16 Diabetes mellitus and hyperlipidaemia
Diabetes Mellitus
• Carbohydrate metabolism. Basal levels of insulin, present when fasting and between meals, inhibit hepatic enzymes that control the critical limiting steps in both gluconeogenesis (glucose synthesis from amino acids and lactate) and glycogenolysis. Thus hepatic glucose production, a major contributor to fasting glycaemic levels, is reduced by insulin. Post-prandial peaks of insulin stimulate glucose uptake into skeletal muscle (where it is used for energy) and adipose tissue (where it is used for the synthesis of triglycerides.)
• Fat metabolism. Insulin promotes triglyceride synthesis and inhibits its breakdown into free fatty acids and ketone bodies.
• Protein metabolism. Insulin inhibits protein breakdown into amino acids, which are precursors for hepatic gluconeogenesis.
Who classification of diabetes
Type 2 diabetes mellitus
Type 2 DM (> 90% of total) results from a progressive fall in insulin secretion with, in addition, resistance to the action of insulin. It is frequently associated with obesity and the ‘metabolic syndrome’ (p. 429). Early in the disease, there may be high levels of circulating insulin, in contrast to type 1 diabetes. Hyperglycaemia results from a progressive failure of the pancreatic β-cells to maintain high levels of insulin secretion to overcome peripheral resistance. The diagnosis is therefore often delayed since endogenous insulin levels are initially sufficient to prevent ketogenesis and a catabolic state. Intercurrent illness, with increased insulin resistance secondary to release of stress response hormones, is associated with worsening glycaemic control and consequent dehydration. The presentation is often with a concurrent illness in an adult with a history of polyuria, polydipsia and malaise over some weeks.
Higher-risk population groups that may benefit from screening for type 2 diabetes include:
• those with markers of cardiovascular disease, such as hypertension, ischaemic heart disease and hypercholesterolaemia.
Other types of diabetes
• Pancreatic disease. Chronic pancreatitis with progressive destruction of the β-cells results in diabetes that requires insulin in about one-third of patients. Simultaneous loss of α-cells with failure of glucagon secretion can result in profound hypoglycaemia, particularly in poorly nourished individuals; this is typically seen in patients with chronic alcohol abuse. Acute pancreatitis may be associated with transient hyperglycaemia.
• Genetic diseases. Genetic diseases such as cystic fibrosis and haemochromatosis have pancreatic damage which may lead to insulin-deficient diabetes, similar in clinical nature to type 1 diabetes.
• Genetic defects of β-cell function. A number of different genetic abnormalities produce type 2 diabetes at a young age (formerly called maturity onset diabetes of the young (MODY)). Presentation is before the age of 25, without features of type 1 diabetes. There is a strong family history of early-onset diabetes. The diabetes is often managed with oral antidiabetic agents alone, although insulin may be needed in some cases.
• Gestational diabetes. Glucose intolerance may develop during pregnancy due, in part, to increases in maternal insulin resistance resulting from circulating placental hormones. Tight control of maternal blood glucose levels in these patients reduces stillbirth rates, macrosomia, hydramnios and pre-eclampsia. Abnormal glucose tolerance returns to normal following delivery. It can be difficult to exclude pre-existing type 2 diabetes presenting for the first time in pregnancy. Gestational diabetes itself is a predictor of diabetes in later life and regular follow-up is required.
Diagnosis
Diagnostic criteria
• Impaired glucose tolerance (IGT)
• Fasting plasma glucose < 7 mmol/L (126 mg/dL) and at 2 hours following a 75 g glucose oral load levels of between 7.8 and 11 mmol/L (140–200 mg/dL).
Management of diabetes
The aims of management are to:
Insulin therapy
Insulin is the only therapy suitable for the treatment of type 1 diabetes and in cases where endogenous insulin production has been significantly reduced, such as haemochromatosis. Interruptions in insulin therapy render these individuals at risk of ketosis. Insulin is also used to cover periods of intercurrent illness in type 2 diabetes when insulin resistance is increased, or there are concerns that hepatic or renal clearance of an oral drug may be impaired. Progressive β-cell failure is seen in type 2 diabetes and thus oral antidiabetic agents may with time fail to control glycaemia adequately. While there is often resistance to injectable therapy, either through patient preference or a fear of weight gain, initiation of insulin in this group of patients should not be delayed.
Insulin formulations (Table 16.1)
• Short-acting ‘soluble’/rapid human insulins are administered intravenously, subcutaneously or intramuscularly. These insulin preparations are typically clear fluids with an onset of action within 15–30 mins when injected subcutaneously. They are therefore used to control mealtime glycaemic swings. They are the only insulins used for IV infusions and SC insulin pumps. The rapid-acting analogue insulins, which have an altered amino acid structure, are more rapidly absorbed than soluble (regular) insulin.
