#17: Insulin Formulations to Treat Diabetes

The following Table summarizes the properties of the various insulin formulations available in the United States from this source.

Post 17 Insulins Available in the United States

Insulin Therapy for Type 2 Diabetes 

The insulin preparations shown at the bottom of the Table are primarily intended for persons with type 2 diabetes (T2D) who are particularly insulin resistant. These insulins are more concentrated (200-500 IU/ml) than most insulins (100 IU/ml). The idea is to give so much insulin that it overcomes the insulin resistance and effectively lowers BG. In the long run this can actually aggravate the metabolic syndrome and its numerous associated medical conditions including atherosclerosis and cancer. Persons with T2D are known to have an increased incidence of atherosclerosis and cancer and this may be part of the reason why. A better solution for T2D is the ketogenic low carbohydrate high fat (KLCHF) diet which directly addresses insulin resistance: a state of carbohydrate intolerance. A KLCHF diet, attaining a normal weight, and regular exercise are enough to control or put T2D in remission in most persons. When this is not enough to control BG in T2D, then insulin sensitizing medications like metformin, GLP-1 agonists, and DDP-4 inhibitors are much preferable to insulin. In other words, insulin is the last option for T2D when all the previously mentioned therapies yield inadequate glycemic control. There is a subset of patients with T2D who develop pancreatic beta-cell failure for which insulin is completely appropriate. For these persons with T2D, a basal insulin is usually started first to control the fasting BG. Once the fasting BG is controlled, if postprandial BG cannot be controlled with a KLCHF diet, then a short- or rapid-acting insulin is added. Note that most persons with diabetes will benefit from a KLCHF diet, attaining a normal weight, and regular exercise.

Insulin Therapy for Type 1 Diabetes

As reviewed in the previous blog post #16, the pancreatic beta-cell normally produces insulin in a pulsatile fashion in response to the blood glucose (BG) concentration, paracrine hormones from surrounding islet cells, incretin hormones from the gut, as well as to nervous system signals. However in the person with type 1 diabetes (T1D) who has lost the vast majority of beta-cells via autoimmune destruction, this elegant system must be approximated with both rapid-acting and long-acting exogenous insulin injections or with rapid-acting insulin via pump. As can be seen in the Table above, there are many options on the market in the US.

Persons with T1D need a fairly constant basal insulin without peaks of action to cover insulin needs between meals and to prevent hypoglycemia especially at night. Nocturnal and afternoon hypoglycemia is not unusual with NPH insulin which has a peak of action about 8 hours after injection. The newer basal insulin analogs glargine and detemir have no peak of action and when properly dosed hypoglycemia is quite uncommon. Persons with T1D also need a mealtime (in most cases, sometimes not needed during the honeymoon period) insulin to cover insulin needs for the glucose rise from dietary carbohydrate and protein. On the KLCHF diet that I follow, the mealtime insulin doses are small due to the low carbohydrate intake, but dietary protein still requires some insulin. In persons with T1D who use a short- or rapid-acting insulin in a pump, the pump can be programmed to accomplish both basal and mealtime insulin needs.

For most persons with T1D who use insulin injections, the combination of a long-acting basal insulin (glargine, detemir, or glargine U-300) and rapid-acting mealtime insulin (aspart, glulisine, or lispro) give the best results with less hypoglycemia especially when combined with a KLCHF diet. In a small percentage of persons with T1D who have diabetic gastroparesis, regular short-acting human insulin is used at mealtime due to the slower stomach emptying which in turn slows the absorption of nutrients (glucose and amino acids) and thus avoids hypoglycemia which could result from using a rapid-acting insulin.

Insulin Mixtures Have More Disadvantages Than Benefits

The insulin mixtures in the Table above (NPH and protamine insulins) are primarily appealing to persons with diabetes who want to avoid extra insulin injections due to the ability to mix these long-acting and short- or rapid-acting insulins together in one syringe i.e. one injection. Note: insulin analogs cannot be drawn up and injected together. From my perspective, I would much prefer more insulin injections to more episodes of hyperglycemia or hypoglycemia. When insulin injections are done properly, they are virtually painless. In addition, I had the direct experience of hypoglycemic episodes at night due to NPH insulin. Remember, the ability to recognize hypoglycemia is diminished while sleeping. I subsequently changed from NPH to Ultralente which helped, but did not stop nocturnal hypoglycemia. After changing from Ultralente to glargine insulin, nocturnal hypoglycemia decreased even further. Since changing to a KLCHF diet in Feb. 2012, I have had no (zero) nocturnal hypoglycemia.

A Guide for Dosing Insulin Analogs for Type 1 Diabetes

For persons with T1D who do choose the combination of a long-acting basal insulin (glargine, detemir, or glargine U-300) and rapid-acting mealtime insulin (aspart, glulisine, or lispro), the following is a rough guide to dose adjustment. You should discuss any changes in your medications with your physician.

