Early Insulin Treatment in Type 2 Diabetes: What are the pros?

Typically, whereas introducing insulin therapy in a more timely fashion would significantly improve glycemic control among subjects with type 2 diabetes, the question of insulin initiation timing in relation to other antiglycemic therapies is the subject of considerable debate (10). While insulin administration has the potential of achieving the most effective reductions in glycemic control, the initiation of insulin therapy requires greater use of resources, time, and effort from provider and patient alike, compared with oral antidiabetic therapies (11). Patient resistance to the use of insulin therapy remains a challenge, especially in populations that may have misgivings and misconceptions regarding the role of insulin replacement in diabetes management.

Notwithstanding these issues, there are specific populations that would clearly benefit from early, aggressive, and targeted introduction of insulin therapy. For instance, patients presenting with significant hyperglycemia may benefit from timely initiation of insulin therapy that can effectively and rapidly correct their metabolic imbalance and reverse the deleterious effects of excessive glucose (glucotoxicity) and lipid (lipotoxicity) exposure on β-cell function and insulin action (12). In vitro studies have demonstrated that chronic hyperglycemia leads to increased production of reactive oxygen species, and subsequent oxidative stress, which appears to affect insulin promoter activity (PDX-1 and MafA binding) and results in diminished insulin gene expression in glucotoxic β-cells (13). Interestingly, in vitro experiments have shown that these glucotoxic effects occur in a continuum of glucose concentrations (no clear threshold effect), are reversible with reinstitution of euglycemic conditions, and result in the greatest recovery of β-cell function with shorter periods of exposure to hyperglycemia (14). Various studies have demonstrated improvement in insulin sensitivity and β-cell function after correction of hyperglycemia with intensive insulin therapy (15).

A number of trials have evaluated the strategy of implementing short-term aggressive insulin replacement as first-line therapy in the management of hyperglycemia in newly diagnosed type 2 diabetes (Table 1), with the goal of improving and preserving β-cell function, reducing insulin resistance, and maintaining optimal glycemic control through disease “remission” (16,–18). In these studies, intensive insulin therapy was delivered via multiple daily insulin injections, or insulin pump therapy (continuous subcutaneous insulin infusion), over a period of 2–3 weeks, with achievement of euglycemia in ∼90% of subjects on completion of insulin treatment. After insulin withdrawal, patients were maintained on diet therapy only, with 42–69% maintaining euglycemia 12 or more months after treatment. Patients who achieved and maintained long-term euglycemia tended to have a better response to insulin therapy, as well as associated improvements in β-cell function, including first-phase insulin release, as measured by homeostasis model assessment of β-cell function (HOMA-B) and intravenous glucose tolerance tests.

Improvements in β-cell function and insulin action have also been reported when euglycemia is achieved with noninsulin therapies (19). Unfortunately, as illustrated by the U.K. Prospective Diabetes Study, long-term glycemic control in type 2 diabetes is difficult to maintain, regardless of the therapeutic intervention due, in part, to progressive loss of β-cell function over time. The recently published A Diabetes Outcome Progression Trial (ADOPT) demonstrated longer maintenance of glycemic control in patients using a thiazolidinedione (rosiglitazone) compared with glyburide or metformin monotherapy, although β-cell function, as measured by HOMA-B was no different at the end of the trial between the rosiglitazone and sulfonylurea groups (20); the benefits in durability of control seemed to have been a result of improved insulin sensitivity.

A recent study comparing intensive insulin therapy (multiple daily insulin injections or continuous subcutaneous insulin infusion) with oral hypoglycemic agents (glicazide and/or metformin) in newly diagnosed patients with type 2 diabetes provided some provocative results (21). In this trial, 92% of 382 subjects with poorly controlled diabetes achieved glycemic targets (fasting and 2-h postprandial capillary glucose levels of <110 mg/dl and <144 mg/dl, respectively) within an average of 8 days from start of therapy (Table 2). Treatment was withdrawn after 2 weeks of normoglycemia, followed by diet and exercise management. A greater proportion of patients randomized to intensive insulin therapy achieved glycemic targets and did so in a shorter period compared with oral agent therapy (Table 2). Shortly after discontinuing antiglycemic treatment, measures of first-phase insulin release, HOMA-B and HOMA-IR were similar among all treatment groups. By the end of 1 year, remission rates were significantly higher in the groups that had received initial insulin therapy (51 and 45% in the continuous subcutaneous insulin infusion and multiple daily insulin injections groups, respectively), compared with 27% in the oral therapy group. Whereas in the oral agent group, acute insulin response at 1 year declined significantly compared with immediate post-treatment, it was maintained in the insulin treatment groups. Of note, responders typically had higher BMI, less baseline hyperglycemia, and greater responsiveness to therapy than nonresponders.

