The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Kaplan NM. Arch Intern Med 1989 Jul;149(7):1514-1520

The contribution of obesity to cardiovascular risk has not been adequately appreciated because of a failure to recognize the involvement of upper-body predominance of body weight with hypertension, diabetes, and hypertriglyceridemia even in the absence of significant overall obesity. This article examines the evidence that upper-body obesity, as usually induced by caloric excess in the presence of androgens, mediates these problems by way of hyperinsulinemia. Because of these interrelationships, there is a need to identify and prevent upper-body obesity or, failing that, to provide therapies that will control the associated problems without aggravating hyperinsulinemia.

and ...

The deadly quartet and the insulin resistance syndrome: an historical overview. Kaplan NM Hypertens Res 1996 Jun;19 Suppl 1:S9-S11

Since the original observations by Vague almost 50 years ago, a massive literature has documented the pathological consequences of upper body or visceral obesity. These consequences likely relate to the presence of hyperinsulinemia. More recently, the presence of hyperinsulinemia has also been recognized in nonobese hypertensives as a feature of the insulin resistance syndrome. This paper will provide an historical overview of the two clinical syndromes.

Hyperinsulinaemia, Obesity, and Syndrome X, J Zavaroni, Reaven GM et al, Intern Med 1994 Jan; 235(1):51-56

OBJECTIVE. The major aim of this study was to compare various aspects of carbohydrate, insulin, and lipoprotein metabolism, serum uric acid concentration, and blood pressure in normal subjects stratified on the basis of both plasma insulin concentration and degree of obesity. The hypothesis to be tested was that hyperinsulinaemia, per se, was associated with relative glucose intolerance, higher triglyceride and uric acid concentrations, lower high-density lipoprotein cholesterol concentration and higher blood pressure, irrespective of degree of obesity. .... RESULTS. Mean (+/- standard error of the mean) integrated plasma glucose response area for 2 h following a 75 g oral glucose load was significantly higher (13.4 +/- 0.4 vs. 11.0 +/- 0.4 mmol l-1, P < 0.001) in the hyperinsulinaemic group, as were the fasting triglyceride levels (2.4 +/- 0.2 vs. 1.4 +/- 0.1 mmol l-1, P < 0.001) and uric acid (5.3 +/- 0.2 vs. 4.4 +/- 0.2 mmol l-1, P < 0.05) concentrations. In contrast, high-density lipoprotein concentrations were lower in the hyperinsulinaemic group ( vs. 1.32 +/- 0.05 mmol l-1, P < 0.001). In addition, blood pressure was higher in the hyperinsulinaemic group (136 +/- 5/87 +/- 2 vs. 123 +/- 2/82 +/- 1 mmHg, P < 0.05). Furthermore, when each of the two groups were divided into obese (n = 16) and non-obese (n =16) groups, all of the differences outlined above persisted. These changes were independent of age, gender distribution, generalized and abdominal obesity, cigarette smoking, and estimated physical activity. CONCLUSIONS. The cluster of changes subsumed under the heading of syndrome X are closely associated with hyperinsulinaemia (and presumably insulin resistance), and can be discerned irrespective of degree of obesity.

Micronutrients as nutriceutical interventions in diabetes mellitus. Cunningham JJ, J Am Coll Nutr 1998 Feb;17(1):7-10

Hyperglycemia portends chronic complications in insulin-dependent diabetes mellitus (IDDM) and substantial benefits are associated with "tight" glycemic control. Other interventions should either enhance glycemic control per se or add benefit to an established degree of glycemic control. Several micronutrients enhance insulin action and others offer promise in countering the untoward consequences of hyperglycemia. Supplements of micronutrients including the vitamins niacin (as niacinamide), C and E and the minerals zinc, chromium and vanadium have been studied. For the purpose of this review, the term "nutriceutic" refers to supplementation on the order of 2 to 10 times the RDA for which a benefit is linked to a mechanism of action. Benefits associated with "nutriceutic" supplementation are reported in small trials for vitamins C and E and these supplements are safe and affordable from food or tablet sources. A dietary strategy adding 200-600 mg of vitamin C and 100 IU of vitamin E to a healthy dietary pattern is worthy of consideration as an intervention for individuals with IDDM.

The glucose/insulin system and vitamin C: implications in insulin-dependent diabetes mellitus. Cunningham JJ, J Am Coll Nutr 1998 Apr;17(2):105-108

The cellular uptake of vitamin C (ascorbic acid, ASC) is promoted by insulin and inhibited by hyperglycemia. If a rise in plasma ASC is uncoupled from insulin replacement in insulin-dependent diabetes mellitus (IDDM) then the degree of hyperglycemia could account for "tissue scurvy" in IDDM. Leukocyte ASC is lower in IDDMs compared with nondiabetics when vitamin C consumption is adequate and our data suggest that this is a variable component of the pathophysiology of IDDM. The complications of diabetes mellitus are believed to result from either the intracellular accumulation of sorbitol or the nonenzymatic glycoxidation of proteins or both. With respect to the abnormal cellular accumulation of sorbitol, vitamin C supplementation has been shown to be effective in several studies of adults with diabetes; the situation regarding the prevention of protein glycoxidations by supplementation is presently unclear. The roles of ASC as an aldose reductase inhibitor and a water soluble antioxidant in body fluids are potentially very important as adjuncts to tight glycemic control in the management of diabetes. Tissue saturation and maximal physiologic function in IDDM may require supplemental vitamin C intake.

Micronutrient status in diabetes mellitus. Mooradian AD, Morley JE, Am J Clin Nutr 1987 May;45(5):877-895

Diabetes mellitus is a chronic metabolic disorder, which can alter the nutritional status of the individual. Some micronutrients, in particular zinc and chromium, have been implicated in the pathogenesis of carbohydrate intolerance. This review evaluates the available published data on the status of 10 mineral elements and seven vitamins in diabetic patients and experimental animal models of diabetes. The role of these micronutrients in insulin secretion and carbohydrate metabolism is discussed in an attempt to determine whether the reported alterations in serum or tissue content of minerals or vitamins contribute to the carbohydrate intolerance of diabetic patients. It is concluded that both Type I and Type II diabetes mellitus can result in changes in certain micronutrients. However, adequately controlled studies to establish the role of trace elements in the pathogenesis of diabetes mellitus are not available. And ...

Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus. Maxwell SR et al, Eur J Clin Invest 1997 Jun;27(6):484-490

Oxidative damage by free radicals has been implicated in the pathogenesis of vascular disease in diabetes. We compared the radical-scavenging antioxidant activity of serum from 28 patients with insulin-dependent diabetes mellitus and 24 patients with non-insulin-dependent diabetes mellitus uncomplicated by vascular disease with age-matched non-diabetic control subjects. Patients with insulin-dependent diabetes had significantly reduced total antioxidant activity (320.2 +/- 11.3 vs. 427.5 +/- 19.2 mumol L-1; P < 0.001). This was attributable to lower urate (209.4 +/- 10.4 vs. 297.1 +/- 16.7 mumol L-1; P < 0.001) and vitamin C levels (63.6 +/- 6.0 vs. 87.5 +/- 4.9 mumol L-1; P < 0.01). Patients with non-insulin-dependent diabetes had lower total antioxidant activity than age-matched control subjects (433.8 +/- 25.4 vs. 473.9 +/- 30.2 mumol L-1; NS), reflecting lower urate (299.5 +/- 19.4 vs. 324.8 +/- 21.4 mumol L-1; NS) and vitamin C levels (38.6 +/- 5.7 vs. 58.5 +/- 5.3 mumol L-1; P < 0.05). Multiple regression analysis showed that urate, vitamin C and vitamin E were the major contributors to serum total antioxidant activity. These results show that diabetic patients have significant defects of antioxidant protection, which may increase vulnerability to oxidative damage and the development of diabetic complications.

Potential therapeutic approaches to the treatment or prevention of diabetic neuropathy: evidence from experimental studies. Cameron NE, Cotter MA, Diabet Med 1993 Aug;10(7):593-605

Recent investigations using experimental models of diabetes mellitus have emphasized the importance of impaired blood flow for the development of nerve dysfunction. Other observations suggest that this may also be the case for patients. A number of studies have revealed that several types of vasodilators can prevent or successfully treat early conduction abnormalities in diabetic

rodents. These include alpha 1-adrenoreceptor antagonists, calcium channel blockers, agents that inhibit the renin-angiotensin system, and vasomodulat or prostanoids. Other treatments applied to animal models, such as omega-6 essential fatty acids, aldose reductase inhibitors, aminoguanidine which prevents the formation of advanced glycation end-products, and anti-oxidants all appear to have vascular-related effects that lead to improvements in nerve conduction. These findings suggest that endothelial dysfunction and oxidative stress could be important factors in the aetiology of diabetic neuropathy. Studies have also focused on deficits in axon growth and regeneration, their relation to impaired neuronal synthesis and transport of growth-related chemicals, and neuronotrophic abnormalities. Taken together, the data give rise to the notion that an optimal therapeutic strategy could consist of improving the microenvironment of damaged nerve fibres by manipulating nerve blood flow while concurrently encouraging repair with trophic agents.