• Longer-acting insulins have a speed of absorption that is prolonged by complexing insulin to compounds such as protamine and zinc. The resulting cloudy crystalline solution is absorbed over a period of hours. These are administered by SC injection only and are used to provide steady levels of background insulin through the day and overnight. Pre-mixed (biphasic) formulations, containing fixed amounts of short- and longer-acting insulins, are available.
• Analogue insulin preparations offer improved profiles, with the rapid-acting insulin being absorbed more quickly, and the longer-acting insulin showing a smoother profile of action. These are intended for SC use. All are clear solutions, which can cause confusion with biosynthetic human short-acting insulin preparations.
Principles of insulin treatment
• Basal bolus regimen. This incorporates a background of longer-acting insulin and prandial short-/rapid-acting insulin. It typically requires four injections per day. This regimen is flexible in that the individual can alter injection times and doses to take into consideration activity levels, portion size, food type and time of eating.
• Pre-mixed insulin. Two injections per day of pre-mixed short-/rapid-acting and longer-acting insulin reduce flexibility and quality of blood sugar control compared to basal bolus, but are more convenient and therefore compliance may be improved. The fraction of short-acting insulin is usually indicated in the name of the mixture preparation (e.g. biphasic insulin aspart 30 contains 30% rapid-acting insulin aspart and 70% aspart protamine.)
• Once-daily insulin. A single injection of long-acting insulin helps in the management of those unable to inject themselves, or as a short-term measure to encourage conversion to insulin from oral therapy. It is also added to oral therapy as an additional agent to help control fasting hyperglycaemia.
• Continuous SC insulin infusion. To achieve this, a small portable insulin device is worn at all times, providing a continuous infusion of insulin at a basal rate designed to control background glycaemic levels. Additional mealtime boluses can be provided through the device by pressing a button, avoiding the need for additional injections. This technique should only be used by patients prepared to monitor their blood glucose levels regularly, as these patients have no protective reservoir of depot insulin.
• Continuous IV insulin infusions (in hospital management of hyperglycaemia). IV insulin infusions are used following admission with hyperglycaemic crises (see below) or when a patient with diabetes is unable to eat or drink. Choice lies between a variable rate of insulin (‘sliding scale’) and a steady rate of insulin infusion (glucose/potassium/insulin ‘GKI’ infusion). When the patient is otherwise stable, e.g. pre-operatively, good glycaemic control may be achieved by fixed rate infusion of soluble insulin and potassium. The variable rate, or sliding scale, of insulin infusion tends to be unsatisfactory on general wards, although it offers flexibility with close monitoring, such as in intensive care. The problem is that the rate of insulin is adjusted frequently in response to glycaemic excursions, rather than to avoid them, and can result in wild fluctuations in blood sugar without achieving good baseline control.
Oral antidiabetic drugs (Table 16.2)
Insulin secretagogues
• Sulphonylureas stimulate insulin release from the pancreatic β-cells, with a peak of insulin levels within 1–2 hours and a duration of action that varies between drugs. They reduce both fasting and post-prandial glucose by 2–4 mmol/L (36–72 mg/dL). They rely on a functional β-cell population, so efficacy may wane with time. Most are taken twice daily. The longer-acting agents are useful as once-daily preparations to aid compliance but hypoglycaemia, especially in the elderly or those with chronic kidney disease (CKD), is frequent. Therapy is associated with weight gain, largely due to the anabolic effects of higher insulin levels increasing appetite and the reduction in urinary glucose loss. Therefore these drugs are used as first-line agents in non-obese patients or those intolerant of metformin.
• Meglitinides act via a similar cellular mechanism as the sulphonylureas to induce pancreatic insulin release but action is augmented by glycaemia. This, together with a rapid onset of action (30–60 mins), makes them a good medication to take at mealtimes to counteract post-prandial blood glucose excursions. They are primarily metabolized in the liver. so have a better safety profile for use in CKD.
Insulin sensitizing agents
• Metformin, a biguanide, is not associated with weight gain and is the drug of choice in the overweight diabetic person. It improves insulin sensitivity and significantly reduces hepatic gluconeogenesis. It is not an insulin secretagogue and will not, therefore, cause hypoglycaemia when used in isolation. It has a similar impact on glycaemia and HbA1C to the sulphonylurea agents. Treatment is associated with gastrointestinal side-effects, e.g. diarrhoea, which can be minimized by a slow dose titration on initiation (e.g. starting dose of 500 mg daily with main meal, increasing by 500 mg increments each month). Anorexic side-effects may be viewed as beneficial in those trying to reduce food intake.
