Targeting the Underlying Pathophysiology of Type 2 Diabetes

Aim Provide practical guidance on improving diabetes care through highlighting the need to: understand that insulin resistance and b-cell dysfunction are core defects of type 2 diabetes address the underlying pathophysiology

Type 2 diabetes Characterized by chronic hyperglycemia Associated with microvascular and macrovascular complications Generally arises from a combination of insulin resistance and -cell dysfunction Type 2 diabetes is a metabolic disorder with multiple causes, characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism. It generally results from a combination of insulin resistance and loss of -cell function.1 Insulin resistance places an increased secretory demand upon the -cell, leading to -cell dysfunction as the disease progresses.2 In the long term, type 2 diabetes affects a number of organs and is associated with microvascular complications such as retinopathy, nephropathy and neuropathy. In addition, individuals with type 2 diabetes are at increased risk of macrovascular disease.1 Often diagnosis of type 2 diabetes is made after the condition has been present for some years. In fact, more than 50% of individuals have evidence of vascular disease at diagnosis.3 1Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance, World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc 2International Diabetes Center (IDC), Minneapolis, 2000. Available at: http://www.parknicollet.com/diabetes/aboutdiabetes/type2.html 3Laakso M. Int J Clin Pract Suppl. 2001; 121:8–12. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance, World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc

What is insulin resistance? Major defect in individuals with type 2 diabetes1 Reduced biological response to insulin1–3 Strong predictor of type 2 diabetes4 Closely associated with obesity5 IR Insulin resistance is the inability of the body to use its own insulin. Insulin resistance is present to varying degrees in a high proportion of the general population.1 Insulin resistance may lead to impaired glucose tolerance (IGT) and eventually to the development of type 2 diabetes.2,3 > 80% of individuals with type 2 diabetes are insulin resistant.4 Insulin resistance is also a strong predictor for the development of type 2 diabetes.4 Many people with type 2 diabetes are obese – this can be up to ~85% in some populations,5 which may explain their insulin resistance. 1American Diabetes Association. Diabetes Care 1998; 21:310–314. 2Beck-Nielsen H & Groop LC. J Clin Invest 1994; 94:1714–1721. 3Bloomgarden ZT. Clin Ther 1998; 20:216–231. 4Haffner SM, et al. Circulation 2000; 101:975–980. 5Boden G. Diabetes 1997; 46:3–10. 1American Diabetes Association. Diabetes Care 1998; 21:310–314. 2Beck-Nielsen H & Groop LC. J Clin Invest 1994; 94:1714–1721. 3Bloomgarden ZT. Clin Ther 1998; 20:216–231. 4Haffner SM, et al. Circulation 2000; 101:975–980. 5Boden G. Diabetes 1997; 46:3–10.

What is -cell dysfunction? Major defect in individuals with type 2 diabetes Reduced ability of -cells to secrete insulin in response to hyperglycemia  Together with insulin resistance, -cell dysfunction is one of the two major defects involved in development of type 2 diabetes1 and is often inherited. -cell dysfunction may be a consequence of insulin resistance, but also occurs in insulin-sensitive individuals.2 In the insulin-resistant state, the pancreas is able to initially compensate for insulin resistance through increased production of insulin.1 With time, however, the -cells are unable to maintain increased insulin secretion leading to the development of impaired glucose tolerance and type 2 diabetes.1 1DeFronzo RA, et al. Diabetes Care 1992; 15:318–354. 2Haffner SM, et al. Circulation 2000; 101:975–980. DeFronzo RA, et al. Diabetes Care 1992; 15:318–354.

Genetic susceptibility, obesity, Western lifestyle Insulin resistance and -cell dysfunction are core defects of type 2 diabetes Insulin resistance Genetic susceptibility, obesity, Western lifestyle Type 2 diabetes IR b-cell dysfunction  A number of factors, both genetic and environmental, influence the development of insulin resistance and -cell dysfunction. In addition to the risk posed by inherited factors, a Western lifestyle (i.e. sedentary lifestyle, high-fat diet) can contribute to obesity, a strong risk factor for insulin resistance. Insulin resistance at the tissue level contributes significantly to hyperglycemia and is due primarily to abnormalities in the way that the effects of insulin are carried from the receptor on the cell’s surface to intracellular proteins that regulate glucose transport. The consequences of insulin resistance include reduced glucose uptake into fat and muscle, and increased glucose production by the liver.1 -cell dysfunction is characterized by a reduced ability to respond to raised glucose levels leading to reduced insulin secretion, which in turn results in chronic hyperglycemia. Together, these two factors often lead to the development of type 2 diabetes, and so are key targets for therapeutic intervention. 1Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13. Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.

