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insulin resistance insulin resistance

Abbreviation: BG, blood glucose.

the pharmacy, may demonstrate that it is simply not being taken. It is also important to be aware that metformin may normalize ovulation in girls with PCOS or ovarian hyperan-drogenism, increasing pregnancy risk.

Sulfonylureas and Meglitinide

Sulfonylureas increase insulin secretion and are most useful when there is partial beta cell failure. When plasma glucose levels rise, there is rapid phosphorylation of glucose to glucose-6-phosphate which is metabolized to convert ADP to ATP. When the ATP:ADP ratio increases, K+ channels close, resulting in depolarization of the adjacent cell membrane with opening of the calcium channels. The secretion of insulin is controlled by the intracellular concentration of calcium. The higher the plasma glucose level, the greater the number of K+ channels that close, resulting in more Ca++ channels opening with increased insulin release. Sulfonylureas bind to receptors on the K+/ATP channel complex. A separate site on the K+/ATP channel complex binds meglitinide. Activation of ATP, sulfonylurea, or meglitinide binding sites causes K+ channels to close. The ATP binding sites equilibrate very rapidly, sulfonylurea sites equilibrate slowly and binding persists for prolonged periods; meglitinide has an intermediate time of equilibration. Thus, the traditional sulfonylureas have prolonged effects whereas the newer metiglinides, result in brief increases in insulin secretion (87). The major adverse effects of the traditional sulfonylureas are hypoglycemia and weight gain. Glimepramide, a third-generation sulfonylurea, has been compared with metformin in pediatric type 2 diabetes, with comparable safety and efficacy (88).

Thiazolidinediones

Thiazolidinediones (TZDs) bind to nuclear proteins, activating peroxisome proliferator activator receptors (PPAR), orphan steroid receptors found primarily in adipocytes. Once activated by a TZD, PPAR forms a heterodimer with a retinoid X receptor, enabling it to bind to the promoter region of target genes, resulting in increased formation of proteins involved in nuclear-based actions of insulin, including cell growth and adipose cell differentiation, regulation of insulin receptor activity and glucose transport into the cell. This action increases insulin sensitivity in the liver, muscle, and adipose tissue and decreases hepatic glucose output (89). During long-term therapy with TZD in adults, a reduction in HbA1c levels of 0.5% to 1.3% has been shown. The major side effects are edema, weight gain, anemia, and, in approximately 1% of subjects, liver enzyme elevations. The latter problem led to sufficient numbers of fatalities in adults taking the first available drug of this group, troglitazone, that it was withdrawn from the US market. Newer thiazolidinediones, rosi- and pio-glitazone promise to be safer. Rosiglitazone was compared with metformin in a 24 week double-blind study with 195 pediatric patients with type 2 diabetes; reduction in HbA1c was comparable in the two groups and there were no safety problems. Weight gain, however, occurred in those taking rosiglitazone, as is seen in adults (90).

Alpha Glucosidase Inhibitors

Alpha glucosidase inhibitors (acarbose, miglitol) reduce the absorption of carbohydrates in the upper small intestine by inhibiting the breakdown of oligosaccharides, resulting in their delayed absorption in the lower small intestine. This delay reduces the postprandial rise of plasma glucose. A reduction in HbA1c levels of approximately 0.5% to 1% is expected during long term therapy with acarbose (91). The most frequent side effect is flatulence, making these agents unacceptable to most children and adolescents.

Insulin

There is a greater readiness to use insulin in the treatment of type 2 diabetes in children and adolescents than in adults, which may be related to the greater experience of pediatric practitioners with insulin than with oral agents. In the United Kingdom Prospective Diabetes Study (UKPDS), adults with type 2 diabetes had already lost 50% of their beta cell function at the time of diagnosis, and by 6 or 7 years afterwards had little or no reserve, consistent with the failure of all oral hypoglycemic regimens to maintain early gains in control of HbA1c (92). There is evidence that the deterioration in pancreatic reserve in youth with type 2 diabetes may be more rapid. Glucose clamp studies have shown that young people with type 2 diabetes have first phase insulin secretion ~74% lower and second phase insulin secretion ~53% lower than obese controls without diabetes, along with 50% less insulin sensitivity and greater hepatic glucose output (93). These findings might reflect irreversible deficiency of insulin secretory capacity or reflect deleterious effects of poor glycemic control on insulin secretion (glucotoxicity). A single case report demonstrated a 15% yearly decline in beta cell function in an adolescent with type 2 diabetes followed over 6 years for a cumulative 90% loss, without any change in insulin sensitivity (94), similar to what has been described in the UKPDS (92).

