insulin resistance in human patients: relation to glucose transport and utilization.Am J Physiol. 1999; 276: E754-E761PubMed Google Scholar Insulin resistance may result, in part, from the increase in secretion of catecholamines, cortisol and growth hormone42Halter JB Pflug AE Relationship of impaired insulin secretion during surgical stress to anesthesia and catecholamine release.J Clin Endocrinol Metab. 1980; 51: 1093-1098Crossref PubMed Google Scholar and involves an alteration of post-receptor binding of insulin and subsequent reduction of trans-membrane glucose transport.79Nordenstrom J Sonnenfield T Arner P Characterization of insulin resistance after surgery.Surgery. 1989; 105: 28-35PubMed Google Scholar Some, at least, of the metabolic effects of the suppression of insulin secretion are reversed by intraoperative insulin infusion37Hall GM Walsh ES Paterson JL Mashiter K Low-dose insulin infusion and substrate mobilisation during surgery.Br J Anaesth. 1983; 55: 939-945Crossref PubMed Google Scholar and both oral and i.v. perioperative administration of glucose enhance postoperative glucose utilization rates.56Kingston WJ Livingston JN Moxley RT Enhancement of insulin action after oral glucose ingestion.J Clin Invest. 1986; 77: 1153-1162Crossref PubMed Google Scholar 62Ljungqvist O Thorell A Gutniak M Haggmark T Efendic S Glucose infusion instead of preoperative fasting reduces postoperative insulin resistance.J Am Coll Surg. 1994; 178: 326-329PubMed Google Scholar 80Nygren J Soop M Thorell A Efendic S Nair KS Ljungqvist O Preoperative oral carbohydrate administration reduces postoperative insulin resistance.Clin Nutr. 1998; 17: 65-71Abstract Full Text PDF PubMed Scopus (176) Google Scholar The consequences of a reduction in, or complete lack of, insulin-mediated metabolic processes can be classified according to chronicity and to histopathological effects. Acute consequences of untreated, or inadequately treated, diabetes mellitus include dehydration (resulting from the osmotic diuretic effect of glycosuria), acidaemia (because of accumulation of lactic and/or ketoacids), fatigue, weight loss and muscle wasting (because of lipolysis and proteolysis in absolute insulin deficiency). Ketoacidosis is rare in type 2 diabetics but is frequently a presenting symptom of type 1 disease. It is a medical emergency that still carries a considerable mortality rate of up to 15%.4Basu A Close CE Jenkins D Krentz AJ Nattrass M Wright AD Persisting mortality in diabetic ketoacidosis.Diabet Med. 1993; 10: 282-284Crossref PubMed Scopus (0) Google Scholar 49Japan and Pittsburgh Childhood Diabetes Research Groups Coma at the onset of young insulin-dependent-diabetes in Japan: the results of a nationwide survey.Diabetes. 1985; 34: 1241-1246Crossref PubMed Google Scholar The mortality of hyperosmolar non-ketotic hyperglycaemic coma in type 2 diabetics may be even greater,63Lorber D Nonketotic hypertonicity in diabetes mellitus.Med Clin North Am. 1995; 79: 39-52Abstract Full Text PDF PubMed Google Scholar probably reflecting a more elderly population with a higher incidence of co-existing disease. Ketoacidosis is treated by rehydration and insulin infusion with frequent measurements of serum electrolytes and acid–base status. Sequential estimations of blood β-hydroxybutyrate concentrations and concomitant continuation of intensive insulin therapy may expedite treatment.124Wiggam MI O'Kane MJ Harper R et al.Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management.Diabetes Care. 1997; 20: 1347-1352Crossref PubMed Google Scholar Non-ketotic hyperglycaemic coma is frequently precipitated by infection and is commonly associated with multi-organ system dysfunction. Blood glucose concentrations may be extremely high.33Gupta S Prabhu MR Gupta MS Niblett D Severe non-ketotic hyperosmolar coma—intensive care management.Eur J Anaesthesiol. 1998; 15: 603-606Crossref PubMed Google Scholar Chronic effects of diabetes can be divided into microvascular (including proliferative retinopathy and diabetic nephropathy), neuropathic (autonomic and peripheral neuropathies) and macrovascular complications (atherosclerotic disease). The incidence of microvascular and neuropathic complications in types 1 and 2 diabetics is similar when adjusted for duration of disease and quality of glycaemic control. The cumulative lifetime incidence of proliferative retinopathy, proteinuria and distal neuropathy is roughly 50% for both type 1 and type 2 diabetics. This implies that the primary cause of these complications is hyperglycaemia itself, as the underlying metabolic pathology is different for type 1 and type 2 disease.31Gaster B Hirsch IB The effects of improved glycemic control on complications in type 2 diabetes.Arch Intern Med. 1998; 158: 134-140Crossref PubMed Scopus (0) Google