Il II

overall age 25-44 BMI > 34.9

* Differed significantly from placebo "Differed significantly from metformin or placebo

FIGURE 11.5 Effects of metformin and intensive lifestyle intervention on rates of type 2 diabetes in adults with IGT. Data adapted from Knowler et al., Diabetes Prevention Program, N. Eng. J. Med., 346, 393, 2002. With permission.

development of severe hepatotoxicity in a small number of subjects. The experimental groups were studied for 1.8-4.6 years.

Daily energy and fat intake decreased only in the group randomized to intensive lifestyle modification. Nevertheless, patients in the metformin group also lost weight, though not as much as those in the intensive-lifestyle group. In both groups, weight loss was most significant in the first 6-12 months of the study. The changes in body weight were accompanied by reductions in the rates of progression from IGT to type 2 diabetes. The three-year cumulative incidence of diabetes was 28.9 percent in the placebo group, 21.7 percent in the metformin-treated group, and 14.4 percent in the intensive-lifestyle group. Overall, therefore, intensive-lifestyle intervention was more effective than metformin.

However, metformin was as effective as lifestyle change in subjects with BMI exceeding 34.9 and in those with highest fasting-glucose concentrations (Figure 11.5); these subgroups are at greatest risk for progression to type 2 diabetes. Metformin was also as effective as a lifestyle intervention in younger adults aged 25-44 years. On the other hand, treatment effects did not vary according to gender, race, or ethnic group. In addition to reducing the risk of development of type 2 diabetes, intensive-lifestyle intervention and metformin also had favorable, albeit small effects on blood pressure and serum lipids.

Metformin was well-tolerated by the majority of subjects, though many patients had transient abdominal discomfort which can be prevented by taking the medication with food. There were no instances of hepatic dysfunction or lactic acidosis; nevertheless, the drug should not be administered to patients with underlying cardiac, hepatic, renal, or gastrointestinal disease.

The major effects of lifestyle intervention and metformin were exerted within the first 12-18 months of the study. After the first year, fasting blood-glucose concentrations, HbA1c concentrations, and rates of diabetes increased in both the intensive-lifestyle and metformin groups, and the slopes of the intervention and treatment curves after the first year appeared to parallel the slope of the placebo group. This finding suggests that the interventions may delay, rather than truly prevent, the development of type 2 diabetes. Nevertheless, studies performed in nondiabetic subjects one to two weeks after the trial's conclusion showed that the protective effect of metformin persisted in three-fourths of the drug-treated subjects even after discontinuation of medication. The duration of this protective effect is unknown; prolonged treatment with metformin might be necessary to reduce the rate of progression to diabetes in high-risk subjects.

b. Thiazolidinediones

The thiazolidinediones (TZDs) regulate lipid and carbohydrate metabolism through binding to peroxisome proliferator-activated receptor (PPAR)-y. When activated by TZDs, PPAR-y heterodimerizes with the retinoid X receptor and binds to the promoters of target genes, including lipoprotein lipase, fatty-acid transport protein, acetyl-CoA-synthase, and aP2 [81]. The major effects of the TZDs are exerted in adipose tissue and skeletal muscle (Figure 11.4) [19, 86]. The drugs induce the differentiation of small, insulin-sensitive adipocytes, increase adipose tissue insulin-receptor number, adiponectin expression, and glucose uptake, and reduce expression of TNF alpha and, in mice, resistin. Rates of lipolysis and FFA release are reduced, TG clearance is enhanced, and hepatic VLDL synthesis decreases. Circulating TG levels decline during treatment with pioglitazone and, to a lesser extent, with rosigl-itazone. With adipogenic and antilipolytic actions, the TZDs increase total body-fat mass and body weight; however, the ratio of lower body/subcutaneous (SQ) fat to upper-body/visceral fat may rise [82]. TZDs potentiate the effects of insulin on skeletal-muscle glucose uptake through induction of glucose transporters (GLUTs)

1 and 4 [83]. These actions require the presence of insulin and may be mediated by activation of phosphatidylinositol (PI) 3-kinase. Glucose tolerance improves in type

2 diabetic patients treated with TZDs; plasma insulin concentrations decline, while plasma adiponectin levels rise. The rise in adiponectin, in concert with direct effects of the TZDs on the vascular endothelium, reduces carotid intimal medial thickness and increases arterial distensibility. TZDs also reduce plasma C-reactive protein concentrations in diabetic patients and the percentage of small dense LDL levels in diabetic and nondiabetic hypertensive adults [81-83]. In theory, these changes reduce the risk of development and progression of atheromatous lesions.

