Image: Profile of the actions of the different insulin preparations. Note the very short action profile of the monomeric soluble insulin (fast-acting insulin analogue).

Image: Plasma insulin profiles in (a) a non-diabetic individual eating 3 meals a day compared with diabetic individuals on (b) twice daily mixed insulin, (c) with the evening dose of intermediate-acting insulin moved to bedtime and (d) a basal bolus regime with 3 short-acting injections before meals and intermediate-acting insulin before bedtime.

Insulin regimes

Oral hypoglycaemic agents and nocturnal intermediate-acting insulin: Patients poorly controlled (HbA1c > 8%) on maximum oral hypoglycaemic agents but who still have remaining insulin secretory reserve may be managed on this regime. The oral hypoglycaemic agents are continued and intermediate-acting insulin added in at bedtime (typically 6-10 units, depending on body weight and level of hyperglycaemia). The dose of evening insulin is titrated to the pre-breakfast capillary glucose readings. This type of regime has been found to be both well tolerated and effective; it helps to keep exogenous insulin requirements to a minimum and may help to reduce weight gain.

Some may prefer to continue with metformin because of its insulin sensitizing effects but stop sulphonylurea treatment at this stage, which is also an effective strategy. If daytime control starts to slip, morning NPH lente can be added in.

Nocturnal or twice daily intermediate-acting (NPH lente) insulin:

Some patients may not wish to continue oral hypoglycaemic agents when being switched to insulin, or polypharmacy may make this approach unreasonable. In this instance, in someone with residual insulin secretory reserve, once or twice daily intermediate-acting insulin without oral hypoglycaemic agents may be a reasonable alternative, although most would opt for a combination of short- and intermediate-acting insulins.

Basal bolus regime: Typically this consists of injections of short-acting insulin prior to the three main meals of the day with intermediate-acting insulin at night. A variation is also to give the intermediate- with the short-acting insulin in the morning to provide basal insulin levels throughout the day. This type of regime comes closest to mimicking the body’s natural production of insulin, but there are some important differences (shown in Image: Plasma insulin profiles in (a) a non-diabetic individual eating 3 meals a day compared with diabetic individuals on (b) twice daily mixed insulin, (c) with the evening dose of intermediate-acting insulin moved to bedtime and (d) a basal bolus regime with 3 short-acting injections before meals and intermediate-acting insulin before bedtime):

• First, we do not have a preparation of insulin that produces true “basal” levels but we get peaks and troughs with the intermediate-acting insulin;
• Second, the peak of action of the short-acting insulin is delayed in onset and prolonged in action compared to endogenous secretion.

Therefore, injections of standard short-acting insulin should be 30 minutes prior to a meal in order to counteract the postprandial glucose peak, and a small snack should be taken between meals (2-3 hours after insulin injection) and before bed in order to avoid hypoglycaemia due to the prolonged peak of action of short-acting insulin. Discussion of these issues should be part of the induction onto insulin therapy.

Fast-acting human insulin analogues are now available which have been designed to mimic endogenous insulin production more closely.

Current preparations show the following characteristics:

• Onset of action <30 minutes;

• Peak action 30 minutes to 2 hours;

• Duration of action 3-4.5 hours.

The fact that these insulins can be injected immediately before or after meals (for instance in young children whose eating habits may be unpredictable) and still control postprandial glucose excursions is a potential advantage. Some evidence suggests that the incidence of hypoglycaemia may be reduced using these preparations and that the need for between-meal snacks may be lessened.

Twice daily mixed insulin: This is a commonly used insulin regime. The problem with this type of regime, however, is evident from Image: Plasma insulin profiles in (a) a non-diabetic individual eating 3 meals a day compared with diabetic individuals on (b) twice daily mixed insulin, (c) with the evening dose of intermediate-acting insulin moved to bedtime and (d) a basal bolus regime with 3 short-acting injections before meals and intermediate-acting insulin before bedtime. Injection of intermediate-acting insulin with the evening meal leads to a peak of intermediate-acting insulin in the early hours of the morning, when insulin levels should be at their lowest, and a decline in insulin levels prior to breakfast, when naturally there would be a small rise. The fasting glucose value is used as a guide to adjusting the evening dose of insulin, but a satisfactory fasting blood glucose level is likely to occur at the expense of hypoglycaemia in the early hours of the morning. Nocturnal hypoglycaemia is frequently unreported in this scenario and its presence may have to be sought directly.