Incretins

Incretins are gut-derived factors secreted in the small and large intestine soon after food ingestion. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) stimulate glucose dependent insulin biosynthesis and GLP-1 also suppresses glucagon release, delays gastric emptying, and increases satiety. GLP-1 exerts its effects by binding to receptors on the beta cells. In type 2 diabetes it is able to restore first phase insulin release, decrease glucagon secretion, and slow gastric emptying (95). A GLP-1 mimetic, Exenatide, is being used for the treatment of type 2 diabetes in adults (96). Given as a twice a day injection, it is unlikely to be acceptable treatment for children and adolescents with type 2 diabetes. In any case, safety and efficacy have not been established for young patients.

A promising development that could be important for treatment of pediatric type 2 diabetes is an oral agent that inhibits dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for rapid degradation of incretin hormones. In 58 adult patients with type 2 diabetes who were not on oral hypoglycemic agents, a single oral dose of this inhibitor (Sitagliptin) markedly reduced plasma DPP-4 activity over 24 h, enhanced GLP-1 and GIP levels, increased insulin and C-peptide concentrations, decreased glucagon levels, and reduced glycemia following oral glucose tolerance testing (97).

Treatment Approaches

The UKPDS demonstrated that intensive treatment of adults with type 2 diabetes resulted in improved metabolic control and this, in turn, resulted in decreased risk of microvascular disease (98). The HbA1c goal inferred from the UKPDS data is < 7%. This study further demonstrated that aggressive treatment of blood pressure resulted in even greater reduction in the risk of both microvascular and macrovascular disease over 8-1/2 years with a 37% reduction in microvascular disease, 44% reduction in stroke, and 56% reduction in heart failure (98).

There is evidence that the microvascular complications of diabetes are extraordinarily aggressive in type 2 diabetes in youth and it is, therefore, essential to strive for normal blood glucose levels (99,100). Among 100 Pima Indian children and adolescents at the time of

FIGURE 3 Treatment of type 2 diabetes in children.

diagnosis of type 2 diabetes mellitus, 7% had hypercholesterolemia, 18% hypertension, and 22% microalbuminuria. Ten years after diagnosis, the mean HbAic level was 12%; 60% had microalbuminuria and 17% had macroalbuminuria (100).

Initial therapy is determined by symptoms at diagnosis (Fig. 3). Children who are asymptomatic, diagnosed following a routine physical exam in a doctor's office or by community or family testing, can be treated by nonpharmacologic means. These children need basic education about diabetes and its risks and must be taught to monitor blood glucose levels, be given dietary counseling, and be encouraged to exercise daily.

The essentials of therapy are improved eating habits and increased physical activity, requiring behavior modification. Therefore, a psychologist is an important part of the treatment team along with a dietitian, and, if possible, an exercise specialist. The involvement of the parents and extended family is critical. The entire family should adopt the same healthy eating patterns and exercise either together or individually. Physical activity does not need to be organized sports, but may involve walking to school, not using the elevator, bicycling, etc. Patients should exercise at least 30 minutes daily.

Patients who have not achieved glycemic goals or whose blood glucose and HbA1c values are not improving after three months of an exercise/diet modification program should be started on oral hypoglycemic agents. In the UKPDS, only 3% of patients were able to achieve treatment goals with diet and exercise alone; diet plus metformin resulted in reductions in HbA1c levels comparable to those resulting from sulfonylureas or insulin, but without the weight gain and with fewer episodes of hypoglycemia than observed with the other therapies (92).

