Between 20% and 40% of patients with diabetes ultimately develop diabetic nephropathy, which in the US is the most common cause of end-stage renal disease requiring dialysis. Diabetic nephropathy has several distinct phases of development and multiple mechanisms contribute to the development of the disease and its outcomes. This Review provides a summary of the latest published data dealing with these mechanisms; it focuses not only on candidate genes associated with susceptibility to diabetic nephropathy but also on alterations in various cytokines and their interaction with products of advanced glycation and oxidant stress. Additionally, the interactions between fibrotic and hemodynamic cytokines, such as transforming growth factor beta1 and angiotensin II, respectively, are discussed in the context of new information concerning nephropathy development. We touch on the expanding clinical data regarding markers of nephropathy, such as microalbuminuria, and put them into context; microalbuminuria reflects cardiovascular and not renal risk. If albuminuria levels continue to increase over time then nephropathy is present. Lastly, we look at advances being made to enable identification of genetically predisposed individuals.

Polycystic ovary syndrome (PCOS) is a multifaceted disorder that affects between 5% and 8% of women. As a syndrome, PCOS is comprised of reproductive, metabolic, and cardiovascular components. Hyperandrogenemia and hyperinsulinemia are central to the pathogenesis of PCOS and thus typically serve as the targets for treatment. The spectrum of therapeutic options is broad and ranges from lifestyle intervention to specific pharmacologic agents. This chapter details current pharmacologic treatments for women with PCOS using a symptom-specific approach with a special focus on the metabolic effects of each treatment. Generally, oligomenorrhea mandates regulation of menstrual cyclicity and protection of the endometrium against the development of dysplasia and carcinoma. Progestins, either alone or in combination with estrogen (in the form of an oral contraceptive) are the mainstay of treatment of oligomenorrhea. Insulin lowering therapies also improve menstrual regularity. When androgen excess is the main target for therapy, an antiandrogen and/or oral contraceptives is typically chosen. Metabolic concerns of PCOS include excess body weight and insulin resistance. Metformin and thiazolidenediones both improve hyperinsulinemia but their differential effects on body weight must be considered.

T he incidence of diabetes mellitus and hypertension continues to rise worldwide. The proportion of patients with hypertension at risk for developing diabetes mellitus is also growing secondary to aging and increased obesity rates. 1 Several guidelines recommend thiazide diuretics as either first-line or add-on antihypertensive therapy to achieve blood pressure goals. 2 Concern over negative metabolic effects associated with thiazide diuretics, however, dates back Ͼ3 decades. 3 A substantial fraction of patients with hypertension have additional cardiovascular risk factors, and many have elevated fasting glucose and are at risk for developing diabetes mellitus. 4 Impaired fasting glucose itself increases the risk for cardiovascular events. 5 Any medication that worsens insulin sensitivity, ie, thiazide diuretics or most ␤-blockers will hasten the development of diabetes mellitus in those with impaired fasting glucose. 6 Large observational studies demonstrate that thiazide diuretics and most ␤-blockers increase the incidence of new-onset diabetes mellitus compared with renin-angiotensin system (RAS) blockers or calcium channel blockers. 7 To further support this observation, a network-based meta-analysis of hypertensive agents showed that RAS blockers were the agents least likely to be associated with the development of diabetes mellitus, whereas thiazides had a higher incidence of diabetes mellitus compared with placebo. 7 The mechanism traditionally associated with this increased risk of diuretic-associated diabetes mellitus is a reduction in serum potassium. A meta-analysis of 59 studies involving 83 thiazide diuretic treatment arms found a significant correlation between the degree of diureticinduced hypokalemia and an increase in plasma glucose. 8 Moreover, there is evidence that prevention of hypokalemia with K ϩ supplementation or potassium-sparing agents lessens the degree to which plasma glucose is increased consequent to diuretic therapy. 8 The mechanism of this glucose increase by diuretics may relate to insulin secretion. Mechanisms related to insulin release were reviewed recently, and it was noted that hyperkalemia stimulates insulin secretion and induces cellular uptake of potassium. 9 This suggests that low plasma potassium could impair insulin secretion and thereby increase plasma glucose. Ironically, the significant hypokalemia associated with hyperaldosteronism is not associated with hyperglycemia. The presence of insulin resistance and an impaired glucose response to an oral glucose load, however, are reported in hyperaldosteronism. 9 Thus, the exact relationship between hypokalemia and worsening of insulin resistance is unclear but appears most pronounced in those with preexisting impaired glucose tolerance and not all people.Given this background, combining an agent that reduces potassium loss, ie, an RAS blocker with a thiazide diuretic, should reduce the risk of new-onset diabetes mellitus. Unfortunately, the Study of Trandolapril/Verapamil SR and Insulin Resistance failed to support this...