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Failure to develop diabetic ketoacidosis in a newly presenting type 1 diabetic patient

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Q1: What test may be used to confirm a diagnosis of type 1 (as opposed to type 2) diabetes mellitus?

The intravenous glucagon stimulated C-terminal peptide test is considered the gold standard in confirming that a patient has type 1 (insulin dependent) diabetes mellitus. The insulin precursor proinsulin is released from the pancreas and then broken down into insulin and C-peptide. One milligram of glucagon is given intravenously, the subsequent rise in blood glucose stimulates the pancreas to release proinsulin, and thus pancreatic reserve can be measured by assaying C-peptide levels. In this patient type 1 diabetes was confirmed by a maximal response of 127 pmol/l at five minutes (adequate insulin reserve: >500 pmol/l, borderline insulin reserve: 200–500 pmol/l).

Q2: Given this patient's history before this admission; what other condition are the urea and electrolytes results in box 1 (see p 734) consistent with and how is the diagnosis confirmed?

Addison's disease is a deficiency in both glucocorticoids and mineralcorticoids. Glucocorticoid deficiency may lead to hypoglycaemia, while mineralcorticoid deficiency leads to hypoaldosteronism, thus producing a biochemical picture similar to aldosterone antagonising diuretics: hyponatraemia, hyperkalaemia, and uraemia.

Adrenal sufficiency may be tested with either the insulin tolerance test or the short Synacthen (tetracosactrin) test (standard or low dose). The insulin tolerance test is unpleasant for the patient, potentially hazardous in patients with a history of seizures or coronary heart disease, and requires medical supervision—making it relatively expensive. The short Synacthen test is a safe and easy test to confirm the diagnosis of Addison's disease. An intramuscular injection of 250 μg of synthetic adrenocorticotrophic hormone (ACTH) is given and serum cortisol concentration is measured at time 0 and 30 min. In our patient Addison's disease was diagnosed by a cortisol at 0 min of 15 mmol/l and at 30 min of 16 mmol/l (cortisol at 30 min >550 excludes the diagnosis). She also had a raised ACTH of 239.6 pmol/l (reference range 2.0–11.3) and was strongly positive for adrenal cortex antibodies. Her recovery appeared to be accelerated by glucocorticoid replacement therapy.

Q3.What is the explanation for this profoundly unwell patient with type 1 diabetes and hyperglycaemia not to have developed diabetic ketoacidosis?

While this patient was profoundly unwell with newly presenting type 1 diabetes mellitus and hyperglycaemia, we believe that she failed to develop diabetic ketoacidosis because her insulinopenia was offset by her hypoadrenalism.


Multiple pathologies should always be considered, especially in endocrine disorders. Addison's disease (secondary to adrenal antibodies) and type 1 diabetes are both organ specific autoimmune diseases and are associated. Approximately 10%–18% of patients with Addison's disease have type 1 diabetes, but Addison's disease is rare in type 1 diabetes.1-3 A number of interactions have been reported between these two diseases, with perhaps the best described being reduced insulin requirements and severe unpredictable hypoglycaemia in established type 1 diabetic patients, who develop Addison's disease.4 5

Insulin and catabolic hormones (catecholamines and cortisol) have antagonising effects on fat metabolism (see fig 1). In adipose tissue, insulin inhibits hormone sensitive lipase leading to reduced metabolism of triglyceride to non-esterified fatty acid (NEFA) and reduced ketone body formation, whereas catecholamines and cortisol stimulate the lipase leading to increased metabolism of triglyceride to NEFA with subsequent ketone body formation. In health, activity of this lipid pathway depends on a dynamic interaction between insulin suppressing the pathway and catecholamines and cortisol stimulating it. In newly diagnosed type 1 diabetes, profound hypoinsulinaemia combined with relative catabolic hormone excess favours NEFA production and subsequent ketogenesis which leads to presentation as diabetic ketoacidosis in 10% of newly diagnosed patients. In this woman, the lipolytic and ketogenic effects of insulinopenia were offset by glucocorticoid deficiency and the normal drive towards ketogenesis was much reduced. The absence of diabetic ketoacidosis in this ill woman with newly diagnosed type 1 diabetes illustrates the importance of glucocorticoid sufficiency and insulinopenia in the development of diabetic ketoacidosis.

Figure 1

The metabolism of triglyceride to ketone bodies. Note the directly antagonising roles of insulin and cortisol (DKA = diabetic ketoacidosis; NEFA = non-esterified fatty acid).


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