Another study comparing early and continued insulin treatment versus oral agent therapy (glibenclamide) over a period of 2 years in recently diagnosed patients with type 2 diabetes showed better long-term glycemic control and β-cell function in the insulin-treated group (22). There was no difference in weight gain between insulin and oral agent therapy and no reported cases of severe hypoglycemia, reflecting easier-to-manage glycemia, probably as a result of better endogenous insulin production.

What could account for some of the differences in β-cell function seen in studies with early aggressive insulin therapy? A study evaluating the anti-inflammatory effects of an insulin infusion on obese subjects without diabetes demonstrated suppression of nuclear factor κB. Nuclear factor κB is the key transcription factor responsible for the transcription of proinflammatory cytokines, adhesion molecules and enzymes responsible for producing reactive oxygen species (23). As a consequence, insulin infusion significantly suppressed generation of reactive oxygen species and decreased concentrations of plasma soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemo-attractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1), among other observed anti-inflammatory actions (24).

Could the timing of the intervention affect the metabolic response to insulin therapy? For example, loss of first-phase insulin response, possibly as a consequence of glucotoxicity, is evident with fasting plasma glucose concentrations >115 mg/dl (25). Often, when diabetes is diagnosed, fasting plasma glucose levels are usually significantly higher, and may have been so for quite some time (26), exposing β-cells to chronic hyperglycemia and consequent β-cell decompensation (13). It could be hypothesized that early aggressive physiologic insulin replacement with both prandial and basal coverage results in rapid improvement in glucolipotoxicity, reduction of the inflammatory milieu, and consequent greater preservation of β-cell function. Some of these improvements in β-cell function were also evident after rigorous management with glyburide and metformin.

Whereas the use of insulin therapy in newly diagnosed subjects with type 2 diabetes appears to be associated with a low risk of hypoglycemia and weight gain, the use of algorithm-driven insulin replacement in more advanced disease is often associated with a greater incidence of weight gain and hypoglycemia. Individualizing the insulin prescription may minimize some of these adverse outcomes. Using the A1C status of a patient, the fasting blood glucose, and if available, the postprandial glucose could assist the provider in individualizing insulin replacement. Published trials in suboptimally controlled insulin-naive type 2 diabetes seem to indicate that basal insulin replacement yields similar effectiveness, but with less weight gain, and hypoglycemia risk than basal/prandial or mixed insulin strategies, when baseline A1C is ≤8.5% (27). Thus, in a patient whose predominant glycemic burden occurs overnight and whose A1C level is within 1–2% points of target, starting with a low dose of basal insulin (0.2 units · kg⁻¹ · day⁻¹) and adjusting the dose to achieve fasting blood glucose levels <110–130 mg/dl often proves an effective strategy. With higher A1C levels, replacing prandial insulin, with or without basal insulin coverage, results in greater A1C reduction than basal-only replacement, albeit at the expense of more weight gain and hypoglycemia (28). For example, patients inadequately controlled on basal insulin can be started on one or more doses of rapid-acting insulin (0.05 units/kg/meal) before one or more meals (usually the largest meals), and the insulin dose titrated to achieve postprandial blood glucose levels <180 mg/dl. A basal/bolus insulin replacement, giving patients flexible prandial dosing instructions, as opposed to fixed doses of premeal insulin, has been shown to be associated with equivalent glycemic control, but with less weight gain (29). Furthermore, the use of basal insulin analogs (glargine or detemir) is associated with less hypoglycemia (especially nocturnal hypoglycemia) and, in the case of insulin detemir, less weight gain than human NPH insulin (27,30).

In summary, aggressive and often temporary use of insulin therapy at disease onset in type 2 diabetes is associated with effective glycemic control with minimal weight gain and hypoglycemia. Early restitution of physiologic insulin secretion and glycemic control could be, in theory, followed by therapies to prolong maintenance of euglycemia, such as thiazolidinediones- (20) or glucagons-like peptide 1–based interventions (to date not clinically tested). A more timely and selective introduction of insulin replacement therapy, as β-cell function progresses, could facilitate the achievement and maintenance of euglycemia and thus reduce disease-associated complications.

L.F.M. has received grant support from sanofi-aventis, Novo Nordisk, Hoffmann-La Roche, and Medtronic; consulting fees from Novo Nordisk and NIPRO; and speaker's fees from sanofi-aventis, Eli Lilly, Merck, and Amylin.

No other potential conflicts of interest relevant to this article were reported.