OBJECTIVE Individuals with impaired glucose tolerance (IGT) have a high risk of developing NIDDM. The purpose of this study was to determine whether diet and exercise interventions in those with IGT may delay the development of NIDDM, i.e., reduce the incidence of NIDDM, and thereby reduce the overall incidence of diabetic complications, such as cardiovascular, renal, and retinal disease, and the excess mortality attributable to these complications. RESEARCH DESIGN AND METHODS In 1986, 110,660 men and women from 33 health care clinics in the city of Da Qing, China, were screened for IGT and NIDDM. Of these individuals, 577 were classified (using World Health Organization criteria) as having IGT. Subjects were randomized by clinic into a clinical trial, either to a control group or to one of three active treatment groups: diet only, exercise only, or diet plus exercise. Follow-up evaluation examinations were conducted at 2-year intervals over a 6-year period to identify subjects who developed NIDDM. Cox9s proportional hazard analysis was used to determine if the incidence of NIDDM varied by treatment assignment. RESULTS The cumulative incidence of diabetes at 6 years was 67.7% (95% CI, 59.8–75.2) in the control group compared with 43.8% (95% CI, 35.5–52.3) in the diet group, 41.1% (95% CI, 33.4–49.4) in the exercise group, and 46.0% (95% CI, 37.3–54.7) in the diet-plus-exercise group ( P P 2 ). In a proportional hazards analysis adjusted for differences in baseline BMI and fasting glucose, the diet, exercise, and diet-plus-exercise interventions were associated with 31% ( P P P CONCLUSIONS Diet and/or exercise interventions led to a significant decrease in the incidence of diabetes over a 6-year period among those with IGT.

Effects of Diet and Exercise in Preventing NIDDM in People With Impaired Glucose Tolerance: The Da Qing IGT and Diabetes Study

Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.

Leptin levels in human and rodent : Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1 ) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2 ) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3 ) therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves β-cell function, and exerts antiatherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function.

The natural history of type 2 diabetes has been well described in multiple populations (1–16) (rev. in (17,18). Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19–24). In liver, the insulin resistance is manifested by …

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From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus

Background Insulin resistance appears to be the best predictor of the development of diabetes in the children of patients with type 2 diabetes, but the mechanism responsible is unknown. Methods We performed hyperinsulinemic–euglycemic clamp studies in combination with infusions of [6,6-2H2]glucose in healthy, young, lean, insulin-resistant offspring of patients with type 2 diabetes and insulin-sensitive control subjects matched for age, height, weight, and physical activity to assess the sensitivity of liver and muscle to insulin. Proton (1H) magnetic resonance spectroscopy studies were performed to measure intramyocellular lipid and intrahepatic triglyceride content. Rates of whole-body and subcutaneous fat lipolysis were assessed by measuring the rates of [2H5]glycerol turnover in combination with microdialysis measurements of glycerol release from subcutaneous fat. We performed 31P magnetic resonance spectroscopy studies to assess the rates of mitochondrial oxidative-phosphorylation activity in muscle....

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Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes.

The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes have been debated extensively. The concept that a feedback loop governs the interaction of the insulin-sensitive tissues and the beta cell as well as the elucidation of the hyperbolic relationship between insulin sensitivity and insulin secretion explains why insulin-resistant subjects exhibit markedly increased insulin responses while those who are insulin-sensitive have low responses. Consideration of this hyperbolic relationship has helped identify the critical role of beta-cell dysfunction in the development of Type 2 diabetes and the demonstration of reduced beta-cell function in high risk subjects. Furthermore, assessments in a number of ethnic groups emphasise that beta-cell function is a major determinant of oral glucose tolerance in subjects with normal and reduced glucose tolerance and that in all populations the progression from normal to impaired glucose tolerance and subsequently to Type 2 diabetes is associated with declining insulin sensitivity and beta-cell function. The genetic and molecular basis for these reductions in insulin sensitivity and beta-cell function are not fully understood but it does seem that body-fat distribution and especially intra-abdominal fat are major determinants of insulin resistance while reductions in beta-cell mass contribute to beta-cell dysfunction. Based on our greater understanding of the relative roles of insulin resistance and beta-cell dysfunction in Type 2 diabetes, we can anticipate advances in the identification of genes contributing to the development of the disease as well as approaches to the treatment and prevention of Type 2 diabetes.

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The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes.

Previous data support the idea of heightened sympathetically mediated cardiovascular reactivity in males. However, definitive conclusions cannot be made because of inconsistent reports, possibly stemming from imprecise measurement of sympathetic activity and/or failure to equate the stress stimuli between genders. The present study tested the hypothesis that males exhibit heightened sympathetic reactivity that is associated with heightened cardiovascular and plasma catecholamine responses. In 37 healthy adults (20 males, 17 females: age = 20-42 yr), direct recordings of skeletal muscle sympathetic nerve activity (MSNA), plasma catecholamines, heart rate, blood pressure, and perceived stress were measured before and during three laboratory stressors (isometric handgrip, cold pressor, and mental arithmetic). MSNA, catecholamine, and cardiovascular reactivity (defined as change from rest) were not consistently different between genders. For the isometric handgrip, when expressed as absolute unit changes, males had larger MSNA responses (P < 0.01), which were partially explained by greater contraction force; they did not differ in terms of percent change from baseline or in perceived stress. The responses to the cold pressor and mental arithmetic tasks were similar between genders. These findings indicate that stress-evoked vasoconstrictor neural excitation and the associated increases in blood pressure are not consistently influenced by gender.

Gender does not influence sympathetic neural reactivity to stress in healthy humans

Daily energy expenditure by five-year-old children, measured by doubly labeled water

Differences in sleeping metabolic rate (SMR) among subjects may be related to different levels of energy expenditure associated with sleep stages. The relationship between energy expenditure and sleep stages was investigated overnight in 29 subjects (14 Caucasians and 15 Pima Indians, 18 males and 11 females; mean +/- SD, 31 +/- 7 yr, 83 +/- 26 kg, 27 +/- 11% fat). Sleep stages were determined by electroencephalogram recording, whereas energy expenditure was measured in a 1,000-liter Plexiglas sleep box constructed around a bed as a fast-response open-circuit indirect calorimeter. Eighty-five percent of the interindividual variability in SMR was explained by differences in fat-free mass, fat mass, age, sex, and race (r2 = 0.85). The intra-individual variance in SMR over time was related to sleep stages and to clock time. Within subjects, SMR in stage 3 was significantly lower than in stage 2 (-39 +/- 18 kcal/day; P < 0.05) and rapid eye movement sleep (-51 +/- 23 kcal/day; P < 0.05). Also, sleep stages were associated with different respiratory quotients. Because sleep stages are associated with only small differences in energy metabolism, our results suggest that sleep stages play a minor role in the variance of SMR among subjects. However, the duration of sleep may contribute to the variability of 24-h energy expenditure.

Relationship between sleep stages and metabolic rate in humans

A low body temperature is associated with a low metabolic rate for a given body size and body composition. These two traits might have been assets in the history of a population subjected to cycles of feast and famine, but became part of an obesity-prone syndrome in our westernized society characterized by plenty of food and a sedentary lifestyle. We tested whether Pima Indians have lower body temperatures than Caucasians, a trait which might partly explain the high prevalence of obesity in this population. Twenty-five Pima Indian (28 +/- 6 yrs, 87.8 +/- 22.8 kg, 29 +/- 9% body fat) and 25 Caucasian (30 +/- 5 yrs, 80.7 +/- 18.4 kg, 22 +/- 11% body fat) men had body core temperatures measured by telemetry for 24 h while in a respiratory chamber. Mean daily body core temperature was 36.93 +/- 0.12 and 36.90 +/- 0.22 degrees C in Pima Indians and Caucasians, respectively. Since body core temperature during sleep (SLBCT) correlated with percentage body fat, a subset of 10 Pima Indians and 10 Caucasians were pair-matched for body weight and percentage body fat. In this group, SLBCT was lower in Pima Indians than in Caucasians (36.45 +/- 0.10 vs 36.65 +/- 0.27 degrees C; P < 0.01) and, ethnic group accounted for 20% of the variance in SLBCT (P < 0.01). Surprisingly, the lower SLBCT was not associated with a low metabolic rate and therefore does not seem to play a role in the etiology of obesity in Pima Indians.(ABSTRACT TRUNCATED AT 250 WORDS)

Racial difference in body core temperature between Pima Indian and Caucasian men.

Carbohydrate intake stimulates sympathetic nervous system activity in lean subjects, whereas in obese subjects, the results have been inconsistent. The aim of this study was to directly measure sympathetic neural outflow to skeletal muscle in response to a 75-g oral glucose tolerance test (OGTT) in 15 Pima Indian and 16 Caucasian men, matched for body fat and age, but covering a large range of body weight (57-113 kg) and body fat (4-41%). Fasting muscle sympathetic nerve activity (MSNA) correlated positively with body fat (r = 0.73; P = 0.001) in Caucasians but not in Pima Indians, whereas the increase in MSNA during the OGTT correlated negatively with the percentage of body fat (r = -0.38, P = 0.03) independently of race. In each subject, the increase in MSNA over time correlated positively with the increase in plasma insulin levels, but the slopes of these relationships were inversely related to the percentage of body fat (r = -0.52, P = 0.003) independently of race. In conclusion, obesity is associated with a higher fasting sympathetic neural outflow to muscle but a blunted increase in response to an oral glucose load despite a larger increase in plasma insulin levels. This blunted response may represent another feature of the obesity/insulin resistance syndrome.

M. Spraul

Papers

Gender does not influence sympathetic neural reactivity to stress in healthy humans

Daily energy expenditure by five-year-old children, measured by doubly labeled water

Relationship between sleep stages and metabolic rate in humans

Racial difference in body core temperature between Pima Indian and Caucasian men.

Muscle Sympathetic Nerve Activity in Response to Glucose Ingestion: Impact of Plasma Insulin and Body Fat