Reduced glycogen synthase activity in skeletal muscle from obese patients with and without Type 2 (non-insulin-dependent) diabetes mellitus

Summary In order to evaluate the importance of a defect in insulin mediated non-oxidative glucose metabolism and glycogen synthase activity in skeletal muscles in obese subjects with and without Type 2 (non-insulin-dependent) diabetes mellitus we studied: 10 lean and 10 obese control subjects and 12 obese diabetic patients using the euglycaemic hyperinsulinaemic clamp technique (basal, 20 mU · (m²)^–1 · min^–1, 80mU·(m²)^–1·min^–1) in combination with indirect calorimetry. Muscle biopsies were taken from m. vastus lateralis at each insulin level. We found that non-oxidative glucose metabolism could be stimulated by insulin in all three groups (p<0.01). The values obtained at the highest insulin levels (around 140 U/ml) were lower in both obese groups compared to the lean control subjects (118±21, 185±31, 249±14 mg·(m²)^–1·min^–1 (p< 0.01)). Insulin stimulation of the glycogen synthase activity at a glucose-6-phosphate concentration of 0.1 mmol/l was absent in both obese groups, while activities increased significantly in the lean control subjects (19.6±4.2% to 45.6±6.8%, p< 0.01). Glycogen synthase activities at the highest insulin concentrations only differed significantly between lean control subjects and obese diabetic patients (45±7% and 31±5%, p< 0.05). We conclude that insulin resistance in peripheral tissues in obese subjects with and without Type 2 diabetes may be partly explained by a reduced insulin mediated non-oxidative glucose metabolism and that this abnormality might be due to an absent insulin stimulation of glycogen synthase in skeletal muscles. This enzyme defect is correlated to obesity itself.     

Expression of insulin regulatable glucose transporters in skeletal muscle from Type 2 (non-insulin-dependent) diabetic patients

Summary A prominent feature of Type 2 (non-insulin-dependent) diabetes mellitus is the inability of insulin to appropiately increase the transport of glucose into target tissue. In adipocytes from individuals with Type 2 diabetes, insulin resistance has been shown to be associated with a depletion of glucose transporters. Similarly, streptozotocin induced diabetes causes a diminished expression of the insulin regulatable glucose transporter in rat adipocytes. The expression of this glucose transporter isoform has not yet been investigated in muscle tissue from patients with Type 2 diabetes. We have measured the content of the insulin regulatable glucose transporter in a vesicular fraction isolated from muscle biopsies from fasting individuals with Type 2 diabetes and control subjects, and we found that the number of the insulin regulatable glucose transporters expressed in skeletal muscle was unaffected by Type 2 diabetes (0.208 vs 0.205, arbitrary units, p>0.5, control subjects and diabetic patients). Thus, the decreased glucose disposal in Type 2 diabetes is not associated with a diminished number of insulin regulatable glucose transporters.     

Contribution of glucose/glucose 6-phosphate cycle activity to insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus

Summary It has been suggested that increased glucose/glucose 6-phosphate substrate cycling impairs net hepatic glucose uptake in Type 2 (non-insulin-dependent) diabetes mellitus and contributes to hyperglycaemia. To investigate glucose/glucose 6-phosphate cycle activity and insulin action in Type 2 diabetes we studied eight patients and eight healthy control subjects, using the euglycaemic glucose clamp and isotope dilution techniques with purified [2-³H]- and [6-³H] glucose tracers, in the post-absorptive state and eight patients and five healthy control subjects during consecutive insulin infusions at rates of 0.4 and 2.0 mU·kg^–1·min^–1. [2-³H]glucose and [6-³H]glucose radioactivity in plasma samples were determined using selective enzymatic detritiation, allowing calculation of glucose turnover rates for each isotope, the difference being glucose/glucose 6-phosphate cycling. Endogenous glucose production ([6-³H]glucose) was greater in diabetic than control subjects in the post-absorptive state (15.6±1.5 vs 11.3±0.4 mol·kg^–1·min^–1, p<0.05) and during the 0.4 mU insulin infusion (10.1±1.3 vs 5.2±0.3 mol·kg^–1·min^–1, p<0.01) indicating hepatic insulin resistance. Glucose/glucose 6-phosphate cycling was significantly greater in diabetic than in control subjects in the post-absorptive state (2.6±0.4 vs 1.6±0.2 mol·kg^–1·min^–1, p<0.05) but not during the 0.4 mU insulin infusion (2.0±0.4 vs 2.0±0.3 mol·kg^–1·min^–1). During the 2.0 mU insulin infusion endogenous glucose production was suppressed to a similar degree in both groups (2.6±0.5 vs 3.4±0.7 mol · kg^–1·min^–1) but glucose disappearance was lower in the diabetic subjects (30.8±2.0 vs 52.4±4.6 mol·kg^–1·min^–1, p<0.01). During the 2.0 mU insulin infusion glucose/glucose 6-phosphate cycling was greater in the diabetic subjects (3.8±0.7 vs 0.8±0.6 mol·kg^–1·min^–1, p<0.05). In conclusion, both hepatic and peripheral insulin action are impaired in Type 2 diabetes. Increased glucose/glucose 6-phosphate cycling is seen in the post-absorptive state and also during marked hyperinsulinaemia, when insulin resistance is predominantly due to reduced peripheral tissue glucose uptake.     