How do insulin resistance and -cell dysfunction combine to cause type 2 diabetes? Abnormal glucose tolerance Hyperinsulinemia, then -cell failure Normal IGT* Type 2 diabetes Post-prandial glucose Insulin resistance Increased insulin resistance Fasting glucose Hyperglycemia Insulin secretion *IGT = impaired glucose tolerance Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000. Over time, changes in insulin resistance and secretion lead to the onset of type 2 diabetes. In the early stages, as insulin resistance rises, there is a compensatory increase in insulin secretion and glucose levels remain normal (normoglycemia). In the long term, however, as the b-cells begin to fail, insulin secretion falls, IGT and hyperglycemia become apparent and frank type 2 diabetes develops. IGT may be defined as higher than normal blood glucose levels, but not high enough to be called diabetes. People with IGT may or may not go on to develop diabetes. Glucose levels both before (fasting) and after (post-prandial) meals increase steadily as the individual progresses from normoglycemia to IGT and, finally, type 2 diabetes. International Diabetes Center (IDC), Minneapolis, 2000.

How is insulin resistance measured? Several methods exist, including: continuous sampling of insulin/glucose1 gold standard, but impractical for large-scale use single measure of insulin/glucose2 simple estimate from fasting insulin and glucose useful for assessment on a larger scale Methods to measure insulin resistance include challenging individuals with glucose (known as the clamp) and the mathematical homeostasis model assessment (HOMA).1,2 The clamp technique is considered the ‘gold standard’ for measuring insulin resistance, but this method is demanding and expensive and, therefore, not appropriate for large-scale studies.1 HOMA is more appropriate where rapid or repeated assessment of insulin sensitivity is required on a larger scale.1,3 1Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):35–45. 2Matthews DR, et al. Diabetologia 1985; 28:412–419. 3Bonora E, et al. Diabetes Care 2000; 23:57–63. 1Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):35–45. 2Matthews DR, et al. Diabetologia 1985; 28:412–419.

More than 80% of patients progressing to type 2 diabetes are insulin resistant Insulin sensitive; low insulin secretion (16%) Insulin sensitive; good insulin secretion (1%) Insulin resistant; low insulin secretion (54%) 83% The 7-year follow-up of the San Antonio Heart Study revealed that 195 of 1,734 subjects (11%) progressed to type 2 diabetes. These 195 converters could be characterized into four groups: insulin resistant; low insulin secretion (54%) insulin resistant; good insulin secretion (29%) insulin sensitive; low insulin secretion (16%) insulin sensitive; good insulin secretion (1%). In the study, insulin resistance was most strongly associated with progression to type 2 diabetes, with 83% of converters being insulin resistant. The lowest risk of developing type 2 diabetes was in subjects who were insulin sensitive combined with good insulin secretory capacity (1%). Haffner SM, et al. Circulation 2000; 101:975–980. Insulin resistant; good insulin secretion (29%) Haffner SM, et al. Circulation 2000; 101:975–980.

Insulin resistance – reduced response to circulating insulin Liver Muscle Adipose tissue  Glucose output  Glucose uptake  Glucose uptake The consequences of insulin resistance at the tissue level include reduced glucose uptake into peripheral sites, that is, fat and muscle. Combined with excessive glucose output by the liver, this leads to hyperglycemia. Hyperglycemia

Overall, 75% of patients with type 2 diabetes die from cardiovascular disease Most deaths in type 2 diabetes are due to cardiovascular disease, especially coronary heart disease.1 Overall mortality for coronary heart disease is two to four times higher in diabetic individuals than in those without diabetes.2 IGT is also an independent risk factor for cardiovascular disease.3 1Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences. 2Haffner SM & Miettinen H. Am J Med 1997; 103:152–162. 3Qiao Q, et al. Diabetes Care 2003; 26:2910–2914. Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences.