Three times daily injection regime: A combination of short- and intermediate-acting insulin before breakfast (either as a pre-mixed insulin preparation or drawn up individually) with short-acting insulin before the evening meal and intermediate-acting insulin before bed may help to avoid the problems with hypoglycaemia described above whilst allowing good diabetic control. A mid-morning snack is part of both of these regimes.

The substance, called the INGAP – Islets Neogenesis Associated Protein – Peptide, encourages the growth of insulin-producing cells in the pancreas. Diabetes causes an inability to make or use insulin.

Researchers have found that injections of INGAP in certain diabetic animals can increase insulin levels and lower glucose levels. In tests, some animals were cured of their illness 39 days after beginning the therapy and showed normal blood sugar levels after stopping the treatment for eight days.

If you have type 2 diabetes, an important part of your plan will be regular visits to health care providers. Your symptoms will be reviewed at each check-up. You may undergo a special blood test to find out how glucose levels have averaged over the past few months. Medicines may be prescribed to control blood sugar, blood pressure, or cholesterol. You will meet with specialists to check various parts of the body such as the eyes, feet, and teeth. You also may see mental health professionals for help dealing with the challenges of the disease.

Pills may be prescribed for type 2 diabetes.

If you have type 2 diabetes, you may get prescriptions for one or more diabetes pills. Here’s what they do:

• Oral hypoglycemics work on the pancreas to increase insulin production.

• Starch blockers slow digestion so that glucose does not rise too quickly after eating.

• Metformin slows down glucose production in the liver and speeds glucose uptake by the cells.

• Insulin sensitizers make body cells more receptive to insulin.

Between visits with health care providers, treatment rests in your hands. In diabetes health care this is called self-management, and it is central to the success of any plan. The reason it is so important is that a treatment plan is only good if it is followed. If you have diabetes, self-management training can help you gain the skills and confidence needed to succeed with a treatment plan.

In self-management training you learn how to monitor blood sugar, how to take injections, how to pay attention to your body’s signals and symptoms, and how to take special care of the skin, feet, and teeth. You get advice on how to shop for and cook healthful meals and how to select the right foods off a menu. You learn the best way to exercise and how often to do the workout.

Finally, you learn how to keep a daily log of blood sugar levels, meals, exercise, and symptoms. The log is referred to at check-ups and it is used to fine-tune the treatment plan.

You should be tested for diabetes if you have symptoms or are at risk

You should be tested for diabetes if you have the symptoms described on site.

You should be tested every three years if you have no symptoms but are over age 45. And if you have one or more risk factors (see below), you may want be tested more often and starting at an earlier age.

You should be tested if you are an overweight child or teen with two or more risk factors (see below).

Risk factors:

• Close relative with diabetes

• Belonging to an at-risk group (Native American, Alaska Native, African American, Hispanic American, Asian American)

• High cholesterol

• High blood pressure

• History of impaired glucose tolerance

• Dark and thickened patches of skin, usually on the neck, under the arms, or inside the elbows (this symptom tends to appear in obese members of ethnic minority groups). These patches are called acanthosis nigricans.

• Having diabetes when pregnant OR delivery of a baby that weighs more than nine pounds

Pumps offer convenience and good control

If you have diabetes and want to maintain tight control, discuss the benefits of using a pump with your health care team. A pump is a small device, about the size of a pack of cards, that you wear or carry.

Insulin moves from the pump to your body through a thin tube to a needle that is inserted under your skin. You can program the pump to automatically deliver doses of insulin. You can also control the pump to give extra insulin, or to adjust amounts, based on your blood sugar tests.

