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expert reaction to cell study looking at fat, pancreatic cells, and type 2 diabetes

A lab study published in Diabetologia suggests fat may help the pancreas adapt to excess sugar, potentially slowing down the onset of type 2 diabetes.


Prof Sir Stephen O’Rahilly, Professor of Clinical Biochemistry and Medicine & Director, Medical Research Council Metabolic Diseases Unit, University of Cambridge, said:

“When people gain too much fat their tissues, like muscle and liver, become partially resistant to insulin, so their pancreas has to make more of it. How the pancreas “knows” how to do this has always been a bit of a mystery. This work provides some support for the idea that exposure of the pancreatic islets to fat could be involved  in the maintenance of high levels of insulin secretion. Of course in the long term obesity increases the risk of developing diabetes as the islet cells cannot keep up with this high demand forever and eventually start to make less insulin. And as the liver and muscle actually need more than normal amounts of insulin to keep blood glucose controlled, high levels of blood glucose ensues.”


Prof Francesco Rubino, Chair Metabolic and Bariatric Surgery, Kling’s College London, said:

“The limitations of the study stem primarily from the intrinsic limits of the in-vitro experimental model that was used to investigate the effects of beta cell exposure to fat; this may not totally or closely recapitulate in-vivo physiology.

“Furthermore, researchers only looked at beta cell function, while we know that the underpinning mechanisms of type 2 diabetes involve dysfunctions in other tissues and organs, beyond the pancreas and beta cell that could not be examined.  For instance excess fat is associated with insulin resistance and inflammation, which contribute to type 2 diabetes and metabolic syndrome and these were not obviously part of the study.  Hence, it is difficult to assess the clinical relevance of the observations from this study and specifically the potential role of fat as “protective”  for the development of diabetes as suggested by the authors.

“There are also various ways in which excess fat can interfere with beta cell functions, including causing changes in other signals and mechanisms that link beta cells to other cells within the pancreas (not part of the model in the study) and in other organs.  These cannot be entirely recapitulated in-vitro.

“For all the reasons above, the study has objective limitations.

“Despite such limitations, however, the study provides new insights about the complex relationship between fat metabolism regulation of insulin secretion and this may have relevance for the way we conceptualise the relationship between fat and sugar metabolism.

“Although one may be tempted to dismiss in-vitro findings that conflict – as these do – with conventional wisdom, they are less paradoxical than one may think.  In brief, the study suggests that while exposure of beta cells to sugar alone reduces insulin secretion (as previously known), exposure to both sugar and lipids stimulates fat turnover into the beta cells and this leads to increased secretion of insulin.  Accordingly, fat might protect beta cells rather than the contrary.

“These results seem inconsistent with the evidence and generally accepted notion that excess fat is associated with type 2 diabetes.  However, while the association between excess fat and diabetes is clear, less clear is the nature of such association.

“I am known for being a very vocal critic of the conventional model that considers obesity the “cause” of type 2 diabetes – this is my most important disclosure in commenting on the findings of this study.  But I do think this study provides further evidence to question the validity of the conventional “adipocentric” model of type 2 diabetes, which blames excess fat as a cause of the disease.

“As strange as it may sounds to many, there is, in fact, no conclusive evidence that “too much fat is the cause of diabetes”.  Actually, everything we know, from the physiologic functions of fat tissue itself, to observations at the two extremes of fatness in humans, suggest a possible “anti-diabetic function” of fat tissue.  In fact, people with highest BMI (i.e. > 60Kg/m2) seem to be less likely to have type 2 diabetes than people with lesser degree of obesity.  On the contrary, people with genetic conditions associated with minimal fatness (i.e. lipodystrophies) almost invariably develop type 2 diabetes.  Furthermore, people who undergo bariatric surgery immediately experience resolution of type 2 diabetes even when they are still carrying around large amount of fat tissue, suggesting that such surgery is uncoupling the link between adiposity and diabetes.

“Altogether, these previous observations suggest that the relationship between fatness and diabetes is not as straightforward as conventional thinking would have it.  The evidence to support a “cause-effect” role of fatness in type 2 diabetes is based on epidemiology, not conclusive scientific evidence.  In this context, it would be safer to consider a model where obesity is at best a “symptom” of diabetes, not its cause.

“I acknowledge that these claims may raise eyebrows in some scientific circles, or cause dismay.  The new study, however, supports this point.  If nothing else, it is yet another observation that should serve as a stimulus to think more critically about our long-held assumptions about obesity, diabetes and what links the two conditions.”


Dr Katarina Kos, Senior Lecturer and Honorary Consultant Physician in Diabetes and Endocrinology, University of Exeter Medical School, said:

“Type 2 diabetes is a condition of insulin resistance.  Insulin resistance means that insulin is less effective where it is needed.  The pancreas secretes increasingly more insulin to compensate.  Insulin resistance is attributed to an overall increased lipid deposition and nutritional surplus as found in obesity.

