National Dairy Council - Diabetes Mellitus & Dairy Food Consumption

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Diabetes Mellitus & Dairy Food Consumption
Genetic Basis of Diabetes Mellitus

Diabetes is a genetic disease and numerous mutations have been reported that associate with this condition. Shown in Table 3 are some of these mutations. Not all are listed, for some are variants of the same genes. For example, there are 42 different mutations in the glucokinase gene that phenotype as diabetes of the young (MODY). This is not really a subgroup of type 2 diabetes, yet is different from the severe type 1 disease. People with this form of diabetes have a problem with the responsiveness of the pancreas to changes in blood glucose level. The islet cells do not adequately sense blood glucose change and therefore do not release appropriate amounts of insulin in response. There are three major groups of mutations that phenotype as MODY. One group (MODY1) has mutations in the gene for hepatic nuclear factor 4a. A second group has mutations in the gene for pancreatic glu-cokinase (MODY2) and a third group (MODY3) has mutations in the gene for hepatic nuclear factor 1a. The hepatic nuclear factors are thought to serve as DNA transcription enhancers in the islet cell and are abbreviated HNF 1 or 4a. As can be seen in table 3, MODY is associated with a large number of mutations. Theoretically, people with the MODY gene mutations could, through appropriate food choice, avoid diabetes symptoms. With a problem in glucose sensing, it suggests that these people would benefit from diets that do not challenge the islet cells with excessive loads of glucose. Using low glucose (as well as other simple sugars that can be converted to glucose) diets, these patients could reduce the metabolic problem relating to the sensing of blood glucose by the islet cell. A diet with glucose coming from complex carbohydrates would be a benefit to these people because it would provide a leveling of glucose influx from the diet. As well, a diet where the major energy sources are proteins and fats might be useful since these foods also do not stress the islet cell. There are some amino acids that stimulate insulin release, but these amino acids do this using other sensing systems that do not involve the glucokinase reaction.

While the information provided in Table 3 is useful in understanding the genetic basis of diabetes, it is altogether possible that the mutations listed here are merely characteristic of the disorder not causal. Some of these mutations have been identified as being associated with the diabetic state, and some of the mutations cause other metabolic problems that in turn elicit abnormalities in glucose metabolism. In other words, not all of the mutations listed here are truly causal. The American Diabetes Association reminds diabetologists that there are numerous reasons why diabetes develops, and only some of these reasons are genetic in nature. ⁽³⁾

Endocrine diseases such as Cushing’s disease (adrenal steroid hypersecretion) has as its secondary characteristic, diabetes. When the primary disease is managed, the diabetes disappears. There are other instances as well of diabetes appearing as a secondary consequence of a primary disease. In fact, most of the mutations in the mitochondrial genome could be classified in this way. Mutations in this genome, when mutation load is high enough, elicit some very serious diseases involving the central nervous system, the neuromuscular system, the sensory system as well as intermediary metabolism. When the mutation load is high, these primary diseases receive the clinician’s attention. That diabetes also develops is a secondary concern. Lastly, those mutations that phenotype primarily as obesity may also have diabetes as a secondary condition. If the obesity could be managed (fat stores reduced), then the diabetes might be mitigated. However, most of the cases of genetic obesity are extremely difficult to manage if the mutations have occurred in the genes that encode components of the food intake regulation system. The Prader-Willi syndrome is a prime example of this type of genetic disorder. Persons with this disorder have insatiable appetites and become exceedingly obese. Diabetes is a secondary consequence of this massive obesity that shortens the life span of the affected individual.

However, there are mutations that are shared by both obesity or excessive fat stores and diabetes. Examples here are the mutations in the genes that encode the intracellular glucose transporter. Mutations in one or more of these genes can phenotype as both excessive fatness and diabetes. It is a condition that could be viewed not as a primary/secondary related condition, but as a co-equal syndrome. Both diabetes and excess fat stores develop at similar times. Lastly, there are some genes that seem to have many reported mutations. These genes may be etiological "hotspots" and more subject to mutation than other genes. Hotspots usually are places in the genes where there are several direct base repeats. For some unknown reason these direct repeats leave the DNA vulnerable to attack and mutation.


