Understanding Carbohydrate Metabolism and Insulin Resistance in Acute Intermittent Porphyria

Abstract

Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking α-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP.

A case report of acute intermittent porphyria leading to severe disability

“…In addition to affecting the nervous system, abnormalities in porphyrin metabolism can also cause disorders of the endocrine and metabolic systems. The prevalence of insulin resistance and impaired glucose metabolism is higher among AIP patients compared to the general population ( 34 ). However, there is a scarcity of literature on the impact of porphyrin metabolism on the endocrine system, and further investigation is warranted to elucidate its pathogenesis.…”

Nutritional Interventions with Bacillus coagulans Improved Glucose Metabolism and Hyperinsulinemia in Mice with Acute Intermittent Porphyria

“…In the absence of vomiting, or paralytic ileus, preventive interventions involving increased dietary carbohydrates have been proposed for either AIP prophylaxis or the management of mild attacks [10,38]. On the other hand, a high-glucose diet is reported to increase gut permeability, the translocation of bacterial products, and insulin resistance, indicating that the gut-liver axis is likely to contribute to altered glucose homeostasis in metabolic diseases [39][40][41]. Several experimental models have highlighted that these alterations in glucose metabolism may arise in porphyrias.…”

An Analysis and Literature Review of a Family Case of Acute Intermittent Porphyria With Initial Symptoms of Epileptic Seizure

“…Suppression of disease activity can be aided by intravenous or oral glucose and other carbohydrates, which are part of the initial treatment [ 17 ]. High blood sugar can interfere with ALAS1 transcription, and if the patient has mild symptoms (e.g., no weakness, no vomiting, or no hyponatremia), a high-carbohydrate diet may be considered 48 hours before starting specific therapy [ 18 ]. If the disease is severe, intravenous glucose (300 ~ 500 g/d) is often given.…”