Current Management/ Potential Avenues for the Prevention of Type 2 Diabetes

At an industry-sponsored symposium held in conjunction with the American Association of Clinical Endocrinologists’ 2003 Annual Meeting and Clinical Congress, three leaders in the treatment of diabetes presented the latest information on current management of patients with Type-2 diabetes and insulin resistance, recent research suggesting that thiazolidinedione therapy confers a protective effect on b-cells and ongoing research into the role of free fatty acids in pathophysiology of insulin resistance.

This program was supported by unrestricted educational grants from Takeda Pharmaceuticals North America, Inc., and Eli Lilly & Company.

Current Management of Type 2 Diabetes and Insulin Resistance

When selecting therapies for type 2 diabetes (T2DM), traditional approaches focus only on the glucose lowering effect of specific agents. David M. Kendall, MD, from the International Diabetes Center in Minneapolis, suggests that treating T2DM is becoming more complex.

“There are a number of very practical clinical decisions we are asked to make for our patients,” said Dr. Kendall. “We have to include questions of medication cost, the impact on lipid metabolism, and other insulin-regulated systems and the effect on b-cell function.”

Practitioners are beginning to understand the need to treat a combination of increasing insulin demands related to insulin resistance (IR) and inadequate insulin response or b-cell dysfunction. The latter being the major link in the chain resulting in hyperglycemia.

IR can predate diabetes by more than 20 years. In the early phases of insulin resistance most individuals simply have an “exuberant” insulin response and hyperinsulinemia. When insulin resistance and b-cell function are matched, there is normal fasting and postprandial blood glucose (BG) levels. As the b-cell function declines, there is a gradual increase in both post-challenge and fasting glucose.

“We are now in an era of multiple medications and use of combination therapies,” he said. “There is a need to understand why choosing therapies that
match defects is important.”

Cost is another consideration. Data from Gilmer and O’Connor suggests that the costs of diabetes care are significantly increased with increasing levels of glycemia (Gilmer TP, et al. Diabetes Care. 1997;20:1847).

“We currently spend the majority of diabetes care dollars on inpatient, nursing home care and emergency rooms,” he said. “It is not hyperglycemia that accounts for this cost, but rather the complications of diabetes—specifically cardiovascular complications.”

One area getting more attention is lipid disorders associated with T2DM. This classic disorder is associated with elevated free fatty acid (FFA) levels, increased triglycerides from more VLDL production, lower concentrations of HDL, and an increase in small dense LDL particles- the so-called atherogenic profile.

“We know that sensitizing agents like rosiglitazone and pioglitazone can increase HDL cholesterol and pioglitazone can lower triglycerides in many
patients,” said Dr. Kendall. “These beneficial effects on HDL seem to be greatest in those with lowest levels at baseline. Those with low HDL may be where IR plays the biggest role.”

Cardiovascular diseases remain one of the greatest risks for diabetes patients. This risk for macrovascular disease is more than two fold higher 5 to 15 years before the diagnosis of diabetes. On the day of diagnosis with T2DM, the risk is three-fold higher in observational studies (Hu FB, et al. Diabetes Care. 2002; 25:1129).

“While we understand the importance of intervening in hypertension, lipid disorders, and other abnormalities, we are beginning to understand there is a very large population with pre-diabetes and metabolic syndrome who are likely to benefit from early management of these disorders,” said Dr. Kendall.

Cellular Mechanisms of Insulin Resistance

“I will focus on the mechanisms of insulin resistance in skeletal muscles,” said Gerald I. Shulman, MD, PhD, from the Howard Hughes Medical Institute at the Yale University School of Medicine in New Haven, CT. “IR in skeletal muscles typically predate the defects that occur in b-cell and liver in patients with Type 2 diabetes.”

Using in vivo nuclear magnetic spectroscopy (NMS), Dr. Shulman and colleagues infused a stable isotope of glucose to measure the rate of muscle glycogen synthesis. They demonstrated that T2DM patients synthesized muscle glycogen at half the rate of age-matched controls. This defect was responsible for the majority of whole body insulin resistance (Shulman, G, et al. NEJM. 1990;322:223).

“There are at least three good candidates implicated as potentially being responsible for reduced insulin-stimulated muscle glucose uptake in type 2
diabetes,” he said. “They are glycogen synthase, hexokinase and the insulin stimulated glucose transporter GLUT-4. Each of these steps has previously been implicated as abnormal from muscle biopsy studies in type 2 patients.”

In order to ascertain the rate-controlling step they performed 31P MRS studies to assess intracellular glucose-6-phosphate (G6P) concentrations in the muscle of type 2 diabetic subjects. Since G6P is an intermediate between glucose transport/phosphorylation and glycogen synthase, an increase in G6P concentrations in the diabetic would implicate a glycogen synthase defect. No change in G6P would suggest a defect in glucose transport/phosphorylation activity, which is what the investigators found (Rothman DL, et al. J. Clin. Invest. 1992;89:1069).