Scholar Macrovascular complications (as measured by rates of coronary artery, cerebrovascular and peripheral vascular disease) are also similar for type 1 and 2 diabetics (cardiovascular mortality is 30–54% for type 1 and 38–41% for type 2 diabetes).31Gaster B Hirsch IB The effects of improved glycemic control on complications in type 2 diabetes.Arch Intern Med. 1998; 158: 134-140Crossref PubMed Scopus (0) Google Scholar In type 2 patients, at least, abnormally high concentrations of plasminogen activator inhibitor-1 (PAI-1) and, therefore, impaired fibrinolysis, have been implicated in the accelerated rates of development of atherosclerotic disease.83Panahloo A Yudkin JS Diminished fibrinolysis in diabetes mellitus and its implication for diabetic vascular disease.J Cardiovasc Risk. 1997; 4: 91-99Crossref PubMed Scopus (0) Google Scholar Improved glycaemic control has a beneficial effect on microvascular and neuropathic complications in type 2 diabetes.114UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (14965) Google Scholar Although there is probably no adverse effect,83Panahloo A Yudkin JS Diminished fibrinolysis in diabetes mellitus and its implication for diabetic vascular disease.J Cardiovasc Risk. 1997; 4: 91-99Crossref PubMed Scopus (0) Google Scholar improvement in glycaemic control alone appears not to improve the incidence of macrovascular disease in these patients.114UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (14965) Google Scholar However, tight control of blood pressure (with an angiotensin-converting enzyme inhibitor or a β-blocker) in patients with type 2 diabetes and hypertension reduces the risk of diabetes-related death, including that secondary to macrovascular complications, as well as the risk of other diabetes-related complications and eye disease.115UK Prospective Diabetes Study Group Efficacy of atenolol and captopril in reducing macrovascular and microvascular complications in type 2 diabetes: UKPDS 39.Br Med J. 1998; 317: 713-720Crossref PubMed Google Scholar 116UK Prospective Diabetes Study Group Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes UKPDS 38.Br Med J. 1998; 317: 703-712Crossref PubMed Scopus (0) Google Scholar Insulin is secreted into the bloodstream from pancreatic B cells via the portal system so that there is normally a portal–peripheral insulin concentration gradient which cannot be mimicked by subcutaneous or i.v. insulin administration. Additionally, even the most sophisticated artificial insulin delivery systems cannot hope to replicate the complex local interaction between the B cells and A, D and PP cells of the islets of Langerhans (which secrete glucagon, somatostatin and pancreatic polypeptide, respectively) and the effects of the extrapancreatic neurohormonal system. Insulin secretion in response to varying states of feeding or starvation changes by 20- to 50-fold and maintains a basal insulin secretion during the fasting state. Insulin administered subcutaneously, even if timed optimally, will inevitably have inadequate peak concentrations for expected postprandial periods, and its duration of action may be frequently too short to avoid periods of hypoinsulinaemia and subsequent risk of lipolysis and proteolysis in patients with no endogenous insulin secretion. Insulin is synthesized in the pancreas as part of a longer-chain protein called proinsulin. This is cleaved by membrane-bound proteases producing the polypeptides insulin and C-peptide. These two polypeptides are secreted into the circulation in equimolar amounts. C-peptide is useful experimentally in determining native insulin production in type 2 diabetic subjects receiving insulin. It was once thought that C-peptide had no physiological role other than facilitating the folding of the proinsulin molecule. However, more recent studies point to a possible role for C-peptide in glucose transport in skeletal muscle, renal tubular function and in the prevention of autonomic neuropathy.119Wahren J Johansson B-L Wallberg-Henriksson H Does C-peptide have a physiological role?.Diabetologia. 1994; 37: S99-107Crossref PubMed Scopus (0) Google Scholar Type 1 diabetics require insulin. Type 2 diabetics may require insulin but, in many cases, maintain reasonable glycaemic control with an appropriate diet and often the use of oral hypoglycaemic drugs. Therapeutic insulin may be extracted from beef (now rarely used) or pork pancreas, or synthesized using recombinant DNA technology from Escherichia coli.6British National Formulary. British Medical Association, Royal Pharmaceutical Society of Great Britain, London1999: 302-306Google Scholar The amino acid sequences of insulin differ somewhat between species; however, modifying porcine insulin can produce human-sequence insulin. It was hoped that the replacement of animal- by