In vivo insulin action and muscle glycogen synthase activity in Type 2 (non-insulin-dependent) diabetes mellitus: effects of diet treatment

Summary Insulin resistant glucose metabolism is a key element in the pathogenesis of Type 2 (non-insulin-dependent) diabetes mellitus. Insulin resistance may be of both primary (genetic) and secondary (metabolic) origin. Before and after diet-induced improvement of glycaemic control seven obese patients with newly-diagnosed Type 2 diabetes were studied with the euglycaemic clamp technique in combination with indirect calorimetry and forearm glucose balance. Muscle biopsies were obtained in the basal state and again after 3 h of hyperinsulinaemia (200 mU/l) for studies of insulin receptor and glycogen synthase activities. Similar studies were performed in seven matched control subjects. Insulin-stimulated glucose utilization improved from 110±11 to 183±23 mg·m^–2·min^–1 (p<0.03); control subjects: 219+23 mg·m^–2·min^–1 (p=NS, vs post-diet Type 2 diabetes). Nonoxidative glucose disposal increased from 74±17 to 138+19 mg·m^–2·min^–1 (p<0.03), control subjects: 159±22 mg· m^–2·m^–1 (p=NS, vs post-diet Type 2 diabetic patients). Forearm blood glucose uptake during hyperinsulinaemia increased from 1.58±0.54 to 3.35±0.23 mol·l^–1·min^–1 (p<0.05), control subjects: 2.99±0.86 mol·l^–1·min^–1 (p=NS, vs post-diet Type 2 diabetes). After diet therapy the increase in insulin sensitivity correlated with reductions in fasting plasma glucose levels (r=0.97, p<0.001), reductions in serum fructosamine (r=0.77, p<0.05), and weight loss (r=0.78, p<0.05). Values of muscle glycogen synthase sensitivity to glucose 6-phosphate (A_0.5 for glucose 6-phosphate) were similar in the basal state. However, insulin stimulation of glycogen synthase was more pronounced after diet treatment (A_0.5: 0.43±0.06 (before) vs 0.30±0.04 mmol/l (after); p<0.03; control subjects: 0.22±0.03 mmol/l). Muscle insulin receptor binding and kinase activity were similar before and after diet treatment and comparable to values in the control group. The data suggest that impaired insulin stimulation of in vivo glucose turn-over and muscle glycogen synthase activity tend to be restored during successful diet treatment of patients with Type 2 diabetes.     

Pathogenesis of Type 2 (non-insulin-dependent) diabetes mellitus: candidates for a signal transmitter defect causing insulin resistance of the skeletal muscle

Summary Insulin resistance of skeletal muscle, liver and fat combined with an abnormality of insulin secretion characterizes Type 2 (non-insulin-dependent) diabetes mellitus. There is increasing evidence that the insulin resistance of the skeletal muscle plays a key role early in the development of Type 2 diabetes. As a consequence recent research efforts have focussed on the characterization of insulin signal transduction elements in the muscle which are candidates for a localization of a defect causing insulin resistance i.e. the insulin receptor, phosphatases related to insulin action, glycogen synthase and the glucose transporters. In this review we attempt to summarize present knowledge about abnormalities of these systems in skeletal muscle of Type 2 diabetic and pre-diabetic individuals. We try to classify abnormalities as secondary events or as candidates for putative primary molecular defects which might initiate the development of insulin resistance as early as in the pre-diabetic state.     

