Info

Days

Patients at risk

Control 314 265 230 211 193

Active 306 268 239 223 199

Days

FIGURE 3 Mortality after MI reduced by insulin therapy in the DIGAMI study. Cumulative reinfarction date during the first year of follow-up.

TABLE 1 Major Barriers to Insulin Therapy in Patients with Type 2 Diabetes

Preconceived barriers

Actual effects of insulin therapy

Insulin resistance Cardiovascular (CV) risk Weight gain Hypoglycemia

Improves insulin sensitivity by reducing glucose toxicity No evidence of atherosclerotic effects; may reduce CV risk Typically modest Rarely causes severe events control. Some simple but partial explanation for the weight gain comes from patients typically maintaining the same prior dietary transgressions but no longer having the caloric loss from glycosuria (43,44). Most studies have shown no change in basal metabolic rate (BMR) with improvement in glycemic control, perhaps due to the fact that the increase in BMR attributable to weight gain offsets the decrease in BMR attributable to improved glucose control (45-51). BMR is typically higher in diabetic subjects than that of non-diabetic subjects matched for BMI. Bogardus and colleagues showed an improvement in resting metabolic rate after improved glucose control in obese Pima Indians with T2DM when weight of the subjects was maintained constant from beginning to end of therapy by decreasing daily calorie intake. Insulin therapy is also known to noticeably lower plasma non-esterified fatty acid concentrations, a change which is associated with a lowering of gluconeogenesis (45). A decrease in non-esterified fatty acid concentrations may also lower heat production by decreasing mitochondrial uncoupling, i.e. the ratio between heat and ATP production. This emphasizes the importance of increasing daily activity and decreasing caloric intake to minimize weight gain. Of note, studies in obese patients with type 2 diabetes treated with insulin therapy have shown that, despite weight gain, CV risks factors such as blood pressure remained unchanged, and lipid patterns (triglycerides, lipoproteins) were generally improved (52-55). These findings challenge the notion that insulin therapy negatively affects blood pressure and lipid profiles through weight gain. Importantly, as previously discussed, intensive insulin therapy has been shown to improve rather than worsen insulin sensitivity by virtue of improving glycemic control, thus reducing and to some degree reversing the toxic effects of hyperglycemia (glucotoxicity).

In the UKPDS, patients in both the main study and the metformin sub study gained weight. In the main study, patients assigned to treatment with a sulfonylurea gained more weight than the conventional group, and those assigned insulin gained more weight than those on a sulfonylurea (35). In the cohort followed for 10 years, as compared to the patients on conventional therapy, those assigned to glyburide gained an excess of 1.7 kg and those on insulin gained an excess of 4.0 kg. In the metformin sub study, which included the more obese subjects in the trial (mean BMI ~31 kg/m2), the changes of body weight were similar to those in the main study except that the group randomized to metformin showed weight gain similar to the conventionally treated group but lower than the groups treated with insulin or a sulfonylurea (18). Indeed, combination insulin therapy with metformin is an effective strategy to potentiate the effectiveness of the insulin regimen while limiting weight gain, as it will be reviewed later.

The inevitability of weight gain has been challenged by the unexpected observation that improving glucose control with inhaled insulin or with the newest insulin analogues, glulisine and detemir, was associated with weight loss or, at least, reduced weight gain (56-59). These observations have stimulated a renewed interest in the mechanisms of weight gain as glycemic control improves. The commonly believed mechanism has been that patients are storing the calories instead of losing them as glucose in the urine. Metformin has been believed to minimize weight gain by decreasing overall caloric intake. This observation with the newer insulin's has several theories that are currently being studied. One plausible suggestion has been that with the improved predictability in absorption and action compared with other insulin's, the newer insulin analogues are associated with less risk of hypoglycemia, which may reduce the need for eating to minimize the risk of hypoglycemia (60). This possibility is supported by the reduced incidence of hypoglycemic episodes. However, treatment with insulin glargine similarly reduced hypoglycemia, compared with neutral protamine hagedorn (NPH), in the Treat-to-Target study and both were associated with less weight gain than expected over 24 weeks (5).