A few studies have examined the effects of the TZDs on glucose tolerance, lipid profiles, and other cardiovascular risk factors in nondiabetic adults and in women with PCOS. No such investigations have been performed in children or adolescents.

In obese, non-diabetic subjects [84], troglitazone decreased insulin resistance and improved glucose tolerance. Rates of glucose disposal and the insulin-sensitivity index increased while glycemic responses to oral glucose declined. The mean fasting insulin concentrations decreased by 48 percent, and the plasma insulin responses to oral glucose and mixed meals decreased by 40 percent and 41 percent, respectively. Other studies showed that TZDs reduced blood pressure in nondiabetic obese adults. In women with PCOS, a three-month trial of troglitazone reduced fasting glucose and insulin concentrations and improved, but did not normalize, whole-body insulin sensitivity. Troglitazone also improved endothelial function as measured by leg blood flow.

The results of these studies indicate that the TZDs increase insulin sensitivity, improve glucose tolerance, and reduce cardiovascular risk in insulin-resistant adults and in women with PCOS. That the TZDs, like metformin, can reduce the risk of type 2 diabetes in target populations was established in the TRIPOD study [85], a randomized, placebo-controlled, double-blind investigation of women with IGT. The experimental group consisted of Latino women with a history of gestational diabetes and IGT at the time of initiation of the study. During the 30-month investigation, annual diabetes incidence rates were 12.1 percent in the placebo group and 5.4 percent in the troglitazone group. Those with an increase in whole-body insulin sensitivity following initiation of troglitazone were most likely to benefit.

Interestingly, protection from diabetes persisted for at least three to eight months after the drug was discontinued. This finding suggested that troglitazone may have altered the natural progression of diabetes and not simply masked progression through a pharmacologic action. As with metformin, the duration of this protective action is currently unknown.

Unfortunately, troglitazone was removed from the commercial market because the drug caused fatal hepatic failure in a small number of subjects. Nonlethal hepatotoxicity has also been reported with other currently available TZDs, though at a far lower frequency than with troglitazone. Hepatic dysfunction must be excluded before TZD therapy is initiated, and liver function tests should be measured monthly for the first six months of treatment, every two months for the remainder of the first year, and at regular intervals thereafter. Other potential complications of TZD therapy include edema and anemia, so the drug should not be administered to patients with underlying cardiac disease.

3. Other Pharmacologic Approaches

Pharmacologic agents currently in use indirectly target the complications of insulin resistance. Animal studies suggest that approaches that directly target metabolic signaling and cytokine production may prove useful in the prevention of type 2 diabetes and cardiovascular disease.

An appealing therapeutic candidate is the adipocytokine adiponectin. Adiponec-tin levels decline in obesity and other states accompanied by insulin resistance but rise following treatment with thiazolidinediones. Administration of recombinant adiponectin to obese mice reduces blood-glucose and insulin concentrations, increases insulin sensitivity and hepatic fatty-acid oxidation, reduces hepatic fatty-acid synthesis, reverses hepatic steatosis, and decreases body weight [86].

Targeting of oxygen radicals and PARP also shows promise. Activation of PARP by glucose-induced oxidative stress inhibits glyceraldehyde phosphate dehydrogenase activity and may thereby promote the formation of polyols, glucosamine, and advanced glycation end products and the activation of protein kinase C [87]. These metabolites mediate glucose-dependent endothelial dysfunction. In animal models of diabetes, the pharmacological inhibition of PARP improves endothelial function.

It is likely that future investigations will identify new targets and pharmacothera-peutic agents that will prevent long-term complications in high-risk patients.

4. Recommendations Regarding Pharmacotherapy in Diabetes Prevention

In the opinion of the author, pharmacologic therapy should be considered for severely resistant or glucose-intolerant (IFG or IGT) children or adolescents who fail to respond to a 6- to 12-month trial of lifestyle intervention despite a good-faith effort. Good-faith effort means that the patient has attempted to follow a low-saturated-fat/low-calorie diet recommended by a dietary counselor and has increased his or her energy expenditure through regular exercise. Unsuccessful means that the elevations of fasting or postprandial glucose persist or worsen despite lifestyle intervention. The decision to initiate drug therapy relieves neither the child nor the physician of the commitment to long-term lifestyle change; thus, diet-and-exercise regimens should be maintained, even if they had not proven effective in the absence of medication.