Insulin resistance,hypertension and microalbuminuria in patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary We examined the impact of hypertension and microalbuminuria on insulin sensitivity in patients with Type 2 (non-insulin-dependent) diabetes mellitus using the euglycaemic insulin clamp technique in 52 Type 2 diabetic patients and in 19 healthy control subjects. Twenty-five diabetic patients had hypertension and 19 had microalbuminuria. Hypertension per se was associated with a 27% reduction in the rate of total glucose metabolism and a 40% reduction in the rate of non-oxidative glucose metabolism compared with normotensive Type 2 diabetic patients (both p<0.001). Glucose metabolism was also impaired in normotensive microalbuminuric patients compared with normotensive normoalbuminuric patients (29.4±2.2 vs 40.5±2.8 mol · kg lean body mass^–1 · min^–1; p=0.012), primarily due to a reduction in non-oxidative glucose metabolism (12.7±2.9 vs 21.1±2.6 mol · kg lean body mass^–1 ·min^–1; p=0.06). In a factorial ANOVA design, however, only hypertension (p=0.008) and the combination of hypertension and microalbuminuria (p=0.030) were significantly associated with the rate of glucose metabolism. The highest triglyceride and lowest HDL cholesterol concentrations were observed in Type 2 diabetic patients with both hypertension and microalbuminuria. Of note, glucose metabolism was indistinguishable from that in control subjects in Type 2 diabetic patients without hypertension and microalbuminuria (40.5±2.8 vs 44.4±2.8 mol · kg lean body mass^–1 · min^–1). We conclude that insulin resistance in Type 2 diabetes is predominantly associated with either hypertension or microalbuminuria or with both.     

Insulin action and determinants of glycaemia in a rat model of Type 2 (non-insulin-dependent) diabetes mellitus

Summary We aimed to assess prandial responses, basal glucose turnover and insulin action (euglycaemic clamp) in a very low-dose neonatal streptozotocin model of Type 2 (noninsulin-dependent) diabetes mellitus. Male Wistar rats were injected at 2 days of age with 45 mg/kg streptozotocin or vehicle (control). At 8 weeks, the groups were subdivided and fed either a high-fat or high-starch diet for 3 weeks. Both the fat diet and streptozotocin treatments had independent hyperglycaemic effects (streptozotocin/fat 9.3±0.3 mmol/l; streptozotocin/starch 7.5±0.3 mmol/l; control/fat 7.4±0.1 mmol/l; all p<0.01 vs control/starch 6.4±0.1 mmol/l). The fat diet effect was associated with both a reduction in basal glucose clearance (p<0.001) and in basal hepatic glucose output (p<0.05). Streptozotocin increased basal hepatic glucose output. Significantly higher prandial glycaemia in the streptozotocin/starch group occurred despite similar insulin levels and appeared to be related to an impaired early insulin response. Whole-body and tissue-specific insulin sensitivity were significantly depressed in fat-fed animals compared to starch-fed animals, however there were no significant effects of streptozotocin treatment. We conclude that fasting hyperglycaemia associated with abnormalities in both glucose production and clearance can exist in the presence of a basal hepatic glucose output which is reduced compared to control animals. Furthermore, dietary-fat-induced insulin resistance is not exacerbated by the relative insulin deficiency and/or mild hyper glycaemia observed when dietary fat and neonatal streptozotocin-treatments are combined.     