Although this appears to be the most likely explanation, as the decreased weight gain is consistent across the multiple studies, the question has also been raised as to whether the unique mechanism of absorption of insulin detemir may also have other properties. It is certainly possible that the fatty acid modification of insulin that is unique to insulin detemir may modulate other effects in the liver and brain that do not occur with traditional insulin preparations. While further studies are needed, the important clinical observation is that weight gain is not obligatory and does not need to occur as glucose control improves.

Insulin Therapy and Hypoglycemia

Hypoglycemia is the most important limiting factor for insulin adjustments to improve glycemic control. The risk of hypoglycemia depends on a number of factors including age, weight, degree of insulin resistance, duration of disease, duration of insulin therapy, targeted degree of glycemic control and history of hypoglycemic episodes. Additional causal factors in hypoglycemia include overinsulinization, dietary transgressions, strenuous unplanned exercise, excessive alcohol intake, and unawareness of hypoglycemia. The actual incidence of severe hypoglycemia in type 2 DM patients of <2 to 3% per year as shown by UKPDS is relatively very low (35,61). Indeed, the UKPDS is the largest long-term treatment study using insulin for type 2 diabetes. Hypoglycemic episodes were monitored as a measure of outcome during 10 years of treatment. The groups treated with insulin from the start showed more hypoglycemia, as might be expected, with little difference between the nonobese and the obese groups but most of the hypoglycemia was mild in severity. Severe hypoglycemic events occurred only in 2% to 3% of subjects in this group each year, on average. This rate is certainly not trivial, but it is far less than the rate seen with intensive insulin treatment of type 1 diabetes in the diabetes control and complications trial (DCCT) (62). It is conceivable that in patients with insulin resistance, exogenous insulin and the subsequent fall in glucose concentration into the normal range, leads to a more physiologic endogenous insulin release from the P-cells which may contribute to decreased hypoglycemia (63). However, most interventional insulin studies have failed to achieve target Alc levels and it is possible that hypoglycemia would have become more common if the patients had completely attained near-normoglycemia.

Limitations of Insulin Preparations

Over the years, multiple insulin preparations have been developed with recombinant DNA technology resulting in major improvements in purity but still with significant limitations in pharmacokinetics and pharmacodynamics, after subcutaneous injections (64,65). A comparison of the kinetics of available insulins is listed in Table 2

The time course of action of any insulin may vary between individuals, or at different times in the same individual. Consequently, table data should be considered only as general guidelines. NPH=Neutral Protamine Hagedorn.

Regular human insulin has a slow onset of action with delayed peak concentrations requiring patients to administer their injection 20 to 40 min prior to the meal in an attempt to improve the mismatch with the postprandial hyperglycemic peaks (66). This is inconvenient, is infrequently achieved, and poses the risk of premeal hypoglycemia if the meal is inadvertently delayed. Furthermore, the duration of action of regular insulin is much longer than the normal endogenous insulin peak following meals, typically at least 6 h and up to 12 h when large doses are injected. This persistence of high insulin levels leads to risk of hypoglycemia, which is often countered by between-meal snacks that foster weight gain in type 2 diabetes patients.

The three short-acting insulin analogs, insulin lispro, insulin aspart and insulin glulisine have absorption profiles that more closely match normal mealtime patterns (67-73). Small alterations in their amino acid structure relative to human insulin reduce their tendency to aggregate into dimers or hexamers, thus speeding their absorption after subcutaneous injection. Lispro, aspart and gluclisine have very desirable action profiles at mealtime because they have a rapid onset of action ranging from 5 to 15 min; the peak of action occurs 1 h after injection, and the insulin effect practically vanishes 4 to 5 h after administration. Their quick onset of action matches normal mealtime peaks of plasma insulin better than doe's human regular insulin.

TABLE 2 Pharmacokinetics of Human Insulin and Analogs

Onset of action(h) Peak (h) Duration of action (h)

Onset of action(h) Peak (h) Duration of action (h)

TABLE 2 Pharmacokinetics of Human Insulin and Analogs

Human Insulins

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