Translating aetiological insight into sustainable management of type 2 diabetes

Abstract

Using a low-energy diet as a tool, it has been possible to elucidate the sequence of pathophysiological changes that lead to the onset of type 2 diabetes. Negative energy balance in type 2 diabetes causes a profound fall in liver fat content resulting in normalisation of hepatic insulin sensitivity within 7 days. As the period of negative energy balance extends and liver fat levels fall to low normal, the rate of export of triacylglycerol from the liver falls. Consequent to this, the raised pancreas fat content falls and in early type 2 diabetes, normal first-phase insulin secretion becomes re-established with normal plasma glucose control. This research, driven by the predictions of the 2008 twin cycle hypothesis, has led to a paradigm shift in understanding. Studying the reversed sequence of pathophysiological changes, the linked abnormalities in liver and pancreas have been revealed. Early type 2 diabetes is a potentially reversible condition. Surprisingly, it was observed that the diet devised as an experimental tool was actually liked by research participants. It was associated neither with hunger nor tiredness in most people, but with rapidly increased wellbeing. A defined period of weight loss followed by carefully planned weight maintenance-the 'One, Two' approach-has since been applied in clinical practice. Motivated individuals can reverse their type 2 diabetes and remain normoglycaemic over years. A large study is underway to evaluate the applicability of this general approach to routine primary care practice as a long-term management strategy.

Keywords: Aetiology; Beta cell function; Liver fat; Low-energy diet; Management; Pancreas fat; Pathophysiology; Type 2 diabetes; Weight loss; Weight maintenance.

Fig. 1

The 2008 twin cycle hypothesis. During chronic intake of more energy than is expended each day, any carbohydrate in excess of requirement must undergo conversion to fat in the liver to permit storage of the metabolic energy as fat [4]. As this process is sensitive to endogenous insulin, individuals with a degree of insulin resistance (and hence higher plasma insulin levels) will tend to accumulate liver fat more readily than others. If the subcutaneous adipose tissue stores have reached capacity, the newly synthesised fat will accumulate in the liver together with excess dietary fat. There it inhibits insulin suppression of glucose production by the liver, and a vicious cycle of hyperinsulinaemia and increased glucose production becomes established. Too much fat in the liver leads to increased export of fat in the form of VLDL-triacylglycerol [5] (shown in lighter red to indicate this is secondary to loss of insulin suppression of liver glucose production). When subcutaneous fat storage capacity is exhausted (i.e. exceeds the personal fat threshold), this will increase fat delivery to all tissues, and the pancreatic islets take up fat avidly [6]. Postprandial hyperglycaemia causes increased and prolonged insulin secretion with further stimulation of de novo lipogenesis. This second vicious cycle thus further increases de novo lipogenesis, and fat delivery to the pancreas. Over many years, the excess pancreas fat brings about loss of specialised function and de-differentiation of the beta cell [7]. Eventually, the inhibitory effects of fatty acids and glucose on the islets reach a trigger level leading to a relatively sudden onset of clinical diabetes. The twin cycle hypothesis predicted that both vicious cycles could be reversed by inducing negative energy balance. Figure adapted from [1] and [8]

Fig. 2

The Counterbalance study. Thirty people with type 2 diabetes of up to 23 years duration lost approximately 15 kg in weight then maintained steady weight for 6 months. Those achieving non-diabetic fasting plasma glucose levels were classified as responders and those whose levels remained in the diabetic range, as non-responders. In (b-d) the three columns for each group represent (from left to right) baseline on usual drug therapy; after weight loss, on an isoenergetic diet; and after a further 6 months of weight stability. (a) The change in HbA_1c in responders (circles) and non-responders (triangles). (b) There was a similar and sustained decrease in liver fat content in both groups despite ongoing overweight or obesity. (c) In the responders, pancreas fat decreased to low levels, but in the non-responders only fell to levels equivalent to baseline responder levels. (d) At baseline, the first-phase insulin response was higher in responders and increased to normal levels, whereas the grossly deficient baseline level in non-responders hardly changed. Although non-responders normalise both liver fat content and liver insulin sensitivity, plasma glucose remains elevated in the absence of normalised beta cell function and low fasting plasma insulin levels [9]. *p < 0.05; **p < 0.01 vs baseline. To convert HbA_1c values from % to mmol/mol, subtract 2.15 and multiply by 10.929. Triglyceride is elsewhere referred to as triacylglycerol. Copyright: ADA [9]. Copyright and all rights reserved. Material from this publication has been used with the permission of ADA

Fig. 3

Testing the twin cycle hypothesis. The Counterpoint study established that negative energy balance brought about normalisation of liver fat and insulin sensitivity to suppression of liver glucose production within 7 days, and normalisation of pancreas fat with normalisation of first-phase insulin response over 8 weeks [2]. The Counterbalance study demonstrated that if weight was kept steady after rapid weight loss then the normalisation of liver and pancreas fat content and function was durable during normal, isoenergetic eating [9]. It also showed that reversibility became much less likely after 10 years’ duration of type 2 diabetes. In vitro studies on insulin-producing cells demonstrate that excess fat provision reversibly decreases glucose-stimulated insulin production and that this is due to de-differentiation of beta cells [8, 16, 18]. Studies of acute weight loss produced by bariatric surgery observe a decrease in pancreas fat in people who used to have diabetes and not in non-diabetic individuals [3]. The practicality of achieving long-term reversal of type 2 diabetes in primary care is currently being evaluated in a head-to-head comparison with conventional management [36]

Fig. 4

Components of support to provide long-term weight stability. The major components of support for the individual are indicated. As eating is a social activity, the wider context must be taken into account. Maintenance of support from family/a partner is critical, and understanding from friends and work colleagues is also key, along with coping strategies where such support is absent. All of these points require exploration at ongoing follow-up visits. Not illustrated in the diagram is input of outside agencies as required and the crucial potential for the whole obesogenic environment to be influenced by policy makers