Insulin Therapy in Type Diabetes

The Big Diabetes Lie

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Kathleen L. Wyne and Pablo F. Mora

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.

Type 2 diabetes mellitus is defined by hyperglycemia, which is the result of an inability of the pancreas to make enough insulin for an individual's insulin resistance. Once this relative deficiency in insulin develops, the ability to produce insulin is no longer balanced with the insulin resistance and hepatic glucose production, thus the sugar begins to rise (1). When this mismatch is present, it is a progressive disease with a relentless decline in insulin secretion (2). The therapeutic armamentarium for the management of type 2 diabetes has widely expanded with the introduction of new oral and injectable agents, but their individual blood glucose-lowering potency is limited (3). In contrast, the blood glucose-lowering potential of insulin is only limited by the dose that one is willing to take. Insulin therapy should no longer be viewed as a "last resort" to be used after long-term oral agent combinations have failed, but, rather, as a therapeutic tool for earlier use in achieving glycemic targets. Simple strategies for starting insulin therapy with low doses in combination with oral agents have been shown to be effective (4-7). Once patients on combination oral therapy are started on insulin replacement, a structured titration regimen may suffice to accomplish glycemic targets. Many people will require an insulin regimen that will include prandial insulin to address postprandial hyperglycemia and to achieve and maintain target A1c levels.


Type 2 diabetes results from two fundamental pathogenic defects: impaired insulin secretion (or P-cell dysfunction) and insulin resistance manifested by increased hepatic glucose production and reduced peripheral glucose uptake (8). These defects are both genetically determined and influenced by environmental factors, such as physical inactivity and obesity (9). Preserved P-cell function to secrete sufficient insulin in response to peripheral resistance has emerged as the pivotal point in determining whether or not a patient progresses towards type 2 diabetes. Studies in young and apparently healthy Caucasian populations with normal glucose tolerance (NGT) or impaired fasting glucose (IFG) demonstrated that the P-cell function varied quantitatively with differences in insulin sensitivity (10,11). Analysis of first degree relatives of patients with type 2 diabetes has shown that the relationship between insulin sensitivity and P-cell function is reciprocal in that changes in one directly affect the other but not in a linear or logarithmic fashion (Fig. 1) (12). The natural history has been extensively studied in the Pima Indians of Arizona who have a high percentage of their adult population developing type 2 diabetes by age 40 (13,14). Further characterization of the P-cell dysfunction have demonstrated that insulin secretion defects are indeed present prior to the progression to hyperglycemia and can predict progression from NGT to IGT to diabetes (DM) (12,13).

A longitudinal study that monitored progression at yearly intervals in patients with initial NGT, found that transition from NGT to IGT was associated with an increase in body weight, a decline in insulin-stimulated glucose disposal, and a decline in the acute insulin secretory response to intravenous glucose (AIRglucose), but no change in endogenous glucose output (15). Longitudinal evaluation in the Mexico City study showed that beta cell function and not body weight or IR predicted progression to DM (16).

Similarly, studies in women who have had a history of gestational diabetes shows that the progression to type 2 DM is correlated with the extent of impairment of insulin secretion (17).

FIGURE 1 Percentile lines for the relationship between insulin sensitivity (SI) and the firstphase insulin response (AIRglucose) based on data from normal subjects with type 2 diabetes, healthy older subjects, women with a history of gestational diabetes (GDM), women with polycystic ovarian disease (PCO) and a family history of type 2 diabetes, subjects with IGT, subjects with a first-degree relative with type 2 diabetes.

FIGURE 1 Percentile lines for the relationship between insulin sensitivity (SI) and the firstphase insulin response (AIRglucose) based on data from normal subjects with type 2 diabetes, healthy older subjects, women with a history of gestational diabetes (GDM), women with polycystic ovarian disease (PCO) and a family history of type 2 diabetes, subjects with IGT, subjects with a first-degree relative with type 2 diabetes.

The role of the progressive nature of the insulin secretory defect was classically demonstrated by the UKPDS in newly diagnosed patients with Type 2 DM. Beta cell function, as measured by the homeostasis model assessment method (HOMA), showed an inexorable decline over time which explains why most patients with type 2 DM will eventually necessitate insulin therapy if glycemic targets were to be achieved (18,19). Although individuals in the UKPDS receiving sulfonylurea therapy demonstrated an early increase in P-cell function from 45% to 78% in year 1 of the study (consistent with a secretagogue effect of the sulfonylurea agent) P-cell function subsequently decreased along the same slope as the diet treated group. This inevitable decline in P-cell function also occurred in the metformin group in which P-cell function initially increased (similar to that in the sulfonylurea group) then declined from 66% to 38% by year 6. These data suggest that a significant amount of beta cell function has typically been lost at the time of diagnosis and it continues to decrease rapidly when treated with traditional monotherapies.

Over time, insulin secretion declines, presumably accelerated by glucotoxicity and lipotoxicity (20-23). Any therapeutic strategy that corrects hyperglycemia and reduces free fatty acid levels can potentially improve insulin action and increase the efficiency of insulin secretion. It is conceivable that earlier intervention with a combination of agents that reduce insulin resistance and also promote insulin secretion may preserve P-cell functional integrity to maintain a durable glycemic response but eventually, supplemental insulin replacement will be needed to achieve near-normoglycemia. Insulin replacement should be considered an option as part of the initial therapy in patients with type 2 diabetes in an attempt to correct the pathogenic defects and effectively reach glycemic targets.

The fact that this inexorable decline could not be altered with our traditional monotherapies suggests that a new approach to diabetes is needed. Given that the hyper-glycemia develops because of a relative deficiency of insulin, this raises the question as to why insulin is typically not included in the regimen from the time of diagnosis.