Decreased tyrosine kinase activity in partially purified insulin receptors from muscle of young,non-obese first degree relatives of patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary Recently, we demonstrated insulin resistance due to reduced glucose storage in young relatives of Type 2 diabetic patients. To investigate whether this was associated with a defective insulin receptor kinase, we studied ten of these young (27±1 years old) non-obese glucose tolerant first degree relatives of patients with Type 2 diabetes and eight matched control subjects with no family history of diabetes. Insulin sensitivity was assessed by a hyperinsulinaemic, euglycaemic clamp. Insulin receptors were partially purified from muscle biopsies obtained in the basal and the insulin-stimulated state during the clamp. Insulin binding capacity was decreased by 28% in the relatives (p<0.05) in the basal biopsy. Tyrosine kinase activity in the receptor preparation was decreased by 50% in both basal and insulin-stimulated biopsies from the relatives. After stimulation with insulin in vitro, kinase activity was reduced in the relatives in basal (p<0.005) and insulin-stimulated (p<0.01) biopsies and also when expressed per insulin binding capacity (p0.05). Insulin stimulation of non-oxidative glucose metabolism correlated with in vitro insulin-stimulated tyrosine kinase activity (r=0.61, p<0.01) and also when expressed per binding capacity (r=0.53, p<0.025). We suggest that the marked defect in tyrosine kinase activity in partially purified insulin receptors from skeletal muscle is an early event in the development of insulin resistance and contributes to the pathophysiology of Type 2 diabetes.     

肌糖原合成酶基因多态性与糖尿病及其合并高血压的关系

目的研究肌糖原合成酶基因与非胰岛素依赖型糖尿病（ＮＩＤＤＭ）及其合并高血压的关系。方法采用限制性内切酶Ｘｂａｌ对肌糖原合成酶基因片段的聚合酶链反应（ＰＣＲ）产物酶解的方法，观察１６４例ＮＩＤＤＭ（包括６２例合并高血压病人）的糖原合成酶基因多态性。结果肌糖原合成酶基因型（Ａ１／Ａ１，Ａ１／Ａ２）和等位基因（Ａ１，Ａ２）均与ＮＩＤＤＭ无关，而ＮＩＤＤＭ合并高血压者Ａ２等位基因频率明显高于血压正常的ＮＩＤＤＭ者（Ｐ＜０．０５）。结论糖原合成酶基因多态性作为一种标志，提示与其连锁的基因可能参与ＮＩＤＤＭ病人的高血压的发病。     

Impaired skeletal muscle glycogen synthase activation by insulin in the Goto-Kakizaki (G/K) rat

Summary The Goto-Kakizaki (G/K) rat is an animal model of non-insulin-dependent diabetes mellitus, with early hyperglycaemia, hyperinsulinaemia, and insulin resistance. We have studied the effect of insulin on the activation of glycogen synthase in the G/K rat and in the original parent strain, the Wistar rat. After insulin injection, glycogen synthase I activity, glycogen synthase phosphatase activity and glucose 6-phosphate content in skeletal muscle were significantly increased in the Wistar rats. In the G/K rats, insulin injection resulted in a reduced activation of skeletal muscle glycogen synthase, which was not significant when compared with the control rats without insulin, and no increases in glycogen synthase phosphatase and glucose 6-phosphate were seen. In adipose tissue the activation of glycogen synthase by insulin was normal in the G/K rats. Previous investigations have shown that glucose disappearance rates are low in the G/K rat. However, stimulation of glucose transport was reported to be normal in the G/K rat. A defective activation of glucose accumulation into glycogen by skeletal muscle may contribute to explain the hyperglycaemia in the G/K rat.Abbreviations DTT Dithiothreitol - TLCK tosyl lysyl chloromethyl ketone - GSPase glycogen synthase phosphatase - G3PAT glycerol-3-phosphate acyl transferase - G/K Goto-Kakizaki rat - IPG Inositolphosphoglycan     

Adipose tissue glycogen synthase activation by in vivo insulin in spontaneously insulin-resistant and Type 2 (non-insulin-dependent) diabetic rhesus monkeys