Protective effects of ketogenic diets on signs of hypoglycemia. Johnson WA, Weiner MW, Diabetes 1978 Nov;27(11):1087-1091

The effects of diet-induced ketosis on the signs of hypoglycemia were investigated. Lard, medium chain triglycerides, or 1,3-butylene glycol comprised 43% of the diet fed to mice. The diet containing lard or medium chain triglycerides greatly protected the animals from the manifestations of acute insulin-induced hypoglycemia. Furthermore, both diets protected the animals from the effects of repeated insulin injections (every eight hours) for 10 days. In contrast, 1,3-butylene glycol had no protective effects. These experiments suggest that ketogenic diets may be of value in the treatment of recurrent hypoglycemic conditions.

The following 10 studies by Dr Elliot Blass and others concern sugar's effects on pain in rats and human babies ...

1) Interactions between sucrose, pain and isolation distress. Blass E, Fitzgerald E, Kehoe P, Pharmacol Biochem Behav 1987 Mar;26(3):483-489

Two experiments were conducted that establish an opioid-based, functional-relationship between the taste of sucrose, pain threshold and distress vocalization in isolated 10-day-old albino rats. In the first experiment intraoral infusion of sucrose virtually doubled heat-withdrawal latencies. This elevation was naltrexone (0.5 mg/kg b.wt.) reversible. In the second experiment sucrose infusions caused a rapid and sustained diminution of distress vocalizations in rats totally isolated from dam and siblings. These are the first demonstrations of a causal relationship between a positive affective system and ones mediating pain and stress.

2) Milk-induced analgesia and comforting in 10-day-old rats: opioid mediation. Blass EM, Fitzgerald E, Pharmacol Biochem Behav 1988 Jan;29(1):9-13

The effects of slow intraoral milk infusions on the opioid-mediated behaviors of ultrasonic vocalizations and paw removal from a hot plate (48-49 degrees C) were evaluated in 10-day-old rats. Milk reduced distress vocalization by circa 30% while increasing paw lift latencies by about 60%. Alterations in both behaviors were fully reversed by naltrexone (0.5 mg/kg) pretreatments. These data demonstrate the calming and analgesic effects of milk. Implications for a possible role of opioid peptides in mother-young relationships are discussed.

3) Some comparisons among the calming and pain-relieving effects of sucrose, glucose, fructose and lactose in infant rats. Blass EM, Shide DJ, Chem Senses 1994 Jun;19(3):239-249

Ultrasonic vocalizations were recorded from 10-day-old albino rats while they were isolated from their dam and siblings. Each rat received a 1.0% BW intra-oral infusion of sucrose, fructose, glucose or lactose at a concentration range of 0.22-0.66 M for 3 min and their vocalizations were determined during the infusion and for an additional 7 min. Sucrose, fructose and glucose all significantly reduced vocalizations to about 50% of baseline levels, whereas lactose, the milk sugar, was ineffective. Moreover, the dose-response function was flat for the three effective sugars. In a second experiment, the effects of these sugars on heat escape latency were measured. Sucrose, fructose and glucose each elevated the latency with which infant rats removed a paw from a 48 degrees C surface; lactose did not. These findings of lactose ineffectiveness and the flat dose-response function for the other three sugars exactly parallel those obtained for human newborns. Their implications are discussed.

4) Pain-reducing properties of sucrose in human newborns. Blass EM, Shah A, Chem Senses 1995 Feb;20(1):29-35

To assess the characteristics of sucrose as a pain-reducing substance, crying in 72 newborn humans during and after blood collection via heel prick was determined. In the first study infants drank 2 ml of water or 2 ml of a 0.17-0.34- or 0.51-M sucrose solution 1 min prior to blood collection. In the second experiment, a delay of 30, 60, 90, 120 or 240 s was imposed between sucrose intake and the initiation of blood collection. The dose-response function for concentration was flat. The most effective time delay was 120 s. The effectiveness of the 2-min interval accords with previous findings of endogenous opioid release caused by sucrose taste. The flat dose-response function extends findings in rats and humans that the calming and pain-reducing effects of sucrose are not influenced by either concentration or volume, suggesting that the transduction from gustatory afferent to opioid-mediated efferent is of an on-off nature and not graded.

5) Sugar, opioids and binge eating. Fullerton DT, Getto CJ, Swift WJ, Carlson IH, Brain Res Bull 1985 Jun;14(6):673-680

There is evidence that endogenous opiates are involved in the control of feeding in experimental animals. Several types of experimental obesity are associated with increased opiate production and/or increased numbers and sensitivity of opiate receptors. Research with experimental animals suggests that nutrients, particularly sugar, have an effect on feeding behavior that is mediated by opiates. For instance, the obesity-producing effect of a palatable diet in rodents is blocked by opiate antagonists. Stress induced feeding in rodents leads to preferential sucrose ingestion and is blocked by opiate antagonists and beta-endorphin. The effect of nutrients on the endogenous opiate system of humans is less clear. Clinical experience suggest that carbohydrates (sugar in particular) play a role in binge eating and obesity. Many binge eaters preferentially eat sweets during a binge. Many obese individuals consume more than half of their total daily calories as carbohydrates. Sweet snacking is a frequent behavior at times of stress. Recent evidence suggests that sugar can lead to increased beta-endorphin production in obese subjects.

6) Taste responses and preferences for sweet high-fat foods: evidence for opioid involvement. Drewnowski A, Krahn DD, Demitrack MA, Nairn K, Gosnell BA, Physiol Behav 1992 Feb;51(2):371-379

Preferences and cravings for sweet high-fat foods observed among obese and bulimic patients may involve the endogenous opioid peptide system. The opioid antagonist naloxone, opioid agonist butorphanol, and saline placebo were administered by intravenous infusion to 14 female binge eaters and 12 normal-weight controls. Eight of the binge eaters were obese. During infusion, the subjects tasted 20 sugar/fat mixtures and were allowed to select and consume snack foods of varying sugar and fat content. Naloxone reduced taste preferences relative to baseline in both binge eaters and controls. Total caloric intake from snacks was significantly reduced by naloxone in binge eaters but not in controls. This reduction was most pronounced for sweet high-fat foods such as cookies or chocolate. No consistent effects on taste preferences or food intakes were observed with butorphanol. Endogenous opioid peptides may be involved in mediating taste responses and preferences for palatable foods, notably those rich in sugar and fat.

7) Opioid mediation of odor preferences induced by sugar and fat in 6-day-old rats. Shide DJ, Blass EM, Physiol Behav 1991 Nov;50(5):961-966

Intraoral infusions of sucrose, fat or polycose reduce ultrasonic vocalizations during isolation, and increase pain threshold in infant rats. These effects are naltrexone reversible. The present study determined whether these substances, when paired with an odor, caused a change in preference for that odor. In 6-day-old rats, pairing orange odor with intraoral infusions of sucrose or corn oil, but not polycose, water, mineral oil or 0.01% quinine hydrochloride, caused a substantial increase in preference for orange. Preference formation was blocked by systemic injection of naltrexone (0.25 mg/kg) prior to pairing orange with either sucrose or corn oil. Moreover, preference expression was prevented by naltrexone injection prior to testing. Thus certain substances thought to reduce stress in infant rats via endogenous opioid release can also cause preference for substances that predict their occurrence. Preference formation depends upon the availability of endogenous opioids. Preference expression reflects the conditioned stimulus causing opioid release.

