I. Origin of the Insulin Sensitivity Concept HISTORICALLY, the study of the pathogenesis of diabetes mellitus was in the traditional pattern of endocrinology: removal of the pancreas led to experimental diabetes, and administration of insulin, a pancreatic isolate, ameliorated the diabetic symptoms (1, 2). These observations led to the widely held belief that human diabetes was primarily a disease of the pancreas, characterized by the inability of the B cell to secrete sufficient insulin to control glycemia. After insulin became available, evidence emerged suggesting that human diabetes mellitus has a multifactorial etiology. Early investigators identified an unexpected variability among diabetics in the ability of injected insulin to ameliorate hyperglycemia (3–5). Larger doses of insulin were required to normalize the blood sugar in patients with the milder nonketotic form of the disease common in the older population, whereas smaller doses were adequate for younger, ketosis-prone diabetics.

Assessment of insulin sensitivity in vivo.

Insulin Sensitivity Indices Calculated from Basal and OGTT-Induced Insulin, Glucose, and FFA Levels

We studied the effects of body composition and maximal aerobic power on insulin sensitivity in 23 normal-weight, healthy male subjects. Eight were weight lifters, eight were long-distance runners, and seven were untrained controls. In each subject, the percentage of body weight (BW) made up of muscle and fat tissue (% muscle and % fat, respectively), the maximal aerobic power (VO2max), and the tissue sensitivity to insulin were measured. The weight lifters were characterized by 35% higher % muscle as compared with the runners or controls (P less than 0.01). VO2max in the runners was 30-40% higher than in the weight lifters or controls (P less than 0.001). During the euglycemic clamp studies, similar steady-state plasma glucose and insulin levels were achieved in each group. When calculated per total BW, the rate of glucose metabolism (M) was virtually identical in the weight lifters (10.26 +/- 1.02 mg/kg BW/min) and the runners (10.03 +/- 0.86 mg/kg BW/min), and 4045% higher than in the controls (7.10 +/- 0.75 mg/kg BW/min, P less than 0.05). When calculated per muscle mass (Mm), only the runners had a higher than normal rate of glucose metabolism (P less than 0.02). M was directly proportional to% muscle (r = 0.54, P less than 0.01) and inversely related to % fat (r = -0.72, P less than 0.001). The multiple linear regression analysis revealed a highly significant multivariate correlation between M and the combined effect of % muscle, %fat, and VO2max (r = 0.78, P less than 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Body Composition on Insulin Sensitivity

Diagnosis, prognosis, and treatment of impaired glucose tolerance and impaired fasting glucose.

A gradual diminution in the physiologic reserve or functional capacity over time is the characteristic hallmark of aging, and this has a direct impact on the choice of cancer therapy and its toxicity profile in elderly patients with cancer. With the expected rapid rise of the older population as a subgroup, oncologists will increasingly treat elderly patients. Provision of competent care to this increasing pool of older patients with cancer necessitates that oncology professionals become familiar with age-associated changes in organ physiology and their impact on cancer treatment and toxicity. In this comprehensive review, we have listed changes in cardiovascular, gastrointestinal, pulmonary, and renal physiology with aging. Also enumerated is the impact of these changes on cancer therapy and toxicity in each organ system-based section. Cardiovascular changes primarily lead to reduction of the cardiac functional reserve, with a consequent increase in the risk of congestive heart failure. Changes in gastrointestinal physiology lead to increased mucosal damage. A reduction in pulmonary reserve has implications for postradiation complications, and a decline in renal function leads to an increased potential for nephrotoxicity. These changes impair the ability of older patients with cancer to tolerate cancer therapy and increase their risk of toxicities. This may lead to an overall decline in functional status, resulting frailty, poor quality of life, and ultimately poor outcomes. Becoming familiar with age-related physiologic changes is the first step for oncologists seeking to better tailor their treatments. This, combined with adoption of some of the clinical interventions suggested in this review, can help better manage the geriatric oncology patient. Further research is necessary for the development of more specific evidence-based recommendations.

