GH replacement causing acute hyperglycaemia and ketonuria in a type 1 diabetic patient

Abstract

A state of insulin resistance is common to the clinical conditions of both chronic growth hormone (GH) deficiency and GH excess (acromegaly). GH has a physiological role in glucose metabolism in the acute settings of fast and exercise and is the only anabolic hormone secreted in the fasting state. We report the case of a patient in whom knowledge of this aspect of GH physiology was vital to her care. A woman with well-controlled type 1 diabetes mellitus who developed hypopituitarism following the birth of her first child required GH replacement therapy. Hours after the first dose, she developed a rapid metabolic deterioration and awoke with hyperglycaemia and ketonuria. She adjusted her insulin dose accordingly, but the pattern was repeated with each subsequent increase in her dose. Acute GH-induced lipolysis results in an abundance of free fatty acids (FFA); these directly inhibit glucose uptake into muscle, and this can lead to hyperglycaemia. This glucose-fatty acid cycle was first described by Randle et al. in 1963; it is a nutrient-mediated fine control that allows oxidative muscle to switch between glucose and fatty acids as fuel, depending on their availability. We describe the mechanism in detail.

Learning points: THERE IS A COMPLEX INTERPLAY BETWEEN GH AND INSULIN RESISTANCE: chronically, both GH excess and deficiency lead to insulin resistance, but there is also an acute mechanism that is less well appreciated by clinicians.GH activates hormone-sensitive lipase to release FFA into the circulation; these may inhibit the uptake of glucose leading to hyperglycaemia and ketosis in the type 1 diabetic patient.The Randle cycle, or glucose-fatty acid cycle, outlines the mechanism for this acute relationship.Monitoring the adequacy of GH replacement in patients with type 1 diabetes is difficult, with IGF1 an unreliable marker.

Figure 1

The glucose–fatty acid cycle. A simplified diagram showing the interactions of products of glucose metabolism with free fatty acids (FFA) uptake and vice versa. ACC, acetyl-CoA carboxylase; F16BP, fructose 1,6 bisphosphate; G6P, glucose 6 phosphate; PDH, pyruvate dehydrogenase; PFK, phosphofructokinase; LCFAcyl CoA, long-chain fatty acyl CoA; MDC, malonyl-CoA decarboxylase; ECF, extracellular fluid. Malonyl-CoA is a by-product of glucose oxidation and inhibits carnitine palmitoyl transferase, an enzyme controlling fatty acid entry into the mitochondria. Malonyl-CoA concentrations in the steady state are a balance between the activity of ACC and MDC. When FFA is more abundant, metabolites favour activity of MCD via inhibition of the protein kinase A signalling pathway. When glucose is in excess, this pathway is stimulated, malonyl-CoA levels increase and FFA metabolism is inhibited.