Given its proven efficacy in treating insulin-resistant, as well as diabetic, adolescents, adults, and women with PCOS, its track record of safety in men and women, and its ability to limit weight gain, the author considers metformin the drug of choice for treating the obese child with severe insulin resistance, IFG, or IGT. Though lactic acidosis is extraordinarily rare in pediatric patients, metformin should not be administered to children with underlying cardiac, hepatic, renal, or gastrointestinal disease. Obese subjects with mild elevations in hepatic enzymes (less than threefold higher than established norms) may receive the drug; indeed, some studies suggest that metformin may be useful in treatment of hepatic steatosis. Concurrent use of a multivitamin seems reasonable, because metformin increases urinary excretion of vitamins B1 and B6.

Given the lack of studies of TZDs in insulin-resistant children or adolescents, their potential, albeit rare, for severe hepatic complications, and their tendency to cause weight gain, the author would limit the use of TZDs to adolescents who fail to respond to, or cannot tolerate, metformin. Since the danger of hepatic dysfunction with combined therapy in pediatric patients is unknown, the TZDs should not be used in conjunction with metformin in nondiabetic children pending demonstration in long-term studies that the drug combination is safe. TZDs are contraindicated in patients with preexisting hepatic or cardiac disease. Orlistat, acarbose, and other inhibitors of nutrient absorption are not tolerated by many adolescents, but may be useful in highly motivated subjects.

It is not possible at this time to provide firm or uniform guidelines regarding the duration of pharmacologic intervention. A trial off medication may be warranted if glucose tolerance is normalized, particularly if there has been a decline in BMI z score. If IGT persists despite compliance with the medical/pharmacologic regimen, it may be necessary to intensify lifestyle intervention and to increase the dose of medication. If glucose tolerance declines or the patient develops overt diabetes, it may be necessary to add insulin or another pharmacologic agent to the therapeutic regimen.

VII. PHARMACOLOGIC TREATMENT OF TYPE 2 DIABETES

Some have argued that the pharmacologic treatment of type 2 diabetes in children and adolescents should be similar to that of type 2 diabetes in adults. However, differences in disease presentation and course argue for a distinct approach to treatment of childhood type 2 diabetes. Many adults with type 2 diabetes are diagnosed after a prolonged course characterized by mild or moderate symptomatology. At the time of diagnosis, many have beta-cell failure, insulin deficiency, and established vascular complications. In contrast, most children and adolescents with type 2 diabetes are identified before beta-cell function is exhausted. In such cases, it is essential to rapidly normalize blood-glucose concentrations and correct dyslipidemia in order to prevent beta-cell glucotoxicity and lipotoxicity; in theory, this should prolong beta-cell lifespan, enhance glycemic stability, and limit long-term complications.

Rapid normalization of blood-glucose concentrations generally requires insulin administration, particularly if there is ketosis at diagnosis. Once near-normoglycemia is established, it is useful to begin metformin, increasing the dose gradually until maximal tolerated levels are achieved. The dose of insulin can then be reduced, facilitating weight loss in combination with lifestyle intervention. This author maintains low-level insulin therapy indefinitely if plasma C-peptide concentrations are marginal or low. Insulin corrects the insulin deficiency observed in patients with long-standing disease and can prevent the ketosis that may recur in some children and adolescents with type 2 diabetes.

Clinical studies in adults suggest that blood-glucose control in type 2 diabetes may be facilitated by the addition of amylin at mealtimes [89]. Amylin is a beta-cell hormone that reduces postprandial hyperglucagonemia, slows gastric emptying, and reduces food intake. Amylin may reduce postprandial glucose excursions and limit weight gain, but the hormone increases the risk of severe hypoglycemia, nausea, and headache.

Metformin is not tolerated in a minority of subjects. In such cases, a thiazo-lidinedione may prove useful. However, thiazolidinediones are not approved for use in children and may cause weight gain, edema, and hepatic dysfunction. Ongoing studies will assess the benefits and risks of TZDs and combination therapy (met-formin plus TZD) in children with type 2 diabetes.

Sulfonylureas are mainstays of therapy in adults with type 2 diabetes. Their use as primary agents for treatment of type 2 diabetic children is currently under investigation. However, sulfonylureas increase the risk of weight gain and severe hypogly-cemia; in the opinion of the author, the preferred hypoglycemic agent in (particularly obese) children is insulin itself.

