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1Note: Even locally injected corticosteroids may lead to considerable blood glucose disturbances

1Note: Even locally injected corticosteroids may lead to considerable blood glucose disturbances

For practical purposes, a "limb-oriented" overview of these conditions is given in Table 6. It should be stressed, however, that this may be an oversimplification. A classical example is Dupuytren's disease, which may be observed in up to 42% of adults with diabetes mellitus, typically in patients with long-standing T1D. Dupuytren's is characterized by thickening of the palmar fascia due to fibrosis with nodule formation and contracture, leading to flexion contractures of the digits, most commonly affecting the fourth and fifth digits. These abnormalities are quite readily observed during routine office visits and patients tend to bring up their complaints in an early stage because of perceived limitations in daily life. However, in fact there may be other related fibrosing diseases present as well that are more easily overlooked while patients may not bring forward complaints spontaneously. Other fibrosing conditions that are often seen concurrently with the palmar fibrosis of Dupuytren's are nodular plantar fibrosis of the feet, nodular fasciitis of the popliteal fascia, and Peyronie's disease of the penis (39).

Limited joint mobility or diabetic cheiroarthropathy is attributed to abnormal collagen in connective tissue around joints and is readily recognized by the "prayer sign": when asked to place opposite palmar sides of the hands and fingers together there is an inability to completely close the gap due to contractures in the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints (40, 41). At the "table top test" the patient is unable to flatten the palm of the hand when pressing it against the surface of a table.

It is obvious that one or more of the above-mentioned conditions of the hand, especially when concurring in the presence of distal symmetric senso-rimotor polyneuropathy (or one of the other clinical syndromes of neuropathy with involvement of the hands), lead to incapacities with respect to many aspects of daily life, including self-monitoring of blood glucose levels and injecting insulin.

Foot Care

Foot problems in diabetes are common and comprise ulceration, infection, and gangrene, thus resulting in serious morbidity and disability that may ultimately lead to amputation and even death. The lifetime risk of a foot ulcer for diabetic patients is about 15% (42). Amputation is predictive of a severely diminished life expectation, which in part reflects serious co-morbidity and high age. In addition this may be indicative of the accessibility to appropriate care and the standard of delivered care (43).

Screening, education, and early recognition are the mainstay of the prevention of more serious problems. All patients with diabetes should have an annual foot exam to assess risk factors for ulceration and amputation. At the same time, appropriate education with regard to foot self-care and risk factors can be delivered (Table 7) (44).

Table 7

Annual preventive foot care visit in primary care

Assessment of neuropathy, including a quantitative somatosensory threshold test Visual inspection of the foot and footwear

Screening for peripheral arterial disease

Address educational issues

Assessment of self-care ability and involving a family member if indicated

Semmes-Weinstein 5.07 (10 g) monofilament at specific sites

Skin lesions, especially between the toes and under the metatarsal heads Nail care

Erythema, warmth, callus formation Bony deformities, joint mobility, gait and balance Shoes and socks History for claudication Assessment of pedal pulses Ankle brachial index Selection of appropriate footware Avoiding walking on bare feet Daily self-inspection of feet in case of diminished protective sensibility Importance to seek medical help in case of skin lesions and/or infection Visual impairment Diminished movement ability Impaired cognitive function

Once ulcers or infections are present, health care providers for diabetic patients should have a broad view on therapeutic possibilities. Since foot ulcers are generally multicausal in origin they call for a multidisciplinary approach, preferably using a protocol. In addition, effective record keeping and communication between team members are essential (45).

Several classification systems for diabetic foot ulcers exist, but there is no consensus yet with respect to classifying or even describing foot ulcers. For clinical purposes, description of an ulcer should be thorough and clear including a photograph, if possible. Descriptions of wounds should include depth, extent, area, location, appearance, temperature, and odor. Wound depth is an important determinant of outcome (46, 47). Deep ulcers with cellulitis or abscess formation often involve osteomyelitis. From this stage on parenteral administration of antibiotics and hospitalization are indicated. Radiologic changes occur late in the course of osteomyelitis and negative radiographs certainly do not exclude it. In addition to osteomyelitis, assessment of arterial vascular disease is called for. Revascularization may be indicated in order to promote wound healing. Aggressive revascularization has been shown to decrease amputation at all levels (48, 49).