human-sequence insulins would reduce the induction of antibodies and therefore insulin resistance, but clinical trials have been disappointing.66Maran A Lomas J Archibald H Macdonald IA Gale EA Amiel SA Double blind clinical and laboratory study of hypoglycaemia with human and porcine insulin in diabetic patients reporting hypoglycaemia unawareness after transferring to human insulin.Br Med J. 1993; 306: 167-171Crossref PubMed Google Scholar The three types of insulin preparation are classified according to their length of action. Soluble insulins have a rapid onset and short duration of action (depending upon the route of administration). When injected subcutaneously the duration of action is from 30 min up to 8 h with a peak at 2–4 h. Human-sequence soluble insulin has a slightly shorter onset time and duration of action. Insulin lispro, a recently introduced recombinant human insulin analogue, has an even shorter duration of action. Soluble insulin injected i.v. has a half-life of approximately 5 min.6British National Formulary. British Medical Association, Royal Pharmaceutical Society of Great Britain, London1999: 302-306Google Scholar Longer-acting insulin preparations are made with suspensions of insulin with either protamine ('isophane insulin') or zinc ('crystalline insulin') salts or both together. They are often administered in combination with soluble insulin to obtain rapid onset together with a long duration of action.6British National Formulary. British Medical Association, Royal Pharmaceutical Society of Great Britain, London1999: 302-306Google Scholar They are not suitable for i.v. use. Long-acting insulins may act for up to 36 h for animal-91Rizza RA O'Brien PC Service FJ Use of beef ultralente for basal insulin delivery: plasma insulin concentrations after chronic ultralente administration in patients with IDDM.Diabetes Care. 1986; 9: 120-123Crossref PubMed Google Scholar and 24 h for human-sequence preparations.47Holman RR Steemson J Darling P Reeves WG Turner RC Human ultralente insulin.Br Med J. 1984; 288: 665-668Crossref PubMed Google Scholar There are four groups of oral hypoglycaemic agents: the sulphonylureas, the biguanides, the (recently developed) thiazolidinediones and modifiers of glucose absorption from the gut. In the main, sulphonylureas enhance the secretion of insulin in response to glucose and increase sensitivity to its peripheral actions. Biguanides (metformin is the only compound in this group available in the UK) promote glucose utilization and reduce hepatic glucose production. Thiazolidinediones, which are still under clinical evaluation (and currently under a cloud because of reported hepatotoxicity), enhance insulin action in the periphery and inhibit hepatic gluconeogenesis, perhaps via a specific receptor mechanism. The α-glucosidase inhibitor, acarbose, suppresses the breakdown of complex carbohydrates in the gut and therefore delays the rise in postprandial blood glucose concentrations.100Scheen AJ Lefèbvre PJ Oral antidiabetic agents: a guide to selection.Drugs. 1998; 55: 225-236Crossref PubMed Scopus (0) Google Scholar Intensive, effective glycaemic control of type 2 diabetes results in a reduction of microvascular, but probably not macrovascular, complications of the disease.31Gaster B Hirsch IB The effects of improved glycemic control on complications in type 2 diabetes.Arch Intern Med. 1998; 158: 134-140Crossref PubMed Scopus (0) Google Scholar 114UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (14965) Google Scholar Where adequate control can be achieved (haemoglobin A1c concentration 7–8%31Gaster B Hirsch IB The effects of improved glycemic control on complications in type 2 diabetes.Arch Intern Med. 1998; 158: 134-140Crossref PubMed Scopus (0) Google Scholar) there is no clear advantage for any therapeutic agent; oral hypoglycaemics and insulin have similar effects.76Nathan DM Some answers, more controversy, from UKPDS.Lancet. 1998; 352: 832-833Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Metformin may be a better choice in obese type 2 diabetics. It was associated with a lower incidence of mortality and diabetes-related morbidity when used as a first-line treatment compared with either sulphonylureas or insulin in the recently-reported UK Prospective Diabetes Study (UKPDS).113UK Prospective Diabetes Study (UKPDS) Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (5505) Google Scholar However, addition of metformin to patients receiving sulphonylureas in the UKPDS was associated with a worrying increase in mortality. Despite concerns about rare but potentially lethal lactic acidosis, which may be more likely in the elderly,100Scheen AJ Lefèbvre PJ Oral antidiabetic agents: a guide to selection.Drugs. 1998; 55: 225-236Crossref PubMed Scopus (0) Google Scholar in association with