Summary In skeletal muscle, a defect in the covalent activation of glycogen synthase by insulin has been identified in insulin resistance and in Type 2 (non-insulin-dependent) diabetes mellitus, but a similar defect in insulin action at the adipose tissue has not been demonstrated. We sought to determine whether this defect in insulin action in muscle was also present in the same pathway in adipose tissue. We examined the effect of in vivo insulin on adipose tissue glycogen synthase and phosphorylase activity in normal (n=11), hyperinsulinaemic (n=8), and impaired glucose tolerant and Type 2 diabetic (n=8) rhesus monkeys. Adipose tissue samples were obtained before and during a euglycaemic hyperinsulinaemic clamp. Glycogen synthase fractional velocity, independent and total activities were significantly higher in the insulin-stimulated samples compared to the basal samples in the normal group (p<0.05, respectively). In the hyperinsulinaemic group, however, insulin had no effect on glycogen synthase fractional velocity or independent activity, but did increase the total activity of glycogen synthase and phosphorylase (p<0.05, respectively). Furthermore, both the basal and the insulin-stimulated total activities of these two enzymes were significantly greater in the hyperinsulinaemic group as compared to both the normal and the diabetic groups (p<0.05, respectively). In the diabetic group, insulin was without effect on glycogen synthase fractional velocity, independent activity or total activity. We conclude that the covalent activation of adipose tissue glycogen synthase by insulin is absent in both obese hyperinsulinaemic and in spontaneously diabetic monkeys.     

Different effects of insulin and oral antidiabetic agents on glucose and energy metabolism in Type 2 (non-insulin-dependent) diabetes mellitus

Summary Which therapy should be used in Type 2 (noninsulin-dependent) diabetic patients with secondary sulfonylurea failure, insulin or a combination of sulfonylurea and metformin? To address this question, we have compared the effect of 6 months of insulin therapy twice daily with that of a combination of glibenclamide and metformin in 24 Type 2 diabetic subjects, who no longer responded to treatment with sulfonylureas. Both treatments resulted in an equivalent 30% improvement in mean daily blood glucose (p<0.001), without significant effect on serum lipids. Insulin improved glycaemic control primarily by reducing basal hepatic glucose production (p<0.05), but had no significant effect on peripheral glucose metabolism. The combination of glibenclamide and metformin enhanced significantly total body glucose metabolism (p<0.05), predominantly by stimulating the non-oxidative pathway. Neither insulin nor the combination therapy altered B-cell response to a test meal. Insulin therapy resulted in a 6% increase in body weight, 63% of which was accounted for by increased fat mass. Although body weight was unchanged during sulfonylurea/metformin therapy, lean body mass and energy expenditure decreased significantly (p<0.05). We conclude that insulin and glibenclamide/metformin have different long-term effects on glucose and energy metabolism in Type 2 diabetes.     

Insulin resistance in Type 2 (non-insulin-dependent) diabetic patients and their relatives is not associated with a defect in the expression of the insulin-responsive glucose transporter (GLUT-4) gene in human skeletal muscle

Summary To study whether insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus is due to a defect in the expression of the insulin-responsive glucose transporter gene (GLUT-4) in human skeletal muscle, we measured the level of GLUT-4 mRNA and (in some of the subjects) its protein in muscle biopsies taken from 14 insulin-resistant patients with Type 2 diabetes, 10 first-degree relatives of the diabetic patients and 12 insulin-sensitive control subjects. Insulin sensitivity was measured with a +45 mU· ·min^–1 euglycaemic insulin clamp in combination with indirect calorimetry and infusion of [3-³H]glucose. GLUT-4 mRNA was measured using a human GLUT-4 cDNA probe and GLUT-4 protein with a polyclonal antibody specific for the 15 amino acid carboxyterminal peptide. Both Type 2 diabetic patients and their relatives showed impaired stimulation of total-body glucose disposal by insulin compared with control subjects (29.5±2.1 and 34.0±4.8 vs 57.9±3.1 mol·kg lean body mass^–1·min^–1; p<0.01). This impairment in glucose disposal was primarily accounted for by a reduction in insulin-stimulated storage of glucose as glycogen (13.0±2.4 and 15.6±3.9 vs 36.9±2.2 mol·kg lean body mass^–1·min^–1; p<0.01). The levels of GLUT-4 mRNA expressed both per g of total RNA and per g DNA, were higher in the diabetic patients compared with the control subjects (116±25 vs 53±10 pg/g RNA and 177±35 vs 112±29 pg/g DNA; p<0.05, p<0.01, respectively). The GLUT-4 mRNA levels in the relatives were not significantly different from that observed in the control subjects (90±16 pg/g RNA and 117±23 pg/g DNA; p = NS). The GLUT-4 protein levels did not significantly differ between control subjects, diabetic patients and relatives (494±85, 567±133 and 323±80 cpm/100 g protein). No correlation was observed between the level of GLUT-4 mRNA andits protein. However, the level of GLUT-4 mRNA and the rate of total-body glucose disposal correlated positively in the control group and in the relatives (both p<0.05) but not in the diabetic subjects. A positive correlation between the level of GLUT-4 protein and total-body glucose disposal was also observed in the control subjects (r = 0.759; p<0.05) and in the relatives (r = 0.794; p<0.01) but not in the diabetic subjects. We conclude that insulin resistance in Type 2 diabetes is not related to a defect in the expression of the GLUT-4 gene in skeletal muscle. Nevertheless, the levels of GLUT-4 mRNA and GLUT-4 protein are related to the rate of total-body glucose disposal in subjects with normal fasting glucose concentrations.     