The next step was to ascertain whether these defects in insulin-stimulated muscle glucose transport/phosphorylation were an early or an acquired defect due to “glucose toxicity”. The researchers looked at young, lean insulin resistant offspring of parents with type 2 diabetes, who had a high likelihood of developing diabetes. They found that the subjects had similar defects in insulin-stimulated G6P leading to the conclusion that the defect in glucose transport/ phosphorylation is an early manifestation. (Proc. Natl. Acad. Sci. USA. 1995; 92:983-987)

To pinpoint whether the defect was glucose transport of phosphorylation, Dr. Shulman’s group developed a novel MRS technique to measure intracellular glucose in the muscle of diabetic patients. By infusing 13C labeled glucose and similarly labeled mannitol, they were able to assess intracellular concentrations of glucose in muscle and determine that there was over a 50-fold gradient in the concentration of glucose between the outside and the inside in both control and diabetic patients. More importantly, the intracellular concentration of glucose was more than ten-fold lower than what would be expected if hexokinase were the rate-controlling step responsible for IR in skeletal muscle of patients with type 2 diabetes (Cline GW, et al. N. Eng. J. Med. 1999;341:240).

“We believe that defects in insulin activation of GLUT-4 is the major factor responsible for insulin resistance in skeletal muscle of patients with T2DM,” said Dr. Shulman. “But this doesn’t tell us what is wrong with GLUT-4.”

To try to understand the problem, they revisited the offspring of parents with type 2 diabetes and found that increases in the plasma fatty acid concentration was the best predictor of insulin resistance. Subsequent studies have found that intra-myocellular lipid content was an even better predictor of muscle insulin resistance (Krssak M, et al. Diabetologia 1999;42:113).

“The bottom line is that the more fat you have inside a muscle cell, the more insulin resistant you are,” noted Dr. Shulman. “So, how does fat cause
insulin resistance?”

To examine this question, his group performed hyperinsulinemic-euglycemic clamp studies in young healthy volunteers, once while increasing the concentration of plasma fatty acids and a second time at basal fatty acid concentrations. They used 31P MRS measurements of intracellular glucose-6-phosphate concentrations and 13C MRS measurements of intracellular glucose concentrations to assess glucose transport activity by inhibition of insulin stimulated glucose transport activity, the same block seen in T2DM patients. This occurs via inhibition of phosphatidyl inositol 3-kinase activation (a key enzyme required for insulin stimulation of muscle glucose transport activity). This in turn could be attributed to activation of a serine kinase cascade. These data provide new potential targets for the treatment and possible prevention of type 2 diabetes.

Dr. Shulman’s group is now trying to determine the reason for fat accumulation inside the muscle cell of insulin resistant individuals. They recently found that defects in mitochondrial activity are responsible for fat accumulation and insulin resistance in the elderly (Petersen KF, et al. Science 2003;3001140-1442). Studies are underway to determine whether similar defects in mitochondrial function occur in the young insulin resistant offspring of parents with type 2 diabetes.

Preserving b-Cell Function and Preventing Type 2 Diabetes by Treating Insulin Resistance.

“Diabetes is not simply a disease of hyperglycemia,” said Thomas A. Buchanan, MD, from the University of Southern California Keck School of Medicine in Los Angeles. “It is a disease of pancreatic b-cell dysfunction and our initial treatment and prevention efforts should be directed by that fact.”

Dr. Richard Bergman put forward a concept in the early 1980s that there is a predictable relationship between the insulin requirements of the liver and muscles and how much insulin the pancreas creates. In general, it has the shape of a hyperbolic curve such that increasing insulin needs of the tissues (insulin resistance) results in greater and greater demands for insulin secretion from the b-cells.

People who can make the extra insulin over a long period of time without their b-cells failing do not get diabetes. Those whose b-cells fail under the same conditions get impaired glucose tolerance (IGT) and eventually type 2 diabetes. Cross sectional studies indicate that people with IGT have only 50% of normal b-cell function for their degree of insulin resistance. By the time they develop T2DM, less than 20% of normal b-cell function may remain.

Relationships between b-cell function and IR often change over time. A study of Pima Indians took young adults with normal glucose tolerance and followed them for an average of 7 years. During the follow-up, they all tended to become IR. At the end of the study those maintaining normal glucose tolerance had increased their insulin secretion (Weyer C, et al. J Clin Invest. 1999;104: 787).

“Presumably, the reason they could maintain such high levels of insulin secretion over the long term is that they had robust b-cells,” said Dr. Buchanan. “On the other hand, the people who developed diabetes lost b-cell function as they became insulin resistant. That is precisely the wrong response from the b-cells.”