TREATMENT Insulin

Insulin therapy is mandatory for survival in T1D. The ideal insulin regimen mimics the physiological pattern of insulin secretion with low fasting insulin levels, a slow rise in insulin concentration in the early morning, and with postprandial peaks that closely follow the ingestion of carbohydrates and other food. The blood glucose profile over the day is preferably targeted to near normal glycemia with avoidance of hypoglycemia (see Table 8). The percentage of glucose binding to hemoglobin (HbA1c) reflects glucose concentrations in the preceding 4-8 weeks (50). The therapeutic goal is an HbA1c concentration around 7.0% to prevent microvascular and possibly macrovascular complications, unless hypoglycemia interferes (51, 52). The best approach to reach good glycemic control is either a multiple daily injection (MDI) regimen (also called basal bolus regimen) or continuous subcutaneous insulin infusion (CSII) using a pump. In MDI and CSII a prepran-dial bolus of rapid- or short-acting insulin is injected to prevent postprandial hyperglycemia. For basal insulin supply, intermediate- or long-acting insulin is administered or with CSII low doses of rapid-acting insulin are continuously infused (53).

The dose of long- or intermediate-acting insulin is adjusted according to the fasting glucose concentration, but is limited by nocturnal hypoglycemia. In contrast, some patients show high fasting glucose concentration, which may be attributed to the so-called dawn phenomenon: the physiological early morning cortisol peak results in increased insulin resistance. Another pitfall

Table 8

Typical algorithm for insulin dosage adjustment aiming at near normal glycemia

Table 8

Typical algorithm for insulin dosage adjustment aiming at near normal glycemia

Blood Glucose (BG, mmol/L) target level

Preprandial dose of rapid/short acting insulin

Bedtime dose of intermediate/long acting insulin

Fasting BG 4-6

Preprandial BG 4-6

Postprandial BG 5-7

(2 hours after) BG at bedtime 7-9

Increase dose before previous meal if BG > 6 Increase if BG > 7

Small extra bolus if BG > 9, review evening snacks

Increase if BG > 6 (unless nocturnal hypoglycemia)

is a rebound high fasting glucose after undetected nocturnal hypoglycemia, especially in MDI. One of the advantages of CSII is the possibility of a programmed increase of early morning insulin infusion and variable basal insulin infusion in accordance with exercise.

Most currently available human insulin and insulin analogs are manufactured through recombinant DNA technology. Before DNA technology emerged, chemically modified pork insulin was used (derived from its pancreas) and is still available in some countries (54). Insulin analogs have a change in amino acid sequence of the p chain that influences the absorption rate (55). Insulin compounds are categorized by the rate of acting.

Rapid-acting insulin analogs (lispro [Humalog], aspart [NovoRapid], and glulisine [Apidra]) are available as three different formulations, all showing comparable absorption rates.

The peak insulin concentration is 40 min after injection and comes close to the postprandial insulin profile in healthy volunteers. The rapid-acting analogs show a rapid waning of action in 3-4 h. The advantage for patients is more flexibility since the time of injection is just before the meal and the frequency of hypoglycemia may be reduced with preservation of comparable HbAlc levels. The manufacturer of inhaled insulin Exubera, an effective alternative for rapid-acting subcutaneous insulin, recently stopped its production for financial economic reasons. Exubera was expensive and might have caused long-term adverse events with respect to alveolar function by inhaling insulin which is a potent growth factor.

Regular short-acting insulin is unchanged human insulin. Due to its tendency to form hexamers in the subcutis, preparations of normal human insulin have a slower absorption rate after injection than the rapid-acting insulin analogs. The maximum insulin peak concentration is lower, occurs after 90 min, and the waning of action is 4-6 h. Due to a lag time for the onset of action, patients have to inject regular insulin 30 min before the meal, and because of its longer duration of action, patients often have to take a snack between meals to avoid hypoglycemia before the next meal.

Intermediate-acting insulin is used as basal insulin since it results in a prolonged, relatively low insulin concentration. Neutral protamine Hagedorn (NPH) is human insulin in a buffered solution and has to be stirred before injection. Unfortunately, its absorption rate is quite variable. With an insulin peak level 6 h after an injection with NPH insulin, there is an increased risk of nocturnal hypoglycemia.