8) Hyperendorphinemia in obese children and adolescents. J Genazzani AR, Facchinetti F, Petraglia F, Pintor C, Corda R, Clin Endocrinol Metab 1986 Jan;62(1):36-40

To study the role of opioid peptides in human obesity, plasma beta-endorphin (beta EP), beta-lipotropin (beta LPH), and cortisol resting values, circadian rhythms, and responses to hypoglycemia were studied in 6 prepubertal and 6 pubertal obese adolescents (at least 40% above ideal body weight) and in 10 normal subjects matched for age, sex, and pubertal development. Baseline plasma beta LPH and beta EP concentrations in both obese children and adolescents were twice as high as those in normal controls, while cortisol levels were not different. Cortisol, beta EP, and beta LPH levels had a clear circadian rhythmicity in all subjects, with the exception of obese pubertal boys whose plasma beta EP concentrations were constant throughout the day. After insulin administration, the fall in blood sugar was similar in all groups. Plasma cortisol and beta EP responses were similar in both obese and normal prepubertal subjects. In obese pubertal adolescents, beta EP did not increase significantly after hypoglycemia, although it did increase in normal weight pubertal subjects. In normal prepubertal subjects, the circadian rhythms of beta EP and beta LPH secretion and release induced by hypoglycemia suggest the presence of a well developed neuroendocrine control of proopiomelanocortin-related peptide secretion. In prepubertal obese children, the increased plasma beta EP and beta LPH levels with the maintenance of their circadian rhythm and responsivity to hypoglycemia suggest overactivity of anterior pituitary secretion. In obese adolescents, in spite of the normal rhythm of beta LPH and cortisol, beta EP levels did not change throughout the day, thus suggesting beta EP secretion from nonpituitary sources in these subjects. The present study indicates a possible direct role for hyperendorphinemia in the induction of overeating in obese children and adolescents.

9) Immunoreactive beta-endorphin increases after i.v. glucose in obese human subjects. Getto CJ, Swift WJ, Carlson IH, Fullerton DT, Brain Res Bull 1986 Sep;17(3):435-437

The plasma beta-endorphin of obese human subjects and non-obese controls was compared following the intravenous infusion of 25 grams of glucose. The plasma beta-endorphin of the obese subjects was significantly higher than controls one hour and four and one half hours after glucose infusion. The increased beta-endorphin of the obese subjects was associated with falling blood sugar.

10) Continuous sucrose feeding decreases pain threshold and increases morphine potency. Roane DS, Martin RJ, Pharmacol Biochem Behav 1990 Jan;35(1):225-229

Although an opioid-mediated mechanism appears to be involved in the alteration of pain perception during feeding behavior, little is known about macronutrient effects on nociception. In this report we show that prolonged sucrose feeding alters responsiveness to painful stimuli and the analgesic potency of morphine. Male Sprague-Dawley rats maintained on ad lib laboratory chow with continuous access to a 20% sucrose solution displayed a significant decrease in tail-flick latency as early as 20 hours after introduction of the sucrose. The differences in pain threshold were naloxone sensitive. After 25 days on the diet, morphine sulfate, 8 mg/kg administered IP, proved to be significantly more potent in the sucrose-fed animals. The results indicate that sucrose feeding alters endogenous opioid-mediated nociception.

Diabetes control and complications. Crofford OB, Annu Rev Med 1995;46:267-279

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive treatment of patients with insulin-dependent diabetes mellitus (IDDM) can substantially reduce the onset and progression of diabetic retinopathy, nephropathy, and neuropathy. The major risk associated with intensive treatment is recurrent hypoglycemia. Implementation of intensive treatment recommendations is difficult but should be considered and probably recommended to most patients with IDDM. If intensive treatment is impractical, any improvement in glycemic control is probably beneficial. Improved glycemic control should be recommended to most patients with non-insulin-dependent diabetes mellitus (NIDDM). The use of insulin in patients with NIDDM is controversial, especially in patients who are overweight, overeating, and minimally symptomatic.

Intensive insulin therapy in insulin-dependent diabetes mellitus, the results of the diabetes control and complications trial. Duron F, Biomed Pharmacother 1995;49(6):278-282

Long term complications are the first causes of mortality and morbidity in diabetic patients. In Europe, many diabetologists speculated for a long time that a tight blood glucose control was the best way to avoid these complications, but without any complete evidence. In 1993, the results of the Diabetes Control and Complications Trial (DCCT), the first controlled, randomized, long term trial designed to study the link between metabolic control and complications in a large cohort of patients, has confirmed this hypothesis: in insulin-dependent diabetes mellitus, intensive insulin-therapy, as compared with conventional therapy, significantly reduces the risk of developing microvascular and neuropathic complications. Nevertheless, in some patients, the risk of hypoglycemia may outweight the benefit of intensive insulin therapy, and the results of the DCCT raises some questions about indications, the risk/benefit ratio and the cost/benefit ratio of intensive treatment.

Macrovascular disease and hyperinsulinaemia. Robertson DA, Hale PJ, Nattrass M,Baillieres Clin Endocrinol Metab 1988 May;2(2):407-424

The evidence that hyperinsulinaemia represents an independent risk factor for cardiovascular disease is tantalizing ... The case for attempting to achieve normoglycaemia in diabetes to avoid microvascular complications is strong, and current insulin treatment regimens accept peripheral hyperinsulinaemia as a consequence of achieving portal insulin concentrations sufficient to suppress hepatic glucose output. It is hard to envisage a trial to examine reduced peripheral insulin concentrations which would not give unacceptably poor blood glucose control ..

Vitamins E plus C and interacting conutrients required for optimal health. A critical and constructive review of epidemiology and supplementation data regarding cardiovascular disease and cancer. Gey K, Biofactors 1998;7(1-2):113-174

Antioxidants are crucial components of fruit/vegetable rich diets preventing cardiovascular disease (CVD) and cancer: plasma vitamins C, E, carotenoids from diet correlate prevalence of CVD and cancer inversely, low levels predict an increased risk of individuals which is potentiated by combined inadequacy (e.g., vitamins C + E, C + carotene, A + carotene); self-prescribed rectification of vitamins C and E at adequacy of other micronutrients reduce forthcoming CVD, of vitamins A, C, E, carotene and conutrients also cancer; randomized exclusive supplementation of beta-carotene +/- vitamin A or E lack benefits except prostate cancer reduction by vitamin E, and overall cancer reduction by selenium; randomized intervention with synchronous rectification of vitamins A + C + E + B + minerals reduces CVD and counteracts precancerous lesions; high vitamin E supplements reveal potentials in secondary CVD prevention. Plasma values desirable for primary prevention: > or = 30 mumol/l lipid-standardized vitamin E (alpha-tocopherol/cholesterol > or = 5.0 mumol/mmol); > or = 50 mumol/l vitamin C aiming at vitamin C/vitamin E ratio > 1.3-1.5; > or = 0.4 mumol/l beta- (> or = 0.5 mumol/l alpha+ beta-) carotene. CONCLUSIONS: In CVD vitamin E acts as first risk discriminator, vitamin C as second one; optimal health requires synchronously optimized vitamins C + E, A, carotenoids and vegetable conutrients.

Serum ascorbic acid and cardiovascular disease prevalence in U.S. adults. Simon JA, Hudes ES, Browner WS, Epidemiology 1998 May;9(3):316-321

To examine the relation between serum ascorbic acid level and the prevalence of cardiovascular disease, we analyzed data from 6,624 U.S. men and women enrolled in the Second National Health and Nutrition Examination Survey. We calculated odds ratios and 95% confidence intervals to estimate the relative prevalence of cardiovascular disease, defined as self-reported coronary heart disease or stroke, or a diagnosis of peripheral vascular disease based on physical examination. Serum ascorbic acid levels were independently associated with prevalence of coronary heart disease and stroke; a 0.5-mg per dl increase in serum ascorbic acid level was associated with an 11% reduction in coronary heart disease and stroke prevalence. We also analyzed the relation of ascorbic acid, grouped into low to marginal, normal, and saturation serum categories, to cardiovascular disease. Compared with participants with low to marginally low serum ascorbic acid levels, we found a 27% decreased prevalence of coronary heart disease (95% confidence interval = 10-41%) and a 26% decreased prevalence of stroke (95% confidence interval = 3-44%) among participants in the highest serum ascorbic acid category. Serum ascorbic acid levels were not consistently associated with prevalence of peripheral vascular disease. These results are consistent with the hypothesis that increased ascorbic acid intake may decrease the risk of coronary heart disease and stroke.