VIII. A MULTIFACETED APPROACH TO PREVENTION OF COMPLICATIONS

The major causes of death in adults with type 2 diabetes are myocardial infarction and stroke. Although cardiovascular risk in patients with type 2 diabetes varies with glycemic control, other factors play equal or more important roles. These include obesity, hypertension, smoking, dyslipidemia, ethnic background, and family history. In theory, aggressive lifestyle intervention in children and adolescents should include abolition of smoking and reduction in the intake of caffeine, which may raise blood pressure and postprandial glucose concentrations. Pharmacologic therapy may be necessary to reduce blood pressure, control microalbuminuria, and treat dyslipi-demia. A multifaceted approach that combined dietary counseling, statins, angio-tensin-converting enzyme inhibitors, and low-dose aspirin reduced by 50 percent to 60 percent the long-term (eight-year) risks of nephropathy, retinopathy, autonomic neuropathy, and cardiovascular end points (myocardial disease, stroke, and amputation) in diabetic adults with microalbuminuria [90]. Such an approach may be necessary in the management of obese, insulin-resistant, and glucose-intolerant adolescents, who are commonly hypertensive and hyperlipidemic. The age and intensity of intervention may depend upon the family history of cardiovascular disease, as well as the severity of problems in the individual teenager under the physician's care.