Physiologic aspects of aging : Impact on cancer management and decision making, Part I

In order to select a population at risk for the development of diabetes for a prospective study of the relationship of islet cell antibodies (ICA), islet cell surface antibodies ( ICSA ), and glucose tolerance after mumps infection, we carried out a screening program for diabetes A diabetic survey was conducted among 1581 children (less than 16 yr of age) with mumps infection 14 mo before the survey, using a brief questionnaire combined with urinary glucose analysis Responses to the screening program were obtained from 684% (N = 1080) of the children Out of a total of 1080 subjects, 1069 (99%) had no diabetes mellitus, diabetic symptoms, or glucosuria A "positive urine glucose screen" was obtained in 11 subjects (1%) of the study group These individuals all had a normal oral glucose tolerance test according to the new WHO definition A group of 86 children was randomly selected from the total group of 1080 children for follow-up glucose tolerance, ICA, and ICSA  Irrespective of the negative urine glucose screen impaired glucose tolerance was diagnosed in 35% (N = 3) of the 86 children The prevalence of ICA and ICSA was 78% and 36%, respectively The simultaneous prevalence of ICA and ICSA was 33% The pathogenetic role of mumps infection and ICA/ ICSA and their possible relationship to slow progressive beta cell destruction remain to be elucidated

Mumps Infection and Insulin-dependent Diabetes Mellitus (IDDM)

Influence of target cell preparation on binding of monoclonal islet cell reactive antibodies (mc-ICRA) in cellular enzyme-linked immunosorbent assay (CELISA).

Insulin resistance was studied in seven non-obese male subjects with impaired glucose tolerance and four healthy, age and body-weight matched male control subjects by means of a continuous intravenous infusion of somatostatin, glucose and insulin over 150 min. Glucose tolerance was evaluated by means of a 2-h glucose infusion test. Endogenous insulin (C-peptide), growth hormone, and glucagon secretion were suppressed by somatostatin in both groups. Steady-state plasma insulin and glucose levels were achieved between 90–135 min. Since similar steady-state levels of exogenous insulin were achieved, the resulting steady-state plasma glucose level provided a direct estimate of the ability of insulin to dispose of the infused glucose. The glucose levels were higher in subjects with impaired glucose tolerance with values of 14.6 ± 1.8 mmol/1 compared with 5.1 ± 1.2 mmol/1 in control subjects (p < 0.01), thus indicating insulin resistance. There was a direct correlation between the steady-state plasma glucose level and glucose tolerance suggesting that the degree of glucose intolerance is proportional to the degree of insulin resistance. These results revealed that decreased insulin sensitivity is found in non-obese subjects with impaired glucose tolerance.

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Evaluation of insulin resistance during inhibition of endogenous insulin and glucagon secretion by somatostatin in non-obese subjects with impaired glucose tolerance

Two monoclonal Beta-cell surface antibodies M10H6 und K14D10 were obtained by fusion of spleen cells of Balb/c mice with the myeloma cell line P30. The monoclonal antibody M10H6 was induced by immunization with rat insulinoma cells finally boostered with disintegrated rat islets, whereas the K14D10 was generated after immunization with porcine proinsulin. Both monoclonals belong to the IgG2A isotype and were screened with insulin-producing rat insulinoma cells by an indirect immunofluorescence test as well as by a cellular enzyme linked immunosorbent assay. In addition to the cell surface binding on living Beta cells the monoclonals react with islets on cryostat sections of rat pancreas. The anti-islet cytotoxic potential of these monoclonals was measured by 51Chromium-release in the presence of complement or Fc-receptor bearing leucocytes using 51Chromium-labelled rat islet cells as target. Both antibody secreting hybridomas were propagated in syngeneic mice resulting in high levels of islet cell surface antibodies in ascites and sera from the recipient. High anti-islet cytotoxicity was mediated by ascites fluid, but no mouse developed hyperglycaemia. Furthermore, the repeated injections of the monoclonals into rats did not exert a diabetogenic action and failed to reduce the pancreatic insulin content although the attraction of the K14D10 to the pancreatic islets in vivo could be demonstrated. We conclude that islet cell surface antibody-mediated Beta-cell lysis in vitro may not be relevant to Beta-cell destruction in vivo.