There can be an anorectic effect of metformin with weight loss in some people, resulting in increased insulin sensitivity with consequent improved metabolic control. Intensive glycemic control with metformin as a single mode of therapy in the UKPDS trial was associated with a significant reduction in risk of long-term diabetes complications. The magnitude of this reduction was 32%, greater than that seen with sulfonylureas or insulin alone, which reduced the diabetes related endpoints by only 12% (92). In addition, metformin has very few side effects other than transient abdominal discomfort and diarrhea, which has become far less of a problem with the extended release formulation. Because metformin increases insulin sensitivity, it is not associated with the risk of hypoglycemia that is attendant on the use of sulfonylureas, insulin, and benzoic acid derivatives (meglitinide).

If monotherapy with metformin is not successful over a period of 3 to 6 months, sulfonylureas or meglitinide may be added to the regimen. Until more is known about the newer TZDs it may be prudent to avoid their use in children. Insulin is added if oral agents are not able to achieve treatment goals.

Survey respondents from 130 pediatric endocrine practices in the US and Canada reported that a mean 12% of their diabetes patients had type 2 diabetes and that approximately 48% of them were being treated with insulin, 44% with oral hypoglycemic agents. Those children with type 2 diabetes taking insulin were generally treated with two injections per day. Most children being treated with oral hypoglycemic agents received metformin (71%), with 46% using sulfonylureas, 9% TZDs and 4% meglitinide (83). In the Florida diabetes centers study, 50% of the children with type 2 diabetes were being treated with oral hypoglycemic agents, 23% received insulin alone, 9% were treated with combination oral hypoglycemic/ insulin and 11% with diet and exercise alone (9).

Patients who are mildly symptomatic at onset but who have blood glucose levels < 250 mg/dL (14 mM/L) can usually be started on oral hypoglycemic agents. Patients who have substantial ketosis, ketoacidosis, or markedly elevated blood glucose levels are begun on insulin, usually twice a day, until blood glucose control is established and symptoms subside. Metformin is added while the insulin dose is gradually reduced and stopped.

Patients receiving insulin should have blood glucose (BG) checked before meals and at bedtime. Patients treated with exercise/diet or oral hypoglycemics are asked to monitor fasting BG levels and 2 h post prandial levels after dinner daily. Once target BG levels are achieved, fasting BG and 2 h post prandial dinner BG should be monitored three times a week. Assessments of HbA1c should be done at least twice a year or more frequently if metabolic control is unsatisfactory and requires treatment adjustment.

Treatment of Comorbidities

The major goal of therapy is to reduce the risk of microvascular and macrovascular complications. The coexistence of type 2 diabetes with obesity, hypertension and hyperlipi-demia place these patients at great risk for development of early cardiovascular disease. Lipid lowering agents have been shown to reduce the risk of number of coronary events in patients with coronary heart disease and diabetes (101). Hypertension is also an independent risk factor for the development of albuminuria and retinopathy (98). Therefore, both blood pressure control (UKPDS) and blood glucose control are important for decreasing the frequency and severity of the late complications of diabetes. Patients should have lipid levels and urine albumin checked annually. Dilated eye examination should also be performed annually in adolescents with type 2 diabetes. Unlike in children with type 1 diabetes, these examinations should begin at the time of diagnosis rather than after 3 to 5 years of disease (30).

Blood pressure should be monitored and treated aggressively with angiotensin converting enzyme (ACE) inhibitors if either the systolic or diastolic pressures are above the child's usual percentile or above the 85th percentile for age and sex. Children with type 2 diabetes may have hyperlipidemia as an indication of insulin resistance, which will improve with exercise, weight loss, and glycemic control. Nutritional changes are made with initiation of a reduced fat diet, consistent with step 1 American Heart Association guidelines. Should such attempts to normalize lipids fail after 2 to 3 months of intensive efforts, however, lipid lowering medications are appropriate. The most commonly used lipid lowering agents are the HMG CoA reductase inhibitors. They are contraindicated in pregnancy or if there is a risk of pregnancy.

TZD binding to PPARy receptors is ubiquitous, and includes arterial wall smooth muscle, inhibiting growth and migration in response to growth factors. This effect may be important in reducing the enhanced risk of macrovascular disease associated with type 2 diabetes (102).

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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