Table 3. Mutations That Phenotype as Type 2 Diabetes in Humans*

Genotype	Phenotype

PC1 (prohormone convertase 1)
Gly483Arg ⁽⁷⁾	Extreme childhood obesity, abnormal glucose homeostasis

GCK (glucokinase) A53S, G80A, H137R, T168P, M210T, C213R, V226M, S336L, V367M, E248X, S360X, V401del1, L1221G to T, K161+2del10, R186X, G261R ⁽⁸⁾ G279T ⁽⁹⁾ Ala188Thr ⁽¹⁰⁾ (alleles z+4, z+2, Z22) ⁽¹¹⁾	Maturity onset diabetes of the young (MODY-2)

IRS 1 (insulin receptor substrate) S13 and 972 ⁽¹²⁾	NIDDM and obesity

Beta3 AR 64 ⁽¹³⁾(Beta 3 adrenergic receptor)	NIDDM and obesity

OB D75514 — D7S530 ⁽¹⁴⁾	NIDDM, obesity, hypertension, and insulin resistance

Insulin receptor gene

Codon 897 — nonsense mutation ⁽¹⁵⁾	Leprechaun/Minn 1:Leprechaunism, growth retardation, extreme insulin resistance. Death usually occurs before age 1.

Glu460Lys ⁽¹⁵⁾	Leprechaun/Ark-1 Leprechaunism — intrauterine growth retardation, extreme insulin resistance Death usually occurs before age 1.

Leu233Pro ⁽¹⁵⁾	insulin resistance/NIDDM
Phe382Val ⁽¹⁵⁾	insulin resistance/NIDDM
Lys460Glu ⁽¹⁵⁾	insulin resistance/NIDDM
Gln672stop ⁽¹⁵⁾	insulin resistance/NIDDM
Arg735Ser ⁽¹⁵⁾	insulin resistance/NIDDM

Arg897stop ⁽¹⁵⁾	insulin resistance/NIDDM
Gly1008Val ⁽¹⁵⁾	insulin resistance/NIDDM
Trp1200Ser ⁽¹⁵⁾	insulin resistance/NIDDM
Val382Ser ⁽¹⁵⁾	Rabson-Mendenhall Syndrome insulin resistance (NIDDM), abnormalities of teeth, nails, and pineal hyperplasia

Amber133/Ser462 ⁽¹⁶⁾	NIDDM, acanthosis nigricans, hypoandrogenism

Ser735 ⁽¹⁶⁾	NIDDM, acanthosis nigricans, hypoandrogenism

Genotype	Phenotype

Thr1134Ala ⁽¹⁶⁾	NIDDM, acanthosis nigricans, hypoandrogenism

Arg209His ⁽¹⁷⁾	Lepprechaun/Winnipeg — leprechaunism, extreme insulin resistance

Asn15Lys ⁽¹⁷⁾	Rabson-Mendenhall Syndrome — insulin resistance abnormalities of teeth, nails, and pineal hyperplasia

Asn462Ser ⁽¹⁷⁾	NIDDM — extreme insulin resistance, acanthosis nigricans, hyperandrogenism

Trp133stop ⁽¹⁷⁾	NIDDM

His209Arg ⁽¹⁷⁾	NIDDM

Arg1000stop ⁽¹⁷⁾	NIDDM

Gly996Val ⁽¹⁸⁾	IDDM and acanthosis nigricans

Glu 1135/WT ⁽¹⁹⁾	type A extreme insulin resistance

Ile 1153 ⁽¹⁹⁾	type A extreme insulin resistance

Del exon 3/WT ⁽¹⁹⁾	type A extreme insulin resistance

Del codon 1109/WT ⁽¹⁹⁾	type A extreme insulin resistance

Glu993/Opal 1000 ⁽¹⁹⁾	type A extreme insulin resistance

Leu 1178/WT ⁽¹⁹⁾	type A extreme insulin resistance

Ser 1200 ⁽¹⁹⁾	type A extreme insulin resistance

Lys15/Opal 1000 ⁽¹⁹⁾	type A extreme insulin resistance

AG to GG (intron4) ⁽¹⁹⁾	type A extreme insulin resistance

Glu460/Amber 672 ⁽¹⁹⁾	type A extreme insulin resistance

Pro223 ⁽¹⁹⁾	type A extreme insulin resistance

Arg31 ⁽¹⁹⁾	type A extreme insulin resistance

Opal897 ⁽¹⁹⁾	type A extreme insulin resistance

Del codon 1109/Met910 ⁽¹⁹⁾	type A extreme insulin resistance

Ala28/Arg36619	type A extreme insulin resistance

Genotype	Phenotype

KIR6.2

E23R ⁽²⁰⁾	NIDDM

L270V ⁽²⁰⁾	NIDDM

I337V ⁽²⁰⁾	NIDDM

20q12-q13.1 ⁽²¹⁾	MODY 1

7p15-p13 ⁽²¹⁾	MODY 2

12q24.2 ⁽²¹⁾	MODY 3

13q12.1 ⁽²¹⁾	MODY 4

17cen-q21.3 ⁽²¹⁾	MODY 5

HNF1 _

G31D, R159W, A161T, R200W, R271W, IVS5nt+2T to A, P379fsdelT ⁽²²⁾	MODY — defective insulin secretion