Odds ratio for incident CVD Total cholesterol: HDL cholesterol Insulin resistance is as strong a risk factor for cardiovascular disease as smoking 1.8 1.6 1.4 Odds ratio for incident CVD 1.2 1.0 Insulin resistance is strongly associated with the incidence of cardiovascular disease.1 In a prospective analysis of 1,326 subjects in the Verona Diabetes Complications Study, insulin resistance (as measured by estimates of HOMA) was confirmed as an independent risk factor for cardiovascular disease.2 Moreover, insulin resistance was as strong a risk factor as smoking. Both of these factors carried a greater risk for developing cardiovascular disease than either age or total:HDL cholesterol ratio.2 1Hanley AJ, et al. Diabetes Care 2002; 25:1177–1184. 2Bonora E, et al. Diabetes Care 2002; 25:1135–1141. 0.8 0.6 Age Smoking Total cholesterol: HDL cholesterol Insulin resistance Bonora E, et al. Diabetes Care 2002; 25:1135–1141.

Insulin resistance is closely linked to cardiovascular disease Present in > 80% of people with type 2 diabetes1 Approximately doubles the risk of a cardiac event2 Implicated in almost half of CHD events in individuals with type 2 diabetes2 IR Insulin resistance More than 80% of individuals with type 2 diabetes are insulin resistant.1 Insulin resistance almost doubles the risk of a cardiovascular event.2 Insulin resistance is implicated in almost 50% of annual cardiovascular events in individuals with type 2 diabetes, compared with only 6% in non-diabetic individuals.2 Preventing or modifying insulin resistance should decrease the burden of cardiovascular disease.2 1Haffner SM, et al. Circulation 2000; 101:975–980. 2Strutton D, et al. Am J Manag Care 2001; 7:765–773. 1Haffner SM, et al. Circulation 2000; 101:975–980. 2Strutton D, et al. Am J Man Care 2001; 7:765–773.

Insulin resistance is linked to a range of cardiovascular risk factors Atherosclerosis Hyperglycemia Dyslipidemia Hypertension Damage to blood vessels Clotting abnormalities Inflammation Insulin resistance IR Insulin resistance is closely linked to a number of cardiovascular risk factors, collectively known as the Metabolic Syndrome or Insulin Resistance Syndrome. Components of the Metabolic Syndrome include well known cardiovascular risk factors such as hyperglycemia, dyslipidemia and hypertension. Additional cardiovascular risk factors, that is damage to blood vessels (endothelial dysfunction), clotting abnormalities (hypofibrinolysis) and inflammation, have also been recognized as key components of the Metabolic Syndrome. Together, the cluster of cardiovascular risk factors that make up the Metabolic Syndrome significantly increases the risk of atherosclerosis. Zimmet P. Trends Cardiovasc Med 2002; 12:354–362. Zimmet P. Trends Cardiovasc Med 2002; 12:354–362.

~90% of people with type 2 diabetes are overweight or obese   ~90% of people with type 2 diabetes are overweight or obese The World Health Organization reports that around 90% of individuals with type 2 diabetes are overweight or obese.1 Fat distribution in the body may be either abdominal (android or central obesity – often referred to as ‘apple-shaped’) or affect the lower body (mainly thighs and buttocks; gynoid obesity – often referred to as ‘pear-shaped’).2 Central obesity (indicated by, for example, high waist:hip ratio; that is waist:hip ratio > 0.90 for men, > 0.85 for women) is a strong risk factor for insulin resistance.3 1 World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity 2Basdevant A, et al. Presse Med 1987; 16:167–170. 3Ascaso JF, et al. Eur J Intern Med 2003; 14:101–106. World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity

How is -cell function measured? -cell function is difficult to measure and most methods are impractical for large-scale use1 Homeostasis model assessment (HOMA) provides a simple estimate of -cell function2 Proinsulin:insulin ratio is sometimes used as a marker of -cell dysfunction1 Over the years, a number of techniques have been used to assess -cell function.1 However, -cell function is difficult to measure and most of these methods are impractical for large-scale use. HOMA is more appropriate for large-scale studies and provides a simple estimate of -cell function from fasting insulin and glucose.2 Sometimes used as a marker for -cell dysfunction, the ratio of proinsulin (the precursor of insulin that is converted to insulin) to total insulin provides a measure of the efficiency of proinsulin processing.1 1Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):35–45. 2Matthews DR, et al. Diabetologia 1985; 28:412–419. 1Matthews DR, et al. Diabetologia 1985; 28:412–419. 2Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):35–45.

