Insulin sensitivity in T1 prediction

Insulin secretion and insulin sensitivity jointly determine circulating glucose levels. A mis-match in this relationship results in hyperglycaemia. Whilst considerable effort has been invested into studying the loss of insulin secretion in the development of type 1 diabetes, relatively little attention has been paid to insulin sensitivity. A number of studies have recently demonstrated that insulin sensitivity is associated with protection from type 1 diabetes. Measures of insulin sensitivity may usefully contribute to current algorithms for the prediction of type 1 diabetes. Furthermore, if the relationship between insulin sensitivity and the development plays a causative role, therapies that increase insulin sensitivity may delay the onset of type 1 diabetes.

Insulin sensitivity in established type 1 diabetes

Insulin sensitivity indicates a state in which there is an increased biological effect for any given concentration of insulin. There is no defined cut-off for insulin sensitivity either within the general or type 1 diabetic population, and it varies with age, menses, pregnancy, illness and other forms of stress. In people with type 1 diabetes, insulin sensitivity is measured by euglycaemic hyperinsulinaemic clamp as gold standard, but can also be estimated from simple clinical and biochemical scores[1].

In established type 1 diabetes, insulin sensitivity associates with protection from both large and small vessel complications [2]. People with type 1 diabetes have low insulin sensitivity at the time of diagnosis[3], and insulin sensitivity may improve in the early course of disease as treatment is initiated, although sensitivity subsequently declines with increasing duration of disease.

The relationship between insulin sensitivity and secretion in health

The relationship between insulin secretion and sensitivity is tightly preserved in health. Any decrease in insulin sensitivity (for example during pregnancy) results in a compensatory increase in insulin secretion, such that glucose levels are maintained. Hyperglycaemia results when there is insufficient insulin secretion for a given state of insulin sensitivity. Thus, a deficit in insulin secretory capacity is more likely to be unmasked in an insulin resistant individual than in an insulin sensitive one. The key feature in predicting risk for diabetes is therefore the relationship between insulin secretory capacity and sensitivity, rather than insulin sensitivity per se.

Relative insulin sensitivity in pre-type 1 diabetes

The loss of beta cell function and insulin secretion leading to type 1 diabetes is a gradual process that can last years before the onset of hyperglycaemia and its symptoms. People deemed at risk of developing type 1 diabetes on the basis of genetic susceptibility, islet autoantibodies and falling insulin secretion appear to be at greater risk of disease if they are insulin insensitive for their level of insulin secretion. This has been demonstrated through studies where first-degree relatives of patients with type 1 diabetes who are positive for islet antibodies are followed to disease, and the collected data analysed retrospectively.

Study N Median duration of follow-up (years) Progression to clinical diabetes (%) Measure of insulin sensitivity Adjusted hazard ratio (95% CI)
Seattle Family Study (1999) (Greenbaum, Sears et al. 1999)[4] 85 2.8 11.8 Minimal model of glucose kinetics from IVGTT 1.0 (NS)
Melbourne Pre-Diabetes Family Study (2004) (Fourlanos, Narendran et al. 2004)[5] 104 4.0 41.3 HOMA1-IR:FPIR 2.14 (1.39 – 3.29)
Childhood Diabetes in Finland study (2006) (Mrena, Virtanen et al. 2006)[6] 77 15.0 40.3 HOMA1-IR:FRIR 2.4 (1.2 – 5.0)
Diabetes Prevention Trial- Type 1 (moderate risk group) (2007) (Xu, Cuthbertson et al. 2007)[7] 186 4.3 28.5 HOMA1-IR 2.70 (1.45 – 5.06)
Diabetes Prevention Trial- Type 1 (high risk group) (2007) (Xu 2007)[7] 170 3.7 41.2 HOMA1-IR 1.83 (1.19 -2.82)
European Nicotinamide Diabetes Intervetion Trial (2008) (Bingley 2008)[8] 213 4.2 49.3 HOMA2-IR 1.43 (0.99 – 2.06)

DPT-1 Moderate risk group – 25-50% 5 year risk of developing T1D
DPT-1 High Risk group - ≥ 50% 5 year risk of developing T1D
HOMA1-IR – measure of insulin resistance at steady state based on the formula: fasting insulin (mU/L) × fasting glucose (mmol/l) / 22.5
HOMA2-IR – refined model of HOMA1-IR, taking into account steady state changes in glucose and insulin at higher levels of fasting glucose and interference of insulin assays by proinsulin
FPIR – sum of serum insulin concentration at 1 and 3 minutes after glucose injection in the IVGTT
calculation based on insulin sensitivity index (× 10-5 min-1/[pmol/l]) from frequently sampled IVGTT between progressors (4.47 ± 0.584) and non-progressors (4.48 ± 0.443)

