Treating New-Onset Catabolic Type 2 Diabetes With Glargine and Lispro

N.D., a 38-year-old African-American woman, was admitted to the hospital with a plasma glucose level of 793 mg/dl and 2+ urine ketones. She had no history of diabetes and last saw her primary care provider 6 months ago for her annual examination. Her plasma glucose level was normal at that time. She had lost 30 lb in the past 8 weeks, and she reported having had polyuria and polydipsia for 2 weeks. She reported anorexia with very little oral intake for the past 2 days. Her weight was 220 lb (100 kg). Physical examination showed acanthosis nigricans and morbid obesity.

She had been given 10 units of regular insulin subcutaneously and 2 l of normal saline intravenously in the emergency department, resulting in a plasma blood glucose of 525 mg/dl. Results of a basic chemistry panel were:

• Sodium: 134 mg/dl

• Potassium: 3.9 mg/dl

• Bicarbonate: 20 mg/dl

• Chloride: 100 mg/dl

• Creatinine: 1.0 mg/dl

Overnight, she was given “sliding scale” insulin, 10 units every 6 hours, for glucose levels consistently > 400 mg/dl. The next morning, an insulin drip was started. During the next 24 hours, 100 units of intravenous lispro in a drip resulted in a fasting plasma glucose of 120 mg/dl. Her hemoglobin A_1c (A1C) was 12.2%.

The next evening, she was given 50 units of glargine with premeal supplements of lispro to a total of 50 units (15 units at breakfast, 15 units at lunch, and 20 units at dinner). Her blood glucose levels now were well controlled without initial hypoglycemia.

During the next 3 months, she lost 22 lb (10 kg), and her insulin requirements gradually decreased. She was eventually switched from insulin to metformin. However, she did not continue to limit her calorie intake, and as a result she regained the weight she had lost and required insulin again.

1. Why does N.D. have type 2 diabetes when she has urine ketones?

2. Why didn't the “sliding scale” insulin bring her glucose levels down?

3. Why was this patient started on insulin instead of an oral agent, and how was the insulin regimen selected?

4. Why was N.D. eventually able to stop insulin therapy, at least for a while?

N.D. presented with classic catabolic symptoms of diabetes: weight loss,polydipsia, and polyuria with ketones in her urine. When this happens, even in an obese patient, type 1 diabetes should be considered. In this case, there was a combination of insulin resistance because of N.D.'s obesity and evidenced by her acanthosis nigricans (a sign of hyperinsulinism) and decreased insulin output because of a decrease in pancreatic secretion.

As demonstrated in the U.K. Prospective Diabetes Study(UKPDS),¹  virtually all patients have < 50% insulin secretion at the time of diagnosis. Her ketonuria was most likely caused by her decreased oral intake for the previous 2 days. However, in patients who are less ill and for whom oral agents are being considered, antibody testing may be appropriate if there is a question about whether the patient could have autoimmune type 1 diabetes or latent autoimmune diabetes of adults (LADA).

Because oral agents only lower A1C by 1-2 percentage points as monotherapy or up to 3 percentage points when used in combination, and because N.D.'s A1C was > 12%, insulin was indicated. Initially, insulin was required to overcome her glucose toxicity. Clinically, this is evident because she did not respond to the “sliding scale” regimen of subcutaneous insulin. Additionally, even if she had been given the maximum allowed by the physician orders (i.e., 40 units of subcutaneous regular insulin per 24 hours), her insulin needs were clearly much higher.

In such a situation, a weight-based calculation can be helpful in predicting a patient's insulin needs. A general guideline for starting insulin is to use 0.4-1.0 units of insulin per kilogram of body weight, with up to 2.0 units per kilogram often needed for obese, insulin-resistant patients. Because N.D. weighed 220 lb (100 kg), 100 units of insulin per day was a reasonable dose and was, not coincidentally, what she required.

Once it becomes clear that insulin is needed, a regimen of bedtime glargine with premeal lispro offers clear advantages over more traditional regimens,such as bedtime NPH with mealtime supplements of regular or lispro or twice-daily pre-mix 70/30 insulin. In a trial comparing NPH to glargine,²  patients on glargine experienced better fasting glucose control, equivalent daytime control, and, most importantly, 25% less nocturnal hypoglycemia. The main disadvantages are multiple injections (four versus two with pre-mix 70/30),cost (glargine and lispro are about twice as expensive as NPH or premix 70/30), and perhaps additional blood glucose testing.

In a basal (long-acting)/prandial (premeal) regimen, basal insulin (50% of total daily insulin) covers gluconeogenesis, and prandial insulin (50% of total insulin divided among meals) covers intake. Glargine is a clear, basal insulin that must be given separately because it cannot be mixed with other insulins. Rapid insulin analogs lispro, aspart, and glulisine are convenient for patients because they are administered right at mealtime instead of 30 minutes before eating, as with regular insulin. These analogs have an onset of 15 minutes, a peak at 60-90 minutes, and a duration of 3-5 hours. They are also easily adapted to meal content, using either carbohydrate counting (e.g.,1 unit of insulin per 10-15 g of carbohydrate) or an estimate of the percentage of total daily carbohydrate calories consumed at each meal.

N.D. required 100 units of insulin in 24 hours via insulin drip. To begin her basal/prandial regimen, this amount was divided into 50% basal (50 units of glargine at bedtime) and 50% prandial (50 units of lispro divided based on carbohydrate intake estimates as 15 units before breakfast, 15 units before lunch, and 20 units before dinner).

Glargine is adjusted based on fasting glucose, with a goal of 90-110 mg/dl;if the fasting glucose is > 110 mg/dl for 3 days, the glargine is increased by 2 units. Of note, because the onset of glargine is several hours, N.D.'s insulin drip was continued for 4 hours after her first dose of glargine was given. Her fasting plasma glucose of 129 mg/dl the next morning meant these dosing calculations resulted in control that was very close to optimal.

Finally, N.D.'s initial weight loss after dietary counseling reduced her insulin resistance, and the use of insulin to overcome her glucose toxicity probably “rested” her pancreas. Thus, she was gradually able to stop using insulin.

This is a common scenario in patients with type 2 diabetes. However, in the UKPDS,¹  insulin secretion continued to decline. This is the primary reason for secondary failure of oral agents in most patients with type 2 diabetes by 10 years into their disease. Unfortunately, N.D. was unable to maintain her initial weight loss after she decreased her dietary compliance, and she eventually needed insulin again. It is reasonable to counsel most type 2 diabetic patients that continued weight loss, dietary compliance, and exercise are cornerstones of diabetes therapy, and that they will likely need insulin in the long term.

• Obese patients with catabolic symptoms usually have type 2 diabetes, but autoimmune diabetes should be considered.

• Insulin drips and ongoing insulin therapy are the best treatment initially to overcome glucose toxicity.

• Basal/prandial insulin strategies are easy to initiate based on patients'insulin drip requirements (over 24 hours) and weight-based estimates of their insulin needs.

• Although oral agents, with weight loss, diet, and exercise, may be successful in the short term after initial insulin therapy, patients who have decreased insulin secretion will likely need insulin in the long term.