Pumps have several benefits. You don’t have to stick yourself with a needle every time you need insulin, because the pump’s needle stays painlessly in place for days at a time. You don’t have to remember when to give yourself regular doses of insulin because the pump remembers for you. And if you eat a little extra sugar, work out a little harder than usual, or in any other way cause your blood sugar to go up or down, you can easily adjust the pump.

The most frequent complication of insulin therapy is hypoglycaemia and patients taking insulin need to be educated about its cause, symptoms, and treatment. Most patients can recognise the early warning signs of hypoglycaemia and by taking sugar immediately can prevent more serious symptoms developing. Comatose patients need to be given intravenous glucose or, if this is not practicable, subcutaneous, intramuscular, or intravenous glucagon (although glucose is still required if mere is no response within 10 minutes). Hypoglycaemia can also develop in patients taking oral antidiabetics, notably the sulfonylureas.

Some patients report loss of the warning signs of hypoglycaemia after transferring from animal to human insulin and these patients, if appropriate, may need to be transferred back to animal insulin. However, the most significant factor in loss of hypoglycaemic warning signs may be exposure to hypoglycaemia itself a study found mat total avoidance of hypoglycaemic episodes for 3 weeks while maintaining glycaemic control restored awareness. Loss of hypoglycaemic awareness, which appears to be due to an adaptive conservation of glucose uptake in the brain, is liable to be a particular problem in patients receiving intensive therapy. There is limited data to suggest that caffeine can improve awareness of hypoglycaemia.

Diabetic ketoacidosis

Diabetic ketoacidosis is caused by an absolute or relative lack of insulin and commonly occurs after noncompliance or failure to adjust insulin dosage in the presence of factors such as infection that increase insulin requirements (see Precautions for Insulin). Failure of an insulin pump can be a cause. Also pregnant diabetic women are more prone to development of diabetic ketoacidosis.

Diabetic ketoacidosis is characterised by hyperglycaemia, hyperketonaemia, and acidaemia, with subsequent dehydration and electrolyte abnormalities. Onset may be rapid, or insidious over many days. Initial presenting symptoms such as thirst, polyuria, fatigue, and weight loss are those of any newly presenting type 1 diabetic they then progress to nausea, vomiting, abdominal pain, and impaired consciousness or coma, and, if untreated, death.

Diabetic ketoacidosis is a medical emergency and should be treated immediately with fluid replacement and insulin. Fluid requirements depend on the needs of the individual overvigorous fluid replacement without severe dehydration carries the risk of precipitating cerebral oedema.

Soluble insulin should also be given immediately. Large doses were formerly thought necessary, but lower dose regimens accompanied by adequate hydration have since been shown to be preferable. Insulin resistance in diabetic ketoacidosis is generally exacerbated by hyperosmolarity and other confounding factors, and insulin therapy is therefore most effective when preceded or accompanied by adequate fluid and electrolyte replacement. In the UK, the BNF considers that insulin should preferably be given by intravenous infusion, with the intramuscular route used if facilities for intravenous infusion are not available. However, in the USA some consider that an intravenous bolus followed by subcutaneous injection may be appropriate in certain patients. Intramuscular or subcutaneous injection are not appropriate in patients with hypovolaemic shock, due to poor tissue perfusion. Where the response to insulin is inadequate the intravenous route is generally required and the rate of infusion may be doubled on an hourly basis until an appropriate response is seen. A case report has suggested mat mecasermin may be useful if there is insulin resistance.

When the blood-glucose concentration has fallen to about 12.5 mmol/litre the dose of insulin may be reduced by about half and glucose given intravenously, usually in a strength of 5% with saline although in rare cases a glucose strength of 10% may be necessary. The use of glucose enables insulin to be continued in order to clear ketone bodies without inducing hypoglycaemia. Once glucose concentrations have been controlled and acidosis has completely cleared, subcutaneous injections of insulin can begin but intravenous insulin should not be stopped until subcutaneous dosage has begun.

