Nicole Glaser MD

The Big Diabetes Lie

Diabetes Causes and Treatment

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Department of Pediatrics, University of California Davis, School of Medicine, 2516 Stockton Boulevard, Sacramento, CA 95817, USA

Diabetic ketoacidosis (DKA) is an important complication of childhood diabetes mellitus and the most frequent diabetes-related cause of death in children [1,2]. In various population-based studies, reported rates of DKA at presentation of type 1 diabetes have ranged from as low as 15% to as high as 83% [3-7], with most North American and European studies reporting rates of approximately 40%. Although DKA occurs less frequently in children with type 2 diabetes, case series have documented frequencies of DKA at diagnosis of type 2 diabetes in children ranging from 6% to 33% [8-11]. A diagnosis of type 2 diabetes cannot be excluded based on the occurrence of DKA.

Young children with new onset of type 1 diabetes are more likely to present with DKA [4,6,12], as are children who reside in countries with a low overall prevalence of type 1 diabetes [5]. The higher frequency of DKA at presentation in these groups likely reflects the greater difficulty in recognizing symptoms of diabetes in these populations. In a European study, an educational program directed at parents and primary care pediatricians was shown to decrease the frequency of DKA at diagnosis of type 1 diabetes from almost 80% to just 12.5%, which supported the concept that the frequency of DKA at presentation of diabetes is related to recognition of symptoms of diabetes in the population studied [7].

In children who have established diabetes, DKA may occur with episodes of infection or other illnesses or with insulin omission or malfunction of diabetes care equipment, such as insulin pumps. In children who have established diabetes, DKA occurs at a rate of approximately 1% to 8% per year [4,13-15]. DKA in patients who have established diabetes occurs more frequently in persons with

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doi:10.1016/j.pcl.2005.09.001 lower socioeconomic status, lack of adequate health insurance, higher HbAlc levels, and psychiatric disorders [13]. Insulin omission is the most frequent cause of DKA in children who have known diabetes. One study investigated the frequency of viral and bacterial infections in children who have DKA. Among all children who presented with DKA, bacterial infections were present in only 13% and viral infections in 18% [16]. In the subgroup of children who have known diabetes, bacterial infections were present in 17% and viral infections in 20%. These data contrast with data for adult populations, in which higher frequencies of infection or other illnesses as precipitating factors for DKA have been reported [17,18].

Although the risk of mortality from childhood DKA is less than 0.5%, DKA is still the most frequent diabetes-related cause of death in children [1,2]. Most of these DKA-related deaths are caused by cerebral edema (62%-87%), a complication that is discussed in more detail later.

Pathophysiology of diabetic ketoacidosis

The physiologic abnormalities in patients who have DKA may be viewed as an exaggeration of the normal physiologic mechanisms responsible for maintaining adequate fuel supply to the brain and other tissues during periods of fasting and physiologic stress. The relative concentration of insulin in relation to glucagon and other counterregulatory hormones or stress hormones (eg, epi-nephrine, norepinephrine, cortisol, and growth hormone) primarily mediates these physiologic abnormalities rather than the absolute concentration of insulin itself [19,20].

Pathophysiologic abnormalities early in the development of diabetic ketoacidosis

In a child who has new onset of type 1 diabetes, declining insulin production lowers the ratio of insulin to glucagon. This decrease in relative insulin concentration leads to excess hepatic glucose production (Fig. 1A). Early in the course of evolving DKA, when levels of epinephrine and other stress hormones are normal or minimally elevated, increased hepatic glucose output is mainly caused by stimulation of glycogenolysis, with a smaller contribution from increased gluconeogenesis [21-23]. Low serum insulin concentrations also contribute to hyperglycemia by decreasing peripheral glucose uptake in muscle and adipose tissue. This effect is mediated by diminished translocation of glucose transporter (GLUT)4 glucose transporters to the cell membrane [24,25]. Increased hepatic glucose output and decreased peripheral glucose use contribute to hyperglycemia [26]. When the serum glucose concentration rises above approximately 180 to 200 mg/dL, which exceeds the renal threshold for glucose reabsorption [27,28], osmotic diuresis results, with an increase in urine output. Fluid losses then stimulate compensatory oral intake of fluids, which leads to polydipsia.

Low insulin concentrations also stimulate the release of free fatty acids (FFA) from adipose tissue by allowing activation of hormone-sensitive lipase (Fig. 2). This increase in FFA delivery to the liver is necessary but not sufficient for the stimulation of ketone body formation [29]. For ketogenesis to occur, activation of the hepatic (3-oxidative enzyme sequence is also necessary [20,30,31]. It is mainly a further decline in insulin concentration relative to glucagon that allows this activation to occur. A larger decline in insulin concentration relative to counter-regulatory hormones is necessary to promote lipolysis and ketogenesis, compared with that required to cause hyperglycemia [32]. These findings in part explain the lesser tendency toward the development of DKA in patients who have type 2 diabetes, despite the occurrence of substantial hyperglycemia.

Under fasting conditions in a normal individual, modest ketosis occurs, but marked ketoacidosis is prevented by direct ketone-induced stimulation of insulin, which limits further release of FFAs from adipose tissue [33]. In children who have type 1 diabetes, however, this ''hormonal brake'' is lacking and ketone production proceeds unchecked, eventually resulting in acidosis with an elevated anion gap.

Pathophysiologic abnormalities later in the development of diabetic ketoacidosis

Physiologic stress caused by acidosis and progressive dehydration eventually stimulates release of the counterregulatory hormones, cortisol, catecholamines, and growth hormone (see Fig. 1B) [26,34,35] Coexisting infection or other illness or injury likewise can accelerate the development of ketosis via further elevations in counterregulatory hormone concentrations. Elevated cortisol concentrations augment FFA release from adipose tissue to fuel ketogenesis and decrease peripheral glucose uptake via effects on insulin-dependent mechanisms of glucose uptake and insulin-independent mechanisms (Fig. 2) [36-38]. Increased epinephrine concentrations directly increase glycogenolysis and stimulate release of gluconeogenic precursors from muscle, which allows gluconeogensis to make a more substantial contribution to hyperglycemia [22,23,39]. Epinephrine and norepinephrine also stimulate lipolysis and ( -oxidation of FFAs to form ketone bodies [40,41]. Catecholamines also may inhibit insulin secretion directly via stimulation of a-adrenergic receptors and cause a further decline in serum insulin concentrations [42,43]. Although this effect is inconsequential in children who have longstanding type 1 diabetes (and absent or minimal endogenous insulin production), it may accelerate the development of DKA in patients with a new diagnosis of type 1 diabetes in whom some insulin-producing capacity remains, and it likely contributes more substantially to the development of DKA in children who have type 2 diabetes. Elevated growth hormone concentrations likewise contribute to worsening hyperglycemia, mainly via further decreasing peripheral glucose uptake, and enhance ketone production by increasing FFA release [23,44]. Growth hormone effects occur over a longer time course than those of other counterregulatory hormones that lead to more acute elevations in glucose and FFAs.

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Good Carb Diet

Good Carb Diet

WHAT IT IS A three-phase plan that has been likened to the low-carbohydrate Atkins program because during the first two weeks, South Beach eliminates most carbs, including bread, pasta, potatoes, fruit and most dairy products. In PHASE 2, healthy carbs, including most fruits, whole grains and dairy products are gradually reintroduced, but processed carbs such as bagels, cookies, cornflakes, regular pasta and rice cakes remain on the list of foods to avoid or eat rarely.

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