Resistance to neuroglycopenia: an adaptive response during intensive insulin treatment of diabetes. Jones TW et al, J Clin Endocrinol Metab 1997 Jun;82(6):1713-1718

Counterregulation and awareness of hypoglycemia begins at lower plasma glucose levels in insulin-dependent diabetes mellitus (IDDM) subjects given intensive insulin treatment. To determine whether these changes are associated with an alteration in the susceptibility of the brain to mild hypoglycemia, we compared central nervous system responses to hypoglycemia in 8 intensively treated (hemoglobin A1, 8.3 +/- 0.2%; normal, <8%) and 11 conventionally treated IDDM patients (hemoglobin A1, 14.6 +/- 1.3%) with those in 10 healthy subjects. Plasma glucose was lowered from approximately 4.6 mmol/L in 0.5-0.6 steps using the clamp technique. Glucose levels triggering hormonal responses and perception of hypoglycemic symptoms were significantly lower in intensively treated patients compared to their poorly controlled counterparts (P < 0.05), and hormonal responses were suppressed compared to those in healthy controls. Similarly directed changes occurred in the level of circulating glucose required to alter cortical evoked potentials during hypoglycemia. A greater reduction in plasma glucose was required to alter P300 event-related potentials in the intensively treated patients (2.2 mmol/L) compared to those in the conventionally treated and nondiabetic groups (approximately 3.5 and approximately 3.0 mmol/L, respectively). We conclude that intensively treated IDDM patients are resistant to changes in cortical evoked potentials induced by mild hypoglycemia. This may explain why intensively treated IDDM counterregulate and experience hypoglycemic symptoms at a lower glucose level than conventionally treated patients.

Inverse association of serum ascorbic acid level and blood pressure or rate of hypertension in male adults aged 30-39 years. Yoshioka M, Matsushita T, Chuman Y, Int J Vitam Nutr Res 1984;54(4):343-347

Correlation analyses between serum ascorbic acid and several risk factors of cerebro- and cardio-vascular diseases were performed on apparently healthy adults (194 persons) aged 30-39 in order to estimate possible functions of ascorbic acid in the prevention of the disease. Serum ascorbic acid had an inverse and the strongest association with systolic blood pressure among the risk factors including blood pressure, total cholesterol, triglyceride, gamma-GTP and obesity. The association was independent of the other variables tested. When the subjects were divided into three different serum ascorbic acid level groups, the prevalence of hypertension (140/90 mmHg and above) was decreased with an increase in the ascorbic acid level. The close relationship of serum ascorbic acid and blood pressure observed in the study suggests that ascorbic acid may have a preventive function against hypertension, or a low ascorbic acid status in hypertensives may promote the further development of arteriosclerosis by the lack of favorable effect of ascorbic acid on lipid metabolism and others.

Relation of serum ascorbic acid to serum lipids and lipoproteins in US adults. Simon JA, Hudes ES, J Am Coll Nutr 1998 Jun;17(3):250-255

OBJECTIVE: To examine the relation of serum ascorbic acid level to serum lipid and lipoprotein levels among a random sample of the US adult population. METHODS: Using linear regression, the relation of serum ascorbic acid level to serum lipid and lipoprotein levels was examined among 5,412 women and 5,116 men enrolled in the Second National Health and Nutrition Examination Survey (NHANES II), 1976-1980. Age, race, body mass index, level of physical activity, level of education, alcohol intake, and dietary energy, cholesterol, and fat intakes, and other potential confounders were included in the multivariate models. RESULTS: Serum ascorbic acid level was independently associated with high-density lipoprotein cholesterol (HDL-C) among women; each 1 mg/dl increase in serum ascorbic acid level (range 0.1 to 2.7 mg/dl) was associated with a 2 mg/dl increase in HDL-C level (p = 0.001). Because other investigators have demonstrated an inverse relation between ascorbic acid intake or blood levels and total serum cholesterol in individuals with elevated total serum cholesterol levels, we analyzed four subgroups of NHANES II participants with total serum cholesterol levels > 200 mg/dl. Among women with total serum cholesterol levels > or = 200 mg/dl, each 1 mg/dl increase in serum ascorbic acid level was independently associated with an increase of 2 to 3 mg/dl in HDL-C level (p < or = 0.05). Serum ascorbic acid level was not significantly associated with other serum lipids or lipoproteins. CONCLUSIONS: If the observed associations are linked causally, they would suggest that ascorbic acid is a factor in cholesterol homeostasis among women and may be particularly important for women at increased risk for coronary heart disease.

Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Purnell JQ et al, JAMA 1998 Jul 8;280(2):140-146

CONTEXT: Intensive treatment of type 1 diabetes results in greater weight gain than conventional treatment. OBJECTIVE: To determine the effect of this weight gain on lipid levels and blood pressure. DESIGN: Randomized controlled trial; ancillary study of the Diabetes Control and Complications Trial (DCCT). SETTING: Twenty-one clinical centers. PARTICIPANTS: The 1168 subjects enrolled in DCCT with type 1 diabetes who were aged 18 years or older at baseline. INTERVENTION: Randomized to receive either intensive (n = 586) or conventional (n = 582) diabetes treatment with a mean follow-up of 6.1 years. MAIN OUTCOME MEASURES: Plasma lipid levels and blood pressure in each treatment group categorized by quartile of weight gain. RESULTS: With intensive treatment, subjects in the fourth quartile of weight gain had the highest body mass index (BMI) (a measure of weight adjusted for height), blood pressure, and levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B compared with the other weight gain quartiles with the greatest difference seen when compared with the first quartile (mean values for the highest and lowest quartiles: BMI, 31 vs 24 kg/m2; blood pressure, 120/77 mm Hg vs 113/73 mm Hg; triglyceride, 0.99 mmol/L vs 0.79 mmol/L [88 mg/dL vs 70 mg/dL]; LDL-C, 3.15 mmol/L vs 2.74 mmol/L [122 mg/dL vs 106 mg/dL]; and apolipoprotein B, 0.89 g/L vs 0.78 g/L; all P<.001). In addition, the fourth quartile group had a higher waist-to-hip ratio; more cholesterol in the very low density lipoprotein, intermediate dense lipoprotein, and dense LDL fractions; and lower high-density lipoprotein cholesterol and apolipoprotein A-I levels compared with the first quartile. Baseline characteristics were not different between the first and fourth quartiles of weight gain with intensive therapy except for a higher hemoglobin A1c in the fourth quartile. Weight gain with conventional therapy resulted in smaller increases in BMI, lipids, and systolic blood pressure. CONCLUSIONS: The changes in lipid levels and blood pressure that occur with excessive weight gain with intensive therapy are similar to those seen in the insulin resistance syndrome and may increase the risk of coronary artery disease in this subset of subjects with time.

Effects of feeding rats sucrose in a high fat diet. Hallfrisch J et al, J Nutr 1981 Mar;111(3):531-536

Rats were fed ad libitum a 40% fat diet containing either 30% sucrose or 30% starch by weight for 8-9 weeks. Insulin levels during a meal tolerance test were significantly greater in rats fed sucrose than in rats fed starch, but serum glucose levels were not affected by diet and tended to decrease as time after the meal increased. Insulin levels during an oral glucose tolerance test were significantly greater in the rats fed sucrose. Serum glucose levels were not affected by diet. Body weights and epididymal and perirenal fat pad weights were higher in rats fed sucrose than in rats fed starch. Serum triglyceride and cholesterol levels were not different. These results show that relatively low sucrose levels in a high fat diet can produce higher insulin levels than starch before and after either a glucose load or a meal. This relative insulin resistance is symptomatic of onset diabetes.

Dietary Fat Intake and the Risk of Coronary Heart Disease in Women. Frank B et al, New England J Medicine, N Engl J Med 1997;337:1491-9

Conclusions. Our findings suggest that replacing saturated and trans unsaturated fats with unhydrogenated monounsaturated and polyunsaturated fats is more effective in preventing coronary heart disease in women than reducing overall fat intake. Background. The relation between dietary intake of specific types of fat, particularly trans unsaturated fat, and the risk of coronary disease remains unclear. We therefore studied this relation in women enrolled in the Nurses' Health Study. Methods. We prospectively studied 80,082 women who were 34 to 59 years of age and had no known coronary disease, stroke, cancer, hypercholesterolemia, or diabetes in 1980. Information on diet was obtained at base line and updated during follow-up by means of validated questionnaires. During 14 years of follow-up, we documented 939 cases of nonfatal myocardial infarction or death from coronary heart disease. Multivariate analyses included age, smoking status, total energy intake, dietary cholesterol intake, percentages of energy obtained from protein and specific types of fat, and other risk factors. Results. Each increase of 5 percent of energy intake from saturated fat, as compared with equivalent energy intake from carbohydrates, was associated with a 17 percent increase in the risk of coronary disease (relative risk, 1.17; 95 percent confidence interval, 0.97 to 1.41; P = 0.10). As compared with equivalent energy from carbohydrates, the relative risk for a 2 percent increment in energy intake from trans unsaturated fat was 1.93 (95 percent confidence interval, 1.43 to 2.61; P<0.001); that for a 5 percent increment in energy from monounsaturated fat was 0.81 (95 percent confidence interval, 0.65 to 1.00; P = 0.05); and that for a 5 percent increment in energy from polyunsaturated fat was 0.62 (95 percent confidence interval, 0.46 to 0.85; P = 0.003). Total fat intake was not significantly related to the risk of coronary disease (for a 5 percent increase in energy from fat, the relative risk was 1.02; 95 percent confidence interval, 0.97 to 1.07; P = 0.55). We estimated that the replacement of 5 percent of energy from saturated fat with energy from unsaturated fats would reduce risk by 42 percent (95 percent confidence interval, 23 to 56; P<0.001) and that the replacement of 2 percent of energy from trans fat with energy from unhydrogenated, unsaturated fats would reduce risk by 53 percent (95 percent confidence interval, 34 to 67; P<0.001).

Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus. Cohen N et al, J Clin Invest 1995 Jun;95(6):2501-2509

We examined the in vivo metabolic effects of vanadyl sulfate (VS) in non-insulin-dependent diabetes mellitus (NIDDM). Six NIDDM subjects treated with diet and/or sulfonylureas were examined at the end of three consecutive periods: placebo for 2 wk, VS (100 mg/d) for 3 wk, and placebo for 2 wk. Euglycemic hyperinsulinemic (30 mU/m2.min) clamps and oral glucose tolerance tests were performed at the end of each study period. Glycemic control at baseline was poor (fasting plasma glucose 210 +/- 19 mg/dl; HbA1c 9.6 +/- 0.6%) and improved after treatment (181 +/- 14 mg/dl [P < 0.05], 8.8 +/- 0.6%, [P < 0.002]); fasting and post-glucose tolerance test plasma insulin concentrations were unchanged. After VS, the glucose infusion rate during the clamp was increased (by approximately 88%, from 1.80 to 3.38 mg/kg.min, P < 0.0001). This improvement was due to both enhanced insulin-mediated stimulation of glucose uptake (rate of glucose disposal [Rd], +0.89 mg/kg.min) and increased inhibition of HGP (-0.74 mg/kg.min) (P < 0.0001 for both). Increased insulin-stimulated glycogen synthesis (+0.74 mg/kg.min, P < 0.0003) accounted for > 80% of the increased Rd after VS, and the improvement in insulin sensitivity was maintained after the second placebo period. The Km of skeletal muscle glycogen synthase was lowered by approximately 30% after VS treatment (P < 0.05). These results indicate that 3 wk of treatment with VS improves hepatic and peripheral insulin sensitivity in insulin-resistant NIDDM humans. These effects were sustained for up to 2 wk after discontinuation of VS.

Selenium status, fatty acids, vitamins A and E, and aging: the Nove study. Oliviero O, et al. Am J Clin Nutr 1994 60:510-517

"The results show that in a well nourished population living in an economically developed region, aging is associated with a reduction in selenium and glutathione peroxidase activity, and with a progressively decreasing plasma and erythrocyte ratio of polyunsaturated to saturated fatty acids." Abstract: This study investigated the relationship between age and selenium status, vitamins A, E, and plasma and erythrocyte fatty acids. One hundred five healthy subjects were studied (53 women, 52 men), and were broken into 4 groups: group 1: 20-39y (26 subjects); group 2: 40-59y (26 subjects); group 3: 60-75y (28 subjects); and group 4: >75y (25 subjects). The results demonstrate that the bioavailability of selenium is influenced by aging, together with polyunsaturated fatty acids and antioxidant vitamin A. The activity of the free radical scavenger selenium-dependent glutathione peroxidase (GSH-Px) appears to be modulated by the membrane oleic acid, which is a less susceptible substrate for the lipoperoxidative process that are polyunsaturated fatty acids. The most important metabolic role of selenium is its function in the active site of selenoenzyme GSH-Px. This enzyme, together with superoxide dismutase, protects cells against damage caused by free radicals and hydro- or lipoperoxides. An increased concentration of lipoperoxides has been observed in elderly people by several investigators, supporting the view that accumulation of cell oxidative damage is of pathogenic relevance in the aging process.

Oxidative damage and defense. Jacob RA, et al. Am J Clin Nutr 1996 Jun 63(6):985S-990S

"Dietary antioxidants may be especially important in protecting against human diseases associated with free radical damage to cellular DNA, lipids and proteins. Present data suggest that protection against oxidative damage and related disease is best served by a variety of antioxidant substances."

Abstract: Increased production of reactive oxygen species is a feature of most, if not all, human disease, including cardiovascular disease and cancer. Dietary antioxidants may be especially important in protecting against human diseases associated with free radical damage to cellular DNA, lipids and proteins. Vitamin C is an effective water-soluble antioxidant, and epidemiologic studies suggest that increased vitamin C nutriture is associated with reduced risk of some degenerative diseases, especially cancer and cataracts. Population studies have also shown that high vitamin E intakes are associated with decreased risk of coronary heart disease, possibly as a result of inhibition of atherogenic forms of oxidized low-density lipoprotein. Recent data suggest that beta carotene provides protection against lipid peroxidation in humans, as well as pro-vitamin A activity.

Effects of vitamin B12, folate and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Naurath HJ, et al. Lancet 1995 Jul 8 346:85-89

"Vitamin supplements of B6, folate and B12 lowered homocysteine in an elderly population with normal serum vitamin levels."

Abstract: In a prospective, multicentre, double-blind controlled study, the effect of an intramuscular vitamin supplement containing 1 mg of vitamin B12, 1.1 mg of folate, and 5 mg of vitamin B6 on serum concentrations of methylmalonic acid, homocysteine, 2-methylcitric acid, and cystathione was compared with that of placebo in 175 elderly subjects living at home and 110 in a hospital. Vitamin supplement and placebo were administered 8 times over a 3-week period. Vitamin supplement but not placebo significantly reduced all four metabolite concentrations at the end of the study in both study groups. The maximum effects of treatment were usually seen within 5-12 days. Initially elevated metabolite concentrations returned to normal in a higher proportion of the vitamin than of the placebo group: 92% vs 20% for homocysteine; 82% vs 20% for methylmalonic acid; 62% vs 25% for 2-methylcitric acid; and 42% vs 25% for cystathione.

... and ...

Prevalence of cobalamin (B12) deficiency in the Framingham elderly population. Lindenbaum J, et al. Am J Clin Nutr 1994 60:2-11

Abstract: To determine whether the increased prevalence of low serum B12 concentrations in elderly people represents true deficiency, serum concentrations of B12 and folate and of metabolites that are sensitive indicators of B12 deficiency were measured in 548 surviving members of the original Framingham Study cohort. Serum B12 concentrations <258 pmol/L were found in 222 subjects (40.5%) compared with 17.9% of younger control subjects (P<0.001). Serum methylmalonic acid and total homocysteine concentrations were markedly elevated in association with B12 values <258 pmol/L in 11.3% and 5.7%, respectively, of the cohort. Both metabolites were increased in 3.8% of the cohort, associated with significantly lower erythrocyte counts and higher mean cell volumes. Serum metabolites correlated best with serum B12 values, even when subnormal determinations were excluded.

"The prevalence of B12 deficiency was > 12% in a large sample of free-living elderly Americans. Many elderly people with "normal" serum vitamin concentrations are metabolically deficient in B12 or folate."

Oxidative damage to DNA in diabetes mellitus. Dandona P, et al. Lancet 1996 Feb 17 347:444-445

Abstract: Increased production of reactive oxygen species and lipid peroxidation may contribute to vascular complications in diabetes. To test whether DNA is also oxidatively damaged in diabetes, 8-hydroxydeoxyguanosine (8-OHdG) was measured, an indicator of oxidative damage of DNA in mononuclear cells. Insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) patients had significantly higher median concentrations (p<0.001, U test) of 8-OHdG in their mononuclear cells and their corresponding controls (in fmol/mg DNA): 128.2 (interquartile range 96.0-223.2) and 95.2 (64.0-133.5) vs 28.2 (21.7-43.4) and 21.9 (18.0-24.0), respectively. Reactive oxygen species generation by mononuclear cells was also significantly greater (p<0.01) in diabetic patients than in their controls (in mV): 238.0 (107.0-243.0) and 101.3 (66.0-134.0) vs 69.5 (49.8-91.9) and 56.0 (38.8-62.5), respectively. 

"IDDM and NIDDM patients showed greater oxidative damage to DNA, with increased generation of reactive oxygen species than controls. Such changes may contribute to accelerated aging and atherogenesis in diabetes, and to the micro and macro-angiopathic complications of the disease. Treatment with antioxidants may prevent or reverse abnormalities associated with diabetes mellitus."