Indeed, short-term intensive insulin therapy in type 2 diabetes has been shown to improve insulin action by reversing glucotoxicity/lipotoxicity and possibly inducing " P-cell rest" that results in improved insulin secretion (24-28). It is tempting to speculate, therefore, that much earlier insulin administration, perhaps from the outset of the disease, might be crucial for preserving P-cell function. Preliminary support for this "P-cell rest" hypothesis is provided by a small study in newly diagnosed hyperglycemic patients with type 2 diabetes subjected to a period of 2 weeks of intensive insulin therapy, resulting in near-normoglycemia (29). Most of the patients subsequently sustained good glycemic control for long periods of time without pharmacologic intervention. These intriguing findings, albeit with small numbers of patients, suggest that insulin treatment in recently diagnosed type 2 diabetes might halt disease progression and permit long-term maintenance of nearly normal blood glucose levels with better response to oral agents or to simpler long-term insulin supplementation.

Insulin Therapy Can Improve Insulin Resistance

Insulin resistance, manifested by increased hepatic glucose production and reduced peripheral glucose disposal is a major pathogenic defect in type 2 diabetes, which correlates with obesity and hyperinsulinemia (30,31). Consequently, concern has been raised that treatment with insulin may worsen insulin resistance. However, short term intensive insulin therapy has been shown to improve insulin resistance (24-26). Peripheral insulin sensitivity, using the glucose-insulin clamp method, has been assessed before and after restoration of near-normoglycemic control in type 2 diabetes patients on intensive insulin treatment. In each case the treatment period was short (2 to 4 weeks) and relatively high insulin dosage was required (>100 U daily). Fig. 2 shows the tissue insulin sensitivity before and after treatment, expressed as a percentage of the mean value for insulin sensitivity of a non-diabetic control group that was matched in age, gender, and weight to the diabetic subjects. The three studies had remarkably similar results, with insulin sensitivity before treatment with insulin reduced by half, compared to the non-diabetic values, indicating marked insulin resistance. After treatment, insulin sensitivity improved toward the non-diabetic values, though some insulin resistance persisted, as would be expected. This improvement is presumably due to the resolution of the hyperglycemia and consequent reduced "glucotoxicity". Whether the improvement of insulin sensitivity persists when insulin treatment is continued for longer periods of time was not tested in these studies. However, these data show that, at least in the short term, successful insulin treatment reduces rather than worsens insulin resistance. Defronzo and colleagues showed that aggressive insulin therapy over 12 weeks that resulted in near-normalization of A1cs (decreased from 10.1-6.6%) improved insulin resistance through improving insulin-stimulated glucose disposal but did not fully corrected the inherent insulin resistance (27).

Insulin Therapy and Potential Cardiovascular Benefits

Insulin resistance and the consequent endogenous hyperinsulinemia are strongly associated with central obesity, hypertension and dyslipidemia, all factors that contribute substantially to cardiovascular (CV) risk and in fact characterize the Metabolic Syndrome (31,32). Epidemiological studies in non-diabetic populations have shown an association between endogenous hyperinsulinemia and atherosclerosis (33) thus physicians have been concerned that initiating insulin therapy would be harmful and may accelerate coronary artery disease. However, the association of hyperinsulinemia and atherosclerosis is mainly an association between endogenous hyperproinsulinemia and atherosclerosis (34). In fact, there is no evidence from animal or human studies that exogenous insulin administration causes accelerated atherosclerosis. The UKPDS actually was very reassuring in demonstrating that the insulin treated patients, who presumably had exogenous hyperinsulinemia, showed no evidence at all of increased atherosclerotic-related events (35).

Furthermore, the 5-year diabetes mellitus insulin-glucose infusion in acute myocardial infarction (DIGAMI) trial showed that insulin infusion therapy during acute MI followed by intensive multiple dose insulin therapy reduced the relative mortality risk by 28% as compared to control (conventional therapy) after an average follow-up of 3.4 years (36,37). The subjects were randomized at the time of myocardial infarction to either control (continued management according to the judgment of their physicians) or to intravenous infusion of

FIGURE 2 Improvement in insulin sensitivity as measured by the glucose clamp technique, at baseline and after intensive insulin treatment. Solid bars, after insulin; open bars, baseline. Source: From Refs. 24-26.

insulin and glucose for 48 h followed by a four-injection regimen for as long as 5 years. The rationale underlying the study was the preliminary observations that, in animal experiments and in studies of small numbers of humans, infarct size and outcome were improved by the insulin-glucose-potassium infusion, which is theorized to be related to suppression of otherwise elevated free fatty acid levels in plasma (38-41). Fig. 3 shows the cumulative total mortality rates in the whole population of 620 subjects randomized to the two treatments, as well as the rates for a predefined subgroup of subjects who were judged likely to survive the initial hospitalization and were not previously using insulin (36). The whole population showed an 11% actual and a 28% relative risk reduction in mortality with intensive insulin treatment after 5 years, and the subgroup not previously using insulin showed a 15% actual and a 51% relative risk reduction. Most of the benefit was apparent in the first month of treatment and presumably was partly due to immediate intravenous infusion of insulin; however, the survival curves tended to separate further over time, suggesting an ongoing benefit from intensive insulin treatment. This study suggests that insulin is an entirely appropriate treatment for type 2 diabetes patients with high cardiovascular risk, especially at the time of myocardial infarction. These same investigators then tried to repeat the study but found that the use of insulin had become standard in this patient population thus the DIGAMI 2 study was not able to reproduce the benefits found in DIGAMI (42).

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