Why does the -cell fail? Oversecretion of insulin to compensate for insulin resistance1,2 Glucotoxicity2 Lipotoxicity3 Chronic hyperglycemia Pancreas High circulating free fatty acids At physiological levels, both glucose and free fatty acids stimulate insulin secretion.1,2 -cell dysfunction may occur as a result of genetic factors. Chronic hyperglycemia, however, may negatively affect the -cell through a process known as glucotoxicity.2 Glucotoxicity is the ability of glucose to stimulate the death of -cells.2 Similarly, chronically elevated free fatty acids have a lipotoxic effect upon the pancreas, inducing -cell dysfunction.3 Lipotoxicity is the ability of free fatty acids to stimulate the death of -cells.3 Oversecretion of insulin to compensate for insulin resistance also contributes to -cell dysfunction. 1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23. 2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22. 3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27. -cell dysfunction 1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23. 2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22. 3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.

Glycemic control declines over time Years from randomization Diet Sulfonylurea or insulin 6.2% upper limit of normal range 0 3 6 9 12 15 Median HbA1c (%) 9 8 7 6 The UK Prospective Diabetes Study (UKPDS) was started in 1977 and was designed to establish whether intensive blood glucose control could reduce the risk of macrovascular or microvascular complications in patients with type 2 diabetes. In the diet-treated group, HbA1c increased steadily over the course of the study. In the sulfonylurea- or insulin-treated group, there was an initial decrease in HbA1c during the first year of the study, followed by a subsequent, progressive increase similar to that seen in the diet-treated group. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837–853. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837–853.

Loss of -cell function occurs before diagnosis 100 Up to 50% loss 80 Diagnosis 60 -cell function (%) 40 20 Extrapolation of the observed rate of decline of -cell function in diet-treated subjects in the UKPDS suggests that loss of -cell function can begin at least 10 years before diagnosis. In the UKPDS, long-term increases in fasting plasma glucose were accompanied by progressive -cell dysfunction as assessed by HOMA.1 Mean -cell function was already less than 50% at diagnosis,2 and none of the therapies used in the study (sulfonylureas, metformin and insulin) were able to prevent or delay the progressive deterioration of -cell function.1 On average, -cell function declines by 1% per year with normal aging, compared with 4% per year in diabetes.1,3 1UKPDS Group. UKPDS 16. Diabetes 1995; 44:1249–1258. 2Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25. 3Chiu KC, et al. Clin Endocrinol 2000; 53:569–575. -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 Time from diagnosis (years) Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25.

Oral antidiabetic agents – do they target insulin resistance and -cell dysfunction?

Barriers to achieving good glycemic control Inadequate targeting of underlying pathophysiology A number of factors are likely to contribute to the complexities of controlling blood glucose levels in individuals with type 2 diabetes. The Global Partnership has identified several key areas that can help the diabetes care team to increase the proportion of individuals achieving good glycemic control and thus decrease the risk of complications. These include the need to target the underlying pathophysiology of type 2 diabetes.

Primary sites of action of oral antidiabetic agents  Carbohydrate breakdown/ absorption -glucosidase inhibitors  Insulin secretion Sulfonylureas/ meglitinides Biguanides Thiazolidinediones -glucosidase inhibitors (e.g. acarbose) – delay digestion and absorption of carbohydrates in the gastrointestinal tract.1,2 Sulfonylureas and meglitinides – stimulate insulin secretion from the pancreas.1,2 Biguanides (e.g. metformin) – suppress liver glucose output, enhance insulin sensitivity in the liver and stimulate insulin-mediated glucose disposal. They do not stimulate insulin secretion.1,2 Thiazolidinediones – decrease insulin resistance in fat, muscle and liver. In addition, they improve estimates of -cell function.1,2 1Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40. 2Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.  Glucose output  Insulin resistance  Insulin resistance Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40. Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

The dual action of thiazolidinediones reduces HbA1c IR +  Insulin resistance -cell function Clinical studies have shown that treatment with the thiazolidinediones – rosiglitazone and pioglitazone – significantly decreases insulin resistance and improves -cell function in people with type 2 diabetes (as estimated by HOMA).1,2 1Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288. 2Rosenblatt S, et al. Coron Artery Dis 2001; 12:413–423. HbA1c Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.

