Jens J. Holst

Bio: Jens J. Holst is an academic researcher from University of Copenhagen. The author has contributed to research in topic(s): Glucagon & Insulin. The author has an hindex of 160, co-authored 1536 publication(s) receiving 107858 citation(s). Previous affiliations of Jens J. Holst include Panum Institute & Queen Elizabeth Hospital Birmingham.

The Physiology of Glucagon-like Peptide 1

Abstract: Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in ...

Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.

Abstract: In type-2 diabetes, the overall incretin effect is reduced. The present investigation was designed to compare insulinotropic actions of exogenous incretin hormones (gastric inhibitory peptide [GIP] and glucagon-like peptide 1 [GLP-1] [7-36 amide]) in nine type-2 diabetic patients (fasting plasma glucose 7.8 mmol/liter; hemoglobin A1c 6.3 +/- 0.6%) and in nine age- and weight-matched normal subjects. Synthetic human GIP (0.8 and 2.4 pmol/kg.min over 1 h each), GLP-1 [7-36 amide] (0.4 and 1.2 pmol/kg.min over 1 h each), and placebo were administered under hyperglycemic clamp conditions (8.75 mmol/liter) in separate experiments. Plasma GIP and GLP-1 [7-36 amide] concentrations (radioimmunoassay) were comparable to those after oral glucose with the low, and clearly supraphysiological with the high infusion rates. Both GIP and GLP-1 [7-36 amide] dose-dependently augmented insulin secretion (insulin, C-peptide) in both groups (P < 0.05). With GIP, the maximum effect in type-2 diabetic patients was significantly lower (by 54%; P < 0.05) than in normal subjects. With GLP-1 [7-36 amide] type-2 diabetic patients reached 71% of the increments in C-peptide of normal subjects (difference not significant). Glucagon was lowered during hyperglycemic clamps in normal subjects, but not in type-2 diabetic patients, and further by GLP-1 [7-36 amide] in both groups (P < 0.05), but not by GIP. In conclusion, in mild type-2 diabetes, GLP-1 [7-36 amide], in contrast to GIP, retains much of its insulinotropic activity. It also lowers glucagon concentrations.

Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study

Abstract: Summary Background Glucagon-like peptide 1 (GLP-1) has been proposed as a treatment for type 2 diabetes. We have investigated the long-term effects of continuous administration of this peptide hormone in a 6-week pilot study. Methods 20 patients with type 2 diabetes were alternately assigned continuous subcutaneous infusion of GLP-1 (n=10) or saline (n=10) for 6 weeks. Before (week 0) and at weeks 1 and 6, they underwent β-cell function tests (hyperglycaemic clamps), 8 h profiles of plasma glucose, insulin, C-peptide, glucagon, and free fatty acids, and appetite and side-effect ratings on 100 mm visual analogue scales; at weeks 0 and 6 they also underwent dexascanning, measurement of insulin sensitivity (hyperinsulinaemic euglycaemic clamps), haemoglobin A 1c , and fructosamine. The primary endpoints were haemoglobin A 1c concentration, 8-h profile of glucose concentration in plasma, and β-cell function (defined as the first-phase response to glucose and the maximum insulin secretory capacity of the cell). Analyses were per protocol. Findings One patient assigned saline was excluded because no veins were accessible. In the remaining nine patients in that group, no significant changes were observed except an increase in fructosamine concentration (p=0·0004). In the GLP-1 group, fasting and 8 h mean plasma glucose decreased by 4·3 mmol/L and 5·5 mmol/L (p 1c decreased by 1·3% (p=0·003) and fructosamine fell to normal values (p=0·0002). Fasting and 8 h mean concentrations of free fatty acids decreased by 30% and 23% (p=0·0005 and 0·01, respectively). Gastric emptying was inhibited, bodyweight decreased by 1·9 kg, and appetite was reduced. Both insulin sensitivity and β-cell function improved (p=0·003 and p=0·003, respectively). No important side-effects were seen. Interpretation GLP-1 could be a new treatment for type 2 diabetes, though further investigation of the long-term effects of GLP-1 is needed.

Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans.

Abstract: We examined the effect of intravenously infused glucagon-like peptide 1 (GLP-1) on subjective appetite sensations after an energy-fixed breakfast, and on spontaneous energy intake at an ad libitum lunch. 20 young, healthy, normal-weight men participated in a placebo-controlled, randomized, blinded, crossover study. Infusion (GLP-1, 50 pmol/ kg.h or saline) was started simultaneously with initiation of the test meals. Visual analogue scales were used to assess appetite sensations throughout the experiment and the palatability of the test meals. Blood was sampled throughout the day for analysis of plasma hormone and substrate levels. After the energy-fixed breakfast, GLP-1 infusion enhanced satiety and fullness compared with placebo (treatment effect: P < 0.03). Furthermore, spontaneous energy intake at the ad libitum lunch was reduced by 12% by GLP-1 infusion compared with saline (P = 0.002). Plasma GLP-1, insulin, glucagon, and blood glucose profiles were affected significantly by the treatment (P < 0.002). In conclusion, the results show that GLP-1 enhanced satiety and reduced energy intake and thus may play a physiological regulatory role in controlling appetite and energy intake in humans.

Type 2 diabetes mellitus.

Abstract: Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN.

Human biochemical genetics

Abstract: So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Standards of Medical Care in Diabetes

Abstract: XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Central nervous system control of food intake

Abstract: New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.

Mechanisms linking obesity to insulin resistance and type 2 diabetes

Abstract: Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance When insulin resistance is accompanied by dysfunction of pancreatic islet beta-cells - the cells that release insulin - failure to control blood glucose levels results Abnormalities in beta-cell function are therefore critical in defining the risk and development of type 2 diabetes This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention