Intensive Insulin Therapy
Dr. J. R. Conway, Diabetes Clinic, Smiths Falls, K7A 2H6

17 April 2003 Note: Numbers in parentheses refer to slide numbers of this presentation (click here to download).

Insulin is a hormone produced by the beta cells of the pancreas which assists in transfer of glucose across cell membranes. Glucose is the main source of energy for the body (and is the only energy source for the brain). Glucose is oxidized in the cells producing Carbon Dioxide, Water and Energy (in the form of ATP). The energy is used to keep us alive and to do work. In the absence of glucose, some cells of the body can use fat or muscle as an energy source but waste products of ketones build up causing ketoacidosis. In Diabetes we have a deficiency of insulin or of insulin action, with severe insulin deficiency the body develops ketoacidosis which can lead to death. Insulin is a hormone that is essential for life.

The objective of this discussion (2) is to optimize Diabetes management with particular reference to insulin. As family physicians we are familiar with treatment of Type 2 Diabetes but there is often a care gap when it comes to initiation or adjustment of insulin because of lack of knowledge, fear or attitude. Insulin is frequently seen by both patients and physicians as a sign of failure and a precursor to death. (3)

In Type 1 Diabetes (4) we have absence or severe deficiency of insulin production with normal insulin sensitivity while in Type 2 Diabetes we have a relative deficiency of insulin production (5) coupled to insulin resistance. Our aim in the Diabetic is to minimize the complications of the disease (6) and in order to do this we need to diagnose early and treat aggressively to achieve normal glucose levels and thus a normal A1c below 7%. (7) We need to normalize both pre and post prandial glucose levels. (8) The steps to glycemic control involve establishing glycemic targets in discussion with the patient and with the guidance of the CDA Guidelines. Exercise and Diet counseling with a registered dietician is recommended as well as Diabetes Education, usually at a Diabetes Education Center. If there is significant insulin resistance it will have to be addressed prior to insulin treatment. Before starting insulin treatment we need to make sure that the patient is aware (9) of the symptoms and treatment of Hypoglycemia, is reliably doing Home Glucose Monitoring and Glycemic Targets have been determined. Hypoglycemia (10) is a glucose level below the normal range of 4-7 with symptoms. (11) With mild hypoglycemia (glucose 2.8—3.3) we see neurovegetative symptoms of sweating, trembling, pallor, hunger etc. and the Diabetic needs to be able to recognize these symptoms, do a confirmatory capillary glucose and treat. In more severe hypoglycemia, glucopenic symptoms make it impossible for the patient to understand and treat on his own and assistance may be required or Glucagon may have to be taken if the patient is unable or unwilling to eat or drink. The best treatment (12) is prevention; frequent glucose measurement, carrying rapid acting simple carbohydrate and in intensively managed patients or those with hypoglycemic unawareness, a Glucagon Kit needs to be available along with someone capable of using it. To prevent hypoglycemia requires (13) frequent testing, particularly before driving, at bedtime, when drinking alcohol (which may lower glucose levels) or with exercise. Treatment (14) involves 15 gm of Carbohydrate and a follow up capillary glucose in 15 min with repeated treatment if needed. It is important to try and figure out why the hypoglycemic episode occurred to have the insight to prevent future episodes.

Prevention of Hyperglycemia (15) and DKA also requires monitoring and insight as well as the use of correction boluses (16) of short acting insulin and seeking further care if becoming dehydrated. Patient training 17) about Diabetes is best done at a Diabetes Education Center. Glucose monitoring (18) should be done by all Diabetics but is especially important for the insulin treated diabetic who needs to dynamically alter insulin doses according to glycemic levels. All Diabetics need to monitor daily (19), those on insulin should at least be testing when they give insulin and should do additional tests to see that insulin is having the desired effect. We now have a variety (20) of different injection devices (21) and we need to help the patient select the one that is best for his needs. I haven’t started a patient on a syringe and vial for years.