Vitamin C: An aldose reductase inhibitor that normalizes erythrocyte sorbitol in insulin-dependent diabetes mellitus. Cunningham JJ, et al. J Amer Coll Nutr 1994 13:344-350

"Vitamin C supplementation is effective in reducing sorbitol accumulation in the erythrocytes of diabetics. Given its tissue distribution and low toxicity, the investigators suggest a superiority for vitamin C over pharmaceutic Aldose Reductase Inhibitorss. "

Abstract: Diabetic hyperglycemia promotes sorbitol production from glucose via aldose reductase. Since the intracellular accumulation of sorbitol are postulated to contribute to the progression of chronic diabetes complications, aldose reductase inhibitors (ARI) offer therapeutic promise. Others have shown that vitamin C at pharmacological doses decreases erythrocyte (RBC) sorbitol; this study examined whether smaller, physiologic doses of vitamin C were also effective in individuals with insulin-dependent diabetes mellitus (IDDM) and whether vitamin C was an ARI in vitro. Vitamin C supplements (100 mg or 600 mg) were taken for 58 days by young adults with IDDM and non-diabetic adults in an otherwise free-living design. Diabetic control was monitored by fasting plasma glucose, glycosylated hemoglobin and glycosuria, and was moderate to poor throughout the study. RBC sorbitol was measured at baseline and again at 30 and 58 days. Three-day dietary records and 24-hour urine collections were performed for each sampling day. RBC sorbitol levels were significantly elevated in the IDDM adults, on average doubled despite their more than adequate dietary intakes of vitamin C and normal plasma concentrations. Within 30 days, vitamin C supplementation at either dose normalized the RBC sorbitol in the IDDM adults. This correction of sorbitol accumulation was independent of changes in diabetic control. Furthermore, the in vitro studies show that vitamin C inhibited aldose reductase activity.

Carotenoids, vitamins C and E, and mortality in an elderly population. Sahyoun NR, et al. Am J Epidemiol 1996 Sep 1 144(5):501-511

"In conclusion, the results indicate that high intakes of vitamin C and frequent consumption of vegetables may be protective against early mortality and mortality from heart disease."

Abstract: In 1981-1984 the nutritional status of 747 non-institutionalized Massachusetts residents aged 60 years and over was assessed. Nine to 12 years later, the vital status of these subjects was determined. The data of a subset of 725 community-dwelling volunteers was used to examine associations between mortality and the nutrient antioxidants: carotenoids, vitamin C and vitamin E, in plasma, diet and supplements. Results indicate that subjects with plasma vitamin C levels in the middle and high quintiles had a lower overall mortality (relative risk = 0.64, 95% confidence interval 0.44-0.94 and relative risk = 0.54, 95% confidence interval 0.32-0.90, respectively), than those in the lowest quintile even after adjustment for potential confounders. These associations were largely due to reduced mortality from heart disease. Subjects in the highest quintile of total intake of vitamin C also had a significantly lower risk of overall mortality (relative risk = 0.55, 95% confidence interval 0.32-0.93) and mortality from heart disease (relative risk = 0.38, 95% confidence interval 0.19-0.75) than did those in the lowest quintile after potential confounders were controlled for. Intake of vegetables was inversely associated with overall mortality (p for trend = 0.003) and mortality from heart disease (p for trend = 0.04).

Cognitive function in an elderly population with persistent impaired glucose tolerance. Vanhanen M et al, Diabetes Care 1998 Mar;21(3):398-402

CONCLUSIONS: Our study showed that persistent IGT in the elderly is associated with mildly impaired cognitive function, and hyperinsulinemia may account for this association. OBJECTIVE: To study cognitive function in an elderly population with persistent impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Fasting and postload 2-h plasma glucose and insulin levels were determined at baseline in a population-based sample of 1,300 people and repeated an average of 3.5 years later in 980 subjects. At follow-up, cognitive function was evaluated in subjects with persistent normal glucose tolerance (NGT; n = 506) and IGT (n = 80) with a brief neuropsychological test battery. RESULTS: Subjects with persistent IGT scored lower in the Mini-Mental State Examination (MMSE) and in the Buschke Selective Reminding Test long-term memory scores. Multiple linear regression analysis revealed that age, education, and insulin levels (either fasting or 2-h value) were associated with the MMSE score in subjects with persistent IGT. Other potential risk factors for impaired cognitive function were not significantly associated with the MMSE score.

Effect of isocaloric substitution of chocolate cake for potato in type I diabetic patients. Peters AL et al, Diabetes Care 1990 Aug;13(8):888-892

Traditional dietary advice given to people with diabetes includes eliminating simple sugars (primarily sucrose) from the diet. Many people have difficulty following this recommendation. Because patients with type I (insulin-dependent) diabetes do not need overall calorie restriction, there is no caloric reason to restrict sucrose. In this study, we looked at the effect of the isocaloric substitution of a piece of chocolate cake for a baked potato in a mixed meal to determine whether this would increase the blood glucose in patients with type I diabetes. The glucose response to a cake-added meal was significantly greater than to a standard meal. The glucose response was no different between a cake-substitution meal and a standard meal. The reproducibility studies showed no difference between repeated standard meals. The urinary glucose excretion was significantly greater after a cake-added meal but was no different with the other pairs. There were no significant differences in the counterregulatory hormone responses at baseline between any of the paired studies. In conclusion, patients with type I diabetes may substitute a sucrose-containing dessert for another carbohydrate in their diet without compromising their postprandial glucose response. These data suggest that a dessert exchange may be helpful and not harmful in the management of diabetic patients. There is an inherent variability (at least 16%) in an insulin-requiring patient's response to a meal, making self-monitoring of blood glucose and adjustment of insulin doses necessary to achieve near euglycemia.

Urinary chromium excretion and insulinogenic properties of carbohydrates. Anderson RA et al, Am J Clin Nutr 1990 May;51(5):864-868

Eleven male and nine female adult subjects were given one of the following five carbohydrate-drink combinations (per kg body wt) on five mornings separated by greater than or equal to 2 wk: 1) 1.0 g glucose, 2) 0.9 g uncooked cornstarch, 3) 1.0 g glucose followed 20 min later by 1.75 g fructose, 4) 0.9 g uncooked cornstarch followed 20 min later by 1.75 g fructose, and 5) water followed 20 min later by 1.75 g fructose. Glucose plus fructose was the most insulinogenic followed by glucose alone, starch plus fructose, starch alone, and water plus fructose. The urinary losses of chromium followed a similar pattern. Subjects with the highest concentrations of circulating insulin displayed decreased ability to mobilize chromium on the basis of urinary chromium excretion. Therefore, urinary chromium losses are related to the insulinogenic properties of carbohydrates. And ....

Effects of diets high in simple sugars on urinary chromium losses. Kozlovsky AS et al, Metabolism 1986 Jun;35(6):515-518

Thirty-seven subjects, 19 men and 18 women, consumed reference diets for 12 weeks formulated by nutritionists to contain optimal levels of protein, fat, carbohydrate, and other nutrients; the following 6 weeks, subjects consumed high sugar diets. The reference diets contained 35% of total calories from complex carbohydrates and 15% from simple sugars while the high sugar diets contained 15% complex carbohydrates and 35% simple sugars. Chromium contents of the reference and high sugar diets were both approximately 16 micrograms per 1000 calories. Compared to the reference diets, consumption of the high sugar diets increased urinary Cr losses from 10% to 300% for 27 of 37 subjects. Urinary Cr excretion of males and females was similar, and there was no significant difference in Cr absorption (calculated from urinary excretion divided by intake times 100) between sexes when adjusted for the increased caloric intake of males. These data demonstrate that consumption of diets high in simple sugars stimulates Cr losses; this coupled with marginal intake of dietary Cr may lead to marginal Cr deficiency, which is associated with impaired glucose and lipid metabolism.

Serum uric acid, inorganic phosphorus, and glutamic-oxalacetic transaminase and blood pressure in carbohydrate-sensitive adults consuming three different levels of sucrose. Israel KD, Michaelis OE 4th, Reiser S, Keeney M Ann Nutr Metab 1983;27(5):425-435

12 men and 12 women, classified as carbohydrate-sensitive on the basis of an exaggerated insulin response to a sucrose load, consumed diets containing either 5, 18, or 33% sucrose in a crossover design. The diets simulated the average American diet and consisted of identical natural and processed foods with the exception of a patty. The patty provided the experimental levels of sucrose; the difference was made up by starch. Each level of sucrose was consumed for a 6-week period. Subject body weights were maintained. Fasting serum uric acid and inorganic phosphorus increased as the level of dietary sucrose increased. Diastolic blood pressure was significantly higher when subjects were on the 33% sucrose diet as compared to the 5 and 18% diets. Serum glutamic-oxalacetic transaminase was not affected by diet. In tolerance tests after a sucrose load (2 g/kg body weight), the uric acid response was higher after the 18 and 33% sucrose diets than after the 5% sucrose diet. Serum inorganic phosphorus, which increased significantly with each level of dietary sucrose, decreased following the sucrose load. These results indicate that carbohydrate-sensitive individuals may be affected adversely by the level of sucrose commonly found in the Westernized diet. Since elevated serum uric acid and blood pressure have been identified as risk factors in degenerative diseases, this study suggests that carbohydrate-sensitive individuals should limit their sucrose consumption.