“This new paper specifically examines the well established damage of energy surplus, namely high sugar and fat levels, also on insulin producing beta cells of the pancreas (mostly on those from the rat) in the petri dish under different scenarios of high and low glucose and saturated and unsaturated fat nourishment.  It shows that fat release from these cells as well as their ability to secrete insulin changes under these different conditions.  In particular preceding fat treatment led to a higher insulin secretion which could be potentially a compensatory mechanism.

“Further interpretation especially on human physiology cannot be made.  Apart from demonstration of which genes are switched on and off within human insulin secreting cells, all other experiments are performed on rat cell lines.

“Cell survival and complexity of cellular inflammation as found in obesity and other important pathways which determine insulin secretion were not studied and peripheral insulin resistance not explored.  The test conditions are artificial as they do not allow the study of more than one cell type in concert.  Authors use artificially high glucose concentrations of 25 mmol/mol for 3 days which are unphysiological extremely high sugar levels.  Furthermore, one cannot assume that clearance of lipids and shift to the outside of the cell is beneficial as these lipids/NEFA will need to be used somehow, ‘burned’ by exercise or deposited as fat tissue.  Otherwise high circulatory lipid levels as seen in diabetes lead to atherosclerosis which predisposes to heart disease and stroke.

“It would be wrong to take from this study that fat rescues the pancreatic insulin secreting cell once damaged.  Reduced nutritional intake combined with exercise improves insulin sensitivity and this remains the key recommendation for prevention and treatment of Type 2 diabetes.”


Dr Duane Mellor, Registered Dietitian and Senior Teaching Fellow, Aston Medical School, Aston University, said:

“This is an interesting paper which looks mechanistically how the pancreatic cells which make insulin from the pancreas (but grown in cell culture) respond to two different fatty acids when bathed in different concentrations of glucose (sugar) which ranged from the level you might find in someone without diabetes through to a level that might be seen in newly diagnosed diabetes all within a laboratory.  So, it is important to note, this study was very controlled and does not represent the complex variety of fatty acids and nutrients which would be seen in a person, either before or after a meal.  So, applying the findings of this work needed to be treated with caution.  It does fit with the theory that fat accumulating in these cells can affect how good they are at making and releasing insulin, which has been used to try and help people with diabetes achieve remission – often through weight loss.

“It is vital however that we are careful when we refer to fat that in this type of experiment it is not the same as excess body fat, it refers to the molecules itself and how these cells use them.  What it does support, along with a number of other studies, is that reducing fat in pancreatic cells can help them to function, this can be achieved in people who are overweight or obese through weight loss – the type of diet as long as it is healthy and balanced is less important.  The authors also suggest, although the data is perhaps less clear in this study than others, that gaps between meals or periods of fasting might help the pancreas to function better – this has been studied in people and is known as intermittent fasting, which can help some people with diabetes, but like any change to your diet should be done in discussion with their diabetes care team so that they adjust any medications if necessary to help keep you safe as you change your diet and lifestyle.”


Dr Ian Johnson, Nutrition researcher and Emeritus Fellow, Quadram Institute Bioscience, said:

“I have only had time for a very brief look at this in vitro study.  It does seem to be a technically sound and informative piece of work but it is essentially a piece of cell physiology, a long way from intact human beings and their diets!

“There is nothing in this paper that suggests that being overweight could be protective against type 2 diabetes.  There is no doubt that being overweight or obese is a major risk factor.  The paper gives some interesting insights into pancreatic beta cell physiology but there are no immediate implications for preventative medicine.  The authors do conjecture that their results may suggest that intermittent fasting might help obese patients to delay the development of type 2 diabetes, but that is a hypothesis that would need to be tested in clinical trials.”



‘Glucolipotoxicity promotes the capacity of the glycerolipid/NEFA cycle supporting the secretory response of pancreatic beta cells’ by Lucie Oberhauser et al. was published in Diabetologia at 05:00 UK time on Wednesday 12 January 2022.

DOI: 10.1007/s00125-021-05633-x



Declared interests

Prof Sir Stephen O’Rahilly

“Co-Director, Wellcome-MRC Institute of Metabolic Science

Head of Department of Clinical Biochemistry, University of Cambridge

Scientific Director, Cambridge NIHR Biomedical Research Centre

Hon Consultant Physician, Addenbrooke’s Hospital, Cambridge

He declares no conflicts.”

Prof Francesco Rubino: “Paid consultant for Ethicon, Medtronic, Novo Nordisk and GI Dynamics.”

Dr Katarina Kos: “I have no conflict of interest.”

Dr Duane Mellor: “No competing interests to declare.”

Dr Ian Johnson: “No interest to declare.”

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