Here secretion was measured as first phase insulin release (FPIR), and insulin resistance either through HOMA- R or the frequently sampled IVGTT. Changes in the ratio of insulin insensitivity to secretion was detectable between 3 and 5yrs before type 1 diabetes was diagnosed. This feature was an independent predictor of type 1 diabetes risk, over and above antibodies, genetics and FPIR. As outlined above, these studies showed that the ratio between insulin sensitivity and secretion was a more powerful predictor of type 1 diabetes than insulin sensitivity alone.

Whether low insulin sensitivity for a given level of insulin secretion is associated with delay or real long-term protection from type 1 diabetes is not currently known, but is more likely to be the former.

Why is relative insulin insensitivity associated with protection?

The mechanisms associating reduced insulin sensitivity and the development of type 1 diabetes remains to be fully defined. They could include one or more of the following:

  • As described above, being insulin sensitive in the face of falling insulin secretion will help maintain euglycaemia. Insulin sensitivity may therefore delay the unmasking of any beta cell deficit brought on by islet autoimmunity

  • The ability of the beta cells to sense and respond to ambient glucose may be compromised in those who are less insulin sensitive. Figure 1
    Figure 1

  • Immune and adipose tissue derived cytokines associated with low insulin sensitivity may accelerate the autoimmune process against the beta cell. Factors such as IL6, TNF alpha, IL1, leptin are increased, and adiponectin decreased in states of insulin resistance, and these changes have proinflammatory effects which can influence islet autoimmunity (Figure 1)

Clinical implications

1) Prediction Measures of insulin sensitivity in relation to insulin secretion could potentially refine current risk algorithms for the prediction of type 1 diabetes, particularly later in disease when insulin secretion is impaired. This area requires further research.

2) Prevention Measures that increase insulin sensitivity could potentially delay the development of type 1 diabetes. Potential insulin sensitizing agents include metformin and thiozalinediones. Studies in animal models suggest that at least the latter of these agents may affect a delay in the development of disease.

Exercise also has insulin sensitizing properties (as well as other beneficial effects in type 1 diabetes). Exercise studies in animal models as well as humans suggest that this intervention preserves beta cell function[9][10]. Studies of exercise to preserve beta cell function in T1DM are ongoing (Current controlled trials ISRCTN91388505)

References

  1. ^ Williams K et al, Orchard T. Can clinical factors estimate insulin resistance in Type 1 diabetes? Diabetes 2000; 49: 626–632

  2. ^ Pang TT, Narendran P. Addressing insulin resistance in Type 1 diabetes. Diabet Med. 2008 Sep;25(9):1015-24

  3. ^ Yki-Jarvinen H, Koivisto VA. Natural course of insulin resistance in Type I diabetes. N Engl J Med 1986; 315: 224–230

  4. ^ Greenbaum CJ, et al. Relationship of beta-cell function and autoantibodies to progression and nonprogression of subclinical type 1 diabetes: follow-up of the Seattle Family Study. Diabetes. 1999 Jan;48(1):170-5.

  5. ^ Fourlanos S, et al. Insulin resistance is a risk factor for progression to Type 1 diabetes. Diabetologia 2004; 47: 1661–1667.

  6. ^ Mrena S, et al. Models for predicting Type 1 diabetes in siblings of affected children. Diabetes Care 2006; 29: 662–667.

  7. ^ Xu P, et al. Role of insulin resistance in predicting progression to Type 1 diabetes. Diabetes Care 2007; 30: 2314–2320.

  8. ^ Bingley PJ, et al. Insulin resistance and progression to Type 1 diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT). Diabetes Care 2008; 31: 146–150.

  9. ^ Choi SB, et al. Estrogen and exercise may enhance beta-cell function and mass via insulin receptor substrate 2 induction in ovariectomized diabetic rats. Endocrinology. 2005 Nov;146(11):4786-94.

  10. ^ Bloem CJ and Chang AM. Short-term exercise improves beta cell function and insulin resistance in older people with impaired glucose tolerance. Journal of Clinical Endocrinology and Metabolism. 2008. 93, 387-392

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