Eur J Med Genet. 2014 Feb;57(2-3):71-5.

Modification of severe insulin resistant diabetes in response to lifestyle changes in Alström syndrome.

Paisey RB1, Geberhiwot T2, Waterson M3, Cramb R4, Steeds R5, Williams K6, White A6, Hardy C7.

  • 1Department of Diabetes Research, South Devon Healthcare NHS Foundation Trust, Torquay, UK. Electronic address: richard.paisey@nhs.net.
  • 2Department of Inherited Metabolic Disease, Queen Elizabeth Medical Centre, Birmingham, UK.
  • 3Department of Clinical Biochemistry, South Devon Healthcare NHS Foundation Trust, Torquay, UK.
  • 4Department of Clinical Biochemistry, Queen Elizabeth Medical Centre, Birmingham, UK.
  • 5Department of Cardiology, Queen Elizabeth Medical Centre, Birmingham, UK.
  • 6Department of Diabetes Research, South Devon Healthcare NHS Foundation Trust, Torquay, UK.
  • 7West Midlands Regional Genetics Laboratory, Birmingham Women’s NHS Foundation Trust, Edgbaston, Birmingham, B15 2TG, UK.

 

ABSTRACT

BACKGROUND: Alström syndrome is a recessively inherited condition characterised by severe insulin resistance and metabolic syndrome with progression to type 2 diabetes, hepatic dysfunction and coronary artery disease. The metabolic responses to lifestyle changes in the syndrome have not been reported.

CASE REPORTS: We describe the effects on glycaemia of intense cycling in two insulin treated Alström patients with diabetes, and the effects of opposite lifestyle changes over one year in two others.

METHODS: After practise and clinical assessment two patients aged 21 and 39 years undertook a 380 km cycle ride over 4 days by tandem. The effects of planned reductions in insulin therapies and increased regular carbohydrate ingestion were monitored by frequent capillary blood glucose measurements. Two siblings aged 22 and 25 years underwent assessment of glycaemia, C-peptide/glucose ratio serum lipids, hepatic function and ultrasound, Enhanced Liver Fibrosis test and measures of insulin resistance. Measurements were repeated one year later after profound lifestyle changes.

RESULTS: Aerobic exercise strikingly improved blood glucose control despite reduction in insulin dose and increased carbohydrate intake. Increase in exercise and exclusion of fast foods improved all aspects of the metabolic syndrome and induced remission of diabetes in one sibling. Reduction in exercise and consumption of high energy foods in the other resulted in development of type 2 diabetes, severe metabolic syndrome and fatty liver in the other.

CONCLUSIONS: Despite dual sensory loss and genetic basis for insulin resistance, Alström patients can successfully ameliorate the metabolic syndrome with lifestyle changes. Copyright © 2014 Elsevier Masson SAS.

KEYWORDS: Alström syndrome; Exercise; Insulin resistance; Metabolic syndrome; Nutrition; Type 2 diabetes

PMID: 24462884

 

SUPPLEMENT:

Commentary on Lifestyle modification in Alström syndrome in Diabetes and Obesity

The study highlighted is a good example of success in applying basic principles of life style intervention to young Alström subjects in order to improve their health and well-being. It has been possible to show striking improvement in insulin resistance, glycaemic control of diabetes, dyslipidaemia, fatty liver and hypertension after one year of increased exercise and healthy eating based on restriction of carbohydrate to 100 gram daily and elimination of refined sugars. The precise opposite effects were seen in an Alström sibling in whom deterioration in nutrition and lack of exercise occurred. The two other Alström subjects with insulin requiring diabetes demonstrated a striking improvement in glycaemic control during 50 miles daily strenuous cycling for 4 days.

Taken together known rare diseases affect 5% of the population of Europe [1]These very rare, often genetic conditions are important in their own right as families affected by the condition can face delay in diagnosis and treatment leading to disjointed care and avoidable challenges in accessing timely therapy, social and educational support. In addition the effects of single gene mutations on metabolism can shed more light on mechanisms of disease in more common conditions. All of these circumstances are exemplified by Alström syndrome [2], now categorised as a ciliopathy.

The primordial cilium is an integral component of all eukaryotic cells. The discovery of the genes associated with polycystic kidney disease, primary ciliary dyskinesia, Leber’s optic atrophy, Joubert syndrome, Bardet Biedl syndrome, Meckel Gruber syndrome, Alström syndrome and Usher syndrome quickly led to the association of these conditions with dysfunction of ciliary proteins. The cilium, basal bodies/centrosomes and linked microtubules are now known to be comprised of more than 1000 proteins and to be crucial in cell physiology. This involves sensing external stimuli, transference of proteins between cell compartments, focussing dynamic changes in microtubular generation including cell division, differentiation of cells and genesis of organ shape and symmetry [3–7].

The variable severity of organ dysfunction in Alström patients remains unexplained, but the insulin resistance is ubiquitous. It is likely to be linked to an effect of the mutated protein on intracellular microtubular function resulting in reduced expression of glucose transporters in response to insulin binding [8]. This would particularly affect muscle cells in which glucose transporter 4 is the port of entry for glucose into this tissue and of high affinity. A likely consequence would be diversion of glucose to the liver with excess triglyceride synthesis and VLDL secretion leading to fatty liver, high serum triglyceride and low HDL cholesterol levels typical of both Alström syndrome and the metabolic syndrome. The rapid improvement in glycaemia with exercise during the cycle ride implies that the insulin independent externalisation of GLUT 4 receptors in muscle has occurred effectively despite the genetic cause of the insulin resistance [9]. The effect of lifestyle in modifying all features of the metabolic syndrome in the Alström subjects is equally important. Taken together these findings if confirmed in larger numbers would emphasise the primary importance of lifestyle intervention from infancy in secondary prevention of the consequences of the metabolic syndrome in Alström families. These include risks of hypertriglyceridaemia and pancreatitis, type 2 diabetes, hepatic steatosis leading to hepatic fibrosis, and coronary artery disease [10–15].

The utilisation of serum post-prandial C-peptide/glucose ratio to quantify insulin resistance in our patients is important [16]. The two patients in the report with type 2 diabetes have ratios of > 800 pmol/mmol. This is greater than the range for non-syndromic type 2 diabetes (Berger). In contrast the ratios in the insulin requiring Alström subjects in the study were 71 and 50 pmol/mmol. This striking difference supports exploration of utility of this ratio to plan therapy escalation in all forms of type 2 diabetes [17].

In summary the most helpful treatment in this rare ciliopathy needs to be grounded in engagement of families. Motivation to eat healthily and keep active is crucial, as is provision of family support to facilitate these life style choices in spite of the dual sensory loss.

 

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DSC_4189 Fig 1. Two of the Alström family and their pilots on day 1 of the 230 mile ride

KG-ins-cho-gluc-and-exercise Fig 2. Changes in blood glucose, carbohydrate intake, insulin dosages and miles cycled.

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