REFERENCES

  1. Alberti, G, Zimmet, P, Shaw, J, Bloomgarden, Z, Kaufman, F, and Silink, M, for the Consensus Working Group, Type 2 diabetes in the young: the evolving epidemic: the International Diabetes Federation Consensus Workshop, Diabet. Care, 27, 1798, 2004.
  2. Brooks-Worrell, BM, Greenbaum, CJ, Palmer, JP, and Pihoker, C, Autoimmunity to islet proteins in children diagnosed with new-onset diabetes, J. Clin. Endocrinol. Metab, 89, 2222, 2004.
  3. Bergman, RN, Finegood, DT, and Kahn, SE, The evolution of p-cell dysfunction and insulin resistance in type 2 diabetes, Eur. J. Clin. Invest., 32, 35, 2002.
  4. Goldfine, AB, Bouche, C, Parker, RA, Kim, C, Kerivan, A, Soeldner, JS, Martin, BC, Warram, JH, and Kahn, CR, Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease, Proc. Natl. Acad. Sci. U.S.A., 100, 2724, 2003.
  5. Veening, MA, van Weissenbruch, MM, Heine, RJ, and Delemarre-van de Waa, HA, Beta-cell capacity and insulin sensitivity in prepubertal children born small for ges-tational age: influence of body size during childhood, Diabetes, 52, 1756, 2003.
  6. Hypponen, E, Power, C, and Smith, GD, Prenatal growth, BMI, and risk of type 2 diabetes by early midlife, Diabet. Care, 26, 2512, 2003.
  7. Lindsey, RS, Hanson, RL, Bennett, PH, and Knowler, WC, Secular trends in birth weight, BMI and diabetes in the offspring of diabetic mothers, Diabet. Care, 23, 1249, 2000.
  8. Pettitt, D, Forman, M, Hanson, R, Knowler, W, and Bennett, P, Breast feeding in infancy is associated with lower rates of non-insulin dependent diabetes mellitus, Lancet, 350, 166, 1997.
  9. Sam, S and Dunaif, A, Polycystic ovary syndrome: syndrome XX? Trends Endocrinol. Metab, 14, 365, 2003.
  10. Hu, FB, Manson, JE, Stampfer, MJ, Colditz, G, Liu, S, Solomon, CG, and Willett, WC, Diet, lifestyle and the risk of type 2 diabetes mellitus in women, N. Engl. J. Med., 345, 790, 2001.
  11. Sinha, R, Fisch, G, Teague, B, Tamborlane, WV, Banyas, B, Allen, K, Savoye, M, Rieger, V, Taksali, S, Barbetta, G, Sherwin, RS, and Caprio, S, Prevalence of impaired glucose tolerance among children and adolescents with marked obesity, N. Engl. J. Med., 346, 802, 2002.
  12. Weiss, R, Dziura, J, Burgert, TS, Tamborlane, WV, Taksali, SE, Yeckel, CW, Allen, K, Lopes, M, Savoye, M, Morrison, J, Sherwin, RS, and Caprio, S, Obesity and the metabolic syndrome in children and adolescents, N. Engl. J. Med., 350, 2362, 2004.
  13. Srinivasan, ST, Myers, L, and Berensen, GS, Temporal association between obesity and hyperinsulinemia in children, adolescents and young adults: The Bogalusa Heart Study, Metab. Clinic. Exp., 48, 928, 1999.
  14. Sinaiko, AR, Donahue, RP, Jacobs, DR, Jr. and Prineas, RJ, Relation of weight and rate of increase in weight during childhood and adolescence to body size, blood pressure, fasting insulin and lipids in young adults: The Minneapolis Children's Blood Pressure Study, Circulation, 99, 1471, 1999.
  15. Srinivasan, SR, Myers, L, and Berenson, GS, Predictability of childhood adiposity and insulin for developing insulin resistance syndrome (syndrome X) in young adulthood: The Bogalusa Heart Study, Diabetes, 51, 204, 2002.
  16. Vanhala, MJ, Vanhala, PT, Keinanen-Kiukaanniemi, SM, Kumpusalo, EA, and Takala, JK, Relative weight gain and obesity as a child predict metabolic syndrome as an adult, Int. J. Obes., 23, 656, 1999.
  17. McCance, DR, Pettitt, DJ, Hanson, RL, Jacobsson, LTH, Bennett, PH, and Knowler, WC, Glucose, insulin concentrations and obesity in childhood and adolescence as predictors of NIDDM, Diabetologia, 37, 617, 1994.
  18. Martin, BC, Warram, JH, Krolewski, AS, Bergman, RN, Soeldner, JS, and Kahn, CR, Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25 year follow-up study, Lancet, 340, 925, 1992.
  19. Young-Hyman, D, Schlundt, DG, Herman, L, De Luca, F, and Counts, D, Evaluation of the insulin resistance syndrome in 5- to 10- year old overweight/obese African-American children, Diabet. Care, 24, 1359, 2001.
  20. Boden, G and Shulman, GI, Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and p-cell dysfunction, Eur. J. Clin. Invest., 32, 14, 2002.
  21. Petersen, KF, Dufour, S, Befroy, D, Garcia, R, and Shulman, GI, Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes, N. Engl. J. Med., 350, 664, 2004.
  22. Unger, RH, Minireview: weapons of lean body mass destruction: the role of extopic lipids in the metabolic syndrome, Endocrinology, 144, 5159, 2003.
  23. Molleston, JP, White, F, Teckman, J, and Fitzgerald, JF, Obese children with steato-hepatitis can develop cirrhosis in childhood, Am. J. Gastroenterol., 97, 2460, 2002.
  24. Weiss, R, Dufour, S, Taksall, SE, Tamborlane, WV, Petersen, KF, Bonadonna, RC, Boselli, L, Barbetta, G, Allen, K, Rife, F, Savoye, M, Dziura, J, Sherwin, R, Shulman, GI, and Caprio, S, Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular abdominal fat partitioning, Lancet, 362, 951, 2003.
  25. Kashyap, S, Belfort, R, Gastaldelli, A., Pratipanawatr, T, Berria, R, Pratipanawatr, W, Bajaj, M, Mandarino, L, DeFronzo, R, and Cusi, K, A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes, Diabetes, 52, 2461, 2003.
  26. Fridlyand, LE and Philipson, LH, Does the glucose-dependent insulin secretion mechanism itself cause oxidative stress in pancreatic beta cells? Diabetes, 53, 1942, 2004.
  27. Goran, MI, Bergman, RN, and Gower, BA, Influence of total vs. visceral fat on insulin action and secretion in African American and white children, Obes. Res., 9, 423, 2001.
  28. Arslanian, SA, Saad, R, Lewy, V, Danadian, K, and Janosky, J, Hyperinsulinemia in African American children: decreased insulin clearance and increased insulin secretion and its relationship to insulin sensitivity, Diabetes, 51, 3014, 2002.