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Monoclonal antibody-mediated cytotoxicity against rat Beta cells detected in vitro does not cause Beta-cell destruction in vivo

The relationship of age to insulin sensitivity was studied in 74 non-obese healthy subjects with normal fasting plasma glucose concentration, ranging in age from 17 to 65 years. Glucose tolerance and early as well as late insulin responses were characterized by means of a 2 h glucose infusion test (12 mg/kg/min) primed by an initial injection of 0.33 g/kg body weight glucose. Glucose tolerance did not markedly differ between young (< 30 years; n = 31) and middle-aged subjects (31\\p=n-\\45 years; n = 29) but deteriorated significantly in the elder group (> 45 years; n = 14). Early and late insulin responses to glucose were not appreciably altered during ageing in this selected healthy population. For the determination of insulin sensitivity a 1 h priming dose-constant infusion technique (two 30 min periods of 8 and 16 mU/kg, insulin 'MC-Actrapid', initiated by a start injection of 1 and 2 mU/kg, respectively) was used. The percent decrease of plasma glucose, FFA and glycerol levels serves as a measure of the whole body sensitivity to exogenous insulin. Under condition of identical steady-state insulin levels the decrease in plasma glucose was significantly reduced in elderly (24 \\m=+-\\5%) vs young (34 \\m=+-\\2%)subjects (P < 0.05). However, a marked sensitivity to the antilipolytic effect of insulin was demonstrated in elderly subjects considered to be resistant to its glucose-lowering action. There was no evidence that disappeared time and metabolic clearance rate of insulin were altered with advancing age. In conclusion, the impaired insulin sensitivity to glucose metabolism seems to be the primary factor responsible for the deterioration of glucose tolerance with advancing age. It is generally accepted that glucose tolerance de¬ teriorates with advancing age (Nilsson et al. 1964; Hayner et al. 1965; O'Sullivan et al. 1971; Schreuder 1972; Nolan et al. 1973; Ratzmann 1973a,b; O'Sullivan 1974; Dudl & Ensinck 1977). The cause of declining glucose tolerance with age is not yet clear (Reaven 1977). Some of the studies have not considered the importance of obesity (Welborn et al. 1969) which increases progressively with age (Nilsson et al. 1964; O'Sullivan et al. 1971). The total body fat mass is directly related to the degree of glucose intolerance (Ratzmann et al. 1979). Theoretically, a decrease in glucose tolerance can result from decreased insulin secretion, increased resistance to insulin action or both (Reaven & Olefsky 1977; Ratzmannetal. 1981). Some authors have suggested a decrease of insulin secretion in elderly persons (Crockford et al. 1966). In contrast to this observation other investigators have descri¬ bed that plasma insulin response to glucose tends to increase with age (Chlouverakis et al. 1967; Hales et al. 1968; O'Sullivan et al 1971 ; Schreuder 1972). The discrepancy of increased insulin secre¬ tion and impaired glucose tolerance has been inter¬ preted as a result of an age related increase of insulin resistance (Reaven 1977; Defronzo 1979). Unfortunately, there are conflicting results con¬ cerning insulin sensitivity in elderly persons (Silverstone et al. 1957; Martin et al. 1968; Kimmerling et al. 1977; Defronzo 1979) and this phenomenon also remains unequivocally established. In an effort to provide further information concerning the effect of age on insulin sensitivity, we have studied insulin response to glucose and insulin sensitivity in vivo in healthy non-obese subjects with normal fasting plasma glucose con¬ centration. Investigations in the medical research project 'Diabetes mellitus and disturbances of lipid metabolism' supported by the Ministry of Health, DDR. Central Institutefor Diabetes 'Gerhardt Katsch', Clinical Research Unit, Karlsburg, DDR Downloaded from Bioscientifica.com at 11/24/2018 03:55:42AM via free access

Witt S

Papers

Mumps Infection and Insulin-dependent Diabetes Mellitus (IDDM)

Influence of target cell preparation on binding of monoclonal islet cell reactive antibodies (mc-ICRA) in cellular enzyme-linked immunosorbent assay (CELISA).

Evaluation of insulin resistance during inhibition of endogenous insulin and glucagon secretion by somatostatin in non-obese subjects with impaired glucose tolerance

Monoclonal antibody-mediated cytotoxicity against rat Beta cells detected in vitro does not cause Beta-cell destruction in vivo

The effect of ageing on insulin sensitivity and insulin secretion in non-obese healthy subjects