Total body stores of potassium are depleted in patients with diabetic ketoacidosis. Insulin deficiency appears to be the main initiating factor for hyperkalaemia in diabetic ketoacidosis. Although patients may present with raised, normal, or decreased serum-potassium concentrations, the concentrations will start to fall with the correction of acidosis. Potassium is added to the infusion fluid after initial fluid expansion and once insulin therapy has begun. In hyperkalaemic patients, potassium is given once serum concentrations have fallen to within normal limits. In the rare patient presenting with hypokalaemia potassium replacement should be begun before insulin therapy and the latter withheld until potassium concentrations have risen to normal values.

Intravenous bicarbonate is now generally reserved for patients with severe acidaemia a common practice is to give isotonic bicarbonate to those with a pH of less man 7.0 with the aim of raising the pH to 7.1.

Phosphate concentrations are affected in a similar manner to potassium concentrations in the ketoacidotic state, but there is less agreement on the need for routine doses of phosphate. Phosphate concentrations should be monitored and phosphate given if clinically significant hypophospha-taemia occurs.

The precipitating cause of diabetic ketoacidosis should also be identified and managed appropriately.

Hyperosmolar hyperglycaemic state

Hyperosmolar hyperglycaemic state or hyperosmolar hyperglycaemic nonketotic coma (HONK) occurs mainly in elderly patients with type 2 diabetes and though much

less common man diabetic ketoacidosis it carries a higher mortality. Patients may present in coma with severe hyperglycaemia but with minimal ketosis dehydration and renal impairment are common. Treatment is similar to mat of diabetic ketoacidosis, although potassium requirements are lower and large amounts of fluid and less insulin may be required some suggest the use of hypotonic fluid if necessary. There is an increased likelihood of thrombotic events, so prophylactic anticoagulation should be considered.

The use of corticosteroids in premature labour before 34 weeks of gestation to accelerate fetal lung maturation may dramatically increase insulin resistance. Similarly, the use of intravenous β sympathomimetic agents to treat premature uterine contractions will cause severe hyperglycaemia and ketoacidosis unless appropriately anticipated. Careful glucose monitoring should always accompany this form of treatment and aggressive intravenous insulin treatment must be started if necessary.

During labour the simplest scheme is to use a constant infusion of 10% glucose at a rate of 1 L every 8 hours. An independent insulin infusion of human soluble insulin, initially at 1 unit/h, is also given; this is subsequently adjusted on the basis of hourly bedside blood glucose. This system may be used irrespective of the last subcutaneous insulin dose, but where induction of labour or caesarean section is planned it is best started at breakfast time after a bedtime injection of isophane insulin. As soon as the infant is delivered, the insulin infusion must be reduced or, in women with gestational diabetes, stopped altogether. The glucose infusion is continued until the next meal in patients who had vaginal deliveries or until a normal diet is resumed in those delivered by caesarean section. The pre-pregnancy insulin doses should be resumed at this time and adjusted according to the blood sugar levels. An additional 40-50 g carbohydrate, relative to the pre-pregnancy dietary intake, is generally recommended during lactation. Women should also be warned about the potential risk of hypoglycaemia whilst feeding, especially in the middle of the night. They may need advice on appropriate snacks or fluids that contain carbohydrate. Oral hypoglycaemic agents, where they were being used before pregnancy, are probably best avoided. Small quantities of sulphonylureas are secreted into breast milk and therefore can theoretically induce hypoglycaemia in the infant. This is probably of significance only with the longer acting sulphonylureas such as chlorpropamide. Metformin is not recommended for use in lactation. However, there is no evidence of harm for the infant from the small amount of metformin that is secreted into breast milk. Infant exposure to metformin can be minimised by breastfeeding just before taking the dose and by avoiding feeding for at least 2-3 hours after taking the dose. It has been suggested that prophylactic antibiotics should be given after operative deliveries to offset the increased risk of wound infection in women with diabetes.

Home blood glucose measurement is an essential routine aspect of self-management and should be performed 4-6 times/day to recognise the need for insulin dose modification. This dosage adjustment can be performed by the medical team, but the patient should be encouraged and helped to gain the confidence to undertake this herself. Continuous blood glucose profiling may be a useful additional tool to assessing and optimising glycaemic control. HbAlc levels should be measured regularly as this provides an objective assessment of glycaemic control. Target values should be the middle of the normal non-diabetic range.