Five-year follow-up of islet cell antibodies in Type 2 (non-insulin-dependent) diabetes mellitus

Summary The aim was to study the frequency and appearance of cytoplasmic islet cell antibodies in relation to impairment of insulin secretory capacity and some clinical characteristics in a representative group of middle-aged (45–64 years) patients with Type 2 (non-insulin-dependent) diabetes mellitus (70 male, 63 female) at the time of diagnosis and at five-year follow-up. Non-diabetic control subjects (62 male, 82 female) were similarly examined at five-year intervals. At the baseline five out of 133 (3.8%) diabetic patients were positive for conventional and four (3.0%) for complement-fixing islet cell antibodies. Ten patients had become positive by the second screening for conventional antibodies and six for complement-fixing antibodies, but none showed negative conversion. Two non-diabetic subjects (1.5%) became antibody positive during the follow-up. Insulin treatment was started during the follow-up for four out of 15 (27%) conventional antibody positive and for one out of 121 (0.8%) antibody negative diabetic patients (p=0.001). The sensitivity of the positive conventional and complement-fixing antibody for identifying patients who developed an impairment of insulin secretory capacity (post-glucagon C-peptide 0.60nmol/l at 5-year) was 75%. The respective specificity was 90% and the positive predictive values were highest in the case of high positivity (50%). The negative predictive value of antibody positivity was close to 100%. In conclusion, islet cell antibody positivity in patients classified as Type 2 was persistent during the follow-up and predicted the future development of insulin deficiency especially in those patients with high or increasing antibody titres.     

Hypomagnesaemia in Type 2 (non-insulin-dependent) diabetes mellitus is not corrected by improvement of long-term metabolic control

Summary Low levels of magnesium have frequently been reported in diabetes mellitus especially in poorly controlled Type 1 (insulin-dependent) diabetic patients. Furthermore hypomagnesaemia might contribute to insulin resistance in Type 2 (non-insulin-dependent) diabetes. As the influence of improved metabolic control on plasma magnesium levels is unknown in Type 2 diabetic patients we studied magnesium plasma levels in 50 patients 1) before, 2) one and 3) three months after the initiation of insulin therapy or intensified treatment with oral hypoglycaemic agents. Magnesium plasma levels were measured by a colorimetric method and were significantly reduced in diabetic patients compared to healthy control subjects (0.79±0.01 mmol/l vs 0.88±0.01 mmol/l; p<0.0001). Metabolic control was significantly improved as documented by reduced HbA_1C levels in both insulin-treated patients or the patients on oral hypoglycaemic agents (p<0.003). However, plasma magnesium levels remained unchanged during the follow-up in the insulin-treated group (10.79±0.02 mmol/l; 20.81±0.02 mmol/l; 30.79±0.01 mmol/l) as well as in the patients on oral hypoglycaemic agents (10.79±0.03 mmol/l; 20.78±0.02 mmol/ l; 30.84±0.04 mmol/l). This study shows that even marked improvement of glycaemic control does not correct hypomagnesaemia in Type 2 diabetes. We conclude that hypomagnesaemia might be related to the insulin-resistant state and that possible beneficial effect of chronic magnesium administration should be evaluated in these patients.     

