Control of Diabetes Resistant to Insulin Treatment?

Question

Presently I am treating a lady, 65 yrs of age, suffering from Type 2 Diabetes for the last 15 yrs. Earlier on she used to be treated with oral hypoglycaemic agents but presently she is on insulin, since 2007. Her body weight is 70 kg, BMI 28.5, renal profile within normal limits. Urine Albumin creatinine ratio mildly raised.She is on basal bolus regime with Insulin Glargine 60 units, and Insulin aspart 24 for breakfast, 30 for lunch and 30 for dinner, along with Sitagliptin and metformin combination ( 50/1000 mg) twice daily. Her SMBG is in the range of 180 -320 . Despite increasing the insulin dosage, her blood sugars do not respond adequately. She is compliant with her diet and medications.

I had once admitted her to a local hospital to improve the glycaemic control. She had iv insulin aspart as per sliding scale for 4 days and required about 60 units of insulin in each 24 hrs. On switching over from iv to subcut insulin, her glycaemic control became poor and she required quite heavy dose of insulin as mentioned above.

What else can I give her to improve her glycaemic control? Insulin pump may not be an option due to financial strains. Dr Sagarika Mukherjee, AMRI Hospitals, Kolkata, India.

Response

The first thing to do is rule out syndromic insulin resistance. While most of these are rare, most are also not identified when they are present. I would encourage this patient to be considered for all of these.

For the more common insulin resistance associated with obesity and/or metabolic syndrome, the first thing to appreciate is there are little data to support a glycemic benefit when using over 1 u/kg of the most commonly used basal insulin, insulin glargine. Furthermore, there are data to suggest for a basal insulin, NPH may be preferred. From a cost basis, this is a potential major advantage. Finally, it has been shown that NPH may work better in these patients when administered in two injections (two depots). The thought is there is better absorption from two than one depot. It should be noted gold standard clamp studies have not been preformed to prove this, but clinically this is how many of us have been managing these patients for years.

For the prandial insulin, larger doses result in longer durations of action. While this is true for basal insulins also, the goal with prandial insulin is to match the insulin with the food. For this reason, my preference is to continue to use rapid acting analogues but there are no controlled trials showing in this insulin resistant population one is better than the other. The other point: timing of the meal time insulin is critical-the longer "lag time" (time between giving the insulin and eating) will have a tremendous impact on postprandial hyperglycemia, especially with the higher doses of insulin. Fifteen to 20 min with a rapid-acting analogue should be the rule for these patients.

Many of these patients will not be controlled with these tools. There have been initial reports of dramatic benefits with the use of the GLP-1 analogue liraglutide, but this needs to be confirmed with controlled studies. Most of these patients have already been tried on metformin and that should be continued if tolerated and there are no contraindications. The real issue at this point is moving to U500 regular insulin, which has been available for decades in the US, but is not available in many countries. In the US, we tend to move to U500 regular insulin when the insulin dose is > 2 units/kg or > 200 units/day AND the HbA1c is > 8%. U-500 regular insulin is used as both a prandial and basal insulin. The fine points on how to best use this are beyond the scope of this discussion, but there are excellent reviews noted in the references. There are currently other higher concentrated insulin now in development which should assist in the management of patients like this. Irl B. Hirsch, M.D.

References:

  1. Bota VM Hirsch IB: Insulin glargine or neutral protamine Hagedorn in patients with severe insulin resistance: Is there a benefit? Endocrine Practice 2012;18:e49-51
  2. Crasto W. Jarvis J, Hackett E, et al: Insulin U-500 in severe insulin resistance in type 2 diabetes mellitus. Postgrad Med J 2009;85:219-22
  3. Chukwu JF, Hirsch IB, Trence D: Use of liraglutide in severely insulin resistant patients with type 2 diabetes. Presented Endocrine Society Annual Meeting, 2012
  4. Gagnon-Auger M, du Souich P, Baillargeon JP et al: Dose dependent delay of the hypoglycemic effect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study. Diabetes Care 2010;33:2502-2507
  5. Lane WS, Cochran EK, Jackson JA, et al: High-dose insulin therapy: is it time for U-500 insulin? Endocrine Practice 2009;15:71-79
  6. Lane W, Weinrib S, Rappaport J: The effect of liraglutide added to U-500 insluin in patients with type 2 diabetes and high insulin requirements. Diabetes Technol Ther 2011;13:592-
  7. Wang Z, Hedrington MS, Joy NG, et al: Dose -response of insulin glargine in type 2 diabetes. Diabetes Care 2010 33:1555-1560 8. Wolska A: One vs. two depots for NPH insulin in severely insulin resistant patients with type 2 diabetes. Presented at the European Associatio for the Study of Diabetes, 2011