Hypoglycaemia is an inevitable consequence of achieving strict glycaemic control. All women on insulin should therefore be provided with glucagon 1 mg (Lilly) or GlucaGen (Novo-Nordisk) for use in moderate to severe hypoglycaemia and their relatives should be instructed in its use.

Choice of insulin regimens

It is preferable to use human insulin in diabetic pregnancy, although a very small minority of patients who are still using animal insulins, because of hypoglycaemic unawareness, maybe reluctant to change. Porcine insulin is probably acceptable but bovine insulin is best avoided as it can produce significant levels of insulin antibodies that freely cross the placenta. These have been implicated as a cause of infant morbidity possibly affecting β-cell function of the fetus and influencing neonatal insulin secretion. Whilst the current insulin analogues possess theoretically attractive properties for pregnancy, none are licensed for use in pregnancy. Some of the short-acting analogues are being used more widely, seemingly without problems.

Once daily insulin regimens

These would seldom be appropriate in pregnant mothers with diabetes established before pregnancy, but single daily injections of an intermediate-duration insulin before breakfast maybe very effective in some women with type 2 or mild gestational diabetes. Such individuals can usually produce sufficient insulin in a fasting state overnight to maintain normoglycaemia and thus an intermediate insulin, e.g., an isophane, such as Humulin I (Lilly), Insulatard (Novo-Nordisk) would be suitable. Additional short-acting or soluble insulin, e.g., Actrapid (Novo-Nordisk) or Humulin S (Lilly) may be added later as a fast-acting component to counter postprandial hyperglycaemia. The use of such regimens significantly reduces the incidence of fetal macrosomia in women with gestational diabetes when compared with treatment by diet alone.

The newer short-acting insulin analogues insulin lispro (Humalog (Lilly)) and insulin aspart (Novorapid (Novo-Nordisk)) have rapid absorption characteristics that provide a peak insulin concentration more rapidly than obtained with human insulin. This results in lower postprandial plasma glucose concentrations. This is therapeutically attractive in the context of the increased insulin resistance associated with pregnancy. However, it is unknown whether these analogue insulins are teratogenic. Maternally derived insulin can only cross the placenta if antibody bound. In clinical trials with insulin lispro, there has been no observed increase in antibody response. This means little insulin transfer from mother to fetus and thus no likely increased risk for congenital malformations. A multicentre, multinational study in 500 pregnancies exposed to insulin lispro (Humalog) during organogenesis showed no increase in malformation rates.

Anxieties have been expressed that the use of insulin lispro during pregnancies complicated by diabetes may accelerate retinopa-thy through its influence on the IGF-1 (insulin-like growth factor 1) system. This seems unlikely as insulin lispro binds to the IGF-1 receptor with an affinity of only about 1/1000 that of IGF-1 and with an affinity of only about 1.5 times human insulin. Insulin aspart (Novorapid) has only 69% IGF-1 activity that of human insulin. Whilst remaining unlicensed for use in pregnancy these analogues are being used increasingly in some centres.

Twice daily combinations of short- and intermediate-acting insulins

This type of regimen is still fairly widely used outside pregnancy -although diminishing in preference to basal prandial regimens -and is perfectly capable of providing adequate control during pregnancy as well. The usual combinations are a soluble insulin with an isophane insulin. Pre-mixed formulations of these insulins should be avoided in pregnancy as they do not afford sufficient flexibility. It is preferable to change women using these to free-mixing their insulins during the preconception period. The ability to change the proportion of short- to intermediate-acting insulin is important because as pregnancy progresses, the required balance between the two may change with increasing insulin resistance. Frequently it is found that hyperglycaemia before breakfast cannot be resolved by increasing the evening dose of isophane insulin without incurring frequent hypoglycaemia during the night, partly as a result of continued glucose usage in the fetoplacental unit. The general solution to this is to divide the evening injection, taking the short-acting insulin with the evening meal and the intermediate insulin at bedtime. Similarly, as gestation progresses, the proportion of short-acting insulin required may increase, reflecting increased insulin resistance, and to control postprandial hyperglycaemia in the afternoon it often becomes necessary to abandon the morning dose of intermediate insulin in preference to an additional lunch-time injection of short-acting insulin. From 36-week onwards, there is a tendency for the fasting blood glucose concentration to fall, which may require reduction or even omission of the evening injection of intermediate insulin. Sudden dramatic falls in insulin requirements at this time should alert the clinicians to the possibility of placental insufficiency sufficient to threaten the pregnancy.