Effects of sugars on indices of glucose tolerance in humans. Reiser S et al, Am J Clin Nutr 1986 Jan;43(1):151-159

Ten men and nine women were studied to determine whether replacement of utilizable complex carbohydrate by sugars (mono- and disaccharides) in a high-fiber, low-saturated fat diet would affect indices of glucose tolerance. Diets differed in that the 50% of calories derived from carbohydrate was either 35% complex and 15% sugars (low-sugar) on 15% complex and 35% sugars (high-sugar). Summation of glucose responses 30-180 min following an oral glucose tolerance test was significantly higher in men, but not women, after they consumed the high-sugar diet. Corresponding insulin responses were significantly higher in men consuming the high-sugar compared to the low-sugar diet. Insulin binding was significantly lower during the base line period and after the high-sugar diet compared to the low-sugar diet. Results indicate that sugars adversely affect indices of glucose tolerance when they replace complex carbohydrates even in a high-fiber, low-saturated fat diet. And ...

Effect of dietary sugars on metabolic risk factors associated with heart disease. Reiser S, Nutr Health 1985;3(4):203-216

The results from studies in which the effects of the extended feeding of sugars such as sucrose and fructose as compared to starch and other glucose-based carbohydrates on metabolic risk factors associated with heart disease have been reviewed. In general, the feeding of the sugars as compared to starch produced undesirable changes in metabolic risk factors such as blood triglycerides, total cholesterol and its lipoprotein distribution, insulin and uric acid. Other dietary components (e.g., saturated fat) can magnify the adverse metabolic effects of the sugars. A finite segment of the population characterized by high levels of triglycerides and insulin may be at a substantially higher risk than is the general population from the present level of intake of sucrose or fructose.

Diabetes mellitus, hypertension and ageing: the ionic hypothesis of ageing and cardiovascular-metabolic diseases. Barbagallo M, Resnick LM et al, Diabetes Metab 1997 Sep;23(4):281-294

Ageing in industrialised societies is associated with an increasing prevalence of hypertension, atherosclerotic vascular diseases, reduced insulin sensitivity and non-insulin-dependent diabetes mellitus (NIDDM). It has been suggested that hyperinsulinaemia/insulin resistance and/or hyperglycaemia could play a role in determining and/or exacerbating the hypertension and vascular disease associated with diabetes mellitus and ageing. Insulin-resistant states, such as essential hypertension and NIDDM, as well as "normal" ageing, are characterised by similar intracellular ionic defects, i.e. accumulation of cytosolic free calcium and depletion of free magnesium. The importance of calcium and magnesium ions in regulating cell functions is well-known. A rise in cellular free calcium and a depletion in cellular magnesium may induce cellular insulin resistance and vasoconstriction. Ionic levels quantitatively predict the extent of elevated blood pressure, fasting blood glucose, HBA1c and hyperinsulinaemic response to oral glucose challenge. We suggest that ionic disturbance might be the missing link responsible for the frequent clinical coexistence of hypertension, atherosclerosis and metabolic disorders. Ageing cells may become more vulnerable to ion disturbances, leading to possible elevation of intracellular free calcium and concurrent magnesium depletion. The "ionic hypothesis" of ageing supposes that an alteration in the cellular mechanisms which maintain the homeostasis of cytosolic calcium concentrations may play a key role in the ageing process, and that a sustained accumulation of cellular calcium and/or the depletion of cellular magnesium may also provide the final common pathway for many ageing-associated diseases, including hypertension and NIDDM.

Insulin resistance vs. hyperinsulinemia in hypertension: insulin regulation of Ca2+ transport and Ca(2+)-regulation of insulin sensitivity. Zemel MB, J Nutr 1995 Jun;125(6 Suppl):1738S-1743S

Hypertension in obesity and insulin resistance has been attributed to insulin stimulation of sympathetic neural output and renal sodium retention. However, recent data demonstrates a significant vasodilatory effect of insulin and suggests that vascular smooth muscle resistance to this action may instead be the cause of hypertension in insulin resistance. This concept is supported by the observation that pharmacological amplification of peripheral insulin sensitivity results in reduced arterial pressure. Insulin attenuates vasoconstrictor responses to pressor agonists and accelerates vascular smooth muscle relaxation, while these effects are blunted in obesity and insulin resistance. Insulin regulation of vasoconstriction and vascular relaxation appears to be secondary to regulation of intracellular Ca2+ ([Ca2+]i), as insulin attenuates both voltage- and receptor-mediated Ca2+ influx and stimulates both the transcription and activity of Ca(2+)-ATPase in vascular smooth muscle cells. Further, these effects are also blunted in insulin resistance. Although [Ca2+]i plays a poorly understood role in insulin signalling, increases beyond an optimal range results in impaired insulin sensitivity, possibly by Ca(2+)-inhibition of insulin-induced dephosphorylation of insulin-sensitive substrates. Consistent with this concept, ectopic overexpression of the agouti gene in the viable yellow (Avy) mouse results in increased skeletal myocyte [Ca2+]i. Accordingly, increased [Ca2+]i in primary insulin target tissues appears to result in peripheral insulin resistance which then results in aberrant regulation of vascular smooth muscle [Ca2+]i and increases in arterial pressure.

Cytosolic calcium and insulin resistance. Draznin B, Am J Kidney Dis 1993 Jun;21(6 Suppl 3):32-38

The presence of insulin resistance in many patients with hypertension has become a well-recognized phenomenon. However, the mechanism of this association remains enigmatic. We have hypothesized that abnormal cellular calcium handling, particularly elevations in cytosolic free calcium concentrations, may represent a common intracellular abnormality (a missing link) that is responsible for the frequent co-existence of insulin resistance and hypertension. We have shown recently that sustained elevations of cytosolic free calcium in insulin target cells, such as are observed in patients with obesity and non-insulin-dependent diabetes mellitus and in some patients with hypertension, may lead to the development of insulin resistance. Although the mechanisms that lead to such increases are not yet well understood, they appear to include an enhanced influx of calcium via calcium channels. We found that the presence of the calcium antagonist nitrendipine in the incubation medium prevented increases in cytosolic free calcium concentration and ameliorated the insulin resistance induced by various mechanisms. To further evaluate the existence of an association between elevated levels of cytosolic calcium and diminished cellular sensitivity to insulin in patients with essential hypertension, we studied insulin sensitivity in vivo and in vitro in isolated adipocytes from older hypertensive, nondiabetic subjects. Obese hypertensive individuals demonstrated marked hyperinsulinemia and significantly reduced submaximally stimulated adipocyte 2-deoxyglucose uptake. One month of therapy with nitrendipine (10 mg twice daily) reduced blood pressure in hypertensive subjects, reduced plasma insulin to control values in obese hypertensive individuals, and restored adipocyte 2-deoxyglucose uptake at at submaximally effective insulin concentrations to control values in both obese hypertensive subjects and those of normal weight.

Ionic basis of hypertension, insulin resistance, vascular disease, and related disorders. The mechanism of "syndrome X". Resnick LM. Am J Hypertens 1993 Apr;6(4):123S-134S

Great pathophysiological significance has recently been placed on the association of metabolic abnormalities, such as hyperinsulinemia, insulin resistance, obesity, and frank diabetes mellitus, with essential hypertension and coronary artery disease, and the clinical coincidence of these features has been termed "syndrome X." Despite the suggestion that insulin itself mediates this clinical linkage, the specific mechanisms underlying this syndrome remain poorly understood. We have attempted to understand these phenomena at the cellular level, and have investigated the role of cellular mineral ion species such as cytosolic free calcium (Cai), free magnesium (Mgi), and intracellular pH (pHi) in various insulin resistant states, including essential hypertension, obesity, and type II (non-insulin-dependent) diabetes mellitus (NIDDM). Utilizing nuclear magnetic resonance spectroscopic techniques to noninvasively assess intracellular concentrations of these ions, we observed that each of these disease states is characterized, in whole or in part, by common abnormalities of cellular ion metabolism, including elevated Cai levels and suppressed levels of Mgi and pHi. Furthermore, despite the predominant use of red cells as a tissue source, the measured levels of Cai, Mgi, and pHi were closely related to the ambient blood pressure, the degree of cardiac hypertrophy, and to the hyperinsulinemic response to oral glucose challenge. Altogether, these data suggest an integrated "ionic hypothesis" in which the frequent clinical coexistence of hypertension and altered insulin metabolism derives from common abnormalities of cellular ion handling, resulting in excess steady-state levels of Cai, reciprocal depletion of Mgi, and lowered pHi. These cellular ion alterations would be expected to have tissue-specific consequences, appearing in vascular tissue as vasoconstriction and elevated blood pressure, in skeletal muscle and fat as insulin resistance, in pancreatic beta-cells as hyperinsulinemia, and in neural tissue as potentiated neurotransmitter release and increased sympathetic nerve activity. Thus, according to this hypothesis, essential hypertension, insulin resistance, hyperinsulinemia, and NIDDM are in reality different clinical components of what should be better designated as "generalized cardiovascular-metabolic disease" (GCMD).

