We have shown that patients with less endogenous insulin secretion have greater post meal hyperglycaemia and greater response to prandial exogenous insulin.
In our study of insulin treated patients with Type 1 and Type 2 diabetes postprandial hyperglycaemia is inversely related to endogenous insulin secretion. This is consistent with previous research in non insulin treated Type 2 diabetes has shown that those with low insulin secretion have higher glucose increment after oral glucose tolerance test and higher glycaemic variability [27, 28]. In Type 1 diabetes a reduction in glycaemic variability with restoration of even small amounts of residual insulin secretion has been demonstrated after islet transplantation .
To our knowledge this is the first study to examine the relationship between endogenous insulin secretion and the impact of prandial exogenous insulin administration. We showed that the glucose response to exogenous prandial insulin was greatest in those with the lowest endogenous insulin secretion. In those with the highest endogenous insulin secretion concurrent prandial exogenous insulin had little effect on glucose response despite similar insulin doses and glycaemic control. A probable explanation is that those with high endogenous insulin secretion are exposed to their own endogenous prandial insulin therefore exogenous prandial insulin may be only a small proportion of their total prandial insulin exposure. This is in contrast to those with little endogenous insulin secretion where exogenous insulin makes up their entire prandial insulin exposure. In addition the similar exogenous insulin doses and glycaemic control across tertiles of endogenous insulin secretion mean insulin resistance is likely to be higher in those with preserved insulin secretion.
Our findings have potential practical implications for the management of diabetes. Patients with Type 2 diabetes progressively lose their beta-cell function over time leading to increased treatment requirements. Rates of progression vary widely and progression to severe insulin deficiency may occur rapidly where a patient with LADA or Type 1 diabetes has been misclassified as Type 2[30, 31]. A large proportion of patients with Type 2 diabetes will eventually require insulin. While background insulin alone may achieve initial glycaemic control many patients progress to prandial insulin treatment. The decision when to change to prandial insulin is not well defined and endogenous insulin secretion is rarely measured. Our work suggests that prandial insulin will be most effective when patients have a lower level of endogenous insulin as defined by a C-peptide below the top tertile of our participants; 90 minute post MMT C-peptide <0.8 nmol/L: fasting C peptide <0.29 nmol/L, or UCPCR 2 hours post home evening meal <0.73 nmol/mmol. Prandial fast acting exogenous insulin may have little impact on post meal hyperglycaemia above these levels. Assessment of endogenous insulin secretion could also potentially assist in decisions on rationalising a patient’s insulin regimen, for example where there are potential difficulties with administering multiple insulin doses or where adherence is thought to be poor a move to once or twice daily basal insulin may be justified where endogenous insulin secretion is preserved.
Limitations of our study include that we have recruited participants with a mixture of Type 1 and Type 2 diabetes and that differences seen may reflect differences in insulin secretion between the two diabetes subtypes. However the relationships seen, although weaker, remains when analysing our results by type of diabetes suggesting the relationship between insulin secretion and glucose response is not due to differences between diabetes subtypes alone. It is possible that results could have been influenced by differences in participant’s oral hypoglycaemic agents. While diabetes treatments were withheld on the morning of mixed meal tests, residual levels of treatment taken the previous day could potentially still affect both glucose and C-peptide. However this is unlikely to systematically differ between mixed meal tests (which were conducted in random order) and a longer period without medication might have made results less applicable to clinical practice.
A further potential limitation is that our marker of insulin secretion (90 minute post MMT C-peptide) and measure of post meal glucose increase (glucose increase from 0 to 90 minutes in the MMT) were measured within the same test. Our findings are strengthened by the demonstration of similar results when using fasting C-peptide and UCPCR (measured on a separate occasion) as markers of insulin secretion. The MMT, while well established and likely more reproducible than a conventional meal, may not be a normal physiological stimulus. The more rapid absorption of a liquid meal could lead to an earlier and greater glucose peak than a non liquid meal with the same carbohydrate content. In addition a standardised meal may not reflect a person’s normal intake. The liquid meal given is likely to have higher carbohydrate content than many participants normal breakfast (the carbohydrate content of our mixed meal was 57 g in those >60 kg, equivalent to 3–4 pieces of toast).
While we have shown a clear relationship between insulin secretion and effectiveness of fast acting (prandial) exogenous insulin during a mixed meal test further studies are needed to assess whether C-peptide could be a clinically useful measure to assist choice of insulin regimen. It may be that direct measurement of insulin secretion may assist clinical decisions on optimal insulin treatment. While a formal mixed meal test is unlikely to be an option in mainstream clinical practice the association was preserved using fasting C-peptide and post home meal UCPCR which may be more applicable to clinical practice .