Multiple daily insulin injections

Many younger patients with diabetes already employ such regimens, using pen-type insulin delivery devices. It is a particularly satisfactory means of achieving excellent metabolic control which is readily understood by the patient and can easily be altered to cope with variations in diet and activity. Generally, a short-acting insulin is administered with each of the main meals of the day and an isophane is given at bedtime. Close self-monitoring is essential for this type of regimen, but this will not differ from what is required for pregnancy anyway. Unfortunately, glargine insulin (Lantus (Sanofi-Aventis)), whilst commonly used in both type 1 and type 2 diabetes, is unlicensed for pregnancy and in view of theoretical considerations is not being recommended for use in pregnancy. It has a sixfold higher binding affinity for IGF-1 receptors, and experimental studies suggest an increased mitogenicity on tumour cell lines at high dosage. Until large-scale studies have demonstrated that placental transfer of glargine insulin is similar to the transfer of human insulin, and there is no increased risk to the fetus, this agent is not recommended. Its use is perhaps only justified where severe hypoglycaemia has been a problem, and there must be full discussion of the safety issues with the patient. Furthermore, this means that patients established on glargine insulin have to be switched back to an isophane basal insulin in the preconception period, or immediately an unplanned pregnancy is detected. Detimir insulin (Levemir (Novo-Nordisk)), another long-acting insulin analogue, does not have increased IGF-1 activity, so may eventually prove to be an attractive long-acting insulin alternative, but again is currently unlicensed for use in pregnancy.

Continuous subcutaneous insulin infusion

Open-loop subcutaneous insulin infusion with miniature pumps can achieve near-normal glycaemic control in appropriately selected patients. However, multiple injection regimens remain a simpler solution that can achieve very similar results and continuous subcutaneous insulin infusion is potentially more dangerous in pregnancy. Severe hypoglycaemia is a significant risk and the rapid development of ketoacidosis may occur in the event of pump failure. This option should be considered very carefully and probably only undertaken in centres with extensive pump experience.

There is an immediate decrease in maternal insulin requirements following delivery. The main reason for this decrease is loss of the placenta, which functioned to synthesize many steroids and create an insulin-resistant environment throughout pregnancy. Postpartum, it is best to start with approximately one-half of the normal prepregnancy dose of insulin and check blood glucose levels before meals and at bedtime to regain tight control. Breastfeeding should be encouraged in both type 1 and 2 diabetic populations. However, patients should be advised about the risk of hypoglycemia from loss of carbohydrates during breastfeeding, and therefore aim for a target fasting (preprandial) glucose level in the range of 110­-120 mg/dL. It may even be necessary to take an additional carbohydrate snack prior to breastfeeding and maintain a high calcium and fluid intake.

Neonates of diabetic mothers should be carefully and thoroughly assessed. They are at an increased risk for all the complications previously mentioned and listed in Table 8, including hypoglycemia and respiratory distress syndrome, requiring specialized care.

Conclusion

Table 10 provides a summary of monitoring parameters in a pregnant diabetic patient, from preconception through the first, second, and third trimesters. The overall outlook for the pregnant diabetic patient has improved enormously over the last few decades. The most important aspect of diabetic care for the mother is the need to maintain good glycemic control, with the goal of lessening the risk for congenital malformations and other, later fetal complications. If no major complications are present, good glycemic control and careful monitoring can result in a healthy neonate, with minimal long-term health risk to the mother.