Potential to prevent progression to type 2 diabetes in at-risk women Troglitazone reduced progression to type 2 diabetes by > 50% Troglitazone* 400 mg/day 0.6 Placebo 0.5 0.4 Proportion with diabetes 0.3 0.2 The Troglitazone in Prevention of Diabetes (TRIPOD) study highlighted the potential of thiazolidinediones to reduce progression to type 2 diabetes in at-risk individuals. In this study, women with previous gestational diabetes were treated with placebo (n = 133) or troglitazone 400 mg/day (n = 133) for 5 years. Treatment with troglitazone delayed or prevented the onset of type 2 diabetes (P = 0.009) by at least 50%. Average annual diabetes incidence rates were 12% and 5% in women assigned to placebo and troglitazone, respectively (P < 0.01). This protective effect was associated with preservation of pancreatic b-cell function and seemed to be due to a reduction in the stress placed on b-cells by chronic insulin resistance. Protection from diabetes in the troglitazone group persisted 8 months after study medications were stopped, suggesting that the effect was mediated through changes in the natural history of the condition, rather than through effects on circulating glucose levels. Although troglitazone is no longer available, it is generally thought that other agents in this class are likely to have the same effect. Buchanan TA, et al. Diabetes 2002; 51:2796–2803. 0.1 0.0 10 20 30 40 50 60 Time on trial (months) *Troglitazone is no longer available Buchanan TA, et al. Diabetes 2002; 51:2796–2803.

Can thiazolidinediones delay progression from IGT to T2DM? Placebo Rosiglitazone 8 mg/day 100 T2DM 11% 80 IGT 56% 60 Subjects (%) IGT IGT IGT 100% 89% 100% 40 Thiazolidinediones have the potential to delay the progression from IGT to type 2 diabetes. In a study of subjects with IGT, randomized to rosiglitazone 8 mg/day (n = 9) or placebo (n = 9), participants underwent an oral glucose tolerance test (OGTT, which measures the body's ability to metabolize glucose) at screening and after 12 weeks’ treatment. In the rosiglitazone group, 44% developed normal glucose tolerance (NGT) and 56% retained IGT by week 12 (P = 0.007 versus placebo). By contrast, in the placebo group, no subjects normalized their glucose tolerance; 11% developed type 2 diabetes and 89% remained IGT. Bennett SM, et al. Diabet Med 2004; 21:415–422. NGT 20 44% Screening Week 12 Screening Week 12 Bennett SM, et al. Diabet Med 2004; 21:415–422.

Myocardial infarction Myocardial infarction Does decreasing insulin resistance decrease macrovascular complications? Myocardial infarction Not significant All-cause mortality Sulfonylureas/insulin Myocardial infarction Significant All-cause mortality Metformin 21% 8% 39% 36% The UKPDS showed that use of either sulfonylureas or insulin does not significantly reduce the risk of myocardial infarction (P = 0.11) or all-cause mortality (P = 0.49) in overweight patients compared with diet only. In contrast, metformin treatment significantly reduced the risk of myocardial infarction (P = 0.01) and all-cause mortality (P = 0.02) in overweight patients compared with diet only. The effect of metformin on macrovascular outcomes is believed to occur as a consequence of its weak insulin sensitizing effect. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.

Insulin sensitizers reduce cardiovascular events in type 2 diabetes 60 50 40 12-month combined event rate (%) 30 20 Insulin sensitizers are associated with reduced cardiovascular events in individuals with type 2 diabetes. Individuals were divided into two groups: insulin sensitizers (n = 50; thiazolidinediones or biguanides) or non-sensitizers (n = 67; insulin, sulfonylureas or diet). Clinical events were defined as target vessel revascularization (TVR), myocardial infarction (MI), non-TVR and death. After 12 months, treatment with an insulin sensitizer significantly reduced the combined event rate compared with treatment with non-sensitizers (P = 0.041) and reduced deaths (P = 0.049). Kao JA, et al. J Am Coll Cardiol 2004; 43:37A. 10 Non-sensitizers Sensitizers Kao JA, et al. J Am Coll Cardiol 2004; 43:37A.

How can diabetes care and outcomes be improved? The Global Partnership recommends: Address the underlying pathophysiology, including treatment of insulin resistance Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.