Relationship of skeletal muscle glucose 6-phosphate to glucose disposal rate and glycogen synthase activity in insulin-resistant and non-insulin-dependent diabetic rhesus monkeys

Summary Reduced insulin action on skeletal muscle glycogen synthase activity and reduced whole-body insulin-mediated glucose disposal rates in insulin-resistant subjects may be associated with an alteration in muscle glucose transport (or phosphorylation) or with a defect distal to glucose 6-phosphate. To examine this issue we determined the glucose 6-phosphate concentration and glycogen synthase activity in muscle samples obtained under basal and euglycaemic hyperinsulinaemic clamp conditions in 27 rhesus monkeys (Macaca mulatta). They ranged from metabolically normal (n =11) to insulin-resistant (n =8) to overtly diabetic (non-insulin-dependent) (n =8). The glucose 6-phosphate measured under insulin-stimulated conditions was inversely correlated to insulin-stimulated glycogen synthase independent activity (r = –0.54, p<0.005), the change in glycogen synthase independent activity (insulin-stimulated minus basal) (r = –0.58, p<0.002) and to whole-body insulin-mediated glucose disposal rate (r = –0.60, p<0.002). The insulin-resistant and diabetic monkeys had significantly higher insulin-stimulated glucose 6-phosphate concentrations (0.57±0.11 and 0.62±0.11 nmol/mg dry weight, respectively) compared to the normal monkeys (0.29±0.05 nmol/mg dry weight) (p's <0.05). We conclude that under euglycaemic/hyperinsulinaemic conditions, a defect distal to glucose 6-phosphate is a major contributor to reduced whole-body insulin-mediated glucose disposal rates and to reduced insulin action on glycogen synthase in insulin-resistant and diabetic monkeys. [Diabetologia (1994) 37: 127–133] Received: 28 May 1993 and in revised form: 13 August 1993     

Primary prevention of Type 2 (non-insulin-dependent) diabetes mellitus

Summary Type 2 (non-insulin-dependent) diabetes mellitus is the major form of the disease in all societies. Its public health impact appears to be increasing and the greatest genetic predisposition to the disease is encountered in developing communities. The reduction or elimination of disease in whole populations is a fundamental goal in public health. Whilst several factors are associated with the development of Type 2 diabetes, it is not clear how they cause the disease, if indeed they do, nor whether they act in the same way in all populations. Risk factors may be true determinants of a disease but alternatively they may be associated with its occurrence only by virtue of an innocent relationship with the true causes. Furthermore, known risk factors usually explain only a small proportion of any chronic disease. The role of risk factors in disease causation is therefore of fundamental importance in considering disease prevention. Two alternative strategies for prevention of disease in populations have been proposed. The population strategy seeks to remove the causes of disease in communities as a whole, whilst the high-risk strategy aims to identify subjects at increased risk, and to intervene selectively. The population approach should be tried and carefully evaluated in selected communities at above-average risk of several noncommunicable diseases. However, certain epidemiological features of Type 2 diabetes, including the distributional characteristics of glycaemia and the complications of hyperglycaemia, the clustering of cardiovascular risk factors in the diabetic subpopulation, as well as uncertainties over the causal nature of known risk factors, suggest that a high-risk approach to prevention is also appropriate. Optimal allocation of resources to the two approaches requires a detailed knowledge of the disease process in individual communities.     

Factors associated with basal metabolic rate in patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary To examine determinants of basal metabolic rate we studied 66 Type 2 (non-insulin-dependent) diabetic and 24 healthy age- and weight-matched control subjects with indirect calorimetry and infusion of [³H-3-] glucose. Eight Type 2 diabetic patients were re-studied after a period of insulin therapy. Basal metabolic rate was higher in Type 2 diabetic patients than in control subjects (102.8 ± 1.9 J · kg LBM^–1-min^–1 vs 90.7 ± 2.8 J · kg LBM^–1;min^–1; p<0.01) and decreased significantly with insulin therapy (p <0.01). The basal rate of hepatic glucose production was higher in Type 2 diabetic patients than in control subjects (1044.0 ± 29.9 vs 789.3 ± 41.7 mol/min; p <0.001) and decreased after insulin therapy (p <0.01). Hepatic glucose production correlated positively with basal metabolic rate both in Type 2 diabetic patients (r = 0.49; p <0.001) and in control subjects (r = 0.50; p<0.05). Lipid oxidation was increased in Type 2 diabetic patients compared with control subjects (1.68 ± 0.05 vs 1.37 ± 0.08 mol · kg LBM^–1 · min^–1'; p <0.01) and decreased significantly after insulin therapy (p <0.05). The rate of lipid oxidation correlated positively with basal metabolic rate both in Type 2 diabetic patients (r = 0.36; p <0.01) and in control subjects (r = 0.51; p <0.01). These data demonstrate that basal metabolic rate, rates of hepatic glucose production and lipid oxidation are interrelated in Type 2 diabetic patients. A reduction of the hepatic glucose production, however, is associated with a reduction in lipid oxidation, which in turn, may result in a reduction in basal metabolic rate.     