Results from the Pima Indian study and a separate study by Goldfine et al, in which b-cell function was normal in proven pre-diabetics 12-15 years before they got diabetes suggest that the b-cell defect in T2DM is acquired on a background of insulin resistance (Goldfine AB, et al. Proc Natl Acad Sci USA 2003;100:2724).

Whether IR actually causes loss of b-cell function has been a focus of research by Dr. Buchanan’s group. The basic premise is that if insulin resistance causes b-cell dysfunction, then treating the insulin resistance could stop this loss of function that leads to T2DM and its worsening over time.

Buchanan presented the results of two studies showing that women who develop gestational diabetes respond to reduced insulin resistance by reducing the amount of insulin made by their b-cells with little change in their blood glucose. This allowed their b-cells to “rest” by reducing tissue insulin requirements (Homko C, et al. J Clin Endocrinol Metab. 2001;86;568; Buchanan TA, et al. Diabetes. 2000;49: 782).

Buchanan’s group tested the long-term effects of resting b-cells by treating insulin resistance in the Troglitazone In the Prevention of Diabetes (TRIPOD) study. Two hundred and thirty-five Hispanic women with a recent history of gestational diabetes (GDM) provided evaluable data for the study. The mean age at entry was 35 years and the mean body mass index was 30 kd/m2. On their entry glucose tolerance test (GTT), they had a mean fasting glucose level of 98mg/dl and a mean two-hour level of 155 mg/dl. The mean hemoglobin A1C level was 5.3%. Those enrolled were given troglitazone (400 mg/d) or placebo daily during the term of the study. Median follow-up was 30 months with maximum of 54 months (Figure 1).

In the placebo group 12.1% developed diabetes every year and by 4.5 years half were diabetic. In the active treatment arm, the diabetes incidence was
reduced to 5.4% per year and the cumulative index rate at 4.5 years was only 19%. The relative risk reduction was 55% and the absolute risk reduction was 3.1% (Buchanan TA, et al. Diabetes 2002; 51:2769).

In a separate analysis, Buchanan’s group looked to see what metabolic changes observed three months into the trial were most clearly related to the onset of diabetes in the active treatment group. To their surprise, early changes in glucose levels were completely unrelated to protection from diabetes. An early increase in insulin sensitivity was required.

The third of the women who did have this early increase had a diabetes rate of 10% per year, similar to the rate in the placebo group. Among those who did increase their insulin sensitivity when placed on troglitazone, those who experienced the largest reduction in endogenous insulin requirement were the least likely to get diabetes. In fact, there was a very strong relationship between the reduction in endogenous insulin requirements when started on the medication and their subsequent diabetes rates.

“These findings don’t prove that b-cell rest caused protection from diabetes, but they provide strong evidence of a protective mechanism,” said Dr. Buchanan. “We can say for sure that troglitazone reduced the incidence of diabetes and reduced secretory demands on the b-cells appears to be the operative mechanism. In other words, b-cell rest equals b-cell preservation.”

Women who did not have diabetes during the blinded TRIPOD trial were re-studied 8 months after they stopped their assigned treatment. Among those assigned to placebo, the development of diabetes continued at around 21% per year, not really different from the rate seen during the trial given the short time period. Among those on troglitazone, the rate of diabetes after the trial was only 3% per year.

“When we saw that result we were pretty sure we had altered the biology of the progression to diabetes,” said Dr. Buchanan.

They also tested IR and b-cell function in the two groups 8 months after completion. The women on placebo had lost 30% of their baseline insulin sensitivity and 39% of the ability of the b-cells to compensate for insulin resistance. The women on troglitazone had stable insulin resistance and b-cell function over the 4.5-year period from entry into the study to post-trial testing.

“This finding demonstrated very clearly that resting b-cells can stop their decline,” noted Dr. Buchanan. “From the TRIPOD study we know that we can reduce the incidence of diabetes by 55% using troglitazone. We believe that this shows reducing the secretory demands placed on b-cells by chronic IR preserves b-cell function, delaying or possibly preventing type 2 diabetes if you continue medication for an extended time.”

Data from the UKPDS indicate that continued loss of b-cell function might be one mechanism for diabetes worsening over time. Although the reasons are not yet known, Dr. Buchanan noted there is evidence that b-cell mass declines as people develop diabetes making it harder to “rest” individual cells as they account for more of the total insulin supply. (Butler AE, et al. Diabetes. 2003; 52:102).

In addition, treatment targets are designed to prevent long-term complications but not rest b-cells. In fact, glucose levels in patients with hemoglobin A1C levels of 7%, a common target, are still high enough to stimulate insulin secretion.

Dr. Buchanan suggested that treatment for T2DM should be focused on stopping the loss of b-cell function that leads to diabetes and then to the long-term complications. Interventions should begin early and focus on reducing the demands on b-cells by ameliorating insulin resistance and maintaining normal glucose and A1C levels.