  29. Eriksson, KF and Lingarde, F, Prevention of type 2 (non-insulin dependent) diabetes mellitus by diet and physical exercise. The 6 year Malmo feasibility study, Diabeto-logia, 34, 891, 1991
  30. Pan, XR, Li, GW, Hu, YH, Wang, JX, Yang, WY, An, ZX, Hu, ZX, Lin, J, Xiao, JZ, Cao, HB, Liu, PA, Jiang, XG, Jiang, YY, Wang, JP, Zheng, H, Zhang, H, Bennett, PH, and Howard, BV, The Da Qing IGT and Diabetes Study: effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance, Diabet. Care, 20, 537, 1997.
  31. Uusitupa, M, Lindi, V, Louheranta, A, Salopuro, T, Lindstrom, J, and Tuomilehto, J, Long-term improvement in insulin sensitivity by changing lifestyles of people with impaired glucose tolerance. 4-year results from the Finnish Diabetes Prevention Study, Diabetes, 52, 2532, 2003.
  32. Knowler, WC, Barrett-Connor, E, Fowler, SE, Hamman, RF, Lachin, JM, Walker, EA, and Nathan, DM, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N. Engl. J. Med.., 346, 393, 2002.
  33. Foster, GD, Wyatt, HR, Hill, JO, Mcguckin, BG, Brill, C, Mohammed, BS, Szapary, PO, Rader, DJ, Edman, JS, and Klein, S, A randomized trial of a low-carbohydrate diet for obesity, N. Engl. J. Med., 348, 2082, 2003.
  34. Samaha, FF, Iqbal, N, Seshadri, P, Chicano, KL, Daily, DA, McGrory, J, Williams, T, Williams, M, Gracely, EJ, and Stern, L, A low-carbohydrate as compared with a low-fat diet in severe obesity, N. Engl. J. Med., 348, 2074, 2003.
  35. Bravata, DM, Sanders, L, Huang, J, Krumholz, HM, Olkin, I, and Gardner, CD, Efficacy and safety of low-carbohydrate diets: a systematic review, JAMA, 289, 1837, 2003.
  36. Warren, JM, Henry, CJ, and Simonite, V, Low glycemic index breakfasts and reduced food intake in preadolescent children, Pediatrics, 112(5), e414, 2003.
  37. Elliott, SS, Keim, NL, Stern, JS, Teff, K, and Havel, PJ, Fructose, weight gain, and the insulin resistance syndrome, Am. J. Clin. Nutr, 76, 911, 2002.
  38. Ludwig, DS, Peterson, KE, and Gortmaker, SL, Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational study, Lancet, 357, 505, 2001.
  39. Ebbeling, CB, Leidig, MM, Sinclair, KB, Hangen, JB, and Ludwig, DS, A reduced glycemic load diet in the treatment of adolescent obesity, Arch. Pediatr. Adolesc. Med., 157, 773, 2003.
  40. Montonen, J, Knekt, P, Jarvinene, R, Aromaa, A, and Reunanen, A, Whole-grain and fiber intake and the incidence of type 2 diabetes, Am. J. Clin. Nutr., 77, 622, 2003.
  41. Pereira, MA, Jacobs, DR, Van Horn, L, Slattery, ML, Kartashov, AI, and Ludwig, DS, Dairy consumption, obesity and the insulin resistance syndrome in young adults: the CARDIA Study, JAMA, 287, 2081, 2002.
  42. Rodriguez-Moran, M and Guerrero-Romero, F, Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial, Diabet. Care, 26, 1147, 2003.
  43. Spriet, LL and Watt, MJ, Regulatory mechanisms in the interaction between carbohydrate and lipid oxidation during exercise, Acta. Physiol. Scand, 178, 443, 2003.
  44. McGee, SL, Howlett, KF, Starkie, RL, Cameron-Smith, D, Kemp, BE, and Har-greaves, M, Exercise increases nuclear AMPK in human skeletal muscle, Diabetes 52, 926, 2003.
  45. Santoro, C, Cosmas, A, Forman, D, Morghan, A, Bairos, L, Levesque, S, Roubenoff, R, Hennessey, J, Lamont, L, and Manfredi, T, Exercise training alters skeletal muscle mitochondrial morphometry in heart failure patients, J. Cardiovasc. Risk, 9, 377, 2002.
  46. Singleton, JR, Smith, AG, Russell, JW, and Feldman, EL, Microvascular complications of impaired glucose tolerance, Diabetes, 52, 2867, 2003.
  47. Kuller, LH, Velentgas, P, Barzilay, J, Beauchamp, NJ, O'Leary, DH, and Savage, PJ, Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality, Arterioscler. Thromb. Vasc. Biol., 20, 823, 2000.
  48. Haffner, SM, Lehto, S, Ronnemaa, T, Pyorala, K, and Laasko, M, Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction, N. Engl. J. Med., 339, 229, 1998.
  49. Bonora, E, Kiechl, S, Willeit, J, Oberhollenzer, F, Egger, G, Bonadonna, RO, and Muggeo, M, Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data from the Bruneck Study, Diabet. Care, 26, 1251, 2003.
  50. Oren, A, Vos, LE, Uiterwaal, CSPM, Gorissen, WHM, Grobbee, DE, and Bots, ML, Change in body mass index from adolescence to young adulthood and increased carotid intima-media thickness at 28 year of age: The Atherosclerosis Risk in Young Adults study, Int. J. Obes, 27, 1383, 2003.
  51. Woo, KS, Chook, P, Yu, CW, Sung, RYT, Qiao, M, Leung, SSF, Lam, CWK, Metreweli, C, and Celermajer, DS, Overweight in children is associated with arterial endothelial dysfunction and intima-media thickening, Int. J. Obes., 28, 852, 2004.
  52. Berenson, GS, Srinivasan, SR, Bao, W, Newman, WP III, Tracy, RE, and Wattigney, WA, Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults, N. Engl. J. Med., 338, 1650, 1998.
  53. McGill, HC, Jr., McMahan, CA, Herderick, EE, Zieske, AW, Malcom, GT, Tracy, RE, and Strong, JP, Pathological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Obesity accelerates the progression of coronary atherosclerosis in young men, Circulation, 105, 2712, 2002.
  54. Dean, H and Flett, B, Natural history of type 2 diabetes diagnosed in childhood: long term follow up in young adult years. Presented at 62nd Scientific Sessions, San Francisco, June 2002.
  55. Vincent, MA, Montagnani, M, and Quon, MJ, Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium, Curr. Diab. Rep., 3, 279, 2003.
  56. Deedwania, PC, Mechanisms of endothelial dysfunction in the metabolic syndrome, Curr. Diab. Rep., 3, 289, 2003.