The goal of insulin therapy (22) is to duplicate how a normal pancreas works. What we see in the non Diabetic (23) is rises in glucose with meals stimulating an immediate increase in insulin production peaking in about an hour and tailing off to near normal in about 2 hours as glucose levels fall. There is a constant level of basal insulin and basal glucose. In order to try and duplicate the normal insulin pattern we have many insulin preparations (24) ranging from the very short acting to very long acting as well as various (25) pre-mixed insulins. Normal blood glucose levels (26) vary within a very limited range of 4-7 and are balanced by closely matched insulin levels (27). If we try to match insulin to glucose with 2 injections a day of short & intermediate acting insulin (28) we tend to have periods with too much insulin in the late morning, afternoon and bedtime with inadequate insulin at lunchtime and 5-6 AM (with the Dawn Phenomenon). Increasing to 3 injections a day can improve things (29) but we still haven’t achieved a perfect match and snacks are still required to avoid hypoglycemia in the late morning & afternoon. 4 injections a day (30) gives us a still closer match with the gold standard (31) being the insulin pump which can also vary basal rates according to needs. The problem with regular (Toronto) insulin (32) is that the insulin action doesn’t match the normal insulin in the body, onset of activity is too slow and it lasts too long; in addition very few patients take it as it is supposed to be taken (33), 30-45 min before a meal. The reason for the slow onset and long action (34) is that in the vial, regular insulin forms strong bonds of 6 insulin molecules together as a hexamer which is biologically inactive and takes hours to break down into metabolically active monomers & dimmers. There is therefore a tendency to (35) immediate postprandial hyperglycemia followed hours later by hypoglycemia so this provided the impetus for the development of the short acting insulin analogues, Insulin Aspart and Insulin Lispro which made (36) intensive and aggressive management possible without excessive hypoglycemia. Again looking at the normal insulin profile (37) and comparing it to the profile of the new insulin analogues (38) we have an almost perfect match. The aim of our treatment is to duplicate how the pancreas works (39), the best way to do this is with MDI Therapy (multiple daily injections) (40) of a rapid acting insulin analogue (Novorapid or Humalog) together with a long acting insulin (NPH or a long acting analogue such as Lantus or Levemir.. Basal Insulin (41) is the long acting insulin which acts continuously to cover non-food related insulin needs; Bolus Insulin (42) is the rapid acting insulin analogue given to cover food. The best way of matching the bolus dose to the food ingested (43) is using Carbohydrate Counting a technique in which the insulin dose at a meal depends on the number of grams of carbohydrate ingested, usually 1u for each 10-15 grams. By checking the glucose 2 hours after the meal (44) we can check the adequacy of the Carbohydrate/Insulin ratio and we can apply an adjustment for hyperglycemia. Every time an insulin bolus is given we should also apply a correction factor to cover hyperglycemia. For correction doses we use the short acting analogue. The insulin instructions would therefore be “One unit Novorapid for each 15 gm of Carbohydrate at the meal plus a correction of one extra unit if glucose level is over 7 mmol/l, 2 extra units if glucose is greater than 9, 3 extra units if glucose >11 etc. Basal Rate Adjustment (45) is done by seeing which way glucose levels move when not eating (skipping meals or overnight), if glucose levels are going up then more basal insulin is needed; if glucose levels are falling then less basal (long acting) insulin is needed.

An alternate way of giving insulin is to give regular insulin and NPH (46) twice a day or using a 30/70 premix (47). This is a typical dosage calculation (48) for a pre-mix, 2/3 of the dose is usually given in AM & 1/3 at suppertime. Dosage adjustments are done (49) to treat the highest glucose reading of the day. We may have to change the insulin (50) to get the time/action profile needed. We also have analogue insulin pre-mix available which combines 25 or 30% short acting analogue (lispro or aspart) with 75 or 70% intermediate acting insulin NPL or NPA. (Humalog Mix 25 and Novomix 30).

We need to be aware of the Somogyi effect (51), this is increasing morning hyperglycemia despite increasing evening doses of insulin. It is coused by an undetected episode of hypoglycemia during the night leading to compensatory hyperglycemia caused by the excess glucagon and epinephrine from the reaction. If this occurs we need to decrease the evening insulin.. Follow up always needs to be done (52), since A1c measures average glucose over a 3 month period, the usual time period for follow up of the stable diabetic is every 3 months, more frequently if we are actively adjusting insulin doses.

Case Study No 1:
Obese Type 2 Diabetic with fasting hyperglycemia and elevated A1c. Diabetic for 9 years so Beta cell deterioration has been progressive for some time and insulin production is markedly decreased. Is on full therapeutic doses of all oral agents. Should start bedtime insulin titrating to achieve normal fasting glucose. Caution, as glucose levels return to normal , may develop daytime hypoglycemia and need a reduction in secretagogue (Glyburide dosage). Caution with concurrent use of TZD (Avandia) and insulin as the combination may predispose to fluid retention which may be refractory to furosemide, spironolactone may be a better diuretic choice.

Case Study No 2:
Slim elderly diabetic with longstanding disease. History of Cardiovascular disease. Appropriately treated with Gluconorm to decrease post prandial glucose (which increases cardiovascular risk). Fasting glucose is reasonably good. Length of disease suggests marked beta cell impairment, the hyperglycemia is mostly after meals. Mealtime short acting insulin analogue appropriate. Discontinue Gluconorm.