Hyperinsulinaemia in youth is a predictor of Type 2 (non-insulin-dependent) diabetes mellitus

Summary This study aimed to compare plasma insulin concentrations across the age-range from childhood to old age in the populations of Nauru and Tuvalu, and to assess their relationship to the incidence of impaired glucose tolerance and diabetes in young Nauruans. The studies, performed in 1975 and 1976, found that Nauru had a higher prevalence of Type 2 (non-insulin-dependent) diabetes mellitus than Tuvalu. Both studies included subjects of 8–29 years of age (n=320 in Nauru, n=318 in Tuvalu) and on these subjects glucose tolerance status, body mass index and fasting and 2-h (post 75 g glucose load) plasma insulin concentrations were determined. In Nauru, follow-up surveys in 1982 and 1987 included many of the subjects first seen in 1975/1976, allowing the incidence and natural history of glucose intolerance to be studied. Within the group of subjects with normal glucose tolerance, there was no effect of age on plasma insulin distributions in either population. However, in both populations, 8–19 year old subjects with normal glucose tolerance had higher body mass index-adjusted geometric mean fasting and 2-h insulin concentrations than older age-groups (p < 0.001 for fasting insulin). Body mass index-adjusted geometric mean 2-h plasma insulin was higher in subjects with abnormal glucose tolerance relative to those with normal glucose tolerance in both populations. In Nauruans, 2-h insulin levels at baseline were predictive of impaired glucose tolerance and Type 2 diabetes in 1982, and fasting and 2-h insulin levels predicted development of Type 2 diabetes in 1987. Hyperinsulinaemia in the presence of normal glucose tolerance is evident in young people in Nauru and Tuvalu, as has been demonstrated in other populations known to have high susceptibility to Type 2 diabetes. Even in youth, elevated fasting and 2-h insulin concentration is predictive of subsequent deterioration in glucose tolerance.     

Subclinical diabetic neuropathy: similarities between electrophysiological results of patients with Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus

Summary Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients share many clinical and biochemical characteristics. However, sural nerve biopsies from patients with advanced and chronic neuropathy show ultrastructural differences between these two groups. We investigated whether at a subclinical stage of the illness, when Type 1 and Type 2 diabetic patients are clinically uniform and the histopathological nerve alterations are not advanced, comparison between the two diabetes groups might show differences in nerve fibre involvement related to the different pathogeneses of the neuropathies. A total of 88 diabetic patients (52 Type 1 and 36 Type 2), with a subclinical form of polyneuropathy were selected. The clinical neurophysiological examination consisted of motor and sensory nerve conduction studies, Hoffmann (H)-reflex, single fibre electromyography and static as well as dynamic pupillometry. With regard to clinical neurophysiological abnormalities, the severity of the polyneuropathy appeared to be equal in both groups. Despite the absence of clinical symptoms the neurophysiological abnormalities were pronounced and it was impossible to differentiate Type 1 diabetic patients from Type 2 diabetic patients on a clinical neurophysiology basis when correcting for differences in age, height, and duration of illness. In the Type 1 diabetic group as well as in the Type 2 diabetic group the autonomic nerve fibres and nerves in the legs were more frequently affected than the thick myelinated nerves in the arms. These findings do not support the assumption that there is a difference in the manifestation of polyneuropathy between Type 1 and Type 2 diabetic patients.