Insulin detemir is an analog with a fatty acid chain that binds to albumin. Its time of action is 17.5 h and patients often end up with a twice daily regimen. Patients who use insulin detemir have less nocturnal hypoglycemia, lower fasting glucose, and less weight gain in a once daily regimen, compared to NPH. Disappointingly, recent data with a twice daily regimen of insulin detemir in type 2 diabetes did not show a difference in weight gain compared to other basal insulin regimens (56). Long-acting insulin glargine is an analog that is less soluble in the subcutaneously pH neutral environment because of a changed isoelectric point. The time of action is about 24 h and it results in lower fasting glucose concentration and less frequent nocturnal hypoglycemia. Results of a study reporting a head-to-head comparison of detemir and glargine in T1D are expected to be published soon.

Both long-acting insulin analogs detemir and glargine may cause dermal irritation locally around the injection site. Mixtures of rapid- or short-acting insulin in combination with NPH are available and these are given twice daily. Its use is no longer indicated in the majority of type 1 patients. However, a mixture can be a solution in T1D patients with a short life expectancy or difficulties with the management of an MDI regimen, e.g., in the presence of cognitive impairment.

Metformin is potentially of use in overweight T1D patients with decreased insulin sensitivity calling for high insulin dosages. Metformin inhibits gluconeogenesis and possibly improves insulin sensitivity. A mean decrease of HbAlc levels of about 1% or a decrement of insulin dosages and weight loss has been reported in studies with metformin added to insulin therapy in T1D (57, 58). Most patients with CSII use a rapid-acting insulin analog, since postprandial glucose is better controlled. A recent meta-analysis reported that CSII improved metabolic control (HbA1c), in combination with a decreased frequency of severe hypoglycemia, especially in patients suffering from frequent severe hypoglycemia (53). However, patients eligible for CSII should be motivated by proper education from their health care providers, to perform frequent self-monitoring of blood glucose (SMBG) in order to engage in taking responsibility for self-management. In patients on CSII there is an increased risk of ketoacidosis due to the absence of a subcutaneous insulin reservoir, especially in case of potential technical problems with the pump or its supplies. Currently pumps are becoming available that are able to continuously measure subcutaneous glucose levels and that notify patients by an alarm in case of high or low glucose values. However, closed-loop systems are not available yet.

Devices

Patients receive instructions for SMBG using a small portable meter. Insulin administration is then adjusted using algorithms based on fasting, preprandial, postprandial, and evening glucose concentrations to reach target blood glucose values (see Table 3). Blood glucose measurement devices are reasonably accurate and precise in the euglycemic range, but less exact in the hypoglycemic range. In patients with frequent hypoglycemia or extremely variable blood glucose values use of a continuous glucose monitoring system (CGMS) in combination with a diary may uncover underlying problems and give patients insight into their behavioral actions and reactions as well as the way their body responds.

Insulin injection systems are available in a variety of disposable or reusable devices. For patients with impaired vision, magnifying or sensible-audible options are available, which enable patients to keep track of their adjusted insulin doses and ultimately may help them to preserve their independence in daily life. Patient's preferences should be the predominant determinants for the injection system used and the type of insulin within its class that is prescribed.

In-Hospital Blood Glucose Monitoring

Intercurrent morbidity, such as infections or trauma, frequently worsens hyperglycemia by means of a temporarily diminished sensitivity for insulin, while on the other hand hypoglycemia is at stake in the presence of abdominal discomfort and diminished food intake. Consequently, in order to prevent ketoacidosis due to the absolute deficiency of insulin, patients should obtain either a low dose of basal insulin (50% of their usual dosage) or continuous intravenous insulin infusion. In critical care, currently, blood glucose target levels <6.1 mmol/l are widely implemented because of accumulating evidence for improved survival. Some studies show conflicting data of the hazards of hypoglycemia and related mortality (see also Hypoglycemia in People with Diabetes, Chapter 6) (51). Glycemic targets in medical-surgical wards are not definite, but data suggest improved outcome at lower levels (see also Treatment of Hyperglycemia, Chapter 9). In general, glucose levels below 10 mmol/l are advised in hospitalized patients with avoidance of hypoglycemia.

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