First, the long-acting basal insulin (glargine, detemir, or glargine U-300) dose is usually started based on the person’s weight and then adjusted up or down to attain the goal fasting BG. The goal fasting BG is usually determined by the patient in consultation with their physician. For a person with T1D with no diabetic complications, a long life expectancy, and few hypoglycemic episodes, a normal fasting BG of 83 mg/dl (4.6 mM) is a reasonable goal. Changing from a high carbohydrate diet to a KLCHF diet, may require a small reduction in basal insulin dose. Occasionally, the long-acting basal insulin (detemir or glargine) will not quite last 24 hours and this results in an increase in BG in the hours prior to the next scheduled injection. This occurs more commonly with detemir than with glargine. Possible solutions to this problem include changing from once daily detemir to twice daily detemir, changing from twice daily detemir to once daily glargine, changing from once daily glargine to twice daily glargine, or changing to glargine U-300.

Second, rapid-acting mealtime insulin (aspart, glulisine, or lispro) is also usually started based on weight, but this will need to be reduced to one-third to one-half of that amount if a KLCHF diet is used due to the reduction in dietary carbohydrate content. Rapid-acting mealtime insulin (aspart, glulisine, or lispro) can be injected 15-30 mins prior to the meal if the pre-meal BG is elevated (> 120 mg/dl or > 6.7 mM), at the start of the meal if the pre-meal BG is in an acceptable range (70 – 120 mg/dl or 3.9 – 6.7 mM), and after the meal has been eaten if the pre-meal BG is < 70 mg/dl (< 3.9 mM). If the pre-meal BG is < 70 mg/dl (< 3.9 mM) and associated with symptoms, then a glucose tablet(s) or liquid should be taken to correct the hypoglycemia prior to the meal to prevent over-consumption of food during the meal and subsequent postprandial hyperglycemia. The mealtime dose is also adjusted up or down at each meal based on the pre-meal BG value, prior or planned exercise, or a change in the carbohydrate or protein content of the meal. Keeping meals constant in amount of carbohydrate and protein is helpful in reducing BG variability. The goal post-meal BG is also determined in consultation with your physician, but again, for a T1D with no diabetic complications, a long life expectancy, and few hypoglycemic episodes, a reasonable goal is 80 – 120 mg/dl (4.4 – 6.7 mM). A pre- and postprandial BG should always be measured as part of the management of T1D. The timing of postprandial BG measurement is determined by the duration of action of the insulin one is using. From the Table above, rapid-acting insulin has a duration of action between 3 and 5 hours where as regular insulin has a duration of action between 5 and 8 hours in most persons. However in persons following a KLCHF diet, the mealtime rapid-acting insulin dose is smaller and this in fact shortens the duration of action. For me, lispro lasts at most 2.5 hours, so I usually check my BG 2.5 – 3 hours after a meal. Remember, the time to check BG is after the insulin has finished working and all the mealtime nutrients have been absorbed. You can determine the best time to check postprandial BG by checking BG starting at 2 hours after injection of short- or rapid-acting insulin and every 30 mins thereafter until the BG stabilizes. Rapid-acting insulin can also be used to correct an elevated BG that results from a meal or as a result of exercise (usually high intensity exercise). However, caution should be used in correcting an elevated BG after exercise because exercise improves insulin sensitivity. This means a correction insulin dose can lower BG more than expected when given after exercise possibly resulting in hypoglycemia. Therefore, correction doses after exercise should be small at first. Also, the BG response to exercise varies depending on one’s adaptation to the exercise, type (aerobic vs resistance), intensity, and duration of exercise. In other words, BG can go down, stay the same, or go up during or after exercise. That’s diabetes.

Summary

It is not a simple matter to achieve normal or near-normal glycemic control of diabetes with current technology. A KLCHF diet certainly makes this challenging task much easier since it removes most of the dietary component to which the person with diabetes is intolerant of i.e. carbohydrates. Regular recombinant human insulin was a significant improvement over beef and porcine insulin preparations (the latter two were discontinued in 2005). And the newer insulin analogs aspart, glulisine, or lispro for meals and glargine, detemir, or glargine U-300 for basal insulin requirements are certainly an improvement over regular human insulin for meals and NPH, Lente, and Ultralente insulins (the latter two insulins were removed from the market in 2005) for basal requirements for most persons. But as pointed out in the previous blog post #16, injected insulin does not mimic the function of the pancreatic beta-cell and its many paracrine, incretin, and neural inputs. However, the combination of a KLCHF diet with insulin analogs (lispro and glargine) and exercise gives me close to normal BG, near absence of symptomatic hypoglycemia, lack of diabetic complications, a sense of well-being, and thus a positive outlook on life with diabetes.

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