David Levy, MD, FRCP
Insulin treatment in type 1 diabetes is substitution/replacement hormone treatment, but replacement is much more variable and difficult to achieve than in other hormone deficiencies (e.g. thyroid, adrenal, gonadal hormones) because of the minute-by-minute variation in insulin secretion by the intact pancreas, which cannot yet be emulated precisely by any subcutaneous insulin regimen. Nevertheless, 24-hour glucose profiles almost indistinguishable from those of non-diabetic people can now be achieved with recent technical innovations in insulin pump therapy; this can only further improve with the long-awaited introduction of closed-loop feedback devices (Fig. 4.1)….
Insulin is an anabolic hormone, and results from the DCCT and other studies raise concerns about the following sequence: poor glycemic control → intensification of insulin treatment (often with increased hypoglycemia) → increased weight → increased insulin resistance → increased weight and risk factors for macrovascular and microvascular complications, especially nephropathy. For example, intensively treated patients in the DCCT who gained weight had elevated high-sensitivity CRP levels .
In clinical practice, therefore, there is a difficult balance to achieve between:
- intensifying insulin treatment in order to reduce HbA1c and thereby vascular complications, but risking increased hypoglycemia, weight gain and consequent insulin resistance characteristics;
- reducing the risks of recurrent severe hypoglycemia;
- avoiding persistent hyperglycemia.
With conventional intermittent subcutaneous insulin treatment compromises are inevitable.
Total Daily Insulin Dose Requirements
Total daily insulin production from the pancreas of young insulin-sensitive non-diabetic individuals is about 25–40 units, of which about 50% is basal insulin secretion. Peripheral subcutaneous insulin administration in most type 1 patients requires significantly more, between 0.5 and 1.0 unit/kg body weight daily. Care has to be taken ascribing causality, but long-surviving type 1 patients, for example the ‘Golden (50) Years’ cohort in the UK, have some characteristics of insulin sensitivity, for example low mean BMI of about 25, elevated HDL-cholesterol (~1.8 mmol/L, 70 mg/dL), and daily insulin doses at the lower end of the usual range (0.52 units/kg) . A similar cohort in the USA with at least 50 years of type 1 diabetes had remarkably similar characteristics.
Patients with long-standing type 1 diabetes therefore often have low total daily insulin requirements similar to those of non-diabetic individuals. Insulin antibodies, which may be produced in response to any insulin preparation (though to a much lesser extent with human and analogue insulins), may act as a ‘buffer’ to glucose variability. These patients have often used a wide variety of insulin preparations during their diabetic career. It is important to recognize the phenomenon: even if they require only tiny insulin doses, they remain type 1 patients, fully insulin requiring. Do not attempt to withdraw it .
Glycemic Targets in Type 1 Diabetes
Much sought and debated, there is no agreement on a glycemic ‘threshold’ for microvascular complications, a sustained level of HbA1c below which microvascular risk is abolished. However, other facts are less in dispute.
- Reduction in HbA1c from any given level will, if maintained for about 6 years (median duration of participation in the DCCT), significantly reduce microvascular risk.
- Glycemic memory established during this period is maintained for at least a further 10 years, despite slight deterioration in mean HbA1c, and which results in a continued lower risk of developing complications, including macrovascular as well as microvascular events (EDIC).
- HbA1c, and not other glycemic measures (e.g. glucose variability), overwhelmingly determines microvascular complications.
- Glycemia alone drives all vascular complications until the emergence of albuminuria, when other factors (blood pressure, lipids, inflammatory factors) become important. The contrast with type 2 diabetes could not be more striking.
The limits to achieving long-term normoglycemia are imposed by hypoglycemia.
HbA1c 7.5% (58 mmol/mol; estimated average glucose 9.3 mmol/L, 169 mg/dL) is a widely accepted and realistic target (the ADA proposes < 7.0% for all adults with diabetes). Pump treatment (and also islet and whole pancreas transplants) offers the possibility of HbA1c levels consistently below 6.0–6.5% (42–48 mmol/mol), at which level the development of microvascular complications is unlikely, and regression of some established complications, especially retinopathy, is possible (see below).
Many insulin products are available, but relatively few are now in common use. The trend has been for manufacturers to progressively slim down their insulin ranges over the past decade, and in the UK only about a dozen preparations are now widely used. There is increasing emphasis on the insulin analogues in preference to the established human insulin preparations, a matter of concern to some practitioners and patients , though very recently some manufacturers have started reinforcing their human insulin ranges. It should be remembered that recombinant human insulin preparations began to replace monocomponent (highly purified) pork preparations as recently as the early 1980s, and that the first human analogue insulin (lispro) was introduced only in 1997. Since the mid-1980s, insulin for human use has been standardized at 100 units/ mL (U100). Insulin vials contains 10 mL (1000 units), cartridges 3 mL (300 units).