The role of glucose in diabetic hypertension: effects on intracellular cation metabolism. Barbagallo M, Resnick LM, Am J Med Sci 1994 Feb;307 Suppl 1:S60-S65

The clinical association of hypertension, obesity, noninsulin-dependent diabetes mellitus (NIDDM), and other cardiovascular risk factors has long been recognized. The recent finding that essential hypertension is also an insulin-resistant state associated with hyperinsulinemia led some authors to attribute a role in mediating this association and in the pathogenesis of hypertension itself to insulin. However, evidence also exists independently of insulin per se that alterations in glucose metabolism in general, and of hyperglycemia in particular, may also contribute to the hypertensive process, especially in the hypertension of diabetes. The authors attempted to understand the relationship between glucose and insulin metabolism, diabetes, and hypertension from a cellular ionic point of view. In vitro it was shown that glucose, in a specific, dose- and time-dependent manner, can directly and coordinately alter intracellular ions, increasing cytosolic free calcium, while suppressing intracellular free magnesium and pH levels. These glucose-induced changes exactly parallel those ionic lesions previously observed in vivo in the fasting hyperglycemia of hypertension associated with NIDDM. These and other data led to the hypothesis that circulating blood glucose, independently of insulin and even at normal levels, is a physiologic determinant of cellular ion homeostasis. Furthermore, the cellular ionic consequences of hyperglycemia may contribute to the increased risk of hypertension and vascular diseases present among subjects with NIDDM, impaired glucose tolerance, or both.

The influence of refined carbohydrate on urinary calcium excretion. Thom JA et al, Br J Urol 1978 Dec;50(7):459-464

In the course of study of the influence of varying the amount of refined carbohydrate (sugar and sugar products) in an otherwise standardised diet in 18 normal subjects it was evident that the analysis of 24-h urine collections failed to show the profound diurnal variation in urinary electrolyte excretion and, in particular in this instance, calcium excretion. The analysis of individually voided specimens showed some normal subjects to have spontaneously high peaks of urinary calcium concentration throughout the day even whilst on a diet with low refined carbohydrate content. Increase in the refined carbohydrate content of the otherwise standardised diet caused significant increase in the number of urines with a calcium concentration above 9 mmol/1. Refined carbohydrate, a common cinstituent in Western diets, can therefore influence urinary electrolyte excretion in such a way that there may be an increased risk of over-saturation with calcium oxalate. And ...

Carbohydrate metabolism and urinary excretion of calcium and oxalate after ingestion of polyol sweeteners. Nguyen NU et al, J Clin Endocrinol Metab 1993 Aug;77(2):388-392

Polyols are widely used instead of glucose and sucrose in sweets and dietary products because they are barely cariogenic, and their energy value is lower. In addition, it has been shown that calciuria and oxaluria increase after an oral glucose (Glu) load. We, therefore, investigated the effects of a single polyol ingestion on carbohydrate, calcium, phosphate, and oxalate metabolism in 10 healthy subjects. On 5 experimental days, subjects ingested 20 g Glu, Lycasin (Lyc), Maltisorb (Mal), sorbitol (Sor), or xylitol (Xyl). Glu, Lyc, and Mal intake caused an increase in glycemia [respectively, +34% (P < 0.001), +15% (P < 0.001), and +15% (P < 0.001)], insulinemia [respectively, +358% (P < 0.001), +88% (P < 0.05), and +94% (P < 0.01)], and C-peptide level [respectively, +170% (P < 0.001), +15% (P < 0.01), and +15% (P < 0.001)]. Conversely, no change occurred in glycemia, insulinemia, or C-peptide levels after ingestion of Sor or Xyl. Urinary calcium increased after Glu (+64%; P < 0.01) and Xyl (+74%; P < 0.01) intake, and urinary phosphate increased after Xyl (+27%; P < 0.05), but decreased after a Glu load (-68%; P < 0.01). Only Xyl increased urinary excretion of oxalate (+53%; P < 0.05). Our results suggest that ingestion of polyols causes a much lesser pancreatic stimulation than Glu intake. Also, Lyc, Mal, and Sor sweeteners have no effect on urinary excretion of calcium and oxalate, whereas calciuria and oxaluria increase after Xyl ingestion.

Diabetes and accompanying obesity, hypertension and ECG abnormalities in Yemenite Jews 40 years after immigration to Israel. Cohen AM, Marom L, Diabetes Res 1993;23(2):65-74

Hadassah University Hospital, Jerusalem, Israel. A repeat survey in 1988-1989 on the prevalence of diabetes among Yemenites aged 30 years and over was 3.6% as compared to 2.9% in 1977-78 and 0.25% in 1958-59 soon after their immigration to Israel. In age and gender-matched ethnic Jewish groups at the time it was 5/9% in Ashkenazis (originating in Europe and North America) and 2.5% in Sephardis (originating from Mediterranean and Middle Eastern countries). In Yemenites obesity was associated with a marked increase in the prevalence of diabetes the same as in the other ethnic groups. The prevalence of hypertension and ischemic heart disease ECG changes were higher in diabetic Yemenites than in non-diabetic ones, the same as in the other ethnic groups. There was no difference between the incidence of ischemic heart disease ECG changes among diabetics and subjects with IGT. These facts suggest that the metabolic changes that accompany the development of diabetes lead to the same pathological changes irrespective of the ethnic group. And ...

Diabetes, blood lipids, lipoproteins, and change of environment: restudy of the "new immigrant Yemenites" in Israel. Cohen AM et al, Metabolism 1979 Jul;28(7):716-728

Restudy of 306 "new immigrant Yemenite" Jews, an ethnic group in which, upon their arrival in Israel, no diabetes was detected, revealed, 25 yr after their immigration, an increased incidence of diabetes and higher plasma and lipoprotein-lipid levels. The prevalence of diabetes (defined as "glucose intolerance") rose to 11.8% (13.2% males and 9.7% females). Obesity in females resulted in increased prevalence of diabetes in all age groups, while in males it affected the older age group only. The male/female diabetic ratio was affected by weight status--in the underweight, diabetes was more prevalent in males, in the overweight, the rate of diabetes in females equaled that of males. In nondiabetics (those with normal glucose tolerance), neither the glucose tolerance nor the insulin response deteriorated with aging. Most diabetics had a delayed insulin response. However, about 50% of nondiabetics and diabetics had insulin response peak at 60 min and similar insulin levels. It appears that in newly discovered adult-onset diabetics in this population there is no shortage of insulin, but rather shortage of insulin action. In nondiabetics, the levels of plasma cholesterol and triglycerides (TG) were higher than levels upon their arrival. In diabetics, the plasma TG, cholesterol, and LDL-cholesterol levels were higher when compared to those of nondiabetics, especially in the group of overweight males. Hyperlipoproteinemia was diagnosed in 27.7% of diabetics and 11.0% of nondiabetics. In diabetics, the HDL/LDL cholesterol ratio was found to be reduced, significantly so in overweight diabetics.

Genetically determined response to different ingested carbohydrates in the production of diabetes. Cohen AM, Horm Metab Res 1978 Mar;10(2):86-92

It has been shown that the metabolic responses to the ingestion of carbohydrates depend upon a) the type of the ingested carbohydrate and b) the genetic build-up of the recipient. In the non-susceptible animal, the ingestion of high sucrose, fructose or glucose diets will ensue in "normal" metabolic responses. In the susceptible animal the ingestion of these same carbohydrates will result in impairment of the carbohydrate and lipid metabolism, which will ultimately lead to the development of diabetes and diabetic angiopathy while their siblings with the same genetic build-up consuming starch, will not.