• Caution/contraindications: there is a small risk of lactic acidosis due, at least in part, to inhibition of hepatic gluconeogenesis, which consumes lactate. Situations where lactate production is increased (cardiac and respiratory failure), where lactate clearance is reduced (hepatic failure) or where metformin excretion is reduced (renal failure) predispose to lactic acidosis. Metformin should be stopped where creatinine clearance is < 60 mL/min. Metformin should be stopped for 48 hours after administration of iodinated contrast media to avoid consequent renal dysfunction.
• Thiazolidinediones (glitazones) influence glycaemic control at the level of gene transcription via nuclear receptors, so their maximal effect is not seen for up to 8 weeks after initiation of therapy. They enhance glucose utilization by skeletal muscle and adipocytes, and act via the peroxisome proliferator-activated receptor (PPAR) family, which is also implicated in the control of many genes, including those involved in lipid metabolism.
• Cautions/contraindications: avoid in pregnancy and breast feeding. This group of drugs should not be used in hepatic impairment, and liver biochemistry should be assessed prior to therapy and every 2 months for the first 12 months. Fluid retention and exacerbation of cardiac failure are also seen. Rosiglitazone is no longer recommended for general use.
Intestinal enzyme inhibitors
• Alpha-glucosidase inhibitor, e.g. acarbose 50 mg daily, increasing to a maximum of 200 mg daily, reduces post-prandial hyperglycaemia by inhibiting intestinal breakdown of complex starches and thus delaying carbohydrate absorption. It should be chewed with the first mouthful of food or swallowed whole with a little liquid before the meal. It is not as efficacious as other oral antidiabetic agents. Side-effects include abdominal bloating and diarrhoea.
Other therapies
• Incretins
• Glucagon-like peptide (GLP)-1. This is produced from the L-cells of the small intestine and is secreted after a meal. Oral glucose stimulates insulin secretion more than an IV glucose load (the incretin effect), partly due to GLP-1 release. Exenatide and liraglutide are GLP-1 analogues and bind to the GLP receptor. These drugs increase insulin secretion, inhibit glucagon secretion and slow gastric emptying. They are given by SC injection to patients with type 2 diabetes on metformin, sulphonylurea or both, if glycaemic control is poor. They produce weight loss, which is beneficial. Side-effects include persistent nausea and pancreatitis. Long-term studies are awaited.
• Dipeptidyl peptidase (DPP)-4 inhibitors. DPP-4 deactivates both glucose-dependent insulinotropic peptide (GIP) and GLP-1. Saxagliptin, sitagliptin and vildagliptin inhibit this enzyme to increase insulin secretion and lower glucagon. They can be given orally with metformin in type 2 diabetes. There is no associated hypoglycaemia.
• Amylin analogue. Amylin is stored in the pancreatic β-cells and is secreted along with insulin. It is deficient in type 1 diabetes and also, to a lesser extent, in type 2 patients requiring insulin. It decreases gastric emptying, suppresses glucagon secretion and decreases appetite. Pramlintide is an amylin analogue and is given at mealtimes as an SC injection. It is used in poorly controlled type 1 diabetic patients taking insulin and in type 2 patients when they are overweight and not well controlled on insulin. Side-effects include severe hypoglycaemia and nausea.
• Orlistat. Orlistat is a lipase inhibitor that reduces the absorption of fat from the diet. It promotes weight loss in patients on a low-fat diet, thus indirectly benefiting the diabetes. The low-fat diet is necessary to avoid unpleasant steatorrhoea.
• Bariatric surgery, e.g. gastric banding, gastric bypass surgery, roux-en-Y, is used in patients with type 2 diabetes and gross obesity unresponsive to 6 months of intensive attempts at dieting and graded exercise. One-third of patients become non-diabetic after surgery, those with recent onset of diabetes benefiting the most.
Practical management of type 1 DM
Monitoring
• Fasting blood glucose measurements indicate a background glycaemic control and should lie between 4 and 7 mmol/L (72–126 mg/dL). Measuring blood glucose 2 hours post-prandially gives an indication of glycaemic swings following food and levels should be < 10 mmol/L (180 mg/dL).
• HbA1c is a glycosylated haemoglobin reflecting glycaemia over the preceding 3 months. It should be measured every 2–6 months, depending on stability of the disease and changes in treatment. Good glycaemic control benefits both microvascular and macrovascular complications of diabetes. The aim is to achieve an HbA1c between 6.5 and 7.5% (48–59 mmol/mol), which requires good compliance with therapy with an increased risk of iatrogenic hypoglycaemia.
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