G292fsdelG, Y122C, R159Q, S142F R55G56fsdelGACGG, Q7X, R171X, P291fsdelC ⁽²³⁾	MODY — defective insulin secretion

A443fsddCA, P129T, R131W, R159W, P519L T620I ⁽²⁴⁾	MODY — defective insulin secretion

I128N, H143Y, P447L A559fsinsA ⁽²⁵⁾	MODY — defective insulin secretion

CD38 gene

Arg140Trp ⁽²⁶⁾	Type 2 diabetes mellitus

Insulin gene

ValA3Leu, Xaa 65 PheB24Ser, PheB25Leu His 65, AspB10 ⁽²⁷⁾	mild diabetes or glucose intolerance

mGPDH gene

ACA:Thr243-ACG:Thr243, CAT: His264-CGT: Arg264, GCA:Ala305-GCC:Ala305, GCA:Ala306-TCA:Ser306 ⁽²⁸⁾	NIDDM

4p16 between D4S432 D4S431 ⁽²⁹⁾	Wolfram Syn (DM, DI, optic atrophy, deafness)

Glycogen Synthetase

Genotype	Phenotype


GYS1 XbaI, Met416Val ⁽³⁰⁾	Muscle insulin resistance, hypertension

Mitochondrial DNA Mutations (Phenotype depends on % mutated DNA in the heteroplasmic individual)

tRNA ^(Leu)

A3423G ⁽³¹⁾ A3243G, A3252G, C3256T, T3271C, T3290C, T3291C ⁽³²⁾	NIDDM and deafness elevated blood lactate, diabetes, fatty liver

ND1

G3316A, A3348G, T3394C, T3396C, G3423T, A3434G, G3438A, A3447G, A3480G, G3483A, T4216C ⁽³²⁾	Elevated blood lactate, diabetes, fatty liver

ND2

A4917G ⁽³²⁾	Elevated blood lactate, diabetes, fatty liver

tRNA ^(cys)

G5780A ⁽³²⁾	Elevated blood lactate, diabetes, fatty liver

tRNA ^(ser)

C7476T ⁽³²⁾	Elevated blood lactate, diabetes, fatty liver

COX II

A8245G, G8251A ⁽³²⁾	Elevated blood lactate, diabetes, fatty liver

tRNA ^(lys)

A8344G ⁽³²⁾	Elevated blood lactate, diabetes, fatty liver

ATPase 6

T8993G, T8993C, A8860G, G8894A ⁽³²⁾	Elevated blood lactate, diabetes, fatty liver

ND3

C10398T ⁽³²⁾	Elevated blood lactate diabetes, fatty liver

tRNA ^(glu)

T14709C ⁽³²⁾	Elevated blood lactate, diabetes, fatty liver

tRNA ^(thr)

C15904T, A15924G, G15927A, G15928A ⁽³²⁾	Elevated blood lactate, diabetes, fatty liver


*This table is by no means complete. New diabetes associated mutations are being reported monthly. Many of the references cited are review articles having compilations of reported mutations.

All of the population surveys show diabetes as a single entity when, in fact, this is not the case. As described in table 3, there are many different genetic causes of the disease. It is not possible to genetically screen people to determine their genetic cause. If we could do this then we could devise better treatment strategies that would give us better control of the disease or even predict the disease before it develops. This would be ideal for developing intervention strategies. However, screening technology is not yet available. It is needed. Instead, diabetes management is based on the therapies needed to keep blood glucose within normal limits.

Thus, for practical reasons, clinicians divide the population with diabetes based on disease management. Where insulin is required on a daily basis the disease is classed as type 1 diabetes mellitus; where insulin is not required on a daily basis, the disease is type 2 diabetes mellitus. Type 1 diabetes is much more severe and more difficult to manage than is type 2 diabetes. There is considerable overlap between the two groups. In addition, there are two groups of people with diabetes that do not fall into these categories: those with impaired glucose tolerance and women who develop diabetes during pregnancy. These two groups are managed as though they actually had lifelong diabetes. Attention is paid to body fatness, and to diet choice and physical activity. Some women with gestational diabetes require insulin treatment towards the end of their pregnancy. Some of these women go on to develop type 2 diabetes. A few go on to develop type 1 diabetes. Most however, revert to the non-diabetic state upon completion of their pregnancy. In the text that follows these groups will be described.

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