Du, XL, Matsumura, T, Edelstein, D, Rossetti, L, Zsengeller, Z, Szabo, C, and Brownlee, M, Inhibition of GAPDH activity by poly (ADPribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells, J. Clin. Invest, 112, 1049, 2003.

Montani, JP, Antic, V, Yang, Z, and Dulloo, A, Pathways from obesity to hypertension: from the perspective of a vicious triangle, Int. J. Obes, 26, s28, 2002. Long SD, O'Brien K, MacDonald KG, Leggett-Frazier N, Swanson MS, Pories WJ, and Caro JF. Weight loss in severely obese subjects prevents the progression of impaired glucose tolerance to type 2 diabetes. A longitudinal interventional study. Diabetes Care, 17, 372, 1994.

Ferguson, MA, Gutin, B, Le, NA, Karp, W, Litaker, M, Humphries, M, Okuyama, T, Riggs, S, and Owens, S, Effects of exercise training and its cessation on components of the insulin resistance syndrome in obese children, Int. J. Obes., 22, 889, 1999. Watts, K, Beye, P, Siafarikas, A, Davis, EA, Jones, TW, O'Driscoll, G, and Green, DJ, Exercise training normalizes vascular dysfunction and improves central adiposity in obese adolescents, J. Amer. Coll. Cardiol., 2004, in press. A parallel study in obese pre-teens is in press in the J. of Pediatr.

Inui, A, Asakawa, A, Bowers, CY, Mantovani, G, Laviano, A, Meguid, MM, and Fujimiya, M, Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ, FASEB J., 18, 439, 2004.

Douyon, L and Schteingart, DE, Effect of obesity and starvation on thyroid hormone, growth hormone and cortisol secretion, Endocrinol. Metab. Clin. North. Am., 31, 173, 2002.

Kratzsch, J, Dehme, B, Pulzer, F, Keller, E, Englaro, P, Blum, WF, and Wabitsch, M, Increased serum GHBP levels in obese pubertal children and adolescents: relationship to body composition, leptin and indicators of metabolic disturbances, Int. J. Obes., 21, 1130, 1997.

Norgren, S, Danielsson, P, Jurold, R, Lotborn, M, and Marcus, C, Orlistat treatment in obese prepubertal children: a pilot study, Acta. Paediatr., 92, 666, 2003. Chiasson, JL, Josse, RG, Gomis, R, Hanefeld, M, Karasik, A, and Laakso, M, STOP-NIDDM Trial Research Group, Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial, JAMA, 290(4), 486, 2003.

Zhou, G, Myers, R, Li, Y, Chen, Y, Shen, X, Fenyk-Melody, J, Wu, M, Ventre, J, Doebber, T, Fujii, N, Musi, N, Hirshman, MF, Goodyear, LJ, and Moller, DE, Role of AMP-activated protein kinase in mechanism of metformin action, J. Clin. Invest., 108, 1167, 2001.

Hallsten, K, Virtanen, KA, Lonnqvist, F, Sipila, H, Oksanen, A, Viljanen, T, Ronne-maa, T, Viikari, J, Knuuti, J, and Nuutila, P, Rosiglitazone but not Metformin enhances insulin-and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes, Diabetes, 51, 3479, 2002.

Virtanen, KA, Hallsten, K, Parkkola, R, Janatuinen, T, Lonnqvist, F, Viljanen, T, Ronnemaa, T, Knuuti, J, Huupponen, R, Lonnroth, P, and Nuutila, P, Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects, Diabetes, 52, 283, 2003.

Schwimmer, JBMM, Deutsch, R, and Lavine, JE, Metformin as a treatment for non-diabetic NASH, J. Pediatr. Gastroenterol., 37, 342, 2003.

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34), UK Prospective Diabetes Study (UKPDS) Group, Lancet, 352, 854, 1998.

  1. Paolisso, G, Amato, L, Eccellente, R, Gambardella, M, Tagliamonte, MR, Varricchio, G, Carrella, C, Giugliano, D, and D'Onofrio, F, Effect of metformin on food intake in obese subjects, Eur. J. Clin. Invest., 28(6), 441, 1998.
  2. Glueck, CJ, Fontaine, RN, Wang, P, Subbiah, MTR, Weber, K, Illig, E, Streicher, P, Sieve-Smith, L, Tracy, TM, Lang, JE, and McCullough, P, Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondi-abetic, morbidly obese subjects with body mass index greater than 30, Metabolism, 50, 856, 2001.
  3. Pasquali, R, Gambineri, A, Biscotti, D, Vicennati, V, Gagliardi, L, Colitta, D, Fiorini, S, Cognigni, GE, Filicori, M, and Morselli-Labate, AM, Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome, J. Clin. Endocrinol. Metab., 85, 2767, 2000.
  4. Ibanez, L, Valls, C, Potau N, Marcos MV, and deZegher F, Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dys-lipidmeia and hyperinsulinism after precocious pubarche, J. Clin. Endocrinol. Metab., 85, 3526, 2000.
  5. Ibanez, L, Valls, C, Ferrer, A, Ong, K, Dunger, DB, and DeZegher, F, Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation, J. Clin. Endocrinol. Metab., 87, 2870, 2002.
  6. Ibanez, L, Ong, K, Ferrer, A, Amin, R, Dunger, D, and deZegher, F, Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism, J. Clin. Endocrinol. Metab., 88:2600, 2003.
  7. Freemark, M and Bursey, D, The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes, Pediatrics, 107(4), e55, 2001.
  8. Freemark, M, Pharmacologic approaches to the prevention of type 2 diabetes in high risk pediatric patients, J. Clin. Endocrinol. Metab., 88, 3, 2003.
  9. Kay, JP, Alemzadeh, R, Langley, G, D'Angelo, L, Smith, P, and Holshouser, S, Beneficial effects of metformin in normoglycemic morbidly obese adolescents, Metabolism, 50, 1457, 2001.
  10. Spiegelman, BM, PPAR-gamma: Adipogenic regulator and thiazolidinedione receptor, Diabetes, 47, 507, 1998.
  11. Gurnell, M, Savage, DB, Chatterjee, KK, and O'Rahilly, S, The metabolic syndrome: PPAR gamma and its therapeutic modulation, J. Clin. Endocrinol. Metab., 88, 2412, 2003.
  12. Hauner, H, The mode of action of thiazolidinediones, Diabet. Metab. Res. Rev., 18, Suppl. 2, S10, 2002.
  13. Nolan, JJ, Ludvik, B, Beerdsen, P, Joyce, M, and Olefsky, J, Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone, N. Engl. J. Med., 331, 1188, 1994.
  14. Buchanan, TA, Xiang, AH, Peters, RK, Kjos, SL, Marroquin, A, Goico, J, Ochoa, C, Tan, S, Berkowitz, K, Hodis, HN, and Azen, SP, Preservation of pancreatic (beta)-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women, Diabetes, 51, 2796, 2002.
  15. Berg, AH, Combs TP, Du, X, Brownlee M, and Scherer, PE, The adipocyte-secreted protein Acrp30 enhances hepatic insulin action, Nat. Med., 7, 947, 2001.
  16. Soriano, FG, Pacher, P, Mabley, J, Liaudet, L, and Szabo, C, Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly (ADPribose) polymerase, Circ. Res., 89, 684, 2001.
  17. Artz, E and Freemark, M. The pathogenesis of insulin resistance in children: metabolic complications and the roles of diet, exercise and pharmacotherapy in the prevention of type 2 diabetes, J. Pediatr. Endocronol. Metab., 3, 296, 2004.
  18. Hollander, PA, Levy, P, Fineman, MS, Maggs, DG, Shen, LZ, Strobel, SA, Weyer, C, and Kolterman, OC, Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes, Diabet. Care, 26, 784, 2003.
  19. Gaede, P, Vedel, P, Larsen, N, Jensen, GV, Parving, HH, and Pedersen, O, Multifac-torial intervention and cardiovascular disease in patients with type 2 diabetes. N. Engl. J. Med, 348, 383, 2003.
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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